Reciprocal interactions between the prefrontal cortex (PFC) and thalamus play a critical role in cognition, but the underlying circuits remain poorly understood. Here we use optogenetics to dissect the specificity and dynamics of cortico-thalamo-cortical networks in the mouse brain. We find that cortico-thalamic (CT) neurons in prelimbic PFC project to both mediodorsal (MD) and ventromedial (VM) thalamus, where layer 5 and 6 inputs activate thalamo-cortical (TC) neurons with distinct temporal profiles. We show that TC neurons in MD and VM in turn make distinct connections in PFC, with MD preferentially and strongly activating layer 2/3 cortico-cortical (CC) neurons. Finally, we assess local connections from superficial CC to deep CT neurons, which link thalamo-cortical and cortico-thalamic networks within the PFC. Together our findings indicate that PFC strongly drives neurons in the thalamus, whereas MD and VM indirectly influence reciprocally connected neurons in the PFC, providing a mechanistic understanding of these circuits.

The study focused on projections from the posterior parietal cortex (PPC) to the ventral lateral thalamic nucleus (VL) and three thalamic association nuclei, mediodorsal (MD), lateral posterior (LP) and pulvinar. For light microscopic analysis small biotinylated dextran amine (BDA) or biocytin injections were placed in midrostral and dorsal portions of the inferior parietal lobule (IPL), respectively. The distribution of anterograde and retrograde labeling was charted, and representative axons and terminal fields were reconstructed in the sagittal plane to examine their features. Two types of fibers were identified--those of thin diameter forming diffuse terminal fields with small boutons, and thick fibers forming focal terminal fields with large boutons. Area PFG injection of BDA resulted in labeling of both types of fibers in LP, MD, and pulvinar, whereas only fibers of the first type were found in VL. Biocytin injection in area Opt resulted in preferential labeling of large fibers terminating in LP and pulvinar. Further electron microscopic analysis of labeled boutons in VL and LP, following a large wheat germ agglutinin conjugated horseradish peroxidase injection in the middle of IPL, confirmed the existence of small and large corticothalamic boutons and their different termination sites: the small boutons formed synapses on distal dendrites while the large boutons were found close to somata of thalamocortical projection neurons, on the dendrites of local circuit neurons and in complex synaptic arrangements, such as glomeruli. The results demonstrate that projections from small loci of the PPC to functionally and connectionally different thalamic nuclei differ anatomically, implying a different functional impact on these diverse targets.

Although the mechanisms by which the cerebral cortex controls its ascending input are still poorly understood, it is known that cortical control at the thalamic level is via direct glutamatergic projections to relay nuclei and to the reticular nucleus. Here we confirm previous light microscopic reports of a high expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluR4, in reticular and ventral posterior thalamic nuclei of the rat, and moderate staining using an antibody recognizing both GluR2 and GluR3. In contrast only low levels of staining for GluR2, and barely detectable levels of GluR1 immunoreactivity were observed. After injections of biotinylated dextran, electron microscopy revealed that anterogradely-labeled cortical synapses in both thalamic nuclei were small with fewer mitochondria and more densely-packed vesicles than terminals likely to arise from intrinsic and ascending pathways. We performed post-embedding immunogold to provide quantitative data on the density of AMPA receptor subunits at morphologically-defined groups of synapses. We found that corticothalamic synapses in the reticular thalamic nucleus contain twice as much GluR2/3, and at least three times more GluR4 protein than do intrathalamic synapses. In the ventral posterior nucleus, corticothalamic synapses contain similar amounts of GluR2/3, but four times more GluR4 than do those from ascending afferents. Corticothalamic synapses in reticular nucleus contain slightly more GluR2/3, and three times more GluR4, than those in ventral posterior nucleus. We conclude that enrichment of GluR4 at morphologically-defined cortical synapses is a feature common to both thalamic nuclei, and those in the reticular nucleus express higher levels of AMPA receptors. The rapid kinetics of GluR4-rich AMPA receptors we suggest indicate that cortical descending control may be more temporally precise than previously recognized.

Verticality misperception after stroke is a frequent neurological deficit that leads to postural imbalance and a higher risk of falls. The posterior thalamic nuclei are described to be involved with verticality perception, but it is unknown if extra-thalamic lesions can have the same effect via diaschisis and degeneration of thalamic nuclei. We investigated the relationship between thalamic fractional anisotropy (FA, a proxy of structural integrity), and verticality perception, in patients after stroke with diverse encephalic extra-thalamic lesions. We included 11 first time post-stroke patients with extra-thalamic primary lesions, and compared their region-based FA to a group of 25 age-matched healthy controls. For the patient sample, correlation and regression analyses evaluated the relationship between thalamic nuclei FA and error of postural vertical (PV) and haptic vertical (HV) in the roll (PVroll/HVroll) and pitch planes (PVpitch/HVpitch). Relative to controls, patients showed decreased FA of anterior, ventral anterior, ventral posterior lateral, dorsal, and pulvinar thalamic nuclei, despite the primary lesions being extra-thalamic. We found a significant correlation between HVroll, and FA in the anterior and dorsal nuclei, and PVroll with FA in the anterior nucleus. FA in the anterior, ventral anterior, ventral posterior lateral, dorsal and pulvinar nuclei predicted PV, and FA in the ventral anterior, ventral posterior lateral and dorsal nuclei predicted HV. While prior studies indicate that primary lesions of the thalamus can result in verticality misperception, here we present evidence supporting that secondary degeneration of thalamic nuclei via diaschisis can also be associated with verticality misperception after stroke.

Deep brain stimulation (DBS) requires precise localization, which is especially difficult at the thalamus, and even more difficult in anesthetized patients. We aimed to characterize the neurophysiological properties of the ventral intermediate (V.im), ventral caudal (V.c), and centromedian parvo (Ce.pc) and the magnocellular (Ce.mc) thalamic nuclei. We obtained microelectrode recordings from five patients with refractory epilepsy under general anesthesia. Somatosensory evoked potentials recorded by microelectrodes were used to identify the V.c nucleus. Trajectories were reconstructed off-line to identify the nucleus recorded, and the amplitude of the action potential (AP) and the tonic (i.e., mean frequency, density, probability of interspike interval) and phasic (i.e., burst index, pause index, and pause ratio) properties of the pattern discharges were analyzed. The Mahalanobis metric was used to evaluate the similarity of the patterns. The mean AP amplitude was higher for the V.im nucleus (172.7 ± 7.6 µV) than for the other nuclei, and the mean frequency was lower for the Ce.pc nucleus (7.2 ± 0.8 Hz) and higher for the V.c nucleus (11.9 ± 0.8 Hz) than for the other nuclei. The phasic properties showed a bursting pattern for the V.c nucleus and a tonic pattern for the centromedian and V.im nuclei. The Mahalanobis distance was the shortest for the V.im/V.c and Ce.mp/Ce.pc pairs. Therefore, the different properties of the thalamic nuclei, even for patients under general anesthesia, can be used to positively define the recorded structure, improving the exactness of electrode placement in DBS.

We aimed to investigate the alterations of thalamic nuclei volumes and intrinsic thalamic network in patients with primary restless legs syndrome (RLS) compared to healthy controls. Seventy-one patients with primary RLS and 55 healthy controls were recruited. They underwent brain MRI using a three-tesla MRI scanner, including three-dimensional T1-weighted images. The intrinsic thalamic network was determined using graph theoretical analysis. The right and left whole thalamic volumes, and the right pulvinar inferior, left ventral posterolateral, left medial ventral, and left pulvinar inferior nuclei volumes in the patients with RLS were lower than those in healthy controls (0.433 vs. 0.447%, p = 0.034; 0.482 vs. 0.502%, p = 0.016; 0.013 vs. 0.015%, p = 0.031; 0.062 vs. 0.065%, p = 0.035; 0.001 vs. 0.001%, p = 0.034; 0.018 vs. 0.020%, p = 0.043; respectively). There was also a difference in the intrinsic thalamic network between the groups. The assortative coefficient in patients with RLS was higher than that in healthy controls (0.0318 vs. - 0.0358, p = 0.048). We demonstrated the alterations of thalamic nuclei volumes and intrinsic thalamic network in patients with RLS compared to healthy controls. These changes might be related to RLS pathophysiology and suggest the pivotal role of the thalamus in RLS symptoms.

Microstates (MS), the fingerprints of the momentarily and time-varying states of the brain derived from electroencephalography (EEG), are associated with the resting state networks (RSNs). However, using MS fluctuations along different EEG frequency bands to model the functional MRI (fMRI) signal has not been investigated so far, or elucidated the role of the thalamus as a fundamental gateway and a putative key structure in cortical functional networks. Therefore, in the current study, we used MS predictors in standard frequency bands to predict blood oxygenation level dependent (BOLD) signal fluctuations. We discovered that multivariate modeling of BOLD-fMRI using six EEG-MS classes in eight frequency bands strongly correlated with thalamic areas and large-scale cortical networks. Thalamic nuclei exhibited distinct patterns of correlations for individual MS that were associated with specific EEG frequency bands. Anterior and ventral thalamic nuclei were sensitive to the beta frequency band, medial nuclei were sensitive to both alpha and beta frequency bands, and posterior nuclei such as the pulvinar were sensitive to delta and theta frequency bands. These results demonstrate that EEG-MS informed fMRI can elucidate thalamic activity not directly observable by EEG, which may be highly relevant to understand the rapid formation of thalamocortical networks.

Precise neurosurgical targeting of electrode arrays within the brain is essential to the successful treatment of a range of brain disorders with deep brain stimulation (DBS) therapy. Here, we describe a set of computational tools to generate in vivo, subject-specific atlases of individual thalamic nuclei thus improving the ability to visualize thalamic targets for preclinical DBS applications on a subject-specific basis. A sequential nonlinear atlas warping technique and a Bayesian estimation technique for probabilistic crossing fiber tractography were applied to high field (7T) susceptibility-weighted and diffusion-weighted imaging, respectively, in seven rhesus macaques. Image contrast, including contrast within thalamus from the susceptibility-weighted images, informed the atlas warping process and guided the seed point placement for fiber tractography. The susceptibility-weighted imaging resulted in relative hyperintensity of the intralaminar nuclei and relative hypointensity in the medial dorsal nucleus, pulvinar, and the medial/ventral border of the ventral posterior nuclei, providing context to demarcate borders of the ventral nuclei of thalamus, which are often targeted for DBS applications. Additionally, ascending fiber tractography of the medial lemniscus, superior cerebellar peduncle, and pallidofugal pathways into thalamus provided structural demarcation of the ventral nuclei of thalamus. The thalamic substructure boundaries were validated through in vivo electrophysiological recordings and post-mortem blockface tissue sectioning. Together, these imaging tools for visualizing and segmenting thalamus have the potential to improve the neurosurgical targeting of DBS implants and enhance the selection of stimulation settings through more accurate computational models of DBS.

The thalamus is an essential relay station in the cortical-subcortical connections. It is characterized by a complex anatomical architecture composed of numerous small nuclei, which mediate the involvement of the thalamus in a wide range of neurological functions. We present a novel framework for segmenting the thalamic nuclei, which explores the orientation distribution functions (ODFs) from diffusion magnetic resonance images at 3 T. The differentiation of the complex intra-thalamic microstructure is improved by using the spherical harmonic (SH) representation of the ODFs, which provides full angular characterization of the diffusion process in each voxel. The clustering was performed using the k-means algorithm initialized in a data-driven manner. The method was tested on 35 healthy volunteers and our results show a robust, reproducible and accurate segmentation of the thalamus in seven nuclei groups. Six of them closely matched the anatomy and were labeled as anterior, ventral anterior, medio-dorsal, ventral latero-ventral, ventral latero-dorsal and pulvinar, while the seventh cluster included the centro-lateral and the latero-posterior nuclei. Results were evaluated both qualitatively, by comparing the segmented nuclei to the histological atlas of Morel, and quantitatively, by measuring the clusters' extent and the clusters' spatial distribution across subjects and hemispheres. We also showed the robustness of our approach across different sequences and scanners, as well as intra-subject reproducibility of the segmented clusters using additional two scan-rescan datasets. We also observed an overlap between the path of the main long-connection tracts passing through the thalamus and the spatial distribution of the nuclei identified with our clustering algorithm. Our approach, based on SH representations of the ODFs, outperforms the one based on angular differences between the principle diffusion directions, which is considered so far as state-of-the-art method. Our findings show an anatomically reliable segmentation of the main groups of thalamic nuclei that could be of potential use in many clinical applications.

It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic nuclei and how nuclear-specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non-refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting-state functional magnetic resonance imaging (MRI) in patients with refractory and non-refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed-to-voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non-refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non-refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting-state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE.

Traumatic brain injury (TBI) may increase susceptibility to neurodegenerative diseases later in life. One neurobiological parallel between chronic TBI and neurodegeneration may be accelerated aging and the nature of atrophy across subcortical gray matter structures. The main aim of the present investigation is to evaluate and rank the degree that subcortical gray matter atrophy differentiates chronic moderate-severe TBI from non-TBI participants by evaluating morphometric differences between groups. Forty individuals with moderate-severe chronic TBI (9.23 yrs from injury) and 33 healthy controls (HC) underwent high resolution 3D T1-weighted structural magnetic resonance imaging. Whole brain volume was classified into white matter, cortical and subcortical gray matter structures with hippocampi and thalami further segmented into subfields and nuclei, respectively. Extensive atrophy was observed across nearly all brain regions for chronic TBI participants. A series of multivariate logistic regression models identified subcortical gray matter structures of the hippocampus and thalamus as the most sensitive to differentiating chronic TBI from non-TBI participants (McFadden R2 = .36, p < .001). Further analyses revealed the pattern of hippocampal atrophy to be global, occurring across nearly all subfields. The pattern of thalamic atrophy appeared to be much more selective and non-uniform, with largest between-group differences evident for nuclei bordering the ventricles. Subcortical gray matter was negatively correlated with time since injury (r = -.31, p = .054), while white matter and cortical gray matter were not. Cognitive ability was lower in the chronic TBI group (Cohen's d = .97, p = .003) and correlated with subcortical structures including the pallidum (r2 = .23, p = .038), thalamus (r2 = .36, p = .007) and ventral diencephalon (r2 = .23, p = .036). These data may support an accelerated aging hypothesis in chronic moderate-severe TBI that coincides with a similar neuropathological profile found in neurodegenerative diseases.

The respective roles of the ventral posterior complex (VP) and of the more recently described VMpo (posterior part of the ventral medial nucleus) as thalamic relays for pain and temperature pathways have recently been the subject of controversy. Data we obtained in one patient after a limited left thalamic infarct bring some new insights into this debate. This patient presented sudden right-sided hypesthesia for both lemniscal (touch, vibration, joint position) and spinothalamic (pain and temperature) modalities. He subsequently developed right-sided central pain with allodynia. Projection of 3D magnetic resonance images onto a human thalamic atlas revealed a lesion involving the anterior two thirds of the ventral posterior lateral nucleus (VPL) and, to a lesser extent, the ventral posterior medial (VPM) and inferior (VPI) nuclei. Conversely, the lesion did not extend posterior and ventral enough to concern the putative location of the spinothalamic-afferented nucleus VMpo. Neurophysiological studies showed a marked reduction (67%) of cortical responses depending on dorsal column-lemniscal transmission, while spinothalamic-specific, CO2-laser induced cortical responses were only moderately attenuated (33%). Our results show that the VP is definitely involved in thermo-algesic transmission in man, and that its selective lesion can lead to central pain. However, results also suggest that much of the spino-thalamo-cortical volley elicited by painful heat stimuli does not transit through VP, supporting the hypothesis that a non-VP locus lying more posteriorly in the human thalamus is important for thermo-algesic transmission.

A hierarchical scheme proposed by Kaas and colleagues suggests that primate auditory cortex can be divided into core and belt regions based on anatomic connections with thalamus and distinctions among response properties. According to their model, core auditory cortex receives predominantly unimodal sensory input from the ventral nucleus of the medial geniculate body (MGBv); whereas belt cortex receives predominantly cross-modal sensory input from nuclei outside the MGBv. We previously characterized distinct response properties in rat primary (A1) versus ventral auditory field (VAF) cortex; however, it has been unclear whether VAF should be categorized as a core or belt auditory cortex. The current study employed high-resolution functional imaging to map intrinsic metabolic responses to tones and to guide retrograde tracer injections into A1 and VAF. The size and density of retrogradely labeled somas in the medial geniculate body (MGB) were examined as a function of their position along the caudal-to-rostral axis, subdivision of origin, and cortical projection target. A1 and VAF projecting neurons were found in the same subdivisions of the MGB but in rostral and caudal parts, respectively. Less than 3% of the cells projected to both regions. VAF projecting neurons were smaller than A1 projecting neurons located in dorsal (MGBd) and suprageniculate (SG) nuclei. Thus, soma size varied with both caudal-rostral position and cortical target. Finally, the majority (>70%) of A1 and VAF projecting neurons were located in MGBv. These MGB connection profiles suggest that rat auditory cortex, like primate auditory cortex, is made up of multiple distinct core regions.

The thalamus and its nuclei are largely indistinguishable on standard T1 or T2 weighted MRI. While diffusion tensor imaging based methods have been proposed to segment the thalamic nuclei based on the angular orientation of the principal diffusion tensor, these are based on echo planar imaging which is inherently limited in spatial resolution and suffers from distortion. We present a multi-atlas segmentation technique based on white-matter-nulled MP-RAGE imaging that segments the thalamus into 12 nuclei with computation times on the order of 10 min on a desktop PC; we call this method THOMAS (THalamus Optimized Multi Atlas Segmentation). THOMAS was rigorously evaluated on 7T MRI data acquired from healthy volunteers and patients with multiple sclerosis by comparing against manual segmentations delineated by a neuroradiologist, guided by the Morel atlas. Segmentation accuracy was very high, with uniformly high Dice indices: at least 0.85 for large nuclei like the pulvinar and mediodorsal nuclei and at least 0.7 even for small structures such as the habenular, centromedian, and lateral and medial geniculate nuclei. Volume similarity indices ranged from 0.82 for the smaller nuclei to 0.97 for the larger nuclei. Volumetry revealed that the volumes of the right anteroventral, right ventral posterior lateral, and both right and left pulvinar nuclei were significantly lower in MS patients compared to controls, after adjusting for age, sex and intracranial volume. Lastly, we evaluated the potential of this method for targeting the Vim nucleus for deep brain surgery and focused ultrasound thalamotomy by overlaying the Vim nucleus segmented from pre-operative data on post-operative data. The locations of the ablated region and active DBS contact corresponded well with the segmented Vim nucleus. Our fast, direct structural MRI based segmentation method opens the door for MRI guided intra-operative procedures like thalamotomy and asleep DBS electrode placement as well as for accurate quantification of thalamic nuclear volumes to follow progression of neurological disorders.

Ligands of the mu-opioid receptor are known to inhibit nociceptive transmission in the dorsal horn, yet the cellular site(s) of action for this inhibition remain to be fully elucidated. Neurons located in lamina I of the dorsal horn are involved in distinct aspects of nociceptive transmission. Neurons projecting to the thalamus are thought to be involved in sensory-discriminative aspects of pain perception, while neurons projecting to the parabrachial nucleus are thought to be important for emotional and/or autonomic responses to noxious stimuli. The present study examined these two populations of lamina I projection neurons in the trigeminal dorsal horn to determine if the mu-opioid receptor protein (MOR1) is differentially located in these populations of neurons. Lamina I projection neurons were identified using the retrograde tracer FluoroGold (FGold). FGold was injected into either the contralateral thalamus (ventral posterolateral (VPM)/ventral posterolateral (VPL) thalamic region) or into the ipsilateral parabrachial nuclei. The distribution of MOR1 in these neurons was determined using immunocytochemistry. The distribution of MOR1-ir within these two populations of lamina I projection neurons was examined by both confocal and electron microscopy. We found that both populations of projection neurons contained MOR1. Immunogold analyses revealed the presence of MOR1-ir at membrane sites and within the cytoplasm of these neurons. Cytoplasmic receptor labeling may represent sites of synthesis, recycling or reserve populations of receptors. MOR1 was primarily found in the somata and proximal dendrites of projection neurons. In addition, these neurons rarely received synaptic input from MOR1-containing axon terminals. These results indicate that lamina I neurons in trigeminal dorsal horn that project to the thalamic and parabrachial nuclei contain MOR1 and are likely sites of action for MOR ligands that modulate sensory and/or autonomic aspects of pain transmission in the trigeminal dorsal horn.

The thalamus is a central link between cortical and subcortical brain motor systems. Axons from the deep nuclei of the cerebellum (DCN), or the output nuclei of the basal ganglia system (substantia nigra reticulata, SNr; and internal pallidum GPi/ENT) monosynaptically innervate the thalamus, prominently some nuclei of the ventral nuclear group. In turn, axons from these ventral nuclei innervate the motor and premotor areas of the cortex, where their input is critical for planning, execution and learning of rapid and precise movements. Mice have in recent years become a widely used model in motor system research. However, information on the distribution of cerebellar and basal ganglia inputs in the rodent thalamus remains poorly defined. Here, we mapped the distribution of inputs from DCN, SNr, and GPi/ENT to the ventral nuclei of the mouse thalamus. Immunolabeling for glutamatergic and GABAergic neurotransmission markers delineated two distinct main territories, characterized each by the presence of large vesicular glutamate transporter type 2 (vGLUT2) puncta or vesicular GABA transporter (vGAT) puncta. Anterograde labeling of axons from DCN revealed that they reach virtually all parts of the ventral nuclei, albeit its axonal varicosities (putative boutons) in the vGAT-rich sector are consistently smaller than those in the vGLUT2-rich sector. In contrast, the SNr axons innervate the whole vGAT-rich sector, but not the vGLUT2-rich sector. The GPi/ENT axons were found to innervate only a small zone of the vGAT-rich sector which is also targeted by the other two input systems. Because inputs fundamentally define thalamic cell functioning, we propose a new delineation of the mouse ventral motor nuclei that is consistent with the distribution of DCN, SNr and GPi/ENT inputs and resembles the general layout of the ventral motor nuclei in primates.

The primary cause of harmaline tremor, which is a model of essential tremor (ET) in animals, is excessive activation of olivocerebellar glutamatergic climbing fibers. Our recent study indicated that 5'-chloro-5'-deoxy-(±)-N6-(±)-(endo-norborn-2-yl)adenosine (5'Cl5'd-(±)-ENBA), a potent and selective adenosine A1 receptor (A1) agonist, inhibited harmaline tremor. The present study was aimed to evaluate the role of glutamatergic transmission system in 5'Cl5'd-(±)-ENBA tremorolytic action in the harmaline model in rats, by analyzing glutamate release in the motor nuclei of the thalamus and mRNA expression of glutamatergic neuron markers (vGlut1/2) in reference to the general neuronal activity marker (zif-268) in different brain structures. The extracellular glutamate level in the motor thalamus was evaluated by in vivo microdialysis and the vGlut1/vGlut2 and zif-268 mRNA expression was analyzed by in situ hybridization. The intensity of tremor was measured automatically using Force Plate Actimeters (FPAs). 5'Cl5'd-(±)-ENBA (0.5 mg/kg) given 30 min before harmaline (30 mg/kg) decreased the harmaline-induced excessive glutamate release in the motor thalamus and reversed harmaline-induced molecular effects, such as elevation of the vGlut1 mRNA expression in the inferior olive (IO) and decrease in the motor cortex, as well as an increase of the zif-268 mRNA expression in the IO, motor thalamus and motor cortex. Moreover, 5'Cl5'd-(±)-ENBA reduced harmaline tremor by lowering its power in 9-15 Hz frequency band. Our findings show that A1 stimulation decreases glutamate release in the motor thalamic nuclei in the harmaline model of ET, suggesting that A1 receptors, especially in this structure, may be a potential therapeutic target in this disorder.

Repetitive electrical stimulation to the cortical masticatory areas (CMA) evokes rhythmical jaw movements (RJM), whose patterns vary depending on the stimulation site, in various species. In guinea pigs, although alternating bilateral jaw movements are usually seen during natural chewing, it is still unclear which cortical areas are responsible for chewing-like RJM. To address this issue, we first defined the cortical areas inducing chewing-like RJM by intracortical microstimulation. Stimulation of the most lateral area of the CMA, the granular cortex, induced chewing-like RJM, but from the region medial to this area, simple vertical RJM were induced. Subsequently, to reveal the properties of these two areas in the CMA, the connections between the CMA and the dorsal thalamus were examined by neuronal tract-tracing techniques. The area inducing chewing-like RJM possessed strong reciprocal connections, mainly with the medial part of the ventral posteromedial nucleus, which is the sensory-relay thalamus. On the other hand, the simple vertical RJM-inducing area had reciprocal connections with the motor thalamus. The present study suggests that the CMA inducing chewing-like RJM is different from the CMA inducing simple vertical RJM, and plays a role in cortically induced chewing-like RJM under the influence of the sensory thalamus in guinea pigs.

The ventral lateral geniculate nucleus (LGNv) is a retinorecipient part of the ventral thalamus and in cats, it consists of medial (M), medial intermediate (IM), lateral intermediate (IL), lateral (L), and dorsal (D) subdivisions. These subdivisions can be differentiated not only by their cytoarchitecture, but also by their connectivity and putative functions. The LGNv may play a role in visuomotor gating, in that there is evidence of cerebellar afferent projections to the intermediate subdivisions. The cerebellar posterior interpositus (IP) and lateral (LC) nuclei are known to project to IM and IL, but the specifics of these projections are unclear. We hypothesized that the IP and LC project differentially to IM and IL. To evaluate LGNv innervation by the deep cerebellar nuclei, we injected the tract-tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into several different regions of the LGNv and cerebellar nuclei of adult cats in either sex. Small injections into the middle and posterior LGNv retrogradely labeled cells in the ventral part of the IP. However, injections in the anterior regions of the LGNv, with or without diffusion into the thalamic reticular nucleus (Re), retrogradely labeled cells in the ventral part of both the IP and the LC. Confirmatory injections into the IP and LC produced terminal-like labeling distributed in IM, IL, and Re; injections mostly localized to the LC resulted in labeling mainly in IM and Re. We concluded that the IP projects to IL whereas the LC projects to IM and Re.

The thalamus is a key cerebral hub relaying a multitude of corticoefferent and corticoafferent connections and mediating distinct extrapyramidal, sensory, cognitive and behavioural functions. While the thalamus consists of dozens of anatomically well-defined nuclei with distinctive physiological roles, existing imaging studies in motor neuron diseases typically evaluate the thalamus as a single structure. Based on the unique cortical signatures observed in ALS and PLS, we hypothesised that similarly focal thalamic involvement may be observed if the nuclei are individually evaluated. A prospective imaging study was undertaken with 100 patients with ALS, 33 patients with PLS and 117 healthy controls to characterise the integrity of thalamic nuclei. ALS patients were further stratified for the presence of GGGGCC hexanucleotide repeat expansions in C9orf72. The thalamus was segmented into individual nuclei to examine their volumetric profile. Additionally, thalamic shape deformations were evaluated by vertex analyses and focal density alterations were examined by region-of-interest morphometry. Our data indicate that C9orf72 negative ALS patients and PLS patients exhibit ventral lateral and ventral anterior involvement, consistent with the 'motor' thalamus. Degeneration of the sensory nuclei was also detected in C9orf72 negative ALS and PLS. Both ALS groups and the PLS cohort showed focal changes in the mediodorsal-paratenial-reuniens nuclei, which mediate memory and executive functions. PLS patients exhibited distinctive thalamic changes with marked pulvinar and lateral geniculate atrophy compared to both controls and C9orf72 negative ALS. The considerable ventral lateral and ventral anterior pathology detected in both ALS and PLS support the emerging literature of extrapyramidal dysfunction in MND. The involvement of sensory nuclei is consistent with sporadic reports of sensory impairment in MND. The unique thalamic signature of PLS is in line with the distinctive clinical features of the phenotype. Our data confirm phenotype-specific patterns of thalamus involvement in motor neuron diseases with the preferential involvement of nuclei mediating motor and cognitive functions. Given the selective involvement of thalamic nuclei in ALS and PLS, future biomarker and natural history studies in MND should evaluate individual thalamic regions instead overall thalamic changes.