Posteromedial Nucleus Research Articles

Contributions of neuroimaging in central poststroke pain: a review.

Central neuropathic poststroke pain (CNPSP) affects up to 12% of patients with stroke in general and up to 18% of patients with sensory deficits. This pain syndrome is often incapacitating and refractory to treatment. Brain computed tomography and magnetic resonance imaging (MRI) are widely used methods in the evaluation of CNPSP. The present study aims to review the role of neuroimaging methods in CNPSP. We performed a literature review of the main clinical aspects of CNPSP and the contribution of neuroimaging methods to study its pathophysiology, commonly damaged brain sites, and possible differential diagnoses. Lastly, we briefly mention how neuroimaging can contribute to the non-pharmacological CNPSP treatment. Additionally, we used a series of MRI from our institution to illustrate this review. Imaging has been used to explain CNPSP pathogenesis based on spinothalamic pathway damage and connectome dysfunction. Imaging locations associated with CNPSP include the brainstem (mainly the dorsolateral medulla), thalamus (especially the ventral posterolateral/ventral posteromedial nuclei), cortical areas such as the posterior insula and the parietal operculum, and, more recently, the thalamocortical white matter in the posterior limb of the internal capsule. Imaging also brings the prospect of helping search for new targets for non-pharmacological treatments for CNPSP. Other neuropathic pain causes identified by imaging include syringomyelia, multiple sclerosis, and herniated intervertebral disc. Imaging is a valuable tool in the complimentary evaluation of CNPSP patients in clinical and research scenarios.

Ventral posteromedial nucleus of the thalamus gates the spread of trigeminal neuropathic pain

BackgroundWidespread neuropathic pain usually affects a wide range of body areas and inflicts huge suffering on patients. However, little is known about how it happens and effective therapeutic interventions are lacking.MethodsWidespread neuropathic pain was induced by partial infraorbital nerve transection (p-IONX) and evaluated by measuring nociceptive thresholds. In vivo/vitro electrophysiology were used to evaluate neuronal activity. Virus tracing strategies, combined with optogenetics and chemogenetics, were used to clarify the role of remodeling circuit in widespread neuropathic pain.ResultsWe found that in mice receiving p-IONX, along with pain sensitization spreading from the orofacial area to distal body parts, glutamatergic neurons in the ventral posteromedial nucleus of the thalamus (VPMGlu) were hyperactive and more responsive to stimulations applied to the hind paw or tail. Tracing experiments revealed that a remodeling was induced by p-IONX in the afferent circuitry of VPMGlu, notably evidenced by more projections from glutamatergic neurons in the dorsal column nuclei (DCNGlu). Moreover, VPMGlu receiving afferents from the DCN extended projections further to glutamatergic neurons in the posterior insular cortex (pIC). Selective inhibition of the terminals of DCNGlu in the VPM, the soma of VPMGlu or the terminals of VPMGlu in the pIC all alleviated trigeminal and widespread neuropathic pain.ConclusionThese results demonstrate that hyperactive VPMGlu recruit new afferents from the DCN and relay the extra-cephalic input to the pIC after p-IONX, thus hold a key position in trigeminal neuropathic pain and its spreading. This study provides novel insights into the circuit mechanism and preclinical evidence for potential therapeutic targets of widespread neuropathic pain.

Optimizing indirect targeting of the centromedian nucleus for deep brain stimulation by incorporating third ventricular anatomy.

Deep brain stimulation (DBS) of the centromedian nucleus (CM) is used to treat diverse brain diseases including epilepsy, Tourette syndrome, and disorders of consciousness. However, the CM is challenging to visualize on routine MRI. Many surgeons use an indirect targeting method based on established stereotactic coordinates. The authors aimed to quantify how often a DBS electrode's contacts were positioned within the CM using this approach, and to identify alternative indirect coordinates that are more accurate. Indirect targeting of the CM was performed on 100 MR images obtained in healthy adults, and the resulting coordinates were warped to a common brain template. To estimate positions of DBS contacts along this trajectory, the authors developed a probable electrode location (PEL) mask, modeled on trajectory angles obtained from prior clinical cases. Euclidean and x, y, and z distances between the centroids of the PEL mask and an atlas-based CM mask were measured and defined as error. The percentage of overlaps between the PEL mask and nearby thalamic nuclei was determined. To assess the clinical utility of this methodology, the analysis was validated using 20 MR images obtained in patients with generalized epilepsy, a common clinical indication for CM-DBS. Using standard indirect coordinates, the authors found the average Euclidean error to be 4.40 ± 1.05 mm, and the x, y, and z errors were 4.19 ± 0.97 mm, 0.73 ± 0.65 mm, and 0.66 ± 0.69 mm, respectively. The PEL mask overlap was 52% with the CM and 65% with the ventral posteromedial nucleus. Variation in third ventricular width was the dominant contributor to these errors (r = -0.71). To overcome this variation, the authors developed alternative indirect coordinates: 4.5 mm lateral to the posterolateral corner of the third ventricle at the level of the posterior commissure. With this refinement, the average Euclidean error was reduced to 1.24 ± 0.5 mm, with 84% of the PEL mask within the CM. The unavailability of advanced MRI for direct targeting limits access to CM-DBS in resource-constrained neurosurgical programs. Standard indirect coordinates do not provide optimal targeting of the CM, with most contacts laterally placed in the sensory thalamus. The proposed indirect approach may therefore increase the accuracy and availability of CM-DBS, while reducing side effects.

Effectiveness of deep brain stimulation on refractory aggression in pediatric patients with autism and severe intellectual disability: meta-analytic review

Some patients with autism and severe intellectual disability may experience uncontrolled aggression, causing serious injury or harm to others, and the therapeutic ineffectiveness of traditional pharmacological and behavioral treatment may aggravate symptoms. Deep brain stimulation (DBS) has been tested in patients with little evidence in children and adolescents. Therefore, we analyzed the efficacy and safety of DBS in refractory aggression in pediatric subjects with autism (ASD) and severe intelligence deficit (ID).Methods A meta-analytic review of Web of Science (WOS) and Scopus articles, following Prisma criteria. A total of 555 articles were identified, but after applying the inclusion criteria, only 18 were analyzed. The review of the registries and the extraction of information was performed by 2 independent groups, to reduce the evaluator’s bias. For the description of the results, pediatric patients with ASD or ID present in each registry, with an application of specialized scales (Overt aggression scale, OAS, and THE modified version of the OAS, MOAS) pre and post-DBS, with a clinical follow-up of at least 12 months, were considered valid. Clinical improvement was calculated using tests of aggressiveness. In each registry with available data and then pooling the means of all patients in the OAS and MOAS, the effect size of DBS (overall and per study) was estimated. Finally, the adapted NOS scale was applied to rate the studies’ quality and level of bias.Results In the studies analyzed, 65/100 were pediatric patients, with a mean age of 16.8 years. Most of the studies were conducted in South America and Europe. In all teams, aggressive behavior was intractable, but only 9 groups (53/65) applied specialized scales to measure aggressiveness, and of these, only 51 subjects had a follow-up of at least 12 months. Thus, in 48/51 a clinical improvement of patients was estimated (94.2%), with a considerable overall effect size (OAS: d = 4.32; MOAS: d = 1.46). However, adverse effects and complications were found in 13/65 subjects undergoing DBS. The brain target with the most evidence and the fewest side effects was the posteromedial hypothalamic nuclei (pHypN). Finally, applying the adapted NOS scale, quality, and bias, only 9 studies show the best indicators.Conclusion An optimal level of efficacy was found in only half of the publications. This is mainly due to design errors and irrelevant information in the reports. We believe that DBS in intractable aggressiveness in children and adolescents with ASD and severe ID can be safe and effective if working groups apply rigorous criteria for patient selection, interdisciplinary assessments, objective scales for aggressiveness, and known surgical targets.

The cortical amygdala consolidates a socially transmitted long-term memory

Social communication guides decision-making, which is essential for survival. Social transmission of food preference (STFP) is an ecologically relevant memory paradigm in which an animal learns a desirable food odour from another animal in a social context, creating a long-term memory1,2. How food-preference memory is acquired, consolidated and stored is unclear. Here we show that the posteromedial nucleus of the cortical amygdala (COApm) serves as a computational centre in long-term STFP memory consolidation by integrating social and sensory olfactory inputs. Blocking synaptic signalling by the COApm-based circuit selectively abolished STFP memory consolidation without impairing memory acquisition, storage or recall. COApm-mediated STFP memory consolidation depends on synaptic inputs from the accessory olfactory bulb and on synaptic outputs to the anterior olfactory nucleus. STFP memory consolidation requires protein synthesis, suggesting a gene-expression mechanism. Deep single-cell and spatially resolved transcriptomics revealed robust but distinct gene-expression signatures induced by STFP memory formation in the COApm that are consistent with synapse restructuring. Our data thus define a neural circuit for the consolidation of a socially communicated long-term memory, thereby mechanistically distinguishing protein-synthesis-dependent memory consolidation from memory acquisition, storage or retrieval.

Beta Oscillations in the Sensory Thalamus During Severe Facial Neuropathic Pain Using Novel Sensing Deep Brain Stimulation

ObjectiveAdvancements in deep brain stimulation (DBS) devices provide a unique opportunity to record local field potentials longitudinally to improve the efficacy of treatment for intractable facial pain. We aimed to identify potential electrophysiological biomarkers of pain in the ventral posteromedial nucleus (VPM) of the thalamus and periaqueductal gray (PAG) using a long-term sensing DBS system. Materials and MethodsWe analyzed power spectra of ambulatory pain-related events from one patient implanted with a long-term sensing generator, representing different pain intensities (pain >7, pain >9) and pain qualities (no pain, burning, stabbing, and shocking pain). Power spectra were parametrized to separate oscillatory and aperiodic features and compared across the different pain states. ResultsOverall, 96 events were marked during a 16-month follow-up. Parameterization of spectra revealed a total of 62 oscillatory peaks with most in the VPM (77.4%). The pain-free condition did not show any oscillations. In contrast, β peaks were observed in the VPM during all episodes (100%) associated with pain >9, 56% of episodes with pain >7, and 50% of burning pain events (center frequencies: 28.4 Hz, 17.8 Hz, and 20.7 Hz, respectively). Episodes of pain >9 indicated the highest relative β band power in the VPM and decreased aperiodic exponents (denoting the slope of the power spectra) in both the VPM and PAG. ConclusionsFor this patient, an increase in β band activity in the sensory thalamus was associated with severe facial pain, opening the possibility for closed-loop DBS in facial pain.

Dynamic corticothalamic modulation of the somatosensory thalamocortical circuit during wakefulness

The feedback projections from cortical layer 6 (L6CT) to the sensory thalamus have long been implicated in playing a primary role in gating sensory signaling but remain poorly understood. To causally elucidate the full range of effects of these projections, we targeted silicon probe recordings to the whisker thalamocortical circuit of awake mice selectively expressing Channelrhodopsin-2 in L6CT neurons. Through optogenetic manipulation of L6CT neurons, multi-site electrophysiological recordings, and modeling of L6CT circuitry, we establish L6CT neurons as dynamic modulators of ongoing spiking in the ventral posteromedial nucleus of the thalamus (VPm), either suppressing or enhancing VPm spiking depending on L6CT neurons’ firing rate and synchrony. Differential effects across the cortical excitatory and inhibitory sub-populations point to an overall influence of L6CT feedback on cortical excitability that could have profound implications for regulating sensory signaling across a range of ethologically relevant conditions.

Impact of Impedance Levels on Recording Quality in Flexible Neural Probes.

Flexible neural probes are attractive emerging technologies for brain recording because they can effectively record signals with minimal risk of brain damage. Reducing the electrode impedance of the probe before recording is a common practice of many researchers. However, studies investigating the impact of low impedance levels on high-quality recordings using flexible neural probes are lacking. In this study, we electrodeposited Pt onto a commercial flexible polyimide neural probe and investigated the relationship between the impedance level and the recording quality. The probe was inserted into the brains of anesthetized mice. The electrical signals of neurons in the brain, specifically the ventral posteromedial nucleus of the thalamus, were recorded at impedance levels of 50, 250, 500 and 1000 kΩ at 1 kHz. The study results demonstrated that as the impedance decreased, the quality of the signal recordings did not consistently improve. This suggests that extreme lowering of the impedance may not always be advantageous in the context of flexible neural probes.

Separation of bimodal fMRI responses in mouse somatosensory areas into V1 and non-V1 contributions

Multisensory integration is necessary for the animal to survive in the real world. While conventional methods have been extensively used to investigate the multisensory integration process in various brain areas, its long-range interactions remain less explored. In this study, our goal was to investigate interactions between visual and somatosensory networks on a whole-brain scale using 15.2-T BOLD fMRI. We compared unimodal to bimodal BOLD fMRI responses and dissected potential cross-modal pathways with silencing of primary visual cortex (V1) by optogenetic stimulation of local GABAergic neurons. Our data showed that the influence of visual stimulus on whisker activity is higher than the influence of whisker stimulus on visual activity. Optogenetic silencing of V1 revealed that visual information is conveyed to whisker processing via both V1 and non-V1 pathways. The first-order ventral posteromedial thalamic nucleus (VPM) was functionally affected by non-V1 sources, while the higher-order posterior medial thalamic nucleus (POm) was predominantly modulated by V1 but not non-V1 inputs. The primary somatosensory barrel field (S1BF) was influenced by both V1 and non-V1 inputs. These observations provide valuable insights for into the integration of whisker and visual sensory information.

Somatotopic organization of the ventral nuclear group of the dorsal thalamus: deep brain stimulation for neuropathic pain reveals new insights into the facial homunculus.

Deep Brain Stimulation (DBS) is an experimental treatment for medication-refractory neuropathic pain. The ventral posteromedial (VPM) and ventral posterolateral (VPL) nuclei of the thalamus are popular targets for the treatment of facial and limb pain, respectively. While intraoperative testing is used to adjust targeting of patient-specific pain locations, a better understanding of thalamic somatotopy may improve targeting of specific body regions including the individual trigeminal territories, face, arm, and leg. To elucidate the somatotopic organization of the ventral nuclear group of the dorsal thalamus using in vivo macrostimulation data from patients undergoing DBS for refractory neuropathic pain. In vivo macrostimulation data was retrospectively collected for 14 patients who underwent DBS implantation for neuropathic pain syndromes at our institution. 56 contacts from 14 electrodes reconstructed with LeadDBS were assigned to macrostimulation-related body regions: tongue, face, arm, or leg. 33 contacts from 9 electrodes were similarly assigned to one of three trigeminal territories: V1, V2, or V3. MNI coordinates in the x, y, and z axes were compared by using MANOVA. Across the horizontal plane of the ventral nuclear group of the dorsal thalamus, the tongue was represented significantly medially, followed by the face, arm, and leg most laterally (p < 0.001). The trigeminal territories displayed significant mediolateral distribution, proceeding from V1 and V2 most medial to V3 most lateral (p < 0.001). Along the y-axis, V2 was also significantly anterior to V3 (p = 0.014). While our results showed that the ventral nuclear group of the dorsal thalamus displayed mediolateral somatotopy of the tongue, face, arm, and leg mirroring the cortical homunculus, the mediolateral distribution of trigeminal territories did not mirror the established cortical homunculus. This finding suggests that the facial homunculus may be inverted in the ventral nuclear group of the dorsal thalamus.

Basal forebrain nuclei volume is associated with hematoencephalic barrier dysfunction in early Alzheimer’s disease

AbstractBackgroundHematoencephalic barrier (HEB) is a protective layer of cells that separates the circulatory system from the brain. Its dysfunction is one of the possible mechanisms leading to the development of Alzheimer’s disease (AD), a progressive neurodegenerative disease and a leading cause of dementia worldwide. The albumin quotient (QAlb), the ratio between cerebrospinal fluid (CSF) and serum albumin concentrations, is a frequently used measure of HEB breakdown. Elevated levels of QAlb were previously reported in early AD. Here we explored the relationship between QAlb and volumes of the hippocampus and entorhinal cortex (EC) subregions and basal forebrain (BF) nuclei, the brain structures affected early in the course of AD.Method92 participants, including 20 AD biomarker negative cognitively normal (CN), 42 AD biomarker positive with mild cognitive impairment (AD‐MCI) and 30 AD biomarker positive with mild dementia (AD‐DEM), from the Czech Brain Aging Study underwent structural MRI and CSF sampling. CSF levels of amyloid beta 1‐42, total tau, phosphorylated tau 181 and QAlb, as well as volumes of the hippocampal subregions (i.e., head, body and tail), anterolateral and posteromedial EC and BF nuclei were obtained. Associations between regional brain volumes, normalized to total intracranial volume, and QAlb were assessed using MANOVA controlled for gender and age.ResultIn the AD‐MCI group, volumes of the anterior and posterior parts of the nucleus basalis of Meynert (NBM), one of the BF nuclei, were positively associated with QAlb levels (β = 0.317 and 0.345, p = 0.045 and 0.029, respectively). There were no other significant associations of regional brain volumes with QAlb in CN, AD‐MCI or AD‐DEM groups. All measured volumes, except for BF nuclei of medial septum in AD‐DEM (p = 0.058), were smaller in AD‐MCI and AD‐DEM v.s. CN group (p&lt;0.05). There were no differences in volumes between AD‐MCI and AD‐DEM groups. QAlb did not differ between groups.ConclusionOur results show that severity of HEB dysfunction is associated with increased volume of the NBM in individuals with AD‐MCI, suggesting a link between HEB dysfunction and early pathological changes in the BF nuclei.

Translating single-neuron axonal reconstructions into meso-scale connectivity statistics in the mouse somatosensory thalamus.

Characterizing the connectomic and morphological diversity of thalamic neurons is key for better understanding how the thalamus relays sensory inputs to the cortex. The recent public release of complete single-neuron morphological reconstructions enables the analysis of previously inaccessible connectivity patterns from individual neurons. Here we focus on the Ventral Posteromedial (VPM) nucleus and characterize the full diversity of 257 VPM neurons, obtained by combining data from the MouseLight and Braintell projects. Neurons were clustered according to their most dominantly targeted cortical area and further subdivided by their jointly targeted areas. We obtained a 2D embedding of morphological diversity using the dissimilarity between all pairs of axonal trees. The curved shape of the embedding allowed us to characterize neurons by a 1-dimensional coordinate. The coordinate values were aligned both with the progression of soma position along the dorsal-ventral and lateral-medial axes and with that of axonal terminals along the posterior-anterior and medial-lateral axes, as well as with an increase in the number of branching points, distance from soma and branching width. Taken together, we have developed a novel workflow for linking three challenging aspects of connectomics, namely the topography, higher order connectivity patterns and morphological diversity, with VPM as a test-case. The workflow is linked to a unified access portal that contains the morphologies and integrated with 2D cortical flatmap and subcortical visualization tools. The workflow and resulting processed data have been made available in Python, and can thus be used for modeling and experimentally validating new hypotheses on thalamocortical connectivity.

Thalamic Neuron Resilience during Osmotic Demyelination Syndrome (ODS) Is Revealed by Primary Cilium Outgrowth and ADP-ribosylation factor-like protein 13B Labeling in Axon Initial Segment.

A murine osmotic demyelinating syndrome (ODS) model was developed through chronic hyponatremia, induced by desmopressin subcutaneous implants, followed by precipitous sodium restoration. The thalamic ventral posterolateral (VPL) and ventral posteromedial (VPM) relay nuclei were the most demyelinated regions where neuroglial damage could be evidenced without immune response. This report showed that following chronic hyponatremia, 12 h and 48 h time lapses after rebalancing osmolarity, amid the ODS-degraded outskirts, some resilient neuronal cell bodies built up primary cilium and axon hillock regions that extended into axon initial segments (AIS) where ADP-ribosylation factor-like protein 13B (ARL13B)-immunolabeled rod-like shape content was revealed. These AIS-labeled shaft lengths appeared proportional with the distance of neuronal cell bodies away from the ODS damaged epicenter and time lapses after correction of hyponatremia. Fine structure examination verified these neuron abundant transcriptions and translation regions marked by the ARL13B labeling associated with cell neurotubules and their complex cytoskeletal macromolecular architecture. This necessitated energetic transport to organize and restore those AIS away from the damaged ODS core demyelinated zone in the murine model. These labeled structures could substantiate how thalamic neuron resilience occurred as possible steps of a healing course out of ODS.

Analyzing Thalamocortical Tract-Tracing Experiments in a Common Reference Space

Current mesoscale connectivity atlases provide limited information about the organization of thalamocortical projections in the mouse brain. Labeling the projections of spatially restricted neuron populations in thalamus can provide a functionally relevant level of connectomic analysis, but these need to be integrated within the same common reference space. Here, we present a pipeline for the segmentation, registration, integration and analysis of multiple tract-tracing experiments. The key difference with other workflows is that the data is transformed to fit the reference template. As a test-case, we investigated the axonal projections and intranuclear arrangement of seven neuronal populations of the ventral posteromedial nucleus of the thalamus (VPM), which we labeled with an anterograde tracer. Their soma positions corresponded, from dorsal to ventral, to cortical representations of the whiskers, nose and mouth. They strongly targeted layer 4, with the majority exclusively targeting one cortical area and the ones in ventrolateral VPM branching to multiple somatosensory areas. We found that our experiments were more topographically precise than similar experiments from the Allen Institute and projections to the primary somatosensory area were in agreement with single-neuron morphological reconstructions from publicly available databases. This pilot study sets the basis for a shared virtual connectivity atlas that could be enriched with additional data for studying the topographical organization of different thalamic nuclei. The pipeline is accessible with only minimal programming skills via a Jupyter Notebook, and offers multiple visualization tools such as cortical flatmaps, subcortical plots and 3D renderings and can be used with custom anatomical delineations.

Inhibitory Gating of Thalamocortical Inputs onto Rat Gustatory Insular Cortex.

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 GABAA and GABAB receptors onto VPMpc terminals. These results provide a novel insight into the complex features of thalamocortical circuits for taste processing.SIGNIFICANCE STATEMENT 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.

Loss of Ephaptic Contacts in the Murine Thalamus during Osmotic Demyelination Syndrome

ABSTRACT Background and aim A murine model mimicking osmotic demyelination syndrome (ODS) revealed with histology in the relay posterolateral (VPL) and ventral posteromedial (VPM) thalamic nuclei adjoined nerve cell bodies in chronic hyponatremia, amongst the damaged 12 h and 48 h after reinstatement of osmolality. This report aims to verify and complement with ultrastructure other neurophysiology, immunohistochemistry, and molecular biochemistry data to assess the connexin-36 protein, as part of those hinted close contacts. This ODS investigation included four groups of mice: Sham (NN; n = 13), hyponatremic (HN; n = 11), those sacrificed 12 h after a fast restoration of normal natremia (ODS12h; n = 6) and mice sacrificed 48 h afterward, or ODS48 h (n = 9). Out of these, thalamic zones samples included NN (n = 2), HN (n = 2), ODS12h (n = 3) and ODS48h (n = 3). Results Ultrastructure illustrated junctions between nerve cell bodies that were immunolabeled with connexin36 (Cx36) with light microscopy and Western blots. These cell’s junctions were reminiscent of low resistance junctions characterized in other regions of the CNS with electrophysiology. Contiguous neurons showed neurolemma contacts in intact and damaged tissues according to their location in the ODS zones, at 12 h and 48 h post correction along with other demyelinating alterations. Neurons and ephaptic contact measurements indicated the highest alterations, including nerve cell necrosis in the ODS epicenter and damages decreased toward the outskirts of the demyelinated zone. Conclusion Ephapses contained C × 36between intact or ODS injured neurons in the thalamus appeared to be resilient beyond the core degraded tissue injuries. These could maintain intercellular ionic and metabolite exchanges between these lesser injured regions and, thus, would partake to some brain plasticity repairs.

The cerebellum contributes to generalized seizures by altering activity in the ventral posteromedial nucleus

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.

Emergence of consciousness from anesthesia through ubiquitin degradation of KCC2 in the ventral posteromedial nucleus of the thalamus.

The emergence of consciousness from anesthesia, once assumed to be a passive process, is now considered as an active and controllable process. In the present study, we show in mice that, when the brain is forced into a minimum responsive state by diverse anesthetics, a rapid downregulation of K+/Cl- cotransporter 2 (KCC2) in the ventral posteromedial nucleus (VPM) serves as a common mechanism by which the brain regains consciousness. Ubiquitin-proteasomal degradation is responsible for KCC2 downregulation, which is driven by ubiquitin ligase Fbxl4. Phosphorylation of KCC2 at Thr1007 promotes interaction between KCC2 and Fbxl4. KCC2 downregulation leads to γ-aminobutyric acid type A receptor-mediated disinhibition, enabling accelerated recovery of VPM neuron excitability and emergence of consciousness from anesthetic inhibition. This pathway to recovery is an active process and occurs independent of anesthetic choice. The present study demonstrates that ubiquitin degradation of KCC2 in the VPM is an important intermediate step en route to emergence of consciousness from anesthesia.

Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability.

Deep brain stimulation (DBS) is a surgical technique used to manage aggression in patients who do not improve despite the use of appropriate drug treatment. The objective of this study is to assess the impact of DBS on aggressive behavior refractory to the pharmacological and behavioral treatment of patients with Intellectual Disabilities (ID). A follow-up was conducted on a cohort of 12 patients with severe ID, undergoing DBS in posteromedial hypothalamic nuclei; evaluated with the Overt Aggression Scale (OAS), before the intervention, at 6, 12, and 18 months of medical follow-up. After the surgical procedure, there was a significant reduction in the aggressiveness of patients in the follow-up medical evaluation at 6months (t=10.14; p < 0.01), 12 months (t=14.06; p < 0.01), and 18 months (t=15.34; p < 0.01), respect to the initial measurement; with a very large effect size (6months: d=2.71; 12 months: d=3.75; 18 months: d=4.10). From 12 months onward, emotional control stabilized and is sustained at 18 months (t=1.24; p > 0.05). DBS in posteromedial hypothalamic nuclei may be an effective treatment for the management of aggression in patients with ID refractory to pharmacological treatment.

Activation of the VpdmVGLUT1-VPM pathway contributes to anxiety-like behaviors induced by malocclusion.

Occlusal disharmony has a negative impact on emotion. The mesencephalic trigeminal nucleus (Vme) neurons are the primary afferent nuclei that convey proprioceptive information from proprioceptors and low-threshold mechanoreceptors in the periodontal ligament and jaw muscles in the cranio-oro-facial regions. The dorsomedial part of the principal sensory trigeminal nucleus (Vpdm) and the ventral posteromedial nucleus (VPM) of thalamus have been proven to be crucial relay stations in ascending pathway of proprioception. The VPM sends numerous projections to primary somatosensory areas (SI), which modulate emotion processing. The present study aimed to demonstrate the ascending trigeminal-thalamic-cortex pathway which would mediate malocclusion-induced negative emotion. Unilateral anterior crossbite (UAC) model created by disturbing the dental occlusion was applied. Tract-tracing techniques were used to identify the existence of Vme-Vpdm-VPM pathway and Vpdm-VPM-SI pathway. Chemogenetic and optogenetic methods were taken to modulate the activation of VpdmVGLUT1 neurons and the Vpdm-VPM pathway. Morphological evidence indicated the involvement of the Vme-Vpdm-VPM pathway, Vpdm-VPM-SI pathway and VpdmVGLUT1-VPM pathway in orofacial proprioception in wild-type mice and vesicular glutamate transporter 1 (VGLUT1): tdTomato mice, respectively. Furthermore, chemogenetic inhibition of VpdmVGLUT1 neurons and the Vpdm-VPM pathway alleviated anxiety-like behaviors in a unilateral anterior crossbite (UAC) model, whereas chemogenetic activation induced anxiety-like behaviors in controls and did not aggravate these behaviors in UAC mice. Finally, optogenetic inhibition of the VpdmVGLUT1-VPM pathway in VGLUT1-IRES-Cre mice reversed UAC-induced anxiety comorbidity. In conclusion, these results suggest that the VpdmVGLUT1-VPM neural pathway participates in the modulation of malocclusion-induced anxiety comorbidity. These findings provide new insights into the links between occlusion and emotion and deepen our understanding of the impact of occlusal disharmony on brain dysfunction.