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Background: Pain thresholds and primary headaches, including cluster headache attacks, have circadian rhythmicity. Thus, they might share a common neuronal mechanism. Objective: This study aimed to elucidate how the modulation of nociceptive input in the brainstem changes from noon to midnight. Insights into the mechanism of these fluctuations could allow for new hypotheses about the pathophysiology of cluster headache. Methods: This repeated measure observational study was conducted at the University Hospital Zurich from December 2019 to November 2022. Healthy adults between 18 and 85 years of age were eligible. All participants were examined at noon and midnight. We tested the pain threshold on both sides of the foreheads with quantitative sensory testing, assessed tiredness levels, and obtained high‐field (7 Tesla) and high‐resolution functional magnetic resonance imaging (MRI) at each visit. Functional connectivity was assessed at the two visits by performing a region‐of‐interest analysis. We defined nuclei in the brainstem implicated in processing nociceptive input as well as the thalamus and suprachiasmatic nucleus as the region‐of‐interest. Results: Ten people were enrolled, and seven participants were included. First, we did not find statistically significant differences between noon and midnight of A‐delta‐mediated pain thresholds (median mechanical pain threshold at noon: left 9.2, right 9.2; at night: left 6.5, right 6.1). Second, after correction for a false discovery rate, we found changes in the mechanical pain sensitivity to have a statistically significant effect on changes in the functional connectivity between the left parabrachial nucleus and the suprachiasmatic nucleus (T = −40.79). Conclusion: The MRI data analysis suggested that brain stem nuclei and the hypothalamus modulate A‐delta‐mediated pain perception; however, these changes in pain perception did not lead to statistically significantly differing pain thresholds between noon and midnight. Hence, our findings shed doubt on our hypothesis that the physiologic circadian rhythmicity of pain thresholds could drive the circadian rhythmicity of cluster headache attacks. Plain Language Summary: We wanted to find out if cluster headache attacks occur primarily at night because even healthy persons are more likely to feel pain at that time. Our sample of healthy participants did not have lower pain thresholds in the evening than at noon, and brain imaging suggested that the measurements were accurate. Thus, we could not prove our idea. [ABSTRACT FROM AUTHOR]

Background: This study aimed to provide an up-to-date account of the frequency of "the absence of interthalamic adhesion (AITA) as a risk factor or association" in healthy subjects and neuropsychiatric patients. Owing to the increased interest in the contribution of ITA to neurological function in previous literature, a meta-analysis of its frequency and sex dependency is required. Aim: This study aimed to study whether the AITA is associated with neuropsychiatric disorders. Settings and Design: This study is a meta-analysis and systemic review. Methods and Material: Literature searches were conducted in PubMed, Web of Science, and Google Scholar using the keywords "interthalamic adhesion," "massa intermedia," "adhesio interthalamica," and "adhesion" along with the Boolean operators (OR, AND, and NOT). Three reviewers independently assessed the abstracts and full texts for validation based on the inclusion criteria. The meta-analysis was performed using Microsoft Excel 2019 for descriptive studies and RevMan 5.2 for comparative studies. Results: The incidence of absent ITA was 15.3% in healthy subjects and 28.76% in neuropsychiatric subjects. The relative probability of AITA was 2.30 [95% confidence interval (CI), 1.96-2.70] in neuropsychiatric illness. Healthy men were 1.91 times more likely, and men with neuropsychiatric disorders were 1.82 times more likely to have absent ITA than women. Conclusions and Relevance: In this study, a consistent association of AITA with psychiatric disorders was observed, rendering the condition to be treated as an associated risk factor affecting the function of the habenula nuclear complex via the stria medullaris thalami. A cohort or longitudinal study is needed to compare the incidence of psychiatric disorders in individuals with or without ITA and to calculate the attributed risk. [ABSTRACT FROM AUTHOR]

Background: The trigeminal vascular system is an important part of the anatomical and physiological basis of migraine. The effective connectivity (EC) among the regions of interest (ROIs) in the trigeminal vascular system involved in migraine without aura (MWoA) remains unclear. Methods: In this cross‐sectional study, 48 patients (mean [SD] age 38.06 [10.35] years; male, 14/48 [29%]) with MWoA during the interictal phase and 48 healthy controls of similar age and sex (mean [SD] age 38.96 [10.96] years; male, 14/48 [29%]) underwent resting‐state functional magnetic resonance imaging (fMRI). Dynamic causal modeling analysis was conducted to investigate directional EC among ROIs in the trigeminal vascular system including the bilateral brainstem, the primary somatosensory cortex (S1), the thalamus, and the insula. Results: Compared with the healthy control group, MWoA represented significantly reduced EC from the left brainstem (Brainstem.L) to the left insula (MWoA: mean [SD] −0.16 [0.36]; healthy controls: mean [SD] 0.11 [0.41]; Pcorrected = 0.021), reduced EC from the Brainstem.L to the right insula (MWoA: mean [SD] −0.15 [0.39]; healthy controls: mean [SD] 0.03 [0.35]; Pcorrected = 0.021), and decreased EC from the left thalamus (Thalamus.L) to the Brainstem.L (MWoA: mean [SD] −0.13 [0.56]; healthy controls: mean [SD] 0.10 [0.45]; Pcorrected = 0.021). Altered EC parameters were not significantly correlated with MWoA clinical data. Conclusion: These results further provide increasing evidence that disturbed homeostasis of the trigeminovascular nociceptive pathway is involved in the pathophysiological mechanisms of migraine. Patients with MWoA exhibited a regional interaction distinct from healthy controls in the neural pathway of the Bilateral Insula–Brainstem.L–Thalamus.L, which may shed light on the future understanding of brain mechanisms for MWoA. Future brain‐based interventions are suggested to consider the dysregulation in the Bilateral Insula–Brainstem.L–Thalamus.L circuits. [ABSTRACT FROM AUTHOR]

Global Developmental Delay (GDD) and Intellectual Disability (ID) are two of the most common presentations encountered by physicians taking care of children. GDD/ID is classified into non-syndromic GDD/ID, where GDD/ID is the sole evident clinical feature, or syndromic GDD/ID, where there are additional clinical features or co-morbidities present. Careful evaluation of children with GDD and ID, starting with detailed history followed by a thorough examination, remain the cornerstone for etiologic diagnosis. However, when initial history and examination fail to identify a probable underlying etiology, further genetic testing is warranted. In recent years, genetic testing has been shown to be the single most important diagnostic modality for clinicians evaluating children with non-syndromic GDD/ID. In this review, we discuss different genetic testing currently available, review common underlying copy-number variants and molecular pathways, explore the recent evidence and recommendations for genetic evaluation and discuss an approach to the diagnosis and management of children with non-syndromic GDD and ID. [ABSTRACT FROM AUTHOR]

Paroxysmal kinesigenic dyskinesia (PKD) is a kind of nervous system disease characterized by paroxysmal involuntary movements induced by sudden movements. Neuroimaging studies have found that there are structural changes or abnormal functional connectivity in the basal ganglia, thalamus, cortex and other brain regions in PKD patients. The weakened inhibitory and regulatory function of the basal ganglia to the thalamus or the dysfunction of the thalamus itself may cause over-activation of the cortical region, resulting in involuntary movements. Recent studies have found that abnormal cerebellar function plays an important role in the pathogenesis of PKD, and abnormal cerebellar cortex can affect its normal inhibitory effect on deep cerebellar nuclei, also leading to excessive activation of thalamic - cortical pathway. This paper reviewed the mechanism and research progress of PKD in recent years, mainly focusing on the basal ganglia-thalamic-cortical circuit and the cerebellar-thalamic-cortical circuit, so as to improve clinicians' understanding of the pathogenesis of movement disorders. [ABSTRACT FROM AUTHOR]

The primary motor cortex (M1) is involved in the control of voluntary movements and is extensively mapped in this capacity. Although the M1 is implicated in modulation of pain, the underlying circuitry and causal underpinnings remain elusive. We unexpectedly unraveled a connection from the M1 to the nucleus accumbens reward circuitry through a M1 layer 6-mediodorsal thalamus pathway, which specifically suppresses negative emotional valence and associated coping behaviors in neuropathic pain. By contrast, layer 5 M1 neurons connect with specific cell populations in zona incerta and periaqueductal gray to suppress sensory hypersensitivity without altering pain affect. Thus, the M1 employs distinct, layer-specific pathways to attune sensory and aversive-emotional components of neuropathic pain, which can be exploited for purposes of pain relief. [ABSTRACT FROM AUTHOR]

Background: Post-operative delirium (POD), a common post-operative complication that aects up to 73. 5% of surgical patients, could prolong hospital stays, triple mortality rates, cause long-term cognitive decline and dementia, and boost medical expenses. However, the underlying mechanisms, especially the circuit mechanisms of POD remain largely unclear. Previous studies demonstrated that cannabis use might cause delirium-like behavior through the endocannabinoid system (eCBs), a widely distributed retrograde presynaptic neuromodulator system. We also found that the prelimbic (PrL) and intralimbic (IL) prefrontal cortex, a crucial hub for cognition and emotion, was involved in the eCBs-associated general anesthesia recovery. Objectives: The present study aimed to investigate the role of eCBs in POD development, and further clarify its neuronal specificity and circuit specificity attributed to POD. Methods: According to a previous study, 2 h of 1.4% isoflurane anesthesia and simple laparotomy were conducted to establish the POD model in C57/BL6 mice aged 8–12 weeks. A battery of behavioral tests, including the buried food, open field, and Y maze tests, were performed at 24 h before anesthesia and surgery (AS) and 6 and 9 h after AS. The behavioral results were calculated as a composite Z score for the POD assessment. To explore the dynamics of eCBs and their eect on POD regulation, an endocannabinoid (eCB) sensor was microinjected into the PrL, and the antagonists (AM281 and hemopressin) and agonist (nabilone) of type 1 cannabinoid receptor (CB1R), were administered systemically or locally (into PrL). Chemogenetics, combined Cre-loxP and Flp-FRT system, were employed in mutant mice for neuronal specificity and circuit specificity observation. Results: After AS, the composite Z score significantly increased at 6 and 9 but not at 24 h, whereas blockade of CB1R systemically and intra-PrL could specifically decrease the composite Z score at 6 and 9 h after AS. Results of fiber photometry further confirmed that the activity of eCB in the PrL was enhanced by AS, especially in the Y maze test at 6 h post-operatively. Moreove the activation of glutamatergic neurons in the PrL could reduce the composite Z score, which could be significantly reversed by exogenous cannabinoid (nabilone) at 6 and 9 h post-operatively. However, activation of GABAergic neurons only decreased composite Z score at 9 h post-operatively, with no response to nabilone application. Further study revealed the glutamatergic projection from mediodorsal thalamus (MD) to PrL glutamatergic neurons, but not hippocampus (HIP)-PrL circuit, was in charge of the eect of eCBs on POD. Conclusion: Our study firstly demonstrated the involvement of eCBs in the POD pathogenesis and further revealed that the eCBs may regulate POD through the specific MDglu-PrLglu circuit. These findings not only partly revealed the molecular and circuit mechanisms of POD, but also provided an applicable candidate for the clinical prevention and treatment of POD. [ABSTRACT FROM AUTHOR]

Background: The thalamus plays a crucial role in transmitting nociceptive information to various cortical regions involving migraine-related allodynia and photophobia. Abnormal structural and functional alterations related to the thalamus have been well established. However, it is unknown whether the brain structure and function of the thalamic subregions are differentially affected in this disorder. In this study, we aimed to clarify this issue by comparing the structure and function of 16 thalamic subregions between patients with episodic migraine (EM) and healthy controls (HCs). Methods: Twenty-seven patients with EM and 30 sex-, age- and education-matched HCs underwent resting-state functional and structural magnetic resonance imaging scans. Functional connectivity (rsFC), grey matter volume (GMV), and diffusion tensor imaging (DTI) parameters of each subregion of the thalamus were calculated and compared between the two groups. Furthermore, correlation analyses between neuroimaging changes and clinical features were performed in this study. Results: First, compared with HCs, patients with EM exhibited decreased rsFC between the anterior-medial-posterior subregions of the thalamus and brain regions mainly involved in the medial system of the pain processing pathway and default mode network (DMN). Second, for the whole thalamus and each of its subregions, there were no significant differences in GMV between patients with EM and HCs (P > 0.05, Bonferroni corrected). Third, there was no significant difference in DTI parameters between the two groups (P > 0.05). Finally, decreased rsFC was closely related to scores on the Hamilton Rating Scale for Anxiety (HAMA) and Big Five Inventory (BFI) scales. Conclusion: Selective functional hypoconnectivity in the thalamic subregions provides neuroimaging evidence supporting the important role of thalamocortical pathway dysfunction in episodic migraine, specifically, that it may modulate emotion and different personality traits in migraine patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the alterations of thalamic nuclei volumes and the intrinsic thalamic network in patients with cluster headache and healthy controls. Methods: We retrospectively enrolled 24 patients with episodic cluster headache and 24 healthy controls. We calculated the thalamic nuclei volumes in the patients with cluster headache and healthy controls based on three-dimensional T1-weighted imaging with automated segmentation using the FreeSurfer program. We also investigated the intrinsic thalamic network using structural co-variance analysis based on the thalamic nuclei volumes and graph theory under the BRAPH program. We compared the thalamic nuclei volumes and intrinsic thalamic networks in patients with cluster headaches and healthy controls. Results: The right and left whole thalamic volumes did not differ in the patients with cluster headaches and healthy controls (0.4199 vs. 0.4069%, p = 0.2008; 0.4386 vs. 0.4273%, p = 0.3437; respectively). However, there were significant alterations of right and left medial geniculate nuclei volumes in the patients with cluster headaches and the healthy controls. The right and left medial geniculate nuclei volumes of the patients with cluster headaches were greater than those of the healthy controls (0.0088 vs. 0.0075%, p < 0.0001; 0.0086 vs. 0.0072%, p < 0.0001; respectively). The intrinsic thalamic networks of the groups were not different. Conclusion: This study demonstrates significant alterations in the bilateral medial geniculate nuclei volumes in patients with cluster headache compared to healthy controls. These alterations may be related to the pathophysiology of cluster headache. However, there are no changes in the intrinsic thalamic network in patients with cluster headache. [ABSTRACT FROM AUTHOR]

In the neocortex, ~90 Hz ripples couple to ~12 Hz sleep spindles on the ~1 Hz Down-to-Up state transition during non-rapid eye movement sleep. This conjunction of sleep waves is critical for the consolidation of memories into long-term storage. The widespread co-occurrences of ripples ("co-ripples") may integrate information across the neocortex and hippocampus to facilitate consolidation. While the thalamus synchronizes spindles and Up states in the cortex for memory, it is not known whether it may also organize co-ripples. Using human intracranial recordings during NREM sleep, we investigated whether cortico-cortical co-ripples and hippocampo-cortical co-ripples are either: (1) driven by directly projected thalamic ripples; or (2) coordinated by propagating thalamic spindles or Up states. We found ripples in the anterior and posterior thalamus, with similar characteristics as hippocampal and cortical ripples, including having a center frequency of ~90 Hz and coupling to local spindles on the Down-to-Up state transition. However, thalamic ripples rarely co-occur or phase-lock with cortical or hippocampal ripples. By contrast, spindles and Up states that propagate from the thalamus strongly coordinate co-ripples in the cortex and hippocampus. Thus, thalamo-cortical spindles and Up states, rather than thalamic ripples, may provide input facilitating spatially distributed co-rippling that integrates information for memory consolidation during sleep in humans., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dickey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Reactive inhibitory control is crucial for survival. Traditionally, this control in mammals was attributed solely to the hyperdirect pathway, with cortical control signals flowing unidirectionally from the subthalamic nucleus (STN) to basal ganglia output regions. Yet recent findings have put this model into question, suggesting that the STN is assisted in stopping actions through ascending control signals to the striatum mediated by the external globus pallidus (GPe). Here, we investigate this suggestion by harnessing a biologically constrained spiking model of the cortico-basal ganglia-thalamic (CBGT) circuit that includes pallidostriatal pathways originating from arkypallidal neurons. Through a series of experiments probing the interaction between three critical inhibitory nodes (the STN, arkypallidal cells, and indirect pathway spiny projection neurons), we find that the GPe acts as a critical mediator of both ascending and descending inhibitory signals in the CBGT circuit. In particular, pallidostriatal pathways regulate this process by weakening the direct pathway dominance of the evidence accumulation process driving decisions, which increases the relative suppressive influence of the indirect pathway on basal ganglia output. These findings delineate how pallidostriatal pathways can facilitate action cancellation by managing the bidirectional flow of information within CBGT circuits., Competing Interests: Competing interests statement:The authors declare no competing interest.

Normal aging is accompanied by changes in brain structure and function associated with cognitive decline. Structural and functional abnormalities, particularly the prefrontal cortex (PFC) and subcortical regions, contributed to cognitive aging. However, it remains unclear how the synchronized changes in structure and function of individual brain regions affect the cognition in aging. Using 3D T1-weighted structural data and movie watching functional magnetic resonance imaging data in a sample of 422 healthy individuals (ages from 18 to 87 years), we constructed regional structure-function coupling (SFC) of cortical and subcortical regions by quantifying the distribution similarity of gray matter volume (GMV) and amplitude of low-frequency fluctuation (ALFF). Further, we investigated age-related changes in SFC and its relationship with cognition. With aging, increased SFC localized in PFC, thalamus and caudate nucleus, decreased SFC in temporal cortex, lateral occipital cortex and putamen. Moreover, the SFC in the PFC was associated with executive function and thalamus was associated with the fluid intelligence, and partially mediated age-related cognitive decline. Collectively, our results highlight that tighter structure-function synchron of the PFC and thalamus might contribute to age-related cognitive decline, and provide insight into the substrate of the thalamo-prefrontal pathway with cognitive aging., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

For decades, the external globus pallidus (GPe) has been viewed as a passive way-station in the indirect pathway of the cortico-basal ganglia-thalamic (CBGT) circuit, sandwiched between striatal inputs and basal ganglia outputs. According to this model, one-way descending striatal signals in the indirect pathway amplify the suppression of downstream thalamic nuclei by inhibiting GPe activity. Here, we revisit this assumption, in light of new and emerging work on the cellular complexity, connectivity and functional role of the GPe in behaviour. We show how, according to this new circuit-level logic, the GPe is ideally positioned for relaying ascending and descending control signals within the basal ganglia. Focusing on the problem of inhibitory control, we illustrate how this bidirectional flow of information allows for the integration of reactive and proactive control mechanisms during action selection. Taken together, this new evidence points to the GPe as being a central hub in the CBGT circuit, participating in bidirectional information flow and linking multifaceted control signals to regulate behaviour., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

During non-rapid eye movement (NREM) sleep, neural ensembles in the entorhinal-hippocampal circuit responsible for encoding recent memories undergo reactivation to facilitate the process of memory consolidation. This reactivation is widely acknowledged as pivotal for the formation of stable memory and its impairment is closely associated with memory dysfunction. To date, the neural mechanisms driving the reactivation of neural ensembles during NREM sleep remain poorly understood. Here, we show that the neural ensembles in the medial entorhinal cortex (MEC) that encode spatial experiences exhibit reactivation during NREM sleep. Notably, this reactivation consistently coincides with isolated theta waves. In addition, we found that the nucleus reuniens (RE) in the midline thalamus exhibits typical theta waves during NREM sleep, which are highly synchronized with those occurring in the MEC in male mice. Closed-loop optogenetic inhibition of the RE-MEC pathway specifically suppressed these isolated theta waves, resulting in impaired reactivation and compromised memory consolidation following a spatial memory task in male mice. The findings suggest that theta waves originating from the ventral midline thalamus play a role in initiating memory reactivation and consolidation during sleep., (© 2024. The Author(s).)

Thalamocortical pathways from the rodent ventral posterior (VP) thalamic complex to the somatosensory cerebral cortex areas are a key model in modern neuroscience. However, beyond the intensively studied projection from medial VP (VPM) to the primary somatosensory area (S1), the wiring of these pathways remains poorly characterized. We combined micropopulation tract-tracing and single-cell transfection experiments to map the pathways arising from different portions of the VP complex in male mice. We found that pathways originating from different VP regions show differences in area/lamina arborization pattern and axonal varicosity size. Neurons from the rostral VPM subnucleus innervate trigeminal S1 in point-to-point fashion. In contrast, a caudal VPM subnucleus innervates heavily and topographically second somatosensory area (S2), but not S1. Neurons in a third, intermediate VPM subnucleus innervate through branched axons both S1 and S2, with markedly different laminar patterns in each area. A small anterodorsal subnucleus selectively innervates dysgranular S1. The parvicellular VPM subnucleus selectively targets the insular cortex and adjacent portions of S1 and S2. Neurons in the rostral part of the lateral VP nucleus (VPL) innervate spinal S1, while caudal VPL neurons simultaneously target S1 and S2. Rostral and caudal VP nuclei show complementary patterns of calcium-binding protein expression. In addition to the cortex, neurons in caudal VP subnuclei target the sensorimotor striatum. Our finding of a massive projection from VP to S2 separate from the VP projections to S1 adds critical anatomical evidence to the notion that different somatosensory submodalities are processed in parallel in S1 and S2., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

In mammals, action potentials fired by rapidly adapting mechanosensitive afferents are known to reliably time lock to the cycles of a vibration. How and where along the ascending neuraxis is the peripheral afferent temporal code transformed into a rate code are currently not clear. Here, we probed the encoding of vibrotactile stimuli with electrophysiological recordings along major stages of the ascending somatosensory pathway in mice. We discovered the main transformation step was identified at the level of the thalamus, and parvalbumin-positive interneurons in thalamic reticular nucleus participate in sharpening frequency selectivity and in disrupting the precise spike timing. When frequency-specific microstimulation was applied within the brainstem, it generated frequency selectivity reminiscent of real vibration responses in the somatosensory cortex and could provide informative and robust signals for learning in behaving mice. Taken together, these findings could guide biomimetic stimulus strategies to activate specific nuclei along the ascending somatosensory pathway for neural prostheses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cerebral white matter lesions prevent cortico-spinal descending inputs from effectively activating spinal motoneurons, leading to loss of motor control. However, in most cases, the damage to cortico-spinal axons is incomplete offering a potential target for therapies aimed at improving volitional muscle activation. Here we hypothesize that, by engaging direct excitatory connections to cortico-spinal motoneurons, stimulation of the motor thalamus could facilitate activation of surviving cortico-spinal fibers thereby immediately potentiating motor output. To test this hypothesis, we identify optimal thalamic targets and stimulation parameters that enhance upper-limb motor-evoked potentials and grip forces in anesthetized monkeys. This potentiation persists after white matter lesions. We replicate these results in humans during intra-operative testing. We then design a stimulation protocol that immediately improves strength and force control in a patient with a chronic white matter lesion. Our results show that electrical stimulation targeting surviving neural pathways can improve motor control after white matter lesions., (© 2024. The Author(s).)

During paradoxical sleep (PS, aka REM sleep) the cerebral cortex displays rapid electroencephalographic activity similar to that of wakefulness, whereas in the posterior associative thalamus, rapid activity is interrupted by frequent periods of slow-wave (delta) oscillations at 2-3 Hz, thereby dissociating the intrinsic frequency in thalamus and cortex. Here we studied the functional consequences of such a dissociation using intrathalamic and intracortical recordings in 21 epileptic patients, applying coherence analysis to examine changes in functional connectivity between the posterior thalamus (mainly medial pulvinar) and six cortical functional networks, and also between each cortical network with respect to the others. Periods of slow-wave thalamic activity ('delta PS') were more prevalent than phases of 'rapid PS,' and the delta/rapid thalamic alternance did not overlap with the classical tonic/phasic dichotomy based on rapid eye movements. Thalamo-cortical and cortico-cortical functional connectivity significantly decreased during delta PS, relative to both rapid PS periods and to wakefulness. The fact that delta thalamic activity and low thalamo-cortical binding coincided with a suppression of cortico-cortical connectivity supports a crucial role for the posterior associative thalamus, and particularly the medial pulvinar, in ensuring trans-thalamic communication between distant cortical areas. Disruption of such a trans-thalamic communication during delta PS compromises the functional binding between cortical areas, and consequently might contribute to the alteration of perceptual experiences commonly reported during dreams. KEY POINTS: During paradoxical, or REM, sleep (PS), rapid thalamic activity is interrupted by frequent periods of slow delta waves at 2-3 Hz. During these periods of thalamic delta activity there was a drastic drop of functional connectivity between associative thalamus and cortex, and also among different cortical networks. The delta/rapid alternance did not overlap with the classically defined 'tonic/phasic' periods and therefore suggests a distinct dichotomy of functional states in PS. Recurrent decrease in thalamo-cortical and cortico-cortical functional connectivity during PS may compromise the spatio-temporal binding between cortical areas, which in turn could hinder the formation of coherent mental content during dreams., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Perceptual decisions rely on learned associations between sensory evidence and appropriate actions, involving the filtering and integration of relevant inputs to prepare and execute timely responses 1,2 . Despite the distributed nature of task-relevant representations 3-10 , it remains unclear how transformations between sensory input, evidence integration, motor planning and execution are orchestrated across brain areas and dimensions of neural activity. Here we addressed this question by recording brain-wide neural activity in mice learning to report changes in ambiguous visual input. After learning, evidence integration emerged across most brain areas in sparse neural populations that drive movement-preparatory activity. Visual responses evolved from transient activations in sensory areas to sustained representations in frontal-motor cortex, thalamus, basal ganglia, midbrain and cerebellum, enabling parallel evidence accumulation. In areas that accumulate evidence, shared population activity patterns encode visual evidence and movement preparation, distinct from movement-execution dynamics. Activity in movement-preparatory subspace is driven by neurons integrating evidence, which collapses at movement onset, allowing the integration process to reset. Across premotor regions, evidence-integration timescales were independent of intrinsic regional dynamics, and thus depended on task experience. In summary, learning aligns evidence accumulation to action preparation in activity dynamics across dozens of brain regions. This leads to highly distributed and parallelized sensorimotor transformations during decision-making. Our work unifies concepts from decision-making and motor control fields into a brain-wide framework for understanding how sensory evidence controls actions., (© 2024. Crown.)

Sleep is a brain state characterised by a low vigilance level and diminished consciousness. Reaction to and processing of external stimuli is attenuated in sleep. During sleep, the reticular thalamic nucleus reduces the flow of sensory activity to the cerebral cortex through inhibition of the thalamus. This sensory gating process facilitates sleep. After reaching the afferent layers of primary cortex, the reduced sensory flow is adjusted, gained, and processed within various cortical layers before being transferred by the corticofugal system back to appropriate subdivisions of the thalamus as feedback. Thalamic subdivisions then dispatch this sensory information to related areas of the cerebral cortex, where it is (sub)consciously perceived. When necessary, a sleeping individual can be awakened by a wake-up call, either by stimuli indicating danger, or by personally meaningful stimuli. It is safe for a sleeping individual that it can be aroused when necessary. Evidently, there are two processes by which the brain adjusts the response to sensory stimuli before entering (sub)consciousness. Firstly 'sensory gating', a process favourable to the maintenance of sleep by reducing the sensory input to the brain through the reticular thalamic nucleus and secondly 'sensory gaining', a process implying that the gained preserved sensory input is continuously analysed by the corticofugal system to detect dangerous and relevant environmental elements, indispensable for safeness and well-being of the sleeper., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Audio-visual approaches involving visual inputs have laid the foundation for recent progress in speech separation. However, the optimization of the concurrent usage of auditory and visual inputs is still an active research area. Inspired by the cortico-thalamo-cortical circuit, in which the sensory processing mechanisms of different modalities modulate one another via the non-lemniscal sensory thalamus, we propose a novel cortico-thalamo-cortical neural network (CTCNet) for audio-visual speech separation (AVSS). First, the CTCNet learns hierarchical auditory and visual representations in a bottom-up manner in separate auditory and visual subnetworks, mimicking the functions of the auditory and visual cortical areas. Then, inspired by the large number of connections between cortical regions and the thalamus, the model fuses the auditory and visual information in a thalamic subnetwork through top-down connections. Finally, the model transmits this fused information back to the auditory and visual subnetworks, and the above process is repeated several times. The results of experiments on three speech separation benchmark datasets show that CTCNet remarkably outperforms existing AVSS methods with considerably fewer parameters. These results suggest that mimicking the anatomical connectome of the mammalian brain has great potential for advancing the development of deep neural networks.

Background: The complexities of unilateral dystonia have led to exploring simultaneous (dual) globus pallidus internus (GPi) and motor ventral thalamus (Vim/Vop) deep brain stimulation (DBS), yet detailed assessments are lacking., Objectives: To assess the efficacy of GPi, Vim/Vop, and dual DBS in unilateral dystonia., Methods: Three patients with unilateral dystonia (two idiopathic, one acquired), implanted with two DBS electrodes targeting ipsilateral Vim/Vop and GPi, were included. Three stimulation modalities were assessed. First, one electrode was activated, then the other, and finally, both electrodes were activated simultaneously., Results: DBS yielded substantial symptomatic reductions in all three evaluated stimulation modalities. Patients exhibited varying responses regarding quality-of-life and depressive symptoms. Treatment satisfaction didn't align with clinical improvements, potentially affected by unrealistic expectations., Conclusions: This study contributes critical insights into GPi, Vim/Vop and simultaneous stimulation for unilateral dystonia. The safety of the procedure underscores the promise of this approach., (© 2024 International Parkinson and Movement Disorder Society.)

Cognitive flexibility is a fundamental ability that enables humans and animals to exhibit appropriate behaviors in various contexts. The thalamocortical interactions between the prefrontal cortex (PFC) and the mediodorsal thalamus (MD) have been identified as crucial for inferring temporal context, a critical component of cognitive flexibility. However, the neural mechanism responsible for context inference remains unknown. To address this issue, we propose a PFC-MD neural circuit model that utilizes a Hebbian plasticity rule to support rapid, online context inference. Specifically, the model MD thalamus can infer temporal contexts from prefrontal inputs within a few trials. This is achieved through the use of PFC-to-MD synaptic plasticity with pre-synaptic traces and adaptive thresholding, along with winner-take-all normalization in the MD. Furthermore, our model thalamus gates context-irrelevant neurons in the PFC, thus facilitating continual learning. We evaluate our model performance by having it sequentially learn various cognitive tasks. Incorporating an MD-like component alleviates catastrophic forgetting of previously learned contexts and demonstrates the transfer of knowledge to future contexts. Our work provides insight into how biological properties of thalamocortical circuits can be leveraged to achieve rapid context inference and continual learning., (© 2024. The Author(s).)

Background: While it is well-established that humans possess an innate need for social belonging, the neural mechanisms underlying motivation for connection are still largely unknown. We propose that inclusion motivation - measured through the effort that individuals are willing to invest to be included in social interactions - may serve as one of the basic building blocks of social behavior and may change in lonely individuals., Methods: Following the screening of 303 participants, we scanned 30 low- and 28 high-loneliness individuals with functional magnetic resonance imaging while they performed the Active Inclusion Task (AIT). The AIT assesses the participants' levels of effort invested in influencing their inclusion during classic Cyberball conditions of fair play and exclusion., Results: High- compared to low-loneliness individuals showed higher urgency for inclusion, specifically during fair play, which correlated with higher activity in the right thalamus. Furthermore, in high-loneliness individuals, we found increased functional connectivity between the thalamus and the temporoparietal junction, putamen, and insula., Limitations: Participants interacted with computerized avatars, reducing ecological validity. Additionally, although increasing inclusion in the task required action, the physical demand was not high. Additional limitations are discussed., Conclusions: Inclusion motivation in loneliness is heightened during fair but not exclusionary interactions, and is linked to activity in brain regions implicated in appetitive behavior and social cognition. The findings indicate that lonely individuals may view threat in inclusionary interactions, prompting them to take action to regain connection. This suggests that inclusion motivation may help explain social difficulties in loneliness., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Research into the role of thalamocortical circuits in anesthesia-induced unconsciousness is difficult due to anatomical and functional complexity. Prior neuroimaging studies have examined either the thalamus as a whole or focused on specific subregions, overlooking the distinct neuronal subtypes like core and matrix cells. We conducted a study of heathy volunteers and functional magnetic resonance imaging during conscious baseline, deep sedation, and recovery. We advanced the functional gradient mapping technique to delineate the functional geometry of thalamocortical circuits, within a framework of the unimodal-transmodal functional axis of the cortex. Here we show a significant shift in this geometry during deep sedation, marked by a transmodal-deficient geometry. This alteration is closely linked to the spatial variations in the matrix cell composition within the thalamus. This research bridges cellular and systems-level understanding, highlighting the crucial role of thalamic core-matrix functional architecture in understanding the neural mechanisms of states of consciousness., (© 2024. The Author(s).)

Thalamic brain areas play an important role in adaptive behaviors. Nevertheless, the population dynamics of thalamic relays during learning across sensory modalities remain unknown. Using a cross-modal sensory reward-associative learning paradigm combined with deep brain two-photon calcium imaging of large populations of auditory thalamus (medial geniculate body, MGB) neurons in male mice, we identified that MGB neurons are biased towards reward predictors independent of modality. Additionally, functional classes of MGB neurons aligned with distinct task periods and behavioral outcomes, both dependent and independent of sensory modality. During non-sensory delay periods, MGB ensembles developed coherent neuronal representation as well as distinct co-activity network states reflecting predicted task outcome. These results demonstrate flexible cross-modal ensemble coding in auditory thalamus during adaptive learning and highlight its importance in brain-wide cross-modal computations during complex behavior., (© 2024. The Author(s).)

Numerous studies from different international groups have demonstrated that sensations can be propagated along acupuncture channel pathways. The propagated sensation along the channel pathway (PSCP) can be elicited by electroacupuncture (EA), transcutaneous electrical nerve stimulation (TENS), manual acupuncture (MA), and heat applied to distal acupuncture points (acupoints). Nitric oxide (NO) levels were reported to be elevated in the gracile nucleus and skin regions near to the EA sites, with higher levels at acupoints associated with an enhanced expression of NO synthase and transient receptor potential vanilloid type 1. The stimuli, EA, MA, TENS, and heat, have been used to elicit axonal reflexes, which increase local release of NO and neuropeptides such as calcitonin gene related peptide. Furthermore, the sensation of PSCP along the body surface occurs only ipsilaterally to the stimulated acupoints in various human studies, which does not support the involvement of the spinal-thalamic pathway, which would involve cross over transmission of the signals. The gracile nucleus receives ascending input from the sciatic nerve and responds to somatosensory stimulation mainly on the ipsilateral side via the dorsal column pathway. EA at Zusanli (ST36) increases NO release and expression of NO synthase mainly in the ipsilateral side of the gracile nucleus, while the cardiovascular effects and analgesic responses to EA at ST36 are changed by influences of l-arginine-derived NO synthesis in the ipsilateral gracile nucleus in rats. The stimuli-induced release of NOergic molecules and neuropeptides exist high levels in the acupoints, which contain rich neuronal components and blood vessels. Enhanced NOergic molecules at acupoints cause axon reflexes during the stimuli, which elevate cutaneous blood flow. Elevated NOergic molecules and local blood flow may spread over acupoints one after another along the meridian lines differing from nerve pathways following the stimuli to induce PSCP. The same types of stimulation also elicit NO release in the gracile nucleus, which contributes to the somatosensory signal transduction of PSCP through the dorsal medulla-thalamic pathways. Other substances such as serotonin and catecholamines are proposed to mediate responses and certain effects of acupuncture-like stimulation but their mechanisms are poorly-understood. In this review we summarize the current understanding of the neurobiological processes of PSCP research with an emphasis on recent developments of NO mediating stimulation-evoked axon reflexes and somatosensory signal transduction for PSCP perceptions through the dorsal medulla-thalamic pathways. Please cite this article as: Ma SX. Stimuli-evoked NOergic molecules and neuropeptides at acupuncture points and gracile nucleus contribute to signal transduction of propagated sensation along the meridian through the dorsal medulla-thalamic pathways. J Integr Med. 2024; 22(5): 515-522., Competing Interests: Declaration of competing interest The author declares that there are no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

The brain functions as a prediction machine, utilizing an internal model of the world to anticipate sensations and the outcomes of our actions. Discrepancies between expected and actual events, referred to as prediction errors, are leveraged to update the internal model and guide our attention towards unexpected events 1-10 . Despite the importance of prediction-error signals for various neural computations across the brain, surprisingly little is known about the neural circuit mechanisms responsible for their implementation. Here we describe a thalamocortical disinhibitory circuit that is required for generating sensory prediction-error signals in mouse primary visual cortex (V1). We show that violating animals' predictions by an unexpected visual stimulus preferentially boosts responses of the layer 2/3 V1 neurons that are most selective for that stimulus. Prediction errors specifically amplify the unexpected visual input, rather than representing non-specific surprise or difference signals about how the visual input deviates from the animal's predictions. This selective amplification is implemented by a cooperative mechanism requiring thalamic input from the pulvinar and cortical vasoactive-intestinal-peptide-expressing (VIP) inhibitory interneurons. In response to prediction errors, VIP neurons inhibit a specific subpopulation of somatostatin-expressing inhibitory interneurons that gate excitatory pulvinar input to V1, resulting in specific pulvinar-driven response amplification of the most stimulus-selective neurons in V1. Therefore, the brain prioritizes unpredicted sensory information by selectively increasing the salience of unpredicted sensory features through the synergistic interaction of thalamic input and neocortical disinhibitory circuits., (© 2024. The Author(s).)

How cellular adaptations give rise to opioid analgesic tolerance to opioids like morphine is not well understood. For one, pain is a complex phenomenon comprising both sensory and affective components, largely mediated through separate circuits. Glutamatergic projections from the medial thalamus (MThal) to the anterior cingulate cortex (ACC) are implicated in processing of affective pain, a relatively understudied component of the pain experience. The goal of this study was to determine the effects of chronic morphine exposure on mu-opioid receptor (MOR) signaling on MThal-ACC synaptic transmission within the excitatory and feedforward inhibitory pathways. Using whole cell patch-clamp electrophysiology and optogenetics to selectively target these projections, we measured morphine-mediated inhibition of optically evoked postsynaptic currents in ACC layer V pyramidal neurons in drug-naïve and chronically morphine-treated mice. We found that morphine perfusion inhibited the excitatory and feedforward inhibitory pathways similarly in females but caused greater inhibition of the inhibitory pathway in males. Chronic morphine treatment robustly attenuated morphine presynaptic inhibition within the inhibitory pathway in males, but not females, and mildly attenuated presynaptic inhibition within the excitatory pathway in both sexes. These effects were not observed in MOR phosphorylation-deficient mice. This study indicates that chronic morphine treatment induces cellular tolerance to morphine within a thalamo-cortical circuit relevant to pain and opioid analgesia. Furthermore, it suggests this tolerance may be driven by MOR phosphorylation. Overall, these findings improve our understanding of how chronic opioid exposure alters cellular signaling in ways that may contribute to opioid analgesic tolerance. NEW & NOTEWORTHY Opioid signaling within the anterior cingulate cortex (ACC) is important for opioid modulation of affective pain. Glutamatergic medial thalamus (MThal) neurons synapse in the ACC and opioids, acting through mu opioid receptors (MORs), acutely inhibit synaptic transmission from MThal synapses. However, the effect of chronic opioid exposure on MThal-ACC synaptic transmission is not known. Here, we demonstrate that chronic morphine treatment induces cellular tolerance at these synapses in a sex-specific and phosphorylation-dependent manner.

Background: Deep brain stimulation of the central thalamus (CT-DBS) has potential for modulating states of consciousness, but it can also trigger electrographic seizures, including poly-spike-wave trains (PSWT)., Objectives: To report the probability of inducing PSWTs during CT-DBS in awake, freely-moving mice., Methods: Mice were implanted with electrodes to deliver unilateral and bilateral CT-DBS at different frequencies while recording electroencephalogram (EEG). We titrated stimulation current by gradually increasing it at each frequency until a PSWT appeared. Subsequent stimulations to test arousal modulation were performed at the current one step below the current that caused a PSWT during titration., Results: In 2.21% of the test stimulations (10 out of 12 mice), CT-DBS caused PSWTs at currents lower than the titrated current, including currents as low as 20 μA., Conclusion: Our study found a small but significant probability of inducing PSWTs even after titration and at relatively low currents. EEG should be closely monitored for electrographic seizures when performing CT-DBS in both research and clinical settings., Competing Interests: Declaration of competing interest Emery N. Brown holds patents on anesthetic state monitoring and control; holds founding interest in PASCALL, a start-up developing physiological monitoring systems; receives royalties from intellectual property through Massachusetts General Hospital licensed to Masimo. The interests of Emery N. Brown were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. The rest of the authors do not have any interest to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The axons containing arginine vasopressin (AVP) from the hypothalamus innervate a variety of structures including the cerebral cortex, thalamus, hippocampus and amygdala. A plethora amount of evidence indicates that activation of the V 1a subtype of the vasopressin receptors facilitates anxiety-like and fear responses. As an essential structure involved in fear and anxiety responses, the amygdala, especially the lateral nucleus of amygdala (LA), receives glutamatergic innervations from the auditory cortex and auditory thalamus where high density of V 1a receptors have been detected. However, the roles and mechanisms of AVP in these two important areas have not been determined, which prevents the understanding of the mechanisms whereby V 1a activation augments anxiety and fear responses. Here, we used coronal brain slices and studied the effects of AVP on neuronal activities of the auditory cortical and thalamic neurons. Our results indicate that activation of V 1a receptors excited both auditory cortical and thalamic neurons. In the auditory cortical neurons, AVP increased neuronal excitability by depressing multiple subtypes of inwardly rectifying K + (Kir) channels including the Kir2 subfamily, the ATP-sensitive K + channels and the G protein-gated inwardly rectifying K + (GIRK) channels, whereas activation of V 1a receptors excited the auditory thalamic neurons by depressing the Kir2 subfamily of the Kir channels as well as activating the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a persistent Na + channel. Our results may help explain the roles of V 1a receptors in facilitating fear and anxiety responses. Categories: Cell Physiology., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Thalamic neuromodulation has emerged as a treatment option for drug-resistant epilepsy (DRE) with widespread and/or undefined epileptogenic networks. While deep brain stimulation (DBS) and responsive neurostimulation (RNS) depth electrodes offer means for electrical stimulation of the thalamus in adult patients with DRE, the application of thalamic neuromodulation in pediatric epilepsy remains limited. To address this gap, the Neuromodulation Expert Collaborative was established within the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Surgery Special Interest Group. In this expert review, existing evidence and recommendations for thalamic neuromodulation modalities using DBS and RNS are summarized, with a focus on the anterior (ANT), centromedian(CMN), and pulvinar nuclei of the thalamus. To-date, only DBS of the ANT is FDA approved for treatment of DRE in adult patients based on the results of the pivotal SANTE (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy) study. Evidence for other thalamic neurmodulation indications and targets is less abundant. Despite the lack of evidence, positive responses to thalamic stimulation in adults with DRE have led to its off-label use in pediatric patients. Although caution is warranted due to differences between pediatric and adult epilepsy, the efficacy and safety of pediatric neuromodulation appear comparable to that in adults. Indeed, CMN stimulation is increasingly accepted for generalized and diffuse onset epilepsies, with recent completion of one randomized trial. There is also growing interest in using pulvinar stimulation for temporal plus and posterior quadrant epilepsies with one ongoing clinical trial in Europe. The future of thalamic neuromodulation holds promise for revolutionizing the treatment landscape of childhood epilepsy. Ongoing research, technological advancements, and collaborative efforts are poised to refine and improve thalamic neuromodulation strategies, ultimately enhancing the quality of life for children with DRE., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetes can damage both the peripheral sensory organs, causing retinopathy, and the central visual system, leading to contrast sensitivity and impaired color vision in patients without retinopathy. Orientation discrimination is important for shape recognition by the visual system. Our psychophysical findings in this study show diminished orientation discrimination in patients with diabetes without retinopathy. To reveal the underlying mechanism, we established a diabetic mouse model and recorded in vivo electrophysiological data in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1). Reduced orientation selectivity was observed in both individual and populations of neurons in V1 and dLGN, which increased in severity with disease duration. This diabetes-associated neuronal dysfunction appeared earlier in the V1 than dLGN. Additionally, neuronal activity and signal-to-noise ratio are reduced in V1 neurons of diabetic mice, leading to a decreased capacity for information processing by V1 neurons. Notably, the V1 in diabetic mice exhibits reduced excitatory neuronal activity and lower levels of phosphorylated mammalian target of rapamycin (mTOR). Our findings show that altered responses of both populations of and single V1 neurons may impair fine vision, thus expanding our understanding of the underlying causes of diabetes-related impairment of the central nervous system. [ABSTRACT FROM AUTHOR]

Fibromyalgia is characterized by chronic and persistent widespread pain and generalized muscle tenderness, and it is refractory to treatment. The central nervous system (CNS) plays an important role, pain signalling, in fibromyalgia subjects. Electroacupuncture (EA) has been practiced for thousand years to treat many diseases that involve pain. We established fibromyalgia-like pain in mice using intermittent cold stress and investigated therapeutic effects and modes of action with EA. EA of 2 Hz and 1 mA was performed for 20 min at the ST36 acupoint in mice from Day 3 to Day 5. Our results showed that mechanical and thermal hyperalgesia were induced by intermittent cold stress (Day 5: mechanical: 1.43 ± 0.34 g; thermal: 3.98 ± 0.73 s) and were subsequently reversed by EA (Day 5: mechanical: 4.62 ± 0.48 g; thermal: 7.68 ± 0.68 s) or Trpv1−/− (Day 5: mechanical: 4.38 ± 0.51 g; thermal: 7.48 ± 0.98 s). Activity in the HMGB1, S100B, and TRPV1 pathways was increased in the mouse prefrontal cortex, somatosensory cortex, thalamus, and amygdala with the stress treatment. This increase was attenuated by EA or Trpv1−/−. These results suggest potential targets for the treatment of TRPV1-dependant fibromyalgia pain. [ABSTRACT FROM AUTHOR]

The human brain is a complex organ with an intricate neuronal connectivity and diverse functional regions. Neurological disorders often disrupt the delicate balance among these anatomical compartments, resulting in severe impairments. The available therapeutic options constitute an incomplete solution as many patients respond partially, highlighting the need for continued research into causes and treatments. Bottom-up approaches, like in vitro models, offer insights into brain functions as they recreate the in vivo microenvironment that allows studying how specific features affect physiological and pathological conditions. In this work, we engineered the cortical-striatal-thalamic (CST) circuit, involved in many brain functions such as action initiation and selection, using a three-compartment polymeric device. We characterized the emerging spontaneous electrophysiological activity by using Micro-Electrode Arrays (MEAs). Cortical neurons exhibited complex bursting activity, which influenced the entire circuit. Striatal and thalamic neurons displayed predominantly tonic firing when isolated, while interconnections with the cortex synchronized and organized their neuronal activity, highlighting the cortical pivotal role in bursting activity and information processing. The CST circuit demonstrated self-organization abilities and displayed high entropy values, indicative of dynamic richness and information encoding potential. Furthermore, we proved the CST's involvement in learning and memory. Our CST model provides a platform for further exploration into brain circuitry and potential therapeutic interventions, underscoring the necessity of realistic in vitro models to fully understand neurological diseases' pathophysiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Seizure waves of epilepsy can propagate in a coupled thalamocortical model, which typically occurs in malfunctioning neuronal networks. However, it remains unclear whether thalamic feed-forward inhibition (FFI) and feed-back inhibition (FBI), the two most important microcircuits in this network, have propagation effects. In this study, we first investigated the importance of the pyramidal neuronal population-thalamic reticular nucleus and specific relay nucleus-thalamic reticular nucleus pathways in the Taylor model for seizure control as FFI and FBI, respectively. Subsequently, using the FBI as a crucial parameter, we constructed 2- and 3-compartment coupling models and evaluated their impact on seizure propagation in other chambers by varying the degree of coupling strength. Finally, we replicated the above study in a 10-compartment model to ensure the robustness of the findings. We confirmed that FBI is more effective by analyzing the combined effect of FFI and FBI, and the pathology state does advance as the coupling strength is increased. These findings elucidate the roles that these two pathways play in the propagation of epileptic seizures and may offer fresh perspectives on the clinical management of epilepsy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The thalamus is crucial for supporting various cognitive behaviors due to its extensive connectivity with multiple cortical regions. However, the role of the thalamus and its functional connections with cortical regions in cognitive reasoning remains unclear, since previous research has mainly focused on cortical regions when studying the neural mechanisms underlying cognitive reasoning. To fill this knowledge gap, we utilized 7 T functional magnetic resonance imaging (fMRI) to study the activation patterns of the thalamus and its functional connections with cortical regions during cognitive reasoning task, while also examining how the complexity of reasoning tasks affects thalamic activation and functional connections with cortical regions. Our findings showed that cognitive reasoning processes are related to increased activation of the thalamus and its functional connections with a specific set of cortical regions, consisting of dorsolateral prefrontal cortex, inferior frontal sulcus, intraparietal sulcus, anterior cingulate cortex/presupplementary motor area, precuneus, and ventral medial prefrontal cortex. Moreover, the increase in relational complexity of the reasoning tasks led to a corresponding increase in thalamic activation and functional connectivity with cortical regions. Given the complex thalamus structure, including multiple distinct nuclei exhibiting specific functional connections with particular cortical regions, we used an atlas defined thalamic subdivisions based on its structural connectivity with different cortical regions. Our findings indicated that these different thalamic subregions not only exhibited distinct connectivity patterns with specific cortical regions during performance of cognitive reasoning, but also showed distinct connectivity patterns varied with task complexity. Overall, our study presents evidence of the thalamus's role and its connections with cortical regions in supporting increasingly complex cognitive reasoning behavior, illuminating its contribution to higher-order cognitive functions, such as reasoning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

The cerebellum and its thalamic projections to the primary motor cortex (M1) are well known to play an essential role in executing daily actions. Anatomic investigations in animals and postmortem humans have established the reciprocal connections between these regions; however, how these pathways can shape cortical activity in behavioral contexts and help promote recovery in neuropathological conditions remains not well understood. The present review aims to provide a comprehensive description of these pathways in animals and humans and discuss how novel noninvasive brain stimulation (NIBS) methods can be used to gain a deeper understanding of the cerebellar-M1 connections. In the first section, we focus on recent animal literature that details how information sent from the cerebellum and thalamus is integrated into an broad network of cortical motor neurons. We then discuss how NIBS approaches in humans can be used to reliably assess the connectivity between the cerebellum and M1. Moreover, we provide the latest perspectives on using advanced NIBS approaches to investigate and modulate multiple cerebellar-cortical networks involved in movement behavior and plasticity. Finally, we discuss how these emerging methods have been used in translation research to produce long-lasting modifications of cerebellar-thalamic-M1 to restore cortical activity and motor function in neurologic patients., Competing Interests: Authors’ NoteDanny Adrian Spampinato and Elias Paolo Casula are also affiliated to Santa Lucia Foundation IRCCS, Rome, Italy; Giacomo Koch is also affiliated to University of Ferrara, Ferrara, Italy. Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Study Objectives: Sleep spindles play a crucial role in multiple neuronal network functions. Initiation and termination of spindles are regulated by the thalamic reticular nucleus and thalamocortical network, and the spindle can be an index for brain organization. We conducted a preliminary study of the parameters of sleep spindles, focusing on sleep-stage temporal distribution in children with autism spectrum disorder (ASD) with normal intelligence/developmental quotients. Methods: We performed overnight polysomnography in 14 children with ASD (4-10 years) with normal full-scale intelligence quotient/developmental quotient (≥75) and 14 community samples (CS) of children. Sleep stages were scored according to the Rechtschaffen and Kales criteria. Spindle parameters were quantified and compared between these groups and the identified subgroups. Results: Sleep parameters did not differ between the ASD and CS groups, except for a higher rate of rapid eye movement (REM) sleep duration in ASD. Spindle parameters did not significantly differ between the groups, but spindle density was distributed in a broader range in the ASD group. Five children with ASD had a higher spindle density in stage 3 than in stage 2. The ratio of spindle density in stage 3 to that in stage 2 (stage 3/2 ratio) was significantly higher in ASD than in CS cases. Conclusions: The lower spindle density in stage 2 and relatively higher density in stage 3 in children with ASD may represent an abnormal generation of spindles due to insufficient maturation of the thalamic reticular nucleus and thalamocortical network. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the ventralis intermedius (VIM) nucleus of the thalamus has been successful in mitigating upper limb tremor, but the effect on gait and balance performance is unclear. Here, we aim to examine the effectiveness of VIM DBS on stride length variability, sway path length, and task-relevant tremor of various body segments in essential tremor (ET). Methods: Seventeen ET individuals treated with DBS (ET DBS) and 17 age-and sexmatched healthy controls (HC) performed a postural balance and overground walking task. In separate and consecutive visits, ET DBS performed gait and balance tasks with DBS ON or OFF. The main outcome measures were sway path length, stride length variability, and tremor quantified from upper limb, lower limb, upper and lower trunk (axial) during the gait and balance tasks. Results: With DBS OFF, ET DBS exhibited significantly greater stride length variability, sway path length, and tremor during gait and balance task relative to HC. Relative to DBS OFF, DBS ON reduced stride length variability and sway path length in ET DBS. The DBS-induced reduction in stride length variability was associated with the reduction in both upper trunk tremor and upper limb tremor. The DBS-induced reduction in sway path length was associated with the reduction in upper trunk tremor. Discussion: The findings of this study revealed that VIM DBS was effective in improving gait and balance in ET DBS and that improvements in gait and postural balance were associated with a reduction of axial tremor during the tasks. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence has shown that amyotrophic lateral sclerosis (ALS) can result in abnormal energy metabolism and sleep disorders, even before motor dysfunction. Although the hypothalamus and thalamus are important structures in these processes, few ALS studies have reported abnormal MRI structural findings in the hypothalamus and thalamus. Purpose: We aimed to investigate volumetric changes in the thalamus and hypothalamus by using the automatic brain structure volumetry tool AccuBrain®. Methods: 3D T1-weighted magnetization-prepared gradient echo imaging (MPRAGE) scans were acquired from 16 patients with ALS with normal cognitive scores and 16 age-, sex- and education-matched healthy controls. Brain tissue and structure volumes were automatically calculated using AccuBrain®. Results: There were no significant differences in bilateral thalamic (F = 1.31, p = 0.287) or hypothalamic volumes (F = 1.65, p = 0.213) between the ALS and control groups by multivariate analysis of covariance (MANCOVA). Left and right hypothalamic volumes were correlated with whole-brain volume in patients with ALS (t = 3.19, p = 0.036; t = 3.03, p = 0.044), while the correlation between age and bilateral thalamic volumes tended to be significant after Bonferroni correction (t = 2.76, p = 0.068; t = 2.83, p = 0.06). In the control group, left and right thalamic volumes were correlated with whole-brain volume (t = 4.26, p = 0.004; t = 4.52, p = 0.004). Conclusion: Thalamic and hypothalamic volumes did not show differences between patients with normal frontotemporal function ALS and healthy controls, but further studies are still needed. [ABSTRACT FROM AUTHOR]

Background Thalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia. Methods Both n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis. Results During both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d′ score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively. Conclusions The thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function. [ABSTRACT FROM AUTHOR]

Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Petersen et al.)

Primates must adapt to changing environments by optimizing their behavior to make beneficial choices. At the core of adaptive behavior is the orbitofrontal cortex (OFC) of the brain, which updates choice value through direct experience or knowledge-based inference. Here, we identify distinct neural circuitry underlying these two separate abilities. We designed two behavioral tasks in which two male macaque monkeys updated the values of certain items, either by directly experiencing changes in stimulus-reward associations, or by inferring the value of unexperienced items based on the task's rules. Chemogenetic silencing of bilateral OFC combined with mathematical model-fitting analysis revealed that monkey OFC is involved in updating item value based on both experience and inference. In vivo imaging of chemogenetic receptors by positron emission tomography allowed us to map projections from the OFC to the rostromedial caudate nucleus (rmCD) and the medial part of the mediodorsal thalamus (MDm). Chemogenetic silencing of the OFC-rmCD pathway impaired experience-based value updating, while silencing the OFC-MDm pathway impaired inference-based value updating. Our results thus demonstrate dissociable contributions of distinct OFC projections to different behavioral strategies, and provide new insights into the neural basis of value-based adaptive decision-making in primates., (© 2024. The Author(s).)

The cerebral cortex contains multiple, distinct areas that individually perform specific computations. A particular strength of the cortex is the communication of signals between cortical areas that allows the outputs of these compartmentalized computations to influence and build on each other, thereby dramatically increasing the processing power of the cortex and its role in sensation, action, and cognition. Determining how the cortex communicates signals between individual areas is, therefore, critical for understanding cortical function. Historically, corticocortical communication was thought to occur exclusively by direct anatomical connections between areas that often sequentially linked cortical areas in a hierarchical fashion. More recently, anatomical, physiological, and behavioral evidence is accumulating indicating a role for the higher-order thalamus in corticocortical communication. Specifically, the transthalamic pathway involves projections from one area of the cortex to neurons in the higher-order thalamus that, in turn, project to another area of the cortex. Here, we consider the evidence for and implications of having two routes for corticocortical communication with an emphasis on unique processing available in the transthalamic pathway and the consequences of disorders and diseases that affect transthalamic communication., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Synaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell-derived thalamic and cortical organoids. Single-nucleus RNA sequencing revealed that >80% of cells in thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway, but little is known about their function. Given their anatomy, they are expected to be multiplexors, integrating many different retinal channels along their dendrites. Here, using targeted single-cell-initiated rabies tracing, we found that mouse dLGN interneurons exhibit a degree of retinal input specialization similar to thalamocortical neurons. Some are anatomically highly specialized, for example, toward motion-selective information. Two-photon calcium imaging performed in vivo revealed that interneurons are also functionally specialized. In mice lacking retinal horizontal direction selectivity, horizontal direction selectivity is reduced in interneurons, suggesting a causal link between input and functional specialization. Functional specialization is not only present at interneuron somata but also extends into their dendrites. Altogether, inhibitory interneurons globally display distinct visual features which reflect their retinal input specialization and are ideally suited to perform feature-selective inhibition., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

A major challenge in neuroscience is to understand how neural representations of sensory information are transformed by the network of ascending and descending connections in each sensory system. By recording from neurons at several levels of the auditory pathway, we show that much of the nonlinear encoding of complex sounds in auditory cortex can be explained by transformations in the midbrain and thalamus. Modeling cortical neurons in terms of their inputs across these subcortical populations enables their responses to be predicted with unprecedented accuracy. By contrast, subcortical responses cannot be predicted from descending cortical inputs, indicating that ascending transformations are irreversible, resulting in increasingly lossy, higher-order representations across the auditory pathway. Rather, auditory cortex selectively modulates the nonlinear aspects of thalamic auditory responses and the functional coupling between subcortical neurons without affecting the linear encoding of sound. These findings reveal the fundamental role of subcortical transformations in shaping cortical responses., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Animals must simultaneously select and balance multiple action contingencies in ambiguous situations: for instance, evading danger during feeding. This has rarely been examined in the context of information selection; despite corticothalamic pathways that mediate sensory attention being relatively well characterized, neural mechanisms filtering conflicting actions remain unclear. Here, we develop a new loom/feed test to observe conflict between naturally induced fear and feeding and identify a novel anterior cingulate cortex (ACC) output to the ventral anterior and ventral lateral thalamus (VA/VL) that adjusts selectivity between these innate actions. Using micro-endoscopy and fiber photometry, we reveal that activity in corticofugal outputs was lowered during unbalanced/singularly occupied periods, as were the resulting decreased thalamic initiation-related signals for less-favored actions, suggesting that the integration of ACC-thalamic firing may directly regulate the output of behavior choices. Accordingly, the optoinhibition of ACC-VA/VL circuits induced high bias toward feeding at the expense of defense. To identify upstream "commander" cortical cells gating this output, we established dual-order tracing (DOT)-translating ribosome affinity purification (TRAP)-a scheme to label upstream neurons with transcriptome analysis-and found a novel population of neurotensin-positive interneurons (ACC Nts ). The photoexcitation of ACC Nts cells indeed caused similarly hyper-selective behaviors. Collectively, this new "corticofugal action filter" scheme suggests that communication in multi-step cingulate circuits may critically influence the summation of motor signals in thalamic outputs, regulating bias between innate action types., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Predictive learning can engage a selective form of cognitive control that biases choice between actions based on information about future outcomes that the learning provides. This influence has been hypothesized to depend on a feedback circuit in the brain through which the basal ganglia modulate activity in the prefrontal cortex; however, direct evidence for this functional circuit has proven elusive. Here, using an animal model of cognitive control, we found that the influence of predictive learning on decision making is mediated by an inhibitory feedback circuit linking the medial ventral pallidum and the mediodorsal thalamus, the activation of which causes disinhibition of the orbitofrontal cortex via reduced activation of inhibitory parvalbumin interneurons during choice. Thus, we found that, for this function, the mediodorsal thalamus serves as a pallidal-cortical relay through which predictive learning controls action selection, which has important implications for understanding cognitive control and its vicissitudes in various psychiatric disorders and addiction., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)