Synchronization between prefrontal and posterior association cortex during human working memory

We measured coherence between the electroencephalogram at different scalp sites while human subjects performed delayed response tasks. The tasks required the retention of either verbalizable strings of characters or abstract line drawings. In both types of tasks, a significant enhancement in coherence in the θ range (4–7 Hz) was found between prefrontal and posterior electrodes during 4-s retention intervals. During 6-s perception intervals, far fewer increases in θ coherence were found. Also in other frequency bands, coherence increased; however, the patterns of enhancement made a relevance for working memory processes seem unlikely. Our results suggest that working memory involves synchronization between prefrontal and posterior association cortex by phase-locked, low frequency (4–7 Hz) brain activity.

Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias

The cortex of the brain is organized into clear horizontal layers, laminae, which subserve much of the connectional anatomy of the brain. We hypothesize that there is also a vertical anatomical organization that might subserve local interactions of neuronal functional units, in accord with longstanding electrophysiological observations. We develop and apply a general quantitative method, inspired by analogous methods in condensed matter physics, to examine the anatomical organization of the cortex in human brain. We find, in addition to obvious laminae, anatomical evidence for tightly packed microcolumnar ensembles containing approximately 11 neurons, with a periodicity of about 80 μm. We examine the structural integrity of this new architectural feature in two common dementing illnesses, Alzheimer disease and dementia with Lewy bodies. In Alzheimer disease, there is a dramatic, nearly complete loss of microcolumnar ensemble organization. The relative degree of loss of microcolumnar ensembles is directly proportional to the number of neurofibrillary tangles, but not related to the amount of amyloid-β deposition. In dementia with Lewy bodies, a similar disruption of microcolumnar ensemble architecture occurs despite minimal neuronal loss. These observations show that quantitative analysis of complex cortical architecture can be applied to analyze the anatomical basis of brain disorders.

Réorganisation fonctionnelle et structurale des cortex auditifs, visuels et associatifs chez les sourds profonds congénitaux ou prélinguaux

En raison de l’utilisation d’un mode de communication totalement différent de celui des entendants, le langage des signes, et de l’absence quasi-totale d’afférences en provenance du système auditif, il y a de fortes chances que d’importantes modifications fonctionnelles et structurales s’effectuent dans le cerveau des individus sourds profonds. Les études antérieures suggèrent que cette réorganisation risque d’avoir des répercussions plus importantes sur les structures corticales situées le long de la voie visuelle dorsale qu’à l’intérieur de celles situées à l’intérieur de la voie ventrale. L’hypothèse proposée par Ungerleider et Mishkin (1982) quant à la présence de deux voies visuelles dans les régions occipitales, même si elle demeure largement acceptée dans la communauté scientifique, s’en trouve aussi relativement contestée. Une voie se projetant du cortex strié vers les régions pariétales postérieures, est impliquée dans la vision spatiale, et l’autre se projetant vers les régions du cortex temporal inférieur, est responsable de la reconnaissance de la forme. Goodale et Milner (1992) ont par la suite proposé que la voie dorsale, en plus de son implication dans le traitement de l’information visuo-spatiale, joue un rôle dans les ajustements sensori-moteurs nécessaires afin de guider les actions. Dans ce contexte, il est tout à fait plausible de considérer qu’un groupe de personne utilisant un langage sensori-moteur comme le langage des signes dans la vie de tous les jours, s’expose à une réorganisation cérébrale ciblant effectivement la voie dorsale. L’objectif de la première étude est d’explorer ces deux voies visuelles et plus particulièrement, la voie dorsale, chez des individus entendants par l’utilisation de deux stimuli de mouvement dont les caractéristiques physiques sont très similaires, mais qui évoquent un traitement relativement différent dans les régions corticales visuelles. Pour ce faire, un stimulus de forme définie par le mouvement et un stimulus de mouvement global ont été utilisés. Nos résultats indiquent que les voies dorsale et ventrale procèdent au traitement d’une forme définie par le mouvement, tandis que seule la voie dorsale est activée lors d’une tâche de mouvement global dont les caractéristiques psychophysiques sont relativement semblables. Nous avons utilisé, subséquemment, ces mêmes stimulations activant les voies dorsales et ventrales afin de vérifier quels pourraient être les différences fonctionnelles dans les régions visuelles et auditives chez des individus sourds profonds. Plusieurs études présentent la réorganisation corticale dans les régions visuelles et auditives en réponse à l’absence d’une modalité sensorielle. Cependant, l’implication spécifique des voies visuelles dorsale et ventrale demeure peu étudiée à ce jour, malgré plusieurs résultats proposant une implication plus importante de la voie dorsale dans la réorganisation visuelle chez les sourds. Suite à l’utilisation de l’imagerie cérébrale fonctionnelle pour investiguer ces questions, nos résultats ont été à l’encontre de cette hypothèse suggérant une réorganisation ciblant particulièrement la voie dorsale. Nos résultats indiquent plutôt une réorganisation non-spécifique au type de stimulation utilisé. En effet, le gyrus temporal supérieur est activé chez les sourds suite à la présentation de toutes nos stimulations visuelles, peu importe leur degré de complexité. Le groupe de participants sourds montre aussi une activation du cortex associatif postérieur, possiblement recruté pour traiter l’information visuelle en raison de l’absence de compétition en provenance des régions temporales auditives. Ces résultats ajoutent aux données déjà recueillies sur les modifications fonctionnelles qui peuvent survenir dans tout le cerveau des personnes sourdes, cependant les corrélats anatomiques de la surdité demeurent méconnus chez cette population. Une troisième étude se propose donc d’examiner les modifications structurales pouvant survenir dans le cerveau des personnes sourdes profondes congénitales ou prélinguales. Nos résultats montrent que plusieurs régions cérébrales semblent être différentes entre le groupe de participants sourds et celui des entendants. Nos analyses ont montré des augmentations de volume, allant jusqu’à 20%, dans les lobes frontaux, incluant l’aire de Broca et d’autres régions adjacentes impliqués dans le contrôle moteur et la production du langage. Les lobes temporaux semblent aussi présenter des différences morphométriques même si ces dernières ne sont pas significatives. Enfin, des différences de volume sont également recensées dans les parties du corps calleux contenant les axones permettant la communication entre les régions temporales et occipitales des deux hémisphères.

Mitempfindung in synaesthetes: co-incidence or meaningful association?

Mitempfindung is the referral of a tactile sensation to a location far away from the stimulation site. This brief note reports a 40% incidence of Mitempfindung in a sample of 20 digit-color synaesthetes which contrasts with a 10% incidence in two control groups of non-synaesthetes. Phenomenological similarities between Mitempfindung and synaesthesia are discussed, and we propose that an erratic neural connectivity underlies both phenomena. To better characterize the nature of the purported neurophysiological peculiarities, prospective studies are needed that characterize Mitempfindung in synaesthetes and nonsynaesthetes.

Neocortical maturation during adolescence: change in neuronal soma dimension.

During adolescence, cognitive abilities increase robustly. To search for possible related structural alterations of the cerebral cortex, we measured neuronal soma dimension (NSD = width times height), cortical thickness and neuronal densities in different types of neocortex in post-mortem brains of five 12-16 and five 17-24 year-olds (each 2F, 3M). Using a generalized mixed model analysis, mean normalized NSD comparing the age groups shows layer-specific change for layer 2 (p < .0001) and age-related differences between categorized type of cortex: primary/primary association cortex (BA 1, 3, 4, and 44) shows a generalized increase; higher-order regions (BA 9, 21, 39, and 45) also show increase in layers 2 and 5 but decrease in layers 3, 4, and 6 while limbic/orbital cortex (BA 23, 24, and 47) undergoes minor decrease (BA 1, 3, 4, and 44 vs. BA 9, 21, 39, and 45: p = .036 and BA 1, 3, 4, and 44 vs. BA 23, 24, and 47: p = .004). These data imply the operation of cortical layer- and type-specific processes of growth and regression adding new evidence that the human brain matures during adolescence not only functionally but also structurally.

Regional and cellular gene expression changes in human Huntington's disease brain.

Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.

Topographic abnormality of slow cortical potentials in schizophrenia

A recent study from our laboratory has provided evidence for the generation of slow potentials occurring in anticipation to task-performance feedback stimuli, in multiple association cortical areas, consistently including two prefrontal areas. In the present study, we intended to determine whether these slow potentials would indicate some abnormality (topographic) in schizophrenic patients, and thus serve as an indication of abnormal association cortex activity. We recorded slow potentials while subjects performed a paired-associates memory task. A 123-channel EEG montage and common average reference were used for 20 unmedicated schizophrenic (mean duration of illness: 11.3 ± 9.2 years; mean number of previous hospitalizations: 1.2 ± 1.9) and 22 healthy control subjects during a visual paired-associates matching task. For the topographic analysis, we used a simple index of individual topographic deviation from normality, corrected for absolute potential intensities. Slow potentials were observed in all subjects. Control subjects showed a simple spatial pattern of voltage extrema (left central positive and right prefrontal negative), whereas schizophrenic patients presented a more complex, fragmented pattern. Topographic deviation was significantly different between groups (P < 0.001). The increased topographic complexity in schizophrenics could be visualized in grand averages computed across subjects. Increased topographic complexity could also be seen when grand averages were computed for subgroups of patients assembled either according to task-performance (high versus low) or by their scores on psychopathological scales. There was no significant correlation between topographic deviation and psychopathology scores. We conclude that the slow potential topographic abnormalities of schizophrenia indicate an abnormality in the configuration of large-scale electrical activity in association cortices.

N-methyl-D-aspartate channel and consciousness: From signal coincidence detection to quantum computing

Research on Blindsight, Neglect/Extinction and Phantom limb syndromes, as well as electrical measurements of mammalian brain activity, have suggested the dependence of vivid perception on both incoming sensory information at primary sensory cortex and reentrant information from associative cortex. Coherence between incoming and reentrant signals seems to be a necessary condition for (conscious) perception. General reticular activating system and local electrical synchronization are some of the tools used by the brain to establish coarse coherence at the sensory cortex, upon which biochemical processes are coordinated. Besides electrical synchrony and chemical modulation at the synapse, a central mechanism supporting such a coherence is the N-methyl-D-aspartate channel, working as a 'coincidence detector' for an incoming signal causing the depolarization necessary to remove Mg 2+, and reentrant information releasing the glutamate that finally prompts Ca 2+ entry. We propose that a signal transduction pathway activated by Ca 2+ entry into cortical neurons is in charge of triggering a quantum computational process that accelerates inter-neuronal communication, thus solving systemic conflict and supporting the unity of consciousness. © 2001 Elsevier Science Ltd.

Toward an Explanation of the Genesis of Ketamine-Induced Perceptual Distortions and Hallucinatory States

The NMDA receptor (NMDAR) channel has been proposed to function as a coincidence-detection mechanism for afferent and reentrant signals, supporting conscious perception, learning, and memory formation. In this paper we discuss the genesis of distorted perceptual states induced by subanesthetic doses of ketamine, a well-known NMDA antagonist. NMDAR blockage has been suggested to perturb perceptual processing in sensory cortex, and also to decrease GABAergic inhibition in limbic areas (leading to an increase in dopamine excitability). We propose that perceptual distortions and hallucinations induced by ketamine blocking of NMDARs are generated by alternative signaling pathways, which include increase of excitability in frontal areas, and glutamate binding to AMPA in sensory cortex prompting Ca++ entry through voltage-dependent calcium channels (VDCCs). This mechanism supports the thesis that glutamate binding to AMPA and NMDARs at sensory cortex mediates most normal perception, while binding to AMPA and activating VDCCs mediates some types of altered perceptual states. We suggest that Ca++ metabolic activity in neurons at associative and sensory cortices is an important factor in the generation of both kinds of perceptual consciousness.

Análise comparativa dos padrões neurodegenerativos da substância cinzenta em diferentes áreas corticais de ratos adultos submetidos à lesão isquêmica focal

O acidente vascular encefálico (AVE) pode ocorrer em qual região do Sistema Nervoso Central (SNC), sendo o córtex cerebral é uma das regiões mais frequentemente afetadas por essa desordem neural aguda, embora inexistam investigações que tenham comparado o padrão lesivo em diferentes regiões corticais após isquemia focal de mesma intensidade. O objetivo desta investigação foi avaliar o padrão degenerativo de diferentes áreas corticais após lesão isquêmica focal. Para isso, induziu-se isquemia focal por microinjeções estereotáxicas de endotelina-1 (ET-1) nos córtices somestésico, motor e de associação de ratos adultos (N=45). Nos animais controle injetou-se o mesmo volume de solução salina estéril (N=27). Os animais foram perfundidos 1, 3, e 7 dias após o evento isquêmico. O encéfalo foi removido, pós-fixado, crioprotegido e seccionado em criostato. A histopatologia geral foi avaliada em secções de 50 coradas pela violeta de cresila. Secções de 20μm foram submetidas à imunoistoquímica para marcação de astrócitos (anti-GFAP), micróglia/macrófagos ativados (anti-ED1) e microglia em geral (anti-Iba1). Avaliou-se os padrões lesivos qualitativamente (por inspeção em microscópio óptico) e quantitativamente (pela contagem do número de células nos lados ipsi e contralateral à lesão), pela estatística descritiva e comparações intra e intergrupos com análise de variância com correção a posteriori de Tukey. Os animais isquêmicos apresentaram conspícua perda tecidual, ativação microglial e astrocitose entre 3 e 7 dias após a indução isquêmica, o que não foi observado nos animais controle. A perda tecidual e a ativação de células gliais foram mais intensas no córtex somestésico, depois no córtex motor, com intensidade reduzida na área de associação, o que foi confirmado por análise quantitativa. Os resultados sugerem que uma lesão isquêmica de mesma intensidade induz um padrão diferencial de perda tecidual e neuroinflamação, dependendo da área cortical, e que as áreas sensoriais primárias e motoras são mais susceptíveis ao processo isquêmico do que áreas de associação.

Development of a novel fMRI compatible visual perception prototype battery to test older people with and without dementia

Background: Visuoperceptual deficits in dementia are common and can reduce quality of life. Testing of visuoperceptual function is often confounded by impairments in other cognitive domains and motor dysfunction. We aimed to develop, pilot, and test a novel visuocognitive prototype test battery which addressed these issues, suitable for both clinical and functional imaging use. Methods: We recruited 23 participants (14 with dementia, 6 of whom had extrapyramidal motor features, and 9 age-matched controls). The novel Newcastle visual perception prototype battery (NEVIP-B-Prototype) included angle, color, face, motion and form perception tasks, and an adapted response system. It allows for individualized task difficulties. Participants were tested outside and inside the 3T functional magnetic resonance imaging (fMRI) scanner. Functional magnetic resonance imaging data were analyzed using SPM8. Results: All participants successfully completed the task inside and outside the scanner. Functional magnetic resonance imaging analysis showed activation regions corresponding well to the regional specializations of the visual association cortex. In both groups, there was significant activity in the ventral occipital-temporal region in the face and color tasks, whereas the motion task activated the V5 region. In the control group, the angle task activated the occipitoparietal cortex. Patients and controls showed similar levels of activation, except on the angle task for which occipitoparietal activation was lower in patients than controls. Conclusion: Distinct visuoperceptual functions can be tested in patients with dementia and extrapyramidal motor features when tests use individualized thresholds, adapted tasks, and specialized response systems.

When that tune runs through your head: A PET investigation of auditory imagery for familiar melodies

The present study used positron emission tomography (PET) to examine the cerebral activity pattern associated with auditory imagery forfamiliar tunes. Subjects either imagined the continuation of nonverbaltunes cued by their first few notes, listened to a short sequence of notesas a control task, or listened and then reimagined that short sequence. Subtraction of the activation in the control task from that in the real-tune imagery task revealed primarily right-sided activation in frontal and superior temporal regions, plus supplementary motor area(SMA). Isolating retrieval of the real tunes by subtracting activation in the reimagine task from that in the real-tune imagery task revealedactivation primarily in right frontal areas and right superior temporal gyrus. Subtraction of activation in the control condition from that in the reimagine condition, intended to capture imagery of unfamiliarsequences, revealed activation in SMA, plus some left frontal regions. We conclude that areas of right auditory association cortex, together with right and left frontal cortices, are implicated in imagery for familiartunes, in accord with previous behavioral, lesion and PET data. Retrieval from musical semantic memory is mediated by structures in the right frontal lobe, in contrast to results from previous studies implicating left frontal areas for all semantic retrieval. The SMA seems to be involved specifically in image generation, implicating a motor code in this process.

When that tune runs through your head: a PET investigation of auditory imagery for familiar melodies

The present study used positron emission tomography (PET) to examine the cerebral activity pattern associated with auditory imagery for familiar tunes. Subjects either imagined the continuation of nonverbal tunes cued by their first few notes, listened to a short sequence of notes as a control task, or listened and then reimagined that short sequence. Subtraction of the activation in the control task from that in the real-tune imagery task revealed primarily right-sided activation in frontal and superior temporal regions, plus supplementary motor area (SMA). Isolating retrieval of the real tunes by subtracting activation in the reimagine task from that in the real-tune imagery task revealed activation primarily in right frontal areas and right superior temporal gyrus. Subtraction of activation in the control condition from that in the reimagine condition, intended to capture imagery of unfamiliar sequences, revealed activation in SMA, plus some left frontal regions. We conclude that areas of right auditory association cortex, together with right and left frontal cortices, are implicated in imagery for familiar tunes, in accord with previous behavioral, lesion and PET data. Retrieval from musical semantic memory is mediated by structures in the right frontal lobe, in contrast to results from previous studies implicating left frontal areas for all semantic retrieval. The SMA seems to be involved specifically in image generation, implicating a motor code in this process.

Tracking the Flow of Information through the Hippocampal Formation in the Rat

The hippocampus receives input from upper levels of the association cortex and is implicated in many mnemonic processes, but the exact mechanisms by which it codes and stores information is an unresolved topic. This work examines the flow of information through the hippocampal formation while attempting to determine the computations that each of the hippocampal subfields performs in learning and memory. The formation, storage, and recall of hippocampal-dependent memories theoretically utilize an autoassociative attractor network that functions by implementing two competitive, yet complementary, processes. Pattern separation, hypothesized to occur in the dentate gyrus (DG), refers to the ability to decrease the similarity among incoming information by producing output patterns that overlap less than the inputs. In contrast, pattern completion, hypothesized to occur in the CA3 region, refers to the ability to reproduce a previously stored output pattern from a partial or degraded input pattern. Prior to addressing the functional role of the DG and CA3 subfields, the spatial firing properties of neurons in the dentate gyrus were examined. The principal cell of the dentate gyrus, the granule cell, has spatially selective place fields; however, the behavioral correlates of another excitatory cell, the mossy cell of the dentate polymorphic layer, are unknown. This report shows that putative mossy cells have spatially selective firing that consists of multiple fields similar to previously reported properties of granule cells. Other cells recorded from the DG had single place fields. Compared to cells with multiple fields, cells with single fields fired at a lower rate during sleep, were less likely to burst, and were more likely to be recorded simultaneously with a large population of neurons that were active during sleep and silent during behavior. These data suggest that single-field and multiple-field cells constitute at least two distinct cell classes in the DG. Based on these characteristics, we propose that putative mossy cells tend to fire in multiple, distinct locations in an environment, whereas putative granule cells tend to fire in single locations, similar to place fields of the CA1 and CA3 regions. Experimental evidence supporting the theories of pattern separation and pattern completion comes from both behavioral and electrophysiological tests. These studies specifically focused on the function of each subregion and made implicit assumptions about how environmental manipulations changed the representations encoded by the hippocampal inputs. However, the cell populations that provided these inputs were in most cases not directly examined. We conducted a series of studies to investigate the neural activity in the entorhinal cortex, dentate gyrus, and CA3 in the same experimental conditions, which allowed a direct comparison between the input and output representations. The results show that the dentate gyrus representation changes between the familiar and cue altered environments more than its input representations, whereas the CA3 representation changes less than its input representations. These findings are consistent with longstanding computational models proposing that (1) CA3 is an associative memory system performing pattern completion in order to recall previous memories from partial inputs, and (2) the dentate gyrus performs pattern separation to help store different memories in ways that reduce interference when the memories are subsequently recalled.

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.