Strokes restricted to the insular cortex

Résumé: L'objectif de l'étude est de caractériser la manifestation clinique d'une atteinte vasculaire cérébrale ischémique aiguë limitée au cortex insulaire, région intrigante et méconnue du cerveau humain. Dans la pratique clinique, une atteinte vasculaire aiguë limitée à l'insula, sans compromission d'autres régions cérébrales, est exceptionnelle et sa manifestation clinique neurologique est souvent non reconnue. L'étude est focalisée sur quatre patients, inscrits dans le Lausanne Stroke Registry, présentant une nouvelle atteinte vasculaire cérébrale avec une lésion unique purement limitée au cortex insulaire, objectivée à l'aide de la résonance magnétique (IRM). L'étude a mis en évidence cinq manifestations cliniques principales : 1) Troubles de la sensibilité corporelle sont révélé chez trois patients avec une atteinte insulaire postérieure (deux avec un syndrome pseudothalamique, un avec un déficit à distribution partielle). 2) Un patient avec une lésion insulaire postérieure gauche présent des troubles du goût. 3) Un syndrome pseudovestibulaire avec vertiges non rotatoires, instabilité à la marche sans nystagmus, est mis en évidence chez trois patients avec une atteinte ischémique insulaire postérieure. 4) Un patient avec atteinte de l'insula postérieure droite présente des épisodes d'hypertension artérielle d'origine cryptique. 5) Des troubles neuropsychologiques tels qu'aphasie et dysarthrie sont détectés chez les patients avec une atteinte insulaire postérieure gauche, un épisode de somatoparaphrénie est rapporté avec une atteinte insulaire postérieure droite. En conclusion, les atteintes vasculaires cérébrales ischémiques aiguës limitées au cortex insulaire postérieur peuvent se manifester principalement avec un tableau clinique caractérisé par un syndrome pseudothalamique associé à une symptomatologie pseudovertigineuse. Les lésions insulaires postérieures peuvent se manifester avec une dysarthrie et des troubles du goût, une aphasie (gauche), une somatoparaphrénie et une dysfonction hypertensive (droite). L'étude n'a pas mis en évidence de dysphagie, reportée dans les atteintes insulaires antérieures. Abstract: Objective: To characterize clinically acute insular strokes from four patients with, a first ever acute stroke restricted to the insula on MRI. Methods: The authors studied the clinical presentation of four patients with a first ever acute stroke restricted to the insula on MRI. Results: The authors found five main groups of clinical presentations: 1) somatosensory deficits in three patients with posterior insular stroke (two with a transient pseudothalamic sensory syndrome, one with partial distribution); 2) gustatory disorder in a patient with left posterior insular infarct; 3) vestibular-like syndrome, with dizziness, gait instability, and tendency to fall, but no nystagmus, in three patients with posterior insular strokes; 4) cardiovascular disturbances, consisting of hypertensive episodes in a patient with a right posterior insular infarct; and 5) neuropsychological disorders, including aphasia (left posterior insula), dysarthria, and transient somatoparaphrenia (right posterior insula). Conclusion: Strokes restricted to the posterior insula may present with pseudothalamic sensory and vestibular-like syndromes as prominent clinical manifestations, but also dysarthria and aphasia (in left lesions), somatoparaphrenia (right lesions) and gustatory dysfunction and blood pressure with hypertensive episodes in right lesions; we did not find acute dysphagia reported in anterior, insular strokes.

The roles of the somatosensory cortices in the perception of noxious and innocuous stimuli

Résumé Les premières études électrophysiologiques et anatomiques ont établi le rôle crucial du cortex somatosensoriel primaire et secondaire (SI et SII) dans le traitement de l'information somatosensorielle. Toutefois, les récentes avancées en techniques d’imagerie cérébrale ont mis en question leur rôle dans la perception somatosensorielle. La réorganisation du cortex somatosensoriel est un phénomène qui a été proposé comme cause de la douleur du membre fantôme chez les individus amputés. Comme la plupart des études se sont concentrées sur le rôle du SI, une étude plus approfondie est nécessaire. La présente série d'expériences implique une exploration du rôle des régions somatosensorielles dans la perception des stimuli douleureux et non-douleureux chez des volontaires sains et patients avec des douleurs de membre fantôme. La première étude expérimentale présentée dans le chapitre 3 est une méta-analyse des études de neuro-imagerie employant des stimuli nociceptifs chez des volontaires sains. En comparaison aux précédentes, la présente étude permet la génération de cartes quantitatives probabilistes permettant la localisation des régions activées en réponse à des stimuli nociceptifs. Le rôle du cortex somatosensoriel dans la perception consciente de stimuli chauds a été étudié dans le chapitre 4 grâce à une étude d'imagerie par résonance magnétique fonctionnelle, dans laquelle des stimuli thermiques douloureux et non-douloureux ont été administrés de manière contrebalancée. Grâce à cette procédure, la perception de la chaleur fut atténuée par les stimuli douloureux, ce qui permit la comparaison des stimuli consciemment perçus avec ceux qui ne le furent pas. Les résultats ont montrés que les stimulations chaudes perçues ont engendré l’activation de l’aire SI controlatérale, ainsi que de la région SII. Grâce à l’évaluation clinique de patients amputés présentant une altération de leurs perceptions somatosensorielles, il est également possible de dessiner un aperçu des régions corticales qui sous-tendent ces modifications perceptuelles. Dans le chapitre 5 nous avons émis l'hypothèse proposant que les sensations du membre fantôme représentent un corrélat perceptuel de la réorganisation somatotopique des représentations sensorielles corticales. En effet, la réorganisation des sensations peut donner des indices sur les régions impliquées dans la genèse des sensations référées. Ainsi, un protocole d’évaluation sensoriel a été administré à un groupe de patients affligés de douleur au niveau du membre fantôme. Les résultats ont montré que, contrairement aux études précédentes, les sensations diffèrent grandement selon le type et l'intensité des stimuli tactiles, sans évidence de la présence d’un modèle spatialement localisé. Toutefois, les résultats actuels suggèrent que les régions corticales à champs récepteurs bilatéraux présentent également des modifications en réponse à une déafférentation. Ces études présentent une nouvelle image des régions corticales impliquées dans la perception des stimuli somatosensoriels, lesquelles comprennent les aires SI et SII, ainsi que l'insula. Les résultats sont pertinents à notre compréhension des corrélats neurologiques de la perception somatosensorielle consciente.

Classification of cortical microcircuits based on micro-electrode-array data from slices of rat barrel cortex

The bewildering complexity of cortical microcircuits at the single cell level gives rise to surprisingly robust emergent activity patterns at the level of laminar and columnar local field potentials (LFPs) in response to targeted local stimuli. Here we report the results of our multivariate data-analytic approach based on simultaneous multi-site recordings using micro-electrode-array chips for investigation of the microcircuitary of rat somatosensory (barrel) cortex. We find high repeatability of stimulus-induced responses, and typical spatial distributions of LFP responses to stimuli in supragranular, granular, and infragranular layers, where the last form a particularly distinct class. Population spikes appear to travel with about 33 cm/s from granular to infragranular layers. Responses within barrel related columns have different profiles than those in neighbouring columns to the left or interchangeably to the right. Variations between slices occur, but can be minimized by strictly obeying controlled experimental protocols. Cluster analysis on normalized recordings indicates specific spatial distributions of time series reflecting the location of sources and sinks independent of the stimulus layer. Although the precise correspondences between single cell activity and LFPs are still far from clear, a sophisticated neuroinformatics approach in combination with multi-site LFP recordings in the standardized slice preparation is suitable for comparing normal conditions to genetically or pharmacologically altered situations based on real cortical microcircuitry.

The anatomical connections of the macaque monkey orbitofrontal cortex. A review

The orbitofrontal cortex (OfC) is a heterogeneous prefrontal sector selectively connected with a wide constellation of other prefrontal, limbic, sensory and premotor areas. Among the limbic cortical connections, the ones with the bippocampus and parabippocampal cortex are particularly salient. Sensory cortices connected with the OfC include areas involved in olfactory, gustatory, somatosensory, auditory and visual processing. Subcortical structures with prominent OfC connections include the amygdala, numerous thalamic nuclei, the striatum, hypothalamus, periaqueductal gray matter, and biochemically specific cell groups in the basal forebrain and brainstem. Architectonic and connectional evidence supports parcellation of the OfC. The rostrally placed isocortical sector is mainly connected with isocortical areas, including sensory areas of the auditory, somatic and visual modalities, whereas the caudal non-isocortical sector is principally connected with non-isocortical areas, and, in the sensory domain, with olfactory and gustatory areas. The connections of the isocortical and non- isocortical orbital sectors with the amygdala, thalamus, striatum, hypotbalamus and periaqueductal gray matter are also specific. The medial sector of the OfC is selectively connected with the bippocampus, posterior parabippocampal cortex, posterior cingulate and retrosplenial areas, and area prostriata, while the lateral orbitofrontal sector is the most heavily connected with sensory areas of the gustatory, somatic and visual modalities, with premotor regions, and with the amygdala.

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: Influence of theta burst stimulation priming

Background Conventional protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than conventional protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of conventional 10?Hz-rTMS. Methods In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10?Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. Results Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. Conclusions The present results show that the analgesic effects of conventional 10?Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity.

The posterior parietal cortex: a bridge between vision and action

The present work takes into account three posterior parietal areas, V6, V6A, and PEc, all operating on different subsets of signals (visual, somatic, motor). The work focuses on the study of their functional properties, to better understand their respective contribution in the neuronal circuits that make possible the interactions between subject and external environment. In the caudalmost pole of parietal lobe there is area V6. Functional data suggest that this area is related to the encoding of both objects motion and ego-motion. However, the sensitivity of V6 neurons to optic flow stimulations has been tested only in human fMRI experiments. Here we addressed this issue by applying on monkey the same experimental protocol used in human studies. The visual stimulation obtained with the Flow Fields stimulus was the most effective and powerful to activate area V6 in monkey, further strengthening this homology between the two primates. The neighboring areas, V6A and PEc, show different cytoarchitecture and connectivity profiles, but are both involved in the control of reaches. We studied the sensory responses present in these areas, and directly compared these.. We also studied the motor related discharges of PEc neurons during reaching movements in 3D space comparing also the direction and depth tuning of PEc cells with those of V6A. The results show that area PEc and V6A share several functional properties. Area PEc, unlike V6A, contains a richer and more complex somatosensory input, and a poorer, although complex visual one. Differences emerged also comparing the motor-related properties for reaches in depth: the incidence of depth modulations in PEc and the temporal pattern of modulation for depth and direction allow to delineate a trend among the two parietal visuomotor areas.

Combined voltage and calcium epifluorescence imaging in vitro and in vivo reveals subthreshold and suprathreshold dynamics of mouse barrel cortex

Cortical dynamics can be imaged at high spatiotemporal resolution with voltage-sensitive dyes (VSDs) and calcium-sensitive dyes (CaSDs). We combined these two imaging techniques using epifluorescence optics together with whole cell recordings to measure the spatiotemporal dynamics of activity in the mouse somatosensory barrel cortex in vitro and in the supragranular layers in vivo. The two optical signals reported distinct aspects of cortical function. VSD fluorescence varied linearly with membrane potential and was dominated by subthreshold postsynaptic potentials, whereas the CaSD signal predominantly reflected local action potential firing. Combining VSDs and CaSDs allowed us to monitor the synaptic drive and the spiking activity of a given area at the same time in the same preparation. The spatial extent of the two dye signals was different, with VSD signals spreading further than CaSD signals, reflecting broad subthreshold and narrow suprathreshold receptive fields. Importantly, the signals from the dyes were differentially affected by pharmacological manipulations, stimulation strength, and depth of isoflurane anesthesia. Combined VSD and CaSD measurements can therefore be used to specify the temporal and spatial relationships between subthreshold and suprathreshold activity of the neocortex.

Nondermatomal somatosensory deficits in patients with chronic pain disorder: clinical findings and hypometabolic pattern in FDG-PET

Patients with chronic pain disorders often show somatosensory disturbances that are considered to be functional. This paper aims at a more precise clinical description and at a documentation of functional neuroimaging correlates of this phenomenon. We examined 30 consecutive patients with unilaterally accentuated chronic pain not explained by persistent peripheral tissue damage and ipsilateral somatosensory disturbances including upper and lower extremities and trunk. The patients were assessed clinically and with conventional brain CT or MRI scan. In the last 11 patients functional neuroimaging was carried out (18-fluordeoxyglucose positron emission tomography=FDG-PET). Depressive symptoms were assessed with the Hamilton depression scale (HAMD-17) and pain intensity was rated with a visual analogue scale for pain (VAS). All patients suffered from mild to moderate depressive symptoms. All patients had experienced a prolonged antecedent phase of severe emotional distress; most of them remembered a "trigger episode of somatic pain" on the affected side. Somatosensory deficits were a replicable hyposensitivity to touch and heat perception of nondermatomal distribution. Conventional imaging procedures (brain CT or MRI scans) showed no structural changes. However, in 11 patients functional imaging with FDG-PET showed a significant hypometabolic pattern of changes in cortical and subcortical areas, mainly in the post-central gyrus, posterior insula, putamen, and anterior cingulate cortex. In summary, pain-related nondermatomal somatosensory deficits (NDSDs) are a phenomenon involving biological as well as psychosocial factors with replicable neuroperceptive clinical findings and a complex neurodysfunctional pattern in the FDG-PET.

Impaired verbal memory in Parkinson disease: relationship to prefrontal dysfunction and somatosensory discrimination

OBJECTIVE: To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception. METHODS: Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices. RESULTS: We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients. CONCLUSION: PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.

The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis.

The vestibular system contributes to the control of posture and eye movements and is also involved in various cognitive functions including spatial navigation and memory. These functions are subtended by projections to a vestibular cortex, whose exact location in the human brain is still a matter of debate (Lopez and Blanke, 2011). The vestibular cortex can be defined as the network of all cortical areas receiving inputs from the vestibular system, including areas where vestibular signals influence the processing of other sensory (e.g. somatosensory and visual) and motor signals. Previous neuroimaging studies used caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory stimulation (clicks and short-tone bursts) to activate the vestibular receptors and localize the vestibular cortex. However, these three methods differ regarding the receptors stimulated (otoliths, semicircular canals) and the concurrent activation of the tactile, thermal, nociceptive and auditory systems. To evaluate the convergence between these methods and provide a statistical analysis of the localization of the human vestibular cortex, we performed an activation likelihood estimation (ALE) meta-analysis of neuroimaging studies using CVS, GVS, and auditory stimuli. We analyzed a total of 352 activation foci reported in 16 studies carried out in a total of 192 healthy participants. The results reveal that the main regions activated by CVS, GVS, or auditory stimuli were located in the Sylvian fissure, insula, retroinsular cortex, fronto-parietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that regions showing convergence between two stimulation methods were located in the median (short gyrus III) and posterior (long gyrus IV) insula, parietal operculum and retroinsular cortex (Ri). The only area of convergence between all three methods of stimulation was located in Ri. The data indicate that Ri, parietal operculum and posterior insula are vestibular regions where afferents converge from otoliths and semicircular canals, and may thus be involved in the processing of signals informing about body rotations, translations and tilts. Results from the meta-analysis are in agreement with electrophysiological recordings in monkeys showing main vestibular projections in the transitional zone between Ri, the insular granular field (Ig), and SII.

Nondermatomal somatosensory deficits in chronic pain are associated with cerebral grey matter changes

OBJECTIVES Widespread sensory deficits occur in 20-40% of chronic pain patients on the side of pain, independent of pain aetiology, and are known as nondermatomal sensory deficits (NDSDs). NDSDs can occur in absence of central or peripheral nervous system lesions. We hypothesised that NDSDs were associated with cerebral grey matter changes in the sensory system and in pain processing regions, detectable with voxel-based morphometry. METHODS Twenty-five patients with NDSDs, 23 patients without NDSDs ("pain-only"), and 29 healthy controls were studied with high resolution structural MRI of the brain. A comprehensive clinical and psychiatric evaluation based on Diagnostic and Statistical Manual was performed in all patients. RESULTS Patients with NDSDs and "pain-only" did not differ concerning demographic data and psychiatric diagnoses, although anxiety scores (HADS-A) were higher in patients with NDSDs. In patients with NDSDs, grey matter increases were found in the right primary sensory cortex, thalamus, and bilaterally in lateral temporal regions and the hippocampus/fusiform gyrus. "Pain-only" patients showed a bilateral grey matter increase in the posterior insula and less pronounced changes in sensorimotor cortex. CONCLUSIONS Dysfunctional sensory processing in patients with NDSDs is associated with complex changes in grey matter volume, involving the somatosensory system and temporal regions.

Neonatal lead exposure impairs development of rodent barrel field cortex

Childhood exposure to low-level lead can permanently reduce intelligence, but the neurobiologic mechanism for this effect is unknown. We examined the impact of lead exposure on the development of cortical columns, using the rodent barrel field as a model. In all areas of mammalian neocortex, cortical columns constitute a fundamental structural unit subserving information processing. Barrel field cortex contains columnar processing units with distinct clusters of layer IV neurons that receive sensory input from individual whiskers. In this study, rat pups were exposed to 0, 0.2, 1, 1.5, or 2 g/liter lead acetate in their dam's drinking water from birth through postnatal day 10. This treatment, which coincides with the development of segregated columns in the barrel field, produced blood lead concentrations from 1 to 31 μg/dl. On postnatal day 10, the area of the barrel field and of individual barrels was measured. A dose-related reduction in barrel field area was observed (Pearson correlation = −0.740; P < 0.001); mean barrel field area in the highest exposure group was decreased 12% versus controls. Individual barrels in the physiologically more active caudoventral group were affected preferentially. Total cortical area measured in the same sections was not altered significantly by lead exposure. These data support the hypothesis that lead exposure may impair the development of columnar processing units in immature neocortex. We demonstrate that low levels of blood lead, in the range seen in many impoverished inner-city children, cause structural alterations in a neocortical somatosensory map.

A study of pyramidal cell structure in the cingulate cortex of the macaque monkey with comparative notes on inferotemporal and primary visual cortex

Recent studies have revealed a marked degree of variation in the pyramidal cell phenotype in visual, somatosensory, motor and prefrontal cortical areas in the brain of different primates, which are believed to subserve specialized cortical function. In the present study we carried out comparisons of dendritic structure of layer III pyramidal cells in the anterior and posterior cingulate cortex and compared their structure with those sampled from inferotemporal cortex (IT) and the primary visual area (V1) in macaque monkeys. Cells were injected with Lucifer Yellow in flat-mounted cortical slices, and processed for a light-stable DAB reaction product. Size, branching pattern, and spine density of basal dendritic arbors was determined, and somal areas measured. We found that pyramidal cells in anterior cingulate cortex were more branched and more spinous than those in posterior cingulate cortex, and cells in both anterior and posterior cingulate were considerably larger, more branched, and more spinous than those in area V1. These data show that pyramidal cell structure differs between posterior dysgranular and anterior granular cingulate cortex, and that pyramidal neurons in cingulate cortex have different structure to those in many other cortical areas. These results provide further evidence for a parallel between structural and functional specialization in cortex.

Regional specialization in pyramidal cell structure in the limbic cortex of the vervet monkey (Cercopithecus pygerythrus): an intracellular injection study of the anterior and posterior cingulate gyrus

The pyramidal cell phenotype varies quite dramatically in structure among different cortical areas in the primate brain. Comparative studies in visual cortex, in particular, but also in sensorimotor and prefrontal cortex, reveal systematic trends for pyramidal cell specialization in functionally related cortical areas. Moreover, there are systematic differences in the extent of these trends between different primate species. Recently we demonstrated differences in pyramidal cell structure in the cingulate cortex of the macaque monkey; however, in the absence of other comparative data it remains unknown as to whether the neuronal phenotype differs in cingulate cortex between species. Here we extend the basis for comparison by studying the structure of the basal dendritic trees of layer III pyramidal cells in the posterior and anterior cingulate gyrus of the vervet monkey (Brodmann's areas 23 and 24, respectively). Cells were injected with Lucifer Yellow in flat-mounted cortical slices, and processed for a light-stable DAB reaction product. Size, branching pattern, and spine density of basal dendritic arbors were determined, and somal areas measured. As in the macaque monkey, we found that pyramidal cells in anterior cingulate gyrus (area 24) were more branched and more spinous than those in posterior cingulate gyrus (area 23). In addition, the extent of the difference in pyramidal cell structure between these two cortical regions was less in the vervet monkey than in the macaque monkey.

Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats

The rodent ventrobasal (VB) thalamus receives sensory inputs from the whiskers and projects to the cortex, from which it receives reciprocal excitatory afferents. Much is known about the properties and functional roles of these glutamatergic inputs to thalamocortical neurons in the VB, but no data are available on how these afferents can affect thalamic glial cells. In this study, we used combined electrophysiological recordings and intracellular calcium ([Ca(2+)](i)) imaging to investigate glial cell responses to synaptic afferent stimulation. VB thalamus glial cells can be divided into two groups based on their [Ca(2+)](i) and electrophysiological responses to sensory and corticothalamic stimulation. One group consists of astrocytes, which stain positively for S100B and preferentially load with SR101, have linear current-voltage relations and low input resistance, show no voltage-dependent [Ca(2+)](i) responses, but express mGluR5-dependent [Ca(2+)](i) transients following stimulation of the sensory and/or corticothalamic excitatory afferent pathways. Cells of the other glial group, by contrast, stain positively for NG2, and are characterized by high input resistance, the presence of voltage-dependent [Ca(2+)](i) elevations and voltage-gated inward currents. There were no synaptically induced [Ca(2+)](i) elevations in these cells under control conditions. These results show that thalamic glial cell responses to synaptic input exhibit different properties to those of thalamocortical neurons. As VB astrocytes can respond to synaptic stimulation and signal to neighbouring neurons, this glial cell organization may have functional implications for the processing of somatosensory information and modulation of behavioural state-dependent thalamocortical network activities.