Comparative Immunohistochemical Characteristics of Thalamic Glioarchitectonics of Young and Senile Persons

The aim of the investigation was to establish morphological differences between the human thalamus in young and senile age by using an immunohistochemical marker – glial fibrillary acidic protein (GFAP).Material and methods. The results of the sectional study of both thalami of 94 deceased of both sexes were analyzed. Depending on their age (young and senile), they were divided into two groups. The deceased had no history of diseases and injuries of the central and peripheral nervous system organs as well as alcohol and/or drug addiction, no macroscopic signs of brain tissue pathology were detected when material was taken for microscopic examination. Morphological characterization of thalamic tissue in both hemispheres of the large brain using hematoxylin and eosin staining was given. Immunohistochemical study of the samples used antibodies to GFAP.Results. Histological examination of the thalamus in both young and senile age revealed groups of irregularly arranged neuronal bodies with granular cytoplasm and swollen ectopic nuclei. When the immunohistochemical reaction was performed, the product of the reaction was distributed in the bodies and outgrowths of astrocytes. In young age, single bodies of fibrous astrocytes with a moderate number of poorly visualized outgrowths were found. At senile age, in addition to a statistically significant increase in the numerical density of fibrous astrocyte bodies (p<0.01), there is a clear increase in the number of their outgrowths.Conclusion. The results obtained provide a detailed insight into the morphological characteristics of the thalamic tissue of men and women at young and senile age. The use of antibodies to GFAP is a sensitive marker of age-related changes in thalamic cytoarchitectonics. The increase in the numerical density of astrocytes as well as the outgrowth of their processes allows a more precise understanding of age-related involution of nervous tissue, which will allow to use these data in future prospective basic research.

Anterior Nucleus of Thalamus Deep Brain Stimulation: A Clinical-Based Analysis of the Ideal Target in Drug-Resistant Epilepsy

<b><i>Introduction:</i></b> Deep brain stimulation of the anterior nucleus of thalamus (ANT-DBS) is an approved procedure for drug-resistant epilepsy. However, the preferred location inside ANT is not well known. In this study, we investigated the relationship between stereotactical coordinates of stimulated contacts and clinical improvement, in order to define the ideal target for ANT-DBS. <b><i>Methods:</i></b> Individual contact’s coordinates were obtained in the Montreal Neurological Institute (MNI) 152 space, with the utilization of advanced normalization tools and co-registration of pre- and postoperative MRI and CT images in open-source toolbox lead-DBS with the “Atlas of the Human Thalamus.” Each contact’s pair was either classified as a responder (≥50% seizure reduction and absence of intolerable adverse effects) or nonresponder, with a minimum follow-up of 11 continuous months of stimulation. <b><i>Results:</i></b> A total of 19 contacts’ pairs were tested in 14 patients. The responder rate was 9 out of 14 patients (64.3%). In 4 patients, a change in contacts’ pairs was needed to achieve this result. A highly encouraging location inside ANT (HELIA) was delimited in MNI space, corresponding to an area in the anterior and inferior portion of the anteroventral (AV) nucleus, medially to the endpoint of the mammillothalamic tract (ANT-mtt junction) (<i>x</i> [3.8; 5.85], <i>y</i> [−2.1; −6.35] and <i>z</i> [6.2; 10.1] in MNI space). Statistically significant difference was observed between responders and nonresponders, in terms of the number of coordinates inside this volume. Seven responders and two nonresponders had at least 5 of 6 coordinates (2 electrodes) inside HELIA (77.8% sensitivity and 80% specificity). In 3 patients, changing to contacts that were better placed inside HELIA changed the status from nonresponder to responder. <b><i>Conclusions:</i></b> A relationship between stimulated contacts’ coordinates and responder status was observed in drug-resistant epilepsy. The possibility to target different locations inside HELIA may help surpass anatomical variations and eventually obtain increased clinical benefit.

The human thalamus orchestrates neocortical oscillations during NREM sleep.

A hallmark of non-rapid eye movement (NREM) sleep is the coordinated interplay of slow oscillations (SOs) and sleep spindles. Traditionally, a cortico-thalamo-cortical loop is suggested to coordinate these rhythms: neocortically-generated SOs trigger spindles in the thalamus that are projected back to neocortex. Here, we used direct intrathalamic recordings from human epilepsy patients to test this canonical interplay. We show that SOs in the anterior thalamus precede neocortical SOs, whereas concurrently-recorded SOs in the mediodorsal thalamus are led by neocortical SOs. Furthermore, sleep spindles, detected in both thalamic nuclei, preceded their neocortical counterparts and were initiated during early phases of thalamic SOs. Our findings indicate an active role of the anterior thalamus in organizing the cardinal sleep rhythms in the neocortex and highlight the functional diversity of specific thalamic nuclei in humans. The concurrent coordination of sleep oscillations by the thalamus could have broad implications for the mechanisms underlying memory consolidation.

Neuropsychological evidence of multi-domain network hubs in the human thalamus

Hubs in the human brain support behaviors that arise from brain network interactions. Previous studies have identified hub regions in the human thalamus that are connected with multiple functional networks. However, the behavioral significance of thalamic hubs has yet to be established. Our framework predicts that thalamic subregions with strong hub properties are broadly involved in functions across multiple cognitive domains. To test this prediction, we studied human patients with focal thalamic lesions in conjunction with network analyses of the human thalamocortical functional connectome. In support of our prediction, lesions to thalamic subregions with stronger hub properties were associated with widespread deficits in executive, language, and memory functions, whereas lesions to thalamic subregions with weaker hub properties were associated with more limited deficits. These results highlight how a large-scale network model can broaden our understanding of thalamic function for human cognition.

Fluctuations in Arousal Correlate with Neural Activity in the Human Thalamus

The neural basis of consciousness has been explored in humans and animals; however, the exact nature of consciousness remains elusive. In this study, we aimed to elucidate which brain regions are relevant to arousal in humans. Simultaneous recordings of brain activity and eye-tracking were conducted in 20 healthy human participants. Brain activity was measured by resting-state functional magnetic resonance imaging with a multiband acquisition protocol. The subjective levels of arousal were investigated based on the degree of eyelid closure recorded using a near-infrared eye camera within the scanner. The results showed that the participants were in an aroused state for 79% of the scan time, and the bilateral thalami were significantly associated with the arousal condition. Among the major thalamic subnuclei, the mediodorsal nucleus showed greater involvement in arousal, compared with other subnuclei. A receiver operating characteristic analysis with leave-one-out cross validation conducted using template-based brain activity and arousal level data from eye-tracking showed that in most participants, thalamic activity significantly predicted the subjective levels of arousal. These results indicate a significant role of the thalamus, and in particular, the mediodorsal nucleus, which has rich connectivity with the prefrontal cortices and the limbic system in human consciousness.

Neural activity in the human anterior thalamus during natural vision

In natural vision humans and other primates explore environment by active sensing, using saccadic eye movements to relocate the fovea and sample different bits of information multiple times per second. Saccades induce a phase reset of ongoing neuronal oscillations in primary and higher-order visual cortices and in the medial temporal lobe. As a result, neuron ensembles are shifted to a common state at the time visual input propagates through the system (i.e., just after fixation). The extent of the brain’s circuitry that is modulated by saccades is not yet known. Here, we evaluate the possibility that saccadic phase reset impacts the anterior nuclei of the thalamus (ANT). Using recordings in the human thalamus of three surgical patients during natural vision, we found that saccades and visual stimulus onset both modulate neural activity, but with distinct field potential morphologies. Specifically, we found that fixation-locked field potentials had a component that preceded saccade onset. It was followed by an early negativity around 50 ms after fixation onset which is significantly faster than any response to visual stimulus presentation. The timing of these events suggests that the ANT is predictively modulated before the saccadic eye movement. We also found oscillatory phase concentration, peaking at 3–4 Hz, coincident with suppression of Broadband High-frequency Activity (BHA; 80–180 Hz), both locked to fixation onset supporting the idea that neural oscillations in these nuclei are reorganized to a low excitability state right after fixation onset. These findings show that during real-world natural visual exploration neural dynamics in the human ANT is influenced by visual and oculomotor events, which supports the idea that ANT, apart from their contribution to episodic memory, also play a role in natural vision.

Sleep spindles, ripples, and interictal epileptiform discharges in the human anterior and mediodorsal thalamus

Sleep spindles are major oscillatory components of Non-Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization-rebound sequences of thalamocortical neurons, the inhibition of which is caused by the NREM-dependent activation of GABAergic neurons in the reticular thalamic nucleus. Reports suggest a link between sleep spindles and several forms of interictal epileptic discharges (IEDs) which are considered as expressions of pathological off-line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles, IEDs and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole-night LFP from the ANT and MD were co-registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing Deep Brain Stimulation protocol. Slow (~12 Hz) and fast (~14 Hz) sleep spindles were present in the human ANT and MD. Roughly, one third of thalamic sleep spindles were associated with IEDs or ripples. Both IED- and ripple-associated spindles were longer than pure spindles. IED-associated thalamic sleep spindles were characterized by broadband increase in thalamic and cortical activity, both below and above the spindle frequency range, whereas ripple-associated thalamic spindles exceeded pure spindles in terms of 80-200 Hz thalamic, but not cortical activity as indicated by time-frequency analysis. These result show that thalamic spindles coupled with IEDs are reflected at the scalp slow and beta-gamma oscillation as well. IED density during sleep spindles in the MD, but not in the ANT was identified as correlates of years spent with epilepsy, whereas no signs of pathological processes were correlated with measures of ripple and spindle association. Furthermore, the density of ripple-associated sleep spindles in the ANT showed a positive correlation with general intelligence. Our findings indicate the complex and multifaceted role of the human thalamus in sleep spindle-related physiological and pathological neural plasticity.

The genetic architecture of the human thalamus and its overlap with ten common brain disorders

The thalamus is a vital communication hub in the center of the brain and consists of distinct nuclei critical for consciousness and higher-order cortical functions. Structural and functional thalamic alterations are involved in the pathogenesis of common brain disorders, yet the genetic architecture of the thalamus remains largely unknown. Here, using brain scans and genotype data from 30,114 individuals, we identify 55 lead single nucleotide polymorphisms (SNPs) within 42 genetic loci and 391 genes associated with volumes of the thalamus and its nuclei. In an independent validation sample (n = 5173) 53 out of the 55 lead SNPs of the discovery sample show the same effect direction (sign test, P = 8.6e-14). We map the genetic relationship between thalamic nuclei and 180 cerebral cortical areas and find overlapping genetic architectures consistent with thalamocortical connectivity. Pleiotropy analyses between thalamic volumes and ten psychiatric and neurological disorders reveal shared variants for all disorders. Together, these analyses identify genetic loci linked to thalamic nuclei and substantiate the emerging view of the thalamus having central roles in cortical functioning and common brain disorders.

Neuropsychological evidence of multi-domain network hubs in the human thalamus

Hubs in the human brain support behaviors that arise from brain network interactions. Previous studies have identified hub regions in the human thalamus that are connected with multiple functional networks. However, the behavioral significance of thalamic hubs has yet to be established. Our framework predicts that thalamic subregions with strong hub properties are broadly involved in functions across multiple cognitive domains. To test this prediction, we studied human patients with focal thalamic lesions in conjunction with network analyses of the human thalamocortical functional connectome. In support of our prediction, lesions to thalamic subregions with stronger hub properties were associated with widespread deficits in executive, language, and memory functions, whereas lesions to thalamic subregions with weaker hub properties were associated with more limited deficits. These results highlight how a large-scale network model can broaden our understanding of thalamic function for human cognition.

Network Localization of Executive Function Deficits in Patients with Focal Thalamic Lesions

The human thalamus has been suggested to be involved in executive function, based on animal studies and correlational evidence from functional neuroimaging in humans. Human lesion studies, examining behavioral deficits associated with focal brain injuries, can directly test the necessity of the human thalamus for executive function. The goal of our study was to determine the specific lesion location within the thalamus as well as the potential disruption of specific thalamocortical functional networks, related to executive dysfunction. We assessed executive function in 15 patients with focal thalamic lesions and 34 comparison patients with lesions that spared the thalamus. We found that patients with mediodorsal thalamic lesions exhibited more severe impairment in executive function when compared to both patients with thalamic lesions that spared the mediodorsal nucleus and to comparison patients with lesions outside the thalamus. Furthermore, we employed a lesion network mapping approach to map cortical regions that show strong functional connectivity with the lesioned thalamic subregions in the normative functional connectome. We found that thalamic lesion sites associated with more severe deficits in executive function showed stronger functional connectivity with ACC, dorsomedial PFC, and frontoparietal network, compared to thalamic lesions not associated with executive dysfunction. These are brain regions and functional networks whose dysfunction could contribute to impaired executive functioning. In aggregate, our findings provide new evidence that delineates a thalamocortical network for executive function.