Cerebral Cortex - Advance Access

Vesicular Glutamate Transporter VGLUT1 Has a Role in Hippocampal Long-Term Potentiation and Spatial Reversal Learning

2009-07-02

Vesicular glutamate transporters 1 and 2 (VGLUT1, VGLUT2) show largely complementary distribution in the mature rodent brain and tend to segregate to synapses with different physiological properties. In the hippocampus, VGLUT1 is the dominate subtype in adult animals, whereas VGLUT2 is transiently expressed during early postnatal development. We generated and characterized VGLUT1 knockout mice in order to examine the functional contribution of this transporter to hippocampal synaptic plasticity and hippocampus-dependent spatial learning. Because complete deletion of VGLUT1 resulted in postnatal lethality, we used heterozygous animals for analysis. Here, we report that deletion of VGLUT1 resulted in impaired hippocampal long-term potentiation (LTP) in the CA1 region in vitro. In contrast, heterozygous VGLUT2 mice that were investigated for comparison did not show any changes in LTP. The reduced ability of VGLUT1-deficient mice to express LTP was accompanied by a specific deficit in spatial reversal learning in the water maze. Our data suggest a functional role of VGLUT1 in forms of hippocampal synaptic plasticity that are required to adapt and modify acquired spatial maps to external stimuli and changes.

Auditory Attentional Control and Selection during Cocktail Party Listening

Hill, K. T., Miller, L. M. — 2009-07-02

In realistic auditory environments, people rely on both attentional control and attentional selection to extract intelligible signals from a cluttered background. We used functional magnetic resonance imaging to examine auditory attention to natural speech under such high processing-load conditions. Participants attended to a single talker in a group of 3, identified by the target talker's pitch or spatial location. A catch-trial design allowed us to distinguish activity due to top-down control of attention versus attentional selection of bottom-up information in both the spatial and spectral (pitch) feature domains. For attentional control, we found a left-dominant fronto-parietal network with a bias toward spatial processing in dorsal precentral sulcus and superior parietal lobule, and a bias toward pitch in inferior frontal gyrus. During selection of the talker, attention modulated activity in left intraparietal sulcus when using talker location and in bilateral but right-dominant superior temporal sulcus when using talker pitch. We argue that these networks represent the sources and targets of selective attention in rich auditory environments.

Experience-Dependent Gene Expression in Adult Visual Cortex

Chen, J., Yamahachi, H., Gilbert, C. D. — 2009-07-01

Experience-dependent plasticity of the adult visual cortex underlies perceptual learning and recovery of function following central nervous system lesions. To reveal the signal transduction cascades involved in adult cortical plasticity, we utilized a model of remapping of cortical topography following binocular retinal lesions. In this model, the lesion projection zone (LPZ) of primary visual cortex (V1) recovers visually driven activity by the sprouting of horizontal axonal connections originating from the cells in the surrounding region. To explore the molecular mechanism underlying this process, we used gene microarrays from an expression library prepared from Macaque V1. By microarray analysis of gene expression levels in the LPZ and the surrounding region, and subsequent confirmation with Quantitative Real-Time polymerase chain reaction and in situ hybridization, the participation of a number of genes was observed, including the Rho GTPase family. Its role in regulation of cytoskeleton assembly provides a possible link between the alteration of neural activity and cortical functional reorganization.

IQ-Related fMRI Differences during Cognitive Set Shifting

2009-07-01

This event-related functional magnetic resonance imaging study compared neural correlates of executive function (cognitive set-shifting) in 28 healthy participants with either high (HIQ) or average (AIQ) intelligence. Despite comparable behavioral performance (except for slower reactions), the AIQ participants showed greater (especially prefrontal) activation during response selection; the HIQ participants showed greater activation (especially parietal) during feedback evaluation. HIQ participants appeared to engage cognitive resources to support more efficient strategies (planning during feedback in preparation for the upcoming response) which resulted in faster responses and less need for response inhibition and conflict resolution. Whether greater intelligence is associated with more or less brain activity (the "neural efficiency" debate) depends therefore on the specific component of the task being examined as well as the brain region recruited. One implication is that caution must be exercised when drawing conclusions from differences in activation between groups of individuals in whom IQ may differ (e.g., psychiatric vs. control samples).

Auditory Selective Attention to Speech Modulates Activity in the Visual Word Form Area

Yoncheva, Y. N., Zevin, J. D., Maurer, U., McCandliss, B. D. — 2009-07-01

Selective attention to speech versus nonspeech signals in complex auditory input could produce top-down modulation of cortical regions previously linked to perception of spoken, and even visual, words. To isolate such top-down attentional effects, we contrasted 2 equally challenging active listening tasks, performed on the same complex auditory stimuli (words overlaid with a series of 3 tones). Instructions required selectively attending to either the speech signals (in service of rhyme judgment) or the melodic signals (tone-triplet matching). Selective attention to speech, relative to attention to melody, was associated with blood oxygenation level–dependent (BOLD) increases during functional magnetic resonance imaging (fMRI) in left inferior frontal gyrus, temporal regions, and the visual word form area (VWFA). Further investigation of the activity in visual regions revealed overall deactivation relative to baseline rest for both attention conditions. Topographic analysis demonstrated that while attending to melody drove deactivation equivalently across all fusiform regions of interest examined, attending to speech produced a regionally specific modulation: deactivation of all fusiform regions, except the VWFA. Results indicate that selective attention to speech can topographically tune extrastriate cortex, leading to increased activity in VWFA relative to surrounding regions, in line with the well-established connectivity between areas related to spoken and visual word perception in skilled readers.

Synapses of Horizontal Connections in Adult Rat Somatosensory Cortex Have Different Properties Depending on the Source of their Axons

Hickmott, P. W. — 2009-07-01

In somatosensory cortex (S1) tactile stimulation activates specific regions. The borders between representations of different body parts constrain the spread of excitation and inhibition: connections that cross from one representation to another (cross-border, CB) are weaker than those remaining within the representation (noncross border, NCB). Thus, physiological properties of CB and NCB synapses onto layer 2/3 pyramidal neurons were compared using whole-cell recordings in layer 2/3 neurons close to the border between the forepaw and lower jaw representations. Electrical stimulation of CB and NCB connections was used to activate synaptic potentials. Properties of excitatory (EPSPs) and inhibitory (IPSPs) postsynaptic potentials (PSP) were determined using 3 methods: 1) minimal stimulation to elicit single-fiber responses; 2) stimulation in the presence of extracellular Sr²⁺ to elicit asynchronous quantal responses; 3) short trains of stimulation at various frequencies to examine postsynaptic potential (PSP) dynamics. Both minimal and asynchronous quantal EPSPs were smaller when evoked by CB than NCB stimulation. However, the dynamics of EPSP and IPSP trains were not different between CB and NCB stimulation. These data suggest that individual excitatory synapses from connections that cross a border (CB) have smaller amplitudes than those that come from within a representation (NCB), and suggest a postsynaptic locus for the difference.

Expectancy Constraints in Degraded Speech Modulate the Language Comprehension Network

Obleser, J., Kotz, S. A. — 2009-06-26

In speech comprehension, the processing of auditory information and linguistic context are mutually dependent. This functional magnetic resonance imaging study examines how semantic expectancy ("cloze probability") in variably intelligible sentences ("noise vocoding") modulates the brain bases of comprehension. First, intelligibility-modulated activation along the superior temporal sulci (STS) was extended anteriorly and posteriorly in low-cloze sentences (e.g., "she weighs the flour") but restricted to a mid-superior temporal gyrus/STS area in more predictable high-cloze sentences (e.g., "she sifts the flour"). Second, the degree of left inferior frontal gyrus (IFG) (Brodmann's area 44) involvement in processing low-cloze constructions was proportional to increasing intelligibility. Left inferior parietal cortex (IPC; angular gyrus) activation accompanied successful speech comprehension that derived either from increased signal quality or from semantic facilitation. The results show that successful decoding of speech in auditory cortex areas regulates language-specific computation (left IFG and IPC). In return, semantic expectancy can constrain these speech-decoding processes, with fewer neural resources being allocated to highly predictable sentences. These findings offer an important contribution toward the understanding of the functional neuroanatomy in speech comprehension.

Spatial Distribution of Deep Sulcal Landmarks and Hemispherical Asymmetry on the Cortical Surface

Im, K., Jo, H. J., Mangin, J.-F., Evans, A. C., Kim, S. I., Lee, J.-M. — 2009-06-26

The locally deepest regions of major sulci, the sulcal pits, are thought to be the first cortical folds to develop and are closely related to functional areas. We examined the spatial distribution of sulcal pits across the entire cortical region, and assessed the hemispheric asymmetry in their frequency and distribution in a large group of normal adult brains. We automatically extracted sulcal pits from magnetic resonance imaging data using surface-based methods and constructed a group map from 148 subjects. The spatial distribution of the sulcal pits was relatively invariant between individuals, showing high frequency and density in specific focal areas. The left and right sulcal pits were spatially covariant in the regions of the earliest developed sulci. The sulcal pits with great spatial invariance appear to be useful as stable anatomical landmarks. We showed the most significant asymmetry in the frequency and spatial variance of sulcal pits in the superior temporal sulcus, which might be related to the lateralization of language function to the left hemisphere, developing more consistently and strongly than for the right. Our analyses support previous empirical and theoretical studies, and provide additional insights concerning the anatomical and functional development of the brain.

Reading Aloud Boosts Connectivity through the Putamen

Seghier, M. L., Price, C. J. — 2009-06-26

Functional neuroimaging and lesion studies have frequently reported thalamic and putamen activation during reading and speech production. However, it is currently unknown how activity in these structures interacts with that in other reading and speech production areas. This study investigates how reading aloud modulates the neuronal interactions between visual recognition and articulatory areas, when both the putamen and thalamus are explicitly included. Using dynamic causal modeling in skilled readers who were reading regularly spelled English words, we compared 27 possible pathways that might connect the ventral anterior occipito-temporal sulcus (aOT) to articulatory areas in the precentral cortex (PrC). We focused on whether the neuronal interactions within these pathways were increased by reading relative to picture naming and other visual and articulatory control conditions. The results provide strong evidence that reading boosts the aOT–PrC pathway via the putamen but not the thalamus. However, the putamen pathway was not exclusive because there was also evidence for another reading pathway that did not involve either the putamen or the thalamus. We conclude that the putamen plays a special role in reading but this is likely to vary with individual reading preferences and strategies.

Output Properties and Organization of the Forelimb Representation of Motor Areas on the Lateral Aspect of the Hemisphere in Rhesus Macaques

Boudrias, M.-H., McPherson, R. L., Frost, S. B., Cheney, P. D. — 2009-06-26

Motor output capabilities of the forelimb representation of dorsal motor area (PMd) and ventral motor area (PMv) were compared with primary motor cortex (M1) in terms of latency, strength, sign, and distribution of effects. Stimulus-triggered averages (60 µA) of electromyographic activity collected from 24 forelimb muscles were computed at 314 tracks in 2 monkeys trained to perform a reach-to-grasp task. The onset latency and magnitude of facilitation effects from PMd and PMv were significantly longer and 7- to 9-fold weaker than those from M1. Proximal muscles were predominantly represented in PMd and PMv. A joint-dependent flexor or extensor preference was also present. Distal and proximal muscle representations were intermingled in PMd and PMv. A gradual increase in latency and decrease in magnitude of effects were observed in moving from M1 surface sites toward more anterior sites in PMd. For many muscles, segregated areas producing suppression effects were found along the medial portion of PMd and adjacent M1. Although some facilitation effects from PMd and PMv had onset latencies as short as those from M1 in the same muscle, suggesting equal direct linkage, the vast majority had properties consistent with a more indirect linkage to motoneurons either through corticocortical connections with M1 and/or interneuronal linkages in the spinal cord.

Regional Response Differences Across the Human Amygdaloid Complex during Social Conditioning

Davis, F. C., Johnstone, T., Mazzulla, E. C., Oler, J. A., Whalen, P. J. — 2009-06-25

The amygdala is consistently implicated in biologically relevant learning tasks such as Pavlovian conditioning. In humans, the ability to identify individual faces based on the social outcomes they have predicted in the past constitutes a critical form of associative learning that can be likened to "social conditioning." To capture such learning in a laboratory setting, participants learned about faces that predicted negative, positive, or neutral social outcomes. Participants reported liking or disliking the faces in accordance with their learned social value. During acquisition, we observed differential functional magnetic resonance imaging activation across the human amygdaloid complex consistent with previous lesion, electrophysiological, and functional neuroimaging data. A region of the medial ventral amygdala and a region of the dorsal amygdala/substantia innominata showed signal increases to both Negative and Positive faces, whereas a lateral ventral region displayed a linear representation of the valence of faces such that Negative > Positive > Neutral. This lateral ventral locus also differed from the dorsal and medial loci in that the magnitude of these responses was more resistant to habituation. These findings document a role for the human amygdala in social learning and reveal coarse regional dissociations in amygdala activity that are consistent with previous human and nonhuman animal data.

Common and Dissociable Prefrontal Loci Associated with Component Mechanisms of Analogical Reasoning

2009-06-23

The ability to draw analogies requires 2 key cognitive processes, relational integration and resolution of interference. The present study aimed to identify the neural correlates of both component processes of analogical reasoning within a single, nonverbal analogy task using event-related functional magnetic resonance imaging. Participants verified whether a visual analogy was true by considering either 1 or 3 relational dimensions. On half of the trials, there was an additional need to resolve interference in order to make a correct judgment. Increase in the number of dimensions to integrate was associated with increased activation in the lateral prefrontal cortex as well as lateral frontal pole in both hemispheres. When there was a need to resolve interference during reasoning, activation increased in the lateral prefrontal cortex but not in the frontal pole. We identified regions in the middle and inferior frontal gyri which were exclusively sensitive to demands on each component process, in addition to a partial overlap between these neural correlates of each component process. These results indicate that analogical reasoning is mediated by the coordination of multiple regions of the prefrontal cortex, of which some are sensitive to demands on only one of these 2 component processes, whereas others are sensitive to both.

Altered Water Diffusivity in Cortical Association Tracts in Children with Early Deprivation Identified with Tract-Based Spatial Statistics (TBSS)

Govindan, R. M., Behen, M. E., Helder, E., Makki, M. I., Chugani, H. T. — 2009-06-22

Institutional rearing is associated with neurocognitive and behavioral difficulties. Although such difficulties are thought to reflect abnormal neurologic development resulting from early social deprivation (ED) and there is evidence for functional abnormality in children with histories of ED, the impact of early deprivation on brain anatomy has received little study in humans. The present study utilized an objective and sensitive neuroimaging analysis technique (Tract-Based Spatial Statistics) to evaluate white matter fractional anisotropy (FA) and diffusivity in a group of right-handed children with histories of ED (n = 17; mean age = 10.9 + 2.6 years) as compared with age-matched healthy controls (n = 15; mean age = 11.7 ± 2.8 years). Participants underwent magnetic resonance imaging diffusion tensor imaging sequences and comprehensive neuropsychological evaluations. Results revealed reduced FA in frontal, temporal, and parietal white matter including components of uncinate and superior longitudinal fasciculi, in children with histories of ED, providing further support for limbic and paralimbic abnormalities in children with such histories. Furthermore, white matter abnormalities were associated with duration of time in the orphanage and with inattention and hyperactivity scores. It is suspected that the observed white matter abnormalities are associated with multiple depriving factors (e.g., poor prenatal care, postnatal stress) associated with institutional caregiving.

Topographical Functional Connectivity Pattern in the Perisylvian Language Networks

Xiang, H.-D., Fonteijn, H. M., Norris, D. G., Hagoort, P. — 2009-06-22

We performed a resting-state functional connectivity study to investigate directly the functional correlations within the perisylvian language networks by seeding from 3 subregions of Broca's complex (pars opercularis, pars triangularis, and pars orbitalis) and their right hemisphere homologues. A clear topographical functional connectivity pattern in the left middle frontal, parietal, and temporal areas was revealed for the 3 left seeds. This is the first demonstration that a functional connectivity topology can be observed in the perisylvian language networks. The results support the assumption of the functional division for phonology, syntax, and semantics of Broca's complex as proposed by the memory, unification, and control (MUC) model and indicated a topographical functional organization in the perisylvian language networks, which suggests a possible division of labor for phonological, syntactic, and semantic function in the left frontal, parietal, and temporal areas.

Cerebellar Engagement in an Action Observation Network

Sokolov, A. A., Gharabaghi, A., Tatagiba, M. S., Pavlova, M. — 2009-06-22

The cerebellum has traditionally been viewed as a brain structure subserving skilled motor behaviors. However, the cerebellum might be involved not only in movement coordination, but also in action observation and understanding of others’ actions. Veridical visual perception of human body motion is of immense importance for a variety of daily-life situations and for successful social interactions. Here, by combining visual psychophysics with a lesion analysis, we assessed visual sensitivity to human walking in patients with lesions to the left cerebellum. Patients with left lateral cerebellar lesions exhibit deficits in visual sensitivity to body motion, whereas medial lesions do not substantially affect visual perception of human locomotion. The findings point to left lateral cerebellar involvement in an action observation network. We discuss possible mechanisms of cerebellar engagement in visual social perception revealed by body motion.

Activation of Sensory-Motor Areas in Sentence Comprehension

Desai, R. H., Binder, J. R., Conant, L. L., Seidenberg, M. S. — 2009-06-22

The sensory–motor account of conceptual processing suggests that modality-specific attributes play a central role in the organization of object and action knowledge in the brain. An opposing view emphasizes the abstract, amodal, and symbolic character of concepts, which are thought to be represented outside the brain's sensory–motor systems. We conducted a functional magnetic resonance imaging study in which the participants listened to sentences describing hand/arm action events, visual events, or abstract behaviors. In comparison to visual and abstract sentences, areas associated with planning and control of hand movements, motion perception, and vision were activated when understanding sentences describing actions. Sensory–motor areas were activated to a greater extent also for sentences with actions that relied mostly on hands, as opposed to arms. Visual sentences activated a small area in the secondary visual cortex, whereas abstract sentences activated superior temporal and inferior frontal regions. The results support the view that linguistic understanding of actions partly involves imagery or simulation of actions, and relies on some of the same neural substrate used for planning, performing, and perceiving actions.

Dissociation Between Memory Accuracy and Memory Confidence Following Bilateral Parietal Lesions

Simons, J. S., Peers, P. V., Mazuz, Y. S., Berryhill, M. E., Olson, I. R. — 2009-06-19

Numerous functional neuroimaging studies have observed lateral parietal lobe activation during memory tasks: a surprise to clinicians who have traditionally associated the parietal lobe with spatial attention rather than memory. Recent neuropsychological studies examining episodic recollection after parietal lobe lesions have reported differing results. Performance was preserved in unilateral lesion patients on source memory tasks involving recollecting the context in which stimuli were encountered, and impaired in patients with bilateral parietal lesions on tasks assessing free recall of autobiographical memories. Here, we investigated a number of possible accounts for these differing results. In 3 experiments, patients with bilateral parietal lesions performed as well as controls at source recollection, confirming the previous unilateral lesion results and arguing against an explanation for those results in terms of contralesional compensation. Reducing the behavioral relevance of mnemonic information critical to the source recollection task did not affect performance of the bilateral lesion patients, indicating that the previously observed reduced autobiographical free recall might not be due to impaired bottom-up attention. The bilateral patients did, however, exhibit reduced confidence in their source recollection abilities across the 3 experiments, consistent with a suggestion that parietal lobe lesions might lead to impaired subjective experience of rich episodic recollection.

Serotoninergic Fine-Tuning of the Excitation-Inhibition Balance in Rat Visual Cortical Networks

William Moreau, A., Amar, M., Le Roux, N., Morel, N., Fossier, P. — 2009-06-19

Fundamental brain functions depend on a balance between excitation (E) and inhibition (I) that is highly adjusted to a 20–80% set point in layer 5 pyramidal neurons (L5PNs) of rat visual cortex. Dysregulations of both the E–I balance and the serotonergic system in neocortical networks lead to serious neuronal diseases including depression, schizophrenia, and epilepsy. However, no link between the activation of neuronal 5-hydroxytryptamine receptors (5-HTRs) and the cortical E–I balance has yet been reported. Here we used a combination of patch-clamp recordings of composite stimulus-locked responses in L5PN following local electrical stimulations in either layer 2/3 or 6, simultaneous measurement of excitatory and inhibitory conductance dynamics, together with selective pharmacological targeting and single-cell reverse transcriptase-polymerase chain reaction. We show that cortical serotonin shifts the E–I balance in favor of more E and we reveal fine and differential modulations of the E–I balance between 5-HTR subtypes, in relation to whether layer 2/3 or 6 was stimulated and in concordance with the specific expression pattern of these subtypes in pyramidal cells and deep interneurons. This first evidence for the functional segregation of 5-HTR subtypes sheds new light on their coherent functioning in polysynaptic sensory circuits.

The Contribution of the Parietal Lobes to Speaking and Writing

Brownsett, S. L. E., Wise, R. J. S. — 2009-06-16

The left parietal lobe has been proposed as a major language area. However, parietal cortical function is more usually considered in terms of the control of actions, contributing both to attention and cross-modal integration of external and reafferent sensory cues. We used positron emission tomography to study normal subjects while they overtly generated narratives, both spoken and written. The purpose was to identify the parietal contribution to the modality-specific sensorimotor control of communication, separate from amodal linguistic and memory processes involved in generating a narrative. The majority of left and right parietal activity was associated with the execution of writing under visual and somatosensory control irrespective of whether the output was a narrative or repetitive reproduction of a single grapheme. In contrast, action-related parietal activity during speech production was confined to primary somatosensory cortex. The only parietal area with a pattern of activity compatible with an amodal central role in communication was the ventral part of the left angular gyrus (AG). The results of this study indicate that the cognitive processing of language within the parietal lobe is confined to the AG and that the major contribution of parietal cortex to communication is in the sensorimotor control of writing.

How Reliable Are Visual Context Effects in the Parahippocampal Place Area?

Epstein, R. A., Ward, E. J. — 2009-06-16

The parahippocampal place area (PPA) is a region of human cortex that responds more strongly to visual scenes (e.g., landscapes or cityscapes) than to other visual stimuli. It has been proposed that the primary function of the PPA is encoding of contextual information about object co-occurrence. Supporting this context hypothesis are reports that the PPA responds more strongly to strong-context than to weak-context objects and more strongly to famous faces (for which contextual associations are available) than to nonfamous faces. We reexamined the reliability of these 2 effects by scanning subjects with functional magnetic resonance imaging while they viewed strong- and weak-context objects, scrambled versions of these objects, and famous and nonfamous faces. "Contextual" effects for objects were observed to be reliable in the PPA at slow presentation rates but not at faster presentation rates intended to discourage scene imagery. We were unable to replicate the earlier finding of preferential PPA response to famous versus nonfamous faces. These results are difficult to reconcile with the hypothesis that the PPA encodes contextual associations but are consistent with a competing hypothesis that the PPA encodes scenic layout.

Brain Maturation in Adolescence and Young Adulthood: Regional Age-Related Changes in Cortical Thickness and White Matter Volume and Microstructure

2009-06-11

The development of cortical gray matter, white matter (WM) volume, and WM microstructure in adolescence is beginning to be fairly well characterized by structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) studies. However, these aspects of brain development have rarely been investigated concurrently in the same sample and hence the relations between them are not understood. We delineated the age-related changes in cortical thickness, regional WM volume, and diffusion characteristics and investigated the relationships between these properties of brain development. One hundred and sixty-eight healthy participants aged 8–30 years underwent sMRI and DTI. The results showed regional age-related cortical thinning, WM volume increases, and changes in diffusion parameters. Cortical thickness was the most strongly age-related parameter. All classes of measures showed unique associations with age. The results indicate that cortical thinning in adolescence cannot be explained by WM maturation in underlying regions as measured by volumetry or DTI. Moderate associations between cortical thickness and both volume and diffusion parameters in underlying WM regions were also found, although the relationships were not strong. It is concluded that none of the measures are redundant and that the integration of the 3 will yield a more complete understanding of brain maturation.

Identification of the Hippocampal Input to Medial Prefrontal Cortex In Vitro

Parent, M. A., Wang, L., Su, J., Netoff, T., Yuan, L.-L. — 2009-06-10

To delineate the cellular mechanisms underlying the function of medial prefrontal cortex (mPFC) networks, it is critical to understand how synaptic inputs from various afferents are integrated and drive neuronal activity in this region. Using a newly developed slice preparation, we were able to identify a bundle of axons that contain extraneocortical fibers projecting to neurons in the prelimbic cortex. The anatomical origin and functional connectivity of the identified fiber bundle were probed by in vivo track tracing in combination with optic and whole-cell recordings of neurons in layers 2/3 and 5/6. We demonstrate that the identified bundle contains afferent fibers primarily from the ventral hippocampus but does not include contributions from the mediodorsal nucleus of the thalamus, amygdala, or lateral hypothalamus/medial forebrain bundle. Further, we provide evidence that activation of this fiber bundle results in patterned activity of neurons in the mPFC, which is distinct from that of laminar stimulation of either the deep layers 5/6 or the superficial layer 1. Evoked excitatory postsynaptic potentials are monosynaptic and glutamatergic and exhibit bidirectional changes in synaptic efficacy in response to physiologically relevant induction protocols. These data provide the necessary groundwork for the characterization of the hippocampal pathway projecting to the mPFC.

Attenuation of Somatosensory Responses to Self-Produced Tactile Stimulation

Hesse, M. D., Nishitani, N., Fink, G. R., Jousmaki, V., Hari, R. — 2009-06-08

Sensory stimulation resulting from one's own behavior or the outside world is easily differentiated by healthy persons who are able to predict the sensory consequences of their own actions. This ability has been related to cortical attenuation of activation elicited by self-produced stimulation. To date, however, the neural processes underlying this modulation remain to be elucidated. We therefore recorded whole-scalp magnetoencephalographic (MEG) signals from 10 young adults either when they were touched by another person with a brush or when they touched themselves with the same device. The main MEG responses peaked at the primary somatosensory cortex at 54 ± 2 ms. Signals and source strengths were about a fifth weaker to self-produced than external touch. Importantly, attenuation was present in each subject. Control recordings indicated that the suppression was neither caused by hand movements as such nor by visual cues. The very early start of the attenuation already about 30 ms after stimulation onset is in line with the hypothesis of forward mechanisms, based on motor commands, as the basis of differentiation between self-produced and externally produced tactile sensations.

On Emotional Conflict: Interference Resolution of Happy and Angry Prosody Reveals Valence-Specific Effects

2009-06-08

To comprehend emotional prosodic cues in speech is a critical function of human social life. However, it is common in everyday communication that conflicting information in emotional prosody and semantic content co-occur. Here, we sought to specify brain regions involved in conflict monitoring of these interfering communication channels. By means of functional magnetic resonance imaging, we obtained signal increases in the right dorsal anterior cingulate cortex and right superior temporal gyrus (STG) and superior temporal sulcus when participants listened to incongruous compared with congruous sentences. Moreover, valence-specific effects were found in the left inferior frontal gyrus and left STG for happily intoned sentences expressing a negative content. The left caudate nucleus along with the thalamus was active when angrily intoned sentences were coupled with positive semantic content. Our results suggest a brain network that monitors conflict in emotional prosody and emotional semantic content comprising of medial prefrontal areas that have previously been associated with cognitive conflict processing. Furthermore, our study extends the knowledge of these processes by suggesting valence-specific differences of emotional conflict processing.

Preserving Syntactic Processing across the Adult Life Span: The Modulation of the Frontotemporal Language System in the Context of Age-Related Atrophy

2009-06-08

Although widespread neural atrophy is an inevitable consequence of normal aging, not all cognitive abilities decline as we age. For example, spoken language comprehension tends to be preserved, despite atrophy in neural regions involved in language function. Here, we combined measures of behavior, functional activation, and gray matter (GM) change in a younger (19–34 years) and older group (49–86 years) of participants to identify the mechanisms leading to preserved language comprehension across the adult life span. We focussed primarily on syntactic functions because these are strongly left lateralized, providing the potential for contralateral recruitment. In an functional magnetic resonance imaging study, we used a word-monitoring task to minimize working memory demands, manipulating the availability of semantics and syntax to ask whether syntax is preserved in aging because of the functional recruitment of other brain regions, which successfully compensate for neural atrophy. Performance in the older group was preserved despite GM loss. This preservation was related to increased activity in right hemisphere frontotemporal regions, which was associated with age-related atrophy in the left hemisphere frontotemporal network activated in the young. We argue that preserved syntactic processing across the life span is due to the shift from a primarily left hemisphere frontotemporal system to a bilateral functional language network.

Human V6: The Medial Motion Area

2009-06-05

Cortical-surface-based functional Magnetic Resonance Imaging mapping techniques and wide-field retinotopic stimulation were used to verify the presence of pattern motion sensitivity in human area V6. Area V6 is highly selective for coherently moving fields of dots, both at individual and group levels and even with a visual stimulus of standard size. This stimulus is a functional localizer for V6. The wide retinotopic stimuli used here also revealed a retinotopic map in the middle temporal cortex (area MT/V5) surrounded by several polar-angle maps that resemble the mosaic of small areas found around macaque MT/V5. Our results suggest that the MT complex (MT+) may be specialized for the analysis of motion signals, whereas area V6 may be more involved in distinguishing object and self-motion.

Tis21 Expression Marks Not Only Populations of Neurogenic Precursor Cells but Also New Postmitotic Neurons in Adult Hippocampal Neurogenesis

Attardo, A., Fabel, K., Krebs, J., Haubensak, W., Huttner, W. B., Kempermann, G. — 2009-05-29

During embryonic cortical development, expression of Tis21 is associated with cell cycle lengthening and neurogenic divisions of progenitor cells. We here investigated if the expression pattern of Tis21 also correlates with the generation of new neurons in the adult hippocampus. We used Tis21 knock-in mice expressing green fluorescent protein (GFP) and studied Tis21-GFP expression together with markers of adult hippocampal neurogenesis in newly generated cells. We found that Tis21-GFP 1) was absent from the radial glia–like putative stem cells (type-1 cells), 2) first appeared in transient amplifying progenitor cells (type-2 and 3 cells), 3) did not colocalize with markers of early postmitotic maturation stage, 4) was expressed again in maturing neurons, and 5) finally decreased in mature granule cells. Our data show that, in the course of adult neurogenesis, Tis21 is expressed in a phase additional to the one of the embryonic neurogenesis. This additional phase of expression might be associated with a new and different function of Tis21 than during embryonic brain development, where no Tis21 is expressed in mature neurons. We hypothesize that this function is related to the final functional integration of the newborn neurons. Tis21 can thus serve as new marker for key stages of adult neurogenesis.

Separate Processing of Texture and Form in the Ventral Stream: Evidence from fMRI and Visual Agnosia

Cavina-Pratesi, C., Kentridge, R. W., Heywood, C. A., Milner, A. D. — 2009-05-28

Real-life visual object recognition requires the processing of more than just geometric (shape, size, and orientation) properties. Surface properties such as color and texture are equally important, particularly for providing information about the material properties of objects. Recent neuroimaging research suggests that geometric and surface properties are dealt with separately within the lateral occipital cortex (LOC) and the collateral sulcus (CoS), respectively. Here we compared objects that differed either in aspect ratio or in surface texture only, keeping all other visual properties constant. Results on brain-intact participants confirmed that surface texture activates an area in the posterior CoS, quite distinct from the area activated by shape within LOC. We also tested 2 patients with visual object agnosia, one of whom (DF) performed well on the texture task but at chance on the shape task, whereas the other (MS) showed the converse pattern. This behavioral double dissociation was matched by a parallel neuroimaging dissociation, with activation in CoS but not LOC in patient DF and activation in LOC but not CoS in patient MS. These data provide presumptive evidence that the areas respectively activated by shape and texture play a causally necessary role in the perceptual discrimination of these features.

Mentalizing under Uncertainty: Dissociated Neural Responses to Ambiguous and Unambiguous Mental State Inferences

Jenkins, A. C., Mitchell, J. P. — 2009-05-28

The ability to read the minds of others (i.e., to mentalize) requires that perceivers understand a wide range of different kinds of mental states, including not only others’ beliefs and knowledge but also their feelings, desires, and preferences. Moreover, although such inferences may occasionally rely on observable features of a situation, perceivers more typically mentalize under conditions of "uncertainty," in which they must generate plausible hypotheses about a target's mental state from ambiguous or otherwise underspecified information. Here, we use functional neuroimaging to dissociate the neural bases of these 2 distinct social–cognitive challenges: 1) mentalizing about different types of mental states (beliefs vs. preferences) and 2) mentalizing under conditions of varying ambiguity. Although these 2 aspects of mentalizing have typically been confounded in earlier research, we observed a double dissociation between the brain regions sensitive to type of mental state and ambiguity. Whereas ventral and dorsal aspects of medial prefrontal cortex responded more during ambiguous than unambiguous inferences regardless of the type of mental state, the right temporoparietal junction was sensitive to the distinction between beliefs and preferences irrespective of certainty. These results underscore the emerging consensus that, rather than comprising a single mental operation, social cognition makes flexible use of different processes as a function of the particular demands of the social context.

The Impact of Second Language Learning on Semantic and Nonsemantic First Language Reading

Nosarti, C., Mechelli, A., Green, D. W., Price, C. J. — 2009-05-28

The relationship between orthography (spelling) and phonology (speech sounds) varies across alphabetic languages. Consequently, learning to read a second alphabetic language, that uses the same letters as the first, increases the phonological associations that can be linked to the same orthographic units. In subjects with English as their first language, previous functional imaging studies have reported increased left ventral prefrontal activation for reading words with spellings that are inconsistent with their orthographic neighbors (e.g., PINT) compared with words that are consistent with their orthographic neighbors (e.g., SHIP). Here, using functional magnetic resonance imaging (fMRI) in 17 Italian–English and 13 English–Italian bilinguals, we demonstrate that left ventral prefrontal activation for first language reading increases with second language vocabulary knowledge. This suggests that learning a second alphabetic language changes the way that words are read in the first alphabetic language. Specifically, first language reading is more reliant on both lexical/semantic and nonlexical processing when new orthographic to phonological mappings are introduced by second language learning. Our observations were in a context that required participants to switch between languages. They motivate future fMRI studies to test whether first language reading is also altered in contexts when the second language is not in use.

Cortical Connections to Area TE in Monkey: Hybrid Modular and Distributed Organization

Borra, E., Ichinohe, N., Sato, T., Tanifuji, M., Rockland, K. S. — 2009-05-23

To investigate the fine anatomical organization of cortical inputs to visual association area TE, 2–3 small injections of retrograde tracers were made in macaque monkeys. Injections were made as a terminal procedure, after optical imaging and electrophysiological recording, and targeted to patches physiologically identified as object-selective. Retrogradely labeled neurons occurred in several unimodal visual areas, the superior temporal sulcus, intraparietal sulcus (IPS), and prefrontal cortex (PFC), consistent with previous studies. Despite the small injection size (<0.5 mm wide), the projection foci in visual areas, but not in IPS or PFC, were spatially widespread (4–6 mm in extent), and predominantly consisted of neurons labeled by only one of the injections. This can be seen as a quasi-modular organization. In addition, within each projection focus, there were scattered neurons projecting to one of the other injections, together with some double-labeled (DL) neurons, in a more distributed pattern. Finally, projection foci included smaller "hotspots," consisting of intermixed neurons, single-labeled by the different injections, and DL neurons. DL neurons are likely the result of axons having extended, spatially separated terminal arbors, as demonstrated by anterograde experiments. These results suggest a complex, hybrid connectivity architecture, with both modular and distributed components.

Adaptive Changes in Firing of Primary Auditory Cortical Neurons following Illumination Shift from Light to Dark in Freely Moving Guinea Pigs

Ojima, H., Taoka, M., Iriki, A. — 2009-05-22

Some animals are forced to rely more on non-visual signals, such as audition or olfaction, than on vision when a bright environment becomes dark. By recording from a primary-like auditory cortex (field A) in freely moving guinea pigs, possible changes in the responsiveness of single units were explored in association with illumination changes. For a subset of units, we found that robust decreases (off-decrease) or increases (off-increase) in baseline discharge (BsD) were initiated soon after room light was silently extinguished. These neuronal changes were accompanied by the initiation of explorative locomotion, possibly reflecting a changed internal brain state. Preferred acoustic stimuli evoked salient excitatory responses against the reduced BsD level in the dark for the off-decrease units, and salient inhibitory responses against the increased BsD level for the off-increase units. Histological verification indicated that the units showing such BsD changes were located predominantly in layer V or its vicinity. These results are discussed in the context of the effects of the brainstem neuromodulatory systems that are activated during behavioral adaptation to new environments.

The Cortical Site of Visual Suppression by Transcranial Magnetic Stimulation

Thielscher, A., Reichenbach, A., Ugurbil, K., Uludag, K. — 2009-05-22

In visual suppression paradigms, transcranial magnetic stimulation (TMS) applied ~90 ms after visual stimulus presentation over occipital visual areas can robustly interfere with visual perception, thereby most likely affecting feedback activity from higher areas (Amassian VE, Cracco RQ, Maccabee PJ, Cracco JB, Rudell A, Eberle L. 1989. Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Electroencephalogr Clin Neurophysiol 74:458–462.). It is speculated that the observed effects might stem primarily from the disruption of V1 activity. This hypothesis, although under debate, argues in favor of a special role of V1 in visual awareness. In this study, we combine TMS, functional magnetic resonance imaging, and calculation of the induced electric field to study the neural correlates of visual suppression. For parafoveal visual stimulation in the lower right half of the visual field, area V2d is shown to be the likely TMS target based on its anatomical location close to the skull surface. Furthermore, isolated stimulation of area V3 also results in robust visual suppression. Notably, V3 stimulation does not directly affect the feedback from higher visual areas that is relayed mainly via V2 to V1. These findings support the view that intact activity patterns in several early visual areas (rather than merely in V1) are likewise important for the perception of the stimulus.

Cerebellar Inputs to Intraparietal Cortex Areas LIP and MIP: Functional Frameworks for Adaptive Control of Eye Movements, Reaching, and Arm/Eye/Head Movement Coordination

Prevosto, V., Graf, W., Ugolini, G. — 2009-05-22

Using retrograde transneuronal transfer of rabies virus in combination with a conventional tracer (cholera toxin B), we studied simultaneously direct (thalamocortical) and polysynaptic inputs to the ventral lateral intraparietal area (LIPv) and the medial intraparietal area (MIP) in nonhuman primates. We found that these areas receive major disynaptic inputs from specific portions of the cerebellar nuclei, the ventral dentate (D), and ventrolateral interpositus posterior (IP). Area LIPv receives inputs from oculomotor domains of the caudal D and IP. Area MIP is the target of projections from the ventral D (mainly middle third), and gaze- and arm-related domains of IP involved in reaching and arm/eye/head coordination. We also showed that cerebellar cortical "output channels" to MIP predominantly stem from posterior cerebellar areas (paramedian lobe/Crus II posterior, dorsal paraflocculus) that have the required connectivity for adaptive control of visual and proprioceptive guidance of reaching, arm/eye/head coordination, and prism adaptation. These findings provide important insight about the interplay between the posterior parietal cortex and the cerebellum regarding visuospatial adaptation mechanisms and visual and proprioceptive guidance of movement. They also have potential implications for clinical approaches to optic ataxia and neglect rehabilitation.

Structural Correlates of Semantic and Phonemic Fluency Ability in First and Second Languages

Grogan, A., Green, D. W., Ali, N., Crinion, J. T., Price, C. J. — 2009-05-21

Category and letter fluency tasks are commonly used clinically to investigate the semantic and phonological processes central to speech production, but the neural correlates of these processes are difficult to establish with functional neuroimaging because of the relatively unconstrained nature of the tasks. This study investigated whether differential performance on semantic (category) and phonemic (letter) fluency in neurologically normal participants was reflected in regional gray matter density. The participants were 59 highly proficient speakers of 2 languages. Our findings corroborate the importance of the left inferior temporal cortex in semantic relative to phonemic fluency and show this effect to be the same in a first language (L1) and second language (L2). Additionally, we show that the pre-supplementary motor area (pre-SMA) and head of caudate bilaterally are associated with phonemic more than semantic fluency, and this effect is stronger for L2 than L1 in the caudate nuclei. To further validate these structural results, we reanalyzed previously reported functional data and found that pre-SMA and left caudate activation was higher for phonemic than semantic fluency. On the basis of our findings, we also predict that lesions to the pre-SMA and caudate nuclei may have a greater impact on phonemic than semantic fluency, particularly in L2 speakers.

Severe Scene Learning Impairment, but Intact Recognition Memory, after Cholinergic Depletion of Inferotemporal Cortex Followed by Fornix Transection

Browning, P. G. F., Gaffan, D., Croxson, P. L., Baxter, M. G. — 2009-05-15

To examine the generality of cholinergic involvement in visual memory in primates, we trained macaque monkeys either on an object-in-place scene learning task or in delayed nonmatching-to-sample (DNMS). Each monkey received either selective cholinergic depletion of inferotemporal cortex (including the entorhinal cortex and perirhinal cortex) with injections of the immunotoxin ME20.4-saporin or saline injections as a control and was postoperatively retested. Cholinergic depletion of inferotemporal cortex was without effect on either task. Each monkey then received fornix transection because previous studies have shown that multiple disconnections of temporal cortex can produce synergistic impairments in memory. Fornix transection mildly impaired scene learning in monkeys that had received saline injections but severely impaired scene learning in monkeys that had received cholinergic lesions of inferotemporal cortex. This synergistic effect was not seen in monkeys performing DNMS. These findings confirm a synergistic interaction in a macaque monkey model of episodic memory between connections carried by the fornix and cholinergic input to the inferotemporal cortex. They support the notion that the mnemonic functions tapped by scene learning and DNMS have dissociable neural substrates. Finally, cholinergic depletion of inferotemporal cortex, in this study, appears insufficient to impair memory functions dependent on an intact inferotemporal cortex.

Neurotrophin-3 Is Involved in the Formation of Apical Dendritic Bundles in Cortical Layer 2 of the Rat

2009-05-15

Apical dendritic bundles from pyramidal neurons are a prominent feature of cortical neuropil but with significant area specializations. Here, we investigate mechanisms of bundle formation, focusing on layer (L) 2 bundles in rat granular retrosplenial cortex (GRS), a limbic area implicated in spatial memory. By using microarrays, we first searched for genes highly and specifically expressed in GRS L2 at postnatal day (P) 3 versus GRS L2 at P12 (respectively, before and after bundle formation), versus GRS L5 (at P3), and versus L2 in barrel field cortex (BF) (at P3). Several genes, including neurotrophin-3 (NT-3), were identified as transiently and specifically expressed in GRS L2. Three of these were cloned and confirmed by in situ hybridization. To test that NT-3–mediated events are causally involved in bundle formation, we used in utero electroporation to overexpress NT-3 in other cortical areas. This produced prominent bundles of dendrites originating from L2 neurons in BF, where L2 bundles are normally absent. Intracellular biocytin fills, after physiological recording in vitro, revealed increased dendritic branching in L1 of BF. The controlled ectopic induction of dendritic bundles identifies a new role for NT-3 and a new in vivo model for investigating dendritic bundles and their formation.

Functional Organization of the Somatosensory Cortical Layer 6 Feedback to the Thalamus

Lam, Y.-W., Sherman, S. M. — 2009-05-15

The pathway from cortical layer 6 to the thalamus is a property of all thalamic relay nuclei. This pathway, as a population, directly excites relay cells and indirectly inhibits them via the thalamic reticular nucleus. To understand the circuit organization of this cortical feedback, we used laser-scanning photostimulation, which specifically activates somata or dendrites, to stimulate the primary somatosensory cortex in an in vitro thalamocortical slice preparation while recording from neurons of the ventral posterior medial nucleus. Layer 6 photostimulation evoked biphasic excitatory postsynaptic current/inhibitory postsynaptic current (EPSC/IPSC) responses in the neurons of the ventral posterior medial nucleus, indicating that such photostimulation strongly activates reticular cells. These disynaptic IPSCs were greatly suppressed or abolished by bath application of the muscarinic agonist acetyl-β-methylcholine. Our results suggest that the top-down modulation of thalamic neurons from cortical layer 6 involves an inhibitory component via the thalamic reticular nucleus, and this component can be selectively reduced by cholinergic input. Finally, we found the footprints for the excitatory corticothalamic and the inhibitory cortico-reticulo-thalamic inputs to be located in similar positions, though in some cases they are offset. Both patterns have implications for cortico-reticulo-thalamic circuitry.

Population-Based Corticospinal Interactions in Macaques Are Correlated with Visuomotor Processing

Asher, I., Zinger, N., Yanai, Y., Israel, Z., Prut, Y. — 2009-05-14

Visuomotor transformation is a fundamental process in executing voluntary actions. The final steps of this transformation are presumed to take place in the corticospinal (CS) system, yet the way in which the motor cortex (MC) interacts with spinal circuitry during this process is unclear. We studied neural correlates of visuomotor transformation in the MC and cervical spinal cord while monkeys performed an isometric wrist task. We recorded 2 measures of population activity: local field potential (LFP), reflecting local synaptic inputs and multi-unit activity (MUA), reflecting spiking activity emitted by nearby neurons. We found robust cortical and spinal responses locked to visual and motor events. In motor cortex, LFP responses were predominantly visually related; MUA responses were mostly motor related. Spinal LFP responses were generally weak, yet spinal MUAs showed visual and motor responses with distinctive patterns. For both structures, amplitudes of visual responses were positively correlated with amplitudes of motor responses and negatively correlated with reaction times. The temporal relations of cortical and spinal responses shifted from weak coactivation before movement to increased coupling following torque onset, with cortical leading spinal activity. Thus, ongoing CS interactions may exist at early stages of movement preparation. These interactions are dynamic and may shape the executed motor action.

The Truth about Lying: Inhibition of the Anterior Prefrontal Cortex Improves Deceptive Behavior

2009-05-14

Recent neuroimaging studies have indicated a predominant role of the anterior prefrontal cortex (aPFC) in deception and moral cognition, yet the functional contribution of the aPFC to deceptive behavior remains unknown. We hypothesized that modulating the excitability of the aPFC by transcranial direct current stimulation (tDCS) could reveal its functional contribution in generating deceitful responses. Forty-four healthy volunteers participated in a thief role-play in which they were supposed to steal money and then to attend an interrogation with the Guilty Knowledge Test. During the interrogation, participants received cathodal, anodal, or sham tDCS. Remarkably, inhibition of the aPFC by cathodal tDCS did not lead to an impairment of deceptive behavior but rather to a significant improvement. This effect manifested in faster reaction times in telling lies, but not in telling the truth, a decrease in sympathetic skin-conductance response and feelings of guilt while deceiving the interrogator and a significantly higher lying quotient reflecting skillful lying. Increasing the excitability of the aPFC by anodal tDCS did not affect deceptive behavior, confirming the specificity of the stimulation polarity. These findings give causal support to recent correlative data obtained by functional magnetic resonance imaging studies indicating a pivotal role of the aPFC in deception.

Hedonic and Informational Functions of the Human Orbitofrontal Cortex

Elliott, R., Agnew, Z., Deakin, J.F.W. — 2009-05-12

Functional imaging studies have revealed roles for orbitofrontal cortex (OFC) in reward processing and decision making. In many situations, rewards signal that the current behavior should be maintained, whereas punishments cue a change in behavior. Thus, hedonic responses to reinforcers are conflated with their function as behavioral cues. In an attempt to disambiguate these functions, we performed a functional magnetic resonance imaging study of a 2-choice decision-making task. After each trial, subjects were rewarded or punished and independently provided with a cue to maintain or change behavior. We identified key regions of OFC involved in these processes. An anterior medial focus responded to reward, whereas bilateral lateral foci responded to punishment. The right-sided lateral region that responded to punishment also responded to cues for behavior change (shift), whereas a more ventral and anterior bilateral region responded to cues for behavioral maintenance (stay). The right-sided stay region responded specifically when stay cues were combined with punishment. These results support the view that OFC codes both hedonic responses to reinforcers and their behavioral consequences. Punishments and shift cues are associated with the same right lateral OFC focus, suggesting a fundamental connection between emotive response to negative reinforcement and use of negative information to cue behavioral change.

A Simple Rule for Axon Outgrowth and Synaptic Competition Generates Realistic Connection Lengths and Filling Fractions

Kaiser, M., Hilgetag, C. C., van Ooyen, A. — 2009-05-12

Neural connectivity at the cellular and mesoscopic level appears very specific and is presumed to arise from highly specific developmental mechanisms. However, there are general shared features of connectivity in systems as different as the networks formed by individual neurons in Caenorhabditis elegans or in rat visual cortex and the mesoscopic circuitry of cortical areas in the mouse, macaque, and human brain. In all these systems, connection length distributions have very similar shapes, with an initial large peak and a long flat tail representing the admixture of long-distance connections to mostly short-distance connections. Furthermore, not all potentially possible synapses are formed, and only a fraction of axons (called filling fraction) establish synapses with spatially neighboring neurons. We explored what aspects of these connectivity patterns can be explained simply by random axonal outgrowth. We found that random axonal growth away from the soma can already reproduce the known distance distribution of connections. We also observed that experimentally observed filling fractions can be generated by competition for available space at the target neurons—a model markedly different from previous explanations. These findings may serve as a baseline model for the development of connectivity that can be further refined by more specific mechanisms.

Functional Neuroanatomy of Mirroring during a Unimanual Force Generation Task

Sehm, B., Perez, M.A., Xu, B., Hidler, J., Cohen, L.G. — 2009-05-11

Performance of a unimanual motor task often induces involuntary mirror electromyographic (EMG) activity in the opposite, resting hand. In spite of the ubiquitous presence of mirroring, little is known regarding the underlying cortical contributions. Here, we used functional magnetic resonance imaging (fMRI) to study brain regions activated in association with parametric increases in right isometric wrist flexion force (10%, 20%, 30%, and 70%) in 12 healthy volunteers. During scanning, EMG activity was recorded bilaterally from flexor carpi radialis (FCR), extensor carpi radialis (ECR), biceps brachii (BB), and triceps brachii (TB). Mirror EMG was observed in left FCR during 20%, 30%, and 70% of force. Left ECR, BB, and TB showed mirror EMG only at 70% of force. Increasing force was associated with a linear increase of blood-oxygen-level–dependent (BOLD) signal in bilateral primary motor cortex (M1), supplementary motor area (SMA), caudal cingulate, and cerebellum. Mirroring in the left FCR correlated with activity in bilateral M1, SMA, and the cerebellum. Overall, our results suggest that activity in these regions might reflect sensorimotor processes operating in association with mirroring and suggest caution when interpreting fMRI activity in studies that involve unilateral force generation tasks in the absence of simultaneous bilateral EMG/kinematics measurements.

Mapping Surface Variability of the Central Sulcus in Musicians

2009-05-11

We employed a sulcal geometry–based approach to investigate the morphology of the central sulcus (CS) in musicians (pianists). The anterior and posterior walls of the CS were first manually outlined from high-resolution magnetic resonance (MR) images of 41 right-handed subjects (20 musicians and 21 controls), followed by a surface reconstruction and parameterization procedure to ensure the anatomical correspondence of surface locations across subjects. The intrasulcal length, surface area, and local variability of the CS were measured. There were no significant differences in either the intrasulcal length or surface area of the anterior or posterior walls between the 2 groups. However, we observed that the controls had a pronounced left-larger-than-right asymmetry that was reduced in the musicians. Importantly, we found that the musicians showed greater local variability in the middle section (i.e., somatotopic hand area) of the right CS and the lower section of the left CS as compared with the controls. Further analysis revealed significantly negative correlations between the variability of the middle section of the right CS and the age of commencement of musical training. Our findings suggest that the musicians might be associated with plastic changes in the 3D morphology of the CS in response to long-term motor skill training.

Locus Coeruleus Activation Facilitates Memory Encoding and Induces Hippocampal LTD that Depends on {beta}-Adrenergic Receptor Activation

Lemon, N., Aydin-Abidin, S., Funke, K., Manahan-Vaughan, D. — 2009-05-11

Spatial memory formation is enabled through synaptic information processing, in the form of persistent strengthening and weakening of synapses, within the hippocampus. It is, however, unclear how relevant spatial information is selected for encoding, in preference to less pertinent information. As the noradrenergic locus coeruleus (LC) becomes active in response to novel experiences, we hypothesized that the LC may provide the saliency signal required to promote hippocampal encoding of relevant information through changes in synaptic strength. Test pulse stimulation evoked stable basal synaptic transmission at Schaffer collateral (SC)–CA1 stratum radiatum synapses in freely behaving adult rats. Coupling of these test pulses with electrical stimulation of the LC induced long-term depression (LTD) at SC–CA1 synapses and induced a transient suppression of theta-frequency oscillations. Effects were N-methyl-D-aspartate and β-adrenergic receptor dependent. Activation of the LC also increased CA1 noradrenalin levels and facilitated the encoding of spatial memory for a single episode via a β-adrenoceptor–dependent mechanism. Our results demonstrate that the LC plays a key role in the induction of hippocampal LTD and in promoting the encoding of spatial information. This LC–hippocampal interaction may reflect a means by which salient information is distinguished for subsequent synaptic processing.

Interacting Outcome Retrieval, Anticipation, and Feedback Processes in the Human Brain

Walsh, N. D., Phillips, M. L. — 2009-05-08

Cognitive control is an inherently multivariate phenomenon, and its neural basis is currently unclear. Here we examined using functional magnetic resonance imaging how participants retrieve prelearnt information from memory, use this information to guide responses for an impending decision, and adjust their responses based on outcome feedback. We developed a behavioral task designed to manipulate memory outcome–retrieval load, outcome-anticipation interval, and outcome-feedback processes. This allowed us to understand the neural basis of these cognitive processes in isolation and how they interact. Extending previous work, we found a retrieval-load by outcome-feedback interaction in the left globus pallidus; an outcome-feedback by anticipation-interval interaction in the inferior prefrontal cortex; a retrieval-load by anticipation-interval interaction in the midcingulate gyrus and a load by interval by outcome interaction in the right frontal pole. These results further advance our knowledge of how fundamental cognitive processes interact physiologically to give rise to higher-level behavioral control.

Neural Signatures of Stimulus Features in Visual Working Memory--A Spatiotemporal Approach

2009-05-08

We examined the neural signatures of stimulus features in visual working memory (WM) by integrating functional magnetic resonance imaging (fMRI) and event-related potential data recorded during mental manipulation of colors, rotation angles, and color–angle conjunctions. The N200, negative slow wave, and P3b were modulated by the information content of WM, and an fMRI-constrained source model revealed a progression in neural activity from posterior visual areas to higher order areas in the ventral and dorsal processing streams. Color processing was associated with activity in inferior frontal gyrus during encoding and retrieval, whereas angle processing involved right parietal regions during the delay interval. WM for color–angle conjunctions did not involve any additional neural processes. The finding that different patterns of brain activity underlie WM for color and spatial information is consistent with ideas that the ventral/dorsal "what/where" segregation of perceptual processing influences WM organization. The absence of characteristic signatures of conjunction-related brain activity, which was generally intermediate between the 2 single conditions, suggests that conjunction judgments are based on the coordinated activity of these 2 streams.

The Origins of Cortical Interneurons: Mouse versus Monkey and Human

Jones, E. G. — 2009-05-08

The neocortex of primates, including humans, is thought to contain significantly higher numbers and more diverse forms of -aminobutyric acidergic (GABAergic) interneurons than that of rodents. The mouse cortex displays a number of other features that distinguish it from the cortex of primates and suggest a somewhat less complex pattern of organization. Nevertheless, dramatic findings on the origins and migratory patterns of newly specified GABAergic cortical interneurons in the embryonic mouse have led to a prevailing view that GABAergic cortical interneurons of all species are born in the ganglionic eminence and undergo the same long tangential migration toward the cortex that is seen in the mouse. Recent observations in fetal human and monkey brains, although clearly identifying GABAergic neurons that reach the neocortex via the tangential route, also demonstrate that substantial numbers of GABA neurons are generated in the lateral ventricular neuroepithelium and migrate into the cortex via the same radial route followed by glutamatergic neurons. In the course of evolution of the higher primate cortex, it is likely that new forms of cortical interneuron with origins in the ventricular neuroepithelium have been added to an older population derived from the ganglionic eminence.

Number Processing Pathways in Human Parietal Cortex

Santens, S., Roggeman, C., Fias, W., Verguts, T. — 2009-05-08

Numerous studies have identified the intraparietal sulcus (IPS) as an area critically involved in numerical processing. IPS neurons in macaques are tuned to a preferred numerosity, hence neurally coding numerosity in a number-selective way. Neuroimaging studies in humans have demonstrated number-selective processing in the anterior parts of the IPS. Nevertheless, the processes that convert visual input into a number-selective neural code remain unknown. Computational studies have suggested that a neural coding stage that is sensitive, but not selective to number, precedes number-selective coding when processing nonsymbolic quantities but not when processing symbolic quantities. In Experiment 1, we used functional magnetic resonance imaging to localize number-sensitive areas in the human brain by searching for areas exhibiting increasing activation with increasing number, carefully controlling for nonnumerical parameters. An area in posterior superior parietal cortex was identified as a substrate for the intermediate number-sensitive steps required for processing nonsymbolic quantities. In Experiment 2, the interpretation of Experiment 1 was confirmed with a connectivity analysis showing that a shared number-selective representation in IPS is reached through different pathways for symbolic versus nonsymbolic quantities. The preferred pathway for processing nonsymbolic quantities included the number-sensitive area in superior parietal cortex, whereas the pathway for processing symbolic quantities did not.

Priming and Backward Influences in the Human Brain: Processing Interactions during the Stroop Interference Effect

Appelbaum, L. G., Meyerhoff, K. L., Woldorff, M. G. — 2009-05-08

This study investigated neural processing interactions during Stroop interference by varying the temporal separation of relevant and irrelevant features of congruent, neutral, and incongruent colored-bar/color-word stimulus components. High-density event-related potentials (ERPs) and behavioral performance were measured as participants reported the bar color as quickly as possible, while ignoring the color words. The task-irrelevant color words could appear at 1 of 5 stimulus onset asynchronies (SOAs) relative to the task-relevant bar-color occurrence: –200 or –100 ms before, +100 or +200 ms after, or simultaneously. Incongruent relative to congruent presentations elicited slower reaction times and higher error rates (with neutral in between), and ERP difference waves containing both an early, negative-polarity, central-parietal deflection, and a later, more left-sided, positive-polarity component. These congruency-related differences interacted with SOA, showing the greatest behavioral and electrophysiological effects when irrelevant stimulus information preceded the task-relevant target and reduced effects when the irrelevant information followed the relevant target. We interpret these data as reflecting 2 separate processes: 1) a ‘priming influence’ that enhances the magnitude of conflict-related facilitation and conflict-related interference when a task-relevant target is preceded by an irrelevant distractor; and 2) a reduced ‘backward influence’ of stimulus conflict when the irrelevant distractor information follows the task-relevant target.

Function-based Intersubject Alignment of Human Cortical Anatomy

2009-05-06

Making conclusions about the functional neuroanatomical organization of the human brain requires methods for relating the functional anatomy of an individual's brain to population variability. We have developed a method for aligning the functional neuroanatomy of individual brains based on the patterns of neural activity that are elicited by viewing a movie. Instead of basing alignment on functionally defined areas, whose location is defined as the center of mass or the local maximum response, the alignment is based on patterns of response as they are distributed spatially both within and across cortical areas. The method is implemented in the two-dimensional manifold of an inflated, spherical cortical surface. The method, although developed using movie data, generalizes successfully to data obtained with another cognitive activation paradigm—viewing static images of objects and faces—and improves group statistics in that experiment as measured by a standard general linear model (GLM) analysis.

Cortical Connections of the Macaque Caudal Ventrolateral Prefrontal Areas 45A and 45B

Gerbella, M., Belmalih, A., Borra, E., Rozzi, S., Luppino, G. — 2009-04-30

We have found that the 2 architectonic subdivisions of the prefrontal area 45, 45A and 45B, display connectivity patterns that clearly distinguish them from one another and from their neighboring architectonic areas. Area 45A is primarily connected to the frontal areas 45B, 12l, caudal 12r, 12o, 10, rostrodorsal 46, 9/8B, 44, 8/FEF (frontal eye field), and the SEF (supplementary eye field), temporal area IPa, and unique among all the studied areas, to the superior temporal polysensory (STP) area and auditory parabelt areas. Area 45B displayed much stronger frontal connections with the oculomotor areas 8/FEF, 8r, and the SEF than those of area 45A, primary connections with areas 12l, caudal 12r, 12o, and 8B, and unlike area 45A, with areas ventrorostral 46, rostral 12r, 12m, and 13m. Temporal connections were all virtually confined to areas IPa, intermediate TEa/m, and TE. Additional labeling was found in lateral intraparietal area. Our data suggest that 45A and 45B are 2 distinct areas, possibly playing a differential role in nonspatial information processing: area 45A corresponds to the prefrontal sector for which a role in communication behavior and homology with the human area 45 was proposed, whereas area 45B is a distinct prearcuate area, possibly affiliated to the oculomotor frontal system.

Structural Connectivity for Visuospatial Attention: Significance of Ventral Pathways

2009-04-30

In the present study, we identified the most probable trajectories of point-to-point segregated connections between functional attentional centers using a combination of functional magnetic resonance imaging and a novel diffusion tensor imaging–based algorithm for pathway extraction. Cortical regions activated by a visuospatial attention task were subsequently used as seeds for probabilistic fiber tracking in 26 healthy subjects. Combining probability maps of frontal and temporoparietal regions yielded a network that consisted of dorsal and ventral connections. The dorsal connections linked temporoparietal cortex with the frontal eye field and area 44 of the inferior frontal gyrus (IFG). Traveling along superior longitudinal and arcuate fascicles, these fibers are well described in relation to spatial attention. However, the ventral connections, which traveled in the white matter between insula (INS) cortex and putamen parallel to the sylvian fissure, were not previously described for visuospatial attention. Linking temporoparietal cortex with anterior INS and area 45 of IFG, these connections may provide an anatomical substrate for crossmodal cortical integration needed for stimulus perception and response in relation to current intention. The newly anatomically described integral network for visuospatial attention might improve the understanding of spatial attention deficits after white matter lesions.

What Motivates the Adolescent? Brain Regions Mediating Reward Sensitivity across Adolescence

2009-04-30

The relation between brain development across adolescence and adolescent risky behavior has attracted increasing interest in recent years. It has been proposed that adolescents are hypersensitive to reward because of an imbalance in the developmental pattern followed by the striatum and prefrontal cortex. To date, it is unclear if adolescents engage in risky behavior because they overestimate potential rewards or respond more to received rewards and whether these effects occur in the absence of decisions. In this study, we used a functional magnetic resonance imaging paradigm that allowed us to dissociate effects of the anticipation, receipt, and omission of reward in 10- to 12-year-old, 14- to 15-year-old, and 18- to 23-year-old participants. We show that in anticipation of uncertain outcomes, the anterior insula is more active in adolescents compared with young adults and that the ventral striatum shows a reward-related peak in middle adolescence, whereas young adults show orbitofrontal cortex activation to omitted reward. These regions show distinct developmental trajectories. This study supports the hypothesis that adolescents are hypersensitive to reward and adds to the current literature in demonstrating that neural activation differs in adolescents even for small rewards in the absence of choice. These findings may have important implications for understanding adolescent risk-taking behavior.

Functional Heterogeneity of Inferior Parietal Cortex during Mathematical Cognition Assessed with Cytoarchitectonic Probability Maps

Wu, S. S., Chang, T. T., Majid, A., Caspers, S., Eickhoff, S. B., Menon, V. — 2009-04-30

Although the inferior parietal cortex (IPC) has been consistently implicated in mathematical cognition, the functional roles of its subdivisions are poorly understood. We address this problem using probabilistic cytoarchitectonic maps of IPC subdivisions intraparietal sulcus (IPS), angular gyrus (AG), and supramarginal gyrus. We quantified IPC responses relative to task difficulty and individual differences in task proficiency during mental arithmetic (MA) tasks performed with Arabic (MA-A) and Roman (MA-R) numerals. The 2 tasks showed similar levels of activation in 3 distinct IPS areas, hIP1, hIP2, and hIP3, suggesting their obligatory role in MA. Both AG areas, PGa and PGp, were strongly deactivated in both tasks, with stronger deactivations in posterior area PGp. Compared with the more difficult MA-R task, the MA-A task showed greater responses in both AG areas, but this effect was driven by less deactivation in the MA-A task. AG deactivations showed prominent overlap with lateral parietal nodes of the default mode network, suggesting a nonspecific role in MA. In both tasks, greater bilateral AG deactivation was associated with poorer performance. Our findings suggest a close link between IPC structure and function and they provide new evidence for behaviorally salient functional heterogeneity within the IPC during mathematical cognition.

Dual Mechanisms for the Cross-Sensory Spread of Attention: How Much Do Learned Associations Matter?

Fiebelkorn, I. C., Foxe, J. J., Molholm, S. — 2009-04-24

The spread of attention-related processing across anatomically separated cortical regions plays an important role in the binding of an object's features, both within and across sensory modalities. We presented multiple exemplars of semantically congruent multisensory objects (e.g., dogs with barks) and semantically incongruent multisensory objects (e.g., guitars with barks) while recording high-density event-related potentials and tested whether highly learned associations among the multisensory features of well-known objects modulated the spread of attention from an attended visual stimulus to its paired, task-irrelevant sound. Our findings distinguish dual mechanisms for the cross-sensory spread of attention: 1) a stimulus-driven spread of attention that occurs whenever a task-irrelevant sound is simultaneously presented with an attended visual stimulus, independent of highly learned associations, and 2) a representation-driven spread of attention that occurs in response to a task-irrelevant sound that is semantically congruent with a visual target and is therefore dependent on highly learned associations. The first mechanism is thought to reflect bottom-up feature binding, whereas the second mechanism is thought to reflect the top-down activation of a stored object representation that includes the well-known object's multisensory features. When a semantically congruent, task-irrelevant sound is simultaneously presented with a well-known visual target, the combined spread of attention through both mechanisms appears additive.

Connections of Auditory and Visual Cortex in the Prairie Vole (Microtus ochrogaster): Evidence for Multisensory Processing in Primary Sensory Areas

Campi, K. L., Bales, K. L., Grunewald, R., Krubitzer, L. — 2009-04-24

In prairie voles, primary sensory areas are dominated by neurons that respond to one sensory modality, but some neurons also respond to stimulation of other modalities. To reveal the anatomical substrate for these multimodal responses, we examined the connections of the primary auditory area + the anterior auditory field (A1 + AAF), the temporal anterior area (TA), and the primary visual area (V1). A1 + AAF had intrinsic connections and connections with TA, multimodal cortex (MM), V1, and primary somatosensory area (S1). TA had intrinsic connections and connections with A1 + AAF, MM, and V2. Callosal connections were observed in homotopic locations in auditory cortex for both fields. A1 + AAF and TA receive thalamic input primarily from divisions of the medial geniculate nucleus but also from the lateral geniculate nucleus (LGd), the lateral posterior nucleus, and the ventral posterior nucleus (VP). V1 had dense intrinsic connections and connections with V2, MM, auditory cortex, pyriform cortex (Pyr), and, in some cases, somatosensory cortex. V1 had interhemispheric connections with V1, V2, MM, S1, and Pyr and received thalamic input from LGd and VP. Our results indicate that multisensory integration occurs in primary sensory areas of the prairie vole cortex, and this may be related to behavioral specializations associated with its niche.

An fMRI Study of Functional Abnormalities in the Verbal Working Memory System and the Relationship to Clinical Symptoms in Chronic Schizophrenia

Hashimoto, R.-i., Lee, K., Preus, A., McCarley, R. W., Wible, C. G. — 2009-04-24

There has been evidence for functional abnormalities of the verbal working memory system in schizophrenia. Verbal working memory crucially involves the interplay between the anterior and posterior language systems, and previous studies have shown converging evidence for abnormalities in the posterior language system in schizophrenia. In this functional magnetic resonance imaging study, we measured cortical activity in chronic schizophrenic patients and matched healthy controls during auditory and visual verbal working memory tasks. We employed 1) regional analyses specifically targeting the posterior language system and 2) analyses of functional connectivity between anterior and posterior language regions. We performed these analyses separately for each memory stage and modality. In the regional analyses, the left sylvian–parietal–temporal (Spt) area consistently showed reduced activation during encoding and retrieval stages in schizophrenia. Magnitudes of activation in the left posterior superior temporal sulcus were correlated with the severity of delusions at every memory stage. Functional connectivity analyses revealed reduced connectivity between the left Spt and the anterior insula during the encoding of auditory words. In addition, the connectivity strength was correlated with the severity of auditory hallucinations. These findings identify abnormal components in the verbal working memory system and illustrate their possible overlap with the mechanisms of core schizophrenic symptoms.

The Brain Network Underlying Serial Visual Search: Comparing Overt and Covert Spatial Orienting, for Activations and for Effective Connectivity

Fairhall, S.L., Indovina, I., Driver, J., Macaluso, E. — 2009-04-24

We used functional magnetic resonance imaging (fMRI) to investigate the brain basis of overt and covert forms of attention during search, while employing stringent control of both eye movements and attentional shifts. A factorial design compared overt and covert forms of goal-directed serial search versus stimulus-driven tracking. To match ocular changes and the number and magnitude of attention shifts across cells in the design, stimulus-driven tracking involved trial-specific "replay" of previous goal-directed eye movements. We found that, in terms of cortical activations, engagement of the dorsal fronto-parietal network by goal-directed attention did not depend on oculomotor requirements, being found similarly for covert attention, in accord with other work. However, analyses of effective connectivity (or "functional coupling") revealed that information flow within this network changed significantly as a function of both the task (goal-directed or stimulus-driven) and the overt versus covert form of attention. Additionally, we observed a distinct set of subcortical regions (pulvinar and caudate nucleus) engaged primarily during the covert form of goal-directed search. We conclude that dynamics within the dorsal fronto-parietal attentional system flexibly reorganize to integrate task demands and oculomotor requirements.

Quantifying the Adequacy of Neural Representations for a Cross-Language Phonetic Discrimination Task: Prediction of Individual Differences

Raizada, R. D. S., Tsao, F.-M., Liu, H.-M., Kuhl, P. K. — 2009-04-22

In order for stimuli to be perceptually discriminable, their representations in the brain must be distinct. Investigating the task of discriminating the syllables /ra/ and /la/, we hypothesized that the more distinct a person's neural representations of those sounds were, the better their behavioral ability to discriminate them would be. Standard neuroimaging approaches are ill-suited to testing this hypothesis as they have problems differentiating between neural representations spatially intermingled within the same brain area. We therefore performed multi-voxel pattern-based analysis of the functional magnetic resonance imaging (fMRI) activity elicited by these syllables, in native speakers of English and Japanese. In right primary auditory cortex, the statistical separability of these fMRI patterns predicted subjects’ behavioral ability to tell the sounds apart, not only across groups but also across individuals. This opens up a new approach for identifying neural representations and for quantifying their task suitability.

Integrating Visual and Tactile Information in the Perirhinal Cortex

Holdstock, J. S., Hocking, J., Notley, P., Devlin, J. T., Price, C. J. — 2009-04-22

By virtue of its widespread afferent projections, perirhinal cortex is thought to bind polymodal information into abstract object-level representations. Consistent with this proposal, deficits in cross-modal integration have been reported after perirhinal lesions in nonhuman primates. It is therefore surprising that imaging studies of humans have not observed perirhinal activation during visual–tactile object matching. Critically, however, these studies did not differentiate between congruent and incongruent trials. This is important because successful integration can only occur when polymodal information indicates a single object (congruent) rather than different objects (incongruent). We scanned neurologically intact individuals using functional magnetic resonance imaging (fMRI) while they matched shapes. We found higher perirhinal activation bilaterally for cross-modal (visual–tactile) than unimodal (visual–visual or tactile–tactile) matching, but only when visual and tactile attributes were congruent. Our results demonstrate that the human perirhinal cortex is involved in cross-modal, visual–tactile, integration and, thus, indicate a functional homology between human and monkey perirhinal cortices.

Analysis of c-fos and zif268 Expression Reveals Time-Dependent Changes in Activity Inside and Outside the Lesion Projection Zone in Adult Cat Area 17 after Retinal Lesions

Hu, T.-T., Laeremans, A., Eysel, U. T., Cnops, L., Arckens, L. — 2009-04-22

Retinal lesions induce a topographic reorganization in the corresponding lesion projection zone (LPZ) in the visual cortex of adult cats. To gain a better insight into the reactivation dynamics, we investigated the alterations in cortical activity throughout area 17. We implemented in situ hybridization and real-time polymerase chain reaction to analyze the spatiotemporal expression patterns of the activity marker genes zif268 and c-fos. The immediate early gene (IEG) data confirmed a strong and permanent activity decrease in the center of the LPZ as previously described by electrophysiology. A recovery of IEG expression was clearly measured in the border of the LPZ. We were able to register reorganization over 2.5–6 mm. We also present evidence that the central retinal lesions concomitantly influence the activity in far peripheral parts of area 17. Its IEG expression levels appeared dependent of time and distance from the LPZ. We therefore propose that coupled changes in activity occur inside and outside the LPZ. In conclusion, alterations in activity reporter gene expression throughout area 17 contribute to the lesion-induced functional reorganization.

Connecting Long Distance: Semantic Distance in Analogical Reasoning Modulates Frontopolar Cortex Activity

Green, A. E., Kraemer, D. J. M., Fugelsang, J. A., Gray, J. R., Dunbar, K. N. — 2009-04-21

Solving problems often requires seeing new connections between concepts or events that seemed unrelated at first. Innovative solutions of this kind depend on analogical reasoning, a relational reasoning process that involves mapping similarities between concepts. Brain-based evidence has implicated the frontal pole of the brain as important for analogical mapping. Separately, cognitive research has identified semantic distance as a key characteristic of the kind of analogical mapping that can support innovation (i.e., identifying similarities across greater semantic distance reveals connections that support more innovative solutions and models). However, the neural substrates of semantically distant analogical mapping are not well understood. Here, we used functional magnetic resonance imaging (fMRI) to measure brain activity during an analogical reasoning task, in which we parametrically varied the semantic distance between the items in the analogies. Semantic distance was derived quantitatively from latent semantic analysis. Across 23 participants, activity in an a priori region of interest (ROI) in left frontopolar cortex covaried parametrically with increasing semantic distance, even after removing effects of task difficulty. This ROI was centered on a functional peak that we previously associated with analogical mapping. To our knowledge, these data represent a first empirical characterization of how the brain mediates semantically distant analogical mapping.

Hypoxic Injury during Neonatal Development in Murine Brain: Correlation between In Vivo DTI Findings and Behavioral Assessment

2009-04-20

Preterm birth results in significant neurodevelopmental disability. A neonatal rodent model of chronic sublethal hypoxia (CSH), which mimics effects of preterm birth, was used to characterize neurodevelopmental consequences of prolonged exposure to hypoxia using tissue anisotropy measurements from diffusion tensor imaging. Corpus callosum, cingulum, and fimbria of the hippocampus revealed subtle, yet significant, hypoxia-induced modifications during maturation (P15–P51). Anisotropy differences between control and CSH mice were greatest at older ages (>P40) in these regions. Neither somatosensory cortex nor caudate putamen revealed significant differences between control and CSH mice at any age. We assessed control and CSH mice using tests of general activity and cognition for behavioral correlates of morphological changes. Open-field task revealed greater locomotor activity in CSH mice early in maturation (P16–P18), whereas by adolescence (P40–P45) differences between control and CSH mice were insignificant. These results may be associated with lack of cortical and subcortical anisotropy differences between control and CSH mice. Spatial-delayed alternation and free-swim tasks in adulthood revealed lasting impairments for CSH mice in spatial memory and behavioral laterality. These differences may correlate with anisotropy decreases in hippocampal and callosal connectivities of CSH mice. Thus, CSH mice revealed developmental and behavioral deficits that are similar to those observed in low birth weight preterm infants.

Additive Effects of Attention and Stimulus Contrast in Primary Visual Cortex

Thiele, A., Pooresmaeili, A., Delicato, L. S., Herrero, J. L., Roelfsema, P. R. — 2009-04-16

Previous studies have proposed a variety of mechanisms by which attention influences neuronal activity. Here we investigated the mechanisms of attention in the striate cortex of monkeys performing a spatial or an object-based attention task at various stimulus contrasts and compared neuronal contrast response functions with and without attention. Our data are best described by an "additive" interaction: The influence of attention on the neuronal response is relatively independent of the stimulus contrast, at least when the stimulus has enough contrast to become visible. This shows that attention adds to the neuronal responses in a largely contrast invariant manner. These data support recent functional magnetic resonance imaging studies and suggest that feedback from higher areas exerts a constant attentional drive that is mostly task not stimulus driven.

Sex Differences in Resting-State Neural Correlates of Openness to Experience among Older Adults

Sutin, A. R., Beason-Held, L. L., Resnick, S. M., Costa, P. T. — 2009-04-14

We investigated sex differences in the resting-state neural correlates of Openness to Experience, a universal personality trait defined by cognitive flexibility, attention to feelings, creativity, and preference for novelty. Using resting-state positron-emission tomography from 100 older individuals (>55 years of age), we identified associations between Openness and resting-state regional cerebral blood flow that replicated across 2 assessments of the same sample, approximately 2 years apart. Openness correlated positively with prefrontal activity in women, anterior cingulate activity in men, and orbitofrontal activity in both sexes, which suggests that areas linked to cognitive flexibility (women), monitoring processes (men), and reward and emotional processing (both) underlie individual differences in Openness. The results challenge the implicit assumption that the same trait will rely on the same neural mechanisms across all who express it.

Paraneoplastic Antigen-Like 5 Gene (PNMA5) Is Preferentially Expressed in the Association Areas in a Primate Specific Manner

Takaji, M., Komatsu, Y., Watakabe, A., Hashikawa, T., Yamamori, T. — 2009-04-14

To understand the relationship between the structure and function of primate neocortical areas at a molecular level, we have been screening for genes differentially expressed across macaque neocortical areas by restriction landmark cDNA scanning (RLCS). Here, we report enriched expression of the paraneoplastic antigen-like 5 gene (PNMA5) in association areas but not in primary sensory areas, with the lowest expression level in primary visual cortex. In situ hybridization in the primary sensory areas revealed PNMA5 mRNA expression restricted to layer II. Along the ventral visual pathway, the expression gradually increased in the excitatory neurons from the primary to higher visual areas. This differential expression pattern was very similar to that of retinol-binding protein (RBP) mRNA, another association-area-enriched gene that we reported previously. Additional expression analysis for comparison of other genes in the PNMA gene family, PNMA1, PNMA2, PNMA3, and MOAP1 (PNMA4), showed that they were widely expressed across areas and layers but without the differentiated pattern of PNMA5. In mouse brains, PNMA1 was only faintly expressed and PNMA5 was not detected. Sequence analysis showed divergence of PNMA5 sequences among mammals. These findings suggest that PNMA5 acquired a certain specialized role in the association areas of the neocortex during primate evolution.

Too Little, Too Late: Reduced Visual Span and Speed Characterize Pure Alexia

Starrfelt, R., Habekost, T., Leff, A. P. — 2009-04-14

Whether normal word reading includes a stage of visual processing selectively dedicated to word or letter recognition is highly debated. Characterizing pure alexia, a seemingly selective disorder of reading, has been central to this debate. Two main theories claim either that 1) Pure alexia is caused by damage to a reading specific brain region in the left fusiform gyrus or 2) Pure alexia results from a general visual impairment that may particularly affect simultaneous processing of multiple items. We tested these competing theories in 4 patients with pure alexia using sensitive psychophysical measures and mathematical modeling. Recognition of single letters and digits in the central visual field was impaired in all patients. Visual apprehension span was also reduced for both letters and digits in all patients. The only cortical region lesioned across all 4 patients was the left fusiform gyrus, indicating that this region subserves a function broader than letter or word identification. We suggest that a seemingly pure disorder of reading can arise due to a general reduction of visual speed and span, and explain why this has a disproportionate impact on word reading while recognition of other visual stimuli are less obviously affected.

Double Dissociation of Spike Timing-Dependent Potentiation and Depression by Subunit-Preferring NMDA Receptor Antagonists in Mouse Barrel Cortex

2009-04-10

Spike timing–dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit–containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit–preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.

Regional Patterns of Cerebral Cortical Differentiation Determined by Diffusion Tensor MRI

Kroenke, C. D., Taber, E. N., Leigland, L. A., Knutsen, A. K., Bayly, P. V. — 2009-04-10

The morphology of axonal and dendritic arbors in the immature cerebral cortex influences the degree of anisotropy in water diffusion. This enables cortical maturation to be monitored by the noninvasive technique of diffusion tensor magnetic resonance imaging (DTI). Herein, we utilized DTI of postmortem ferret brain to quantify regional and temporal patterns in cortical maturation. We found that diffusion anisotropy within the isocortex decreases over the first month of life, coinciding closely in time with expansion of axonal and dendritic cellular processes of pyramidal neurons. Regional patterns consist of differences between allocortex and isocortex, a regional anisotropy gradient that closely parallels the transverse neurogenetic gradient, and differences between primary and nonprimary isocortical areas. By combining the temporal and regional factors, the isocortical developmental gradient magnitude corresponds to a 5-day difference in maturity between relatively developed rostral/caudal isocortex at the gradient source and less mature isocortex at the occipital pole. Additionally, the developmental trajectory of primary areas precedes nonprimary areas by 2.7 days. These quantitative estimates coincide with previous histological studies of ferret development. Similarities in cerebral cortical diffusion anisotropy observed between ferret and other species suggest the framework developed here is of general potential relevance.

Experience-Dependent, Rapid Structural Changes in Hippocampal Pyramidal Cell Spines

Kitanishi, T., Ikegaya, Y., Matsuki, N., Yamada, M. K. — 2009-04-10

Morphological changes in dendritic spines may contribute to the fine tuning of neural network connectivity. The relationship between spine morphology and experience-dependent neuronal activity, however, is largely unknown. In the present study, we combined 2 histological analyses to examine this relationship: 1) Measurement of spines of neurons whose morphology was visualized in brain sections of mice expressing membrane-targeted green florescent protein (Thy1-mGFP mice) and 2) Categorization of CA1 neurons by immunohistochemical monitoring of Arc expression as a putative marker of recent neuronal activity. After mice were exposed to a novel, enriched environment for 60 min, neurons that expressed Arc had fewer small spines and more large spines than Arc-negative cells. These differences were not observed when the exploration time was shortened to 15 min. This net-balanced structural change is consistent with both synapse-specific enhancement and suppression. These results provide the first evidence of rapid morphological changes in spines that were preferential to a subset of neurons in association with an animal's experiences.

GABAergic Inhibitory Interneurons in the Posterior Piriform Cortex of the GAD67-GFP Mouse

Young, A., Sun, Q.-Q. — 2009-04-09

-Aminobutyric acid (GABA)–releasing inhibitory interneurons, a critical component of cortical circuitry, are involved in myriad known functional roles. However, information regarding the cytoarchitectural, physiological, and molecular properties of interneurons in posterior piriform cortex (PPC) is sparse. Taking advantage of the glutamic acid decarboxylase (GAD)67–enhanced green fluorescent protein (EGFP) mouse, we used in vitro whole-cell patch-clamp techniques to record from GABAergic interneurons across all 3 layers of PPC and, subsequently, to reconstruct their morphology. For the first time, 5 groups of interneurons are identified, whose firing types are defined based on those described within neocortex. Interestingly, each interneuron group with a distinct firing type also exhibits unique morphological properties, laminar distributions, and excitatory synaptic properties. The dendritic and axonal processes demonstrate subtype-specific orientations and a differential expression of spines and boutons, respectively. In addition, the active and passive electrophysiological properties of these cells show marked intergroup differences. Immunohistochemical techniques revealed a laminar-specific distribution of calcium-binding proteins and vasoactive intestinal peptide (VIP) expression. Surprisingly, excitatory synaptic properties in several groups lack target-specific differences seen in neocortical circuits, reflecting a circuit arranged with less complexity. These data aid in the identification of PPC interneurons and allow us to make well-supported postulations about their functional properties.

Axon Morphologies and Convergence Patterns of Projections from Different Sensory-Specific Cortices of the Anterior Ectosylvian Sulcus onto Multisensory Neurons in the Cat Superior Colliculus

Fuentes-Santamaria, V., Alvarado, J. C., McHaffie, J. G., Stein, B. E. — 2009-04-09

Corticofugal projections to the thalamus reveal 2 axonal morphologies, each associated with specific physiological attributes. These determine the functional characteristics of thalamic neurons. It is not clear, however, whether such features characterize the corticofugal projections that mediate multisensory integration in superior colliculus (SC) neurons. The cortico-collicular projections from cat anterior ectosylvian sulcus (AES) are derived from its visual, auditory, and somatosensory representations and are critical for multisensory integration. Following tracer injections into each subdivision, 2 types of cortico-collicular axons were observed. Most were categorized as type I and consisted of small-caliber axons traversing long distances without branching, bearing mainly small boutons. The less frequent type II had thicker axons, more complex branching patterns, larger boutons, and more complex terminal boutons. Following combinatorial injections of 2 different fluorescent tracers into defined AES subdivisions, fibers from each were seen converging onto individual SC neurons and indicate that such convergence, like that in the corticothalamic system, is mediated by 2 distinct morphological types of axon terminals. Nevertheless, and despite the conservation of axonal morphologies across different subcortical systems, it is not yet clear if the concomitant physiological attributes described in the thalamus are directly applicable to multisensory integration.

Cortical Mechanisms for Online Control of Hand Movement Trajectory: The Role of the Posterior Parietal Cortex

Archambault, P. S., Caminiti, R., Battaglia-Mayer, A. — 2009-04-09

The parietal mechanisms for the control of hand movement trajectory were studied by recording cell activity in area 5 of monkeys making direct reaches to visual targets and online corrections of movement trajectory, after change of target location in space. The activity of hand-related cells was fitted with a linear model including hand position, movement direction, and speed. The neural activity modulation mostly led, but also followed, hand movement. When a change of hand trajectory occurred, the pattern of activity associated with the movement to the first target evolved into that typical of the movement to the second one, thus following the corresponding variations of the hand kinematics. The visual signal concerning target location in space did not influence the firing activity associated with the direction of hand movement within the first 150 ms after target presentation. This might be the time necessary for the visuo-motor transformation underlying reaching. We conclude that online control of hand trajectory not only resides in the relationships between neural activity and kinematics, but, under specific circumstances, also on the coexistence of signals about ongoing and future hand movement direction.

Developmental Trajectories of Magnitude Processing and Interference Control: An fMRI Study

Wood, G., Ischebeck, A., Koppelstaetter, F., Gotwald, T., Kaufmann, L. — 2009-04-08

Neurodevelopmental changes regarding interference and magnitude processing were assessed in 3 age groups (children, n = 10; young adults, n = 11; elderly participants, n = 9) by using an functional magnetic resonance imaging version of the numerical Stroop task. Behaviorally, comparable distance and size congruity effects were found in all 3 age groups. Distance effects were most pronounced in the more difficult numerical task, whereas size congruity effects were comparable across tasks. In response to interference, an age-linear trend in the pattern of activation in left and right prefrontal and left middle temporal regions of the brain was observed. This implicates that with increasing age interference control requires increasing effort (possible explanations for children's relatively lower interference effects are provided). In contrast, the distance effect produced a negative linear trend in right prefrontal, supplementary motor area, and intraparietal cortex. This suggests that relative to old adults, children and young adults had to recruit a larger network upon processing magnitude. The latter findings are even more remarkable considering that the behavioral effects were similar across groups. In summary, the developmental trajectories of interference control and magnitude processing differ, although these cognitive functions activate partially overlapping brain regions.

Differences in Intrinsic Properties and Local Network Connectivity of Identified Layer 5 and Layer 6 Adult Mouse Auditory Corticothalamic Neurons Support a Dual Corticothalamic Projection Hypothesis

Llano, D. A., Sherman, S. M. — 2009-04-07

Intrinsic properties, morphology, and local network circuitry of identified layer 5 and layer 6 auditory corticothalamic neurons were compared. We injected fluorescent microspheres into the mouse auditory thalamus to prelabel corticothalamic neurons, then recorded and filled labeled layer 5 or layer 6 auditory cortical neurons in vitro. We observed low-threshold bursting in adult, but not juvenile, layer 5 corticothalamic neurons that was voltage and time dependent with nonlinear input–output properties, whereas adult layer 6 corticothalamic neurons demonstrated a regular spiking. Layer 5 corticothalamic neurons had larger somata, thicker apical dendrites and were more likely to have a layer 1 apical dendrite than layer 6 neurons. Using laser photostimulation, identified layer 5 corticothalamic neurons received excitatory input from a wide area of layers 2/3, 4, and 5 with widespread -aminobutyric acidergic input from layer 2/3 and lower layer 5, whereas layer 6 corticothalamic neurons from the same cortical column received circumscribed excitatory input and discrete patches of inhibition derived from layer 6 of adjacent columns. These data demonstrate that layer 5 and layer 6 corticothalamic neurons receive unique sets of inputs and process them in different manners, supporting the hypothesis that layer-specific corticothalamic projections play distinct roles in information processing.

In Vivo MRI of Altered Brain Anatomy and Fiber Connectivity in Adult Pax6 Deficient Mice

2009-03-27

The impact of developmental ablation of Pax6 function on morphology and functional connectivity of the adult cerebrum was studied in cortex-specific Pax6 knockout mice (Pax6cKO) using structural magnetic resonance imaging (MRI), manganese-enhanced MRI, and diffusion tensor MRI in conjunction with fiber tractography. Mutants presented with decreased volumes of total brain and olfactory bulb, reduced cortical thickness, and altered layering of the piriform cortex. Tracking of major neuronal fiber bundles revealed a disorganization of callosal fibers with an almost complete lack of interhemispheric connectivity. In Pax6cKO mice intrahemispheric callosal fibers as well as intracortical fibers were predominantly directed along a rostrocaudal orientation instead of a left–right and dorsoventral orientation found in controls. Fiber disorganization also involved the septohippocampal connection targeting mostly the lateral septal nucleus. The hippocampus was rostrally extended and its volume was increased relative to that of the forebrain and midbrain. Manganese-induced MRI signal enhancement in the CA3 region suggested a normal function of hippocampal pyramidal cells. Noteworthy, several morphologic disturbances in gray and white matter of Pax6cKO mice were similar to observations in human aniridia patients. The present findings indicate an important role of Pax6 in the development of both the cortex and cerebral fiber connectivity.

Where Is the Semantic System? A Critical Review and Meta-Analysis of 120 Functional Neuroimaging Studies

Binder, J. R., Desai, R. H., Graves, W. W., Conant, L. L. — 2009-03-27

Semantic memory refers to knowledge about people, objects, actions, relations, self, and culture acquired through experience. The neural systems that store and retrieve this information have been studied for many years, but a consensus regarding their identity has not been reached. Using strict inclusion criteria, we analyzed 120 functional neuroimaging studies focusing on semantic processing. Reliable areas of activation in these studies were identified using the activation likelihood estimate (ALE) technique. These activations formed a distinct, left-lateralized network comprised of 7 regions: posterior inferior parietal lobe, middle temporal gyrus, fusiform and parahippocampal gyri, dorsomedial prefrontal cortex, inferior frontal gyrus, ventromedial prefrontal cortex, and posterior cingulate gyrus. Secondary analyses showed specific subregions of this network associated with knowledge of actions, manipulable artifacts, abstract concepts, and concrete concepts. The cortical regions involved in semantic processing can be grouped into 3 broad categories: posterior multimodal and heteromodal association cortex, heteromodal prefrontal cortex, and medial limbic regions. The expansion of these regions in the human relative to the nonhuman primate brain may explain uniquely human capacities to use language productively, plan, solve problems, and create cultural and technological artifacts, all of which depend on the fluid and efficient retrieval and manipulation of semantic knowledge.

Distracters Impair and Create Working Memory-Related Neuronal Activity in the Prefrontal Cortex

2009-03-27

The prefrontal cortex (PFC) has a central role in working memory (WM). Resistance to distraction is considered a fundamental feature of WM and PFC neuronal activity. However, although unexpected stimuli often disrupt our work, little is known about the underlying neuronal mechanisms involved. In the present study, we investigated whether irregularly presented distracters disrupt WM task performance and underlying neuronal activity. We recorded single neuron activity in the PFC of 2 monkeys performing WM tasks and investigated effects of auditory and visual distracters on WM performance and neuronal activity. Distracters impaired memory task performance and affected PFC neuronal activity. Distraction that was of the same sensory modality as the memorandum was more likely to impair WM performance and interfere with memory-related neuronal activity than information that was of a different sensory modality. The study also shows that neurons not involved in memory processing in less demanding conditions may become engaged in WM processing in more demanding conditions. The study demonstrates that WM performance and underlying neuronal activity are vulnerable to irregular distracters and suggests that the PFC has mechanisms that help to compensate for disruptive effects of external distracters.

Engagement of Fusiform Cortex and Disengagement of Lateral Occipital Cortex in the Acquisition of Radiological Expertise

2009-03-25

The human visual pathways that are specialized for object recognition stretch from lateral occipital cortex (LO) to the ventral surface of the temporal lobe, including the fusiform gyrus. Plasticity in these pathways supports the acquisition of visual expertise, but precisely how training affects the different regions remains unclear. We used functional magnetic resonance imaging to measure neural activity in both LO and the fusiform gyrus in radiologists as they detected abnormalities in chest radiographs. Activity in the right fusiform face area (FFA) correlated with visual expertise, measured as behavioral performance during scanning. In contrast, activity in left LO correlated negatively with expertise, and the amount of LO that responded to radiographs was smaller in experts than in novices. Activity in the FFA and LO correlated negatively in experts, whereas in novices, the 2 regions showed no stable relationship. Together, these results suggest that the FFA becomes more engaged and left LO less engaged in interpreting radiographic images over the course of training. Achieving expert visual performance may involve suppressing existing neural representations while simultaneously developing others.

Movement-Specific Repetition Suppression in Ventral and Dorsal Premotor Cortex during Action Observation

Majdandzic, J., Bekkering, H., van Schie, H. T., Toni, I. — 2009-03-25

There are several models of premotor cortex contributions to sensorimotor behavior. For instance, the ventral premotor cortex (PMv) appears to be involved in processing visuospatial object properties for grasping, whereas the dorsal premotor cortex (PMd) is involved in using arbitrary rules to guide advance motor planning. These models have focused on individual movements. Here, we examine the premotor responses evoked during the processing of individual movements functionally embedded in an action. We tested whether processing hand–object interactions and action end states would differentially engage PMv and PMd. We used a repetition suppression (RS)–functional magnetic resonance imaging paradigm in which we independently manipulated the observed grip, the end position of the object (independent of its spatial location), and the hand trajectory. By comparing novel and repeated trials for each of these action components, we could isolate RS effects specific to each of them. Repeating the grasp component attenuated activity in right PMv, whereas repeating the end state of the action reduced blood oxygen level–dependent activity in the left PMd. These results suggest that PMv is involved in controlling the kinematic means of an appropriate hand–object interaction, whereas PMd is focused on specifying the desired end state of an action.

Medial Prefrontal Cortex 5-HT2A Density Is Correlated with Amygdala Reactivity, Response Habituation, and Functional Coupling

2009-03-25

Feedback inhibition of the amygdala via medial prefrontal cortex (mPFC) is an important component in the regulation of complex emotional behaviors. The functional dynamics of this corticolimbic circuitry are, in part, modulated by serotonin (5-HT). Serotonin 2A (5-HT_2A) receptors within the mPFC represent a potential molecular mechanism through which 5-HT can modulate this corticolimbic circuitry. We employed a multimodal neuroimaging strategy to explore the relationship between threat-related amygdala reactivity, assessed using blood oxygen level–dependent functional magnetic resonance imaging, and mPFC 5-HT_2A density, assessed using [¹⁸F]altanserin positron emission tomography in 35 healthy adult volunteers. We observed a significant inverse relationship wherein greater mPFC 5-HT_2A density was associated with reduced threat-related right amygdala reactivity. Remarkably, 25–37% of the variability in amygdala reactivity was explained by mPFC 5-HT_2A density. We also observed a positive correlation between mPFC 5-HT_2A density and the magnitude of right amygdala habituation. Furthermore, functional coupling between the amygdala and mPFC was positively correlated with 5-HT_2A density suggesting that effective integration of emotionally salient information within this corticolimbic circuitry may be modulated, at least in part, by mPFC 5-HT_2A. Collectively, our results indicate that mPFC 5-HT_2A is strongly associated with threat-related amygdala reactivity as well as its temporal habituation and functional coupling with prefrontal regulatory regions.

Dopaminergic Neuromodulation of Semantic Processing: A 4-T fMRI Study with Levodopa

Copland, D. A., McMahon, K. L., Silburn, P. A., de Zubicaray, G. I. — 2009-03-25

There is emerging evidence that alterations in dopaminergic transmission can influence semantic processing, yet the neural mechanisms involved are unknown. The influence of levodopa (L-DOPA) on semantic priming was investigated in healthy individuals (n = 20) using event-related functional magnetic resonance imaging with a randomized, double-blind crossover design. Critical prime–target pairs consisted of a lexical ambiguity prime and 1) a target related to the dominant meaning of the prime (e.g., bank–money), 2) a target related to the subordinate meaning (e.g., fence–sword), or 3) an unrelated target (e.g., ball–desk). Behavioral data showed that both dominant and subordinate meanings were primed on placebo. In contrast, there was preserved priming of dominant meanings and no significant priming of subordinate meanings on L-DOPA, the latter associated with decreased anterior cingulate and dorsal prefrontal cortex activity. Dominant meaning activation on L-DOPA was associated with increased activity in the left rolandic operculum and left middle temporal gyrus. These findings suggest that L-DOPA enhances frequency-based semantic focus via prefrontal and temporal modulation of automatic semantic priming and through engagement of anterior cingulate mechanisms supporting attentional/controlled priming.

Not What You Expect: Experience but not Expectancy Predicts Conditioned Responses in Human Visual and Supplementary Cortex

Moratti, S., Keil, A. — 2009-03-20

When paired with aversive events, visual conditioned stimuli (CS) provoke increased activations in visual cortex. It is unclear however whether these changes reflect cognitive processes such as expectancy of the aversive unconditioned stimulus (US), or implicit associative learning of the contingencies outside awareness. Here, we used the "gambler's fallacy" phenomenon to parametrically and inversely manipulate the expectancy of an US and the number of conditioning trials: Increasing the number of CS–US pairings was associated with participants expecting the US to be less likely and vice versa. Magnetocortical activity evoked by the CS in occipital and supplementary motor areas was linearly related to the associative strength (number of CS–US pairings), but decreased as a function of expectancy. These results suggest that the cortical facilitation of fear cue processing is determined by associative strength and previous exposure to learning contingencies rather than by the cognitive anticipation for the US.

Distinct Genetic Influences on Cortical Surface Area and Cortical Thickness

2009-03-18

Neuroimaging studies examining the effects of aging and neuropsychiatric disorders on the cerebral cortex have largely been based on measures of cortical volume. Given that cortical volume is a product of thickness and surface area, it is plausible that measures of volume capture at least 2 distinct sets of genetic influences. The present study aims to examine the genetic relationships between measures of cortical surface area and thickness. Participants were men in the Vietnam Era Twin Study of Aging (110 monozygotic pairs and 92 dizygotic pairs). Mean age was 55.8 years (range: 51–59). Bivariate twin analyses were utilized in order to estimate the heritability of cortical surface area and thickness, as well as their degree of genetic overlap. Total cortical surface area and average cortical thickness were both highly heritable (0.89 and 0.81, respectively) but were essentially unrelated genetically (genetic correlation = 0.08). This pattern was similar at the lobar and regional levels of analysis. These results demonstrate that cortical volume measures combine at least 2 distinct sources of genetic influences. We conclude that using volume in a genetically informative study, or as an endophenotype for a disorder, may confound the underlying genetic architecture of brain structure.

Gonadal Hormones Modulate the Dendritic Spine Densities of Primary Cortical Pyramidal Neurons in Adult Female Rat

Chen, J.-R., Yan, Y.-T., Wang, T.-J., Chen, L.-J., Wang, Y.-J., Tseng, G.-F. — 2009-03-17

Adult dendritic arbors and spines can be modulated by environment and gonadal hormones that have been reported to affect also those of hippocampal and prefrontal cortical neurons. Here we investigated whether female gonadal hormones and estrous cycle alter the dendrites of primary cortical neurons. We employed intracellular dye injection in semifixed brain slices and 3-dimensional reconstruction to study the dendritic arbors and spines of the major cortical output cells, layer III and V pyramidal neurons, during different stages of the estrous cycle. Dendritic spines of both pyramidal neurons were more numerous during proestrus than estrus and diestrus, whereas dendritic arbors remained unaffected. Ovariohysterectomy (OHE) reduced dendritic spines by 24–30% in 2 weeks, whereas subcutaneous estrogen or progesterone supplement restored it to normal estrous/diestrous level in 14 days; neither treatment affected the dendritic arbors. Reduction of dendritic spines following OHE was associated with decrease of PSD-95 suggesting decrease of excitatory synapses. Thus, fluctuation of gonadal hormones during the female sex cycle is likely to modulate primary cortical functions and loss of gonadal hormones for instance following menopause might compromise cortical function, and the effect could be reversed by exogenous female sex hormones.

New Horizons for the Subplate Zone and Its Pioneering Neurons

Ayoub, A. E., Kostovic, I. — 2009-03-17

Transitional neuronal layers are a hallmark of the prenatal and neonatal brain yet their contribution to the development of higher functions is not clear. Evidence accumulated over the last 3 decades shows that early connectivity and functional activity start in a transitional layer called the subplate zone (SPZ). The SPZ is host to a heterogenous population of neurons and its evolutionary complexity peaked in the human brain. In this issue of Cerebral Cortex, three reports (Hoerder-Suabedissen et al., 2008; McKellar and Shatz, 2008; Moore et al., 2008) present new data and evidence in three species (mouse, rat, human) as to the function of the SPZ, to the heterogenity of its cellular composition, and to the genetic basis of its development.

Reading and Subcortical Auditory Function

Banai, K., Hornickel, J., Skoe, E., Nicol, T., Zecker, S., Kraus, N. — 2009-03-17

Although it is largely agreed that phonological processing deficits are a major cause of poor reading, the neural origins of phonological processing are not well understood. We now show, for the first time, that phonological decoding, measured with a test of single-nonword reading, is significantly correlated with the timing of subcortical auditory processing and also, to a lesser extent, with the robustness of subcortical representation of the harmonic content of speech, but not with pitch encoding. The relationships we observe between reading and subcortical processing fall along a continuum, with poor readers at one end and good readers at the other. These data suggest that reading skill may depend on the integrity of subcortical auditory mechanisms and are consistent with the idea that subcortical representation of the acoustic features of speech may play a role in normal reading as well as in the development of reading disorders. These data establish a significant link between subcortical auditory function and reading, thereby contributing to the understanding of the biological bases of reading. At a more general level, these findings are among the first to establish a direct relationship between subcortical sensory function and a specific cognitive skill (reading). We argue that this relationship between cortical and subcortical function could be shaped during development by the corticofugal pathway and that this cortical–subcortical link could contribute to the phonological processing deficits experienced by poor readers.

Background Dopamine Concentration Dependently Facilitates Long-term Potentiation in Rat Prefrontal Cortex through Postsynaptic Activation of Extracellular Signal-Regulated Kinases

Kolomiets, B., Marzo, A., Caboche, J., Vanhoutte, P., Otani, S. — 2009-03-12

Altered levels of tonic/background dopamine in prefrontal cortex (PFC) may underlie modifications of executive cognitive function. We showed previously in rat PFC slices that exogenously supplied background dopamine facilitates induction of long-term potentiation (LTP), a possible cellular substrate for the long-term component of executive cognitive function. In the present study, we characterized cellular and molecular mechanisms underlying this modulatory dopamine effect. We show first that the LTP-facilitating effect of tonic/background dopamine follows an inverted-U shape concentration curve and that the effective level of background dopamine slowly activates postsynaptic extracellular signal-regulated kinases (ERKs) to facilitate LTP. Furthermore, we show the evidence that LTP-inducing high-frequency stimulation evokes endogenous release of dopamine in PFC slices. This fast dopamine serves as a trigger for LTP in the presence of the background dopamine. In its absence, the endogenous dopamine triggered, instead, long-term depression. These results indicate that appropriate levels of tonic/background dopamine serve to activate critical molecular factors in PFC neurons and thereby facilitate induction of synaptic potentiation.

No Neglect-Specific Deficits in Reaching Tasks

2009-03-12

It is well established that patients with hemispatial neglect present with severe visuospatial impairments, but studies that have directly investigated visuomotor control have revealed diverging results, with some studies showing that neglect patients perform relatively better on such tasks. The present study compared the visuomotor performance of patients with and without neglect after right-hemisphere stroke with those of age-matched controls. Participants were asked to point either directly towards targets or halfway between two stimuli, both with and without visual feedback during movement. Although we did not find any neglect-specific impairment, both patient groups showed increased reaction times to leftward stimuli as well as decreased accuracies for open loop leftward reaches. We argue that these findings agree with the view that neglect patients code spatial parameters for action veridically. Moreover, we suggest that lesions in the right hemisphere may cause motor deficits irrespective of the presence of neglect and we performed an initial voxel-lesion symptom analysis to assess this. Lesion-symptom analysis revealed that the reported deficits did not result from damage to neglect-associated areas alone, but were further associated with lesions to crucial nodes in the visuomotor control network (the basal ganglia as well as occipito-parietal and frontal areas).

Detecting Wrong Notes in Advance: Neuronal Correlates of Error Monitoring in Pianists

Ruiz, M. H., Jabusch, H.-C., Altenmuller, E. — 2009-03-10

Music performance is an extremely rapid process with low incidence of errors even at the fast rates of production required. This is possible only due to the fast functioning of the self-monitoring system. Surprisingly, no specific data about error monitoring have been published in the music domain. Consequently, the present study investigated the electrophysiological correlates of executive control mechanisms, in particular error detection, during piano performance. Our target was to extend the previous research efforts on understanding of the human action-monitoring system by selecting a highly skilled multimodal task. Pianists had to retrieve memorized music pieces at a fast tempo in the presence or absence of auditory feedback. Our main interest was to study the interplay between auditory and sensorimotor information in the processes triggered by an erroneous action, considering only wrong pitches as errors. We found that around 70 ms prior to errors a negative component is elicited in the event-related potentials and is generated by the anterior cingulate cortex. Interestingly, this component was independent of the auditory feedback. However, the auditory information did modulate the processing of the errors after their execution, as reflected in a larger error positivity (Pe). Our data are interpreted within the context of feedforward models and the auditory–motor coupling.

Inactivation of the Somatosensory Cortex Prevents Paroxysmal Oscillations in Cortical and Related Thalamic Neurons in a Genetic Model of Absence Epilepsy

Polack, P.-O., Mahon, S., Chavez, M., Charpier, S. — 2009-03-10

Absence seizures consist of bilateral spike-and-wave discharges (SWDs) occurring over widespread cortical and thalamic regions. In genetic models of absence epilepsy, recent in vivo investigations indicate that SWDs emerge first in the facial somatosensory cortex and then propagate via the corticothalamocortical loop. The specific involvement of this cortical region in ictogenic processes remained to be established and the participation of its related thalamocortical system in seizure initiation remained unclear. Here, using electrocorticographic (ECoG) and intracellular recordings in vivo from cortex and thalamus in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), we obtained novel evidence for the cortical focus theory of absence epilepsy. We report that blockade of action potential discharge and synaptic activities in facial somatosensory cortical neurons, by topical application of tetrodotoxin, prevents the occurrence of paroxysmal activities in local and distant cortical neurons and ECoGs, as well as in thalamocortical neurons in register with the somatosensory cortex. In contrast, pharmacological inhibition of a remote motor cortical region or of the related thalamic nuclei did not suppress ictal activities in the somatosensory cortex. This study demonstrates that SWDs in GAERS have a focal origin within the facial somatosensory cortex, which is sufficient and necessary to generate ictal activities.

Consonants and Vowels Contribute Differently to Visual Word Recognition: ERPs of Relative Position Priming

Carreiras, M., Dunabeitia, J. A., Molinaro, N. — 2009-03-08

This paper shows that the nature of letters—consonant versus vowel—modulates the process of letter position assignment during visual word recognition. We recorded Event Related Potentials while participants read words in a masked priming semantic categorization task. Half of the words included a vowel as initial, third, and fifth letters (e.g., acero [steel]). The other half included a consonant as initial, third, and fifth (e.g., farol [lantern]). Targets could be preceded 1) by the initial, third, and fifth letters (relative position; e.g., aeo—acero and frl—farol), 2) by 3 consonants or vowels that did not appear in the target word (control; e.g., iui—acero and tsb—farol), or 3) by the same words (identity: acero–acero, farol–farol). The results showed modulation in 2 time windows (175–250 and 350–450 ms). Relative position primes composed of consonants produced similar effects to the identity condition. These 2 differed from the unrelated control condition, which showed a larger negativity. In contrast, relative position primes composed of vowels produced similar effects to the unrelated control condition, and these 2 showed larger negativities as compared with the identity condition. This finding has important consequences for cracking the orthographic code and developing computational models of visual word recognition.

Aging Influences the Neural Correlates of Lexical Decision but Not Automatic Semantic Priming

Gold, B. T., Andersen, A. H., Jicha, G. A., Smith, C. D. — 2009-03-08

Human behavioral data indicate that older adults are slower to perform lexical decisions (LDs) than young adults but show similar reaction time gains when these decisions are primed semantically. The present study explored the functional neuroanatomic bases of these frequently observed behavioral findings. Young and older groups completed unprimed and primed LD tasks while functional magnetic resonance imaging (fMRI) was recorded, using a fully randomized trial design paralleling those used in behavioral research. Results from the unprimed task found that age-related slowing of LD was associated with decreased activation in perceptual extrastriate regions and increased activation in regions associated with higher level linguistic processes, including prefrontal cortex. In contrast to these age-related changes in brain activation, the older group showed a preserved pattern of fMRI decreases in inferior temporal cortex when LD was primed semantically. These findings provide evidence that older adults’ LD abilities benefit from contexts that reduce the need for frontally mediated strategic processes and capitalize on the continued sensitivity of inferior temporal cortex to automatic semantic processes in aging.

Cortical and Subcortical Mechanisms for Precisely Controlled Force Generation and Force Relaxation

Spraker, M. B., Corcos, D. M., Vaillancourt, D. E. — 2009-03-02

Gripping objects during everyday manual tasks requires the coordination of muscle contractions and muscle relaxations. The vast majority of studies have focused on muscle contractions. Although previous work has examined the motor cortex during muscle relaxation, the role of brain areas beyond motor cortex remains to be elucidated. The present study used functional magnetic resonance imaging to directly compare slow and precisely controlled force generation and force relaxation in humans. Contralateral primary motor cortex and bilateral caudate nucleus had greater activity during force generation compared with force relaxation. Conversely, right dorsolateral prefrontal cortex (DLPFC) had greater activity while relaxing force compared with generating force. Also, anterior cingulate cortex had greater deactivation while relaxing force compared with generating force. These findings were further strengthened by the fact that force output parameters such as the amplitude, rate, duration, variability, and error did not affect the brain imaging findings. These results demonstrate that the neural mechanisms underlying slow and precisely controlled force relaxation differ across prefrontal–striatal and motor cortical–striatal circuits. Moreover, this study demonstrates that the DLPFC is not only involved in slow and precisely controlled force generation, but has greater involvement in regulating slow and precisely controlled muscle relaxation.

Relationships between Brain Activation and Brain Structure in Normally Developing Children

2009-02-24

Dynamic changes in brain structure, activation, and cognitive abilities co-occur during development, but little is known about how changes in brain structure relate to changes in cognitive function or brain activity. By using cortical pattern matching techniques to correlate cortical gray matter thickness and functional brain activity over the entire brain surface in 24 typically developing children, we integrated structural and functional magnetic resonance imaging data with cognitive test scores to identify correlates of mature performance during orthographic processing. Fast-naming individuals activated the right fronto-parietal attention network in response to novel fonts more than slow-naming individuals, and increased activation of this network was correlated with more mature brain morphology in the same fronto-parietal region. These relationships remained even after effects of age or general cognitive ability were statistically controlled. These results localized cortical regions where mature morphology corresponds to mature patterns of activation, and may suggest a role for experience in mediating brain structure–activation relationships.

The Neural Architecture of Music-Evoked Autobiographical Memories

Janata, P. — 2009-02-24

The medial prefrontal cortex (MPFC) is regarded as a region of the brain that supports self-referential processes, including the integration of sensory information with self-knowledge and the retrieval of autobiographical information. I used functional magnetic resonance imaging and a novel procedure for eliciting autobiographical memories with excerpts of popular music dating to one's extended childhood to test the hypothesis that music and autobiographical memories are integrated in the MPFC. Dorsal regions of the MPFC (Brodmann area 8/9) were shown to respond parametrically to the degree of autobiographical salience experienced over the course of individual 30 s excerpts. Moreover, the dorsal MPFC also responded on a second, faster timescale corresponding to the signature movements of the musical excerpts through tonal space. These results suggest that the dorsal MPFC associates music and memories when we experience emotionally salient episodic memories that are triggered by familiar songs from our personal past. MPFC acted in concert with lateral prefrontal and posterior cortices both in terms of tonality tracking and overall responsiveness to familiar and autobiographically salient songs. These findings extend the results of previous autobiographical memory research by demonstrating the spontaneous activation of an autobiographical memory network in a naturalistic task with low retrieval demands.

The Influence of Multiple Primes on Bottom-Up and Top-Down Regulation during Meaning Retrieval: Evidence for 2 Distinct Neural Networks

Whitney, C., Grossman, M., Kircher, T. T. J. — 2009-02-24

Meaning retrieval of a word can proceed fast and effortlessly or can be characterized by a controlled search for candidate lexical items and a subsequent selection process. In the current study, we facilitated meaning retrieval by increasing the number of words that were related to the final target word in a triplet (e.g., lion–stripes–tiger). To induce higher search and selection demands, we presented ambiguous words as targets (i.e., homonyms like ball) in half of the trials. Hereby, the dominant (game), low-frequent (dance), or both meanings of the homonym were primed. Participants performed a relatedness judgment during functional magnetic resonance imaging. Activation in a bilateral network (angular gyrus, rostromedial prefrontal cortex) increased linearly with multiple related primes, whereas the posterior left inferior prefrontal cortex (pLIPC) showed the reverse activation pattern for unambiguous trials. When homonyms served as targets, pLIPC responded strongest when both meanings or low-frequent concepts were addressed. Additional anterior left inferior prefrontal cortex activation was observed for the latter trials only. The data support an interaction between 2 distinct cerebral networks that can be linked to automatic bottom-up support and top-down control during meaning retrieval. They further imply a functional specialization of the LIPC along an anterior–posterior dimension.

Stimulus-Response Profile during Single-Pulse Transcranial Magnetic Stimulation to the Primary Motor Cortex

2009-02-20

We examined the stimulus–response profile during single-pulse transcranial magnetic stimulation (TMS) by measuring motor-evoked potentials (MEPs) with electromyographic monitoring and hemodynamic responses with functional magnetic resonance imaging (fMRI) at 3 Tesla. In 16 healthy subjects, single TMS pulses were irregularly delivered to the left primary motor cortex at a mean frequency of 0.15 Hz with a wide range of stimulus intensities. The measurement of MEP proved a typical relationship between stimulus intensity and MEP amplitude in the concurrent TMS-fMRI environment. In the population-level analysis of the suprathreshold stimulation conditions, significant increases in hemodynamic responses were detected in the motor/somatosensory network, reflecting both direct and remote effects of TMS, and also the auditory/cognitive areas, perhaps related to detection of clicks. The stimulus–response profile showed both linear and nonlinear components in the direct and remote motor/somatosensory network. A detailed analysis suggested that the nonlinear components of the motor/somatosensory network activity might be induced by nonlinear recruitment of neurons in addition to sensory afferents resulting from movement. These findings expand our basic knowledge of the quantitative relationship between TMS-induced neural activations and hemodynamic signals measured by neuroimaging techniques.

Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia

2009-02-20

Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.

Greater Working Memory Load Results in Greater Medial Temporal Activity at Retrieval

Schon, K., Quiroz, Y. T., Hasselmo, M. E., Stern, C. E. — 2009-02-18

Most functional magnetic resonance imaging (fMRI) studies examining working memory (WM) load have focused on the prefrontal cortex (PFC) and have demonstrated increased prefrontal activity with increased load. Here we examined WM load effects in the medial temporal lobe (MTL) using an fMRI Sternberg task with novel complex visual scenes. Trials consisted of 3 sequential events: 1) sample presentation (encoding), 2) delay period (maintenance), and 3) probe period (retrieval). During sample encoding, subjects saw either 2 or 4 pictures consecutively. During retrieval, subjects indicated whether the probe picture matched one of the sample pictures. Results revealed that activity in the left anterior hippocampal formation, bilateral retrosplenial area, and left amygdala was greater at retrieval for trials with larger memory load, whereas activity in the PFC was greater at encoding for trials with larger memory load. There was no load effect during the delay. When encoding, maintenance, and retrieval periods were compared with fixation, activity was present in the hippocampal body/tail and fusiform gyrus bilaterally during encoding and retrieval, but not maintenance. Bilateral dorsolateral prefrontal activity was present during maintenance, but not during encoding or retrieval. The results support models of WM predicting that activity in the MTL should be modulated by WM load.

The Resting Brain: Unconstrained yet Reliable

2009-02-16

Recent years have witnessed an upsurge in the usage of resting-state functional magnetic resonance imaging (fMRI) to examine functional connectivity (fcMRI), both in normal and pathological populations. Despite this increasing popularity, concerns about the psychologically unconstrained nature of the "resting-state" remain. Across studies, the patterns of functional connectivity detected are remarkably consistent. However, the test–retest reliability for measures of resting state fcMRI measures has not been determined. Here, we quantify the test–retest reliability, using resting scans from 26 participants at 3 different time points. Specifically, we assessed intersession (>5 months apart), intrasession (<1 h apart), and multiscan (across all 3 scans) reliability and consistency for both region-of-interest and voxel-wise analyses. For both approaches, we observed modest to high reliability across connections, dependent upon 3 predictive factors: 1) correlation significance (significantly nonzero > nonsignificant), 2) correlation valence (positive > negative), and 3) network membership (default mode > task positive network). Short- and long-term measures of the consistency of global connectivity patterns were highly robust. Finally, hierarchical clustering solutions were highly reproducible, both across participants and sessions. Our findings provide a solid foundation for continued examination of resting state fcMRI in typical and atypical populations.

The Operating Regime of Local Computations in Primary Visual Cortex

2009-02-16

In V1, local circuitry depends on the position in the orientation map: close to pinwheel centers, recurrent inputs show variable orientation preferences; within iso-orientation domains, inputs are relatively uniformly tuned. Physiological properties such as cell's membrane potentials, spike outputs, and temporal characteristics change systematically with map location. We investigate in a firing rate and a Hodgkin–Huxley network model what constraints these tuning characteristics of V1 neurons impose on the cortical operating regime. Systematically varying the strength of both recurrent excitation and inhibition, we test a wide range of model classes and find the likely models to account for the experimental observations. We show that recent intracellular and extracellular recordings from cat V1 provide the strongest evidence for a regime where excitatory and inhibitory recurrent inputs are balanced and dominate the feed-forward input. Our results are robust against changes in model assumptions such as spatial extent and strength of lateral inhibition. Intriguingly, the most likely recurrent regime is in a region of parameter space where small changes have large effects on the network dynamics, and it is close to a regime of "runaway excitation," where the network shows strong self-sustained activity. This could make the cortical response particularly sensitive to modulation.

Thalamocortical Connections of Parietal Somatosensory Cortical Fields in Macaque Monkeys are Highly Divergent and Convergent

2009-02-16

We examined the organization and cortical projections of the somatosensory thalamus using multiunit microelectrode recording techniques in anesthetized monkeys combined with neuroanatomical tracings techniques and architectonic analysis. Different portions of the hand representation in area 3b were injected with different anatomical tracers in the same animal, or matched body part representations in parietal areas 3a, 3b, 1, 2, and areas 2 and 5 were injected with different anatomical tracers in the same animal to directly compare their thalamocortical connections. We found that the somatosensory thalamus is composed of several representations of cutaneous and deep receptors of the contralateral body. These nuclei include the ventral posterior nucleus, the ventral posterior superior nucleus, the ventral posterior inferior nucleus, and the ventral lateral nucleus. Each nucleus projects to several different cortical fields, and each cortical field receives projections from multiple thalamic nuclei. In contrast to other sensory systems, each of these somatosensory cortical fields is uniquely innervated by multiple thalamic nuclei. These data indicate that multiple inputs are processed simultaneously within and across several, "hierarchically connected" cortical fields.

Inhibition of cAMP Response Element-Binding Protein Reduces Neuronal Excitability and Plasticity, and Triggers Neurodegeneration

Jancic, D., Lopez de Armentia, M., Valor, L. M., Olivares, R., Barco, A. — 2009-02-12

The cAMP-responsive element-binding protein (CREB) pathway has been involved in 2 major cascades of gene expression regulating neuronal function. The first one presents CREB as a critical component of the molecular switch that controls long-lasting forms of neuronal plasticity and learning. The second one relates CREB to neuronal survival and protection. To investigate the role of CREB-dependent gene expression in neuronal plasticity and survival in vivo, we generated bitransgenic mice expressing A-CREB, an artificial peptide with strong and broad inhibitory effect on the CREB family, in forebrain neurons in a regulatable manner. The expression of A-CREB in hippocampal neurons impaired L-LTP, reduced intrinsic excitability and the susceptibility to induced seizures, and altered both basal and activity-driven gene expression. In the long-term, the chronic inhibition of CREB function caused severe loss of neurons in the CA1 subfield as well as in other brain regions. Our experiments confirmed previous findings in CREB-deficient mutants and revealed new aspects of CREB-dependent gene expression in the hippocampus supporting a dual role for CREB-dependent gene expression regulating intrinsic and synaptic plasticity and promoting neuronal survival.

Attention Reshapes Center-Surround Receptive Field Structure in Macaque Cortical Area MT

Anton-Erxleben, K., Stephan, V. M., Treue, S. — 2009-02-11

Directing spatial attention to a location inside the classical receptive field (cRF) of a neuron in macaque medial temporal area (MT) shifts the center of the cRF toward the attended location. Here we investigate the influence of spatial attention on the profile of the inhibitory surround present in many MT neurons. Two monkeys attended to the fixation point or to 1 of 2 random dot patterns (RDPs) placed inside or next to the cRF, whereas a third RDP (the probe) was briefly presented in quick succession across the cRF and surround. The probe presentation responses were used to compute a map of the excitatory receptive field and its inhibitory surround. Attention systematically reshapes the receptive field profile, independently shifting both center and surround toward the attended location. Furthermore, cRF size is changed as a function of relative distance to the attentional focus: attention inside the cRF shrinks it, whereas directing attention next to the cRF expands it. In addition, we find systematic changes in surround inhibition and cRF amplitude. This nonmultiplicative push–pull modulation of the receptive field's center-surround structure optimizes processing at and near the attentional focus to strengthen the representation of the attended stimulus while reducing influences from distractors.

When the Brain Changes Its Mind: Flexibility of Action Selection in Instructed and Free Choices

Fleming, S. M., Mars, R. B., Gladwin, T. E., Haggard, P. — 2009-02-11

The neural mechanisms underlying the selection and initiation of voluntary actions in the absence of external instructions are poorly understood. These mechanisms are usually investigated using a paradigm where different movement choices are self-generated by a participant on each trial. These "free choices" are compared with "instructed choices," in which a stimulus informs subjects which action to make on each trial. Here, we introduce a novel paradigm to investigate these modes of action selection, by measuring brain processes evoked by an instruction to either reverse or maintain free and instructed choices in the period before a "go" signal. An unpredictable instruction to change a response plan had different effects on free and instructed choices. In instructed trials, change cues evoked a larger P300 than no-change cues, leading to a significant interaction of choice and change condition. Free-choice trials displayed a trend toward the opposite pattern. These results suggest a difference between updating of free and instructed action choices. We propose a theoretical framework for internally generated action in which representations of alternative actions remain available until a late stage in motor preparation. This framework emphasizes the high modifiability of voluntary action.

Detection of Fixed and Variable Targets in the Monkey Prefrontal Cortex

Kusunoki, M., Sigala, N., Gaffan, D., Duncan, J. — 2009-02-04

Behavioral significance is commonly coded by prefrontal neurons. The significance of a stimulus can be fixed through experience; in complex behavior, however, significance commonly changes with short-term context. To compare these cases, we trained monkeys in 2 versions of visual target detection. In both tasks, animals monitored a series of pictures, making a go response (saccade) at the offset of a specified target picture. In one version, based on "consistent mapping" in human visual search, target and nontarget pictures were fixed throughout training. In the other, based on "varied mapping," a cue at trial onset defined a new target. Building up over the first 1 s following this cue, many cells coded short-term context (cue/target identity) for the current trial. Thereafter, the cell population showed similar coding of behavioral significance in the 2 tasks, with selective early response to targets, and later, sustained activity coding target or nontarget until response. This population similarity was seen despite quite different activity in the 2 tasks for many single cells. At the population level, the results suggest similar prefrontal coding of fixed and short-term behavioral significance.

Stress-Induced Dendritic Remodeling in the Prefrontal Cortex is Circuit Specific

Shansky, R. M., Hamo, C., Hof, P. R., McEwen, B. S., Morrison, J. H. — 2009-02-04

Chronic stress exposure has been reported to induce dendritic remodeling in several brain regions, but it is not known whether individual neural circuits show distinct patterns of remodeling. The current study tested the hypothesis that the projections from the infralimbic (IL) area of the medial prefrontal cortex (mPFC) to the basolateral nucleus of the amygdala (BLA), a pathway relevant to stress-related mental illnesses like depression and post-traumatic stress disorder, would have a unique pattern of remodeling in response to chronic stress. The retrograde tracer FastBlue was injected into male rats’ BLA or entorhinal cortex (EC) 1 week prior to 10 days of immobilization stress. After cessation of stress, FastBlue-labeled and unlabeled IL pyaramidal neurons were loaded with fluorescent dye Lucifer Yellow to visualize dendritic arborization and spine density. As has been previously reported, randomly selected (non-FastBlue-labeled) neurons showed stress-induced dendritic retraction in apical dendrites, an effect also seen in EC-projecting neurons. In contrast, BLA-projecting neurons showed no remodeling with stress, suggesting that this pathway may be particularly resilient against the effects of stress. No neurons showed stress-related changes in spine density, contrasting with reports that more dorsal areas of the mPFC show stress-induced decreases in spine density. Such region- and circuit-specificity in response to stress could contribute to the development of stress-related mental illnesses.

Functional Selectivity of Interhemispheric Connections in Cat Visual Cortex

2009-02-04

The functional specificity of callosal connections was investigated in visual areas 17 and 18 of adult cats, by combining in vivo optical imaging of intrinsic signals with labeling of callosal axons. Local injections of neuronal tracers were performed in one hemisphere and eight single callosal axons were reconstructed in the opposite hemisphere. The distributions of injection sites and callosal axon terminals were analyzed with respect to functional maps in both hemispheres. Typically, each callosal axon displayed 2 or 3 clusters of synaptic boutons in layer II/III and the upper part of layer IV. These clusters were preferentially distributed in regions representing the same orientation and the same visuotopic location as that at the corresponding injection sites in the opposite hemisphere. The spatial distribution of these clusters was elongated and its main axis correlated well with the preferred orientation at the injection site. These results demonstrate a specific organization of interhemispheric axons that link cortical regions representing the same orientation and the same location of visual stimuli. Visual callosal connections are thus likely involved in the processing of coherent information in terms of shape and position along the midline of the visual field, which may facilitate the fusion of both hemifields into the percept of a single visual scene.

Input Specificity and Dependence of Spike Timing-Dependent Plasticity on Preceding Postsynaptic Activity at Unitary Connections between Neocortical Layer 2/3 Pyramidal Cells

2009-02-04

Layer 2/3 (L2/3) pyramidal cells receive excitatory afferent input both from neighbouring pyramidal cells and from cortical and subcortical regions. The efficacy of these excitatory synaptic inputs is modulated by spike timing–dependent plasticity (STDP). Here we report that synaptic connections between L2/3 pyramidal cell pairs are located proximal to the soma, at sites overlapping those of excitatory inputs from other cortical layers. Nevertheless, STDP at L2/3 pyramidal to pyramidal cell connections showed fundamental differences from known STDP rules at these neighbouring contacts. Coincident low-frequency pre- and postsynaptic activation evoked only LTD, independent of the order of the pre- and postsynaptic cell firing. This symmetric anti-Hebbian STDP switched to a typical Hebbian learning rule if a postsynaptic action potential train occurred prior to the presynaptic stimulation. Receptor dependence of LTD and LTP induction and their pre- or postsynaptic loci also differed from those at other L2/3 pyramidal cell excitatory inputs. Overall, we demonstrate a novel means to switch between STDP rules dependent on the history of postsynaptic activity. We also highlight differences in STDP at excitatory synapses onto L2/3 pyramidal cells which allow for input specific modulation of synaptic gain.

Thalamic Input to Distal Apical Dendrites in Neocortical Layer 1 Is Massive and Highly Convergent

Rubio-Garrido, P., Perez-de-Manzo, F., Porrero, C., Galazo, M. J., Clasca, F. — 2009-02-02

Input to apical dendritic tufts is now deemed crucial for associative learning, attention, and similar "feedback" interactions in the cerebral cortex. Excitatory input to apical tufts in neocortical layer 1 has been traditionally assumed to be predominantly cortical, as thalamic pathways directed to this layer were regarded relatively scant and diffuse. However, the sensitive tracing methods used in the present study show that, throughout the rat neocortex, large numbers (mean ~4500/mm²) of thalamocortical neurons converge in layer 1 and that this convergence gives rise to a very high local density of thalamic terminals. Moreover, we show that the layer 1–projecting neurons are present in large numbers in most, but not all, motor, association, limbic, and sensory nuclei of the rodent thalamus. Some layer 1–projecting axons branch to innervate large swaths of the cerebral hemisphere, whereas others arborize within only a single cortical area. Present data imply that realistic modeling of cortical circuitry should factor in a dense axonal canopy carrying highly convergent thalamocortical input to pyramidal cell apical tufts. In addition, they are consistent with the notion that layer 1-projecting axons may be a robust anatomical substrate for extensive "feedback" interactions between cortical areas via the thalamus.

A Common Network in the Left Cerebral Hemisphere Represents Planning of Tool Use Pantomimes and Familiar Intransitive Gestures at the Hand-Independent Level

Kroliczak, G., Frey, S. H. — 2009-01-30

Evidence from neuropsychology and neuroimaging implicates parietal and frontal areas of the left cerebral hemisphere in the representation of skills involving the use of tools and other artifacts. On the basis of neuropsychological data, it has been claimed that 1) independent mechanisms within the left hemisphere may support the representation of these skills (transitive actions) versus meaningful gestures that do not involve manipulating objects (intransitive actions), and 2) both cerebral hemispheres may participate in the representation of intransitive gestures. Functional magnetic resonance imaging was used to test these hypotheses in 12 healthy adults while they planned and executed tool use pantomimes or intransitive gestures with their dominant right (Exp. 1) or nondominant left (Exp. 2) hands. Even when linguistic processing demands were controlled, planning either type of action was associated with asymmetrical increases in the same regions of left parietal (the intraparietal sulcus, supramarginal gyrus, and caudal superior parietal lobule) and dorsal premotor cortices. Effects were greater for tool use pantomimes, but only when the right hand was involved. Neither group nor individual analyses revealed evidence for greater bilateral activity during intransitive gesture planning. In summary, at the hand-independent level, transitive and intransitive actions are represented in a common, left-lateralized praxis network.

From Phonemes to Articulatory Codes: An fMRI Study of the Role of Broca's Area in Speech Production

2009-01-29

We used event-related functional magnetic resonance imaging to investigate the neuroanatomical substrates of phonetic encoding and the generation of articulatory codes from phonological representations. Our focus was on the role of the left inferior frontal gyrus (LIFG) and in particular whether the LIFG plays a role in sublexical phonological processing such as syllabification or whether it is directly involved in phonetic encoding and the generation of articulatory codes. To answer this question, we contrasted the brain activation patterns elicited by pseudowords with high– or low–sublexical frequency components, which we expected would reveal areas related to the generation of articulatory codes but not areas related to phonological encoding. We found significant activation of a premotor network consisting of the dorsal precentral gyrus, the inferior frontal gyrus bilaterally, and the supplementary motor area for low– versus high–sublexical frequency pseudowords. Based on our hypothesis, we concluded that these areas and in particular the LIFG are involved in phonetic and not phonological encoding. We further discuss our findings with respect to the mechanisms of phonetic encoding and provide evidence in support of a functional segregation of the posterior part of Broca's area, the pars opercularis.

Involvement of Nicotinic and Muscarinic Receptors in the Endogenous Cholinergic Modulation of the Balance between Excitation and Inhibition in the Young Rat Visual Cortex

Lucas-Meunier, E., Monier, C., Amar, M., Baux, G., Fregnac, Y., Fossier, P. — 2009-01-28

This study aims to clarify how endogenous release of cortical acetylcholine (ACh) modulates the balance between excitation and inhibition evoked in visual cortex. We show that electrical stimulation in layer 1 produced a significant release of ACh measured intracortically by chemoluminescence and evoked a composite synaptic response recorded intracellularly in layer 5 pyramidal neurons of rat visual cortex. The pharmacological specificity of the ACh neuromodulation was determined from the continuous whole-cell voltage clamp measurement of stimulation-locked changes of the input conductance during the application of cholinergic agonists and antagonists. Blockade of glutamatergic and -aminobutyric acid (GABAergic) receptors suppressed the evoked response, indicating that stimulation-induced release of ACh does not directly activate a cholinergic synaptic conductance in recorded neurons. Comparison of cytisine and mecamylamine effects on nicotinic receptors showed that excitation is enhanced by endogenous evoked release of ACh through the presynaptic activation of ^*β4 receptors located on glutamatergic fibers. DHβE, the selective 4β2 nicotinic receptor antagonist, induced a depression of inhibition. Endogenous ACh could also enhance inhibition by acting directly on GABAergic interneurons, presynaptic to the recorded cell. We conclude that endogenous-released ACh amplifies the dominance of the inhibitory drive and thus decreases the excitability and sensory responsiveness of layer 5 pyramidal neurons.

Associative Motor Cortex Plasticity: Direct Evidence in Humans

2009-01-28

Previous studies have shown that paired associative stimulation (PAS) protocol, in which peripheral nerve stimuli are followed by transcranial magnetic stimulation (TMS) of the motor cortex at intervals that produce an approximately synchronous activation of cortical networks, enhances the amplitude of motor evoked potentials (MEPs) evoked by cortical stimulation. Indirect data support the hypothesis that the enhancement of MEPs produced by PAS involves long-term potentiation like changes in cortical synapses. The aim of present paper was to investigate the central nervous system level at which PAS produces its effects. We recorded corticospinal descending volleys evoked by single pulse TMS of the motor cortex before and after PAS in 4 conscious subjects who had an electrode implanted in the cervical epidural space for the control of pain. The descending volleys evoked by TMS represent postsynaptic activity of corticospinal neurones that can provide indirect information about the effectiveness of synaptic inputs to these neurones. PAS significantly enhanced the amplitude of later descending waves, whereas the earliest descending wave was not significantly modified by PAS. The present results show that PAS may increase the amplitude of later corticospinal volleys, consistent with a cortical origin of the effect of PAS.

Glutamatergic Inhibition in Sensory Neocortex

Lee, C. C., Sherman, S. M. — 2009-01-28

In the mammalian brain, glutamate and -aminobutyric acid are considered major excitatory and inhibitory neurotransmitters, respectively. However, we have found evidence that glutamate can also act as a postsynaptic inhibitory neurotransmitter in layer 4 of the neocortex. Using whole-cell recordings from layer 4 neurons in slice preparations from the mouse visual, auditory, and somatosensory cortices, we found that metabotropic glutamate receptor (mGluR) agonists (ACPD, APDC, and DCG IV) elicit a robust, long-lasting hyperpolarization that is abolished by the group II mGluR antagonist, MCCG. This response largely involves a K⁺ conductance mediated by G-protein activity and GIRK channels. Furthermore, electrical and photostimulation of the intracortical inputs to layer 4 elicits a similar hyperpolarization that is blocked by group II mGluR antagonists. This novel inhibition mediated by group II mGluRs may be an unappreciated mechanism for refining cortical receptive fields in layer 4 and may enable synaptic gain control during periods of high activity.

Different Spatial Scales of Shape Similarity Representation in Lateral and Ventral LOC

Drucker, D. M, Aguirre, G. K — 2009-01-28

We investigated the relationship between stimulus similarity for a set of parameterized shapes and the spatial scale of neural representation within subregions of the lateral occipital complex (LOC) using a carryover functional magnetic resonance imaging design. In ventral but not lateral LOC, a linear recovery from adaptation proportional to shape dissimilarity was seen. In contrast, a strong correspondence of the distributed neural pattern and stimulus similarity was observed in lateral LOC but not ventral LOC. Further, ventral LOC voxels were found to be broadly tuned and represent all aspects of stimulus similarity, whereas lateral LOC voxels were narrowly tuned and preferentially represented the shape of small features rather than their orientation within the shape. The results, indicating a coarse spatial coding of shape features in lateral LOC and a more focused coding of the entire shape space within ventral LOC, may be related to hierarchical models of object processing.

Two Types of Thalamocortical Projections from the Motor Thalamic Nuclei of the Rat: A Single Neuron-Tracing Study Using Viral Vectors

Kuramoto, E., Furuta, T., Nakamura, K. C., Unzai, T., Hioki, H., Kaneko, T. — 2009-01-27

The axonal arborization of single motor thalamic neurons was examined in rat brain using a viral vector expressing membrane-targeted palmitoylation site-attached green fluorescent protein (palGFP). We first divided the ventral anterior-ventral lateral motor thalamic nuclei into 1) the rostromedial portion, which was designated inhibitory afferent-dominant zone (IZ) with intense glutamate decarboxylase immunoreactivity and weak vesicular glutamate transporter 2 immunoreactivity, and 2) the caudolateral portion, named excitatory subcortical afferent-dominant zone (EZ) with the reversed immunoreactivity profile. We then labeled 38 motor thalamic neurons in 29 hemispheres by injecting a diluted palGFP-Sindbis virus solution and isolated 10 IZ and EZ neurons for reconstruction. All the reconstructed IZ neurons widely projected not only to the cerebral cortex but also to the neostriatum, whereas the EZ neurons sent axons almost exclusively to the cortex. More interestingly, 47–66% of axon varicosities of IZ neurons were observed in layer I of cortical areas. In contrast, only 2–15% of varicosities of EZ neurons were found in layer I, most varicosities being located in middle layers. These results suggest that 2 forms of information from the basal ganglia and cerebellum are differentially supplied to apical and basal dendrites, respectively, of cortical pyramidal neurons and integrated to produce a motor execution command.

Intermediate Neuronal Progenitors (Basal Progenitors) Produce Pyramidal-Projection Neurons for All Layers of Cerebral Cortex

2009-01-23

The developing cerebral cortex contains apical and basal types of neurogenic progenitor cells. Here, we investigated the cellular properties and neurogenic output of basal progenitors, also called intermediate neuronal progenitors (INPs). We found that basal mitoses expressing transcription factor Tbr2 (an INP marker) were present throughout corticogenesis, from embryonic day 10.5 through birth. Postnatally, Tbr2⁺ progenitors were present in the dentate gyrus, subventricular zone (SVZ), and posterior periventricle (pPV). Two morphological subtypes of INPs were distinguished in the embryonic cortex, "short radial" in the ventricular zone (VZ) and multipolar in the SVZ, probably corresponding to molecularly defined INP subtypes. Unexpectedly, many short radial INPs appeared to contact the apical (ventricular) surface and some divided there. Time-lapse video microscopy suggested that apical INP divisions produced daughter INPs. Analysis of neurogenic divisions (Tis21-green fluorescent protein [GFP]⁺) indicated that INPs may produce the majority of projection neurons for preplate, deep, and superficial layers. Conversely, proliferative INP divisions (Tis21-GFP^–) increased from early to middle corticogenesis, concomitant with SVZ growth. Our findings support the hypothesis that regulated amplification of INPs may be an important factor controlling the balance of neurogenesis among different cortical layers.

Inverse Mapping the Neuronal Substrates of Face Categorizations

Smith, M. L., Fries, P., Gosselin, F., Goebel, R., Schyns, P. G. — 2009-01-23

Face perception is a complex process involving a network of brain structures, dynamically processing information to enable judgments about a face to be made (e.g., familiarity, identity, and expression). Here we introduce an analysis methodology that makes it possible to directly study this information processing in the brain from spatially and temporally resolved magnetoencephalographic signals. We apply our methodology to the study of 2 face categorization tasks, gender and expressiveness, and track the processing of 3 key visual features that underlie behavioral performance, over time and throughout the cortex. We find information processing correlates beginning from 90 ms following stimulus onset, where features are processed in isolation in occipital extrastriate regions. Over time, processing of successively more features and feature combinations takes place in occipitotemporal regions, with maximal information processing of visual information coinciding with the well-established face-selective M170 component at 170 ms. Later still, around 250–400 ms, cortical activity responds significantly more to task-specific features and their complex combinations. These results indicate a complex process of visual information processing during face perception with face parts processed in isolation at very early stages, and task-specific processing of combinations of features taking place within 300 ms. Crucially, our approach specifically establishes which information in the visual stimulus the brain signal is responding to and how this varies with time, cortical location, and task demands to establish a more precise tracking of information processing mechanisms in the cortex during face perception.

Overlap and Segregation in Predorsal Premotor Cortex Activations Related to Free Selection of Self-Referenced and Target-Based Finger Movements

Beudel, M., de Jong, B. M. — 2009-01-23

In reaching movements, parietal contributions can be distinguished that are based on representations of external space and body scheme. By functional magnetic resonance imaging, we examined 16 healthy subjects to see whether such segregation similarly exists in the frontal lobes when visuomotor actions are not specified but when free choices are allowed. Free selection was button based (target based) or finger based (self-referenced), with invariant instructions as control. To avoid a visual attention bias, instructions were auditory presented. Statistical parametric mapping revealed that free button selection with the same finger was associated with increased activations in the anterior cingulate cortex (ACC), right posterodorsal prefrontal cortex (PFC) including the rostral extension of the dorsal premotor cortex (pre-PMd), and the anterodorsal PFC. Prefrontal activation related to free finger selection (pressing the same button) was restricted to an anteromedial segment of the posterodorsal PFC/pre-PMd. Bilateral inferior parietal activations were present in both free-choice conditions. Pre-PMd and parietal contributions to free selection support concepts on early-stage action selection in dorsal visuomotor pathways. The rostral–caudal segregation in pre-PMd activations reflected that in anterior direction, frontal processing is gradually less involved in selection of environmental information but increasingly committed to self-referenced selection. ACC particularly contributes to free selection between external goals.

Proteomic Analysis Illuminates a Novel Structural Definition of the Claustrum and Insula

Mathur, B. N., Caprioli, R. M., Deutch, A. Y. — 2009-01-23

The claustrum is a prominent but ill-defined forebrain structure that has been suggested to integrate multisensory information and perhaps transform percepts into consciousness. The claustrum's shape and vague borders have hampered experimental assessment of its functions. We used matrix-assisted laser desorption ionization–imaging mass spectrometry to reveal a novel protein marker, G-protein gamma2 subunit (Gng2), which is enriched in the claustrum but not adjacent structures of the rat forebrain. The spatial pattern of Gng2 expression suggests key differences from commonly held views of the claustrum's structure. Using anatomical methods, we found that the rat claustrum is present only at striatal levels of the telencephalon and does not extend to frontal cortical territories. Moreover, the claustrum is surrounded on all sides by layer VI insular cortex cells in both the rat and primate. Using these defining characteristics of the claustrum, we found that the claustrum projects to cortical but not to subcortical sites. The definition of the claustrum as a cortical site is considered. The identification of a claustrum-specific protein opens the door to selective molecular lesions and the subsequent evaluation of the role of the claustrum in cognition.

Damage to White Matter Fiber Tracts in Acute Spatial Neglect

Karnath, H.-O., Rorden, C., Ticini, L. F. — 2009-01-23

Previous statistical voxelwise lesion-behavior mapping (VLBM) studies have demonstrated that spatial neglect is associated with cortical and subcortical gray matter damage. However, it has also been suggested that the disorder may result from white matter injury. Our aim was to investigate the white matter connectivity in a large sample of 140 stroke patients. We combined a VLBM approach with the histological maps of the human white matter fiber tracts provided by the Jülich probabilistic cytoarchitectonic atlas. We found that damage of right perisylvian white matter connections—the superior longitudinal fasciculus, the inferior occipitofrontal fasciculus, and the superior occipitofrontal fasciculus—is a typical finding in patients with spatial neglect. However, the analysis also revealed that the largest portion of the lesion area, namely between 89.1% and 96.6%, affected brain structures other than the perisylvian white matter fiber tracts. Predominantly, these included gray matter structures such as the superior temporal, inferior parietal, inferior frontal, and insular cortices, as well as subcortically the putamen and the caudate nucleus. Damage of gray matter structures thus appears to be a strong predictor of spatial neglect.

Double Dissociation between Motor and Visual Imagery in the Posterior Parietal Cortex

Pelgrims, B., Andres, M., Olivier, E. — 2009-01-23

Because motor imagery (MI) and visual imagery (VI) are influenced differently by factors such as biomechanical constraints or stimulus size, it is conceivable that they rely on separate processes, possibly involving distinct cortical networks, a view corroborated by neuroimaging and neuropsychological studies. In the posterior parietal cortex, it has been suggested that the superior parietal lobule (SPL) underlies VI, whereas MI relies on the supramarginalis gyrus (SMG). However, because several brain imaging studies have also shown an overlap of activations in SPL and SMG during VI or MI, the question arises as to which extent these 2 subregions really contribute to distinct imagery processes. To address this issue, we used repetitive transcranial magnetic stimulation to induce virtual lesions of either SMG or SPL in subjects performing a MI (hand drawing rotation) or a VI (letter rotation) task. Whatever hemisphere was stimulated, SMG lesions selectively altered MI, whereas SPL lesions only affected VI, demonstrating a double dissociation between MI and VI. Because these deficits were not influenced by the angular distance of the stimuli, we suggest that SMG and SPL are involved in the reenactment of the motor and visual representations, respectively, and not in mental rotation processes per se.

The Brain's Intention to Imitate: The Neurobiology of Intentional versus Automatic Imitation

Bien, N., Roebroeck, A., Goebel, R., Sack, A. T. — 2009-01-19

Whenever we observe a movement of a conspecific, our mirror neuron system becomes activated, urging us to imitate the observed movement. However, because such automatic imitation is not always appropriate, an inhibitive component keeping us from imitating everything we see seems crucial for an effective social behavior. This becomes evident from neuropsychological conditions like echopraxia, in which this suppression is absent. Here, we unraveled the neurodynamics underlying this proposed inhibition of automatic imitation by measuring and manipulating brain activity during the execution of a stimulus–response compatibility paradigm. Within the identified connectivity network, right middle/inferior frontal cortex sends neural input concerning general response inhibition to right premotor cortex, which is involved in automatic imitation. Subsequently, the fully prepared imitative response is sent to left opercular cortex that functions as a final gating mechanism for intentional imitation. We propose an informed neurocognitive model of inhibition of automatic imitation, suggesting a functional dissociation between automatic and intentional imitation.

Feature Binding in the Feedback Layers of Area V2

Shipp, S., Adams, D. L., Moutoussis, K., Zeki, S. — 2009-01-19

The visual features of an object are processed by multiple, functionally specialized areas of cerebral cortex. When several objects are seen simultaneously, what mechanism preserves the association of features that belong to a single item? We address this question—known as the "binding problem"—by examining combinatorial feature selectivity of neurons in area V2. In recording from anesthetized macaques, we estimate that dual selectivity for chromatic and spatiotemporal attributes is 50% more common (27% vs. 18% sampling frequency) in superficial and deep layer neurons receiving feedback connections from higher areas, compared with layer 4-3 neurons relaying ascending signals. The operation of feedback pathways is thought to mediate attentional modulation of activity that may achieve binding through acting to select one single object for higher representation and filtering out competing objects. We propose that dual-selective neurons perform a "bridging" function, mediating the transfer of feedback-induced bias between feature dimensions. The bias can be propagated through V2 output neurons (of unitary selectivity) to higher levels of specialized processing and so promote selection of the target object's representation among multiple feature maps. The bridging function would thus act to unify the outcome of parallel, object-selective processes taking place along segregated visual pathways.

Mapping the Regulator of G Protein Signaling 4 (RGS4): Presynaptic and Postsynaptic Substrates for Neuroregulation in Prefrontal Cortex

Paspalas, C. D., Selemon, L. D., Arnsten, A. F.T. — 2009-01-19

Regulator of G protein signaling 4 (RGS4) regulates intracellular signaling via G proteins and is markedly reduced in the prefrontal cortex (PFC) of patients with schizophrenia. Characterizing the expression of RGS4 within individual neuronal compartments is thus key to understanding its actions on individual G protein–coupled receptors (GPCRs). Here we present an ultrastructural reference map of RGS4 protein in macaque PFC based on immunogold electron microscopic analysis. At the soma, all labeling was asynaptic and affiliated with subsurface cistern microdomains of pyramidal neurons. The nucleus displayed most of immunoreactivity. RGS4 levels were particularly high along proximal apical dendrites and markedly decreased with distance from the soma; clustered label was present at the bifurcation into second-order branches. In distal dendrites and in spines, the protein was found flanking or directly facing the postsynaptic density of symmetric and asymmetric synapses. Axons also expressed RGS4. In fact, the density and distribution of pre- and postsynaptic labeling was correlated with the axon ultrastructure and the type of established synapses. The data indicate that RGS4 is strategically positioned to regulate not only postsynaptic but also presynaptic signaling in response to synaptic and nonsynaptic GPCR activation, having broad yet highly selective influences on multiple aspects of PFC cellular physiology.

TMS-Adaptation Reveals Abstract Letter Selectivity in the Left Posterior Parietal Cortex

Cattaneo, Z., Rota, F., Walsh, V., Vecchi, T., Silvanto, J. — 2009-01-15

Activation of the left posterior parietal cortex (PPC) has been associated with the encoding of letters independent of visual form. Here we used transcranial magnetic stimulation (TMS)-adaptation to investigate whether this abstract letter selectivity plays a causal role in letter processing. Visual adaptation was used to manipulate the initial activation state of neurons tuned to different letters prior to the application of TMS, after which subjects performed a detection task on letters that were presented in a different case from the adapting letter. After adaptation, TMS applied over the left PPC facilitated the detection of the adapted letter, whereas it had no impact on the detection of nonadapted letters. TMS applied over the right PPC had no significant effect on either type of letter. This interaction between adaptation and the effects of left PPC TMS demonstrates that adaptation modulated neural activity in the left PPC and thus demonstrates abstract letter selectivity in this region. Importantly, as the adapted letter and the target letters were presented in different cases, this finding demonstrates that the left PPC plays a causal role in letter processing independent of visual form.

The Electrotonic Structure of Pyramidal Neurons Contributing to Prefrontal Cortical Circuits in Macaque Monkeys Is Significantly Altered in Aging

Kabaso, D., Coskren, P. J., Henry, B. I., Hof, P. R., Wearne, S. L. — 2009-01-15

Whereas neuronal numbers are largely preserved in normal aging, subtle morphological changes occur in dendrites and spines, whose electrotonic consequences remain unexplored. We examined age-related morphological alterations in 2 types of pyramidal neurons contributing to working memory circuits in the macaque prefrontal cortex (PFC): neurons in the superior temporal cortex forming "long" projections to the PFC and "local" projection neurons within the PFC. Global dendritic mass homeostasis, measured by 3-dimensional scaling analysis, was conserved with aging in both neuron types. Spine densities, dendrite diameters, lengths, and branching complexity were all significantly reduced in apical dendrites of long projection neurons with aging, but only spine parameters were altered in local projection neurons. Despite these differences, voltage attenuation due to passive electrotonic structure, assuming equivalent cable parameters, was significantly reduced with aging in the apical dendrites of both neuron classes. Confirming the electrotonic analysis, simulated passive backpropagating action potential efficacy was significantly higher in apical but not basal dendrites of old neurons. Unless compensated by changes in passive cable parameters, active membrane properties, or altered synaptic properties, these effects will increase the excitability of pyramidal neurons, compromising the precisely tuned activity required for working memory, ultimately resulting in age-related PFC dysfunction.

Resection of the Medial Temporal Lobe Disconnects the Rostral Superior Temporal Gyrus from Some of its Projection Targets in the Frontal Lobe and Thalamus

Munoz, M., Mishkin, M., Saunders, R. C. — 2009-01-15

Auditory memory in the monkey does not appear to extend beyond the limits of working memory. It is therefore surprising that this ability is impaired by medial temporal lobe (MTL) resections, because such lesions spare working memory in other sensory modalities. To determine whether MTL ablations might have caused the auditory deficit through inadvertent transection of superior temporal gyrus (STG) projections to its downstream targets, and, if so, which targets might have been compromised, we injected anterograde tracer (biotinylated dextran amine) in the STG of both the normal and MTL-lesioned hemispheres of split-brain monkeys. Interhemispheric comparison of label failed to show any effect of the MTL ablation on efferents from caudal STG, which projects to the inferior prefrontal convexity. However, the ablation did consistently interrupt the normally dense projections from rostral STG to both the ventral medial prefrontal cortex and medial thalamic nuclei. The findings support the possibility that the auditory working memory deficit after MTL ablation is due to transection of downstream auditory projections, and indicate that the candidate structures for mediating auditory working memory are the ventral medial prefrontal cortical areas, the medial thalamus, or both.

High Consistency of Regional Cortical Thinning in Aging across Multiple Samples

2009-01-15

Cross-sectional magnetic resonance imaging (MRI) studies of cortical thickness and volume have shown age effects on large areas, but there are substantial discrepancies across studies regarding the localization and magnitude of effects. These discrepancies hinder understanding of effects of aging on brain morphometry, and limit the potential usefulness of MR in research on healthy and pathological age-related brain changes. The present study was undertaken to overcome this problem by assessing the consistency of age effects on cortical thickness across 6 different samples with a total of 883 participants. A surface-based segmentation procedure (FreeSurfer) was used to calculate cortical thickness continuously across the brain surface. The results showed consistent age effects across samples in the superior, middle, and inferior frontal gyri, superior and middle temporal gyri, precuneus, inferior and superior parietal cortices, fusiform and lingual gyri, and the temporo-parietal junction. The strongest effects were seen in the superior and inferior frontal gyri, as well as superior parts of the temporal lobe. The inferior temporal lobe and anterior cingulate cortices were relatively less affected by age. The results are discussed in relation to leading theories of cognitive aging.

The Thalamocortical Projection Systems in Primate: An Anatomical Support for Multisensory and Sensorimotor Interplay

Cappe, C., Morel, A., Barone, P., Rouiller, E. M. — 2009-01-15

Multisensory and sensorimotor integrations are usually considered to occur in superior colliculus and cerebral cortex, but few studies proposed the thalamus as being involved in these integrative processes. We investigated whether the organization of the thalamocortical (TC) systems for different modalities partly overlap, representing an anatomical support for multisensory and sensorimotor interplay in thalamus. In 2 macaque monkeys, 6 neuroanatomical tracers were injected in the rostral and caudal auditory cortex, posterior parietal cortex (PE/PEa in area 5), and dorsal and ventral premotor cortical areas (PMd, PMv), demonstrating the existence of overlapping territories of thalamic projections to areas of different modalities (sensory and motor). TC projections, distinct from the ones arising from specific unimodal sensory nuclei, were observed from motor thalamus to PE/PEa or auditory cortex and from sensory thalamus to PMd/PMv. The central lateral nucleus and the mediodorsal nucleus project to all injected areas, but the most significant overlap across modalities was found in the medial pulvinar nucleus. The present results demonstrate the presence of thalamic territories integrating different sensory modalities with motor attributes. Based on the divergent/convergent pattern of TC and corticothalamic projections, 4 distinct mechanisms of multisensory and sensorimotor interplay are proposed.

Differences of Migratory Behavior between Direct Progeny of Apical Progenitors and Basal Progenitors in the Developing Cerebral Cortex

Tabata, H., Kanatani, S., Nakajima, K. — 2009-01-15

Cerebral cortical neurons are known to be produced from both apical progenitors in the ventricular zone (VZ) and basal (intermediate) progenitors in the subventricular zone (SVZ). On the other hand, we have shown that many SVZ cells assume multipolar morphology and show a characteristic movement termed "multipolar migration." The relationship between multipolar cells and basal progenitors in the SVZ has yet to be investigated. Herein, we followed postmitotic cells generated in the VZ and found that they stayed for more than 10 h in the VZ after becoming postmitotic and then accumulated in the lower part of the SVZ (multipolar cell accumulation zone: MAZ) as multipolar cells (slowly exiting population: SEP), whereas basal progenitors rapidly migrated into the SVZ or intermediate zone (IZ) (rapidly exiting population: REP) with somal translocation morphology. Although REP reached the SVZ/IZ earlier than the SEP, REP stayed within in the SVZ/IZ, whereas SEP moved steadily and entered the CP prior to the REP. We also observed SEP to eventually differentiate into pyramidal neurons in layers II/III. This study provides in vivo evidence of differences in migration modes between postmitotic cells generated from apical progenitors and basal progenitors.

Which Way Do I Go? Neural Activation in Response to Feedback and Spatial Processing in a Virtual T-Maze

Baker, T. E., Holroyd, C. B. — 2009-01-15

In 2 human event-related brain potential (ERP) experiments, we examined the feedback error–related negativity (fERN), an ERP component associated with reward processing by the midbrain dopamine system, and the N170, an ERP component thought to be generated by the medial temporal lobe (MTL), to investigate the contributions of these neural systems toward learning to find rewards in a "virtual T-maze" environment. We found that feedback indicating the absence versus presence of a reward differentially modulated fERN amplitude, but only when the outcome was not predicted by an earlier stimulus. By contrast, when a cue predicted the reward outcome, then the predictive cue (and not the feedback) differentially modulated fERN amplitude. We further found that the spatial location of the feedback stimuli elicited a large N170 at electrode sites sensitive to right MTL activation and that the latency of this component was sensitive to the spatial location of the reward, occurring slightly earlier for rewards following a right versus left turn in the maze. Taken together, these results confirm a fundamental prediction of a dopamine theory of the fERN and suggest that the dopamine and MTL systems may interact in navigational learning tasks.

Hemispheric Asymmetry of Auditory Evoked Fields Elicited by Spectral versus Temporal Stimulus Change

Okamoto, H., Stracke, H., Draganova, R., Pantev, C. — 2009-01-08

The investigation of functional hemispheric asymmetries regarding auditory processing in the human brain still remains a challenge. Classical lesion and recent neuroimaging studies indicated that speech is dominantly processed in the left hemisphere, whereas music is dominantly processed in the right. However, recent studies demonstrated that the functional hemispheric asymmetries were not limited to the processing of highly cognitive sound signals like speech and music but rather originated from the basic neural processing of elementary sound features, that is, spectral and temporal acoustic features. Here, in contrast to previous studies, we used carefully composed tones and pulse trains as stimuli, balanced the overall physical sound input between spectral and temporal change conditions, and demonstrated the time course of neural activity evoked by spectral versus temporal sound input change by means of magnetoencephalography (MEG). These original findings support the hypothesis that spectral change is dominantly processed in the right hemisphere, whereas temporal change is dominantly processed in the left.

Prefrontostriatal Circuitry Regulates Effort-Related Decision Making

Hauber, W., Sommer, S. — 2009-01-08

The anterior cingulate cortex (ACC), the basolateral amygdala (BLA), and the dopamine in the nucleus accumbens (NAc) are part of a neural system that is critically involved in making decisions on how much effort to invest for rewards. In the present study, we sought to identify functional interactions between ACC and NAc regulating effort-based decision making. Rats were tested in a T-maze cost–benefit task in which they could either choose to climb a barrier to obtain a large reward (LR) in one arm or a small reward in the other arm without a barrier. Experiment 1 revealed that bilateral excitotoxic lesions of the core subregion of the NAc impaired effort-based decision making, that is, reduced the preference for the high effort–LR option when having the choice to obtain a low reward with little effort. Experiment 2 showed that disconnection of the ACC and NAc core using an asymmetrical excitotoxic lesion procedure impaired effort-based decision making. The present data provide evidence that effort-based decision making is governed by an interconnected neural system that requires serial information transfer between ACC and NAc core.

Excitatory GABAergic Activation of Cortical Dividing Glial Cells

2009-01-08

Adult neocortex contains dividing satellite glia population even though their characteristics and functions have still remained unknown. Nestin⁺/NG2⁺ cells as major fraction of dividing glial cells express bicuculline-sensitive -aminobutyric acid A (GABA_A) receptors and receive GABAergic inputs. Due to their high [Cl^–]_i, GABAergic activation depolarized the cells and then induced Ca²⁺ influx into them. To assess an effect of this GABAergic excitation, we looked for the expression of neurotrophic factors. Among them, we detected the expression of brain-derived neurotrophic factor (BDNF) on the cells. The level of BDNF expression was elevated after cortical ischemia, and this elevation was blocked by bumetanide, an inhibitor for NKCC1 that blocks the GABAergic depolarization. Furthermore, performing a modified adhesive removal test, we observed that the treatment of bumetanide significantly attenuated the recovery in somatosensory dysfunction. Our results may shed a light on satellite glia population in the cortex and imply their roles in the functional recovery after ischemic injuries.

The Morphology of Supragranular Pyramidal Neurons in the Human Insular Cortex: A Quantitative Golgi Study

2009-01-06

Although the primate insular cortex has been studied extensively, a comprehensive investigation of its neuronal morphology has yet to be completed. To that end, neurons from 20 human subjects (10 males and 10 females; N = 600) were selected from the secondary gyrus brevis, precentral gyrus, and postcentral gyrus of the left insula. The secondary gyrus brevis was generally more complex in terms of dendritic/spine extent than either the precentral or postcentral insular gyri, which is consistent with the posterior–anterior gradient of dendritic complexity observed in other cortical regions. The male insula had longer, spinier dendrites than the female insula, potentially reflecting sex differences in interoception. In comparing the current insular data with regional dendritic data quantified from other Brodmann's areas (BAs), insular total dendritic length (TDL) was less than the TDL of high integration cortices (BA6β, 10, 11, 39), but greater than the TDL of low integration cortices (BA3-1-2, 4, 22, 44). Insular dendritic spine number was significantly greater than both low and high integration regions. Overall, the insula had spinier, but shorter neurons than did high integration cortices, and thus may represent a specialized type of heteromodal cortex, one that integrates crude multisensory information crucial to interoceptive processes.

Direct Evidence for Cortical Suppression of Somatosensory Afferents during Visuomotor Adaptation

Bernier, P.-M., Burle, B., Vidal, F., Hasbroucq, T., Blouin, J. — 2009-01-06

Upon exposure to novel visuomotor relationships, the information carried by visual and proprioceptive signals becomes discrepant, often disrupting motor execution. It has been shown that degradation of the proprioceptive sense (arising either from disease or experimental manipulation) enhances performance when drawing with mirror-reversed vision. Given that the central nervous system can exert a dynamic control over the transmission of afferent signals, reducing proprioceptive inflow to cortical areas could be part of the normal adaptive mechanisms deployed in healthy humans upon exposure to novel visuomotor environments. Here we address this issue by probing the transmission of somatosensory afferents throughout the course of adaptation to a visuomotor conflict, by recording median nerve somatosensory evoked potentials. We show that early exposure to tracing with mirror-reversed vision is accompanied by substantial proprioceptive suppression occurring in the primary somatosensory cortex (S1). This proprioceptive gating is gradually alleviated as performance increases with adaptation, returning to baseline levels. Peripheral and spinal evoked potentials were not modulated throughout, suggesting that the gating acted to reduce cortico-cortico excitability directly within S1. These modulations provide neurophysiological evidence for flexibility in sensory integration during visuomotor adaptation, which may functionally serve to reduce the sensory conflict until the visuo-proprioceptive mapping is updated.

Role of Corticospinal Suppression during Motor Preparation

Duque, J., Ivry, R. B. — 2009-01-06

Behavior arises from a constant competition between potential actions. For example, movements performed unimanually require selecting one hand rather than the other. Corticospinal (CS) excitability of the nonselected hand is typically decreased prior to movement initiation, suggesting that response selection may involve mechanisms that inhibit nonselected candidate movements. To examine this hypothesis, participants performed a reaction time task, responding with the left, right, or both indexes. Transcranial magnetic stimulation was applied over the right primary motor cortex (M1) to induce motor-evoked potentials (MEPs) in a left hand muscle at various stages during response preparation. To vary the time of response selection, an imperative signal was preceded by a preparatory cue that was either informative or uninformative. Left MEPs decreased following the cue. Surprisingly, this decrease was greater when an informative cue indicated that the response might require the left hand than when it indicated a right hand response. In the uninformative condition, we did not observe additional attenuation of left MEP after an imperative indicating a right hand response. These results argue against the "deselection" hypothesis. Rather, CS suppression seems to arise from "impulse control" mechanisms that ensure that responses associated with potentially selected actions are not initiated prematurely.

Normalizing Motor Cortex Representations in Focal Hand Dystonia

Schabrun, S. M., Stinear, C. M., Byblow, W. D., Ridding, M. C. — 2008-12-12

Task-specific focal dystonia is thought to have a neurological basis where stereotypical synchronous inputs and maladaptive plasticity play a role. As afferent input is a powerful driver of cortical reorganization, we propose that a period of asynchronous afferent stimulation may reverse maladaptive cortical changes and alleviate symptoms. Using transcranial magnetic stimulation (TMS), 3 hand muscles were mapped in 10 dystonics and 10 healthy controls. Mapping occurred before and after 1 h of nonassociative stimulation (NAS) to first dorsal interosseous (FDI) and abductor pollicis brevis (APB). Participants performed grip lift, handwriting, and cyclic drawing before and after NAS. Prior to NAS, dystonics had larger maps, and the centers of gravity (CoGs) of the FDI and APB maps were closer together. Dystonics demonstrated impairments in grip-lift, handwriting, and cyclic drawing tasks. Following NAS, map size was reduced in all muscles in dystonic participants and FDI and APB CoGs moved further apart. Among dystonics, NAS produced a reduction in movement variability during cyclic drawing. Thus, 1 h of NAS can reduce the magnitude, and increase the separation, of TMS representational maps. We suggest that these changes reflect some normalization of the representational abnormalities seen in focal dystonia and provide initial, limited evidence that such changes are associated with improvements in circle drawing.

Performance Effects of Nicotine during Selective Attention, Divided Attention, and Simple Stimulus Detection: An fMRI Study

2008-12-10

Attention-enhancing effects of nicotine appear to depend on the nature of the attentional function. Underlying neuroanatomical mechanisms, too, may vary depending on the function modulated. This functional magnetic resonance imaging study recorded blood oxygen level–dependent (BOLD) activity in minimally deprived smokers during tasks of simple stimulus detection, selective attention, or divided attention after single-blind application of a transdermal nicotine (21 mg) or placebo patch. Smokers’ performance in the placebo condition was unimpaired as compared with matched nonsmokers. Nicotine reduced reaction time (RT) in the stimulus detection and selective attention but not divided attention condition. Across all task conditions, nicotine reduced activation in frontal, temporal, thalamic, and visual regions and enhanced deactivation in so-called "default" regions. Thalamic effects correlated with RT reduction selectively during stimulus detection. An interaction with task condition was observed in middle and superior frontal gyri, where nicotine reduced activation only during stimulus detection. A visuomotor control experiment provided evidence against nonspecific effects of nicotine. In conclusion, although prefrontal activity partly displayed differential modulation by nicotine, most BOLD effects were identical across tasks, despite differential performance effects, suggesting that common neuronal mechanisms can selectively benefit different attentional functions. Overall, the effects of nicotine may be explained by increased functional efficiency and downregulated task-independent "default" functions.

Sex Differences in the Effects of Acute and Chronic Stress and Recovery after Long-Term Stress on Stress-Related Brain Regions of Rats

2008-12-10

Studies show that sex plays a role in stress-related depression, with women experiencing a higher vulnerability to its effect. Two major targets of antidepressants are brain-derived neurotrophic factor (BDNF) and cyclic adenosine monophosphate response element–binding protein (CREB). The aim of this study was to investigate the levels of CREB, phosphorylation of CREB (pCREB), and BDNF in stress-related brain regions of male and female rats after stress and recovery. CREB and pCREB levels were examined in CA1, CA2, CA3, paraventricular nucleus of the thalamus (PVT), amygdala, anterior cingulate area, dorsal part (ACAd), and infralimbic area of prefrontal cortex (PFC), whereas dentate gyrus (DG) and prelimbic area (PL) of PFC were examined for BDNF levels. Our results demonstrate that levels of CREB and pCREB in male CA1, CA2 and CA3, PVT, amygdala, and ACAd were reduced by stress, whereas the same brain regions of female rats exhibited no change. BDNF levels were decreased by chronic stress in female PL but were increased by acute stress in female DG. BDNF levels in male DG and PL were found not to undergo change in response to stress. Abnormalities in morphology occurred after chronic stress in males but not in females. In all cases, the levels of CREB, pCREB, and BDNF in recovery animals were comparable to the levels of these proteins in control animals. These findings demonstrate a sexual dimorphism in the molecular response to stress and suggest that these differences may have important implications for potential therapeutic treatment of depression.

Differential Expression Patterns of occ1-Related Genes in Adult Monkey Visual Cortex

2008-12-10

We have previously revealed that occ1 is preferentially expressed in the primary visual area (V1) of the monkey neocortex. In our attempt to identify more area-selective genes in the macaque neocortex, we found that testican-1, an occ1-related gene, and its family members also exhibit characteristic expression patterns along the visual pathway. The expression levels of testican-1 and testican-2 mRNAs as well as that of occ1 mRNA start of high in V1, progressively decrease along the ventral visual pathway, and end of low in the temporal areas. Complementary to them, the neuronal expression of SPARC mRNA is abundant in the association areas and scarce in V1. Whereas occ1, testican-1, and testican-2 mRNAs are preferentially distributed in thalamorecipient layers including "blobs," SPARC mRNA expression avoids these layers. Neither SC1 nor testican-3 mRNA expression is selective to particular areas, but SC1 mRNA is abundantly observed in blobs. The expressions of occ1, testican-1, testican-2, and SC1 mRNA were downregulated after monocular tetrodotoxin injection. These results resonate with previous works on chemical and functional gradients along the primate occipitotemporal visual pathway and raise the possibility that these gradients and functional architecture may be related to the visual activity–dependent expression of these extracellular matrix glycoproteins.

Cortical Atrophy and Language Network Reorganization Associated with a Novel Progranulin Mutation

2008-12-10

Progressive nonfluent aphasia (PNFA) is an early stage of frontotemporal degeneration. We identified a novel Cys521Tyr progranulin gene variant in a PNFA family that potentially disrupts disulphide bridging causing protein misfolding. To identify early neurodegeneration changes, we performed neuropsychological and neuroimaging studies in 6 family members (MRI [magnetic resonance imaging], fMRI [functional MRI], and 18f-fluorodeoxygenlucose positron emission tomography, including 4 mutation carriers, and in 9 unrelated controls. Voxel-based morphometry (VBM) of the carriers compared with controls showed significant cortical atrophy in language areas. Grey matter loss was distributed mainly in frontal lobes, being more prominent on the left. Clusters were located in the superior frontal gyri, left inferior frontal gyrus, left middle frontal gyrus, left middle temporal gyri and left posterior parietal areas, concordant with ¹⁸FDG-PET hypometabolic areas. fMRI during semantic and phonemic covert word generation (CWGTs) and word listening tasks (WLTs) showed recruitment of attentional and working memory networks in the carriers indicative of functional reorganization. During CWGTs, activation in left prefrontal cortex and bilateral anterior insulae was present whereas WLT recruited mesial prefrontal and anterior temporal cortex. These findings suggest that Cys521Tyr could be associated with early brain impairment not limited to language areas and compensated by recruitment of bilateral auxiliary cortical areas.

Cortical Columnar Organization Is Reconsidered in Inferior Temporal Cortex

Sato, T., Uchida, G., Tanifuji, M. — 2008-12-09

The object selectivity of nearby cells in inferior temporal (IT) cortex is often different. To elucidate the relationship between columnar organization in IT cortex and the variability among neurons with respect to object selectivity, we used optical imaging technique to locate columnar regions (activity spots) and systematically compared object selectivity of individual neurons within and across the spots. The object selectivity of a given cell in a spot was similar to that of the averaged cellular activity within the spot. However, there was not such similarity among different spots (>600 µm apart). We suggest that each cell is characterized by 1) a cell-specific response property that cause cell-to-cell variability in object selectivity and 2) one or potentially a few numbers of response properties common across the cells within a spot, which provide the basis for columnar organization in IT cortex. Furthermore, similarity in object selectivity among cells within a randomly chosen site was lower than that for a cell in an activity spot identified by optical imaging beforehand. We suggest that the cortex may be organized in a region where neurons with similar response properties were densely clustered and a region where neurons with similar response properties were sparsely clustered.

Grasping Ideas with the Motor System: Semantic Somatotopy in Idiom Comprehension

Boulenger, V., Hauk, O., Pulvermuller, F. — 2008-12-09

Single words and sentences referring to bodily actions activate the motor cortex. However, this semantic grounding of concrete language does not address the critical question whether the sensory–motor system contributes to the processing of abstract meaning and thought. We examined functional magnetic resonance imaging activation to idioms and literal sentences including arm- and leg-related action words. A common left fronto-temporal network was engaged in sentence reading, with idioms yielding relatively stronger activity in (pre)frontal and middle temporal cortex. Crucially, somatotopic activation along the motor strip, in central and precentral cortex, was elicited by idiomatic and literal sentences, reflecting the body part reference of the words embedded in the sentences. Semantic somatotopy was most pronounced after sentence ending, thus reflecting sentence-level processing rather than that of single words. These results indicate that semantic representations grounded in the sensory–motor system play a role in the composition of sentence-level meaning, even in the case of idioms.

Mapping of Functional Areas in the Human Cortex Based on Connectivity through Association Fibers

2008-12-09

In the human brain, different regions of the cortex communicate via white matter tracts. Investigation of this connectivity is essential for understanding brain function. It has been shown that trajectories of white matter fiber bundles can be estimated based on orientational information that is obtained from diffusion tensor imaging (DTI). By extrapolating this information, cortical regions associated with a specific white matter tract can be estimated. In this study, we created population-averaged cortical maps of brain connectivity for 4 major association fiber tracts, the corticospinal tract (CST), and commissural fibers. It is shown that these 4 association fibers interconnect all 4 lobes of the hemispheres. Cortical regions that were assigned based on association with the CST and the superior longitudinal fasciculus (SLF) agreed with locations of their known (CST: motor) or putative (SLF: language) functions. The proposed approach can potentially be used for quantitative assessment of the effect of white matter abnormalities on associated cortical regions.

Behavioral and Movement Disorders Induced by Local Inhibitory Dysfunction in Primate Striatum

2008-12-09

The current model of basal ganglia organization postulates their functional division into sensorimotor, associative, and limbic territories, implicated, respectively, in motor, cognitive, and motivational aspects of behavior. Based on this model, we previously demonstrated, in the external segment of globus pallidus of monkeys, that the same neuronal dysfunction induced dyskinesia or abnormal behavior depending on the functional territory. To extend these findings, we performed bicuculline microinjections into the different functional territories of the striatum in 6 monkeys. Abnormal movements were observed after microinjections into the posterior putamen, corresponding to the sensorimotor territory, and into the dorsal part of the anterior striatum, corresponding to the associative functional territory. Within the ventral striatum, referred to as the limbic functional territory, we identified 3 subregions corresponding to different types of abnormal behaviors. Simultaneous neuronal recordings performed close to the microinjection sites confirmed that bicuculline produced a focal increase of neuronal activity surrounded by a zone with neuronal hypoactivity. This study provides new evidence for the involvement of specific striatal regions in movement as well as in a large spectrum of behavioral disorders and suggests that local inhibitory dysfunction could be a pathological mechanism of various neurological and psychiatric disorders.

Functional Connectivity of the Inferior Frontal Cortex Changes with Age in Children with Autism Spectrum Disorders: A fcMRI Study of Response Inhibition

2008-12-09

Unmasking the neural basis of neurodevelopmental disorders, such as autism spectrum disorders (ASD), requires studying functional connectivity during childhood when cognitive skills develop. A functional connectivity magnetic resonance imaging (fcMRI) analysis was performed on data collected during Go/NoGo task performance from 24 children ages 8–12 years (12 with ASD; 12 controls matched on age and intellectual functioning). We investigated the connectivity of the left and right inferior frontal cortex (IFC; BA 47), key regions for response inhibition, with other active regions in frontal, striatal, and parietal cortex. Groups did not differ on behavioral measures or functional connectivity of either IFC region. A trend for reduced connectivity in the right IFC for the ASD group was revealed when controlling for age. In the ASD group, there was a significant negative correlation between age and 2 right IFC correlation pairs: right IFC–bilateral presupplementary motor area (BA 6) and right IFC–right caudate. Compared with typical controls, children with ASD may not have gross differences in IFC functional connectivity during response inhibition, which contrasts with an adult study of ASD that reported reduced functional connectivity. This discrepancy suggests an atypical developmental trajectory in ASD for right IFC connectivity with other neural regions supporting response inhibition.

Motor-Related Signals in the Intraparietal Cortex Encode Locations in a Hybrid, rather than Eye-Centered Reference Frame

Mullette-Gillman, O. A., Cohen, Y. E., Groh, J. M. — 2008-12-09

The reference frame used by intraparietal cortex neurons to encode locations is controversial. Many previous studies have suggested eye-centered coding, whereas we have reported that visual and auditory signals employ a hybrid reference frame (i.e., a combination of head- and eye-centered information) (Mullette-Gillman et al. 2005). One possible explanation for this discrepancy is that sensory-related activity, which we studied previously, is hybrid, whereas motor-related activity might be eye centered. Here, we examined the reference frame of visual and auditory saccade-related activity in the lateral and medial banks of the intraparietal sulcus (areas lateral intraparietal area [LIP] and medial intraparietal area [MIP]) of 2 rhesus monkeys. We recorded from 275 single neurons as monkeys performed visual and auditory saccades from different initial eye positions. We found that both visual and auditory signals reflected a hybrid of head- and eye-centered coordinates during both target and perisaccadic task periods rather than shifting to an eye-centered format as the saccade approached. This account differs from numerous previous recording studies. We suggest that the geometry of the receptive field sampling in prior studies was biased in favor of an eye-centered reference frame. Consequently, the overall hybrid nature of the reference frame was overlooked because the non–eye-centered response patterns were not fully characterized.

Enriched Expression of Serotonin 1B and 2A Receptor Genes in Macaque Visual Cortex and their Bidirectional Modulatory Effects on Neuronal Responses

2008-12-04

To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid (<3 h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs.

The Representation of Abstract Task Rules in the Human Prefrontal Cortex

Bengtsson, S. L., Haynes, J.-D., Sakai, K., Buckley, M. J., Passingham, R. E. — 2008-12-01

We have previously reported sustained activation in the ventral prefrontal cortex while participants prepared to perform 1 of 2 tasks as instructed. But there are studies that have reported activation reflecting task rules elsewhere in prefrontal cortex, and this is true in particular when it was left to the participants to decide which rule to obey. The aim of the present experiment was to use functional magnetic resonance imaging (fMRI) to find whether there was activation in common, irrespective of the way that the task rules were established. On each trial, we presented a word after a variable delay, and participants had to decide either whether the word was abstract or concrete or whether it had 2 syllables. The participants either decided before the delay which task they would perform or were instructed by written cues. Comparing the self-generated with the instructed trials, there was early task set activation during the delay in the middle frontal gyrus. On the other hand, a conjunction analysis revealed sustained activation in the ventral prefrontal and polar cortex for both conditions. We argue that the ventral prefrontal cortex is specialized for handling conditional rules regardless of how the task rules were established.

Visual Awareness, Emotion, and Gamma Band Synchronization

2008-12-01

What makes us become aware? A popular hypothesis is that if cortical neurons fire in synchrony at a certain frequency band (gamma), we become aware of what they are representing. We tested this hypothesis adopting brain-imaging techniques with good spatiotemporal resolution and frequency-specific information. Specifically, we examined the degree to which increases in event-related synchronization (ERS) in the gamma band were associated with awareness of a stimulus (its detectability) and/or the emotional content of the stimulus. We observed increases in gamma band ERS within prefrontal–anterior cingulate, visual, parietal, posterior cingulate, and superior temporal cortices to stimuli available to conscious awareness. However, we also observed increases in gamma band ERS within the amygdala, visual, prefrontal, parietal, and posterior cingulate cortices to emotional relative to neutral stimuli, irrespective of their availability to conscious access. This suggests that increased gamma band ERS is related to, but not sufficient for, consciousness.

Aging Affects the Neural Representation of Speed in Macaque Area MT

2008-11-26

Human perception of speed declines with age. Much of the decline is probably mediated by changes in the middle temporal (MT) area, an extrastriate area whose neural activity is linked to the perception of speed. In the present study, we used random-dot patterns to study the effects of aging on speed-tuning curves in cortical area MT of macaque visual cortex. Our results provide evidence for a significant degradation of speed selectivity in MT. Cells in old animals preferred lower speeds than did those in young animals. Response modulation and discriminative capacity for speed in old monkeys were also significantly weaker than those in young ones. Concurrently, MT cells in old monkeys showed increased baseline responses, peak responses and response variability, and these changes were accompanied by decreased signal-to-noise ratios. We also found that speed discrimination thresholds in old animals were higher than in young ones. The foregoing neural changes may mediate the declines in visual motion perception that occur during senescence.

Cortical Interneurons Require p35/Cdk5 for their Migration and Laminar Organization

Rakic, S., Yanagawa, Y., Obata, K., Faux, C., Parnavelas, J. G., Nikolic, M. — 2008-11-26

Projection neurons and interneurons populate the cerebral cortex in a layer-specific manner. Here, we studied the role of Cyclin-dependent kinase 5 (Cdk5) and its activator p35 in cortical interneuron migration and disposition in the cortex. We found that mice lacking p35 (p35^–/–) show accumulation of interneurons in the upper part of the cortex. We also observed an inverted distribution of both early- and late-born interneurons, with the former showing a preference for the upper and the latter for the lower aspects of the cortex. We investigated the causes of the altered laminar organization of interneurons in p35^–/– mice and found a cell-autonomous delay in their tangential migration that may prevent them from reaching correct positions. Incomplete splitting of the preplate in p35^–/– mice, which causes accumulation of cells in the superficial layer and defects in the "inward" and "outward" components of their radial movement, may also account for the altered final arrangement of interneurons. We, therefore, propose that p35/Cdk5 plays a key role in guiding cortical interneurons to their final positions in the cortex.

Differences in Response to Serotonergic Activation between First and Higher Order Thalamic Nuclei

Varela, C., Sherman, S. M. — 2008-11-21

Two types of thalamic nuclei have been recognized: first order, which relay information from subcortical sources, and higher order, which may relay information from one cortical area to another. We have recently shown that muscarinic agonists depolarize all first order and most higher order relay cells but hyperpolarize a significant proportion of higher order relay cells. We now extend this result to serotonergic agonists, using rat thalamic brain slices and whole-cell, current- and voltage-clamp recordings from relay cells in various first order (the lateral geniculate nucleus, the ventral posterior nucleus, and the ventral portion of the medial geniculate body) and higher order nuclei (the lateral posterior, the posterior medial nucleus, and the dorsal portion of the medial geniculate body). Similar to the effects of muscarinic agonists, we found that first and most higher order relay cells were depolarized by serotonergic agonists, but 15% of higher order relay cells responded with hyperpolarization. Thus different subsets of higher order relay cells are hyperpolarized by these modulatory systems, which could have implications for the transfer of information between cortical areas.

Synaptogenesis in Purified Cortical Subplate Neurons

McKellar, C. E., Shatz, C. J. — 2008-11-21

An ideal preparation for investigating events during synaptogenesis would be one in which synapses are sparse, but can be induced at will using a rapid, exogenous trigger. We describe a culture system of immunopurified subplate neurons in which synaptogenesis can be triggered, providing the first homogeneous culture of neocortical neurons for the investigation of synapse development. Synapses in immunopurified rat subplate neurons are sparse, and can be induced by a 48-h exposure to feeder layers of neurons and glia, an induction more rapid than any previously reported. Induced synapses are electrophysiologically functional and ultrastructurally normal. Microarray and real-time PCR experiments reveal a new program of gene expression accompanying synaptogenesis. Surprisingly few known synaptic genes are upregulated during the first 24 h of synaptogenesis; Gene Ontology annotation reveals a preferential upregulation of synaptic genes only at a later time. In situ hybridization confirms that some of the genes regulated in cultures are also expressed in the developing cortex. This culture system provides both a means of studying synapse formation in a homogeneous population of cortical neurons, and better synchronization of synaptogenesis, permitting the investigation of neuron-wide events following the triggering of synapse formation.

Dopamine D1 and D5 Receptors Are Localized to Discrete Populations of Interneurons in Primate Prefrontal Cortex

Glausier, J. R., Khan, Z. U., Muly, E. C. — 2008-11-19

Working memory (WM) is a core cognitive process that depends upon activation of D1 family receptors (D1R) and inhibitory interneurons in the prefrontal cortex (PFC). D1R are comprised of the D₁ and D₅ subtypes, and D₅ has a 10-fold higher affinity for dopamine. Parvalbumin (PV) and calretinin (CR) are 2 interneuron populations that are differentially affected by D1R stimulation and have discrete postsynaptic targets, such that PV interneurons provide strong inhibition to pyramidal cells, whereas CR interneurons inhibit other interneurons. The distinct properties of both the D1R and interneuron subtypes may contribute to the "inverted-U" relationship of D1R stimulation and WM ability. To determine the prevalence of D₁ and D₅ in PV and CR interneurons, we performed quantitative double-label immunoelectron microscopy in layer III of macaque area 9. We found that D₁ was the predominant D1R subtype in PV interneurons and was found mainly in dendrites. In contrast, D₅ was the predominant D1R subtype in CR interneurons and was found mainly in dendrites. Integrating these findings with previously published electrophysiological data, we propose a circuitry model as a framework for understanding the inverted-U relationship between dopamine stimulation of D1R and WM performance.

Interocular Transfer of Adaptation in the Primary Visual Cortex

Howarth, C. M., Vorobyov, V., Sengpiel, F. — 2008-11-17

Prolonged viewing of an unchanging pattern causes adaptation, which can be demonstrated by visual aftereffects such as the tilt and waterfall illusions. In normal observers, these typically exhibit interocular transfer (IOT), being observed when the adapting and test stimuli are shown to different eyes. Convergence of inputs from both eyes upon binocular neurons only occurs in the primary visual cortex (V1), and adaptation is substantially a cortical phenomenon. However, little is known about a physiological substrate of IOT in V1 and how it relates to the binocularity of neurons and local ocular dominance (OD) column architecture. We employed optical imaging to obtain OD maps in cat V1 and recorded from single neurons at targeted penetration sites to quantify their adaptation by drifting gratings when adapter and test stimulus were presented either to the same or to the opposite eyes. In contrast to earlier reports, clear IOT of adaptation was observed for binocular as well as monocular neurons; at population level, its strength amounted to 55%. Moreover, the position of the cells with respect to OD column borders had no significant effect on the strength of IOT. IOT does not appear to strongly depend on conventional binocularity of neurons.

Object Representations for Multiple Visual Categories Overlap in Lateral Occipital and Medial Fusiform Cortex

Pourtois, G., Schwartz, S., Spiridon, M., Martuzzi, R., Vuilleumier, P. — 2008-11-17

How representations of visual objects are maintained across changes in viewpoint is a central issue in visual perception. Whether neural processes underlying view-invariant recognition involve distinct subregions within extrastriate visual cortex for distinct categories of visual objects remains unresolved. We used event-related functional magnetic resonance imaging in 16 healthy volunteers to map visual cortical areas responding to a large set (156) of exemplars from 3 object categories (faces, houses, and chairs), each repeated once after a variable time lag (3–7 intervening stimuli). Exemplars were repeated with the same viewpoint (but different retinal size) or with different viewpoint and size. The task was kept constant across object categories (judging items as "young" vs. "old"). We identified object-selective adaptation effects by comparing neural responses to the first presentation versus repetition of each individual exemplar. We found that exemplar-specific adaptation effects partly overlapped with regions showing category-selective responses (as identified using a separate localizer scan). These included the lateral fusiform gyrus (FG) for faces, parahippocampal gyrus for houses, and lateral occipital complex (LOC) for chairs. In face-selective fusiform gyrus (FG), adaptation effects occurred only for faces repeated with the same viewpoint, but not with a different viewpoint, confirming previous studies using faces only. By contrast, a region in right medial FG, adjacent to but nonoverlapping with the more lateral and face-selective FG, showed repetition effects for faces and to a lesser extent for other objects, regardless of changes in viewpoint or in retinal image-size. Category- and viewpoint-independent repetition effects were also found in bilateral LOC. Our results reveal a common neural substrate in bilateral LOC and right medial FG underlying view-invariant and category-independent recognition for multiple object identities, with only a relative preference for faces in medial FG but no selectivity in LOC.

Electrical Excitability of Early Neurons in the Human Cerebral Cortex during the Second Trimester of Gestation

Moore, A. R., Filipovic, R., Mo, Z., Rasband, M. N., Zecevic, N., Antic, S. D. — 2008-11-17

Information about development of the human cerebral cortex (proliferation, migration, and differentiation of neurons) is largely based on postmortem histology. Physiological properties of developing human cortical neurons are difficult to access experimentally and therefore remain largely unexplored. Animal studies have shown that information about the arousal of electrical activity in individual cells within fundamental cortical zones (subventricular zone [SVZ], intermediate zone, subplate [SP], and cortical plate [CP]) is necessary for understanding normal brain development. Here we ask where, in what cortical zone, and when, in what gestational week (gw), human neurons acquire the ability to generate nerve impulses (action potentials [APs]). We performed electrical recordings from individual cells in acute brain slices harvested postmortem from the human fetal cerebral cortex (16–22 gw). Tetrodotoxin-sensitive Na⁺ current occurs more frequently among CP cells and with significantly greater peak amplitudes than in SVZ. As early as 16 gw, a relatively small population of CP neurons (27%) was able to generate sodium APs upon direct current injection. Neurons located in the SP exhibited the highest level of cellular differentiation, as judged by their ability to fire repetitive APs. At 19 gw, a fraction of human CP and SP neurons possess βIV spectrin–positive axon initial segments populated with voltage-gated sodium channels (PanNav). These results yield the first physiological characterization of developing human fetal cortical neurons with preserved morphologies in intact surrounding brain tissue.

Novel Markers Reveal Subpopulations of Subplate Neurons in the Murine Cerebral Cortex

2008-11-13

The subplate lays the foundation of the developing cerebral cortex, and abnormalities have been suggested to contribute to various brain developmental disorders. The causal relationship between cellular pathologies and cognitive disorders remains unclear, and therefore, a better understanding of the role of subplate cells in cortical development is essential. Only by determining the molecular taxonomy of this diverse class of neurons can we identify the subpopulations that may contribute differentially to cortical development. We identified novel markers for murine subplate cells by comparing gene expression of subplate and layer 6 of primary visual and somatosensory cortical areas of postnatal day (P)8 old mice using a microarray-based approach. We examined the utility of these markers in well-characterized mutants (reeler, scrambler, and p35-KO) where the subplate is displaced in relation to the cortical plate. In situ hybridization or immunohistochemistry confirmed subplate-selective expression of complexin 3, connective tissue growth factor, nuclear receptor–related 1/Nr4a2, and monooxygenase Dbh-like 1 while transmembrane protein 163 also had additional expression in layer 5, and DOPA decarboxylase was also present in the white matter. Localization of marker-positive cells in the reeler and p35-KO cortices suggests different subpopulations of subplate cells. These new markers open up possibilities for further identification of subplate subpopulations in research and in neuropathological diagnosis.