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PubMed2006

Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness.

Psychiatric illnesses, particularly schizophrenia, are associated with disrupted markers for interneuronal function and interneuron-mediated brain rhythms such as gamma frequency oscillations. Here we investigate a possible link between these two observations in the entorhinal cortex and hippocampus by using a genetic and an acute model of psychiatric illness. Lysophosphatidic acid 1 receptor-deficient (LPA1-deficient) mice show psychomotor-gating deficits and neurochemical changes resembling those seen in postmortem schizophrenia studies. Similar deficits are seen acutely with antagonism of the NMDA subtype of glutamate receptor. Neither model induced any change in power or frequency of gamma rhythms generated by kainate in hippocampal slices. In contrast, a dramatic decrease in the power of gamma oscillations was seen in superficial, but not deep, medial entorhinal cortex layers in both models. Immunolabeling for GABA, parvalbumin, and calretinin in medial entorhinal cortex from LPA1-deficient mice showed an approximately 40% reduction in total GABA- and parvalbumin-containing neurons, but no change in the number of calretinin-positive neurons. This deficit was specific for layer II (LII). No change in the number of neurons positive for these markers was seen in the hippocampus. Acute NMDA receptor blockade, which selectively reduces synaptic drive to LII entorhinal interneurons, also disrupted gamma rhythms in a similar manner in superficial entorhinal cortex, but not in hippocampus. These data demonstrate an area-specific deficit in gamma rhythmogenesis in animal models of psychiatric illness and suggest that loss, or reduction in function, of interneurons having a large NMDA receptor expression may underlie the network dysfunction that is seen.

Animals↗
PubMed2005

Brain networks underlying the clinical effects of long-term subthalamic stimulation for Parkinson's disease: a 4-year follow-up study with rCBF SPECT.

UNLABELLED: The motor improvement derived from high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's disease (PD) is maintained over time after surgery. The aim of the present prospective follow-up study was to assess regional cerebral blood flow (rCBF) changes related to such improvement in the long term. METHODS: Ten PD patients with STN-DBS underwent 3 rCBF SPECT studies at rest-once preoperatively in the off-drug condition and the other 2 postoperatively in the off-drug/on-stimulation conditions at 5 +/- 2 and 42 +/- 7 mo. Patients were administered with Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, and Schwab and England (S&E) scale. Statistical parametric mapping was used to investigate rCBF changes during long-term STN stimulation in comparison with preoperative rCBF and the relationship between rCBF and UPDRS scores was used as a covariate of interest. RESULTS: All patients showed a maximum clinical improvement during the first months after surgery and remained rather stable during further follow-up. The effect of STN-DBS from the pre- to the postoperative condition at 5 mo was to produce rCBF increases in the presupplementary motor area (pre-SMA), premotor (PMC), and dorsolateral prefrontal cortices. From the postoperative condition at 5 mo to that at 42 mo, the STN stimulation produced further rCBF increases in these frontal areas, and also in the primary motor/sensory cortices, globus pallidi, ventral lateral thalamic nuclei, cerebellum, pons, and midbrain entailing the substantia nigra (P < 0.0001). A correlation was detected between the improvement in motor scores and the rCBF increase in the pre-SMA and PMC (P < 0.0001). No correlation was present between the daily consumption of levodopa and the rCBF. CONCLUSION: Our study suggests that the long-term STN stimulation leads to improvement in neural activity in the frontal motor/associative areas. After an rCBF increase during the first months of stimulation, these regions showed a further increment in the later phase, which was accompanied by an increased activity in subcortical structures. The correlation between motor improvement and rCBF increase in higher order motor cortical areas suggests that even in the long term, as well as in the short term, the STN-DBS achieves its therapeutic benefit by restoring the activity within these cortical regions.

Antiparasitic Agents↗
PubMed2003

An fMRI study of semantic processing in men with schizophrenia.

As a means toward understanding the neural bases of schizophrenic thought disturbance, we examined brain activation patterns in response to semantically and superficially encoded words in patients with schizophrenia. Nine male schizophrenic and 9 male control subjects were tested in a visual levels of processing (LOP) task first outside the magnet and then during the fMRI scanning procedures (using a different set of words). During the experiments visual words were presented under two conditions. Under the deep, semantic encoding condition, subjects made semantic judgments as to whether the words were abstract or concrete. Under the shallow, nonsemantic encoding condition, subjects made perceptual judgments of the font size (uppercase/lowercase) of the presented words. After performance of the behavioral task, a recognition test was used to assess the depth of processing effect, defined as better performance for semantically encoded words than for perceptually encoded words. For the scanned version only, the words for both conditions were repeated in order to assess repetition-priming effects. Reaction times were assessed in both testing scenarios. Both groups showed the expected depth of processing effect for recognition, and control subjects showed the expected increased activation of the left inferior prefrontal cortex (LIPC) under semantic encoding relative to perceptual encoding conditions as well as repetition priming for semantic conditions only. In contrast, schizophrenics showed similar patterns of fMRI activation regardless of condition. Most striking in relation to controls, patients showed decreased LIFC activation concurrent with increased left superior temporal gyrus activation for semantic encoding versus shallow encoding. Furthermore, schizophrenia subjects did not show the repetition priming effect, either behaviorally or as a decrease in LIPC activity. In patients with schizophrenia, LIFC underactivation and left superior temporal gyrus overactivation for semantically encoded words may reflect a disease-related disruption of a distributed frontal temporal network that is engaged in the representation and processing of meaning of words, text, and discourse and which may underlie schizophrenic thought disturbance.

Adult↗
PubMed2003

Electrophysiology of sensory and sensorimotor processing in mice under general anesthesia.

Like many other complex biological phenomena, sensory processing is starting to be studied at the level of the gene. Whereas the mouse is the standard organism for molecular neurobiology, somatosensation and pain are mainly investigated in the rat. The in-vitro electrophysiological technique is well established in mice. The effect of manipulations of the mouse genome on neuronal systems and networks has to be investigated under in-vivo conditions. Thus, the step from the rat to the smaller mouse seems to be important in terms of progress in molecular neurobiology. So far, there is no published study of sensory processing by electrophysiological means in mice under controlled general anesthesia. In this paper we describe a technique for electrophysiological recordings of sensory and sensorimotor processing in anesthetized mice. The mouse is anesthetized by continuous administration of the short-acting general anesthetic methohexital sodium salt via the jugular vein and artificially ventilated via a tracheotomy. The electrocardiogram and the carotid artery blood pressure are monitored. The sensorimotor jaw-opening reflex and the hindpaw withdrawal reflex are elicited by electric stimulation of the tongue and the sole of the hindpaw, respectively. The jaw-opening reflex is inhibited by deep brain stimulation of the rostral ventromedial medulla. On- and off-cells of the rostral ventromedial medulla and sensory neurons of the spinal trigeminal nucleus are extracellularly recorded by tungsten electrodes. General anesthesia can be reliably induced, maintained and sufficiently controlled in mice. Under this condition, studies can be performed on sensory processing in mice.

Action Potentials↗
PubMed2003

Modeling cross-modal enhancement and modality-specific suppression in multisensory neurons.

Cross-modal enhancement (CME) occurs when the neural response to a stimulus of one modality is augmented by another stimulus of a different modality. Paired stimuli of the same modality never produce supra-additive enhancement but may produce modality-specific suppression (MSS), in which the response to a stimulus of one modality is diminished by another stimulus of the same modality. Both CME and MSS have been described for neurons in the deep layers of the superior colliculus (DSC), but their neural mechanisms remain unknown. Previous investigators have suggested that CME involves a multiplicative amplifier, perhaps mediated by N-methyl D-aspartate (NMDA) receptors, which is engaged by cross-modal but not modality-specific input. We previously postulated that DSC neurons use multisensory input to compute the posterior probability of a target using Bayes' rule. The Bayes' rule model reproduces the major features of CME. Here we use simple neural implementations of our model to simulate both CME and MSS and to argue that multiplicative processes are not needed for CME, but may be needed to represent input variance and covariance. Producing CME requires only weighted summation of inputs and the threshold and saturation properties of simple models of biological neurons. Multiplicative nodes allow accurate computation of posterior target probabilities when the spontaneous and driven inputs have unequal variances and covariances. Neural implementations of the Bayes' rule model account better than the multiplicative amplifier hypothesis for the effects of pharmacological blockade of NMDA receptors on the multisensory responses of DSC neurons. The neural implementations also account for MSS, given only the added hypothesis that input channels of the same modality have more spontaneous covariance than those of different modalities.

Animals↗
PubMed1995

Amygdalo-entorhinal relations and their reflection in the hippocampal formation: generation of sharp sleep potentials.

While the anatomical relations between the amygdala, parahippocampal cortices, and hippocampus have been studied extensively, little is known about how they interact. To address this issue, we studied the timing of entorhinal (ENT), subicular, and basolateral amygdaloid (BL) discharges with respect to previously unknown population events, hereafter termed sharp potentials (SPs), that appear in the ENT cortex of cats during EEG-synchronized states. SPs occurred in two forms. Simple SPs were monophasic potentials, negative in deep ENT layers and positive in layer I. Complex SPs appeared as simple SPs interrupted by a brief potential of opposite polarity. Simple SPs had no hippocampal correlate whereas complex SPs were followed by large potentials that could be recorded at several levels of the hippocampal loop under barbiturate anesthesia, but not beyond the dentate gyrus in natural sleep. In agreement with this, layer II ENT neurons and most subicular cells fired only in relation to complex SPs under anesthesia. Layer II ENT neurons fired in phase with SPs whereas subicular neurons fired 20-40 msec later. In contrast, BL cells, layers IV-VI and layer III ENT neurons fired sequentially in relation to SPs with BL cells discharging as early as 40 msec before SPs. Finally, amygdala lesions abolished ENT SPs. These results suggest that the BL complex plays an essential role in the generation of population events that are transmitted to the ENT cortex. This is the first demonstration that spontaneous events occurring in the amygdala are reflected in the activity of related cortices. In turn, layer II ENT neurons gate the transfer of incoming inputs to the hippocampus. These findings shed light on the elaboration of normal and pathological activities in the amygdalo-hippocampal network.

Action Potentials↗
PubMed2001

Area 3a: topographic organization and cortical connections in marmoset monkeys.

The functional organization of area 3a, a cortical field proposed to be involved in somato-motor-vestibular integration, has never been described for any primate. In the present investigation, the topographic organization and connections of area 3a were examined in marmosets using electrophysiological recording and anatomical tracing techniques. Multi-unit neuronal activity was recorded at a number of closely spaced sites; receptive fields (RFs) for neurons were determined, and the optimal stimulus was identified. In all cases, neurons in area 3a responded to the stimulation of deep receptors on the contralateral body. The representation of the body in area 3a was from the toes and foot, to the hindlimb, trunk, forelimb, hand and face in a mediolateral progression. In all cases electrophysiological results were related to myeloarchitecture, and the map in area 3a was found to be coextensive with a strip of lightly to moderately myelinated cortex just rostral to the darkly myelinated 3b. To examine the cortical connections of area 3a, injections of anatomical tracers were made into electrophysiologically identified body part representations. Area 3a has dense intrinsic connections and receives substantial inputs from the primary motor cortex (M1), the supplementary motor area (SMA), areas 1 and 2, the second somatosensory area (S2), and areas in posterior parietal cortex (PP). The connections of area 3a indicate that integration of cortical representations of body parts occurs both within area 3a and between area 3a and other somatosensory and motor areas. In addition, there are differential patterns of interconnections between behaviorally relevant body part representations of area 3a, such as the forelimb, compared to other body part representations (hindlimb/ trunk), especially with 'higher order' cortical fields. This suggests that 3a may be an important component in a network that generates a common frame of reference for hand and eye coordinated reaching tasks.

Animals↗
PubMed2004

Lamina-specific differences in GABA(B) autoreceptor-mediated regulation of spontaneous GABA release in rat entorhinal cortex.

Spontaneous synaptic inhibition plays an important role in regulating the excitability of cortical networks. Here we have investigated the role of GABA(B) autoreceptors in regulating spontaneous GABA release in the entorhinal cortex (EC), a region associated with temporal lobe epilepsies. We have previously shown that the level of spontaneous inhibition in superficial layers of the EC is much greater than that seen in deeper layers. In the present study, using intracellular and whole cell patch clamp recordings in rat EC slices, we have demonstrated that evoked GABA responses are controlled by feedback inhibition via GABA(B) autoreceptors. Furthermore, recordings of spontaneous, activity-independent inhibitory postsynaptic currents in layer II and layer V neurones showed that the GABA(B) receptor agonist, baclofen, reduced the frequency of GABA-mediated currents indicating the presence of presynaptic GABA(B) receptors in both layers. Application of the antagonist, CGP55845, blocked the effects of baclofen and also increased the frequency of GABA-mediated events above baseline, but the latter effect was restricted to layer V. This demonstrates that GABA(B) autoreceptors are tonically activated by synaptically released GABA in layer V, and this may partly explain the lower level of spontaneous GABA release in the deep layer.

Action Potentials↗
PubMed2005

Connectivity of the human periventricular-periaqueductal gray region.

OBJECT: The periventricular gray (PVG) zone and its continuation, the periaqueductal gray (PAG) substance, have been targets for deep brain stimulation (DBS) in the alleviation of intractable pain for longer than two decades. Nevertheless, the anatomical connectivity of this region has been fairly poorly defined. The effects of DBS in this region are probably related to the release of endogenous endorphins, but until the connectivity of this region is better understood the mechanisms will remain unclear. METHODS: Diffusion tractography was used to trace the pathways of the PVG-PAG region in seven healthy human volunteers. Images were acquired with the aid of a 1.5-tesla magnetic resonance imaging system. The region of interest was located just lateral to the posterior commissure and extended caudally to the level of the superior colliculus. Probabilistic diffusion tractography was performed from each voxel in each patient's PVG-PAG region. The PVG-PAG region was found to yield descending projections to the spinal cord and cerebellum. Ascending projections to the thalamus and frontal lobes were also observed. CONCLUSIONS: These findings suggest that the PVG-PAG region may modulate pain by two mechanisms: one involving the antinociceptive system in the spinal cord and the other involving influences on the central pain network.

Afferent Pathways↗
PubMed2005

A putative generalized model of the effects and mechanism of action of high frequency electrical stimulation of the central nervous system.

High-frequency stimulation (HFS) of neural structures has been used since 1997 as an alternative to lesions in functional neurosurgery of movement disorders, and more recently, it has been applied to the treatment of epilepsies, obsessive-compulsive disorders, cluster headaches, and has other applications in experimental models, particularly for obesity. Although their clinical efficacy is not questioned, and that the effects most of the time parallel those of ablative techniques, leading to the concept of functional inhibition, the intimate mechanisms by which HFS induces excitation within fiber bundles and seems to inhibit cellular nuclei is still strongly debated. Principally due to the observation of long-term clinical effects over a period up to 15 years, it is clear that the mechanism is not due to a progressive lesion, as at every moment the interruption of stimulation reverses totally the effects. There is no current proof that long-term HFS is able to reset neural networks, or to induce profound modifications of the functional organization or of the synaptic connectivity. To understand what is responsible for the immediate, reversible and adaptable effects of HFS, several mechanisms must be considered, which might be involved simultaneously or in sequence: i) Jamming of neural transmission through stimulated nuclei is one possibility, based on the principle that the regular imposed activity might drive the neurons to fire in a regular pattern, making it impossible to transmit more subtle messages, either normal or abnormal. Although it is difficult to prove this type of mechanism, it might account for the reports of increased activity following HFS in various structures. ii) Direct inhibition of spike initiation at the level of the membrane could be due to activation of inhibitory terminals, particularly gaba-ergic, or by a blockade of the voltage gated ion channels. iii) Recent data show that HFS decreases the production and release of low molecular weight proteic neurotransmitters, which could account for the functional inhibition while the efferent axon is still excited by the electrical stimulus. iv) Retrograde activation of upstream neuronal structures, as reported in the external pallidum during stimulation of STN, might be responsible of additional jamming-like effects due to collisions with descending spikes.

Animals↗
PubMed2005

Synaptic targets of calretinin-containing axon terminals in macaque monkey prefrontal cortex.

The coordinated activity of specific populations of pyramidal cells and GABA-containing, local circuit neurons in the primate prefrontal cortex (PFC) appears to be critical for working memory. Different subclasses of GABA-containing neurons can be distinguished by their content of the calcium-binding proteins parvalbumin (PV) and calretinin (CR). The postsynaptic targets of PV-containing cells have been well characterized in the primate PFC, but the postsynaptic targets of CR-containing neurons in this cortical region remain unknown. In the present study, we used immuno-electron microscopy to examine the synaptic type and postsynaptic targets of CR-immunoreactive (IR) axon terminals in the superficial and deep layers of macaque monkey PFC. Labeled axon terminals formed both symmetric and asymmetric synapses. Within the superficial layers, 93% of the synapses formed by CR-IR were symmetric, whereas in the deep layers the labeled axon terminals forming synapses were more evenly divided between symmetric (57%) and asymmetric (43%). The primary postsynaptic target of these two populations of CR-IR axon terminals also differed; unlabeled dendritic shafts were the predominant target of the symmetric synapses, whereas dendritic spines were the most common target of the asymmetric synapses. In addition, the mean cross-sectional area of the terminals forming asymmetric synapses was significantly larger than that of the terminals forming symmetric synapses. The presence of CR-IR asymmetric synapses suggested that they might arise from neurons that do not utilize GABA; indeed, dual-label fluorescent immunocytochemistry revealed that a subpopulation (23%) of CR-containing neurons in monkey PFC were not GABA-IR. These findings indicate that the synaptology of CR-containing neurons is more heterogeneous than that of PV-containing cells and suggests that the contributions of CR-containing neurons to cognitive processes mediated by the PFC may be more diverse.

Animals↗
PubMed2004

Synaptic activation patterns of the perirhinal-entorhinal inter-connections.

Ample neuropsychological evidence supports the role of rhinal cortices in memory. The perirhinal cortex (PRC) represents one of the main conduits for the bi-directional flow of information between the entorhinal-hippocampal network and the cortical mantle, a process essential in memory formation. However, despite anatomical evidence for a robust reciprocal connectivity between the perirhinal and entorhinal cortices, neurophysiological understanding of this circuitry is lacking. We now present the results of a series of electrophysiological experiments in rats that demonstrate robust synaptic activation patterns of the perirhinal-entorhinal inter-connections. First, using silicon multi-electrode arrays placed under visual guidance in vivo we performed current source density (CSD) analysis of lateral entorhinal cortex (LEC) responses to PRC stimulation, which demonstrated a current sink in layers II-III of the LEC with a latency consistent with monosynaptic activation. To further substantiate and extend this conclusion, we developed a PRC-LEC slice preparation where CSD analysis also revealed a current sink in superficial LEC layers in response to PRC stimulation. Importantly, intracellular recording of superficial LEC layer neurons confirmed that they receive a major monosynaptic excitatory input from the PRC. Finally, CSD analysis of the LEC to PRC projection in vivo also allowed us to document robust feedback synaptic activation of PRC neurons to deep LEC layer activation. We conclude that a clear bidirectional pattern of synaptic interactions exists between the PRC and LEC that would support a dynamic flow of information subserving memory function in the temporal lobe.

Animals↗
PubMed2005

Evolving concepts on the pathophysiology of absence seizures: the cortical focus theory.

Four main theories on the pathophysiology of generalized absence seizures have been proposed. The "centrencephalic" theory, proposed in 1954, suggested that discharges originate from a deep-seated diffusely projecting subcortical pacemaker in the midline thalamus. This concept was refined in 1991 with the "thalamic clock" theory, implying that the reticular thalamic nucleus contains the pacemaker cells for the thalamic clock, imposing its rhythm to the cortex. According to other investigators, however, the cortex seems to play a leading role. They suggested that spike-wave discharges have a focal onset in the cortex and are generalized through a rapid propagation. In the "corticoreticular" theory, postulated in 1968, spike-wave discharges are linked to the thalamocortical mechanisms that generate spindles. Rhythmic spindle oscillations generated in the thalamus are transformed into spike-wave discharges when the cortex is hyperexcitable. A 2002 study confirmed in epileptic rats that a functionally intact thalamocortical network is required for the generation of spike-wave discharges. The corticothalamic interrelationships were investigated by means of nonlinear association signal analyses of multiple spike-wave discharges. This showed a consistent focus within the perioral region of the somatosensory cortex. From this focus, seizure activity generalizes rapidly over the cortex. During the first cycles of the seizure the cortex drives the thalamus, while thereafter cortex and thalamus drive each other, thus amplifying and maintaining the rhythmic discharge. In this way the "cortical focus" theory for generalized absence epilepsy bridges cortical and thalamic theories.

Animals↗
PubMed2026

Development of a PCR-based technique for genotyping UGT1A1 gene and distribution of rs3064744 alleles in the Russian population.

BACKGROUND: Accurate determination of tandem thymine-adenine (TA) repeat numbers in the UGT1A1 promoter region (rs3064744) is essential for diagnosing Gilbert's syndrome and personalizing therapy with toxic agents like irinotecan and atazanavir. However, traditional polymerase chain reaction (PCR) assays face severe limitations due to the AT-rich sequence and overlapping melting temperatures (Tm) of the highly homologous 7TA and 8TA alleles. In this context, melting curve analysis (MCA) employing fluorophore-quencher systems has emerged as a promising alternative. The purpose of this study was to develop a novel genotyping approach combining optimized aPCR-MCA analysis with an automated classifier to overcome the limitations posed by the differentiation of highly homologous alleles and to demonstrate its practical application, providing the distribution of rs3064744 genotypes across four regional cohorts of the Russian population. METHODS: A specialized Dual Head 1D-convolutional neural network (1D-CNN) ensemble with Test-Time Augmentation (TTA) was developed. The model was trained and internally validated on 1,620 engineered plasmid samples, and independently evaluated on an external clinical test set of 440 unique patient genomic DNA specimens. Real-time PCR was performed on CFX96 and DTprime platforms. Additionally, population-wide screening was conducted on 997 archival clinical samples from Moscow, Sakha (Yakutia), Dagestan, and Rostov regions. RESULTS: While 5TA and 6TA alleles were easily separated, absolute Tm distributions of 7TA and 8TA alleles overlapped significantly, and non-uniform Tm shifts of 0.8&#xa0;&#xb0;C-1.4&#xa0;&#xb0;C occurred across platforms. Conventional absolute Tm thresholding was therefore inadequate. By assessing relative morphological curve divergence against co-amplified 7TA/7TA and 7TA/8TA reference anchors, the 1D-CNN ensemble neutralized instrument noise. It achieved 100% accuracy on internal validation and 100% concordance (440/440) with clinical reference pyrosequencing. Population screening revealed that Dagestan, Yakutia, and Rostov cohorts closely align with the European population. Rare 5TA and 8TA alleles were detected at low frequencies in Yakutia and Moscow. CONCLUSION: Combining LNA-modified aPCR-MCA with a comparative 1D-CNN model successfully circumvents thermodynamic limitations and eliminates human operator bias. This integrated system offers an accessible, high-throughput, and clinically valid solution for routine UGT1A1 pharmacogenetic testing.

1D-CNN↗
PubMed2006

Neural lineages of the Drosophila brain: a three-dimensional digital atlas of the pattern of lineage location and projection at the late larval stage.

The late larval brain consists of embryonically produced primary neurons forming a deep core cortex, surrounded at the surface by approximately 100 secondary lineages. Each secondary lineage forms a tract (secondary lineage tract) with an invariant and characteristic trajectory. Within the neuropile, tracts of neighboring lineages bundle together to form secondary tract systems. In this paper, we visualized secondary lineages by the global marker BP106 (neurotactin), as well as green fluorescent protein-labeled clones and thereby establish a comprehensive digital atlas of secondary lineages. The information contained in this atlas is the location of the lineage within the cortex, the neuropile compartment contacted by the lineage tract, and the projection pattern of the lineage tract within the neuropile. We have digitally mapped the expression pattern of three genes, sine oculis, period, and engrailed into the lineage atlas. The atlas will enable us and others to analyze the phenotype of mutant clones in the larval brain. Mutant clones can only be interpreted if the corresponding wild-type clone is well characterized, and our lineage atlas, which visualizes all wild-type lineages, will provide this information. Secondly, secondary lineage tracts form a scaffold of connections in the neuropile that foreshadows adult nerve connections. Thus, starting from the larval atlas and proceeding forward through pupal development, one will be able to reconstruct adult brain connectivity at a high level of resolution. Third, the atlas can serve as a repository for genes expressed in lineage-specific patterns.

Anatomy, Artistic↗
PubMed2004

Derivation and analysis of basic computational operations of thalamocortical circuits.

Shared anatomical and physiological features of primary, secondary, tertiary, polysensory, and associational neocortical areas are used to formulate a novel extended hypothesis of thalamocortical circuit operation. A simplified anatomically based model of topographically and nontopographically projecting ("core" and "matrix") thalamic nuclei, and their differential connections with superficial, middle, and deep neocortical laminae, is described. Synapses in the model are activated and potentiated according to physiologically based rules. Features incorporated into the models include differential time courses of excitatory versus inhibitory postsynaptic potentials, differential axonal arborization of pyramidal cells versus interneurons, and different laminar afferent and projection patterns. Observation of the model's responses to static and time-varying inputs indicates that topographic "core" circuits operate to organize stored memories into natural similarity-based hierarchies, whereas diffuse "matrix" circuits give rise to efficient storage of time-varying input into retrievable sequence chains. Examination of these operations shows their relationships with well-studied algorithms for related functions, including categorization via hierarchical clustering, and sequential storage via hash- or scatter-storage. Analysis demonstrates that the derived thalamocortical algorithms exhibit desirable efficiency, scaling, and space and time cost characteristics. Implications of the hypotheses for central issues of perceptual reaction times and memory capacity are discussed. It is conjectured that the derived functions are fundamental building blocks recurrent throughout the neocortex, which, through combination, gives rise to powerful perceptual, motor, and cognitive mechanisms.

Algorithms↗
PubMed2003

Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition.

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.

Action Potentials↗
PubMed2005

Physiological changes in chronic epileptic rats are prominent in superficial layers of the medial entorhinal area.

PURPOSE: We investigated whether the functional network properties of the medial entorhinal area (MEA) of the entorhinal cortex were altered in a rat model of chronic epilepsy that is characterized by extensive cell loss in MEA layer III. METHODS: Responses were evoked in the entorhinal cortex by electrical stimulation of the subiculum in anesthetized chronic epileptic rats, 2-4 months after status epilepticus, induced by systemic kainate (KA) injections. Laminar field potentials were measured using a 16-channel silicon probe that covered all six layers of the MEA; an estimate of the local transmembrane currents was made using current source density analysis. RESULTS: Double-pulse stimulation of the subiculum evoked responses in deep and superficial layers of the MEA in control and KA rats. A current sink in layer I and at the border of layer I and II that was induced by antidromic activation of MEA-II, was much more prominent in KA rats with extensive neuronal loss in MEA-III than in control rats or KA rats with minor MEA-III loss. Furthermore, KA rats that displayed MEA-III loss presented a series of oscillations induced by subicular stimulation in the beta/gamma-frequency range (20-100 Hz), which were confined to superficial layers of MEA. These oscillations were never observed in control rats or KA rats with minor MEA-III loss. CONCLUSIONS: These results indicate that the observed alterations in the superficial MEA responses to subiculum stimulation and the occurrence of beta/gamma-oscillations are related phenomena, which are a consequence of altered and impaired inhibition within these MEA layers in chronic epileptic rats.

Animals↗