Cerebral Cortex - Advance Access

Involvement of Insula and Cingulate Cortices in Control and Suppression of Natural Urges

2008-05-09

The physiology of control and suppression of natural urges is not well understood. We used [¹⁵O]H₂O positron-emission tomography imaging to identify neural circuits involved in suppression of spontaneous blinking as a model of normal urges. Suppression of blinking was associated with prominent activation of bilateral insular-claustrum regions, right more than left; activation was also found in bilateral anterior cingulate cortex (ACC), supplementary motor areas, and the face area of the primary motor cortex bilaterally. These results suggest a central role for the insula possibly together with ACC in suppression of blinking.

The Roles of Human Lateral Temporal Cortical Neuronal Activity in Recent Verbal Memory Encoding

Ojemann, G. A., Schoenfield-McNeill, J., Corina, D. — 2008-05-09

Activity of 98 single neurons in human lateral temporal cortex was measured during memory encoding for auditory words, text, or pictures and compared with identification of material of the same modality in extracellular recordings during awake neurosurgery for epilepsy. Frequency of activity was divided into early or late epochs or activity sustained throughout both; 44 neurons had significant changes in one or more categories. Polymodal and sustained changes lateralized to dominant hemisphere and late changes to nondominant. The majority of polymodal neurons shifted categories for different modalities. In dominant hemisphere, the timing and nature of changes in activity provide the basis for a model of the roles of temporal cortex in encoding. Superior temporal gyrus excitatory activity was related to the early epoch, when perception and processing occur, and middle gyrus to the late epoch, when semantic labeling occurs. The superior two-thirds of middle gyrus also demonstrated sustained inhibition. In a subset of lateral temporal neurons, memory-encoding activity reflected simultaneous convergence of sustained attentional and early perceptual inputs.

Spatiotemporal Signatures Of Large-Scale Synfire Chains for Speech Processing as Revealed by MEG

Pulvermuller, F., Shtyrov, Y. — 2008-05-05

We report a new brain signature of memory trace activation in the human brain revealed by magnetoencephalography and distributed source localization. Spatiotemporal patterns of cortical activation can be picked up in the time course of source images underlying magnetic brain responses to speech and noise stimuli, especially the generators of the magnetic mismatch negativity. We found that acoustic signals perceived as speech elicited a well-defined spatiotemporal pattern of sequential activation of superior–temporal and inferior–frontal cortex, whereas the same identical stimuli, when perceived as noise, did not elicit temporally structured activation. Strength of local sources constituting large-scale spatiotemporal patterns reflected additional lexical and syntactic features of speech. Morphological processing of the critical sound as verb inflection led to particularly pronounced early left inferior–frontal activation, whereas the same sound functioning as inflectional affix of a noun activated superior–temporal cortex more strongly. We conclude that precisely timed spatiotemporal patterns involving specific cortical areas may represent a brain code of memory circuit activation. These spatiotemporal patterns are best explained in terms of synfire mechanisms linking neuronal populations in different cortical areas. The large-scale synfire chains appear to reflect the processing of stimuli together with the context-dependent perceptual and cognitive information bound to them.

Enhanced Processing of Threat Stimuli under Limited Attentional Resources

De Martino, B., Kalisch, R., Rees, G., Dolan, R. J. — 2008-05-03

The ability to process stimuli that convey potential threat, under conditions of limited attentional resources, confers adaptive advantages. This study examined the neurobiology underpinnings of this capacity. Employing an attentional blink paradigm, in conjunction with functional magnetic resonance imaging, we manipulated the salience of the second of 2 face target stimuli (T2), by varying emotionality. Behaviorally, fearful T2 faces were identified significantly more than neutral faces. Activity in fusiform face area increased with correct identification of T2 faces. Enhanced activity in rostral anterior cingulate cortex (rACC) accounted for the benefit in detection of fearful stimuli reflected in a significant interaction between target valence and correct identification. Thus, under conditions of limited attention resources activation in rACC correlated with enhanced processing of emotional stimuli. We suggest that these data support a model in which a prefrontal "gate" mechanism controls conscious access of emotional information under conditions of limited attentional resources.

Visuokinesthetic Perception of Hand Movement Is Mediated by Cerebro-Cerebellar Interaction between the Left Cerebellum and Right Parietal Cortex

2008-05-02

Combination of visual and kinesthetic information is essential to perceive bodily movements. We conducted behavioral and functional magnetic resonance imaging experiments to investigate the neuronal correlates of visuokinesthetic combination in perception of hand movement. Participants experienced illusory flexion movement of their hand elicited by tendon vibration while they viewed video-recorded flexion (congruent: CONG) or extension (incongruent: INCONG) motions of their hand. The amount of illusory experience was graded by the visual velocities only when visual information regarding hand motion was concordant with kinesthetic information (CONG). The left posterolateral cerebellum was specifically recruited under the CONG, and this left cerebellar activation was consistent for both left and right hands. The left cerebellar activity reflected the participants' intensity of illusory hand movement under the CONG, and we further showed that coupling of activity between the left cerebellum and the "right" parietal cortex emerges during this visuokinesthetic combination/perception. The "left" cerebellum, working with the anatomically connected high-order bodily region of the "right" parietal cortex, participates in online combination of exteroceptive (vision) and interoceptive (kinesthesia) information to perceive hand movement. The cerebro–cerebellar interaction may underlie updating of one's "body image," when perceiving bodily movement from visual and kinesthetic information.

Coupling of Theta Oscillations between Anterior and Posterior Midline Cortex and with the Hippocampus in Freely Behaving Rats

Young, C. K., McNaughton, N. — 2008-05-02

Theta oscillations in the hippocampus support cognitive processing. Theta-range rhythmicity has also been reported in frontal and posterior cortical areas—where it tends to show consistent phase-relations with hippocampal rhythmicity. Theta-range rhythmicity may, then, be important for cortico-cortical and/or cortico-hippocampal interactions. Here, we surveyed the rat frontal and posterior midline cortices for theta-related oscillations and examined their relationships with hippocampal activity in freely moving rats. Variation in electroencephalography across 4 general classes of spontaneous behavior demonstrated different profiles of theta-like activities through the rat midline cortices. Analysis of cortico-cortical and cortico-hippocampal coherences showed distinct, behavior-dependent, couplings of theta and delta oscillations. Increased theta coherence between structures was most obvious during nonautomatic behaviors and least during immobility or grooming. Extensive coupling of theta oscillations throughout the rat midline cortices and hippocampus occurred during rearing, and exploratory behavior. Such increases in coherence could reflect binding of cortico-hippocampal pathways into temporary functional units by behavioral demands. Extensive coupling of frontal delta, which lacked coherence with posterior areas (including the hippocampus), suggests that different frequencies of rhythmicity may act to bind groups of structures into different functional circuits on different occasions.

The Human Dorsal Action Control System Develops in the Absence of Vision

Fiehler, K., Burke, M., Bien, S., Roder, B., Rosler, F. — 2008-04-29

The primate dorsal pathway has been proposed to compute vision for action. Although recent findings suggest that dorsal pathway structures contribute to somatosensory action control as well, it is yet not clear whether or not the development of dorsal pathway functions depends on early visual experience. Using functional magnetic resonance imaging, we investigated the pattern of cortical activation in congenitally blind and matched blindfolded sighted adults while performing kinesthetically guided hand movements. Congenitally blind adults activated similar dorsal pathway structures as sighted controls. Group-specific activations were found in the extrastriate cortex and the auditory cortex for congenitally blind humans and in the precuneus and the presupplementary motor area for sighted humans. Dorsal pathway activity was in addition observed for working memory maintenance of kinesthetic movement information in both groups. Thus, the results suggest that dorsal pathway functions develop in the absence of vision. This favors the idea of a general mechanism of movement control that operates regardless of the sensory input modality. Group differences in cortical activation patterns imply different movement control strategies as a function of visual experience.

Functional Dissociation in Right Inferior Frontal Cortex during Performance of Go/No-Go Task

2008-04-28

The contribution of the right inferior frontal cortex to response inhibition has been demonstrated by previous studies of neuropsychology, electrophysiology, and neuroimaging. The inferior frontal cortex is also known to be activated during processing of infrequent stimuli such as stimulus-driven attention. Response inhibition has most often been investigated using the go/no-go task, and the no-go trials are usually given infrequently to enhance prepotent response tendency. Thus, it has not been clarified whether the inferior frontal activation during the go/no-go task is associated with response inhibition or processing of infrequent stimuli. In the present functional magnetic resonance imaging study, we employed not only frequent-go trials but also infrequent-go trials that were presented as infrequently as the no-go trials. The imaging results demonstrated that the posterior inferior frontal gyrus (pIFG) was activated during response inhibition as revealed by the no-go vs. infrequent-go trials, whereas the inferior frontal junction (IFJ) region was activated primarily during processing of infrequent stimuli as revealed by the infrequent-go versus frequent-go trials. These results indicate that the pIFG and IFJ within the inferior frontal cortex are spatially close but are associated with different cognitive control processes in the go/no-go paradigm.

The Human Brain Distinguishes between Single Odorants and Binary Mixtures

Boyle, J. A., Djordjevic, J., Olsson, M. J., Lundstrom, J. N., Jones-Gotman, M. — 2008-04-28

Single odors are processed differently from odor mixtures in the cortex of rodents. We investigated whether single and binary odor mixtures activate different regions also in the human brain. We analyzed data from positron emission tomography scans using pyridine, citral, and 5 mixtures of pyridine and citral in proportions varying from 10/90 to 90/10, with 50/50 being the most impure. Comparing mixtures with single odorants gave activation in the left cingulate and right parietal and superior frontal cortices and bilateral activation in the anterior and lateral orbitofrontal cortices. We also found that brain activity in the lateral orbitofrontal cortex (OFC) increased with odorant impurity, whereas the anterior OFC was activated for binary odor mixtures and deactivated for single components. We conclude that binary odor mixtures and their individual components are processed differently by the human brain. The lateral portion of the OFC responds to mixture impurity in a graded fashion, whereas the anterior portion acts like an on–off detector of odor mixtures.

A Molecular Neuroanatomical Study of the Developing Human Neocortex from 8 to 17 Postconceptional Weeks Revealing the Early Differentiation of the Subplate and Subventricular Zone

2008-04-25

We have employed immunohistochemistry for multiple markers to investigate the structure and possible function of the different compartments of human cerebral wall from the formation of cortical plate at 8 postconceptional weeks (PCW) to the arrival of thalamocortical afferents at 17 PCW. New observations include the subplate emerging as a discrete differentiated layer by 10 PCW, characterized by synaptophysin and vesicular gamma-aminobutyric acid transporter expression also seen in the marginal zone, suggesting that these compartments may maintain a spontaneously active synaptic network even before the arrival of thalamocortical afferents. The subplate expanded from 13 to 17 PCW, becoming the largest compartment and differentiated further, with NPY neurons located in the outer subplate and KCC2 neurons in the inner subplate. Glutamate decarboxylase and calretinin-positive inhibitory neurons migrated tangentially and radially from 11.5 PCW, appearing in larger numbers toward the rostral pole. The proliferative zones, marked by Ki67 expression, developed a complicated structure by 12.5 PCW reflected in transcription factor expression patterns, including TBR2 confined to the inner subventricular and outer ventricular zones and TBR1 weakly expressed in the subventricular zone (SVZ). PAX6 was extensively expressed in the proliferative zones such that the human outer SVZ contained a large reservoir of PAX6-positive potential progenitor cells.

Sensory MEG Responses Predict Successful and Failed Inhibition in a Stop-Signal Task

2008-04-24

In the present study magnetoencephalographic recordings were performed to investigate the neural mechanisms underlying the stopping of manual responses. Subjects performed in a Stop-signal task in which Go-stimuli (S1), requiring a rapid motor response, were sometimes rapidly followed by a Stop-stimulus (S2) indicating to withhold the already initiated response to S1. Success of stopping strongly depended on the early perceptual processing of S1 and S2 reflected by the magnetic N1 component. Enhanced processing of S1 facilitated the execution of the movement, whereas enhanced processing of S2 favored its inhibition. This suggests that the processing resources for the subsequent stimuli are limited and need to be shared. This sharing of resources appeared to arise from adjustments made on a trial-by-trial basis, in that systematic reaction time prolongations on Go-trials following Stop-trials versus following Go-trials were accompanied by attenuated sensory processing to the Go-stimulus similar to that seen in successful versus unsuccessful stopping in Stop-trials.

Cellular Mechanisms of Subplate-Driven and Cholinergic Input-Dependent Network Activity in the Neonatal Rat Somatosensory Cortex

Hanganu, I. L., Okabe, A., Lessmann, V., Luhmann, H. J. — 2008-04-24

Early coordinated network activity promotes the development of cortical structures. Although these early activity patterns have been recently characterized with respect to their developmental, spatial and dynamic properties, the cellular mechanisms by which specific neuronal populations trigger coordinated activity in the neonatal cerebral cortex are still poorly understood. Here we characterize the cellular and molecular processes leading to generation of network activity during early postnatal development. We show that the somatosensory cortex of newborn rats expresses cholinergic-driven calcium transients which are synchronized within the deeply located subplate. Correspondingly, endogenous or agonist-induced activation of predominantly m1/m5-assembled muscarinic acetylcholine receptors elicits bursts of action potentials (up states) as a result of suprathreshold activation of the subplate. Tonic activation by ambient nonsynaptically released gamma-amino butyric acid (GABA) facilitates the generation of up states in the neonatal cortex. Additionally, this network activity critically depends on neuronal gap junctions but not on glutamatergic or GABAergic synaptic transmission. Thus, an early circuit relying on the integrative function of the subplate as well as on cholinergic-driven tonic GABA depolarization and tight electrical coupling is able to generate coordinated network activity, which may shape the architecture and control the function of the developing cerebral cortex.

Morphology and Distribution of Chandelier Cell Axon Terminals in the Mouse Cerebral Cortex and Claustroamygdaloid Complex

Inda, M.C., DeFelipe, J., Munoz, A. — 2008-04-24

Chandelier cells represent a unique type of cortical --aminobutityric acidergic interneuron whose axon terminals (Ch-terminals) only form synapses with the axon initial segments of some pyramidal cells. Here, we have used immunocytochemistry for the high-affinity plasma membrane transporter GAT-1 and the calcium-binding protein parvalbumin to analyze the morphology and distribution of Ch-terminals in the mouse cerebral cortex and claustroamygdaloid complex. In general, 2 types of Ch-terminals were distinguished on the basis of their size and the density of the axonal boutons that made up the terminal. Simple Ch-terminals were made up of 1 or 2 rows of labeled boutons, each row consisting of only 3–5 boutons. In contrast, complex Ch-terminals were tight cylinder-like structures made up of multiple rows of boutons. Simple Ch-terminals were detected throughout the cerebral cortex and claustroamygdaloid complex, the complex type was only occasionally found in certain regions, whereas in others they were very abundant. These results indicate that there are substantial differences in the morphology and distribution of Ch-terminals between different areas and layers of the mouse cerebral cortex. Furthermore, we suggest that the distribution of complex Ch-terminals may be related to the developmental origin of the different brain regions analyzed.

Size Matters: Cerebral Volume Influences Sex Differences in Neuroanatomy

2008-04-24

Biological and behavioral differences between the sexes range from obvious to subtle or nonexistent. Neuroanatomical differences are particularly controversial, perhaps due to the implication that they might account for behavioral differences. In this sample of 200 men and women, large effect sizes (Cohen's d > 0.8) were found for sex differences in total cerebral gray and white matter, cerebellum, and gray matter proportion (women had a higher proportion of gray matter). The only one of these sex differences that survived adjustment for the effect of cerebral volume was gray matter proportion. Individual differences in cerebral volume accounted for 21% of the difference in gray matter proportion, while sex accounted for an additional 4%. The relative size of the corpus callosum was 5% larger in women, but this difference was completely explained by a negative relationship between relative callosal size and cerebral volume. In agreement with Jancke et al., individuals with higher cerebral volume tended to have smaller corpora callosa. There were few sex differences in the size of structures in Broca's and Wernicke's area. We conclude that individual differences in brain volume, in both men and women, account for apparent sex differences in relative size.

Right Parietal Brain Activity Precedes Perceptual Alternation of Bistable Stimuli

Britz, J., Landis, T., Michel, C. M. — 2008-04-18

Momentary fluctuations of baseline activity have been shown to influence responses to sensory stimulation both behaviorally and neurophysiologically. This suggests that perceptual awareness does not solely arise from physical stimulus properties. Here we studied whether the momentary state of the brain immediately before stimulus presentation indicates how a physically unique but perceptually ambiguous stimulus will be perceived. A complex Necker cube was intermittently presented and subjects indicated whether their perception changed with respect to the preceding presentation. EEG was recorded from 256 channels. The prestimulus brain-state was defined as the spatial configuration of the scalp potential map within the 50 ms before stimulus arrival, representing the sum of all momentary ongoing brain processes. Two maps were found that doubly dissociated perceptual reversals from perceptual stability. For EEG sweeps classified as either map, distributed inverse solutions were computed and statistically compared. This yielded activity confined to a region in right inferior parietal cortex that was significantly more active before a perceptual reversal. In contrast, no significant topographic differences of the evoked potentials elicited by stable vs. reversed Necker cubes were found. This indicates that prestimulus activity in right inferior parietal cortex is associated with the perceptual change.

Auditory, Somatosensory, and Multisensory Insular Cortex in the Rat

Rodgers, K. M., Benison, A. M., Klein, A., Barth, D. S. — 2008-04-18

Compared with other areas of the forebrain, the function of insular cortex is poorly understood. This study examined the unisensory and multisensory function of the rat insula using high-resolution, whole-hemisphere, epipial evoked potential mapping. We found the posterior insula to contain distinct auditory and somatotopically organized somatosensory fields with an interposed and overlapping region capable of integrating these sensory modalities. Unisensory and multisensory responses were uninfluenced by complete lesioning of primary and secondary auditory and somatosensory cortices, suggesting a high degree of parallel afferent input from the thalamus. In light of the established connections of the posterior insula with the amygdala, we propose that integration of auditory and somatosensory modalities reported here may play a role in auditory fear conditioning.

An Additional Motor-Related Field in the Lateral Frontal Cortex of Squirrel Monkeys

Dancause, N., Duric, V., Barbay, S., Frost, S. B., Stylianou, A., Nudo, R. J. — 2008-04-18

Our earlier efforts to document the cortical connections of the ventral premotor cortex (PMv) revealed dense connections with a field rostral and lateral to PMv, an area we called the frontal rostral field (FR). Here, we present data collected in FR using electrophysiological and anatomical methods. Results show that FR contains an isolated motor representation of the forelimb that can be differentiated from PMv based on current thresholds and latencies to evoke electromyographic activity using intracortical microstimulation techniques. In addition, FR has a different pattern of cortical connections compared with PMv. Together, these data support that FR is an additional, previously undescribed motor-related area in squirrel monkeys.

Selective Attention Increases the Dependency of Cortical Responses on Visual Motion Coherence in Man

Handel, B., Lutzenberger, W., Thier, P., Haarmeier, T. — 2008-04-18

Attention improves visual discrimination and consequently allows to discern stimuli with low signal-to-noise ratios that otherwise would remain undetected. We used magnetoencephalography (MEG) to test whether neuromagnetic responses recorded from occipito-temporal cortex, reflecting the size of visual motion signals embedded in noise (motion coherence), would mirror the perceptual changes induced by attention. Attention directed to a given hemifield increased and decreased the coherence modulation of the MEG response over contralateral and ipsilateral visual cortex, respectively, indicating a change in the neuronal signal-to-noise ratio at the population level.

Where is a Nose with Respect to a Foot? The Left Posterior Parietal Cortex Processes Spatial Relationships among Body Parts

Corradi-Dell'Acqua, C., Hesse, M. D., Rumiati, R. I., Fink, G. R. — 2008-04-18

Neuropsychological studies suggest that patients with left parietal lesions may show impaired localization of parts of either their own or the examiner's body, despite preserved ability to identify isolated body parts. This deficit, called autotopagnosia, may result from damage to the Body Structural Description (BSD), a representation which codes spatial relationships among body parts. We used functional magnetic resonance imaging to identify the neural mechanisms underlying the BSD. Two human body or building parts (factor: STIMULI) were shown to participants who either identified them or evaluated their distance (factor: TASK). The analysis of the interaction between STIMULI and TASK, which isolates the neural mechanism underlying BSD, revealed an activation of left posterior intraparietal sulcus (IPS) when the distance between body parts was evaluated. The results show that the left IPS processes specifically the information about spatial relationships among body parts and thereby suggest that damage to this area may underlie autotopagnosia.

Language Conflict in the Bilingual Brain

van Heuven, W. J.B., Schriefers, H., Dijkstra, T., Hagoort, P. — 2008-04-18

The large majority of humankind is more or less fluent in 2 or even more languages. This raises the fundamental question how the language network in the brain is organized such that the correct target language is selected at a particular occasion. Here we present behavioral and functional magnetic resonance imaging data showing that bilingual processing leads to language conflict in the bilingual brain even when the bilinguals’ task only required target language knowledge. This finding demonstrates that the bilingual brain cannot avoid language conflict, because words from the target and nontarget languages become automatically activated during reading. Importantly, stimulus-based language conflict was found in brain regions in the LIPC associated with phonological and semantic processing, whereas response-based language conflict was only found in the pre-supplementary motor area/anterior cingulate cortex when language conflict leads to response conflicts.

Hemispheric Asymmetry of Frequency-Dependent Suppression in the Ipsilateral Primary Motor Cortex During Finger Movement: A Functional Magnetic Resonance Imaging Study

Hayashi, M. J., Saito, D. N., Aramaki, Y., Asai, T., Fujibayashi, Y., Sadato, N. — 2008-04-15

Electrophysiological studies have suggested that the activity of the primary motor cortex (M1) during ipsilateral hand movement reflects both the ipsilateral innervation and the transcallosal inhibitory control from its counterpart in the opposite hemisphere, and that their asymmetry might cause hand dominancy. To examine the asymmetry of the involvement of the ipsilateral motor cortex during a unimanual motor task under frequency stress, we conducted block-design functional magnetic resonance imaging with 22 normal right-handed subjects. The task involved visually cued unimanual opponent finger movement at various rates. The contralateral M1 showed symmetric frequency-dependent activation. The ipsilateral M1 showed task-related deactivation at low frequencies without laterality. As the frequency of the left-hand movement increased, the left M1 showed a gradual decrease in the deactivation. This data suggests a frequency-dependent increased involvement of the left M1 in ipsilateral hand control. By contrast, the right M1 showed more prominent deactivation as the frequency of the right-hand movement increased. This suggests that there is an increased transcallosal inhibition from the left M1 to the right M1, which overwhelms the right M1 activation during ipsilateral hand movement. These results demonstrate the dominance of the left M1 in both ipsilateral innervation and transcallosal inhibition in right-handed individuals.

Members of the NuRD Chromatin Remodeling Complex Interact with AUF1 in Developing Cortical Neurons

2008-04-15

Chromatin remodeling plays an important role in coordinating gene expression during cortical development, however the identity of molecular complexes present in differentiating cortical neurons that mediate the process remains poorly understood. The A + U–rich element-binding factor 1 (AUF1) is a known regulator of messenger RNA stability and also acts as a transcription factor upon binding to AT-rich DNA elements. Here we show that AUF1 is specifically expressed in subsets of proliferating neural precursors and differentiating postmitotic neurons of the developing cerebral cortex. Moreover, AUF1 is coexpressed with histone deacetylase 1 (HDAC1) and metastasis-associated protein 2 (MTA2), members of the nucleosome remodeling and histone deacetylase complex. AUF1 specifically and simultaneously binds to HDAC1, MTA2, and AT-rich DNA element, its gene regulatory function is modulated by the extent of histone acetylation and in animals lacking AUF1, the composition of the complex is modified. These results suggest that AUF1 is involved in integrating genetic and epigenetic signals during cortical development through recruiting HDAC1 and MTA2 to AT-rich DNA elements.

Resting-State Functional Connectivity Reflects Structural Connectivity in the Default Mode Network

Greicius, M. D., Supekar, K., Menon, V., Dougherty, R. F. — 2008-04-09

Resting-state functional connectivity magnetic resonance imaging (fcMRI) studies constitute a growing proportion of functional brain imaging publications. This approach detects temporal correlations in spontaneous blood oxygen level–dependent (BOLD) signal oscillations while subjects rest quietly in the scanner. Although distinct resting-state networks related to vision, language, executive processing, and other sensory and cognitive domains have been identified, considerable skepticism remains as to whether resting-state functional connectivity maps reflect neural connectivity or simply track BOLD signal correlations driven by nonneural artifact. Here we combine diffusion tensor imaging (DTI) tractography with resting-state fcMRI to test the hypothesis that resting-state functional connectivity reflects structural connectivity. These 2 modalities were used to investigate connectivity within the default mode network, a set of brain regions—including medial prefrontal cortex (MPFC), medial temporal lobes (MTLs), and posterior cingulate cortex (PCC)/retropslenial cortex (RSC)—implicated in episodic memory processing. Using seed regions from the functional connectivity maps, the DTI analysis revealed robust structural connections between the MTLs and the retrosplenial cortex whereas tracts from the MPFC contacted the PCC (just rostral to the RSC). The results demonstrate that resting-state functional connectivity reflects structural connectivity and that combining modalities can enrich our understanding of these canonical brain networks.

Activity in Face-Responsive Brain Regions is Modulated by Invisible, Attended Faces: Evidence from Masked Priming

Kouider, S., Eger, E., Dolan, R., Henson, R. N. — 2008-04-09

It is often assumed that neural activity in face-responsive regions of primate cortex correlates with conscious perception of faces. However, whether such activity occurs without awareness is still debated. Using functional magnetic resonance imaging (fMRI) in conjunction with a novel masked face priming paradigm, we observed neural modulations that could not be attributed to perceptual awareness. More specifically, we found reduced activity in several classic face-processing regions, including the "fusiform face area," "occipital face area," and superior temporal sulcus, when a face was preceded by a briefly flashed image of the same face, relative to a different face, even when 2 images of the same face differed. Importantly, unlike most previous studies, which have minimized awareness by using conditions of inattention, the present results occurred when the stimuli (the primes) were attended. By contrast, when primes were perceived consciously, in a long-lag priming paradigm, we found repetition-related activity increases in additional frontal and parietal regions. These data not only demonstrate that fMRI activity in face-responsive regions can be modulated independently of perceptual awareness, but also document where such subliminal face-processing occurs (i.e., restricted to face-responsive regions of occipital and temporal cortex) and to what extent (i.e., independent of the specific image).

A Small World of Neuronal Synchrony

Yu, S., Huang, D., Singer, W., Nikolic, D. — 2008-04-09

A small-world network has been suggested to be an efficient solution for achieving both modular and global processing—a property highly desirable for brain computations. Here, we investigated functional networks of cortical neurons using correlation analysis to identify functional connectivity. To reconstruct the interaction network, we applied the Ising model based on the principle of maximum entropy. This allowed us to assess the interactions by measuring pairwise correlations and to assess the strength of coupling from the degree of synchrony. Visual responses were recorded in visual cortex of anesthetized cats, simultaneously from up to 24 neurons. First, pairwise correlations captured most of the patterns in the population's activity and, therefore, provided a reliable basis for the reconstruction of the interaction networks. Second, and most importantly, the resulting networks had small-world properties; the average path lengths were as short as in simulated random networks, but the clustering coefficients were larger. Neurons differed considerably with respect to the number and strength of interactions, suggesting the existence of "hubs" in the network. Notably, there was no evidence for scale-free properties. These results suggest that cortical networks are optimized for the coexistence of local and global computations: feature detection and feature integration or binding.

Interaction of Working Memory and Long-Term Memory in the Medial Temporal Lobe

Axmacher, N., Schmitz, D. P., Weinreich, I., Elger, C. E., Fell, J. — 2008-04-09

Recent findings indicate that regions in the medial temporal lobe (MTL) do not only play a crucial role in long-term memory (LTM) encoding, but contribute to working memory (WM) as well. However, very few studies investigated the interaction between these processes so far. In a new functional magnetic resonance imaging paradigm comprising both a complex WM task and an LTM recognition task, we found not only that some items were successfully processed in WM but later forgotten, but also that a significant number of items which were not successfully processed in the WM task were subsequently recognized. Activation in the parahippocampal cortex (PHC) during successful WM was predictive of subsequent LTM, but was correlated with subsequent forgetting if the WM task was not successfully solved. The contribution of the PHC to LTM encoding thus crucially depends on whether an item was successfully processed in the WM task. Functional connectivity analysis revealed that across-trial fluctuations in PHC activity were correlated with activation in extensive regions if WM and LTM tasks were correctly solved, whereas connectivity broke down during unsuccessful attempts to do the task, suggesting that activity in the PHC during WM has to be well controlled to support LTM formation.

Hearing Loss Alters the Subcellular Distribution of Presynaptic GAD and Postsynaptic GABAA Receptors in the Auditory Cortex

Sarro, E. C., Kotak, V. C., Sanes, D. H., Aoki, C. — 2008-04-09

We have shown previously that auditory experience regulates the maturation of excitatory synapses in the auditory cortex (ACx). In this study, we used electron microscopic immunocytochemistry to determine whether the heightened excitability of the ACx following neonatal sensorineural hearing loss (SNHL) also involves pre- or postsynaptic alterations of GABAergic synapses. SNHL was induced in gerbils just prior to the onset of hearing (postnatal day 10). At P17, the gamma-aminobutyri acid type A (GABA_A) receptor's β2/3-subunit (GABA_Aβ2/3) clusters residing at plasma membranes in layers 2/3 of ACx was reduced significantly in size (P < 0.05) and number (P < 0.005), whereas the overall number of immunoreactive puncta (intracellular + plasmalemmal) remained unchanged. The reduction of GABA_Aβ2/3 was observed along perikaryal plasma membranes of excitatory neurons but not of GABAergic interneurons. This cell-specific change can contribute to the enhanced excitability of SNHL ACx. Presynaptically, GABAergic axon terminals were significantly larger but less numerous and contained 47% greater density of glutamic acid decarboxylase immunoreactivity (P < 0.05). This suggests that GABA synthesis may be upregulated by a retrograde signal arising from lowered levels of postsynaptic GABA_AR. Thus, both, the pre- and postsynaptic sides of inhibitory synapses that form upon pyramidal neurons of the ACx are regulated by neonatal auditory experience.

Medial Temporal Lobe Involvement in an Implicit Memory Task: Evidence of Collaborating Implicit and Explicit Memory Systems from fMRI and Alzheimer's Disease

Koenig, P., Smith, E. E., Troiani, V., Anderson, C., Moore, P., Grossman, M. — 2008-04-09

We used a prototype extraction task to assess implicit learning of a meaningful novel visual category. Cortical activation was monitored in young adults with functional magnetic resonance imaging. We observed occipital deactivation at test consistent with perceptually based implicit learning, and lateral temporal cortex deactivation reflecting implicit acquisition of the category's semantic nature. Medial temporal lobe (MTL) activation during exposure and test suggested involvement of explicit memory as well. Behavioral performance of Alzheimer's disease (AD) patients and healthy seniors was also assessed, and AD performance was correlated with gray matter volume using voxel-based morphometry. AD patients showed learning, consistent with preserved implicit memory, and confirming that AD patients' implicit memory is not limited to abstract patterns. However, patients were somewhat impaired relative to healthy seniors. Occipital and lateral temporal cortical volume correlated with successful AD patient performance, and thus overlapped with young adults' areas of deactivation. Patients' severe MTL atrophy precluded involvement of this region. AD patients thus appear to engage a cortically based implicit memory mechanism, whereas their relative deficit on this task may reflect their MTL disease. These findings suggest that implicit and explicit memory systems collaborate in neurologically intact individuals performing an ostensibly implicit memory task.

Functional Connectivity of Human Striatum: A Resting State fMRI Study

2008-04-09

Classically regarded as motor structures, the basal ganglia subserve a wide range of functions, including motor, cognitive, motivational, and emotional processes. Consistent with this broad-reaching involvement in brain function, basal ganglia dysfunction has been implicated in numerous neurological and psychiatric disorders. Despite recent advances in human neuroimaging, models of basal ganglia circuitry continue to rely primarily upon inference from animal studies. Here, we provide a comprehensive functional connectivity analysis of basal ganglia circuitry in humans through a functional magnetic resonance imaging examination during rest. Voxelwise regression analyses substantiated the hypothesized motor, cognitive, and affective divisions among striatal subregions, and provided in vivo evidence of a functional organization consistent with parallel and integrative loop models described in animals. Our findings also revealed subtler distinctions within striatal subregions not previously appreciated by task-based imaging approaches. For instance, the inferior ventral striatum is functionally connected with medial portions of orbitofrontal cortex, whereas a more superior ventral striatal seed is associated with medial and lateral portions. The ability to map multiple distinct striatal circuits in a single study in humans, as opposed to relying on meta-analyses of multiple studies, is a principal strength of resting state functional magnetic resonance imaging. This approach holds promise for studying basal ganglia dysfunction in clinical disorders.

Human Amygdala Sensitivity to the Pupil Size of Others

Demos, K.E., Kelley, W.M., Ryan, S.L., Davis, F.C., Whalen, P.J. — 2008-04-04

Stimulation of the amygdala produces pupil dilation in animal and human subjects. The present study examined whether the amygdala is sensitive to variations in the pupil size of others. Male subjects underwent event-related functional magnetic resonance imaging while passively viewing unfamiliar female faces whose pupils were either unaltered (natural variations in large and small pupils) or altered to be larger or smaller than their original size. Results revealed that the right amygdala and left amygdala/substantia innominata were sensitive to the pupil size of others, exhibiting increased activity for faces with relatively large pupils. Upon debrief, no subject reported being aware that the pupils had been manipulated. These results suggest a function for the amygdala in the detection of changes in pupil size, an index of arousal and/or interest on the part of a conspecific, even in the absence of explicit knowledge.

Listening to Musical Rhythms Recruits Motor Regions of the Brain

Chen, J. L., Penhune, V. B., Zatorre, R. J. — 2008-04-03

Perception and actions can be tightly coupled; but does a perceptual event dissociated from action processes still engage the motor system? We conducted 2 functional magnetic resonance imaging studies involving rhythm perception and production to address this question. In experiment 1, on each trial subjects 1st listened in anticipation of tapping, and then tapped along with musical rhythms. Recruitment of the supplementary motor area, mid-premotor cortex (PMC), and cerebellum was observed during listen with anticipation. To test whether this activation was related to motor planning or rehearsal, in experiment 2 subjects naively listened to rhythms without foreknowledge that they would later tap along with them. Yet, the same motor regions were engaged despite no action–perception connection. In contrast, the ventral PMC was only recruited during action and action-coupled perceptual processes, whereas the dorsal part was only sensitive to the selection of actions based on higher-order rules of temporal organization. These functional dissociations shed light on the nature of action–perception processes and suggest an inherent link between auditory and motor systems in the context of rhythm.

Cortical Dynamics Subserving Visual Apparent Motion

2008-03-28

Motion can be perceived when static images are successively presented with a spatial shift. This type of motion is an illusion and is termed apparent motion (AM). Here we show, with a voltage sensitive dye applied to the visual cortex of the ferret, that presentation of a sequence of stationary, short duration, stimuli which are perceived to produce AM are, initially, mapped in areas 17 and 18 as separate stationary representations. But time locked to the offset of the 1st stimulus, a sequence of signals are elicited. First, an activation traverses cortical areas 19 and 21 in the direction of AM. Simultaneously, a motion dependent feedback signal from these areas activates neurons between areas 19/21 and areas 17/18. Finally, an activation is recorded, traveling always from the representation of the 1st to the representation of the next or succeeding stimuli. This activation elicits spikes from neurons situated between these stimulus representations in areas 17/18. This sequence forms a physiological mechanism of motion computation which could bind populations of neurons in the visual areas to interpret motion out of stationary stimuli.

Role of Amygdala Connectivity in the Persistence of Emotional Memories Over Time: An Event-Related fMRI Investigation

Ritchey, M., Dolcos, F., Cabeza, R. — 2008-03-28

According to the consolidation hypothesis, enhanced memory for emotional information reflects the modulatory effect of the amygdala on the medial temporal lobe (MTL) memory system during consolidation. Although there is evidence that amygdala–MTL connectivity enhances memory for emotional stimuli, it remains unclear whether this enhancement increases over time, as consolidation processes unfold. To investigate this, we used functional magnetic resonance imaging to measure encoding activity predicting memory for emotionally negative and neutral pictures after short (20-min) versus long (1-week) delays. Memory measures distinguished between vivid remembering (recollection) and feelings of knowing (familiarity). Consistent with the consolidation hypothesis, the persistence of recollection over time (long divided by short) was greater for emotional than neutral pictures. Activity in the amygdala predicted subsequent memory to a greater extent for emotional than neutral pictures. Although this advantage did not vary with delay, the contribution of amygdala–MTL connectivity to subsequent memory for emotional items increased over time. Moreover, both this increase in connectivity and amygdala activity itself were correlated with individual differences in recollection persistence for emotional but not neutral pictures. These results suggest that the amygdala and its connectivity with the MTL are critical to sustaining emotional memories over time, consistent with the consolidation hypothesis.

Locus Coeruleus {alpha}-Adrenergic-Mediated Activation of Cortical Astrocytes In Vivo

Bekar, L. K., He, W., Nedergaard, M. — 2008-03-27

The locus coeruleus (LC) provides the sole source of norepinephrine (NE) to the cortex for modulation of cortical synaptic activity in response to salient sensory information. NE has been shown to improve signal-to-noise ratios, sharpen receptive fields and function in learning, memory, and cognitive performance. Although LC-mediated effects on neurons have been addressed, involvement of astrocytes has thus far not been demonstrated in these neuromodulatory functions. Here we show for the 1st time in live mice, that astrocytes exhibit rapid Ca²⁺ increases in response to electrical stimulation of the LC. Additionally, robust peripheral stimulation known to result in phasic LC activity leads to Ca²⁺ responses in astrocytes throughout sensory cortex that are independent of sensory-driven glutamate-dependent pathways. Furthermore, the astrocytic Ca²⁺ transients are competitively modulated by ₂-specific agonist/antagonist combinations known to impact LC output, are sensitive to the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, and are inhibited locally by an -adrenergic antagonist. Future investigations of LC function must therefore consider the possibility that LC neuromodulatory effects are in part derived from activation of astrocytes.

Functional Lateralization of Face, Hand, and Trunk Representation in Anatomically Defined Human Somatosensory Areas

Eickhoff, S.B., Grefkes, C., Fink, G.R., Zilles, K. — 2008-03-27

We used functional magnetic resonance imaging (fMRI) and cytoarchitectonic probability maps to investigate the responsiveness of individual areas in the human primary and secondary somatosensory cortices to hand, face, or trunk stimulation of either body-side. A Bayesian modeling approach to quantify the probability of ipsilateral activations revealed that areas OP 1, OP 4, and OP 3 of the SII cortex as well as the trunk and face representations within all SI subareas (areas 3b, 1, and 2) show robust bilateral responses to unilateral stimulation. Such bilateral response properties are in good agreement with the transcallosal projections demonstrated for these areas in nonhuman primates and other mammals. In contrast, the SI hand region showed a different pattern. Whereas ipsilateral areas 3b and 1 were deactivated by tactile hand stimulation, particularly on the left, there was strong evidence for ipsilateral processing of information from the right hand in area 2. These results demonstrate not only the behavioral importance of the hand representation, but also suggest that area 2 may have particularly evolved to form the cortical substrate of these specialized demands, in line with recent studies on cortical evolution hypothesizing that area 2 has developed with increasing manual abilities in anthropoid primates featuring opposable thumbs.

Neural Correlates of True Memory, False Memory, and Deception

2008-03-27

We used functional magnetic resonance imaging (fMRI) to determine whether neural activity can differentiate between true memory, false memory, and deception. Subjects heard a series of semantically related words and were later asked to make a recognition judgment of old words, semantically related nonstudied words (lures for false recognition), and unrelated new words. They were also asked to make a deceptive response to half of the old and unrelated new words. There were 3 main findings. First, consistent with the notion that executive function supports deception, 2 types of deception (pretending to know and pretending not to know) recruited prefrontal activity. Second, consistent with the sensory reactivation hypothesis, the difference between true recognition and false recognition was found in the left temporoparietal regions probably engaged in the encoding of auditorily presented words. Third, the left prefrontal cortex was activated during pretending to know relative to correct rejection and false recognition, whereas the right anterior hippocampus was activated during false recognition relative to correct rejection and pretending to know. These findings indicate that fMRI can detect the difference in brain activity between deception and false memory despite the fact that subjects respond with "I know" to novel events in both processes.

Homeostatic Metaplasticity of the Motor Cortex is Altered during Headache-Free Intervals in Migraine with Aura

Antal, A., Lang, N., Boros, K., Nitsche, M., Siebner, H. R., Paulus, W. — 2008-03-27

Preconditioning of the human primary motor cortex (M1) with transcranial direct current stimulation (tDCS) can shape the magnitude and direction of excitability changes induced by a subsequent session of repetitive transcranial magnetic stimulation (rTMS). Here, we examined this form of metaplasticity in migraine patients with visual aura and healthy controls. In both groups, facilitatory preconditioning of left M1 with anodal tDCS increased the mean amplitudes of motor-evoked potentials (MEPs) elicited in the contralateral hand, whereas inhibitory preconditioning with cathodal tDCS produced a decrease in amplitude. Following cathodal tDCS, a short train of low-intensity 5-Hz rTMS antagonized the suppression of the mean MEP amplitude in both groups. In contrast, the homeostatic effects of 5-Hz rTMS differed between groups when rTMS was given after anodal tDCS. In controls 5-Hz rTMS induced a marked decrease in MEP amplitudes, whereas in migraineurs rTMS induced only a modest decrease in MEP amplitudes, which were still facilitated after rTMS when compared with baseline amplitudes. These findings indicate that short-term homeostatic plasticity is altered in patients with visual aura between the attacks.

Spatial Attention Related SEP Amplitude Modulations Covary with BOLD Signal in S1--A Simultaneous EEG--fMRI Study

2008-03-27

Recent studies investigating the influence of spatial-selective attention on primary somatosensory processing have produced inconsistent results. The aim of this study was to explore the influence of tactile spatial-selective attention on spatiotemporal aspects of evoked neuronal activity in the primary somatosensory cortex (S1). We employed simultaneous electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) in 14 right-handed subjects during bilateral index finger Braille stimulation to investigate the relationship between attentional effects on somatosensory evoked potential (SEP) components and the blood oxygenation level–dependent (BOLD) signal. The 1st reliable EEG response following left tactile stimulation (P50) was significantly enhanced by spatial-selective attention, which has not been reported before. FMRI analysis revealed increased activity in contralateral S1. Remarkably, the effect of attention on the P50 component as well as long-latency SEP components starting at 190 ms for left stimuli correlated with attentional effects on the BOLD signal in contralateral S1. The implications are 2-fold: First, the correlation between early and long-latency SEP components and the BOLD effect suggest that spatial-selective attention enhances processing in S1 at 2 time points: During an early passage of the signal and during a later passage, probably via re-entrant feedback from higher cortical areas. Second, attentional modulations of the fast electrophysiological signals and the slow hemodynamic response are linearly related in S1.

Motor Planning, Imagery, and Execution in the Distributed Motor Network: A Time-Course Study with Functional MRI

Hanakawa, T., Dimyan, M. A., Hallett, M. — 2008-03-20

Activation of motor-related areas has consistently been found during various motor imagery tasks and is regarded as the central mechanism generating motor imagery. However, the extent to which motor execution and imagery share neural substrates remains controversial. We examined brain activity during preparation for and execution of physical or mental finger tapping. During a functional magnetic resonance imaging at 3 T, 13 healthy volunteers performed an instructed delay finger-tapping task either in a physical mode or mental mode. Number stimuli instructed subjects about a finger-tapping sequence. After an instructed delay period, cue stimuli prompted them either to execute the tapping movement or to imagine it. Two types of planning/preparatory activity common for movement and imagery were found: instruction stimulus–related activity represented widely in multiple motor-related areas and delay period activity in the medial frontal areas. Although brain activity during movement execution and imagery was largely shared in the distributed motor network, imagery-related activity was in general more closely related to instruction-related activity than to the motor execution–related activity. Specifically, activity in the medial superior frontal gyrus, anterior cingulate cortex, precentral sulcus, supramarginal gyrus, fusiform gyrus, and posterolateral cerebellum likely reflects willed generation of virtual motor commands and analysis of virtual sensory signals.

Effects of Long-Term Stress and Recovery on the Prefrontal Cortex and Dentate Gyrus in Male and Female Rats

2008-03-20

Women show a higher prevalence for depression than men. However, the biological basis of gender differences in stress response and recovery still remain poorly understood. Therefore, the aim of the study was to assess the gender differences in response to acute stress, chronic stress and recovery in rats. Our results showed that stress decreased male body weight but had no effect on female rats. Open field test demonstrated behavioral changes in grooming and velocity after chronic stress and recovery. Increased activity of hypothalamic-pituitary-adrenocortical axis was reflected by adrenal hypertrophy and increase of plasma corticosterone levels except in the socially housed female rats after stress. Gender and brain region differences in response to stress and recovery were found in the expression of cAMP response element–binding protein (CREB) and phosphorylated CREB (pCREB). On the whole, expression of CREB and pCREB in male dentate gyrus (DG) and prefrontal cortex (PFC) was sensitive but in female DG and PFC it was resistant to acute and chronic stress. Interestingly, recovery restored the measured parameters to the normal level in male rats but not in female rats. In conclusion, these results suggest that male and female rats responded to stress and recovery in a different way.

Transient Neuronal Correlations Underlying Goal Selection and Maintenance in Prefrontal Cortex

Tsujimoto, S., Genovesio, A., Wise, S. P. — 2008-03-20

We reported previously that as monkeys used abstract response strategies to choose spatial goals, 1 population of prefrontal cortex neurons encoded future goals (F cells), whereas a largely separate population encoded previous goals (P cells). Here, to better understand the mechanisms of goal selection and maintenance, we studied correlated activity among pairs of these neurons. Among the 3 possible types of pairs, F-F and F-P pairs often exhibited significant correlations when and after monkeys selected future goals but P–P pairs rarely did. These correlations were stronger when monkeys shifted from a previous goal than when they stayed with that goal. In addition, members of F–F pairs usually preferred the same goal and thus shared both prospective coding and spatial tuning properties. In contrast, cells composing F–P pairs usually had different spatial preferences and thus shared neither coding nor spatial tuning properties. On the assumption that the neurons composing a pair send convergent outputs to target neurons, their correlated activity could enhance their efficacy in context-dependent goal selection, goal maintenance, and the transformation of goal choices into action.

Diffusion Tensor Imaging of Frontal Lobe in Autism Spectrum Disorder

2008-03-20

To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 ± 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 ± 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.

The Influence of Moderate Hypercapnia on Neural Activity in the Anesthetized Nonhuman Primate

Zappe, A.C., Uludag, K., Oeltermann, A., Ugurbil, K., Logothetis, N.K. — 2008-03-10

Hypercapnia is often used as vasodilatory challenge in clinical applications and basic research. In functional magnetic resonance imaging (fMRI), elevated CO₂ is applied to derive stimulus-induced changes in the cerebral rate of oxygen consumption (CMRO₂) by measuring cerebral blood flow and blood-oxygenation-level–dependent (BOLD) signal. Such methods, however, assume that hypercapnia has no direct effect on CMRO₂. In this study, we used combined intracortical recordings and fMRI in the visual cortex of anesthetized macaque monkeys to show that spontaneous neuronal activity is in fact significantly reduced by moderate hypercapnia. As expected, measurement of cerebral blood volume using an exogenous contrast agent and of BOLD signal showed that both are increased during hypercapnia. In contrast to this, spontaneous fluctuations of local field potentials in the beta and gamma frequency range as well as multiunit activity are reduced by ~15% during inhalation of 6% CO₂ (pCO₂ = 56 mmHg)_. A strong tendency toward a reduction of neuronal activity was also found at CO₂ inhalation of 3% (pCO₂ = 45 mmHg). This suggests that CMRO₂ might be reduced during hypercapnia and caution must be exercised when hypercapnia is applied to calibrate the BOLD signal.

Deficit in a Neural Correlate of Reality Monitoring in Schizophrenia Patients

Vinogradov, S., Luks, T. L., Schulman, B. J., Simpson, G. V. — 2008-03-06

Patients who suffer from the devastating psychiatric illness schizophrenia are plagued by hallucinations, bizarre behavior, and delusional ideas, such as believing that they are controlled by malevolent outside forces. A fundamental human cognitive operation that may contribute to these hallmark symptoms is the ability to maintain accurate and coherent self-referential processing over time, such as occurs during reality monitoring (distinguishing self-generated from externally perceived information). However, the neural bases for a disturbance in this operation in schizophrenia have not been fully explored. Using functional magnetic resonance imaging, we asked clinically stable schizophrenia patients to remember whether or not they had generated a target word during an earlier sentence completion task. We found that, during accurate performance of this self-referential source memory task, the schizophrenia subjects manifest a deficit in rostral medial prefrontal cortex (mPFC) activity—a brain region critically implicated in both the instantiation and the retrieval of self-referential information in healthy subjects. Impairment in rostral mPFC function likely plays a key role in the profound subjective disturbances that characterize schizophrenia and that are the aspect of the disorder most troubling to patients and to society at large.

Dopaminergic Modulation of Auditory Cortex-Dependent Memory Consolidation through mTOR

2008-03-06

Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils’ FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.

Segregation of Visual Selection and Saccades in Human Frontal Eye Fields

2008-03-06

The premotor theory of attention suggests that target processing and generation of a saccade to the target are interdependent. Temporally precise transcranial magnetic stimulation (TMS) was delivered over the human frontal eye fields, the area most frequently associated with the premotor theory in association with eye movements, while subjects performed a visually instructed pro-/antisaccade task. Visual analysis and saccade preparation were clearly separated in time, as indicated by 2 distinct time points of TMS delivery that resulted in elevated saccade latencies. These results show that visual analysis and saccade preparation, although frequently enacted together, are dissociable processes.

A Rational Account of Memory Predicts Left Prefrontal Activation during Controlled Retrieval

Danker, J. F., Gunn, P., Anderson, J. R. — 2008-03-04

What is the role of the left prefrontal cortex in the controlled retrieval of learned information? We present a theory of declarative retrieval that posits that the amount of control exerted by this region during retrieval is inversely proportional to 1) the frequency and recency of previous experiences with the retrieved memory and 2) the associative strength between the current context and the retrieved memory. This theory is rational in the sense that it claims that declarative retrieval is highly sensitive to the statistical regularities in the environment. We demonstrate how our theory produces precise predictions of response time and neural activity during recall and test these predictions in an experiment that manipulates the frequency of previous experiences and the associative strength to the retrieval cues. Our findings suggest that the control process performed by the left prefrontal cortex directly reflects the demands of the environment on memory.

Organizational Principles of Human Visual Cortex Revealed by Receptor Mapping

Eickhoff, S. B., Rottschy, C., Kujovic, M., Palomero-Gallagher, N., Zilles, K. — 2008-03-04

This receptorarchitectonic study of the human visual cortex investigated interareal differences in mean receptor concentrations and laminar distribution patterns of 16 neurotransmitter receptors in the dorsal and ventral parts of areas V1, V2, V3 as well as in adjoining areas V4 (ventrally) and V3A (dorsally). Both the functional hierarchy of these areas and a distinction between dorsal and ventral visual cortices were reflected by significant receptorarchitectonic differences. The observation that dorso-ventral differences existed in all extrastriate areas (including V2) is particularly important for the discussion about the relationship between dorsal and ventral V3 as it indicates that a receptorarchitectonic distinction between the ventral and dorsal visual cortices is present in but not specific to V3. This molecular specificity is mirrored by previously reported differences in retinal microstructure and functional differences as revealed in behavioral experiments demonstrating differential advantages for stimulus processing in the upper and lower visual fields. We argue that these anatomical and functional differences may be regarded as the result of an evolutionary optimization adapting to the processing of the most relevant stimuli occurring in the upper and lower visual fields.

Spatial Attention Modulates Initial Afferent Activity in Human Primary Visual Cortex

Kelly, S. P., Gomez-Ramirez, M., Foxe, J. J. — 2008-03-04

It is well established that spatially directed attention enhances visual perceptual processing. However, the earliest level at which processing can be affected remains unknown. To date, there has been no report of modulation of the earliest visual event-related potential component "C1" in humans, which indexes initial afference in primary visual cortex (V1). Thus it has been suggested that initial V1 activity is impenetrable, and that the earliest modulations occur in extrastriate cortex. However, the C1 is highly variable across individuals, to the extent that uniform measurement across a group may poorly reflect the dynamics of V1 activity. In the present study we employed an individualized mapping procedure to control for such variability. Parameters for optimal C1 measurement were determined in an independent, preliminary "probe" session and later applied in a follow-up session involving a spatial cueing task. In the spatial task, subjects were cued on each trial to direct attention toward 1 of 2 locations in anticipation of an imperative Gabor stimulus and were required to detect a region of lower luminance appearing within the Gabor pattern 30% of the time at the cued location only. Our data show robust spatial attentional enhancement of the C1, beginning as early as its point of onset (57 ms). Source analysis of the attentional modulations points to generation in striate cortex. This finding demonstrates that at the very moment that visual information first arrives in cortex, it is already being shaped by the brain's attentional biases.

Learning-Dependent, Transient Increase of Activity in Noradrenergic Neurons of Locus Coeruleus during Slow Wave Sleep in the Rat: Brain Stem-Cortex Interplay for Memory Consolidation?

Eschenko, O., Sara, S. J. — 2008-03-04

Memory consolidation during sleep is regaining attention due to a wave of recent reports of memory improvements after sleep or deficits after sleep disturbance. Neuromodulators have been proposed as possible players in this putative off-line memory processing, without much experimental evidence. We recorded neuronal activity in the rat noradrenergic nucleus locus coeruleus (LC) using chronically implanted movable microelectrodes while monitoring the behavioral state via electrocorticogram and online video recording. Extracellular recordings of physiologically identified noradrenergic neurons of LC were made in freely behaving rats for 3 h before and after olfactory discrimination learning. On subsequent days, if LC recording remained stable, additional learning sessions were made within the olfactory discrimination protocol, including extinction, reversals, learning new odors. Contrary to the long-standing dogma about the quiescence of noradrenergic neurons of LC, we found a transient increase in LC activity in trained rats during slow wave sleep (SWS) 2 h after learning. The discovery of learning-dependent engagement of LC neurons during SWS encourages exploration of brain stem–cortical interaction during this delayed phase of memory consolidation and should bring new insights into mechanisms underlying memory formation.

Astrocytes Discriminate and Selectively Respond to the Activity of a Subpopulation of Neurons within the Barrel Cortex

Schipke, C. G., Haas, B., Kettenmann, H. — 2008-03-04

Sensory information from single whiskers in rodents projects to defined morphological units in the cortex, the barrels. We found that astrocytes selectively respond with an increase in the cytosolic Ca²⁺ concentration to activation of layer 4 neurons, the input cells of the barrel columns. The neuronal Ca²⁺ signal also spread across barrel column borders mainly in layer 2/3, but the glutamate-mediated astrocyte response stayed restricted to the barrel column. In contrast, when interfering with inhibitory pathways by blocking either purinergic, adenosine or -aminobutyric acid_A receptors, the stimulation activated a Ca²⁺ response in a much larger astrocyte population no longer restricted to the borders of the barrel column. We also observed spontaneous and evoked Ca²⁺ activity in the synaptic target cells of layer 4 neurons, the layer 2/3 pyramidal cells, but again, we never recorded Ca²⁺ responses in astrocytes following activity in this neuronal population. Our data show that astrocytes can discriminate and selectively respond to the activity of a subpopulation of excitatory neurons within a given brain region. This selectivity in the astrocyte response describes a new level of complexity and integration in the reaction of astrocytes to neuronal activity.

The Spatial Attention Network Interacts with Limbic and Monoaminergic Systems to Modulate Motivation-Induced Attention Shifts

Mohanty, A., Gitelman, D. R., Small, D. M., Mesulam, M. M. — 2008-02-27

How does the human brain integrate information from multiple domains to guide spatial attention according to motivational needs? To address this question, we measured hemodynamic responses to central cues predicting locations of peripheral attentional targets (food or tool images) in a novel covert spatial attention paradigm. The motivational relevance of food-related attentional targets was experimentally manipulated via hunger and satiety. Amygdala, posterior cingulate, locus coeruleus, and substantia nigra showed selective sensitivity to food-related cues when hungry but not when satiated, an effect that did not generalize to tools. Posterior parietal cortex (PPC), including intraparietal sulcus, posterior cingulate, and the orbitofrontal cortex displayed correlations with the speed of attentional shifts that were sensitive not just to motivational state but also to the motivational value of the target. Stronger functional coupling between PPC and posterior cingulate occurred during attentional biasing toward motivationally relevant food targets. These results reveal conjoint limbic and monoaminergic encoding of motivational salience in spatial attention. They emphasize the interactive role of posterior parietal and cingulate cortices in integrating motivational information with spatial attention, a process that is critical for selective allocation of attentional resources in an environment where target position and relevance can change rapidly.

Cytoarchitecture and Transcriptional Profiles of Neocortical Malformations in Inbred Mice

Ramos, R. L., Smith, P. T., DeCola, C., Tam, D., Corzo, O., Brumberg, J. C. — 2008-02-27

Malformations of neocortical development are associated with cognitive dysfunction and increased susceptibility to epileptogenesis. Rodent models are widely used to study neocortical malformations and have revealed important genetic and environmental mechanisms that contribute to neocortical development. Interestingly, several inbred mice strains commonly used in behavioral, anatomical, and/or physiological studies display neocortical malformations. In the present report we examine the cytoarchitecture and myeloarchitecture of the neocortex of 11 inbred mouse strains and identified malformations of cortical development, including molecular layer heterotopia, in all but one strain. We used in silico methods to confirm our observations and determined the transcriptional profiles of cells found within heterotopia. These data indicate cellular and transcriptional diversity present in cells in malformations. Furthermore, the presence of dysplasia in nearly every inbred strain examined suggests that malformations of neocortical development are a common feature in the neocortex of inbred mice.

Semantic Adaptation and Competition during Word Comprehension

Bedny, M., McGill, M., Thompson-Schill, S. L. — 2008-02-27

Word comprehension engages the left ventrolateral prefrontal (lVLPFC) and posterior lateral-temporal cortices (PLTC). The contributions of these brain regions to comprehension remain controversial. We hypothesized that the PLTC activates meanings, whereas the lVLPFC resolves competition between representations. To test this hypothesis, we used functional magnetic resonance imaging (fMRI) to assess the independent effects of adaptation and competition on neural activity. Participants judged the relatedness of word pairs. Some consecutive pairs contained a common ambiguous word. The same or different meanings of this word were primed (e.g., SUMMER-FAN, CEILING-FAN; ADMIRER-FAN, CEILING-FAN). Based on the logic of fMRI adaptation, trials with more semantic overlap should produce more adaptation (less activation) in regions that activate meaning. In contrast, trials with more semantic ambiguity should produce more activation in regions that resolve competition. We observed a double dissociation between activity in the PLTC and lVLPFC. LPLTC activity depended on the amount of semantic overlap, irrespective of the amount of semantic ambiguity. In contrast, lVLPFC activity depended on the amount of semantic ambiguity. Moreover, across participants the size of the competition effect as measured by errors was correlated with the size of the competition effect in the lVLPFC. We conclude that the lVLPFC is an executive mechanism within language processing.