OBJECTIVE:Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy has become a popular tool in the neurosurgical armamentarium for managing tremor in patients with essential tremor (ET) and Parkinson's disease (PD). METHODS:Given the recent exponential growth in the use of this technology, the American Society for Stereotactic and Functional Neurosurgery, which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, provides an update on treatment indications and the efficacy and safety of MRgFUS for the treatment of tremor. RESULTS:In ET, the efficacy of MRgFUS thalamotomy is supported by several open-label and 1 prospective, double-blind, sham-controlled randomized clinical trial (RCT) that showed a 47% improvement in hand tremor in the short term. Follow-up studies demonstrated that the benefits of MRgFUS for ET are sustained in the long term. Studies investigating the effects of bilateral staged MRgFUS thalamotomy in patients with ET have shown that tremor improvement on the second side was as significant as that observed after the first procedure. The efficacy of MRgFUS thalamotomy for PD tremor is supported by a systematic meta-analysis that consisted predominantly of smaller, nonrandomized studies; 1 RCT; and 1 prospective cohort study. Despite a significant short-term improvement in PD tremor, the long-term effects of this therapy remain unknown. Common early adverse effects of MRgFUS thalamotomy include gait disturbance and paresthesias. These, however, tend to subside over time. Other reported side effects are dysarthria, ataxia, taste disturbance, motor deficits, and speech difficulty. CONCLUSIONS:MRgFUS thalamotomy is a safe, effective, and durable intervention for refractory ET in appropriately selected patients. The procedure appears to be safe and effective for PD tremor, although the long-term durability of the technique remains a concern. Early experience with bilateral staged lesions for ET suggests the procedure to be safe and effective.

Chronic neuropathic pain persists for years yet fluctuates markedly from day to day, raising a fundamental question: how do stable neural patterns relate to dynamic pain experience? The insula is a central hub for pain processing, but it remains unclear whether ongoing pain is associated with enduring baseline neural patterns within the insula or day-to-day variation in neural activity. We analysed multiday bilateral intracranial electroencephalography recordings from six individuals with chronic unilateral neuropathic pain, comprising 34 days of resting-state data. Spectral power, peak-derived spectral metrics and intra-insular functional connectivity (coherence and phase-locking value) were quantified across anterior and posterior insular subregions. Linear mixed-effects models were used to distinguish stable within-cohort neural patterns from within-subject, day-to-day pain-related fluctuations in pain intensity and unpleasantness, with explicit control for longitudinal temporal drift. The insula exhibited stable within-cohort spectral organization characterized by an anterior-posterior gradient with lower posterior fast-band power and spectral slowing, together with greater posterior spectral power in the hemisphere contralateral to the chronic pain side. Superimposed on this stable pattern, daily pain intensity was most strongly associated with increased contralateral posterior alpha power, accounting for approximately 33% of within-subject variance. Pain unpleasantness showed its strongest association with increased contralateral posterior beta power, accounting for approximately 19% of within-subject variance. Peak-derived spectral metrics and intra-insular connectivity largely reflected stable baseline patterns, with comparatively modest day-to-day pain-related variation. These exploratory findings suggest that chronic neuropathic pain is associated with stable insular spectral patterns upon which frequency-specific oscillatory variation relates to daily pain experience. Posterior insular alpha and beta oscillations showed partially distinct associations with pain intensity and unpleasantness, respectively, whereas intra-insular connectivity primarily reflected stable network structure. Posterior insular spectral power may therefore provide a candidate physiological signal for tracking pain states.

ABSTRACT Pathophysiological mechanisms underlying the transition from acute to chronic neuropathic pain remain incompletely understood. The somatosensory and insular cortices are key cortical components of the pain matrix. We examined changes in activation of these cortical regions during the transition from acute to chronic neuropathic pain. The right sciatic nerve was ligated in activity reporter TRAP mice using standard procedures. Mechanical allodynia was confirmed after CCI or sham surgery using von Frey monofilaments applied to the hind paws. To label active neurons, 4-hydroxytamoxifen was administered to separate cohorts at 1, 3, and 6 weeks following nerve ligation. Passive tissue clearing of brain sections and confocal imaging was used to assess active neurons. Progressive reduction of ipsilateral hind paw in CCI mice indicated mechanical allodynia development. CCI mice showed robust neuronal activation in the bilateral somatosensory and insular cortices. The somatosensory cortical activation peaked at 3 weeks post-CCI, whereas insular cortical activity increased during the transition from acute to chronic neuropathic pain. These studies revealed that CCI induced progressive mechanical allodynia and distinct temporal patterns of cortical neuronal activation, with transient peak neuronal activity in the somatosensory cortex and sustained, increasing activation in the insular cortex during acute-to-chronic pain transformation.

BACKGROUND:Conditioned pain modulation (CPM) assesses descending pain inhibition, but behavioural approaches are limited by subjectivity and variable reproducibility. We tested a CPM protocol combining nociceptive-selective laser-evoked potentials (LEPs) with a repeated-trial design to determine whether neurophysiological markers complement behavioural measures and improve reliability. METHODS:Twenty-seven healthy adults (mean age 24.6 years; 14 female) completed two sessions ≥ 1 week apart. Nociceptive-selective laser stimuli were applied to the left hand before and after a cold pressor task, and EEG was recorded to extract LEP-N2P2 components. Temporal LEP-N1 was measured as a secondary outcome. Behavioural CPM (B_CPM) was indexed by pain ratings; neurophysiological CPM (N_CPM) was defined by reductions in LEP-N2P2 amplitude. RESULTS:Consistent behavioural responders were observed in 92.6% of participants, and N_CPM responder rates exceeded 74% across electrodes. B_CPM and N_CPM magnitudes correlated at C3, C4, and Cz (ρ = 0.54-0.56; FDR-adjusted p < 0.05). Test-retest reliability was good to excellent for B_CPM (ICC3,1 = 0.69; ICC3,2 = 0.81) and for N_CPM at Cz (ICC3,1 = 0.63; ICC3,2 = 0.77). N1_CPM showed mean attenuation but poorer test-retest reliability (ICC3,1 = -0.21; ICC3,2 = -0.51) and no significant correlation with B_CPM. Psychological measures were stable across visits and unrelated to outcomes in this cohort at baseline. CONCLUSION:The repeated-trial design enabled assessment of within-subject consistency via the B_CPM induction rate. Combining behavioural and neurophysiological measures in this dual-domain framework may improve interpretability and advance standardisation of CPM methodology. LEP-based N_CPM markers showed reproducibility across sessions and may contribute to the development of brain-based biomarkers for patient stratification and treatment selection in chronic pain. SIGNIFICANCE STATEMENT:This study establishes a reproducible dual-domain framework for assessing descending pain inhibition by integrating behavioural conditioned pain modulation with nociceptive-specific laser-evoked potentials. Using a repeated-trial design, both behavioural and cortical measures showed high responder rates, strong correlations, and good test-retest reliability. The findings advance standardisation of CPM methodology and demonstrate that LEP-based neurophysiological markers can objectively index inhibitory function, supporting the development of reliable, brain-based biomarkers to guide mechanism-driven pain assessment and personalised neuromodulation therapies.

Background:Essential tremor (ET) is a common neurologic disorder, with 30-50% of patients experiencing medication-refractory symptoms. Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an approved, effective treatment for medication-refractory ET. In this open-label, continued access study, subjects were enrolled prospectively after the pivotal MRgFUS trial completed enrollment, but before US Food and Drug Administration approval. The objective of this study was to evaluate the long-term (5-year) effectiveness and safety of unilateral MRgFUS thalamotomy in medication-refractory ET patients. Methods:Effectiveness was evaluated by change from baseline in Clinical Rating Scale for Tremor (CRST) scores and quality of life (QoL) with the Quality of life in Essential Tremor (QUEST) questionnaire. Adverse events (AEs) following MRgFUS thalamotomy were recorded. Observed data were utilized for the main analysis. Sensitivity analyses using last observation carried forward and best-worst case scenarios were completed to evaluate the impact of missing data at long-term visits. Results:Of 61 treated subjects, the mean (SD) age was 69.5 (14.0) years, most (67.2%) were male, and 26 (42.6%) were observed for 5 years. MRgFUS thalamotomy improved tremor/motor function (CRST Parts A and B), tremor severity (postural component of CRST Part A for the treated side), and functional disability (CRST Part C) scores throughout the study. At 1- and 5-year follow-up, respective percentage improvements from baseline were: tremor/motor function, 62.2% and 51.9%; tremor severity, 75.6% and 67.4%; and functional disability, 65.4 and 35.4%. QoL improved by 53.6 and 43.7% at 1- and 5-year follow-up, respectively. Almost all related AEs were mild (85%) or moderate (12%) in severity, with 3% being severe. More than half of related events resolved in 6 months. Conclusion:MRgFUS thalamotomy is a safe and effective long-term treatment for patients with medication-refractory ET and is associated with improved QoL.

Temporal summation of pain (TSP) is a psychophysical measure for assessing central facilitation of pain. This study examined sex differences and the effects of body region on TSP using contactless laser stimulation. Thirty-one right-handed healthy participants (16 female; mean age ± SD = 23.9 ± 7.4 years) were tested at the hand, leg, and low back. Painful laser stimulation reliably evoked behavioral TSP responses in a significant proportion of participants (p < 0.01, Cohen's h = 1.67; mean induction rate: 63.5 % ± 18.2 %; mean magnitude: 36.6 % ± 34.5 %). TSP magnitude varied significantly across body regions (p = 0.02, ηₚ² = 0.13 with the lowest responses at the low back (26.2 % ± 17.4 %) and highest at the leg (47.1 % ± 50.0 %). No sex differences were observed. Concurrent EEG recordings also showed TSP related gamma responses (i.e. gamma TSP) in a significant proportion of participants (p < 0.01, Cohen's h = 1.67; mean induction rate: 68.1 % ± 12.9 %; mean magnitude: 41.6 % ± 23.3 %). Gamma TSP magnitude also differed by region (p = 0.04, ηₚ² = 0.11), with the highest response at the low back (48.2 % ± 31.4 %), significantly greater than the leg (35.4 % ± 13.3 %; p = 0.04, r = 0.44). These findings highlight regional variability in central pain facilitation and provide initial insights into the cortical oscillatory mechanisms underlying TSP. PERSPECTIVE: This study identifies body region differences in temporal summation of pain (TSP) and associated gamma-band EEG responses elicited by contactless painful laser stimulation. Clarifying these regional variations in healthy individuals provides foundational insights into central pain processing and may help guide future research on pain mechanisms across different body regions.

INTRODUCTION:Historically, stereotactic mesencephalotomy was developed as a "supraspinal" cordotomy for cancer and neuropathic pain. Early experiences relieved pain, but the procedure was never widely adopted because of the associated morbidity with midbrain lesioning. Contemporary image-guided lesioning could make this a feasible procedure for cancer patients suffering with pain. METHODS:A single-center, nonrandomized, early phase trial was designed to treat patients with severe, refractory pain from head and neck cancer with unilateral MRI-guided focused ultrasound mesencephalotomy. Safety was the primary outcome, but measures of efficacy were assessed with pain intensity and more functional components of pain. RESULTS:A discrete midbrain lesion was created for the 5 patients. All patients with advanced cancer had limited survival of less than 3 months, but they tolerated the procedure and experienced pain relief to different degrees. Two had profound pain relief, one was partial, and two others were very brief. One patient was transiently obtunded and other procedural morbidities were mild: numbness (3), oculomotor disturbance (1), and agitation (1). Electroencephalography, somatosensory evoked potentials, and quantitative sensory testing were obtained when possible. CONCLUSION:Stereotactic focused ultrasound mesencephalotomy is a modern, image-guided, lesioning technique that may be effective for cancer pain.

BACKGROUND:Pain catastrophising is a maladaptive cognitive-emotional trait linked to greater pain severity and poorer outcomes, yet its neurophysiological correlates remain unclear. OBJECTIVES:We tested whether pain catastrophising amplifies cortical responses to nociceptive input, independent of subjective pain intensity. METHODS:Fifty-two healthy adults underwent EEG during painful laser stimulation (n = 29; mean age 24.3 ± 10.9 years; 55.2% female) or non-painful electrical stimulation (n = 23; mean age 23.3 ± 8.5 years; 56.5% female). Each trial comprised a triplet of stimuli (S1, S2, S3) with a 1.5-s interstimulus interval; 30 triplets were delivered per modality. Associations between Pain Catastrophising Scale (PCS) scores and amplitudes of laser-evoked potentials (LEP-N2P2) and somatosensory-evoked potentials (SEP-N1P2) were tested using mixed-effects models, with trial-level pain ratings as a covariate. RESULTS:Higher PCS scores were associated with greater LEP-N2P2 amplitude for the first stimulus (S1) in the painful condition, independent of pain ratings, at the parietal midline electrode (Pz). No associations were observed between PCS and SEP-N1P2 in the non-painful condition, or between PCS and early N1 components of LEP or SEP. CONCLUSIONS:Pain catastrophising selectively amplifies later-stage cortical responses to painful stimuli, strongest at first presentation (S1) and localised to parietal Pz channel, with no effects in non-painful controls stimulation modality. These findings support LEPs as mechanistic biomarkers of catastrophising-related vulnerability. Combined with psychological assessment, such markers could improve early screening, risk stratification, and personalised interventions targeting maladaptive salience and attentional processes in pain. SIGNIFICANCE STATEMENT:Pain catastrophising was associated with amplified laser-evoked potential (LEP-N2P2) responses during painful, but not non-painful, stimulation in healthy adults. The effect was localised to the parietal midline, strongest for the first stimulus in a sequence, and diminished with repetition. These findings suggest modality-dependent cortical modulation and highlight LEP-N2P2 as a potential neural marker of maladaptive pain processing.

BACKGROUND:There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD). OBJECTIVE:Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET. METHODS:We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients. RESULTS:The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute < 0.05), with peak TDPD improvement (87%) at x = -13.5; y = -15.0; z = 1.5, ~3.5 mm anterior and 3 mm dorsal to the ET target. Discriminative connectivity projections were to the motor and premotor regions in TDPD, and to the motor and somatosensory regions in ET. The disorder-specific voxel-wise efficacy map could be used to estimate outcome in TDPD patients with high accuracy (R = 0.8; R2 = 0.64; P < 0.0001). The model was validated using the independent cohort of nine TDPD patients (R = 0.73; R2 = 0.53; P = 0.025-voxel analysis). CONCLUSION:We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Importance:Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option. Objective:To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy. Design, Setting, and Participants:This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category). Intervention:A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation. Main Outcomes and Measures:Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months. Results:The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient. Conclusions and Relevance:Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient. Trial Registration:ClinicalTrials.gov Identifier NCT04112381.

Modern transcranial magnetic resonance-guided focused ultrasound is an incisionless, ablative treatment modality for a growing number of neurologic disorders. This procedure selectively destroys a targeted volume of cerebral tissue and relies on real-time MR thermography to monitor tissue temperatures. By focusing on a submillimeter target through a hemispheric phased array of transducers, ultrasound waves pass through the skull and avoid overheating and brain damage. High-intensity focused ultrasound techniques are increasingly used to create safe and effective stereotactic ablations for medication-refractory movement and other neurologic and psychiatric disorders.

MRI-guided focused ultrasound (MRgFUS) is increasingly used in lesioning for functional neurosurgery and neuro-oncology. Technological advances in transducer design and MR thermometry has allowed for the noninvasive lesioning of deep-seated structures under real-time monitoring. MRgFUS has received FDA approval for the treatment of medication-refractory essential tremor and tremor or dyskinesia in Parkinson's disease. These indications might soon expand to include neuropathic pain, obsessive-compulsive disorder, and major depressive disorder, with the culmination of clinical studies currently underway. In the field of neuro-oncology, sonodynamic ablation and histotripsy might help overcome the inherent limitations of the currently available MRgFUS technology in regard to tumor ablation. FUS-mediated blood–brain barrier disruption is also being currently investigated as a mean toward enhancing the availability of chemotherapeutic agents.

Variability in pain sensitivity arises not only from the differences in peripheral sensory receptors but also from the differences in central nervous system (CNS) pain inhibition and facilitation mechanisms. Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation but is susceptible to confounding when elicited with the skin -contact thermode, which adds the responses of touch-related A beta low-threshold mechanoreceptors to nociceptive receptors. In the present study, we evaluate an alternative method involving the use of a contactless cutaneous laser for TSP assessment. We show that repetitive laser stimulations with a one second inter-stimulus interval evoked reliable TSP responses in a significant proportion of healthy subjects (N = 36). Female subjects (N = 18) reported greater TSP responses than male subjects confirming earlier studies of sex differences in central nociceptive excitability. Furthermore, repetitive laser stimulations during TSP induction elicited increased time-frequency electroencephalography (EEG) responses. The present study demonstrates that repetitive laser stimulation may be an alternative to skin-contact methods for TSP assessment in patients and healthy controls.Perspective: Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation. We show that contactless cutaneous laser stimulation is a reliable alternative to the skin contact approaches during TSP assessment.(R) 2023 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

ObjectivesThe primary objective of this study was to determine whether two neurosurgical procedures, deep brain stimulation (DBS) and focused ultrasound (FUS), to treat essential tremor (ET) of the upper limb also reduce vocal tremor (VT) in patients with comorbid dysphonia.MethodsTwelve patients with ET and concomitant VT scheduled for neurosurgical intervention (FUS or DBS) or returning for follow‐up after DBS implantation were assessed. FUS patients were assessed pre‐ and post‐intervention and DBS patients were assessed with the electrodes turned on and off post‐implantation. Three voice recordings of a sustained /a/ were obtained for each participant condition. Percent fundamental frequency variability (FFV) was calculated for each recorded sustained vowel. Additionally, blinded expert perceptual VT rating (VTR) was performed to assess subjective changes in tremors.ResultsOf the 12 patients, seven underwent unilateral FUS, and five underwent bilateral DBS. Mean FFV without neurosurgical intervention was 18.3%, SD = 7.8 and with neurosurgical intervention was 6.3%, SD = 3.0 (t (70) =8.7, p < 0.001). Mean FFV decreased in the FUS cohort from 22.0%, SD = 7.1 pre‐ablation to 6.7%, SD = 2.4 post‐ablation (t (40) = 7.7, p < 0.001). Mean FFV also decreased in the DBS cohort from 15.7%, SD = 7.0 to 6.0%, SD = 3.3 when stimulation was turned on (t (28)=5.7 p < 0.001). In the FUS group, mean VTR decreased from 4.0 to 1.4 post‐ablation (Z = 7.8, p < 0.001). In the DBS group, mean VTR decreased from 3.3 to 2.1 with stimulation (Z = 4.1, p < 0.001).ConclusionNeurosurgical interventions for ET (bilateral DBS and unilateral FUS) demonstrate acoustic and perceptual benefits for VT.Level of Evidence4 Laryngoscope, 134:367–373, 2024

OBJECTIVE Medial thalamotomy has been shown to benefit patients with neuropathic pain, but widespread adoption of this procedure has been limited by reporting of clinical outcomes in studies without a control group. This study aimed to minimize confounders associated with medial thalamotomy for treating chronic pain by using modern MRI-guided stereotactic lesioning and a rigorous clinical design. METHODS This prospective, double-blinded, randomized controlled trial in 10 patients with trigeminal neuropathic pain used sham procedures as controls. Participants underwent assessments by a pain psychologist and pain management clinician, including use of the following measures: the Numeric Pain Rating Scale (NPRS); patient-reported outcome measures; and patient’s impression of improvement at baseline, 1 day, 1 week, 1 month, and 3 months postprocedure. Patients in the treated group underwent bilateral focused ultrasound (FUS) medial thalamotomy targeting the central lateral nucleus. Patients in the control group underwent sham procedures with energy output disabled. The primary efficacy outcome measure was between-group differences in pain intensity (using the NPRS) at baseline and at 3 months postprocedure. Adverse events were measured for safety and included MRI analysis. Exploratory measures of connectivity and metabolism were analyzed using diffusion tensor imaging, functional MRI, and PET, respectively. RESULTS There were no serious complications from the FUS procedures. MRI confirmed bilateral medial thalamic ablations. There was no significant improvement in pain intensity from baseline to 3 months, either for patients undergoing FUS medial thalamotomy or for sham controls; and the between-group change in NPRS score as the primary efficacy outcome measure was not significantly different. Patient-reported outcome assessments demonstrated improvement (i.e., a decrease) only in pain interference with enjoyment of life at 3 months. There was a perception of benefit at 1 week, but only for patients treated with FUS and not for the sham cohort. Advanced neuroimaging showed that these medial thalamic lesions altered structural connectivity with the postcentral gyrus and demonstrated a trend toward hypometabolism in the insula and amygdala. CONCLUSIONS This randomized controlled trial of bilateral FUS medial thalamotomy did not reduce the intensity of trigeminal neuropathic pain, although it should be noted that the ability to estimate the magnitude of treatment effects is limited by the small cohort.

Focused ultrasound (FUS) thalamotomy is an emerging treatment for tremor-dominant Parkinson’s disease (PD). We report the first postmortem neuropathologic study of FUS thalamotomy in a 68-year-old man with tremor-dominant PD, which was performed seven months before he died. Although the peak voxel temperature at the target was <54 °C, his tremor improved on intraoperative and postoperative assessments. Additionally, postoperative MRI demonstrated a thalamic lesion. Lewy body-related pathology consistent with PD was detected. There was also a 5-mm lesion in the ventral lateral thalamus characterized by demyelination and neuropil loss, with many lipid-laden macrophages, but no lymphocytic infiltrates and relatively preserved neurons and axons. Additional pathological assessments after FUS thalamotomy are needed to determine if the observed brain changes are typical of this procedure.

BACKGROUND:The gamma-aminobutyric acid A (GABAA) receptor is an important mediator of cellular signaling in the globus pallidus and might be implicated in the pathophysiology of Parkinson disease (PD). The goal of the present study was to characterize GABAA receptor subunit expression in the normal and parkinsonian human globus pallidus. METHODS:Postmortem brain specimens were obtained from 8 patients with pathological evidence of PD at autopsy and from 4 control patients without such evidence. These tissues were exposed to primary antibodies directed against the α1 and α3 subunits of the GABAA receptor and were visualized and quantified using fluorescence microscopy. RESULTS:No differences were found in the pallidal neuronal density in the control versus PD tissues. Projection neurons strongly expressed the α1, α3, and β2 GABAA receptor subunits. After normalizing the immunofluorescence intensities in the globus pallidus to those in the adjacent structures, no significant differences were found in GABAA receptor subunit expression in the globus pallidus between the PD specimens and the control specimens. CONCLUSIONS:Compensatory changes in GABAA receptor α1 and α3 subunit expression in response to PD-related signaling abnormalities in the globus pallidus did not occur in our PD cohort.

OBJECTIVE The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported. RESULTS Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported. CONCLUSIONS Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 ( ClinicalTrials.gov )