Comparative effects of topical perfusions of pentylenetetrazol in the mesencephalon and cerebral cortex of cats

Push-pull perfusions of pentylenetetrazol (PTZ) were carried out in the mesencephalon and cerebral cortex (orbitofrontal, motor, and suprasylvian) of “encéphale isolé” cats, while EEG recordings from motor cortices and EMG of facial muscles were obtained. There were significant differences between perfusions in the mesencephalic reticular formation (MRF) and in the cerebral cortex: (i) EEG spikes not accompanied by muscular contractions occurred during perfusion of cerebral cortex (motor cortex included), but never with perfusions in MRF. (ii) In some instances muscular tonic and clonic contractions occurred in the absence of EEG spikes when perfusing the mesencephalon, but never with cortical perfusions. (iii) Both MRF and cortical perfusions induced EEG spikes accompanied by myoclonic seizures; however, muscular seizures were practically of the same amplitude in both sides after perfusion of the MRF and were predominant in the contralateral side after cortical perfusions. In addition, significantly less perfusion time (total dose) of PTZ was needed to induce such events in the MRF than in the cerebral cortex. (iv) Generalized seizures induced by cortical perfusions showed a clear predominance of contractions in the muscles contralateral to the perfusion site, whereas perfusions in the MRF induced generalized seizures indistinguishable from those produced by i.v. administration of PTZ. Results suggest that PTZ generalized seizures, closely resembling the so called “primary generalized seizures,” result from activation of the MRF, whereas PTZ acting in the cerebral cortex produces a model of focal convulsions that may become secondarily generalized.     

Rapid modulation of GABA in sensorimotor cortex induced by acute deafferentation

Recovery of function after acute injury to the central nervous system may be controlled by the availability of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cerebral cortex. Acute lesions as well as manipulation of sensory inputs can lead to rapid reorganization of the cerebral cortex, occurring within minutes to hours. Reduction of cortical inhibitory tone through a decrease in the availability of GABA has been suggested as a possible mechanism; however, the degree and temporal course of the changes in brain GABA are not known. A novel method using two-dimensional J-resolved magnetic resonance spectroscopy showed that GABA levels in the human sensorimotor cortex are quickly reduced within minutes of deafferentation. This finding strongly supports the view that the release of latent corticocortical projections from tonic inhibition through decreased GABA availability is a mechanism of rapid cortical plasticity. Reduction of brain GABA can play a pivotal role in regulating the extent of rapid cortical reorganization after lesions or changes in sensory input.     

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) imaging reveals cholesterol overload in the cerebral cortex of Alzheimer disease patients

Although cholesterol has been involved in the pathophysiology of Alzheimer disease (AD), its distribution in the cerebral cortex over the course of AD is unknown. We describe an original method to quantify cholesterol distribution using time-of-flight secondary ion mass spectrometry imaging. Cholesterol was unevenly distributed along the cortical thickness, being more abundant close to the white matter, in both control and AD cases. However, the mean cholesterol signal was significantly higher in the lower half of the cortex in AD samples compared to controls. This increase, when converted into cortical layers, was statistically significant for layers III and IV and did not reach significance in layers V + VI, the variability being too high at the interface between grey and white matter. The density of neurofibrillary tangles and of senile plaques was not statistically linked to the abundance of cholesterol. Cholesterol overload thus appears a new and independent alteration of AD cerebral cortex. The structure in which cholesterol accumulates and the mechanism of this accumulation remain to be elucidated.     

Convection-enhanced delivery of AAV2 in white matter—A novel method for gene delivery to cerebral cortex

Background

Convection-enhanced delivery (CED) is currently under investigation for delivering therapeutic agents to subcortical targets in the brain. Direct delivery of therapies to the cerebral cortex, however, remains a significant challenge.

New method

We describe a novel method of targeting adeno-associated viral vector (AAV) mediated gene therapies to specific cerebral cortical regions by performing high volume, high flow rate infusions into underlying white matter in a large animal (porcine) model.

Results

Infusion volumes of up to 700 μl at flow rates as high as 10 μl/min were successfully performed in white matter without adverse neurological sequelae. Co-infusion of AAV2/5-GFP with 0.2% Gadolinium in artificial CSF confirmed transgene expression in the deep layers of cerebral cortex overlying the infused areas of white matter.

Comparison with existing methods

AAV-mediated gene therapies have been previously targeted to the cerebral cortex by performing intrathalamic CED and exploiting axonal transport. The novel method described in this study facilitates delivery of gene therapies to specific regions of the cerebral cortex without targeting deep brain structures.

Conclusions

AAV-mediated gene therapies can be targeted to specific cortical regions by performing CED into underlying white matter. This technique could be applied to the treatment of neurological disorders characterised by cerebral cortical degeneration.     

REM sleep - by default?

Elements of three old, overlapping theories of REM sleep (REM) function, the Ontogenetic, Homeostatic and Phylogenetic hypotheses, together still provide a plausible framework — that REM (i) is directed towards early cortical development, (ii) “tones up” the sleeping cortex, (iii) can substitute for wakefulness, (iv) has a calming effect. This framework is developed in the light of recent findings. It is argued that the “primitiveness” of REM and its similarity to wakefulness liken it to a default state of “non-wakefulness” or a waking antagonist, anteceding “true” (non-REM) sleep. The “toning up” is reflected by inhibition of motor, sensory and (importantly) emotional systems, together pointing to integrated “flight or fight” activity, that preoccupies/distracts the organism when non-REM is absent and wakefulness unnecessary. Dreaming facilitates this distraction. In rodents, REM can provide stress coping and calming, but REM deprivation procedures incorporating immobility may further enhance stress and confound outcomes. REM “pressure” (e.g. REM rebounds) may be a default from a loss of inhibition of REM by non-REM. REM can be reduced and/or replaced by wakefulness, without adverse effects. REM has little advantage over wakefulness in providing positive cerebral recovery or memory consolidation.     

Developmental plasticity connects visual cortex to motoneurons after stroke

We report motor cortical function in the left occipital cortex of a subject who suffered a left middle cerebral artery stroke early in development. Transcranial magnetic stimulation of the left occipital cortex evoked contraction of right hand muscles. Electroencephalogram recorded over the left occipital cortex showed: 1) coherence with electromyogram from a right hand muscle; 2) a typical sensorimotor Mu rhythm at rest that was suppressed during contraction of right hand muscles. This is the first evidence that cortical plasticity extends beyond reshaping of primary sensory cortical fields to respecification of the cortical origin of subcortically projecting pathways. ANN NEUROL 2010;67:132–136     

Release of GABA from the guinea-pig neocortex induced by electrical stimulation of the ‘locus coeruleus’ or by norepinephrine

GABA release from the cortical surface was measured in freely moving guinea-pigs using collecting cups and a mass-fragmentographic method. Stimulation of the locus coeruleus caused a prolonged sedation of the animals and a 60% increase of GABA output from their cerebral cortex. Similar results were obtained after intraventricular injections of norepinephrine. Phentolamine antagonized these effects. The results suggest that the noradrenergic innervation of the cortex modulates the function of cortical GABA neurons.     

The volume of the entorhinal cortex in schizophrenia: A controlled MRI study

1. 1. The entorhinal cortex (EC), part of the limbic temporal lobe, is a critical link between the cerebral cortex and the hippocampus, and is considered one of the most important cortical “association” areas. Several postmortem abnormalities in the EC have been reported.

2. 2. Here, the authors report the first study of the volume of the EC in schizophrenia using magnetic resonance imaging (MRI) scans.

3. 3. The authors compared 57 schizophrenic patients and 35 healthy controls. No overall difference in the mean EC volume was found between controls and schizophrenic patients, but there was a strong trend (p = 078) for the schizophrenic females to have a large mean EC than control females and for the early onset schizophrenia group to have a smaller (EC (p = 07) than late onset schizophrenia subjects.

4. 4. The implications of the findings are discussed.

     

Oligodendrocytose réactionnelle au cours de la dégénérescence expérimentale du cortex cérébral

The electrolytic destruction of a thalamic relay centre—in this case the medial geniculate body—provokes manifestations of degeneration in the auditory region of the cerebral cortex, involving the afferent axons and the neurones. It also produces neuroglial reactions of the classical “replacement gliosis” type.

A statistical study of the neuroglial cell population, in particular of the oligodendrocytes, has been undertaken in the cat at various postoperative stages by using cresyl violet-counterstained cerebral cortex preparations impregnated by the Golgi-Cox technique. Electron-microscopic observations complemented the statistical study.

The oligodendrocytosis which is observable in the deeper tissues of the cerebral cortex brings about a hyperplasia. The multiplication process of the nuclei, apparently amitotic, goes through a bi- or tri-nucleation phase, which may be transitory or final. Cellular migration seems likely to be one of the processes which may play a part in the oligodendrocytosis but this hypothesis lacks confirmation.     

Developmental history of the subplate zone, subplate neurons and interstitial white matter neurons: relevance for schizophrenia

The subplate zone is a transient cytoarchitectonic compartment of the fetal telencephalic wall and contains a population of subplate neurons which are the main neurons of the fetal neocortex and play a key role in normal development of cerebral cortical structure and connectivity. While the subplate zone disappears during the perinatal and early postnatal period, numerous subplate neurons survive and remain embedded in the superficial (gyral) white matter of adolescent and adult brain as so-called interstitial neurons. In both fetal and adult brain, subplate/interstitial neurons belong to two major classes of cortical cells: (a) projection (glutamatergic) neurons and (b) local circuit (GABAergic) interneurons. As interstitial neurons remain strategically positioned at the cortical/white matter interface through which various cortical afferent systems enter the deep cortical layers, they probably serve as auxiliary interneurons involved in differential “gating” of cortical input systems.It is widely accepted that prenatal lesions which alter the number of surviving subplate neurons (i.e., the number of interstitial neurons) and/or the nature of their involvement in cortical circuitry represent an important causal factor in pathogenesis of at least some types of schizophrenia - e.g., in the subgroup of patients with cognitive impairment and deficits of frontal lobe functions. The abnormal functioning of cortical circuitry in schizophrenia becomes manifest during the adolescence, when there is an increased demand for proper functioning of the prefrontal cortex.In this review, we describe developmental history of subplate zone, subplate neurons and surviving interstitial neurons, as well as presumed consequences of the increased number of GABAergic interstitial neurons in the prefrontal cortex. We propose that the increased number of GABAergic interstitial neurons leads to the increased inhibition of prefrontal cortical neurons. This inhibitory action of GABAergic interstitial neurons is facilitated by their strategic position at the cortical/white matter interface where limbic and modulatory afferent pathways enter the prefrontal cortex. Thus, enlarged population of inhibitory interstitial neurons (even if they represent a minor fraction of total neuron number, as in the cerebral cortex itself) may alter the differential “gating” of limbic and modulatory inputs (as well as other cortical and subcortical inputs) and cause a functional disconnectivity between the prefrontal and limbic cortex in the adolescent brain. In conclusion, fetal subplate neurons and surviving postnatal interstitial neurons are important modulators of cortical functions in both normal and schizophrenic cerebral cortex.     

Cortical spreading depression recorded from the human brain using a multiparametric monitoring system

The number of parameters (i.e., EEG or ICP-intracranial pressure) routinely monitored under clinical situations is limited. The brain function analyzer described in this paper enables simultaneous, continuous on-line monitoring of cerebral blood flow (CBF) and volume (CBV), intramitochondrial NADH redox state, extracellular K⁺ concentrations, DC potential, electrocorticography and ICP from the cerebral cortex. Brain function of 14 patients with severe head injury (GCS ≤ 8), who were hospitalized in the neurosurgical or general intensive care unit was monitored using this analyzer. Leao cortical spreading depression (SD) has been reported in many experimental animals but not in the human cerebral cortex. In one of the patients monitored, spreading depression was observed. This is the first time that spontaneous repetitive cortical SD cycles have been recorded from the cerebral cortex of a patient suffering from severe head injury. Typical SD cycles appeared 4–5 h after the beginning of monitoring this patient. During the first 3–4 cycles the responses of this patient were very similar to the responses to SD recorded in normoxic experimental animals. Electrocorticography was depressed whereas extracellular K⁺ levels increased. The metabolic response to spreading depression was characterized by oxidation of intramitochondrial NADH concomitant to a large increase in CBF. During brain death, an ischemic depolarization, characterized by decrease in CBF and an irreversible increase in extracellular K⁺, was recorded.     

Gender-Specific Reduction of Estrogen-Sensitive Small RNA,miR-30b,in Subjects With Schizophrenia

Estrogen signaling pathways affect cortical function and metabolism, are thought to play a role in the pathophysiology of schizophrenia, and exert neuroprotective effects in female subjects at risk. However, the molecular signatures of estrogen signaling in normal and diseased cerebral cortex remain largely unexplored. Expression of the estrogen-sensitive small RNA, microRNA-30b (miR-30b), was studied in 30 controls and 30 matched samples from subjects diagnosed with schizophrenia from prefrontal cortex (PFC), as well as in 23 samples from parietal cortex (12 controls and 11 schizophrenia cases). The majority of case and control samples were genotyped for an estrogen receptor α (Esr1) sequence variant (rs2234693) previously associated with genetic risk, and a subset of them were subjected to further analysis to determine expression of mature and precursor forms of miR-30b (pre/pri-miR-30b). Gender-dimorphic expression was also explored in mouse frontal cortex and hippocampus. A significant interaction between gender and diagnosis was discovered for changes in mature miR-30b levels, so that miR-30b expression was significantly reduced in the cerebral cortex of female but not male subjects with schizophrenia. In addition, disease-related changes in miR-30b expression in a subset of female subjects were further modulated by Esr1 genotype. Changes after antipsychotic drug exposure remained insignificant. These preliminary findings point to the possibility that disease-related changes in the expression of small noncoding RNAs such as miR-30b in schizophrenia could be influenced by gender and potentially regulated by estrogen signaling.     

Cortico-subcortical organization of language networks in the right hemisphere: an electrostimulation study in left-handers

We have studied the configuration of the cortico-subcortical language networks within the right hemisphere (RH) in nine left-handers, being operated on while awake for a cerebral glioma. Intraoperatively, language was mapped using cortico-subcortical electrostimulation, to avoid permanent deficit. In frontal regions, cortical stimulation elicited articulatory disorders (ventral premotor cortex), anomia (dorsal premotor cortex), speech arrest (pars opercularis), and semantic paraphasia (dorsolateral prefrontal cortex). Insular stimulation generated dysarthria, parietal stimulation phonemic paraphasias, and temporal stimulation semantic paraphasias. Subcortically, the superior longitudinal fasciculus (inducing phonological disturbances when stimulated), inferior occipito-frontal fasciculus (eliciting semantic disturbances during stimulation), subcallosal fasciculus (generating control disturbances when stimulated), and common final pathway (inducing articulatory disorders during stimulation) were identified. These cortical and subcortical structures were preserved, avoiding permanent aphasia, despite a transient immediate postoperative language worsening. Both intraoperative results and postsurgical transitory dysphasia support the major role of the RH in language in left-handers, and provide new insights into the anatomo-functional cortico-subcortical organization of the language networks in the RH-suggesting a “mirror” configuration in comparison to the left hemisphere.     

Temporal lobe seizure interhemispheric propagation time depends on nonepileptic cortical cerebral blood flow

In some patients with epilepsy, activation of eloquent cortex using various forms of environmental stimulation and mental activity may induce seizures. The increased neuronal activity resulting from cortical stimulation may be associated with increased regional cerebral blood flow. The vascular steal theory of temporal lobe epilepsy suggests that as nonepileptogenic cortical cerebral blood flow (CBFn) increases, temporal lobe epileptogenicity increases as a result, in part, of decreasing interhemispheric propagation time (IHPT). Recently, IHPT has been shown to be a quantitative electrocorticographic measure of temporal lobe epileptogenicity. In the current study, long-term combined subdural-EEG and surface cortical cerebral blood flow (CBF) monitoring was performed to test the hypothesis that IHPT depends upon CBFn. The results show that IHPT is a nonlinear (negative exponential) function of nonepileptic cortical CBF (r=0.507, df=32, t=-2.204, P<0.05). In temporal lobe epilepsy, nonepileptic cortical hypoperfusion may represent a protective mechanism for delaying interhemispheric seizure propagation. The fact that IHPT decreases exponentially with increasing CBFn suggests that small increases in CBFn should substantially decrease IHPT and increase epileptogenicity. This study confirms that inter-hemispheric propagation time depends upon perfusion of nonepileptogenic cortex.     

Impairment of functional inhibition in the contralateral cortex following perinatally acquired malformations in rats

Neonatal freeze lesions in newborn rats induce focal malformations of the cerebral cortex mimicking human polymicrogyria which is a common cause of epilepsy and neuropsychological deficits in children and adults. Experimental and clinical studies demonstrated hyperexcitability in the malformation itself and peridysplastic cortex associated with a widespread imbalance of excitatory and inhibitory function and extensive alterations in cortical connectivity. We investigated the integrity of functional cortical inhibition using a paired pulse paradigm in brain slice preparations of adult freeze-lesioned rats. In contrast to previous electrophysiological studies focusing on the dysplastic cortex and the ipsilateral hemisphere, we here mapped both hemispheres. Extracellular field potentials were evoked by application of double pulses at the border of layer VI/white matter and recorded in layer II/III. Evaluation of the ratio of the field potential amplitudes at different recording positions allowed an assessment of regional functional inhibition. Using this approach, we observed a significant reduction of functional inhibition in the somatosensory cortex of the contralateral hemisphere, whereas only slight alterations were detected in the ipsilateral lesion surround. Our results provide evidence that focal cortical malformations not only impair cortical excitability in the ipsilateral hemisphere but also induce a disinhibition of the contralateral cortex.     

Atrophy of the corpus callosum,cognitive impairment,and cortical hypometabolism in progressive supranuclear palsy

Recent studies disclosed neurofibrillary degeneration in layer 3 of the association cortex in patients with progressive supranuclear palsy. This lesion may be associated with corpus callosum atrophy and may impair the function of cortical regions indispensable for complex cognitive activity. To investigate whether corpus callosum atrophy is associated with cognitive impairment and cerebral cortical hypometabolism, we studied 10 patients with progressive supranuclear palsy using magnetic resonance imaging and positron emission tomography with fluorodeoxyglucose as a tracer. Compared with 23 age-matched control subjects, the patients had significantly decreased callosal area-skull area ratios, with anterior predominance of the degree of atrophy. The corpus callosum atrophy was accompanied by a decreased mean cortical glucose metabolic rate, predominantly in the frontal region of the cortex, and poor performance on the picture arrangement subtest of the Wechsler Adult Intelligence Scale and the verbal fluency task. We conclude that corpus callosum atrophy with anterior predominance is present in progressive supranuclear palsy, and that this atrophy is associated with cognitive impairment and cerebral cortical hypometabolism, especially in the frontal cortical region. Corpus callosum atrophy may reflect the pathological changes in the cerebral cortex, accentuated in the frontal region, that contribute to the development of frontal lobe dysfunction in this disease.     

Multiregional cell assemblies, temporal binding and the representation of conceptual knowledge in cortex: a modern theory by a "classical" neurologist, Carl Wernicke

A contemporary view of conceptual representation in the brain holds that conceptual knowledge is distributed throughout the cerebral cortex, localized to cortical regions involved in their initial processing, and functionally interconnected through synchronized associative processes that are mediated through “convergence zones”. The primary goal of the present paper is to point out that Carl Wernicke proposed a theory of how concepts are acquired and represented in cortex which is strikingly similar to contemporary views. Wernicke sketched his ideas on this topic in his earliest writings on aphasia. But his theory is developed most fully in the Grundriss der Psychiatrie (Outlines of Psychiatry), published in 1900 and never translated into English. We describe Wernicke's views on the distributed nature of conceptual knowledge in the brain using select quotes from his early work, and by providing a translation of relevant sections of the Grundriss der Psychiatrie.     

Cortical Lewy bodies and Alzheimer-type changes in patients with Parkinson’s disease

We investigated the role of cortical Lewy bodies (LB) and Alzheimer-type changes in cognitive impairment in patients with idiopathic Parkinson’s disease (PD). We evaluated 44 cases for the extent of neuropathological lesions with a CERAD neuropathological assessment battery and the stage of dementia using Reisberg’s global deterioration scale (GDS). Substantia nigra, amygdala, hippocampus and cerebral cortex were examined for LB and Alzheimer-type changes. For detection of LB, the cortical areas were stained with polyclonal antibodies against ubiquitin and tau. We found at least one cortical LB in 93% of cases. Furthermore, 43% of the cases had histological findings of definite Alzheimer’s disease (AD). The association between cognitive impairment and the number of cortical LB and Alzheimer-type changes in the amygdala, hippocampus and six selected gyri from cerebral cortex were analyzed using stepwise linear regression. In this analysis the total number of cortical LB, and the amount of neurofibrillary tangles in the temporal cortex remained statistically significant. When the cases with neuropathological changes consistent with a diagnosis of AD were excluded, the correlation between the total number of cortical LB and cognitive impairment was more obvious. A stepwise linear regression analysis in these cases found the total number of cortical LB to be the statistically significant predictor of cognitive impairment. This study revealed that LB densities in the cortex, especially in the temporal neocortex, correlated significantly with the cognitive impairment in PD independent of or in addition to Alzheimer-type pathology. Received: 18 August 1997 / Revised, accepted: 2 December 1997     

Large-scale cortical networks and cognition

The well-known parcellation of the mammalian cerebral cortex into a large number of functionally distinct cytoarchitectonic areas presents a problem for understanding the complex cortical integrative functions that underlie cognition. How do cortical areas having unique individual functional properties cooperate to accomplish these complex operations? Do neurons distributed throughout the cerebral cortex act together in large-scale functional assemblages? This review examines the substantial body of evidence supporting the view that complex integrative functions are carried out by large-scale networks of cortical areas. Pathway tracing studies in non-human primates have revealed widely distributed networks of interconnected cortical areas, providing an anatomical substrate for large-scale parallel processing of information in the cerebral cortex. Functional coactivation of multiple cortical areas has been demonstrated by neurophysiological studies in non-human primates and several different cognitive functions have been shown to depend on multiple distributed areas by human neuropsychological studies. Electriphysiological studies on interareal synchronization have provided evidence that active neurons in different cortical areas may become not only coactive, but also functionally interdependent. The computational advantages of synchronization between cortical areas in large-scale networks have been elucidated by studies using artificial neural network models. Recent observations of time-varying multi-areal cortical synchronization suggest that the functional topology of a large-scale cortical network is dynamically reorganized during visuomotor behavior.