Representation of motor habit in a sequence of repetitive reach and grasp movements performed by macaque monkeys: evidence for a contribution of the dorsolateral prefrontal cortex.

In the context of an autologous cell transplantation study, a unilateral biopsy of cortical tissue was surgically performed from the right dorsolateral prefrontal cortex (dlPFC) in two intact adult macaque monkeys (dlPFC lesioned group), together with the implantation of a chronic chamber providing access to the left motor cortex. Three other monkeys were subjected to the same chronic chamber implantation, but without dlPFC biopsy (control group). All monkeys were initially trained to perform sequential manual dexterity tasks, requiring precision grip. The motor performance and the prehension's sequence (temporal order to grasp pellets from different spatial locations) were analysed for each hand. Following the surgery, transient and moderate deficits of manual dexterity per se occurred in both groups, indicating that they were not due to the dlPFC lesion (most likely related to the recording chamber implantation and/or general anaesthesia/medication). In contrast, changes of motor habit were observed for the sequential order of grasping in the two monkeys with dlPFC lesion only. The changes were more prominent in the monkey subjected to the largest lesion, supporting the notion of a specific effect of the dlPFC lesion on the motor habit of the monkeys. These observations are reminiscent of previous studies using conditional tasks with delay that have proposed a specialization of the dlPFC for visuo-spatial working memory, except that this is in a different context of "free-will", non-conditional manual dexterity task, without a component of working memory.

Differential subcellular localization of phosphorylated neurofilament and tau proteins in degenerating neurons of the human entorhinal cortex.

A panel of novel monoclonal antibodies was tested on the human entorhinal cortex for the recognition of age- and disease-related changes of neurofilament proteins (NF). Several antibodies identified phosphorylated NF-H subunit, which occurred preferentially in those aged between 60 and 80 years and were localized in degenerating neurons. Such neurons also contained neurofibrillary tangles, but neurofilament aggregates did not co-localize with tangles, nor did the quantity nor the number of NF-positive neurons correlate with the severity of Alzheimer's disease. This points to a susceptibility of NF in a subset of neurons for phosphorylation- and metabolically related morphological changes during neurodegeneration.

Human Primary Auditory Cortex Follows the Shape of Heschl's Gyrus.

The primary auditory cortex (PAC) is central to human auditory abilities, yet its location in the brain remains unclear. We measured the two largest tonotopic subfields of PAC (hA1 and hR) using high-resolution functional MRI at 7 T relative to the underlying anatomy of Heschl's gyrus (HG) in 10 individual human subjects. The data reveals a clear anatomical-functional relationship that, for the first time, indicates the location of PAC across the range of common morphological variants of HG (single gyri, partial duplications, and complete duplications). In 20/20 individual hemispheres, two primary mirror-symmetric tonotopic maps were clearly observed with gradients perpendicular to HG. PAC spanned both divisions of HG in cases of partial and complete duplications (11/20 hemispheres), not only the anterior division as commonly assumed. Specifically, the central union of the two primary maps (the hA1-R border) was consistently centered on the full Heschl's structure: on the gyral crown of single HGs and within the sulcal divide of duplicated HGs. The anatomical-functional variants of PAC appear to be part of a continuum, rather than distinct subtypes. These findings significantly revise HG as a marker for human PAC and suggest that tonotopic maps may have shaped HG during human evolution. Tonotopic mappings were based on only 16 min of fMRI data acquisition, so these methods can be used as an initial mapping step in future experiments designed to probe the function of specific auditory fields.

von Economo neurons in autism: A stereologic study of the frontoinsular cortex in children.

The presence of von Economo neurons (VENs) in the frontoinsular cortex (FI) has been linked to a possible role in the integration of bodily feelings, emotional regulation, and goal-directed behaviors. They have also been implicated in fast intuitive evaluation of complex social situations. Several studies reported a decreased number of VENs in neuropsychiatric diseases in which the "embodied" dimension of social cognition is markedly affected. Neuropathological analyses of VENs in patients with autism are few and did not report alterations in VEN numbers. In this study we re-evaluated the possible presence of changes in VEN numbers and their relationship with the diagnosis of autism. Using a stereologic approach we quantified VENs and pyramidal neurons in layer V of FI in postmortem brains of four young patients with autism and three comparably aged controls. We also investigated possible autism-related differences in FI layer V volume. Patients with autism consistently had a significantly higher ratio of VENs to pyramidal neurons (p=0.020) than control subjects. This result may reflect the presence of neuronal overgrowth in young patients with autism and may also be related to alterations in migration, cortical lamination, and apoptosis. Higher numbers of VENs in the FI of patients with autism may also underlie a heightened interoception, described in some clinical observations.

Effects of unilateral motor cortex lesion on ipsilesional hand's reach and grasp performance in monkeys: relationship with recovery in the contralesional hand.

Manual dexterity, a prerogative of primates, is under the control of the corticospinal (CS) tract. Because 90-95% of CS axons decussate, it is assumed that this control is exerted essentially on the contralateral hand. Consistently, unilateral lesion of the hand representation in the motor cortex is followed by a complete loss of dexterity of the contralesional hand. During the months following lesion, spontaneous recovery of manual dexterity takes place to a highly variable extent across subjects, although largely incomplete. In the present study, we tested the hypothesis that after a significant postlesion period, manual performance in the ipsilesional hand is correlated with the extent of functional recovery in the contralesional hand. To this aim, ten adult macaque monkeys were subjected to permanent unilateral motor cortex lesion. Monkeys' manual performance was assessed for each hand during several months postlesion, using our standard behavioral test (modified Brinkman board task) that provides a quantitative measure of reach and grasp ability. The ipsilesional hand's performance was found to be significantly enhanced over the long term (100-300 days postlesion) in six of ten monkeys, with the six exhibiting the best, though incomplete, recovery of the contralesional hand. There was a statistically significant correlation (r = 0.932; P < 0.001) between performance in the ipsilesional hand after significant postlesion period and the extent of recovery of the contralesional hand. This observation is interpreted in terms of different possible mechanisms of recovery, dependent on the recruitment of motor areas in the lesioned and/or intact hemispheres.

Functional mapping of the human visual cortex with intravoxel incoherent motion MRI.

Functional imaging with intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) is demonstrated. Images were acquired at 3 Tesla using a standard Stejskal-Tanner diffusion-weighted echo-planar imaging sequence with multiple b-values. Cerebro-spinal fluid signal, which is highly incoherent, was suppressed with an inversion recovery preparation pulse. IVIM microvascular perfusion parameters were calculated according to a two-compartment (vascular and non-vascular) diffusion model. The results obtained in 8 healthy human volunteers during visual stimulation are presented. The IVIM blood flow related parameter fD* increased 170% during stimulation in the visual cortex, and 70% in the underlying white matter.

GABA receptor subunits in human auditory cortex in normal and stroke cases.

GABA receptors are ubiquitous in the cerebral cortex and play a major role in shaping responses of cortical neurons. GABAA and GABAB receptor subunit expression was visualized by immunohistochemistry in human auditory areas from both hemispheres in 9 normal subjects (aged 43-85 years; time between death and fixation 6-24 hours) and in 4 stroke patients (aged 59-87 years; time between death and fixation 7-24 hours) and analyzed qualitatively for GABAA and semiquantitatively for GABAB receptor subunits. In normal brains, the primary auditory area (TC) and the surrounding areas TB and TA displayed distinct GABAA receptor subunit labeling with differences among cortical layers and areas. In postacute and chronic stroke we found a layer-selective downregulation of the alpha-2 subunit in the anatomically intact cerebral cortex of the intact and of the lesioned hemisphere, whereas the alpha-1, alpha-3 and beta-2/3 subunits maintained normal levels of expression. The GABAB receptors had a distinct laminar pattern in auditory areas and minor differences among areas. Unlike in other pathologies, there is no modulation of the GABAB receptor expression in subacute or chronic stroke.

Multisensory mechanisms in temporo-parietal cortex support self-location and first-person perspective.

Self-consciousness has mostly been approached by philosophical enquiry and not by empirical neuroscientific study, leading to an overabundance of diverging theories and an absence of data-driven theories. Using robotic technology, we achieved specific bodily conflicts and induced predictable changes in a fundamental aspect of self-consciousness by altering where healthy subjects experienced themselves to be (self-location). Functional magnetic resonance imaging revealed that temporo-parietal junction (TPJ) activity reflected experimental changes in self-location that also depended on the first-person perspective due to visuo-tactile and visuo-vestibular conflicts. Moreover, in a large lesion analysis study of neurological patients with a well-defined state of abnormal self-location, brain damage was also localized at TPJ, providing causal evidence that TPJ encodes self-location. Our findings reveal that multisensory integration at the TPJ reflects one of the most fundamental subjective feelings of humans: the feeling of being an entity localized at a position in space and perceiving the world from this position and perspective.

Activity in inferior parietal and medial prefrontal cortex signals the accumulation of evidence in a probability learning task.

In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes.

Distribution of the monocarboxylate transporter MCT2 in human cerebral cortex: an immunohistochemical study

The monocarboxylate transporter MCT2 belongs to a large family of membrane proteins involved in the transport of lactate, pyruvate and ketone bodies. Although its expression in rodent brain has been well documented, the presence of MCT2 in the human brain has been questioned on the basis of low mRNA abundance. In this study, the distribution of the monocarboxylate transporter MCT2 has been investigated in the cortex of normal adult human brain using an immunohistochemical approach. Widespread neuropil staining in all cortical layers was observed by light microscopy. Such a distribution was very similar in three different cortical areas investigated. At the cellular level, the expression of MCT2 could be observed in a large number of neurons, in fibers both in grey and white matter, as well as in some astrocytes, mostly localized in layer I and in the white matter. Double staining experiments combined with confocal microscopy confirmed the neuronal expression but also suggested a preferential postsynaptic localization of synaptic MCT2 expression. A few astrocytes in the grey matter appeared to exhibit MCT2 labelling but at low levels. Electron microscopy revealed strong MCT2 expression at asymmetric synapses in the postsynaptic density and also within the spine head but not in the presynaptic terminal. These data not only demonstrate neuronal MCT2 expression in human, but since a portion of it exhibits a distinct synaptic localization, it further supports a putative role for MCT2 in adjustment of energy supply to levels of activity.

Reduction of the hand representation in the ipsilateral primary motor cortex following unilateral section of the corticospinal tract at cervical level in monkeys.

BACKGROUND: After sub-total hemi-section of cervical cord at level C7/C8 in monkeys, the ipsilesional hand exhibited a paralysis for a couple of weeks, followed by incomplete recovery of manual dexterity, reaching a plateau after 40-50 days. Recently, we demonstrated that the level of the plateau was related to the size of the lesion and that progressive plastic changes of the motor map in the contralesional motor cortex, particularly the hand representation, took place following a comparable time course. The goal of the present study was to assess, in three macaque monkeys, whether the hand representation in the ipsilesional primary motor cortex (M1) was also affected by the cervical hemi-section.¦RESULTS: Unexpectedly, based on the minor contribution of the ipsilesional hemisphere to the transected corticospinal (CS) tract, a considerable reduction of the hand representation was also observed in the ipsilesional M1. Mapping control experiments ruled out the possibility that changes of motor maps are due to variability of the intracortical microstimulation mapping technique. The extent of the size reduction of the hand area was nearly as large as in the contralesional hemisphere in two of the three monkeys. In the third monkey, it represented a reduction by a factor of half the change observed in the contralesional hemisphere. Although the hand representation was modified in the ipsilesional hemisphere, such changes were not correlated with a contribution of this hemisphere to the incomplete recovery of the manual dexterity for the hand affected by the lesion, as demonstrated by reversible inactivation experiments (in contrast to the contralesional hemisphere). Moreover, despite the size reduction of M1 hand area in the ipsilesional hemisphere, no deficit of manual dexterity for the hand opposite to the cervical hemi-section was detected.¦CONCLUSION: After cervical hemi-section, the ipsilesional motor cortex exhibited substantial reduction of the hand representation, whose extent did not match the small number of axotomized CS neurons. We hypothesized that the paradoxical reduction of hand representation in the ipsilesional hemisphere is secondary to the changes taking place in the contralesional hemisphere, possibly corresponding to postural adjustments and/or re-establishing a balance between the two hemispheres.

The expression of GABA receptors in the human auditory cortex

Abstract : GABA, the primary inhibitory neurotransmitter, and its receptors play an important role in modulating neuronal activity in the central nervous system and are implicated in many neurological disorders. In this study, GABAA and GABAB receptor subunit expression was visualized by immunohistochemistry in human auditory areas TC (= primary auditory area), TB, and TA. Both hemispheres from nine neurologically normal subjects and from four patients with subacute or chronic stroke were included. In normal brains, GABAA receptor subunit (α1, α2, & β2/3) labeling produced neuropil staining throughout all cortical layers as well as labeling fibers and neurons in layer VI for all auditory areas. Densitometry profiles displayed differences in GABAA subunit expression between primary and non-primary areas. In contrast to the neuropil labeling of GABAA subunits, GABAB1 and GABAB2 subunit immunoreactivity was revealed on neuronal somata and proximal dendritic shafts of pyramidal and non-pyramidal neurons in layers II-III, more strongly on supra- than in infragranular layers. No differences were observed between auditory areas. In stroke cases, we observed a downregulation of the GABAA receptor α2 subunit in granular and infragranular layers, while the other GABAA and the two GABAB receptor subunits remained unchanged. Our results demonstrate a strong presence of GABAA and GABAB receptors in the human auditory cortex, suggesting a crucial role of GABA in shaping auditory responses in the primary and non-primary auditory areas. The differential laminar and area expression of GABAA subunits that we have found in the auditory areas and which is partially different from that in other cortical areas speaks in favor of a fine turning of GABA-ergic transmission in these different compartments. In contrast, GABAB expression displayed laminar, but not areal differences; its basic pattern was also very similar to that of other cortical areas, suggesting a more uniform role within the cerebral cortex. In subacute and chronic stroke, the selective GABAA α2 subunit downregulation is likely to influence postlesional plasticity and susceptibility to medication. The absence of changes in the GABAB receptors suggests different regulation than in other pathological conditions, such as epilepsy, schizophrenia or bipolar disorder, in which a downregulation has been reported. Résumé : GABA, le principal neurotransmetteur inhibiteur, et ses récepteurs jouent un rôle important en tant que modulateur de l'activité neuronale dans le système nerveux central et sont impliqués dans de nombreux désordres neurologiques. Dans cette étude, l'expression des sous-unités des récepteur GABAA et GABAB a été visualisée par immunohistochimie dans les aires auditives du cortex humains: le TC (= aire auditif primaire), le TB, et le TA. Les deux hémisphères de neuf sujets considérés normaux du point de vue neurologique et de quatre patients ayant subis un accident cérébro-vasculaire et se trouvant dans la phase subaiguë ou chronique étaient inclues. Dans les cerveaux normaux, les immunohistochimies contre les sous-unités α1, α2, & β2/3 du récepteur GABAA ont marqué le neuropil dans toutes les couches corticales ainsi que les fibres et les neurones de la couche VI dans toutes les aires auditives. Le profile densitométrique montre des différences dans l'expression des sous-unités du récepteur GABAA entre les aires primaires et non-primaires. Contrairement au marquage de neuropil par les sous-unités du recepteur GABAA, 1'immunoréactivité des sous-unités GABAB1 et GABAB2 a été révélée sur les corps cellulaires neuronaux et les dendrites proximaux des neurones pyramidaux et non-pyramidaux dans les couches II-III et est plus dense dans les couches supragranulaires que dans les couches infragranulaires. Aucune différence n'a été observée entre les aires auditives. Dans des cas lésionnels, nous avons observé une diminution de la sous-unité α2 du récepteur GABAA dans les couches granulaires et infragranulaires, alors que le marquage des autres sous-unités du récepteur GABAA et des deux sous-unités de récepteur GABAB reste inchangé. Nos résultats démontrent une présence forte des récepteurs GABAA et GABAB dans le cortex auditif humain, suggérant un rôle crucial du neurotransmetteur GABA dans la formation de la réponse auditive dans les aires auditives primaires et non-primaires. L'expression différentielle des sous-unités de GABAA entre les couches corticales et entre les aires auditives et qui est partiellement différente de celle observée dans d'autres aires corticales préconise une modulation fine de la transmission GABA-ergic en ces différents compartiments. En revanche, l'expression de GABAB a montré des différences laminaires, mais non régionales ; son motif d'expression de base est également très semblable à celui d'autres aires corticales, suggérant un rôle plus uniforme dans le cortex cérébral. Dans les phases subaiguë et chronique des accidents cérébro-vasculaires, la diminution sélective de la sous-unité α2 du recepteur GABAA est susceptible d'influencer la plasticité et la susceptibilité postlésionnelle au médicament. L'absence de changement pour les récepteurs GABAB suggère que le récepteur est régulé différemment après un accident cerebro-vasculaire par rapport à d'autres conditions pathologiques, telles que l'épilepsie, la schizophrénie ou le désordre bipolaire, dans lesquels une diminution de ces sous-unités a été rapportée.

Quantifying network properties in multi-electrode recordings: spatiotemporal characterization and inter-trial variation of evoked gamma oscillations in mouse somatosensory cortex in vitro.

Linking the structural connectivity of brain circuits to their cooperative dynamics and emergent functions is a central aim of neuroscience research. Graph theory has recently been applied to study the structure-function relationship of networks, where dynamical similarity of different nodes has been turned into a "static" functional connection. However, the capability of the brain to adapt, learn and process external stimuli requires a constant dynamical functional rewiring between circuitries and cell assemblies. Hence, we must capture the changes of network functional connectivity over time. Multi-electrode array data present a unique challenge within this framework. We study the dynamics of gamma oscillations in acute slices of the somatosensory cortex from juvenile mice recorded by planar multi-electrode arrays. Bursts of gamma oscillatory activity lasting a few hundred milliseconds could be initiated only by brief trains of electrical stimulations applied at the deepest cortical layers and simultaneously delivered at multiple locations. Local field potentials were used to study the spatio-temporal properties and the instantaneous synchronization profile of the gamma oscillatory activity, combined with current source density (CSD) analysis. Pair-wise differences in the oscillation phase were used to determine the presence of instantaneous synchronization between the different sites of the circuitry during the oscillatory period. Despite variation in the duration of the oscillatory response over successive trials, they showed a constant average power, suggesting that the rate of expenditure of energy during the gamma bursts is consistent across repeated stimulations. Within each gamma burst, the functional connectivity map reflected the columnar organization of the neocortex. Over successive trials, an apparently random rearrangement of the functional connectivity was observed, with a more stable columnar than horizontal organization. This work reveals new features of evoked gamma oscillations in developing cortex.

Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia.

The neurochemical profile of the cortex develops in a region and time specific manner, which can be distorted by psychiatric and other neurological pathologies. Pre-clinical studies often involve experimental mouse models. In this study, we determined the neurochemical profile of C57BL/6 mice in a longitudinal study design to provide a reference frame for the normal developing mouse cortex. Using in vivo proton NMR spectroscopy at 14 T, we measured the concentrations of 18 metabolites in the anterior and posterior cortex on postnatal days (P) 10, 20, 30, 60 and 90. Cortical development was marked by alterations of highly concentrated metabolites, such as N-acetylaspartate, glutamate, taurine and creatine. Regional specificity was represented by early variations in the concentration of glutamine, aspartate and choline. In adult animals, regional concentration differences were found for N-acetylaspartate, creatine and myo-inositol. In this study, animals were exposed to recurrent isoflurane anaesthesia. Additional experiments showed that the latter was devoid of major effects on behaviour or cortical neurochemical profile. In conclusion, the high sensitivity and reproducibility of the measurements achieved at 14 T allowed us to identify developmental variations of cortical areas within the mouse cortex.

Sleep loss reduces the DNA-binding of BMAL1, CLOCK, and NPAS2 to specific clock genes in the mouse cerebral cortex.

We have previously demonstrated that clock genes contribute to the homeostatic aspect of sleep regulation. Indeed, mutations in some clock genes modify the markers of sleep homeostasis and an increase in homeostatic sleep drive alters clock gene expression in the forebrain. Here, we investigate a possible mechanism by which sleep deprivation (SD) could alter clock gene expression by quantifying DNA-binding of the core-clock transcription factors CLOCK, NPAS2, and BMAL1 to the cis-regulatory sequences of target clock genes in mice. Using chromatin immunoprecipitation (ChIP), we first showed that, as reported for the liver, DNA-binding of CLOCK and BMAL1 to target clock genes changes in function of time-of-day in the cerebral cortex. Tissue extracts were collected at ZT0 (light onset), -6, -12, and -18, and DNA enrichment of E-box or E'-box containing sequences was measured by qPCR. CLOCK and BMAL1 binding to Cry1, Dbp, Per1, and Per2 depended on time-of-day, with maximum values reached at around ZT6. We then observed that SD, performed between ZT0 and -6, significantly decreased DNA-binding of CLOCK and BMAL1 to Dbp, consistent with the observed decrease in Dbp mRNA levels after SD. The DNA-binding of NPAS2 and BMAL1 to Per2 was also decreased by SD, although SD is known to increase Per2 expression in the cortex. DNA-binding to Per1 and Cry1 was not affected by SD. Our results show that the sleep-wake history can affect the clock molecular machinery directly at the level of chromatin binding thereby altering the cortical expression of Dbp and Per2 and likely other targets. Although the precise dynamics of the relationship between DNA-binding and mRNA expression, especially for Per2, remains elusive, the results also suggest that part of the reported circadian changes in DNA-binding of core clock components in tissues peripheral to the suprachiasmatic nuclei could, in fact, be sleep-wake driven.