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Translational Psychiatry Dec 2023The PD-DLB psychosis complex found in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) includes hallucinations, Somatic Symptom/Functional Disorders, and... (Review)
Review
The PD-DLB psychosis complex found in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) includes hallucinations, Somatic Symptom/Functional Disorders, and delusions. These disorders exhibit similar presentation patterns and progression. Mechanisms at the root of these symptoms also share similarities with processes promoting altered states of consciousness found in Rapid Eye Movement sleep, psychiatric disorders, or the intake of psychedelic compounds. We propose that these mechanisms find a crucial driver and trigger in the dysregulated activity of high-order thalamic nuclei set in motion by ThalamoCortical Dysrhythmia (TCD). TCD generates the loss of finely tuned cortico-cortical modulations promoted by the thalamus and unleashes the aberrant activity of the Default Mode Network (DMN). TCD moves in parallel with altered thalamic filtering of external and internal information. The process produces an input overload to the cortex, thereby exacerbating DMN decoupling from task-positive networks. These phenomena alter the brain metastability, creating dreamlike, dissociative, or altered states of consciousness. In support of this hypothesis, mind-altering psychedelic drugs also modulate thalamic-cortical pathways. Understanding the pathophysiological background of these conditions provides a conceptual bridge between neurology and psychiatry, thereby helping to generate a promising and converging area of investigation and therapeutic efforts.
Topics: Humans; Hallucinogens; Lewy Body Disease; Neurodegenerative Diseases; Psychotic Disorders; Thalamus; Parkinson Disease
PubMed: 38092757
DOI: 10.1038/s41398-023-02691-0 -
Scientific Reports Nov 2023Disorders of consciousness (DoC), namely unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), represent severe conditions with significant...
Disorders of consciousness (DoC), namely unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS), represent severe conditions with significant consequences for patients and their families. Several studies have reported the regaining of consciousness in such patients using deep brain stimulation (DBS) of subcortical structures or brainstem nuclei. Our study aims to present the 10 years' experience of a single center using DBS as a therapy on a cohort of patients with DoC. Eighty Three consecutive patients were evaluated between 2011 and 2022; entry criteria consisted of neurophysiological and neurological evaluations and neuroimaging examinations. Out of 83, 36 patients were considered candidates for DBS implantation, and 32 patients were implanted: 27 patients had UWS, and five had MCS. The stimulation target was the centromedian-parafascicular complex in the left hemisphere in hypoxic brain lesion or the one better preserved in patients with traumatic brain injury. The level of consciousness was improved in seven patients. Three out of five MCS patients emerged to full awareness, with the ability to interact and communicate. Two of them can live largely independently. Four out of 27 UWS patients showed consciousness improvement with two patients emerging to full awareness, and the other two reaching MCS. In patients with DoC lasting longer than 12 months following traumatic brain injury or 6 months following anoxic-ischemic brain lesion, spontaneous recovery is rare. Thus, DBS of certain thalamic nuclei could be recommended as a treatment option for patients who meet neurological, neurophysiological and neuroimaging criteria, especially in earlier phases, before occurrence of irreversible musculoskeletal changes. Furthermore, we emphasize the importance of cooperation between centers worldwide in studies on the potentials of DBS in treating patients with DoC.
Topics: Humans; Consciousness; Deep Brain Stimulation; Consciousness Disorders; Persistent Vegetative State; Brain Injuries, Traumatic
PubMed: 37945710
DOI: 10.1038/s41598-023-46300-y -
Scientific Reports Jun 2023This work aimed to investigate the involvement of the thalamic nuclei in mesial temporal lobe epilepsy (MTLE) and identify the influence of interictal epileptic...
This work aimed to investigate the involvement of the thalamic nuclei in mesial temporal lobe epilepsy (MTLE) and identify the influence of interictal epileptic discharges on the neural basis of memory processing by evaluating the functional connectivity (FC) between the thalamic nuclei and default mode network-related area (DMNRA) using magnetoencephalography. Preoperative datasets of nine patients with MTLE with seizure-free status after surgery and those of nine healthy controls were analyzed. The FC between the thalamic nuclei (anterior nucleus [ANT], mediodorsal nucleus [MD], intralaminar nuclei [IL]), hippocampus, and DMNRA was examined for each of the resting, pre-spike, spike, and post-spike periods in the delta to ripple bands using magnetoencephalography. The FC between the ANT, MD, hippocampus, and medial prefrontal cortex increased in the gamma to ripple bands, whereas the FC between the ANT, IL, and DMNRA decreased in the delta to beta bands, compared with that of the healthy controls at rest. Compared with the rest period, the pre-spike period had significantly decreased FC between the ANT, MD, and DMNRA in the ripple band. Different FC changes between the thalamic nuclei, hippocampus, and DMNRA of specific connections in a particular band may reflect impairment or compensation in the memory processes.
Topics: Humans; Epilepsy, Temporal Lobe; Magnetoencephalography; Default Mode Network; Thalamic Nuclei; Memory
PubMed: 37391474
DOI: 10.1038/s41598-023-37834-2 -
BioRxiv : the Preprint Server For... Aug 2023The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially-distinct nuclei, but the molecular architecture of thalamic...
UNLABELLED
The thalamus plays a central coordinating role in the brain. Thalamic neurons are organized into spatially-distinct nuclei, but the molecular architecture of thalamic development is poorly understood, especially in humans. To begin to delineate the molecular trajectories of cell fate specification and organization in the developing human thalamus, we used single cell and multiplexed spatial transcriptomics. Here we show that molecularly-defined thalamic neurons differentiate in the second trimester of human development, and that these neurons organize into spatially and molecularly distinct nuclei. We identify major subtypes of glutamatergic neuron subtypes that are differentially enriched in anatomically distinct nuclei. In addition, we identify six subtypes of GABAergic neurons that are shared and distinct across thalamic nuclei.
ONE-SENTENCE SUMMARY
Single cell and spatial profiling of the developing thalamus in the first and second trimester yields molecular mechanisms of thalamic nuclei development.
PubMed: 37662287
DOI: 10.1101/2023.08.21.554174 -
The Neuroradiology Journal Oct 2023Histological studies have shown alterations of thalamic nuclei in patients with Down syndrome (DS). The correlation of these changes on MRI (magnetic resonance imaging)...
OBJECTIVES
Histological studies have shown alterations of thalamic nuclei in patients with Down syndrome (DS). The correlation of these changes on MRI (magnetic resonance imaging) is unclear. Therefore, this study investigates volumetric differences of thalamic nuclei in children with DS compared to controls.
METHODS
Patients were retrospectively identified between 01/2000 and 10/2021. Patient inclusion criteria were: (1) 0-18 years of age, (2) diagnosis of DS, and (3) availability of a brain MRI without parenchymal injury and a non-motion-degraded volumetric T1-weighted sequence. Whole thalamus and thalamic nuclei ( = 25) volumes were analyzed bilaterally relative to the total brain volume (TBV). Two-sided t-tests were used to evaluate differences between groups. Differences were considered significant if the adjusted -value was <0.05 after correction for multiple hypothesis testing using the Holm-Bonferroni method.
RESULTS
21 children with DS (11 females, 52.4%, mean age: 8.6 ± 4.3 years) and 63 age- and sex-matched controls (32 females, 50.8%, 8.6 ± 4.3 years) were studied using automated volumetric segmentation. Significantly smaller ratios were found for nine thalamic nuclei and the whole thalamus on the right and five thalamic nuclei on the left. TBV was significantly smaller in patients with DS ( < 0.001). No significant differences were found between the groups for age and sex.
CONCLUSIONS
In this exploratory volumetric analysis of the thalamus and thalamic nuclei, we observed statistically significant volumetric changes in children with DS. Our findings confirm prior neuroimaging and histological studies and extend the range of involved thalamic nuclei in pediatric DS.
PubMed: 36942548
DOI: 10.1177/19714009231166100 -
Cellular and Molecular Life Sciences :... Nov 2023Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately...
BACKGROUND
Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately 30% of those glutamatergic inputs come from thalamic nuclei. Foxp2 is a transcription factor involved in cell differentiation and reported low in patients with HD. However, the role of the Foxp2 in the thalamus in HD remains unexplored.
METHODS
We used two different mouse models of HD, the R6/1 and the HdhQ111 mice, to demonstrate a consistent thalamic Foxp2 reduction in the context of HD. We used in vivo electrophysiological recordings, microdialysis in behaving mice and rabies virus-based monosynaptic tracing to study thalamo-striatal and thalamo-cortical synaptic connectivity in R6/1 mice. Micro-structural synaptic plasticity was also evaluated in the striatum and cortex of R6/1 mice. We over-expressed Foxp2 in the thalamus of R6/1 mice or reduced Foxp2 in the thalamus of wild type mice to evaluate its role in sensory and motor skills deficiencies, as well as thalamo-striatal and thalamo-cortical connectivity in such mouse models.
RESULTS
Here, we demonstrate in a HD mouse model a clear and early thalamo-striatal aberrant connectivity associated with a reduction of thalamic Foxp2 levels. Recovering thalamic Foxp2 levels in the mouse rescued motor coordination and sensory skills concomitant with an amelioration of neuropathological features and with a repair of the structural and functional connectivity through a restoration of neurotransmitter release. In addition, reduction of thalamic Foxp2 levels in wild type mice induced HD-like phenotypes.
CONCLUSIONS
In conclusion, we show that a novel identified thalamic Foxp2 dysregulation alters basal ganglia circuits implicated in the pathophysiology of HD.
Topics: Humans; Animals; Mice; Huntington Disease; Motor Disorders; Thalamus; Corpus Striatum; Movement; Disease Models, Animal; Repressor Proteins; Forkhead Transcription Factors
PubMed: 37987826
DOI: 10.1007/s00018-023-05015-z -
Brain Stimulation 2023MRI-guided transcranial focused ultrasound (MRgFUS) as a next-generation neuromodulation tool can precisely target and stimulate deep brain regions with high spatial...
BACKGROUND
MRI-guided transcranial focused ultrasound (MRgFUS) as a next-generation neuromodulation tool can precisely target and stimulate deep brain regions with high spatial selectivity. Combined with MR-ARFI (acoustic radiation force imaging) and using fMRI BOLD signal as functional readouts, our previous studies have shown that low-intensity FUS can excite or suppress neural activity in the somatosensory cortex.
OBJECTIVE
To investigate whether low-intensity FUS can suppress nociceptive heat stimulation-induced responses in thalamic nuclei during hand stimulation, and to determine how this suppression influences the information processing flow within nociception networks.
FINDINGS
BOLD fMRI activations evoked by 47.5 °C heat stimulation of hand were detected in 24 cortical regions, which belong to sensory, affective, and cognitive nociceptive networks. Concurrent delivery of low-intensity FUS pulses (650 kHz, 550 kPa) to the predefined heat nociceptive stimulus-responsive thalamic centromedial_parafascicular (CM_para), mediodorsal (MD), ventral_lateral (VL_ and ventral_lateral_posteroventral (VLpv) nuclei suppressed their heat responses. Off-target cortical areas exhibited reduced, enhanced, or no significant fMRI signal changes, depending on the specific areas. Differentiable thalamocortical information flow during the processing of nociceptive heat input was observed, as indicated by the time to reach 10% or 30% of the heat-evoked BOLD signal peak. Suppression of thalamic heat responses significantly altered nociceptive processing flow and direction between the thalamus and cortical areas. Modulation of contralateral versus ipsilateral areas by unilateral thalamic activity differed. Signals detected in high-order cortical areas, such as dorsal frontal (DFC) and ventrolateral prefrontal (vlPFC) cortices, exhibited faster response latencies than sensory areas.
CONCLUSIONS
The concurrent delivery of FUS suppressed nociceptive heat response in thalamic nuclei and disrupted the nociceptive network. This study offers new insights into the causal functional connections within the thalamocortical networks and demonstrates the modulatory effects of low-intensity FUS on nociceptive information processing.
Topics: Nociception; Thalamic Nuclei; Thalamus; Brain; Cognition
PubMed: 37741439
DOI: 10.1016/j.brs.2023.09.013 -
BioRxiv : the Preprint Server For... Mar 2024Flexible behavior depends on abstract rules to generalize beyond specific instances, and outcome monitoring to adjust actions. Cortical circuits are posited to read out...
Flexible behavior depends on abstract rules to generalize beyond specific instances, and outcome monitoring to adjust actions. Cortical circuits are posited to read out rules from high-dimensional representations of task-relevant variables in prefrontal cortex (PFC). We instead hypothesized that converging inputs from PFC, directly or via basal ganglia (BG), enable primate-specific thalamus to select rules. To test this, we simultaneously measured spiking activity across PFC and two connected thalamic nuclei of monkeys applying rules. Abstract rule information first appeared in the ventroanterior thalamus (VA) - the main thalamic hub between BG and PFC. The mediodorsal thalamus (MD) also represented rule information before PFC, which persisted after rule cues were removed, to help maintain activation of relevant posterior PFC cell ensembles. MD, a major recipient of midbrain dopamine input, was first to represent information about behavioral outcomes. This persisted after the trial (also in PFC). A PFC-BG-thalamus model reproduced key findings, and thalamic-lesion modeling disrupted PFC rule representations. These results suggest a revised view of the neural basis of flexible behavior in primates, featuring a central role for thalamus in selecting high-level cognitive information from PFC and implementing post-error behavioral adjustments, and of the functional organization of PFC along its anterior-posterior dimension.
PubMed: 38559142
DOI: 10.1101/2024.03.13.584871 -
The Journal of Neuroscience : the... Nov 2023In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is...
In primary gustatory cortex (GC), a subregion of the insular cortex, neurons show anticipatory activity, encode taste identity and palatability, and their activity is related to decision-making. Inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc), dramatically reduces GC taste responses, consistent with the hypothesis that VPMpc-GC projections carry taste information. Recordings in awake rodents reported that taste-responsive neurons can be found across GC, without segregated spatial mapping, raising the possibility that projections from the taste thalamus may activate GC broadly. In addition, we have shown that cortical inhibition modulates the integration of thalamic and limbic inputs, revealing a potential role for GABA transmission in gating sensory information to GC. Despite this wealth of information at the system level, the synaptic organization of the VPMpc-GC circuit has not been investigated. Here, we used optogenetic activation of VPMpc afferents to GC in acute slice preparations from rats of both sexes to investigate the synaptic properties and organization of VPMpc afferents in GC and their modulation by cortical inhibition. We hypothesized that VPMpc-GC synapses are distributed across GC, but show laminar- and cell-specific properties, conferring computationally flexibility to how taste information is processed. We also found that VPMpc-GC synaptic responses are strongly modulated by the activity regimen of VPMpc afferents, as well as by cortical inhibition activating GABA and GABA receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing. We report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared with primary thalamocortical synapses onto other sensory areas. Ventral posteromedial thalamic nucleus afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation; thus, they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Thalamocortical activation of GC is gated by cortical inhibition, providing local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses in GC highlight unique features of the thalamocortical circuit for taste.
Topics: Male; Female; Rats; Animals; Insular Cortex; Thalamus; Ventral Thalamic Nuclei; Neurons; gamma-Aminobutyric Acid; Cerebral Cortex
PubMed: 37704374
DOI: 10.1523/JNEUROSCI.2255-22.2023 -
The Journal of Neuroscience : the... Sep 2023Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain...
Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomic, neurophysiological, and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In eight patients (four male, four female) with drug-resistant epilepsy, we stimulated the limbic system with single-pulse electrical stimulation. Reliable corticocortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the "limbic Hippocampus-Anterior nucleus of the thalamus-Posterior cingulate, HAP-wave." This limbic HAP-wave was visually distinct and separately decoded from the CCEP waveform in ACC after amygdala stimulation. Diffusion MRI data show that the measured end points in the PCC overlap with the end points of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic HAP-wave may travel through fornix, mammillary bodies, and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic HAP-wave but with an earlier latency. Limbic subsystems have unique stimulation-evoked signatures that may be used in the future to help network pathology diagnosis. The limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimer's disease, and characterizing its typical circuit responses may provide diagnostic insight. Stimulation-evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation-evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the "limbic HAP-wave." The limbic HAP-wave follows anatomic white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.
Topics: Humans; Male; Female; Limbic System; Electroencephalography; Evoked Potentials; Epilepsy; Electric Stimulation; Anterior Thalamic Nuclei
PubMed: 37620159
DOI: 10.1523/JNEUROSCI.2201-22.2023