Ventral Nucleus Research Articles

Thalamic changes in patients with chronic facial pain.

To investigate structural alterations in the thalamus in patients with primary trigeminal neuralgia and provide a detailed perspective on thalamic remodeling in response to chronic pain at the level of individual thalamic nuclei. METHODS: We analyzed a sample of 62 patients with primary trigeminal neuralgia who underwent surgical treatment, along with 28 healthy participants. Magnetic resonance imaging (MRI) data were acquired using a 3T system equipped with a 16-channel receiver head coil. Segmentation of the thalamic nuclei was performed using FreeSurfer 7.2.0. We divided the group of patients with trigeminal neuralgia into two subgroups: those with right-sided pain and those with left-sided pain. Each subgroup was compared to a control group by means of one-way ANOVA. Associations between morphometric and clinical variables were assessed with Spearman correlation coefficient. Our results revealed significant gray matter volume changes in thalamic nuclei among patients with trigeminal neuralgia. Notably, the intralaminar nuclei (centromedian/parafascicular) and nuclei associated with visual and auditory signal processing (lateral and medial geniculate bodies) exhibited significant alterations, contrasting with the ventral group nuclei involved in nociceptive processing. Additionally, we found no substantial volume increase in any of the studied nuclei following successful surgical intervention 6 months later. The volumes of thalamic nuclei were negatively correlated with pain intensity and disease duration. The results of this study, although preliminary, hold promise for clinical applications as they reveal previously unknown structural alterations in the thalamus that occur in patients with chronic trigeminal neuralgia.

Histaminergic Innervation of the Ventral Anterior Thalamic Nucleus Alleviates Motor Deficits in a 6-OHDA-Induced Rat Model of Parkinson’s Disease

AbstractThe ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson’s disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K+ channels, or Ca2+-activated K+ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.

Neural modulation by nicotine aerosols and the role of flavor additives: insights from local field potentials in mice

Research on nicotine's neurobiological effects has rarely focused on aerosols, despite their primary role in tobacco product consumption. Here, we utilized in vivo electrophysiology to examine brain activity in mice exposed to nicotine aerosols, both alone and with flavor additives (citric acid and menthol). Local field potential (LFP) recordings from the nucleus accumbens (NAc), basolateral amygdala (BLA), ventral tegmental area (VTA), and ventral posteromedial nucleus (VPM) were analyzed under saline, nicotine, nicotine with citric acid(CA + NIC), and nicotine with menthol(MENT + NIC) conditions. Nicotine exposure significantly reduced power spectral density (PSD) in the NAc-Alpha, NAc-Beta, and BLA-Beta bands, unaffected by flavor additives. Coherence between key brain regions (e.g., VPM-VTA in Beta, VPM-BLA in Alpha) also decreased with nicotine but was restored with citric acid or menthol, suggesting their role in mitigating nicotine's disruptive effects on neural synchronization. Our findings show that LFPs can effectively capture nicotine's neural effects and highlight the modulatory role of flavor additives, offering new insights into nicotine exposure management and tobacco product design.

The effect of paeoniflorin on the rewarding effect of methamphetamine and the associated cognitive impairment in mice.

Chronic exposure to methamphetamine (METH) has been suggested to cause METH use disorder and severe cognitive impairment. Paeoniflorin (PF) is a monoterpenoid glycoside with various beneficial effects, including anti-inflammatory, antioxidant and antidepressant. The current study was designed to investigate the effect of PF (30mg/kg, i.p.) on the rewarding effect of METH (2.5mg/kg, i.p.) and the associated cognitive impairment, using the animal model of conditioned place preference, new location reorganization test, new object reorganization test and Y-maze test. METH induced conditioned place preference, accompanied by increased expression of synapse-associated proteins in the ventral target areas (VTA) and nucleus accumbens (NAc). In addition, METH induced significant cognitive impairment and decreased the expression of synapse-associated proteins in the hippocampus (Hip). Administration of PF decreased the rewarding effect of METH and the expression of synapse-associated proteins in the VTA or NAc. PF was also effective to improve METH-induced cognitive impairment by upregulating the expression of synapse-associated proteins in the Hip. Therefore, PF could be a potential agent for the treatment of METH use disorder and the associated cognitive impairment.

Clinical Evaluation of the NaviNetics Stereotactic System Using Intraoperative Portable Surgical Imaging System in DBS Surgery

BACKGROUND AND OBJECTIVES: A typical workflow for deep brain stimulation (DBS) surgery consists of head frame placement, followed by stereotactic computed tomography (CT) or MRI before surgical implantation of the hardware. At some institutions, this workflow is prolonged when the imaging scanner is located far away from the operating room, thereby increasing workflow times by the addition of transport times. Recently, the intraoperative O-arm has been shown to provide accurate image fusion with preoperative CT or MR imaging, suggesting the possibility of obtaining an intraoperative localization scan and postoperative confirmation. In this article, we aim to evaluate the compatibility of the stereotactic frame system with the intraoperative O-arm system regarding lead accuracy and surgical flow. METHODS: A total of 17 patients undergoing DBS surgery for movement disorders were evaluated. One patient underwent both the stereotactic CT and O-arm localization, while 16 patients underwent only intraoperative O-arm localization. Following lead placement, intraoperative O-arm imaging was obtained to evaluate the accuracy of the lead placement. Accuracy was defined as the error measured as the distance from the center of the planned trajectory to the cannula. RESULTS: Less than 0.1 mm difference was found between the O-arm imaging technique and CT image localization of the NaviNetics stereotactic head frame in DBS surgery. Of the 16 patients who underwent the intraoperative O-arm imaging alone, the targets included bilateral ventral intermediate nucleus (16 leads), bilateral globus pallidus internus (4 leads), and subthalamic nucleus (12 leads). The mean ± SD radial error in the probe's eye view was 0.71 ± 0.33 mm for n = 32 leads. No tract hemorrhage was observed. CONCLUSION: Intraoperative O-arm imaging can be used safely and effectively for stereotactic registration and lead placement confirmation with the stereotactic system in both awake and asleep DBS surgery.

"Quality over quantity:" smaller, targeted lesions optimize quality of life outcomes after MR-guided focused ultrasound thalamotomy for essential tremor.

MRI-guided focused ultrasound (MRgFUS) thalamotomy of the nucleus ventralis intermedius (VIM) has emerged as a powerful and safe treatment modality for refractory essential tremor. While the efficacy of this technique has been extensively described, much remains unclear about how to optimize MRgFUS for patient quality of life (QoL), which may depend as much on a patient's adverse effect profile as on the magnitude of tremor suppression. Diffusion tensor imaging (DTI) has been used to help guide targeting strategies but can pose certain challenges for scalability. In this study, we propose the use of a simplified patient-reported change in QoL assessment to create an unbiased representation of a patient's perception of overall benefit. Further, we propose a large-sample-size, high-resolution, 7 T DTI database from the Human Connectome Project to create a normative tractographic atlas (NTA) with representations of ventral intermediate nucleus subregions most likely to be structurally connected to the motor cortex. The NTA network-based hotspots are then nonlinearly fitted to each patient's T1-weighted MRI. We found that smaller lesion size and higher extent to which the lesion is within the NTA hotspot predicted patients' change in QoL at last follow-up. Though long-term change in clinical rating scale for tremor (CRST) impacted QoL, neither intraoperative tremor suppression nor the patient's long-term perception of tremor suppression correlated with QoL. We provide an intraoperative threshold for accumulated dose volume (<0.06 cc), which along with the network-based hotspot in the NTA, may facilitate an easily scalable approach to help limit treatment to small, safe yet effective lesions that optimize change in QoL after MRgFUS.

Differentiating Postural and Kinetic Tremor Responses to Deep Brain Stimulation in Essential Tremor.

While deep brain stimulation (DBS) targeting the ventral intermediate nucleus (VIM) of thalamus or posterior subthalamic area (PSA) can suppress forms of action tremor in people with Essential Tremor, previous studies have suggested postural tremor may respond more robustly than kinetic tremor to DBS. In this study, we aimed to more precisely quantify the (1) onset/offset dynamics and (2) steady-state effects of VIM/PSA-DBS on postural and kinetic tremor. Tremor data from wireless inertial measurement units were collected from 11 participants with ET (20 unilaterally assessed DBS leads). Three postural hold tasks and one kinetic task were performed with stimulation turned off, in 2-min intervals after enabling unilateral DBS at the clinician-optimized DBS setting (15 min), and in 2-min intervals following cessation of DBS (5 min). At baseline, kinetic tremor had significantly higher amplitudes, standard deviation, and frequency than postural tremor (P < 0.001). DBS had a more robust acute effect on postural tremors (54% decrease, P < 0.001), with near immediate tremor suppression in amplitude and standard deviation, but had non-significant improvement of kinetic tremor on the population-level across the wash-in period (34% decrease). Tremor response was not equivalent between wash-in and wash-out timepoints and involved substantial individual variability including task-specific rebound or long wash-out effects. Programming strategies for VIM/PSA-DBS should consider the individual temporal and effect size variability in postural versus kinetic tremor improvement. Improved targeting and programming strategies around VIM and PSA may be necessary to equivalently suppress both postural and kinetic tremors.

Multifunctional Neural Probes Enable Bidirectional Electrical, Optical, and Chemical Recording and Stimulation In Vivo.

Recording and modulation of neuronal activity enables the study of brain function in health and disease. While translational neuroscience relies on electrical recording and modulation techniques, mechanistic studies in rodent models leverage genetic precision of optical methods, such as optogenetics and fluorescent indicator imaging. In addition to electrical signal transduction, neurons produce and receive diverse chemical signals which motivate tools to probe and modulate neurochemistry. Although the past decade has delivered a wealth of technologies for electrophysiology, optogenetics, chemical sensing, and optical recording, combining these modalities within a single platform remains challenging. This work leverages materials selection and convergence fiber drawing to permit neural recording, electrical stimulation, optogenetics, fiber photometry, drug and gene delivery, and voltammetric recording of neurotransmitters within individual fibers. Composed of polymers and non-magnetic carbon-based conductors, these fibers are compatible with magnetic resonance imaging, enabling concurrent stimulation and whole-brain monitoring. Their utility is demonstrated in studies of the mesolimbic reward pathway by interfacing with the ventral tegmental area and nucleus accumbens in mice and characterizing the neurophysiological effects of a stimulant drug. This study highlights the potential of these fibers to probe electrical, optical, and chemical signaling across multiple brain regions in both mechanistic and translational studies.

Dietary omega-3 polyunsaturated fatty acids reduce cytochrome c oxidase in brain white matter and sensorimotor regions while increasing functional interactions between neural systems related to escape behavior in postpartum rats.

Previously, we showed that omega-3 polyunsaturated fatty acid n-3 (PUFA) supplementation improved the performance of postpartum rats in the shuttle box escape test (SBET). The brains of these rats were used in the current study which examined brain cytochrome c oxidase (CCO) activity in white matter bundles and 39 regions spanning sensorimotor, limbic, and cognitive areas to determine the effects of n-3 PUFAs on neural metabolic capacity and network interactions. We found that n-3 PUFA supplementation decreased CCO activity in white matter bundles, deep and superficial areas within the inferior colliculus, the anterior and barrel field regions of the primary somatic sensorimotor cortex, the secondary somatic sensorimotor cortex, the lateral, anterior regions of the secondary visual cortex and the ventral posterior nucleus of the thalamus, and the medial nucleus of the amygdala. Structural equation modeling revealed that animals consuming diets without n-3 PUFAs exhibited fewer inter-regional interactions when compared to those fed diets with n-3 PUFAs. Without n-3 PUFAs, inter-regional interactions were observed between the posterior cingulate cortex and amygdala as well as among amygdala subregions. With n-3 PUFAs, more inter-regional interactions were observed, particularly between regions associated with fear memory processing and escape. Correlations between regional CCO activity and SBET behavior were observed in rats lacking dietary n-3 PUFAs but not in those supplemented with these nutrients. In conclusion, consumption of n-3 PUFAs results in reduced CCO activity in white matter bundles and sensorimotor regions, reflecting more efficient neurotransmission, and an increase in inter-regional interactions, facilitating escape from footshock.

Translational Insights From Cell Type Variation Across Amygdala Subnuclei in Rhesus Monkeys and Humans.

Theories of amygdala function are central to our understanding of psychiatric and neurodevelopmental disorders. However, limited knowledge of the molecular and cellular composition of the amygdala impedes translational research aimed at developing new treatments and interventions. The aim of this study was to characterize and compare the composition of amygdala cells to help bridge the gap between preclinical models and human psychiatric and neurodevelopmental disorders. Tissue was dissected from multiple amygdala subnuclei in both humans (N=3, male) and rhesus macaques (N=3, male). Single-nucleus RNA sequencing was performed to characterize the transcriptomes of individual nuclei. The results reveal substantial heterogeneity between regions, even when restricted to inhibitory or excitatory neurons. Consistent with previous work, the data highlight the complexities of individual marker genes for uniquely targeting specific cell types. Cross-species analyses suggest that the rhesus monkey model is well-suited to understanding the human amygdala, but also identify limitations. For example, a cell cluster in the ventral lateral nucleus of the amygdala (vLa) is enriched in humans relative to rhesus macaques. Additionally, the data describe specific cell clusters with relative enrichment of disorder-related genes. These analyses point to the human-enriched vLa cell cluster as relevant to autism spectrum disorder, potentially highlighting a vulnerability to neurodevelopmental disorders that has emerged in recent primate evolution. Further, a cluster of cells expressing markers for intercalated cells is enriched for genes reported in human genome-wide association studies of neuroticism, anxiety disorders, and depressive disorders. Together, these findings shed light on the composition of the amygdala and identify specific cell types that can be prioritized in basic science research to better understand human psychopathology and guide the development of potential treatments.

Thalamic Local Field Potentials and Closed-Loop Deep Brain Stimulation in Orthostatic Tremor.

Orthostatic tremor (OT) is a rare movement disorder characterized by a feeling of unsteadiness and a high-frequency tremor in the legs (13-18 Hz) relieved by sitting or walking. The aims were to study the brain electrophysiology captured chronically in a person with medication-refractory OT while standing and walking and in the semi-recumbent position using bilateral ventral intermedius nucleus deep brain stimulation (DBS) (Medtronic Percept PC) and to describe the clinical use of closed-loop DBS. A sensing survey was used to capture baseline local field potentials (LFPs) while standing. Livestreamed LFPs were synchronized with data collected from two accelerometers (legs) and gait analysis during OFF stimulation and continuous and closed-loop DBS. Strong oscillatory coupling between thalamic LFP and leg tremor with significant coherence at 14.65 Hz was found during weight-bearing. Single-threshold adaptive DBS (sensing at this frequency) was superior to continuous stimulation in reducing tremor and stimulation-related gait ataxia. This study provides new insights into both the pathophysiology and management of OT. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Technical Feasibility of Delineating the Thalamic Gustatory Tract Using Tractography.

Magnetic resonance-guided focused ultrasound (MRgFUS) has been increasingly performed in recent years as a minimally invasive treatment of essential tremor and tremor-dominant Parkinson disease. One of the side effects after treatment is dysgeusia. Some centers use tractography to facilitate the treatment planning. However, there have been no reports of identifying gustatory tracts so far. Our aim was to investigate the technical feasibility of isolating and visualizing the gustatory tracts, as well as to explore the relationship between the gustatory tract and the MRgFUS lesion using actual patient data. We used 20 randomly selected individuals from the Human Connectome Project database to perform tractography of the gustatory tracts. We defined region of interest as the dorsal region of the brainstem, Brodmann area 43 associated with taste perception, and a sphere with a 3-mm radius centered around the ventral intermediate nucleus in the anterior commissure-posterior commissure plane. We also examined the position of the gustatory tract in relation with other tracts, including the medial lemniscus, the pyramidal tract, and the dentatorubrothalamic tract. In addition, using the data of real patients with essential tremor, we investigated the distance between MRgFUS lesions and the gustatory tract and its association with the development of dysgeusia. We delineated a mean of 15 streamlines of the gustatory tracts per subject in each hemisphere. There was no statistical difference in the localization of the gustatory tracts between the left and right cerebral hemispheres. The gustatory tract was located anteromedial to the medial lemniscus and posteromedial to the dentatorubrothalamic tract in the anterior commissure-posterior commissure plane. The distance from the MRgFUS lesion to the gustatory tract was significantly shorter in the case where dysgeusia occurred compared with nondysgeusia cases (P-value: .0068). The thalamic gustatory tracts can be reliably visualized using tractography.

Neuroscience of the human thalamus related to acute pain and chronic "thalamic" pain.

The association of posterior thalamic strokes with the presence of chronic "thalamic" pain was described in the early 1900s and revisited in a recent review of these patients. Acute pain in corporal structures is associated with the spinothalamic tract (STT), which originates in the dorsal horn of the spinal cord, whereas that associated with cranial structures is associated with the spinal division of the trigeminal nucleus. These pathways terminate in the ventral posterior nucleus (VP), including its posterior and inferior subnuclei and its core, which is classically associated with tactile and haptic functions. In medial nuclei (medial dorsal and intralaminar) receptive fields are large and stimulation evokes diffuse unpleasant sensations and pain while neurons in these nuclei subserve cognitive processes of attention, alerting, and conditioning. In the lateral nuclei neurons have small receptive and projected fields and high resolution of responses to somatic stimuli. Neurons in the lateral nuclei respond to stimuli producing pain, temperature, and visceral sensations while stimulation evokes similar sensations. Small strokes in VP core versus structures located inferior and posterior are associated with thalamic pain and decreased tactile, painful, and cold sensations and with decreased evoked potentials for painful (laser) heat and median nerve stimulation (electrical). Lesions of VP, but not ventral medial posterior nucleus (VMpo), are associated with thalamic pain, contrary to the recent "disinhibition" model. We review the evidence that the lateral nuclei are associated with multiple processes including tactile, nociceptive, visceral, and thermal content of stimuli, whereas the medial nuclei are related to cognitions about those stimuli.

Deep brain stimulation of the motor thalamus relieves experimentally induced air hunger.

We previously reported that Deep Brain Stimulation (DBS) of motor thalamus (MT), in a patient with post-stroke tremor, relieved breathlessness associated with chronic obstructive pulmonary disease. This raised the question of whether MT DBS mitigates the ascending dyspnoea signal. We therefore sought to conduct a fully powered cohort study of experimentally induced air hunger (AH), an uncomfortable urge to breathe in patients with MT DBS ON and OFF. 16 patients (3 females) with DBS of the ventral intermediate nucleus (VIM) as treatment for tremor, underwent hypercapnic AH tests, with DBS "ON" and "OFF". Patients rated AH on a visual analogue scale (VAS) every 15 s. Hypercapnia and ventilation were matched for ON and OFF states (mean±sd 43±4 and 43±4 mmHg for end-tidal PCO2, 13.7 and 13.4 L·min-1 for ventilation). Participants ventilation was constrained to baseline levels by breathing from a 3-litre inspiratory reservoir with fixed flow of fresh gas while targeting their resting breathing frequency to a metronome. Overall steady state AH was 52±28%VAS for "ON" and 67±20%VAS for "OFF" (p=0.002; two-tailed paired t-test). The mean reduction in AH during VIM DBS was -14.4%VAS. MT DBS relieved AH in thirteen patients, heightened AH in two and caused no change in one. MT DBS for tremor relief also mitigates the AH component of dyspnoea. We posit that DBS of the MT heightens the gating control of the thalamus modulating the ascending air hunger signal. Extent of relief suggests that thalamic DBS may prove to be a viable therapy for intractable dyspnoea.

Olfactory dysfunction decreased local field potential in the reward system and increased EtOH consumption in mice

The relationship between olfactory dysfunction and alcohol intake is unobvious. Chronic alcohol intake results in reduced olfactory acuity and olfactory discrimination and addiction in humans. However, alcohol is a beverage with distinctive odors, which usually works as a cue to induce addictive memories and craving behavior. Whether olfactory impairment increase or decrease alcohol consumption remains an important but unclear issue. In this study, we measured ethanol (EtOH) consumption in the two-bottle choice EtOH drinking test, two bottle choice EtOH/sucrose drinking test and the drinking in the dark (DID) test during the olfactory loss. We also recorded local field potentials (LFPs) from the brain reward system, the ventral tegmental area (VTA), nucleus accumbens (NAc), and piriform cortex (Pir) one and four weeks after the induction of olfactory epithelium lesions using zinc sulfate (ZnSO4) in mice. The results showed that the EtOH consumption and preference were increased during the period of olfactory dysfunction. 1 week after the olfactory injury, LFP powers in the reward system at low- and high-gamma bands decreased significantly, coherence between the Pir and the reward system was also decrease. 4 weeks after the ZnSO4 treatment, LFP powers were reversed, but the coherence between VTA and NAc was decreased, indicating lasting effects post-recovery. This study demonstrates that olfactory dysfunction increased EtOH consumption in mice, which was accompanied by decreased LFP power and coherence in the reward system, which suggest that olfactory deficits changed activities in the reward system and could alter reward-seeking behaviors, which provide insights into the neurobiology of alcohol addiction.

Pre-choice midbrain fluctuations affect self-control in food choice: A functional magnetic resonance imaging (fMRI) study.

Recent studies have shown that spontaneous pre-stimulus fluctuations in brain activity affect higher-order cognitive processes, including risky decision-making, cognitive flexibility, and aesthetic judgments. However, there is currently no direct evidence to suggest that pre-choice activity influences value-based decisions that require self-control. We examined the impact of fluctuations in pre-choice activity in key regions of the reward system on self-control in food choice. In the functional magnetic resonance imaging (fMRI) scanner, 49 participants made 120 food choices that required self-control in high and low working memory load conditions. The task was designed to ensure that participants were cognitively engaged and not thinking about upcoming choices. We defined self-control success as choosing a food item that was healthier over one that was tastier. The brain regions of interest (ROIs) were the ventral tegmental area (VTA), putamen, nucleus accumbens (NAc), and caudate nucleus. For each participant and condition, we calculated the mean activity in the 3-s interval preceding the presentation of food stimuli in successful and failed self-control trials. These activities were then used as predictors of self-control success in a fixed-effects logistic regression model. The results indicate that increased pre-choice VTA activity was linked to a higher probability of self-control success in a subsequent food-choice task within the low-load condition, but not in the high-load condition. We posit that pre-choice fluctuations in VTA activity change the reference point for immediate (taste) reward evaluation, which may explain our finding. This suggests that the neural context of decisions may be a key factor influencing human behavior.

Deep brain stimulation in a patient with dystonic tremor with a novel familial VPS16 gene mutation

Dystonia is a neurological disorder characterized by intermittent muscle contractions or abnormal movements. The pathophysiology and pathogenetic variations are increasingly better understood, but their translation into appropriate treatment is still largely lacking. We present a case of a woman suffering from a dystonic tremor of the upper limbs and head. Both the patient treated with DBS and her sister carry a novel mutation in the VPS16 gene. Treatment proved to be successful through deep brain stimulation targeting the ventral intermediate nucleus of the thalamus.

Quantitative Tractography-Based Evaluations in Essential Tremor Patients after MRgFUS Thalamotomy.

Magnetic resonance-guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug-refractory essential tremor (ET). The relationship between lesion characteristics, dentate-rubro-thalamic-tract (DRTT) involvement and clinical benefit remains unclear. To investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting. Forty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion-tensor 3 T-images and location and volume of the lesion were calculated. Probabilistic tractography identified both decussating (d-DRTT) and non-decussating (nd-DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd-DRTT. Despite the lesions predominantly intersecting the medial portion of the d-DRTT, with a significantly greater overlap in responder patients, we observed only a non-significant correlation between tremor improvement and increased d-DRTT-lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1-day MRI (r = 0.42, P < 0.01). Variability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method.

7934 Tac1-expressing cells in the central premammillary nucleus are essential for induction of the pre-ovulatory LH surge

Abstract Disclosure: S. Leon: None. M. Navarro: None. C. Perdices-Lopez: None. I. Velasco Aguayo: None. E. Torres Jimenez: None. D. Garcia-Galiano: None. V.M. Navarro: None. M. Tena-Sempere: None. Infertility/subfertility is a growing challenge in reproductive medicine. The most common cause of subfertility in females is ovulatory dysfunction. Conditions linked with oligo-/anovulation include polycystic ovary syndrome, hypothalamic amenorrhea and premature ovarian insufficiency. However, the central neuro-endocrine defects affecting the pre-ovulatory LH surge that drives ovulation remain ill defined. While hypothalamic GnRH neurons are the major output pathway for the brain control of ovulation, upstream Kiss1 neurons, particularly in the anteroventral periventricular area (AVPV) of the hypothalamus in rodents, are thought to be crucial for the timed activation of GnRH neurons and generation of the preovulatory surge of gonadotropins. Yet, the major upstream regulators of this Kiss1/GnRH pathway are largely unknown. Substance P (SP, encoded by Tac1), a member of the tachykinin (TAC) family that acts via the receptor, NK1R (encoded by Tacr1), has been shown to centrally regulate gonadotropin release, and, according to our initial data, might modulate the pre-ovulatory surge in mice through its direct action on AVPV Kiss1 neurons. We report herein that Tac1-expressing cells in the ventral premammillary nucleus (PMV) become activated during the preovulatory surge, as denoted by co-expression of c-Fos. Moreover, we document here that these neurons project to key reproductive areas, including the rostral preoptic area (rPOA), AVPV, arcuate nucleus (ARC), and the medial posterodorsal amygdala (MePD). Furthermore, the chemogenetic inhibition of Tac1-expressing neurons in the PMV dramatically decreases the magnitude of the pre-ovulatory LH surge, but has no influence on tonic LH pulsatility. Overall, our findings strongly support a relevant stimulatory role of SP originating from Tac1 neurons at the PMV in the generation of the pre-ovulatory surge of gonadotropins, responsible for ovulation. Presentation: 6/1/2024

Structural Basis for Histaminergic Regulation of Neural Circuits in the Mouse Olfactory Bulb.

Odor information is modulated by centrifugal inputs from other brain regions to the olfactory bulb (OB). Neurons containing monoamines, such as serotonin, acetylcholine, and noradrenaline, are well known as centrifugal inputs; however, the role of histamine, which is also present in the OB, is not well understood. In this study, we examined the histaminergic neurons projecting from the hypothalamus to the OB. We used an antibody against histidine decarboxylase (HDC), a synthesizing enzyme of histamine, to identify histaminergic neurons and assess their localization within the OB and the ultrastructure of their fibers and synapses using multiple immunostaining laser microscopy, ultra-high voltage electron microscopy (EM), and EM to confirm their relationships with other neurons. To further identify the origin nucleus of the histaminergic neurons projecting to the OB, we injected the retrograde tracer FluoroGold and analyzed the pathway to the OB anterogradely. HDC-immunoreactive (-ir) fibers were abundant in the olfactory nerve (ON) layer compared to other monoamines. HDC-ir neurons received asymmetrical synapses from ONs and formed synapses containing pleomorphic vesicles with variable postsynaptic densities to non-ON elements, thus forming serial synapses. We also confirmed that histaminergic neurons project from the rostral ventral tuberomammillary nucleus to the granule cell layer of the OB and, for the first time, successfully visualized their axons from the hypothalamus to the OB. These findings indicate that histamine may regulate odor discrimination in the OB, suggesting a regulatory relationship between hypothalamic function and olfaction. We thus elucidate morphological mechanisms with tuberomammillary nucleus-derived histaminergic neurons involved in olfactory information.