Cortico-thalamocortical Circuits Research Articles

Variable cardiac responses in rhesus macaque monkeys after discrete mediodorsal thalamus manipulations

The control of some physiological parameters, such as the heart rate, is known to have a role in cognitive and emotional processes. Cardiac changes are also linked to mental health issues and neurodegeneration. Thus, it is not surprising that many of the brain structures typically associated with cognition and emotion also comprise a circuit—the central automatic network—responsible for the modulation of cardiovascular output. The mediodorsal thalamus (MD) is involved in higher cognitive processes and is also known to be connected to some of the key neural structures that regulate cardiovascular function. However, it is unclear whether the MD has any role in this circuitry. Here, we show that discrete manipulations (microstimulation during anaesthetized functional neuroimaging or localized cytotoxin infusions) to either the magnocellular or the parvocellular MD subdivisions led to observable and variable changes in the heart rate of female and male rhesus macaque monkeys. Considering the central positions that these two MD subdivisions have in frontal cortico-thalamocortical circuits, our findings suggest that MD contributions to autonomic regulation may interact with its identified role in higher cognitive processes, representing an important physiological link between cognition and emotion.

Mathematical Model Insights into EEG Origin under Transcranial Direct Current Stimulation (tDCS) in the Context of Psychosis.

Schizophrenia is a psychotic disease that develops progressively over years with a transition from prodromal to psychotic state associated with a disruption in brain activity. Transcranial Direct Current Stimulation (tDCS), known to alleviate pharmaco-resistant symptoms in patients suffering from schizophrenia, promises to prevent such a psychotic transition. To understand better how tDCS affects brain activity, we propose a neural cortico-thalamo-cortical (CTC) circuit model involving the Ascending Reticular Arousal System (ARAS) that permits to describe major impact features of tDCS, such as excitability for short-duration stimulation and electroencephalography (EEG) power modulation for long-duration stimulation. To this end, the mathematical model relates stimulus duration and Long-Term Plasticity (LTP) effect, in addition to describing the temporal LTP decay after stimulus offset. This new relation promises to optimize future stimulation protocols. Moreover, we reproduce successfully EEG-power modulation under tDCS in a ketamine-induced psychosis model and confirm the N-methyl-d-aspartate (NMDA) receptor hypofunction hypothesis in the etiopathophysiology of schizophrenia. The model description points to an important role of the ARAS and the -rhythm synchronicity in CTC circuit in early-stage psychosis.

Corticothalamic Pathways From Layer 5: Emerging Roles in Computation and Pathology.

Large portions of the thalamus receive strong driving input from cortical layer 5 (L5) neurons but the role of this important pathway in cortical and thalamic computations is not well understood. L5-recipient “higher-order” thalamic regions participate in cortico-thalamo-cortical (CTC) circuits that are increasingly recognized to be (1) anatomically and functionally distinct from better-studied “first-order” CTC networks, and (2) integral to cortical activity related to learning and perception. Additionally, studies are beginning to elucidate the clinical relevance of these networks, as dysfunction across these pathways have been implicated in several pathological states. In this review, we highlight recent advances in understanding L5 CTC networks across sensory modalities and brain regions, particularly studies leveraging cell-type-specific tools that allow precise experimental access to L5 CTC circuits. We aim to provide a focused and accessible summary of the anatomical, physiological, and computational properties of L5-originating CTC networks, and outline their underappreciated contribution in pathology. We particularly seek to connect single-neuron and synaptic properties to network (dys)function and emerging theories of cortical computation, and highlight information processing in L5 CTC networks as a promising focus for computational studies.

My prolonged collaboration with Ray Guillery.

My active collaboration with Ray Guillery started in 1968, when he was a Full Professor at the University of Wisconsin and I was a graduate student at the University of Pennsylvania. The collaboration lasted almost 50years with virtually no breaks. Among the ideas we proposed are that glutamatergic pathways in thalamus and cortex can be classified into drivers and modulators; that many thalamic nuclei could be classified as higher order, meaning that they receive driving input from layer 5 of cortex and participate in cortico-thalamocortical circuits; and that much of the information relayed by thalamus serves as an efference copy for motor commands initiated by cortex.

Shared reduction of oscillatory natural frequencies in bipolar disorder, major depressive disorder and schizophrenia

IntroductionRecent studies have demonstrated that cortical brain areas tend to oscillate at a specific natural frequency when directly perturbed by transcranial magnetic stimulation (TMS). Fast electroencephalographic (EEG) oscillations, which typically originate from frontal regions, have been reported to be markedly reduced in schizophrenia. MethodsHere we employed TMS/EEG to assess the natural frequency of the premotor area in a sample of 48 age-matched participants (12 each in major depression disorder (MDD)), bipolar disorder (BPD), schizophrenia (SCZ) and healthy controls. Event related spectral perturbations (ERSP) were obtained for each study participant using wavelet decomposition. ResultsTMS resulted in a significant activation of the beta/gamma band response (21–50Hz) to frontal cortical perturbation in healthy control subjects. By contrast, the main frequencies of frontal EEG responses to TMS were significantly reduced in patients with BPD, MDD and SCZ (11–27Hz) relative to healthy subjects. ConclusionsPatients with bipolar disorder, major depression and schizophrenia showed a significantly lower natural frequency of frontal cortico-thalamocortical circuits compared to healthy controls. These results suggest a common neurobiological mechanism of corticothalamic impairment. The most likely candidates include dysfunction of GABAergic circuits. LimitationsFurther studies are needed to consider other biological markers, gene variants, and their interaction with clinical variables.

Theory of Electric Resonance in the Neocortical Apical Dendrite

Pyramidal neurons of the neocortex display a wide range of synchronous EEG rhythms, which arise from electric activity along the apical dendrites of neocortical pyramidal neurons. Here we present a theoretical description of oscillation frequency profiles along apical dendrites which exhibit resonance frequencies in the range of 10 to 100 Hz. The apical dendrite is modeled as a leaky coaxial cable coated with a dielectric, in which a series of compartments act as coupled electric circuits that gradually narrow the resonance profile. The tuning of the peak frequency is assumed to be controlled by the average amplitude of voltage-gated outward currents, which in turn are regulated by the subthreshold noise in the thousands of synaptic spines that are continuously bombarded by local circuits. The results of simulations confirmed the ability of the model both to tune the peak frequency in the 10–100 Hz range and to gradually narrow the resonance profile. Considerable additional narrowing of the resonance profile is provided by repeated looping through the apical dendrite via the corticothalamocortical circuit, which reduced the width of each resonance curve (at half-maximum) to approximately 1 Hz. Synaptic noise in the neural circuit is discussed in relation to the ways it can influence the narrowing process.

Goodbye Ted (An Obituary for Edward G. Jones)

the discipline, characterized by the use of axonal transport tracers. He became a true master of electron microscopy and of the immunocytochemical techniques required to visualize neurotransmitters and their receptors, and moved on to new techniques to study the expression of specific genes and transcription factors. Ted was always capable of using the newest tools to study his two preferred brain regions: the thalamus and cerebral cortex. He also had a special interest in studying the role of the thalamus in the coordination and regulation of cortical function associated with consciousness and perception, as was evident from his many studies into the anatomy, physiology and, recently, the pathology of the corticothalamo-cortical circuit. Ted’s demonstration that the cortico-thalamic system is organized as a means to synchronize the activities of thalamic and cortical neurons has been primordial to understanding the function of the thalamus. Thanks to him, we now know that the focalized corticothalamic axon originating in layer VI, along with diffuse axonal projection from layer V cortical neurons and the cells of the core and of the matrix of the dorsal thalamus, form a substrate for the synchronization of the disperse cortical and thalamic neurons populations during high frequency oscillations; we also know that these synchronizations underlie specific events of consciousness. We cannot end this brief summary of Ted’s main feats without mentioning his extraordinary work to categorize cortical neurons and his classification in function of their morphology, chemical characteristics, and connections, in which we had the great fortune to participate extensively. Ted is one of the most highly cited scientists of all the scientific areas, and his merits are recognized through a number of significant prizes and distinctions that he was awarded. He was invested Doctor Honoris Causa by the University of Salamanca, he served as president of the Society for Neuroscience, and he was elected a member Goodbye Ted (an obituary for Edward G. Jones)

The corticothalamocortical circuit drives higher-order cortex in the mouse

SUMMARYAn unresolved question in neuroscience relates to the extent to which corticothalamocortical circuits emanating from layer 5B play a role in information transfer through the cortical hierarchy. Here, using a novel form of optical imaging in a brain slice preparation, we demonstrate that the corticothalamocortical pathway drives robust activity in higher-order somatosensory cortex. When the direct corticocortical pathway was interrupted, secondary somatosensory cortex showed robust activity in response to stimulation of the barrel field in primary somatosensory cortex (S1BF), which was eliminated after subsequently cutting the somatosensory thalamus, suggesting a highly efficacious corticothalamocortical circuit. Further, after chemically inhibiting the thalamus, activation in secondary somatosensory cortex was eliminated, with a subsequent return after washout. Finally, stimulation of layer 5B in S1BF, and not layer 6, drove corticothalamocortical activation. These findings suggest that the corticothalamocortical circuit is a physiologically viable candidate for information transfer to higher-order cortical areas.

NMDA antagonist and antipsychotic actions in cortico-subcortical circuits

Cognitive deficits in schizophrenia are associated with prefrontal cortex (PFC) abnormalities. Schizophrenic patients show a reduced performance in tasks engaging the PFC and a reduction of markers of cellular integrity and function. Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to exacerbate schizophrenia symptoms in patients and to elicit psychotomimetic actions in healthy volunteers. Also, these drugs evoke behavioral alterations in experimental animals that resemble schizophrenia symptoms. The PFC seems to be a key target area for these agents. However, the cellular and network elements involved are poorly known. Cognitive deficits are of particular interest since an early antipsychotic-induced improvement in cognitive performance predicts a better long-term clinical outcome. Here we report that the non-competitive NMDA receptor antagonist phencyclidine (PCP) induces a marked disruption of the activity of PFC. PCP administration increased the activity of a substantial proportion of pyramidal neurons, as evidenced by an increase in discharge rate and in c-fos expression. Examination of the effects of PCP on other brain areas revealed an increased c-fos expression in a number of cortical and subcortical areas, but notably in thalamic nuclei projecting to the PFC. The administration of classical (haloperidol) and/or atypical (clozapine) antipsychotic drugs reversed PCP effects. These results indicate that PCP induces a marked disruption of the network activity in PFC and that antipsychotic drugs may partly exert their therapeutic effect by normalizing hyperactive cortico-thalamocortical circuits.

IMPAIRED LOW AND HIGH-FREQUENCY OSCILLATORY ACTIVITY DURINGWORKING MEMORY IN ADOLESCENTS WITH SCHIZOPHRENIA

Recent studies have demonstrated that cortical brain areas tend to oscillate at a specific natural frequency when directly perturbed by transcranial magnetic stimulation (TMS). Fast electroencephalographic (EEG) oscillations, which typically originate from frontal regions, have been reported to be markedly reduced in schizophrenia.Here we employed TMS/EEG to assess the natural frequency of the premotor area in a sample of 48 age-matched participants (12 each in major depression disorder (MDD)), bipolar disorder (BPD), schizophrenia (SCZ) and healthy controls. Event related spectral perturbations (ERSP) were obtained for each study participant using wavelet decomposition.TMS resulted in a significant activation of the beta/gamma band response (21–50 Hz) to frontal cortical perturbation in healthy control subjects. By contrast, the main frequencies of frontal EEG responses to TMS were significantly reduced in patients with BPD, MDD and SCZ (11–27 Hz) relative to healthy subjects.Patients with bipolar disorder, major depression and schizophrenia showed a significantly lower natural frequency of frontal cortico-thalamocortical circuits compared to healthy controls. These results suggest a common neurobiological mechanism of corticothalamic impairment. The most likely candidates include dysfunction of GABAergic circuits.Further studies are needed to consider other biological markers, gene variants, and their interaction with clinical variables.

Basal Forebrain Cholinergic Input Is Not Essential for Lesion-Induced Plasticity in Mature Auditory Cortex

The putative role of the basal forebrain cholinergic system in mediating lesion-induced plasticity in topographic cortical representations was investigated. Cholinergic immunolesions were combined with unilateral restricted cochlear lesions in adult cats, demonstrating the consequence of cholinergic depletion on lesion-induced plasticity in primary auditory cortex (AI). Immunolesions almost eliminated the cholinergic input to AI, while cochlear lesions produced broad high-frequency hearing losses. The results demonstrate that the near elimination of cholinergic input does not disrupt reorganization of the tonotopic representation of the lesioned (contralateral) cochlea in AI and does not affect the normal representation of the unlesioned (ipsilateral) cochlea. It is concluded that cholinergic basal forebrain input to AI is not essential for the occurrence of lesion-induced plasticity in AI.

Cortico-thalamocortical operations of multi-target spatial working memory

Representation and manipulation of multiple target locations would be important aspects of spatial working memory (Neurocomputing 44–46 (2002) 1001; Neural Networks 15 (2002) 573). It is, however, unknown how such processes are performed in the prefrontal cortical, corticocortical, and cortico-subcortical circuits. We here propose a model of the prefrontal cortical and cortico-thalamocortical circuits that represent and manipulate multiple targets. The simulation with this model shows that transient inputs to the thalamic relay cells increase the signal transmission of the thalamocortical afferents. This eliminates one or more of the targets represented in the prefrontal cortex. The number of the eliminated targets depends on the width of the directional tuning of the inputs to the relay cells.

Lesions in the Pulvinar in Patients with Alzheimerʼs Disease

The pulvinar nucleus of the thalamus has been implicated in visual attention and in the control of eye movements, and may also help mediate attention-dependent tasks in the auditory and somatosensory systems. Consequently, a hypothetical disruption of functions mediated by the pulvinar may help understand common visual and nonvisual symptoms in patients with Alzheimer's disease. To test this hypothesis, the pulvinar nuclei of nine patients with histologically confirmed Alzheimer's disease and twelve young (9-28 years of age) and age-matched controls (without dementia and with non-Alzheimer dementias) were examined using a battery of histopathological methods. All patients with Alzheimer's disease had numerous amyloid plaques and some neuritic plaques throughout the various subdivisions of the pulvinar. Neuropil threads were also present among the senile plaques, and neurofibrillary tangles occurred in clusters throughout the nucleus. Control patients with and without dementia had very few Alzheimer lesions, which should be expected in normal elderly individuals. The lesions in the pulvinar may help understand some of the clinical manifestations of Alzheimer's disease, including deficits in attention and in a host of visual disturbances. Such deficits may be the result of involvement of reciprocal thalamo-cortical and corticothalamo-cortical circuits that appear to be critical for the function of a vast expanse of association cortices interconnected with the pulvinar, which are heavily laden with lesions themselves.

Involvement of cortical, thalamic and midbrain reticular formation neurons in spike and wave discharges: Extracellular study in feline generalized penicillin epilepsy

Extracellular activity of single units, simultaneously recorded in cortex, thalamus, and midbrain reticular formation was investigated during feline generalized penicillin epilepsy. The firing activity of neurons recorded in the cortex was invariably and consistently enhanced in coincidence with the positive peak and the positive-negative transient of the “spike” of the spike and wave complex, and it was greatly decreased during the wave. In the nonspecific thalamic nuclei three classes of neurons were identified according to their patterns of activity during the spike and wave complex: (i) neurons behaving like cortical units, (ii) neurons with enhanced firing activity during the wave and a decreased activity during the “spike,” and (iii) unmodified neurons. In the nucleus lateralis posterior neurons of the third class were not found. Most midbrain reticular neurons could be classified in the same three classes of the nonspecific thalamic nuclei; however, 11% of those units increased their activity 20 to 30 ms earlier than did the cortical units (class IV). Investigation of the activities of all these neuronal populations immediately prior to a spike and wave discharge showed that the rhythmic cycle of excitation-inhibition commenced earlier in the cortical neurons than in any other subcortical neuron. Moreover, there were some nonspecific thalamic neurons of class II with an inhibitory phase exactly coincident with the activation of class IV midbrain reticular neurons. These data suggest (i) a leading role of cortical neurons in initiating and maintaining a spike and wave burst; (ii) the involvement of a corticothalamocortical circuit in timing the bursts, and (iii) an accessory reticulothalamic loop also involved in regulating the intraburst frequency of the spike and wave complex.