Mapping Subcortico-Cortical Coupling-A Comparison of Thalamic and Subthalamic Oscillations.

BACKGROUND: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation in tremor patients. Despite its therapeutic importance, its oscillatory coupling to cortical areas has rarely been investigated in humans. OBJECTIVES: The objective of this study was to identify the cortical areas coupled to the VIM in patients with essential tremor. METHODS: We combined resting-state magnetoencephalography with local field potential recordings from the VIM of 19 essential tremor patients. Whole-brain maps of VIM-cortex coherence in several frequency bands were constructed using beamforming and compared with corresponding maps of subthalamic nucleus (STN) coherence based on data from 19 patients with Parkinson's disease. In addition, we computed spectral Granger causality. RESULTS: The topographies of VIM-cortex and STN-cortex coherence were very similar overall but differed quantitatively. Both nuclei were coupled to the ipsilateral sensorimotor cortex in the high-beta band; to the sensorimotor cortex, brainstem, and cerebellum in the low-beta band; and to the temporal cortex, brainstem, and cerebellum in the alpha band. High-beta coherence to sensorimotor cortex was stronger for the STN (P = 0.014), whereas low-beta coherence to the brainstem was stronger for the VIM (P = 0.017). Although the STN was driven by cortical activity in the high-beta band, the VIM led the sensorimotor cortex in the alpha band. CONCLUSIONS: Thalamo-cortical coupling is spatially and spectrally organized. The overall similar topographies of VIM-cortex and STN-cortex coherence suggest that functional connections are not necessarily unique to one subcortical structure but might reflect larger frequency-specific networks involving VIM and STN to a different degree. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuronal activity reorganization in motor cortex for successful locomotion after a lesion in the ventrolateral thalamus.

Thalamic stroke leads to ataxia if the cerebellum-receiving ventrolateral thalamus (VL) is affected. The compensation mechanisms for this deficit are not well understood, particularly the roles that single neurons and specific neuronal subpopulations outside the thalamus play in recovery. The goal of this study was to clarify neuronal mechanisms of the motor cortex involved in mitigation of ataxia during locomotion when part of the VL is inactivated or lesioned. In freely ambulating cats, we recorded the activity of neurons in layer V of the motor cortex as the cats walked on a flat surface and horizontally placed ladder. We first reversibly inactivated ∼10% of the VL unilaterally using glutamatergic transmission antagonist CNQX and analyzed how the activity of motor cortex reorganized to support successful locomotion. We next lesioned 50%-75% of the VL bilaterally using kainic acid and analyzed how the activity of motor cortex reorganized when locomotion recovered. When a small part of the VL was inactivated, the discharge rates of motor cortex neurons decreased, but otherwise the activity was near normal, and the cats walked fairly well. Individual neurons retained their ability to respond to the demand for accuracy during ladder locomotion; however, most changed their response. When the VL was lesioned, the cat walked normally on the flat surface but was ataxic on the ladder for several days after lesion. When ladder locomotion normalized, neuronal discharge rates on the ladder were normal, and the shoulder-related group was preferentially active during the stride's swing phase.NEW & NOTEWORTHY This is the first analysis of reorganization of the activity of single neurons and subpopulations of neurons related to the shoulder, elbow, or wrist, as well as fast- and slow-conducting pyramidal tract neurons in the motor cortex of animals walking before and after inactivation or lesion in the thalamus. The results offer unique insights into the mechanisms of spontaneous recovery after thalamic stroke, potentially providing guidance for new strategies to alleviate locomotor deficits after stroke.

GABABR Modulation of Electrical Synapses and Plasticity in the Thalamic Reticular Nucleus.

Two distinct types of neuronal activity result in long-term depression (LTD) of electrical synapses, with overlapping biochemical intracellular signaling pathways that link activity to synaptic strength, in electrically coupled neurons of the thalamic reticular nucleus (TRN). Because components of both signaling pathways can also be modulated by GABAB receptor activity, here we examined the impact of GABAB receptor activation on the two established inductors of LTD in electrical synapses. Recording from patched pairs of coupled rat neurons in vitro, we show that GABAB receptor inactivation itself induces a modest depression of electrical synapses and occludes LTD induction by either paired bursting or metabotropic glutamate receptor (mGluR) activation. GABAB activation also occludes LTD from either paired bursting or mGluR activation. Together, these results indicate that afferent sources of GABA, such as those from the forebrain or substantia nigra to the reticular nucleus, gate the induction of LTD from either neuronal activity or afferent glutamatergic receptor activation. These results add to a growing body of evidence that the regulation of thalamocortical transmission and sensory attention by TRN is modulated and controlled by other brain regions. Significance: We show that electrical synapse plasticity is gated by GABAB receptors in the thalamic reticular nucleus. This effect is a novel way for afferent GABAergic input from the basal ganglia to modulate thalamocortical relay and is a possible mediator of intra-TRN inhibitory effects.

Subcortical short-term plasticity elicited by deep brain stimulation.

OBJECTIVE: To investigate local short-term neuroplasticity elicited by subthalamic, thalamic, and pallidal deep brain stimulation (DBS) for movement disorders. METHODS: During DBS surgery, we delivered pairs of stimulus pulses with both circular and directional leads across 90 interstimulus intervals in 17 participants and recorded local field potentials from unused contacts on the implanted electrode array. We removed the stimulus artifact, validated the neural origin of the underlying signals, and examined short-term plasticity as a function of interstimulus interval and DBS target, using linear mixed effects models. RESULTS: DBS evokes short latency local field potentials that are readily detected with both circular and directional leads at all stimulation targets (0.31 ± 0.10 msec peak latency, mean ± SD). Peak amplitude, area, and latency are modified strongly by interstimulus interval (P < 0.001) and display absolute and relative refractory periods (0.56 ± 0.08 and 2.94 ± 1.05 msec, respectively). We also identified later oscillatory activity in the subthalamic-pallidal circuit (4.50 ± 1.11 msec peak latency) that displays paired pulse facilitation (present in 5/8 subthalamic, 4/5 pallidal, and 0/6 thalamic trajectories, P = 0.018, Fisher's exact test), and correlates with resting beta frequency power (P < 0.001), therapeutic DBS frequencies, and stimulation sites chosen later for therapy in the ambulatory setting (P = 0.031). INTERPRETATION: Paired DBS pulses synchronize local circuit electrophysiology and elicit short-term neuroplasticity in the subthalamic-pallidal circuit. Collectively, these responses likely represent the earliest detectable interaction between the DBS pulse and local neuronal tissue in humans. Evoked subcortical field potentials could serve as a predictive biomarker to guide the implementation of next-generation directional and adaptive stimulation devices.

Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors.

CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.

Repeated group alternation as a programming strategy for essential tremor patients experiencing rapid habituation with deep brain stimulation treatment.

AIM: The term habituation refers to the rapid loss of therapeutic effects that occurs following an initially beneficial adjustment of Deep Brain Stimulation (DBS) parameters. DBS habituation typically occurs over a period of days to weeks and has been observed in a subgroup of essential tremor (ET) patients undergoing stimulation of the ventral intermediate nucleus of the thalamus (VIM). The negative consequences of DBS habituation include protracted periods of ineffective therapy, the exacerbation of symptoms beyond presurgical levels (rebound), and the requirement for repeated office visits for stimulation adjustments. MATERIALS AND METHODS: In this case series, we describe a programming strategy implemented in three patients with ET experiencing DBS habituation. This strategy involves the planned alternation between pre-programmed electrode configurations ('groups'), performed by the patient prior to or in response to the loss of therapeutic efficacy in habituation. Results/Conclusions: We provide here additional support for group alternation as a treatment option for DBS patients with ET complicated by tremor habituation.

Distinct thalamocortical network dynamics are associated with the pathophysiology of chronic low back pain.

Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

Tonic GABAergic Inhibition Is Essential for Nerve Injury-Induced Afferent Remodeling in the Somatosensory Thalamus and Ectopic Sensations.

Peripheral nerve injury induces functional and structural remodeling of neural circuits along the somatosensory pathways, forming the basis for somatotopic reorganization and ectopic sensations, such as referred phantom pain. However, the mechanisms underlying that remodeling remain largely unknown. Whisker sensory nerve injury drives functional remodeling in the somatosensory thalamus: the number of afferent inputs to each thalamic neuron increases from one to many. Here, we report that extrasynaptic γ-aminobutyric acid-type A receptor (GABAAR)-mediated tonic inhibition is necessary for that remodeling. Extrasynaptic GABAAR currents were potentiated rapidly after nerve injury in advance of remodeling. Pharmacological activation of the thalamic extrasynaptic GABAARs in intact mice induced similar remodeling. Notably, conditional deletion of extrasynaptic GABAARs in the thalamus rescued both the injury-induced remodeling and the ectopic mechanical hypersensitivity. Together, our results reveal a molecular basis for injury-induced remodeling of neural circuits and may provide a new pharmacological target for referred phantom sensations after peripheral nerve injury.

Impaired glymphatic system in secondary degeneration areas after ischemic stroke in rats.

BACKGROUND: Pathomechanism of secondary degeneration in remote regions after ischemic stroke has not been totally clarified. Contrast-enhanced MRI with injecting Gd-DTPA in cisterna magna (CM) is regarded as an efficient method to measure glymphatic system function in brain. Our research aimed at evaluating glymphatic system changes in secondary degeneration areas by contrast-enhanced MRI. METHODS: Ischemic stroke was induced by left middle cerebral artery occlusion (MCAO) model. A total of 12 Sprague-Dawley rats were randomly divided into three groups: control group with sham operations (n=4), the group of acute phase (1 day after MCAO) (n=4), and the group of subacute phase (7 days after MCAO) (n=4). Contrast-enhanced MRI was performed in 1days or 7days after operations respectively. All rats received an intrathecal injection of Gd-DTPA (2µl/min, totally 20µl) and high-resolution 3D T1-weighted MRI for 6 h. The time course of the signal-to-noise ratio (SNR) in substantia Nigra (SN) and ventral thalamic nucleus (VTN) was evaluated between two hemispheres in all rats. RESULTS: In control group without ischemia, time-to-peak of SNR in SN was earlier than that in VTN. There were no differences of SNR between two hemispheres after intrathecal Gd-DTPA administration. In the group of acute phase, MRI revealed similar time course and time-to-peak of SNR between ipsilateral and contralateral VTN, while a tendency of higher SNR in ipsilateral SN than contralateral SN at 4h, 5h, 6h after Gd-DTPA injection. And time-to-peak of SNR was similar in bilateral SN. In the group of subacute phase, time-to-peak of SNR was similar in bilateral VTN, while longer in ipsilateral SN compared with contralateral side. In addition, SNR in T1WI in ipsilateral was significantly higher than SNR in contralateral SN and VTN at 5h (VTN, P= 0.003; SN, P=0.004) and 6h (VTN, P=0.015; SN, P=0.006) after Gd-DTPA injection. CONCLUSION: Glymphatic system was impaired in ipsilateral SN and VTN after ischemic stroke, which may contribute to neural degeneration.

Resting-State Functional Connectivity of the Thalamus in Complete Spinal Cord Injury.

Background. Neuroimaging studies of spinal cord injury (SCI) have mostly examined the functional organization of the cortex, with only limited focus on the subcortical substrates of the injury. However, thalamus is an important modulator and sensory relay that requires investigation at a subnuclei level to gain insight into the neuroplasticity following SCI. Objective. To use resting-state functional magnetic resonance imaging to examine the functional connectivity (FC) of thalamic subnuclei in complete SCI patients. Methods. A seed-based connectivity analysis was applied for 3 thalamic subnuclei: pulvinar, mediodorsal, and ventrolateral nucleus in each hemisphere. A nonparametric 2-sample t test with permutations was applied for each of the 6 thalamic seeds to compute FC differences between 22 healthy controls and 19 complete SCI patients with paraplegia. Results. Connectivity analysis showed a decrease in the FC of the bilateral mediodorsal nucleus with right superior temporal gyrus and anterior cingulate cortex in the SCI group. Similarly, the left ventrolateral nucleus exhibited decreased FC with left superior temporal gyrus in SCI group. In contrast, left pulvinar nucleus demonstrated an increase in FC with left inferior frontal gyrus and left inferior parietal lobule in SCI group. Our findings also indicate a negative relationship between postinjury durations and thalamic FC to regions of sensorimotor and visual cortices, where longer postinjury durations (~12 months) is associated with higher negative connectivity between these regions. Conclusion. This study provides evidence for reorganization in the thalamocortical connections known to be involved in multisensory integration and affective processing, with possible implications in the generation of sensory abnormalities after SCI.

Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia.

BACKGROUND: Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model. METHODS: Male C57BL/6 mice of 8-12 week-old were subjected to intra-cerebroventricular (i.c.v.) and/or intra-vlPAG (i.pag.) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice. RESULTS: NPS (i.c.v., but not i.pag.) induced antinociception. This effect was prevented by i.c.v. blockade of NPSRs. Substance P (i.pag.) and orexin-A (i.pag.) also induced antinociception. Substance P (i.pag.)-induced antinociception was prevented by i.pag. Blockade of NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice. CONCLUSIONS: These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

Long-Term Suppression of Disabling Tremor by Thalamic Stimulation in a Patient with Spinocerebellar Ataxia Type 2.

The beneficial effect of thalamic deep brain stimulation (DBS) on action tremor has been reported in a few cases of spinocerebellar ataxia (SCA); however, several factors should be taken into account regarding the indication for DBS in advanced cases. We performed DBS of the ventral intermediate nucleus (Vim) of the thalamus for treatment of coarse action tremor in a patient with SCA2 (spinocerebellar ataxia type 2) in the wheelchair-bound stage. Although improvement of the tremor of the proximal part was incomplete, the patient regained substantial parts of daily functioning. The effect lasted for more than 6 years, and the suppression of tremor significantly contributed to maintaining the level of the patient's expression into the bedridden stage. Vim DBS can be a treatment option for tremor in SCA patients, even in the advanced stage, as long as the tremor is depriving the patient of behavioral expression. As residual proximal tremor may hamper functional recovery, DBS of other targets or multi-targets should be further explored to attain a better outcome.

Neuronal variability of Resting State activity in Eating Disorders: increase and decoupling in Ventral Attention Network and relation with clinical symptoms.

BACKGROUND: Despite the great number of resting state functional connectivity studies on Eating Disorders (ED), no biomarkers could be detected yet. Therefore, we here focus on a different measure of resting state activity that is neuronal variability. The objective of this study was to investigate neuronal variability in the resting state of women with ED and to correlate possible differences with clinical and psychopathological indices. METHODS: 58 women respectively 25 with Anorexia Nervosa (AN), 16 with Bulimia Nervosa (BN) and 17 matched healthy controls (CN) were enrolled for the study. All participants were tested with a battery of psychometric tests and underwent a functional Magnetic Resonance Imaging (fMRI) resting state scanning. We investigated topographical patterns of variability measured by the Standard Deviation (SD) of the Blood-Oxygen-Level-Dependent (BOLD) signal (as a measure of neuronal variability) in the resting-state and their relationship to clinical and psychopathological indices. RESULTS: Neuronal variability was increased in both anorectic and bulimic subjects specifically in the Ventral Attention Network (VAN) compared to healthy controls. No significant differences were found in the other networks. Significant correlations were found between neuronal variability of VAN and various clinical and psychopathological indices. CONCLUSIONS: We here show increased neuronal variability of VAN in ED patients. As the VAN is relevant for switching between endogenous and exogenous stimuli, our results showing increased neuronal variability suggest unstable balance between body attention and attention to external world. These results offer new perspective on the neurobiological basis of ED. Clinical and therapeutic implication will be discussed.

A new central post-stroke pain rat model: autologous blood injected thalamic hemorrhage involved increased expression of P2X4 receptor.

Stroke is the leading cause of disability and death in the world. Central post-stroke pain (CPSP), a central neuropathic pain syndrome occurring after cerebral stroke, is a serious problem. But on account of the lack of reliable animal models, the mechanisms underlying CPSP remains poorly understood. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new rat model of CPSP. This model is based on a hemorrhagic stroke lesion with intra-thalamic autologous blood (ITAB) injection in the ventral posterolateral nucleus of the thalamus. Behavioral analysis demonstrated that the animals displayed a significant decrease in mechanical allodynia threshold. We found a significant increase in P2 × 4 receptor expression in microglia in thalamic peri-lesion tissues post-hemorrhage. The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. Meanwhile, we found a significant decrease in P2 × 4 receptor expression after treatment with these drugs. Taken together, our results suggest that targeting P2 × 4 receptor may be effective in the treatment of CPSP.

A functional micro-electrode mapping of ventral thalamus in essential tremor.

Deep brain stimulation enables the delivery of therapeutic interventions to otherwise inaccessible areas of the brain while, at the same time, offering the unique opportunity to record from these same regions in awake patients. The posterior ventrolateral thalamus has become a reliable deep brain stimulation target for medically-refractory patients suffering from essential tremor. However, the contribution of the thalamus in essential tremor, and even whether posterior ventrolateral thalamus is the optimal target, remains a matter of ongoing debate. There are several lines of evidence supporting clusters of activity within the posterior ventrolateral thalamus that are important for tremor emergence. In this study we sought to map the functional properties of these clusters through microelectrode recordings during deep brain stimulation surgery. Data were obtained from 10 severely affected patients with essential tremor (12 hemispheres) undergoing deep brain stimulation surgery. Our results demonstrate power and coherence maxima located in the inferior posterior ventrolateral thalamus and immediate ventral region. Moreover, we identified distinct yet overlapping clusters of predominantly efferent (driving) and afferent (feedback) activity, with a preference for more efferent contributors, consistent with a net role in the driving of tremor output. Finally, we demonstrate that resolvable thalamic spiking activity directly relates to background activity and that the strength of tremor may be dictated by phase relationships between efferent and afferent pockets in the posterior ventrolateral thalamus. Taken together, these results provide important evidence for the role of the inferior posterior ventrolateral thalamus and its border region in essential tremor pathophysiology. Such results progress our mechanistic understanding and promote the adoption of next-generation therapies such as high resolution segregated deep brain stimulation electrodes.

Neuronal firing rate and oscillatory patterns in the basal ganglia nuclei differ from those of the ventrolateral thalamus in patients with Parkinson disease.

We compared the firing rates and proportion of patterns of oscillatory neurons in the subthalamic nucleus (STN), globus pallidus internus (GPi), and ventrolateral thalamus (VL) in Parkinson disease (PD). Twenty-nine patients with PD who underwent stereotactic neurosurgery were included in the study. Microelectrode recordings in the STN (n = 16), GPi (n = 9), and VL (n = 9) were performed. Power spectral analysis was used to explore neuronal oscillation. Of 76 STN neurons, 39.5% were tremor frequency oscillatory neurons (4-6 Hz, TFB) and 28.9% were ß frequency oscillatory neurons (ßFB); their mean spontaneous firing rate (MSFR) was 44.2 ±â€¯7.6 Hz (n = 52). Of 62 GPi neurons, 37.1% were TFB oscillatory neurons and 27.4% were ßFB oscillatory neurons; the MSFR was 80.9 ±â€¯9.6 Hz. Of 69 V L neurons, 65.2% were TFB oscillatory neurons and 11.6% were ßFB oscillatory neurons; the MSFR was 26.7 ±â€¯5.0 Hz. The increased MSFR of GPi and reduced MSFR of VL oscillatory neurons in parkinsonian patients further support prediction of a pathophysiology model of PD. The high proportion of ßFB oscillatory neurons in the STN and GPi suggests that dopaminergic deficits result in abnormal ß oscillatory synchronization in the basal ganglia in the parkinsonian state. The high proportion of TFB oscillatory neurons in the VL demonstrates that both the basal ganglia and cerebellothalamic circuits are involved in the generation of parkinsonian tremor; the latter circuit might have a more important role in tremor genesis.

Pretherapeutic Motor Thalamus Resting-State Functional Connectivity with Visual Areas Predicts Tremor Arrest After Thalamotomy for Essential Tremor: Tracing the Cerebello-thalamo-visuo-motor Network.

BACKGROUND: Essential tremor (ET) is a common movement disorder. Resting-state functional magnetic resonance imaging is a noninvasive neuroimaging method acquired in absence of task. OBJECTIVE: Our study aimed to correlate pretherapeutic ventrolateral thalamus functional connectivity (FC) with clinical results 1 year after stereotactic radiosurgical thalamotomy (SRS-T) for drug-resistant ET. Data from 12 healthy control individuals were additionally included. METHODS: Resting state was acquired for 17 consecutive (right-handed) patients, before and 1 year after left unilateral SRS-T. Standard tremor scores were evaluated pretherapeutically and 1 year after SRS-T. Tremor network was investigated using region of interest, left ventrolateral ventral (VLV) cluster, obtained from pretherapeutic diffusion magnetic resonance imaging. Seed-based FC was obtained as correlations between the time courses of the VLV and that of every other voxel. The seed-connectivity maps were obtained pretherapeutically and correlated across all patients with clinical outcome 1 year after SRS-T. One-year magnetic resonance signature volume was always located inside VLV and did not correlate with reported seed-FC measures (P > 0.05). RESULTS: We report statistically significant correlations between pretherapeutic VLV FC with clinical outcome for 1) right visual association area (Brodmann area, BA19) predicting 1 year activities of daily living decrease (Punc = 0.02); 2) left fusiform gyrus (BA37) predicting 1 year head tremor score improvement (Punc = 0.04); and 3) posterior cingulate (left BA23, Puncor = 0.009), lateral temporal cortex (right BA21, Punc = 0.02) predicting time to tremor arrest. CONCLUSIONS: Our results suggest that pretherapeutic resting-state seed-FC of left VLV predicts tremor arrest after SRS-T for ET. Visual areas are identified as the main regions in this correlation.

Physiological mechanisms of thalamic ventral intermediate nucleus stimulation for tremor suppression.

Ventral intermediate thalamic deep brain stimulation is a standard therapy for the treatment of medically refractory essential tremor and tremor-dominant Parkinson's disease. Despite the therapeutic benefits, the mechanisms of action are varied and complex, and the pathophysiology and genesis of tremor remain unsubstantiated. This intraoperative study investigated the effects of high frequency microstimulation on both neuronal firing and tremor suppression simultaneously. In each of nine essential tremor and two Parkinson's disease patients who underwent stereotactic neurosurgery, two closely spaced (600 µm) microelectrodes were advanced into the ventral intermediate nucleus. One microelectrode recorded action potential firing while the adjacent electrode delivered stimulation trains at 100 Hz and 200 Hz (2-5 s, 100 µA, 150 µs). A triaxial accelerometer was used to measure postural tremor of the contralateral hand. At 200 Hz, stimulation led to 68 ± 8% (P < 0.001) inhibition of neuronal firing and a 53 ± 5% (P < 0.001) reduction in tremor, while 100 Hz reduced firing by 26 ± 12% (not significant) with a 17 ± 6% (P < 0.05) tremor reduction. The degree of cell inhibition and tremor suppression were significantly correlated (P < 0.001). We also found that the most ventroposterior stimulation sites, closest to the border of the ventral caudal nucleus, had the best effect on tremor. Finally, prior to the inhibition of neuronal firing, microstimulation caused a transient driving of neuronal activity at stimulus onset (61% of sites), which gave rise to a tremor phase reset (73% of these sites). This was likely due to activation of the excitatory glutamatergic cortical and cerebellar afferents to the ventral intermediate nucleus. Temporal characteristics of the driving responses (duration, number of spikes, and onset latency) significantly differed between 100 Hz and 200 Hz stimulation trains. The subsequent inhibition of neuronal activity was likely due to synaptic fatigue. Thalamic neuronal inhibition seems necessary for tremor reduction and may function in effect as a thalamic filter to uncouple thalamo-cortical from cortico-spinal reflex loops. Additionally, our findings shed light on the gating properties of the ventral intermediate nucleus within the cerebello-thalamo-cortical tremor network, provide insight for the optimization of deep brain stimulation technologies, and may inform controlled clinical studies for assessing optimal target locations for the treatment of tremor.

Deep brain stimulation of the thalamic ventral intermediate nucleus for Benedikt's syndrome mainly present as tremor: a long-term case observation.

Benedikt's syndrome (BS) is caused by the lesion in the midbrain and specifically manifests a series of symptoms, including ipsilateral third nerve palsy, contralateral tremor, hemiataxia, and hyperactive tendon reflexes. Deep brain stimulation (DBS) for BS emerges as a new approach and achieves successfully results. We report a successful case report of thalamic ventral intermediate (VIM) nucleus DBS for a patient with BS. During follow-up of 3 years, DBS successfully control the tremor and greatly improve his living and working quality. We consider that VIM DBS may have sustained benefit for refractory BS that mainly presents as tremor.

Ventrolateral Motor Thalamus Abnormal Connectivity in Essential Tremor Before and After Thalamotomy: A Resting-State Functional Magnetic Resonance Imaging Study.

OBJECTIVE: To evaluate functional connectivity (FC) of the ventrolateral thalamus, a common target for drug-resistant essential tremor (ET), resting-state data were analyzed before and 1 year after stereotactic radiosurgical thalamotomy and compared against healthy controls (HCs). METHODS: In total, 17 consecutive patients with ET and 10 HCs were enrolled. Tremor network was investigated using the ventrolateral ventral (VLV) thalamic nucleus as the region of interest, extracted with automated segmentation from pretherapeutic diffusion magnetic resonance imaging. Temporal correlations of VLV at whole brain level were evaluated by comparing drug-naïve patients with ET with HCs, and longitudinally, 1 year after stereotactic radiosurgical thalamotomy. 1 year thalamotomy MR signature was always located inside VLV and did not correlate with any of FC measures (P > 0.05). This suggested presence of longitudinal changes in VLV FC independently of the MR signature volume. RESULTS: Pretherapeutic ET displayed altered VLV FC with left primary sensory-motor cortex, pedunculopontine nucleus, dorsal anterior cingulate, left visual association, and left superior parietal areas. Pretherapeutic negative FC with primary somatosensory cortex and pedunculopontine nucleus correlated with poorer baseline tremor scores (Spearman = 0.04 and 0.01). Longitudinal study displayed changes within right dorsal attention (frontal eye-fields and posterior parietal) and salience (anterior insula) networks, as well as areas involved in hand movement planning or language production. CONCLUSIONS: Our results demonstrated that patients with ET and HCs differ in their left VLV FC to primary somatosensory and supplementary motor, visual association, or brainstem areas (pedunculopontine nucleus). Longitudinal changes display reorganization of dorsal attention and salience networks after thalamotomy. Beside attentional gateway, they are also known for their major role in facilitating a rapid access to the motor system.