Central Thalamus Research Articles

Cognitive Activation by Central Thalamic Stimulation: The Yerkes-Dodson Law Revisited

Central thalamus regulates forebrain arousal, influencing activity in distributed neural networks that give rise to organized actions during alert, wakeful states. Central thalamus has been implicated in working memory by the effects of lesions and microinjected drugs in this part of the brain. Lesions and drugs that inhibit neural activity have been found to impair working memory. Drugs that increase activity have been found to enhance and impair memory depending on the dose tested. Electrical deep brain stimulation (DBS) similarly enhances working memory at low stimulating currents and impairs it at higher currents. These effects are time dependent. They were observed when DBS was applied during the memory delay (retention) or choice response (retrieval) but not earlier in trials during the sample (acquisition) phase. The effects of microinjected drugs and DBS are consistent with the Yerkes-Dodson law, which describes an inverted-U relationship between arousal and behavioral performance. Alternatively these results may reflect desensitization associated with higher levels of stimulation, spread of drugs or current to adjacent structures, or activation of less sensitive neurons or receptors at higher DBS currents or drug doses.

Recovery of consciousness after severe brain injury: The role of arousal regulation mechanisms and some speculation on the heart-brain interface

Recovery of consciousness after severe brain injury involves reconstitution of brain arousal mechanisms and cerebral integrative function. This review discusses several aspects of neuroanatomy and neuropathology relevant to the process of recovery. Particular emphasis is placed on the role of the anterior forebrain and circuit mechanisms linking the frontal lobe, striatum, and central thalamus. The article concludes with some observations on the heart-brain interface and future research directions in the context of recovery from severe brain injury.

Conflicts of Interest in Deep Brain Stimulation Research and the Ethics of Transparency

In this article we will draw on experiences from our own research on deep brain stimulation of the central thalamus in the minimally conscious state. We describe ethical challenges faced in clinical research involving medical devices and offer several cautionary notes about its funding and the interplay of market forces and scientific inquiry and suggest some reforms.

Expression of protocadherin-19 in the nervous system of the embryonic zebrafish

We have analyzed the expression pattern of protocadherin-19, a member of the delta2-protocadherins, in the nervous system of developing zebrafish using in situ hybridization methods. mRNA encoding protocadherin-19 (Pcdh19) began to be expressed at about 12 hours post fertilization (hpf) showing a segmental expression pattern in the anterior 1/3 of the neural keel, with strong expression in the presumptive forebrain, cerebellum/rhombomere 1 and rhombomere 4. Pcdh19 expression in the posterior neural keel was continuous and confined to the midline region. By 24 hpf, Pcdh19 was expressed widely in the brain and spinal cord, with higher expression levels in the ventral telencephalon, dorsal and central thalamus, optic tectum, central tegmentum, cerebellum and dorsolateral regions of the hindbrain. As development proceeded, Pcdh19 expression domains became restricted to the dorsal and/or lateral regions of the central nervous system, and Pcdh19 expression was not detected in the spinal cord of two- and three-day old embryos. Pcdh19 was also expressed by the eye primordium, developing retina, lens and otic vesicle. Similar to its expression in the brain, Pcdh19 expression in the eye and ear was also spatially and temporally regulated.

O.101 Rationale for targeting the thalamic centre median–parafascicular complex in the surgical treatment of Parkinson's disease

O.101 Rationale for targeting the thalamic centre median–parafascicular complex in the surgical treatment of Parkinson's disease

Rationale for targeting the thalamic centre-median parafascicular complex in the surgical treatment of Parkinson's disease

The thalamic centre median-parafascicular complex (CM/Pf), a main input and output station of the basal ganglia, is attracting increasing interest in the field of movement disorders, including Parkinson's disease (PD). CM/Pf undergoes partial neurodegeneration in PD patients and some rodent models. Cellular evidence has been provided in experimental animals that thalamic degeneration may not aggravate but rather counteract the effects of dopamine lesion. But functional changes in the circuits involving the spared neurons could play a detrimental role. This view fits with converging anecdotic and recent direct experience in patients that stress the potential of CM/PF deep brain stimulation (DBS) to alleviate motor disorders, notably tremor and dyskinesias. As a preclinical contribution to the characterization of this target, we investigated the functional impact of CM/Pf-DBS in the 6-hydroxydopamine hemiparkinsonian rat model of PD. When testing different frequencies (25, 60, 130 Hz), only high frequency stimulation (HFS) had significant antiakinetic action as evidenced by alleviation of limb use asymmetry in the cylinder test. Although less efficient than HFS of the subthalamic nucleus in the latter task, CM/PF-HFS completely corrected lateralized neglect in the corridor task. Unlike subthalamic nucleus, CM/Pf-HFS did not induce per se dyskinesias. Finally, the benefits provided by CM/Pf-HFS were associated with widespread impact on the changes in neuronal metabolic activity induced by the dopamine depletion in the basal ganglia. These data point to own particular outcome of CM/Pf-DBS that may be of interest in currently developing multi-target strategies.

Metabolic activity of pigeon thalamic and telencephalic auditory centers

Distribution of activity of mitochondrial oxidative enzyme cytochrome oxidase (CO) was studied in the thalamic (Ov) and telencephalic (field L) auditory centers of the pigeon Columbia livia. Different levels of CO activity are found in the core and belt of the centers: the high CO activity in the core of Ov (nCe) and telencephalic field L2 and the much lower or absent in the peripheral regions (Ovl, Ovm, SPO and L1 and L3). Comparison of our data with those of various avian and reptile species confirms the concept of the common plan of rostral auditory centers in sauropsid amniotes by the principle of the center-periphery (core-belt), which is characteristic of the corresponding mammalian centers. The separation of the central and peripheral parts of these centers is better pronounced in birds than in reptiles.

Central Thalamic Deep‐Brain Stimulation in the Severely Injured Brain

This review outlines the scientific rationale supporting the potential use of deep-brain electrical stimulation (DBS) in the central thalamus as a method to improve behavioral responsiveness following severe brain injury. Neurons within the central thalamus are selectively vulnerable to disconnection and dysfunction following severe brain injuries because of their unique geometry of cerebral connections. Because the central thalamus plays a key role in forebrain arousal regulation, impaired function of these cells has a broad impact. Prior clinical investigations, however, have targeted some components of the thalamus and related subcortical structures to improve behavioral responsiveness after severe brain injuries without providing evidence of sustained and clinically meaningful behavioral effects. Here important differences in conceptual framework, consideration of diagnostic categories for patient selection, and anticipated mechanisms of effect that distinguish earlier approaches and current studies are reviewed. As opposed to targeting chronically unresponsive patients, current efforts focus on identification of conscious patients with significant preservation of large-scale integrative cerebral networks. The potential mechanisms and limitations of this evolving strategy are discussed, including the need to develop frameworks to calibrate patient selection to potential clinical benefits, range of potential effect size, and other present unknowns.

Central Thalamic Contributions to Arousal Regulation and Neurological Disorders of Consciousness

This review focuses on the contributions of the central thalamus to normal mechanisms of arousal regulation and to neurological disorders of consciousness. Forebrain arousal is regulated by ascending influences from brainstem/basal forebrain neuronal populations ("arousal systems") and control signals descending from frontal cortical systems. These subcortical and cortical systems have converging projections to the central thalamus that emphasize their role in maintaining organized behavior during wakefulness. Central thalamic neurons appear to be specialized both anatomically and physiologically to support distributed network activity that maintains neuronal firing patterns across long-range cortico-cortical pathways and within cortico-striatopallidal-thalamocortical loop connections. Recruitment of central thalamic neurons occurs in response to increasing cognitive demand, stress, fatigue, and other perturbations that reduce behavioral performance. In addition, the central thalamus receives projections from brainstem pathways evolved to rapidly generate brief shifts of arousal associated with the appearance of salient stimuli across different sensory modalities. Through activation of the central thalamus, neurons across the cerebral cortex and striatum can be depolarized and their activity patterns selectively gated by descending or ascending signals related to premotor attention and alerting stimuli. Direct injury to the central thalamus or prominent deafferentation of these neurons as a result of complex, multifocal, brain insults are both associated with severe impairment of forebrain functional integration and arousal regulation. Interventions targeting neurons within the central thalamus may lead to rational therapeutic approaches to the treatment of impaired arousal regulation following nonprogressive brain injuries. A model accounting for present therapeutic strategies is proposed.

NEUROSTIMULATION AND THE MINIMALLY CONSCIOUS STATE

Neurostimulation to restore cognitive and physical functions is an innovative and promising technique for treating patients with severe brain injury that has resulted in a minimally conscious state (MCS). The technique may involve electrical stimulation of the central thalamus, which has extensive projections to the cerebral cortex. Yet it is unclear whether an improvement in neurological functions would result in a net benefit for these patients. Quality-of-life measurements would be necessary to determine whether any benefit of neurostimulation outweighed any harm in their response to different degrees of cognitive and physical disability. These measures could also indicate whether the technique could be ethically justified and whether surrogates could give proxy consent to its use on brain-injured patients.

Cholinergic modulation of visuospatial responding in central thalamus

Central thalamus has extensive connections with basal ganglia and frontal cortex that are thought to play a critical role in sensory-guided goal-directed behavior. Central thalamic activity is influenced by cholinergic projections from mesopontine nuclei. To elucidate this function we trained rats to respond to lights in a reaction time (RT) task and compared effects of muscarinic (2.4, 7.3, 22 nmol scopolamine) and nicotinic (5.4, 16, 49, 98 nmol mecamylamine) antagonists with the GABA(A) agonist muscimol (0.1, 0.3, 1.0 nmol) in central thalamus. We compared this with subcutaneous (systemic) effects of mecamylamine (3.2, 9.7, 29 micromol/kg) and scopolamine (0.03, 0.09, 0.26 micromol/kg). Subcutaneous scopolamine increased omissions (failure to respond within a 3-s response window) at the highest dose tested. Subcutaneous mecamylamine increased omissions at the highest dose tested while impairing RT and per cent correct at lower doses. Intrathalamic injections of muscimol and mecamylamine decreased per cent correct at doses that did not affect omissions or RT. Intrathalamic scopolamine increased omissions and RT at doses that had little effect on per cent correct. Anatomical controls indicated that the effects of mecamylamine were localized in central thalamus and those of scopolamine were not. Drug effects did not interact with attention-demanding manipulations of stimulus duration, proximity of stimulus and response locations, or stimulus array size. These results are consistent with the hypothesis that central thalamus mediates decisional processes linking sensory stimuli with actions, downstream from systems that detect sensory signals. They also provide evidence that this function is specifically influenced by nicotinic cholinergic receptors.

Corticotropin-Releasing Hormone and Pro-Opiomelanocortin Gene Expression in Female Monkeys with Differences in Sensitivity to Stress

Background/Aims: The expressions of corticotropin-releasing hormone (CRH) and pro-opiomelanocortin (POMC) were assessed in brain tissue collected from nonstressed female cynomolgus monkeys previously categorized as highly stress resilient (HSR), medium stress resilient (MSR), or stress sensitive (SS) with respect to stress-induced anovulation. Methods: In situ hybridization and quantitative image analysis was used to measure mRNAs coding for CRH in the hypothalamic paraventricular nucleus (PVN) and thalamic center median-subfascicular complex (CM-Sf). Then, CRH neurons in the PVN were immunostained and the area of immunostaining was measured. Also, CRH fibers were immunostained in the central nucleus of the amygdala and the area of immunostaining was obtained. Finally, POMC mRNA expression was characterized in the hypothalamic infundibular nucleus. The groups were compared with ANOVA and Student-Newman-Keul’s (SNK) post hoc comparison. Results: CRH mRNA was significantly elevated in the caudal PVN in the MSR and SS animals compared to HSR animals (p < 0.05, SNK). There was a significant increase in average and total CRH-positive area in the MSR and SS groups compared to the HSR group (p < 0.05, SNK). There was also a significant increase in CRH volume in the MSR and SS groups compared to the HSR group (p < 0.05, SNK). In the CM-Sf, the average CRH optical density was significantly higher in the MSR and SS groups than in the HSR group (p < 0.05, SNK). In the central nucleus of the amygdala, the area of CRH fiber staining was significantly higher in the SS group than in the MSR or HSR groups (p < 0.05, SNK). There was no difference between the groups in POMC mRNA expression in the mediobasal hypothalamus. Conclusion: Macaques that exhibit immediate suppression of reproductive function upon stress are considered stress sensitive. These animals have elevated CRH in the hypothalamus and limbic structures, which may play a role in suppressing the hypothalamic-gonadal axis upon stress initiation.

Metabolic activity of the thalamic and telencephalic auditory centers of reptiles

329 The lemniscal (classical projection) and extralemniscal parts of mammalian sensory systems, including the auditory system have different levels of metabolic activity. The lemniscal parts have a higher activity of cytochrome oxidase (CO) and an increased ability to accumulate 2-deoxyglucose (2-DG), whereas the extralemniscal parts are characterized by a lower level of metabolic activity [1]. A similar distribution of metabolic activity was observed in the auditory system of birds (in the mesencephalic, thalamic, and telencephalic auditory centers) [2‐4]. Earlier, we showed that the mesencephalic auditory center, torus semicircularis (TS), of some reptiles, such as turtles and lizards, has a higher CO activity in the central nucleus of the lemniscal pathway than in the peripheral extralemniscal part [5]. However, it is not clear whether the metabolic activity in the rostral centers of reptilian auditory system, viz. the auditory relay thalamic nucleus (n. reuniens, Re) and its projection zone in the telencephalon (the ventromedial part of anterior dorsal ventricular ridge, Advr), have selective distribution. In this work, we studied the distribution of the activity of the mitochondrial oxidative enzyme CO in the rostral auditory centers of two turtle species, Testudo horsfieldi and Emys orbicularis. The experiments were performed with four T. horsfieldi and four E. orbicularis. The CO activity was measured by the standard histochemical method [6] with the use of bovine heart cytochrome Σ (Sigma). The CO activity was estimated by the density of histochemical staining of frozen frontal brain slices with a thickness of 50 µ m. Thalamus. The distribution of the CO activity in the Re in both turtle species was similar and heterogeneous. In the rostral level of the thalamus, we found a CO-active band-shaped structure that continuously spread from the ventricle in the lateral direction below the ventral border of the thalamic center of the tectofugal visual system (Rot) and coincided with the location of the n. anterior (nA). The medial part of this structure is a rostral pole of Re (Figs. 1a and 2a). The middle Re level had two areas with a high CO activity. The larger dorsocentral area occupied almost the entire nucleus except for a small ventrolateral part and extended to the somatic nucleus n. ventralis (nV) below the Rot. This area was continuously connected with the rostral bandshaped structure (Figs. 1b and 2b). Like the rostral part of the Re, this area was filled with stained punctuate terminals with sparse CO-positive cells located in the lat

Behavioural improvements with thalamic stimulation after severe traumatic brain injury

Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

Neurochemical organization of reptilian thalamus. Comparative analysis of amniote optical centers

Study of neurochemical characteristics of the turtle thalamus was performed using antibodies against several biologically active compounds; monoamines (5-HT, TH), neuropeptides (SP, m-Enk, NPY), against ChAT and by histochemical detection of NADPH-d. Based on our own results and literature data obtained on other representatives of reptiles, birds, and mammals, a comparative analysis was carried out of neurochemical organization of two thalamic optical centers—relay nuclei of thalamofugal (GLd) and tectofugal (Rot/LP-Pulv) systems of amniotes. Features of similarities and differences of these centers in representatives of non-mammalian and mammalian amniotes are revealed. GLd has a great similarity of the studied neurochemical characteristics in all amniotes. It receives innervation from all studied transmitter-modulatory systems with predominance of serotonin-, choline- and NPY-ergic projections. Neurochemical organization of Rot comparable with the tectorecipient part of mammalian LP-Pulv has a great resemblance in reptiles and birds, with considerable interspecies differences inside each class. In the majority of the studied systems, Rot is characterized by scant innervation. On the contrary, LP-Pulv receives sufficiently massive innervation from these systems. The most characteristic of this complex are rich SP- and cholinergic projections that are scant in Rot of reptiles and birds. The similar feature of Rot and LP-Pulv is the presence of massive serotonin- and NO-ergic (NADPH-positive) projections. The revealed similarities and differences of the neurochemical characteristics of thalamic optical centers among amniotes seem to reflect various transformations of thalamo- and tectofugal visual systems in the course of phylogenetic and adaptive evolution.

Cognitive enhancement with central thalamic electrical stimulation.

Central thalamic electrical stimulation has been proposed as a method for remediation of acquired cognitive disability. Long-standing experimental and clinical observations indicate a key role for neurons within the central thalamus in maintaining the alert waking state and facilitating attended behaviors. Here, we show that continuous high frequency (100 Hz) electrical stimulation of the central thalamus generates widespread cortical activation of c-fos across all cortical layers and a selective pattern of regulation of zif268 within the supragranular, granular, and infragranular cortical laminae. Significant elevation of both immediate early genes also is seen in the dentate gyrus of the hippocampus. Use of the same stimulation parameters is shown to facilitate untrained goal-directed seeking behavior and object recognition memory in rodents. An overall increase of exploratory motor behaviors and grooming activity also is observed, consistent with a global increase in arousal. Taken together, these studies indicate that electrical stimulation of the central thalamus may enhance cognitive performance through neocortical and hippocampal neuronal activation and specific regulation of gene expression.

Spatiotemporal Properties of Eye Position Signals in the Primate Central Thalamus

Although both sensory and motor signals in multiple cortical areas are modulated by eye position, the origin of eye position signals for cortical neurons remains uncertain. One likely source is the central thalamus, which contains neurons sensitive to eye position. Because the central thalamus receives inputs from the brainstem, these neurons may transmit eye position signals arising from the neural integrator or from proprioceptive feedback. However, because the central thalamus also receives inputs from many cortical areas, eye position signals in the central thalamus could come from the cerebral cortex. To clarify these possibilities, spatial and temporal properties of eye position signals in the central thalamus were examined in trained monkeys. Data showed that eye position signals were decomposed into horizontal and vertical components, suggesting that the central thalamus lies within pathways that transmit brainstem eye position signals to the cortex. Further quantitative analyses suggested that 2 distinct groups of thalamic neurons mediate eye position signals from different subcortical origins, and that the signals are modified dynamically through ascending pathways. Eye position signals through the central thalamus may play essential roles in spatial transformation performed by cortical networks.

Inactivation of the central thalamus delays self-timed saccades

The central thalamus transmits corollary discharge signals for eye movement control, but its role in eye movement generation remains uncertain. Inactivation of the paralaminar part of the ventrolateral thalamus delayed the initiation of contraversive saccades, particularly during a new memory-guided saccade task that required self-triggering of the movement. The results suggest that signals through the thalamus regulate the timing of self-initiated saccades.

Neuropeptide S and Its Receptor: A Newly Deorphanized G Protein–Coupled Receptor System

Neuropeptide S (NPS) is a recently discovered bioactive peptide that has shed new light on the neurobiology of sleep/wakefulness regulation and anxiety-like behavior. NPS can potently promote arousal and suppress all stages of sleep. This effect might be modulated by NPS receptors expressed in thalamic centers that are relays for transmitting arousing stimuli originating from the brainstem to the cortex. The peptide precursor is expressed most prominently in a novel nucleus located directly adjacent to the nora-drenergic locus coeruleus, a brain structure with well-defined functions in arousal, stress, and anxiety. NPS was also found to induce anxiolytic-like behavior in a battery of four different tests of innate responses to stress. This unique pharmacological profile of NPS offers significant potential for developing new drugs for the treatment of sleep and/or anxiety disorders.

Involvement of the central thalamus in the control of smooth pursuit eye movements.

During maintenance of smooth pursuit eye movements, the brain must keep track of pursuit velocity to reconstruct target velocity from motion of retinal images. Although a recent study showed that corollary discharge signals through the thalamus to the cortex are used for internal monitoring of saccades, it remains unknown whether signals in the thalamus also contribute to monitoring and on-line regulation of smooth pursuit. The present study sought possible roles of the thalamocortical pathways in pursuit by recording activities of single thalamic neurons and by analyzing the effects of local inactivation. Data showed that many neurons in the ventrolateral thalamus exhibited directional modulation during pursuit. Most neurons discharged before or during initiation of pursuit, and the firing rate was proportional to the speed of target motion in a preferred direction. When the tracking target was extinguished briefly during maintenance of pursuit, these neurons continued firing, indicating that they carried extra-retinal, eye movement signals. The majority of neurons showed no change in activity around the time of small catch-up saccades during pursuit but responded transiently to large (16 degrees) memory-guided saccades in the preferred pursuit direction. Local inactivation of the recording sites did not alter pursuit latency but reduced eye velocity modestly during initiation and maintenance of ipsiversive pursuit. The results suggest that the central thalamus lies within pathways that regulate and monitor smooth pursuit eye movements.