Brain volume changes after MR-guided focused ultrasound thalamotomy in patients with essential tremor and Parkinson’s disease

Brain volume changes after MR-guided focused ultrasound thalamotomy in patients with essential tremor and Parkinson’s disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Brain volume changes after MR-guided focused ultrasound thalamotomy in patients with essential tremor and Parkinson’s disease Veronika Purrer, Emily Pohl, Valeri Borger, Henning Boecker, Daniel Paech, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3716028/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy is a recently developed technique for treatment of severe tremor syndromes. Less is known about potential cortical and subcortical structural changes after ablation of the ventral intermediate nucleus and how these are potentially related to tremor relief. Methods Using an automated artificial-intelligence based approach, cortical and subcortical brain volume changes were investigated in 49 patients with essential tremor (ET) and 19 patients with tremor-dominant Parkinson’s disease (tdPD) before and six months after MRgFUS. Clinical outcome was assessed using the Clinical Rating Scale for Tremor. To evaluate differences in brain volumes, patients were further categorized into a high and low tremor improvement (TI) group. Results Brain volumes did not differ significantly between ET and tdPD patients at baseline. In both entities, significant volume reductions were found in the thalamus treated with thalamotomy along with volume increases in the occipital lobe contralateral to the MRgFUS lesion. Furthermore, significant differences between high and low TI groups were found in the contralateral occipital lobe in both entities, and in the contralateral caudate nucleus in tdPD patients. A significant volume reduction was found in tdPD patients with high TI in ipsilateral parietal lobe, ipsilateral putamen, and contralateral pallidum. Conclusion Our results indicate that TI achieved by MRgFUS thalamotomy affects a complex basal ganglia-thalamo-visuo-cortical network in patients with ET and tdPD. We identified a consistent spatial pattern of brain volume changes, particularly occipital lobe enlargement contralateral to the thalamotomy side, strongly suggesting possible restorative/reshaping effects after TI. Health sciences/Neurology/Neurological disorders/Movement disorders/Parkinson's disease Biological sciences/Neuroscience/Computational neuroscience/Learning algorithms Health sciences/Diseases/Neurological disorders/Neurodegenerative diseases/Parkinson's disease Health sciences/Medical research/Outcomes research tremor thalamotomy brain volumes MRgFUS Figures Figure 1 Figure 2 INTRODUCTION Essential tremor (ET) and tremor-dominant Parkinson’s disease (tdPD) are the most common clinical tremor manifestations and often cause significant impairment in quality of life 1 . Despite considerable progress in recent decades, medical treatment remains challenging, and surgical and incisionless interventions, therefore, may provide a potential alternative for severe drug-refractory tremor. One example of a newly developed method is transcranial MRI-guided focused ultrasound (MRgFUS) thalamotomy that provides immediate and sufficient tremor reduction without skull opening by selective thermal ablation of the ventral intermediate nucleus (VIM) of the thalamus 2 . Basal ganglia-thalamocortical and cerebello-thalamocortical networks are hypothesized to drive tremor activity, both of which project to the motor cortex via thalamic nuclei 3 . Thus, disruption of the supposed tremor network at the level of the VIM is expected to cause tremor improvement (TI) and long-term and symptom-associated effects were found mainly within the dentatorubro-thalamo-cortical pathway, emphasizing its distinct role in tremor pathogenesis 4 – 8 . Another recent study examined cortical and subcortical volume changes after MRgFUS thalamotomy in ET and Parkinson’s disease (PD) and reported significant reduction within the thalamus, basal ganglia and cerebellar cortex on the lesion side in ET but not PD patients 9 . Despite these preliminary data, however, there remains a lack of comprehensive knowledge about potential structural changes in the brain and how their extent is potentially related to tremor relief. Therefore, the aim of our study was to detect potential brain volume changes after MRgFUS treatment in patients with ET and tdPD using an investigator-independent cortical and subcortical structure segmentation software based on artificial intelligence (AI) to automatically analyze brain MRI datasets. In addition, correlations with clinical outcomes and differences between good and poor clinical responses were investigated. METHODS Study cohort Between June 2018 and May 2022, patients with severe, medication-refractory ET (n = 49) or tdPD (n = 19) underwent treatment with MRgFUS thalamotomy in the University Hospital Bonn. Diagnosis of ET or PD was confirmed by two neurologists specialized in movement disorders according to the IPMDS consensus criteria 10 . For consideration of MRgFUS thalamotomy, tremor expression was supposed to be moderate to severe (score of ≥ 2 in the dominant hand on the Clinical Rating Scale for Tremor [CRST] 11 ) and to affect daily activities and/or Quality of life (score > 2 in the disability suspicion of the CRST or ≥ 30% self-rated reduction of Quality of life caused by the tremor). All patients with PD showed a tremor dominant subtype classified based on established methods 12 using items from the MDS-Unified Parkinson’s Disease Rating Scale (UPDRS) III 13 . A tremor dominant subtype was defined by a tremor/non-tremor ratio equal or greater than 1. Exclusion criteria involved structural brain damage, epilepsy, coagulopathies, severe cardiac conditions, history of psychiatric disorders or substance abuse, reported cognitive impairment, or a skull density ratio < 0.3. The study was performed according the Declaration of Helsinki and approved by the local Ethics Committee (314/18). All participants provided written, informed consent. Magnetic Resonance-guided Focused Ultrasound Thalamotomy Treatment was performed using a clinical 3-Tesla MRI system (Discovery MR750w, GE Healthcare, Chicago, IL, USA) and the focused ultrasound system (ExAblate 4000 System, InSightec, Haifa, Israel). The patient’s head was immobilized in the ultrasound system using a stereotactic frame. Preoperative anatomical MR-scans were fused with an intraoperative reference scan. Then, the VIM of the thalamus contralateral to the more affected hand was selected as the target. Localization of the VIM followed standard stereotactic coordinates (on the level of anterior commissure to posterior commissure (AC-PC) line, 14mm lateral to midline or 11mm lateral to the third ventricle wall, 25% of the AC-PC line anterior to PC). Adjustment of the target was based on intraoperative clinical evaluations, i.e. the patient’s feedback regarding tremor reduction and possible side effects and the diffusion tensor imaging – based coordinates of the cerebello-thalamic-tract, calculated in advance (detail in 14 ). For further treatment details we refer to previous descriptions 15 – 17 . Clinical evaluation All patients underwent a careful clinical evaluation (conducted by two neurologists with 30 and six years of experience in movement disorders) directly before the treatment (T0), one to three days (T1) as well as six (T2) months after treatment. For tremor assessment the validated CRST 11 was used. The scale consists of three parts: tremor severity in different body parts (part A), motor task performance for both hands (part B), and subjective functional disability related to the tremor (part C). To compare the TI of the treated hand, we used a hand-specific subscore combining part A and B of the treated upper extremity (CRST treated , ranging from 0 to 28). Higher values indicated more severe tremor. Changes in tremor outcome were assessed using the CRST treated and calculated using the Weber-Fechner Eq. 1 8 , which accounts for the logarithmic relationship between tremor rating R and tremor amplitude T = ((T f – T i )/T i = 10 (α/N)*ΔR – 1). Hereby, T is a function of the change in tremor ratings ΔR, α is a coefficient for the 0–4 scale and equals to 0.5, and N is the number of items included in the scale. In DBS and MRgFUS, tremor improvement of the contralateral extremity ranges between 40–80%, given different rating methods and study protocols 19 . In our cohort the mean tremor reduction after 6 months was 76%. We tried various grouping methods (50%, 60% and 70% of tremor improvement); however, only the categorization using 70% resulted in a sufficiently large group size. Therefore, we categorized patients into the higher TI group with T ≥ 0.7 (n = 50) and the lower TI group with T < 0.7 (n = 18) according to the CRST treated score after six months (T2). Image acquisition and analysis Standardized MR imaging according to a clinical protocol was acquired at T0 and T2 using a clinical 3-Tesla scanner (Philips Achieva TX, Best, The Netherlands) equipped with an eight-channel head coil. The protocol comprised a 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) sequence acquired with isotropic resolution of 1mm and the following parameters: TR = 7.286ms, TE = 3.93ms, matrix = 256x256mm, 180 slices in total, scan time = 4.66min. An automated artificial-intelligence (AI)-based software was used to determine quantitative analyses of the volume of different brain areas in ml. This commercially licensed MRI post-processing software named "mdbrain" (v4.4.1 and higher) is provided by mediaire GmbH, Berlin, Germany, which is an approved medical device manufacturer according to the European Medical Device Directive 93/42/EEC and is certified according to DIN EN ISO 13485:2016. The "mdbrain" software is approved as a Conformité Européenne (CE)-marked medical device and performs automatic brain volumetry of different brain regions using native 3D T1-weighted sequences to allow quantitative statements based on an extensive population-based normative database. The algorithm and embedded normative database are trained nationwide, not limited to the experience of a single centre, and have been validated for accuracy 20 . The system leverages a custom deep learning segmentation model based on the U-Net architecture to perform a highly accurate side- and region-specific (e.g. lobes) rapid brain volumetry, which was trained on a heterogeneous dataset of 3D T1w images (n = 2869, balanced m/f). Augmentation techniques (augmentation of contrast, resolution, rotation, elastic deformation) have been used to maximize the model’s applicability in daily routine. The volumetrized structures were the total brain volume (TBV), gray (GM) and white matter (WM), cortical gray matter (cGM), and the cerebellar cortex. Several cortical and subcortical brain areas were additionally assessed for each side separately as follows: frontal lobe, parietal lobe, occipital lobe, temporal lobe, caudate nucleus, putamen, pallidum and thalamus. Statistical Analysis Statistical analysis was carried out using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, N.Y., USA). Shapiro-Wilk test was used to evaluate the normal distribution of the data and parametric or non-parametric tests were applied according to the results. Group differences of demographical and clinical data were evaluated with the χ 2 test (sex, handedness) and the Mann-Whitney-U test or student’s t-test (age, age of onset, disease duration, total CRST score and subscores). For volumetric analysis, all acquired brain volumes were normalized to the intracranial volume (ICV) of each subject. To determine the estimated ICV, the TBV and total ventricle volume were summed up. The Wilcoxon signed-rank test or paired t-test was used to assess significant changes of brain volumes after six months. Brain volume differences between ET and PD as well as the higher and lower TI group were examined using the analysis of covariance (ANCOVA) and adjusting for age and sex. For all patients, a hierarchical multiple linear regression was used to determine the contribution of disease duration and tremor severity (clinical scores) on volumetric measurements while controlling for age and sex. Therefore, age and sex were entered in the first block. Next, disease duration and the CRST score were added as predictors. P-values < 0.05 were considered statistically significant. Continuous variables are presented as mean ± standard deviation and categorial variables as frequency and proportions. RESULTS Demographical and clinical characteristics The mean age in ET (70.6 ± 11.1 years) and PD (63.5 ± 12.0 years) patients differed significantly (p=0.012). No statistically significant difference was found in the other demographic characteristics (i.e., sex and handedness). ET patients reported a significant younger age of onset (p=0.004) and more prolonged disease duration (p<0.001). Total CRST score (T0: p<0.001, T1: p<0.001, T2: p<0.001) and subscores (treated extremity: T0: p=0.002, T1: p=0.03; untreated extremity: T0: p<0.001, T1: p<0.001, T2: p<0.001) were significantly higher in ET patients, except of post-6 months subscores for the treated extremity (Fig. 1A). 39 (80%) ET patients and 11 (58%) PD patients still had a considerable TI after six months. Comparing the high and low TI group in both diseases, demographical characteristics did not differ significantly. Furthermore, CRST scores did not differ significantly except of a significant higher subscore for the treated extremity six months after MRgFUS treatment in ET patients with poor tremor response (p<0.001). In PD patients, the total CRST score (p=0.04) and the subscore for the treated extremity at baseline (p<0.001) showed significant higher values in the high TI group whereas no significant differences could be found after six months (Fig. B). Detailed demographical and clinical characteristics are given in Table 1. Contribution of disease-related factors to brain volumes Hierarchical linear regression was used to determine whether disease duration or clinical scores contributed to the volumetric measurements, while controlling for sex and age. In both, ET and PD patients, no statistically significant association of the single brain volumes with disease-related factors could be detected. Volumetric Results in ET and PD patients No significant volume differences were found between ET and PD patients at baseline and after six months. Relative brain volume changes in ET and PD patients are reported in Table 2. In both ET and PD, the most evident reduction six months after MRgFUS treatment was present in the treated thalamus (ET: -3%, PD: -4%). The most evident increase occurred within the occipital lobe contralateral to the treated hemisphere (ET: +3%, PD: +5%). Moreover, PD patients showed a considerable reduction in the caudate nucleus volume contralateral to the treated hemisphere (-4%). In ET patients, we found additional significant but minor (< ±3%) volume differences of the TBV, WM, GM, cGM, both frontal and parietal lobes, as well as the putamen and pallidum ipsilateral to the treated hemisphere six months after MRgFUS treatment. In PD, the TBV, cGM volumes as well as the parietal lobe ipsilateral and the frontal and temporal lobe contralateral to the treated hemisphere differed significantly. Furthermore, significant volume reduction was observed within the putamen of the ipsilateral hemisphere. Volumetric Results according to TI ET patients: In the higher and lower TI group, significant volume differences after six months could be found within the GM and thalamus ipsilateral to the treated hemisphere. Patients with higher TI showed significant decreases of the ipsilateral frontal lobe, the ipsilateral pallidum and the contralateral putamen but increases in both occipital lobes. In contrast, patients with low TI showed significant volume loss of the cGM and the contralateral frontal and parietal lobe. A considerable reduction was observed within the thalamus ipsilateral to the treated hemisphere in both subgroups (high TI: -3%, low TI: -3%). In contrast, the occipital lobe contralateral to the treated hemisphere showed significant enlargement only in the high TI subgroup (+3%) (Fig.2A, Suppl. Tbl. S1). Compared to the high TI subgroup, significant larger volumes were found in the contralateral occipital lobe at baseline (mean difference (MD)= -0.002, p=0.02) and after six months (MD= -0.002, p=0.02) in the low TI subgroup. PD patients: In PD patients – regardless of tremor outcome – significant reductions were found in the frontal lobe contralateral to the treated hemisphere, the ipsilateral putamen and ipsilateral thalamus. The high TI group showed additional significant volume reductions of the ipsilateral parietal lobe, the contralateral temporal lobe and the contralateral pallidum. Patients with poor tremor outcome had further significant reductions of the cGM. Considerable volume reductions occurred in the ipsilateral thalamus in both groups (high TI: -3%, low TI: -4%). In the high TI group significant volume reductions were found in the ipsilateral parietal lobe (-3%), ipsilateral putamen (-3%) and contralateral pallidum (-3%). The contralateral occipital lobe showed enlargement >5% in both groups, but did not reach statistical significance (Fig. 2B, Suppl. Tbl. S2). At baseline, the higher TI group had significant smaller volumes of the ipsilateral occipital lobe (MD= -0.002, p=0.02) and ipsilateral thalamus (MD= -0.0003, p=0.03) while larger volumes were evident in the ipsilateral caudate nucleus (MD= 0.0002, p=0.02) and contralateral putamen (MD= 0.0002, p=0.04). After six months, significant differences were found only in the contralateral occipital lobe (MD= -0.002, p=0.02) and contralateral caudate nucleus (MD= 0.0001, p=0.03). DISCUSSION MRgFUS is a newly developed method to treat drug-refractory tremor syndromes by selective thermal lesions of defined structures in the central nervous system. The safety and efficacy has been demonstrated in several case series and randomized trials 16 , 17 , 21 , 22 . Moreover, lesion characterization, the association with VIM overlap, tract disruption and clinical outcome has been investigated across numerous previous studies 5 , 14 , 23 , 24 . Nevertheless, to date less is known about possible whole brain volumes changes after MRgFUS thalamotomy. Bruno et al. were the first to examine brain volume changes after 12 months in 16 patients with disabling ET and 15 patients with tdPD using the same fully-automated AI-based volumetry approach as in our study: significant volume reductions of the treated thalamus and ipsilateral basal ganglia structures were noted in ET patients. Furthermore, the authors observed a significant reduction in cerebellar volumes in ET patients and raised the question whether the observed reductions could be attributed to the treatment itself or to pathological atrophy. No significant volume differences could be found in PD patients or in association with age or tremor score. With the mere of a larger caudate nucleus in ET patients, no differences were observed comparing ET and PD patients 9 . In line with these recently published findings, we also observed significant reductions of the treated thalamus and ipsilateral basal ganglia, which were present not only in the ET but also in the PD cohort. Although the underlying pathophysiological mechanisms in ET and PD are different, recent findings also point to certain common features involving basal ganglia and cerebellar circuits 3 , 25 – 27 . Besides the widely known role of the basal ganglia in the pathomechanism of PD, previous research has provided evidence of basal ganglia network hyperactivity caused by an increased excitatory output from the motor cortex (receiving increased excitatory input from the thalamus) also in ET 26 . MRgFUS thalamotomy could therefore explain downregulation and subsequent volume reduction not only of the thalamus but also of basal ganglia structures. In the case of deep brain stimulation (DBS), only a few studies have also investigated structural brain volume changes after DBS. Volume reductions were observed in the caudate nucleus, pallidum, putamen, and thalamus ipsilateral to the implanted hemisphere 28 . In contrast, another study analyzed the brain volumes of 8 PD patients after a mean interval of 15 months following unilateral DBS implantation. This reported significant hippocampal atrophy as well as an increase in volume of the contralateral putamen and a tendency for the contralateral caudate nucleus to enlarge 29 . It should be noted that the aforementioned studies had several methodological differences, such as cohort size and timing of MRI acquisition. Although the previous studies yielded divergent results, they suggest that DBS may contribute to progressive brain volume changes (especially within the basal ganglia), possibly as a result of chronic neuromodulation or Wallerian degeneration 28 . Nevertheless, DBS surgery was performed in PD patients regardless of their clinical phenotype (e.g., tremor dominance) and targeted the subthalamic nucleus, thus limiting comparisons with VIM-MRgFUS in tremor syndromes. In contrast to Bruno et al. 9 , we found no changes in cerebellar volumes. The cerebellum is thought to drive tremor activity in ET, and previous studies have reported volume losses in specific cerebellar regions such as the vermis or in ET patients with head tremor only, suggesting a heterogenous or more advanced pathological course 30 , 31 . However, Bruno et al. did not provide information on the duration or severity of the disease. Less advanced disease progression could therefore be a possible reason for the differing results. Furthermore, in contrast to the reported study, we used relative volumes to investigate volume changes after MRgFUS treatment. This form of normalization to ICV has the substantial advantage of reducing interindividual variation or image distortions in serial imaging measurements. Thus, it can be assumed that the validity and comparability of the normalized whole-brain volumes obtained in our study is substantially increased. Interestingly, we observed a significant increase in volumes of the contralateral occipital lobe, which was particularly significant in ET patients with higher TI. Visual association areas have been reported to be involved in tremor modulation. Tuleasca and colleagues reported several findings in structural and functional network studies supporting a link of visual association areas with tremor generation or arrest after thalamotomy. In a voxel-based morphometry analysis 1 year after left VIM radiosurgery, they reported decreased GM density in a large occipital cluster ipsilateral to the treated VIM correlating with higher TI 32 . Furthermore, pretherapeutic GM density levels in the right Brodmann area 18 (visual association area V2) was found to predict TI of the right treated hand 33 . Investigating functional changes after VIM radiosurgery, the same group observed a widespread visually-sensitive functional network in ET. Moreover, network interconnectivity strength with right visual Brodmann area 19 was found to be related with tremor arrest 27 . Comparisons with healthy controls also suggest normalization of interconnectivity in visual areas after radiosurgery, with patients with pretherapeutic higher functional interconnectivity within these areas showing larger benefits 34 , 35 . Another study investigating functional changes in ET after MRgFUS treatment reported significant lower functional connectivity in visual associated areas compared to healthy controls with partially restoration after the treatment 36 . Consistent with these findings, our group observed negative correlations between tremor severity and several bilateral visual processing areas in 22 patients with severe ET undergoing MRgFUS treatment (Kindler et al., manuscript under review). Furthermore, increased functional connectivity could be detected in all visual clusters six months after thalamotomy (Kindler et al., manuscript under review). Similarly, previous work suggest an involvement of visual areas in PD as well, but has often been primarily linked to visual problems in PD 37 – 39 . Comparing PD patients with different phenotypes, a previous study found hyper-connectivity between the basal ganglia and visual cortex in tdPD patients suggesting a possible relation with tremor 40 . Supporting this thesis, an 18 F-FDG-PET/MRI study revealed an increased metabolic activity in the calcarine cortex after MRgFUS subthalamotomy 41 . Likewise, in another study spontaneous neural activity in the left occipital cortex significantly decreased in nine tdPD patients 12 months after MRgFUS thalamotomy 42 . Although numerous studies indicate an involvement of visual association areas in tremor modulation, the role of visual association areas is still poorly understood. One explanation is the involvement of visual areas in the sensory guidance of movements; herein, contralateral visual areas are found to be connected with the ipsilateral thalamus and motor cortex 43 . Another hypothesis, supported by fMRI studies in ET patients, proposes that the cerebellum acts as a mediator between visual and somatosensory/motor information 44 , 45 . To our knowledge, we investigated for the first time the changes in brain volume after MRgFUS thalamotomy in relation to tremor response. Our study relied on a fully automated, quantitative, and thus objective assessment of spatial clusters of brain volume abnormalities. This approach detected visually inconspicuous findings and potentially demonstrated the impact of MRgFUS on brain integrity, unlike most previous imaging studies. Both ET and PD patients with high and low TI showed decreased volumes of the ipsilateral thalamus six months after thalamotomy. In addition, enlargement of the contralateral occipital lobe was found, but reached significance only in ET patients with high TI. In PD patients with high TI, significant reductions were also observed in the basal ganglia structures (putamen, pallidum). Comparing the volumes in patients with high and poor TI, the differences within the occipital lobes as well as in the thalamus and basal ganglia at baseline and after six months might reflect a complex basal ganglia-thalamo-visuo-cortical network involved in tremor generation. Nevertheless, the volume differences did not exceed 5%. Although no contribution of tremor severity and duration was found, the observed changes could also be related to disease progression. Larger controlled studies are needed to gain further insight into the effects of MRgFUS treatment and TI on changes in subcortical and cortical brain volume. Several limitations of this exploratory study should be noted. Brain volume changes were assessed six months after MRgFUS treatment. Therefore, further effects of possible restoration might not have been evident yet. In view of the initial volume changes shown here after only 6 months, further studies with longer follow-up periods would be of great interest. The outcome of tremor depends mainly on the size and location of the thalamotomy performed, which we did not consider separately in our analysis. Possible (partial) lesioning of adjacent networks, such as the medial lemniscus, may also cause alterations particularly in cortical structures. The aim of our study was to generally investigate potential brain volume changes after a standardized clinical MRgFUS procedure in a relatively large cohort of ET and tremor-dominant PD patients; in this respect, the observation of specific spatial patterns of brain volumetric alterations made here supports the use of brain volumetry despite possibly small interindividual differences in the ablation cavities. However, for this reason, differences in brain volumes should be interpreted with caution as pre-therapeutic prognostic factors. Although we used a fully automated segmentation approach that is approved for clinical use in accordance with CE certification, technical limitations and possible confounding factors such as slice thickness, MRI noise level, MRI orientation, field strength, and anatomic boundary criteria 46 may generally affect the results. However, the initial and follow-up MRI scans were acquired at the same MR scanner according to a standardized imaging protocol, which largely eliminates the influence of these common confounding factors mentioned above. Lastly, the categorization of patients into a lower and higher TI group using a pre-specified cut-off of 70% improvement was arbitrary and therefore may have introduced some interindividual selection bias. In conclusion, our results indicate that TI achieved by MRgFUS thalamotomy affects a complex basal ganglia-thalamo-visuo-cortical network in patients with ET and tdPD. We identified a consistent spatial pattern of brain volume changes, particularly occipital lobe enlargement contralateral to the thalamotomy side, strongly suggesting possible restorative/reshaping effects after TI. Further studies, including a dedicated control group and a longer follow-up period, would be desirable to further explore cortical changes and long-term neurological trajectories after TI. In addition, diffusion tensor imaging or functional imaging could provide additional insights into tremor generation and modulation. Abbreviations AC-PC Anterior commissure to posterior commissure AI Artificial-intelligence ANCOVA Analysis of covariance CE Conformité Européenne cGM Cortical gray matter CRST Clinical Rating Scale for Tremor DBS Deep brain stimulation ET Essential tremor GM Gray matter ICV Intracranial volume MD Mean difference MPRAGE Magnetization-prepared rapid gradient-echo MRgFUS MRI-guided focused ultrasound PD Parkinson’s disease TBV Total brain volume TdPD Tremor dominant Parkinson’s disease TI Tremor improvement UPDRS MDS-Unified Parkinson’s Disease Rating Scale VIM Ventral intermediate nucleus WM White matter Declarations ACKNOWLEDGEMENT We would like to acknowledge Karolina Makowski, clinical study team assistant at University hospital of Bonn, for her support in organisation and data collection. AUTHORS’ ROLES VP contributed to conception and design, data acquisition, data analysis and interpretation, drafted the manuscript and critically revised the manuscript. EP contributed to data acquisition and critically revised the manuscript. VB contributed to data acquisition and critically revised the manuscript. HB contributed to conception and design and critically revised the manuscript. DP contributed to data acquisition and critically revised the manuscript. MS contributed to data acquisition and critically revised the manuscript. SZ contributed to data acquisition and critically revised the manuscript. AR contributed to data acquisition and critically revised the manuscript. UW contributed to data acquisition and critically revised the manuscript. FCS contributed to conception and design, data acquisition, data analysis and interpretation and critically revised the manuscript. All authors gave their final approval and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. FUNDING SOURCES AND CONFLICT OF INTEREST The MRgFUS system was in part funded by the German Research Foundation (INST 1172/64-1) and the University of Bonn’s Faculty of Medicine. The authors declare that there are no conflicts of interest relevant to this work. FINANCIAL DISCLOSURES OF ALL AUTHORS (for the previous 12 months) UW served as consultant and lecturer and on advisory boards for Bayer AG, STADA Pharm and Zambon; he received grant from the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG) and the Deutsche Parkinson Vereinigung e.V.. DATA AVAILABILITY The datasets used and analysed during the current study available from the corresponding author on reasonable request. References Chandran V, Pal PK. 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Elias WJ, Lipsman N, Ondo WG, et al. A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor. N Engl J Med 2016; 375(8):730–39. https://doi.org/10.1056/NEJMoa1600159. Pineda-Pardo JA, Martínez-Fernández R, Rodríguez-Rojas R, et al. Microstructural changes of the dentato-rubro-thalamic tract after transcranial MR guided focused ultrasound ablation of the posteroventral VIM in essential tremor. Hum Brain Mapp 2019; 40(10):2933–42. https://doi.org/10.1002/hbm.24569. Pineda-Pardo JA, Urso D, Martínez-Fernández R, et al. Transcranial Magnetic Resonance-Guided Focused Ultrasound Thalamotomy in Essential Tremor: A Comprehensive Lesion Characterization. Neurosurgery 2020; 87(2):256–65. https://doi.org/10.1093/neuros/nyz395. Hoshi E, Tremblay L, Féger J, Carras PL, Strick PL. The cerebellum communicates with the basal ganglia. Nat Neurosci 2005; 8(11):1491–93. https://doi.org/10.1038/nn1544. Prasad S, Shah A, Bhalsing KS, Ingalhalikar M, Saini J, Pal PK. Clinical correlates of abnormal subcortical volumes in Essential Tremor. J Neural Transm (Vienna) 2019; 126(5):569–76. https://doi.org/10.1007/s00702-019-02004-0. Tuleasca C, Najdenovska E, Régis J, et al. Clinical response to Vim's thalamic stereotactic radiosurgery for essential tremor is associated with distinctive functional connectivity patterns. Acta Neurochir (Wien) 2018; 160(3):611–24. https://doi.org/10.1007/s00701-017-3456-x. Kern DS, Uy D, Rhoades R, Ojemann S, Abosch A, Thompson JA. Discrete changes in brain volume after deep brain stimulation in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 2020; 91(9):928–37. https://doi.org/10.1136/jnnp-2019-322688. Sankar T, Li SX, Obuchi T, et al. Structural brain changes following subthalamic nucleus deep brain stimulation in Parkinson's disease. Mov Disord 2016; 31(9):1423–25. https://doi.org/10.1002/mds.26707. Choi S-M, Kim BC, Chang J, et al. Comparison of the Brain Volume in Essential Tremor and Parkinson's Disease Tremor Using an Automated Segmentation Method. Eur Neurol 2015; 73(5-6):303–09. https://doi.org/10.1159/000381708. Shin H, Lee D-K, Lee J-M, et al. Atrophy of the Cerebellar Vermis in Essential Tremor: Segmental Volumetric MRI Analysis. Cerebellum 2016; 15(2):174–81. https://doi.org/10.1007/s12311-015-0682-8. Tuleasca C, Witjas T, Najdenovska E, et al. Assessing the clinical outcome of Vim radiosurgery with voxel-based morphometry: visual areas are linked with tremor arrest! Acta Neurochir (Wien) 2017; 159(11):2139–44. https://doi.org/10.1007/s00701-017-3317-7. Tuleasca C, Witjas T, van de Ville D, et al. Right Brodmann area 18 predicts tremor arrest after Vim radiosurgery: a voxel-based morphometry study. Acta Neurochir (Wien) 2018; 160(3):603–09. https://doi.org/10.1007/s00701-017-3391-x. Tuleasca C, Bolton TAW, Régis J, et al. Normalization of aberrant pretherapeutic dynamic functional connectivity of extrastriate visual system in patients who underwent thalamotomy with stereotactic radiosurgery for essential tremor: a resting-state functional MRI study. J Neurosurg 2019; 132(6):1792–801. https://doi.org/10.3171/2019.2.JNS183454. Tuleasca C, Najdenovska E, Régis J, et al. Ventrolateral Motor Thalamus Abnormal Connectivity in Essential Tremor Before and After Thalamotomy: A Resting-State Functional Magnetic Resonance Imaging Study. World Neurosurg 2018; 113:e453-e464. https://doi.org/10.1016/j.wneu.2018.02.055. Kato S, Maesawa S, Bagarinao E, et al. Magnetic resonance-guided focused ultrasound thalamotomy restored distinctive resting-state networks in patients with essential tremor. J Neurosurg 2023; 138(2):306–17. https://doi.org/10.3171/2022.5.JNS22411. Göttlich M, Münte TF, Heldmann M, Kasten M, Hagenah J, Krämer UM. Altered resting state brain networks in Parkinson's disease. PLoS One 2013; 8(10):e77336. https://doi.org/10.1371/journal.pone.0077336. Zhang D, Liu X, Chen J, Liu B. Distinguishing Patients with Parkinson's Disease Subtypes from Normal Controls Based on Functional Network Regional Efficiencies. PLoS One 2014; 9(12):e115131. https://doi.org/10.1371/journal.pone.0115131. Zhang D, Liu X, Chen J, Liu B, Wang J. Widespread increase of functional connectivity in Parkinson's disease with tremor: a resting-state FMRI study. Front Aging Neurosci 2015; 7:6. https://doi.org/10.3389/fnagi.2015.00006. Hou Y, Ou R, Yang J, Song W, Gong Q, Shang H. Patterns of striatal and cerebellar functional connectivity in early-stage drug-naïve patients with Parkinson's disease subtypes. Neuroradiology 2018; 60(12):1323–33. https://doi.org/10.1007/s00234-018-2101-6. Rodriguez-Rojas R, Pineda-Pardo JA, Martinez-Fernandez R, et al. Functional impact of subthalamotomy by magnetic resonance-guided focused ultrasound in Parkinson's disease: a hybrid PET/MR study of resting-state brain metabolism. Eur J Nucl Med Mol Imaging 2020; 47(2):425–36. https://doi.org/10.1007/s00259-019-04497-z. Xiong Y, Han D, He J, et al. Correlation of visual area with tremor improvement after MRgFUS thalamotomy in Parkinson's disease. J Neurosurg 2022; 136(3):681–88. https://doi.org/10.3171/2021.3.JNS204329. Glickstein M. How are visual areas of the brain connected to motor areas for the sensory guidance of movement? Trends Neurosci 2000; 23(12):613–17. https://doi.org/10.1016/s0166-2236(00)01681-7. Archer DB, Coombes SA, Chu WT, et al. A widespread visually-sensitive functional network relates to symptoms in essential tremor. Brain 2018; 141(2):472–85. https://doi.org/10.1093/brain/awx338. Tuleasca C, Régis J, Najdenovska E, et al. Visually-sensitive networks in essential tremor: evidence from structural and functional imaging. Brain 2018; 141(6):e47. https://doi.org/10.1093/brain/awy094. Cerasa A, Messina D, Nicoletti G, et al. Cerebellar atrophy in essential tremor using an automated segmentation method. AJNR Am J Neuroradiol 2009; 30(6):1240–43. https://doi.org/10.3174/ajnr.A1544. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations (Not answered) Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3716028","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":263613494,"identity":"f5aff19b-2d71-4c7c-9791-6921c1739293","order_by":0,"name":"Veronika Purrer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYBACgwNgMoGBQR7MYpBj4OEBMxgbCGqRSAALGBOphQGhJbGBkBbJ9t6HjwsK0uQZJHLMPldU3EvfcObswceFOxhk+3Fp6TlubDzDIMewQf6M8cwzZ4pzN5ztSwayGIxn4rBGckYamzSPQQVjgwSPMWNjW0LuhvM8ZtK8bQyJGw5g18Iv/wysxR6i5V9CugFMy35cWiTYQFpyEiFaGhISDM72QG3B4Rc2njRmYx6DtOQ2CbZixoZjCYYzz5xLNuZtkzCegcMWNvZjjI95/iTb9kswb2ZsqEmQ5zuTe/Axb5uNbD8O7yP0ovElCKgfBaNgFIyCUYAPAADGZFKI6Tm/ZwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8972-5483","institution":"University Hospital Bonn","correspondingAuthor":true,"prefix":"","firstName":"Veronika","middleName":"","lastName":"Purrer","suffix":""},{"id":263613495,"identity":"dc9f469c-1507-44cf-9e34-25b49f8a9a91","order_by":1,"name":"Emily Pohl","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"","lastName":"Pohl","suffix":""},{"id":263613496,"identity":"73705cc2-bd58-4907-b811-82b8fe25ad40","order_by":2,"name":"Valeri Borger","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Valeri","middleName":"","lastName":"Borger","suffix":""},{"id":263613497,"identity":"bde8b2b8-aeed-465c-ba71-7934f6c833ae","order_by":3,"name":"Henning Boecker","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Henning","middleName":"","lastName":"Boecker","suffix":""},{"id":263613498,"identity":"c721f5f0-a8dd-485c-91ae-233664ed4206","order_by":4,"name":"Daniel Paech","email":"","orcid":"https://orcid.org/0000-0001-5755-6833","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Paech","suffix":""},{"id":263613499,"identity":"b9fb5c8c-d169-41b0-8413-ab83ec43399a","order_by":5,"name":"Malte Sauer","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Malte","middleName":"","lastName":"Sauer","suffix":""},{"id":263613500,"identity":"e8920a92-0b39-499d-991a-6c38c7a32fa2","order_by":6,"name":"Stefan Zülow","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Stefan","middleName":"","lastName":"Zülow","suffix":""},{"id":263613501,"identity":"2474c8bd-07ac-4e67-9d4b-12db5b24329c","order_by":7,"name":"Alexander Radbruch","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Radbruch","suffix":""},{"id":263613502,"identity":"4a379b30-a5a4-485a-8ea8-e2b4d4b1e12c","order_by":8,"name":"Ullrich Wüllner","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Ullrich","middleName":"","lastName":"Wüllner","suffix":""},{"id":263613503,"identity":"da84dbae-d8a2-4627-bef2-33709b780cdc","order_by":9,"name":"Frederic Schmeel","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Frederic","middleName":"","lastName":"Schmeel","suffix":""}],"badges":[],"createdAt":"2023-12-06 16:27:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3716028/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3716028/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49080810,"identity":"2c19a7a3-60af-4532-b69d-37514a7e1ade","added_by":"auto","created_at":"2024-01-02 19:58:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52748,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTremor improvement after MRI-guided focused ultrasound (MRgFUS) thalamotomy \u003c/strong\u003ein patients with\u003cstrong\u003e \u003c/strong\u003eessential tremor (ET) and Parkinson’s disease (PD) (\u003cstrong\u003eA\u003c/strong\u003e) and patients with higher and lower tremor improvement (TI) after six months, separately (\u003cstrong\u003eB\u003c/strong\u003e). CRST= Clinical Rating Scale of Tremor.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3716028/v1/08091a006330cd802a0d2ab7.png"},{"id":49080811,"identity":"661603e0-f7ff-4769-8640-ced114e8c365","added_by":"auto","created_at":"2024-01-02 19:58:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":120381,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIndividual changes (%) of relative cortical and subcortical volumes six months after MRI-guided focused ultrasound thalamotomy \u003c/strong\u003ein\u003cstrong\u003e \u003c/strong\u003eessential tremor (\u003cstrong\u003eA\u003c/strong\u003e) and Parkinson’s disease (\u003cstrong\u003eB\u003c/strong\u003e)\u003cstrong\u003e. \u003c/strong\u003eCentral black marker represents the average. TI = tremor improvement. Ipsi/contra = ipsilateral/contralateral to thalamotomy side.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3716028/v1/f5655af05f09c78543d7a057.png"},{"id":53138916,"identity":"20737de2-bdf5-4d5f-b6ce-6e3a37c47b8c","added_by":"auto","created_at":"2024-03-21 05:29:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":598583,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3716028/v1/4a648153-3fa0-4235-b343-16eb0a7e3240.pdf"},{"id":49080809,"identity":"7a9b2899-aac7-41d0-b4b7-d33fb7d5a138","added_by":"auto","created_at":"2024-01-02 19:58:04","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":26188,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-3716028/v1/a8f1af8c2bf71949b19f7a55.docx"}],"financialInterests":"(Not answered)","formattedTitle":"Brain volume changes after MR-guided focused ultrasound thalamotomy in patients with essential tremor and Parkinson’s disease","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eEssential tremor (ET) and tremor-dominant Parkinson\u0026rsquo;s disease (tdPD) are the most common clinical tremor manifestations and often cause significant impairment in quality of life \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Despite considerable progress in recent decades, medical treatment remains challenging, and surgical and incisionless interventions, therefore, may provide a potential alternative for severe drug-refractory tremor. One example of a newly developed method is transcranial MRI-guided focused ultrasound (MRgFUS) thalamotomy that provides immediate and sufficient tremor reduction without skull opening by selective thermal ablation of the ventral intermediate nucleus (VIM) of the thalamus \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Basal ganglia-thalamocortical and cerebello-thalamocortical networks are hypothesized to drive tremor activity, both of which project to the motor cortex via thalamic nuclei \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Thus, disruption of the supposed tremor network at the level of the VIM is expected to cause tremor improvement (TI) and long-term and symptom-associated effects were found mainly within the dentatorubro-thalamo-cortical pathway, emphasizing its distinct role in tremor pathogenesis \u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Another recent study examined cortical and subcortical volume changes after MRgFUS thalamotomy in ET and Parkinson\u0026rsquo;s disease (PD) and reported significant reduction within the thalamus, basal ganglia and cerebellar cortex on the lesion side in ET but not PD patients \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Despite these preliminary data, however, there remains a lack of comprehensive knowledge about potential structural changes in the brain and how their extent is potentially related to tremor relief. Therefore, the aim of our study was to detect potential brain volume changes after MRgFUS treatment in patients with ET and tdPD using an investigator-independent cortical and subcortical structure segmentation software based on artificial intelligence (AI) to automatically analyze brain MRI datasets. In addition, correlations with clinical outcomes and differences between good and poor clinical responses were investigated.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy cohort\u003c/h2\u003e \u003cp\u003eBetween June 2018 and May 2022, patients with severe, medication-refractory ET (n\u0026thinsp;=\u0026thinsp;49) or tdPD (n\u0026thinsp;=\u0026thinsp;19) underwent treatment with MRgFUS thalamotomy in the University Hospital Bonn. Diagnosis of ET or PD was confirmed by two neurologists specialized in movement disorders according to the IPMDS consensus criteria \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. For consideration of MRgFUS thalamotomy, tremor expression was supposed to be moderate to severe (score of \u0026ge;\u0026thinsp;2 in the dominant hand on the Clinical Rating Scale for Tremor [CRST] \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e) and to affect daily activities and/or Quality of life (score\u0026thinsp;\u0026gt;\u0026thinsp;2 in the disability suspicion of the CRST or \u0026ge;\u0026thinsp;30% self-rated reduction of Quality of life caused by the tremor). All patients with PD showed a tremor dominant subtype classified based on established methods \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e using items from the MDS-Unified Parkinson\u0026rsquo;s Disease Rating Scale (UPDRS) III \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. A tremor dominant subtype was defined by a tremor/non-tremor ratio equal or greater than 1. Exclusion criteria involved structural brain damage, epilepsy, coagulopathies, severe cardiac conditions, history of psychiatric disorders or substance abuse, reported cognitive impairment, or a skull density ratio\u0026thinsp;\u0026lt;\u0026thinsp;0.3. The study was performed according the Declaration of Helsinki and approved by the local Ethics Committee (314/18). All participants provided written, informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMagnetic Resonance-guided Focused Ultrasound Thalamotomy\u003c/h2\u003e \u003cp\u003eTreatment was performed using a clinical 3-Tesla MRI system (Discovery MR750w, GE Healthcare, Chicago, IL, USA) and the focused ultrasound system (ExAblate 4000 System, InSightec, Haifa, Israel). The patient\u0026rsquo;s head was immobilized in the ultrasound system using a stereotactic frame. Preoperative anatomical MR-scans were fused with an intraoperative reference scan. Then, the VIM of the thalamus contralateral to the more affected hand was selected as the target. Localization of the VIM followed standard stereotactic coordinates (on the level of anterior commissure to posterior commissure (AC-PC) line, 14mm lateral to midline or 11mm lateral to the third ventricle wall, 25% of the AC-PC line anterior to PC). Adjustment of the target was based on intraoperative clinical evaluations, i.e. the patient\u0026rsquo;s feedback regarding tremor reduction and possible side effects and the diffusion tensor imaging \u0026ndash; based coordinates of the cerebello-thalamic-tract, calculated in advance (detail in \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e). For further treatment details we refer to previous descriptions \u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical evaluation\u003c/h2\u003e \u003cp\u003eAll patients underwent a careful clinical evaluation (conducted by two neurologists with 30 and six years of experience in movement disorders) directly before the treatment (T0), one to three days (T1) as well as six (T2) months after treatment.\u003c/p\u003e \u003cp\u003eFor tremor assessment the validated CRST \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e was used. The scale consists of three parts: tremor severity in different body parts (part A), motor task performance for both hands (part B), and subjective functional disability related to the tremor (part C). To compare the TI of the treated hand, we used a hand-specific subscore combining part A and B of the treated upper extremity (CRST\u003csub\u003etreated\u003c/sub\u003e, ranging from 0 to 28). Higher values indicated more severe tremor.\u003c/p\u003e \u003cp\u003eChanges in tremor outcome were assessed using the CRST\u003csub\u003etreated\u003c/sub\u003e and calculated using the Weber-Fechner Eq.\u0026nbsp;1\u003csup\u003e8\u003c/sup\u003e, which accounts for the logarithmic relationship between tremor rating R and tremor amplitude T = ((T\u003csub\u003ef\u003c/sub\u003e \u0026ndash; T\u003csub\u003ei\u003c/sub\u003e)/T\u003csub\u003ei\u003c/sub\u003e = 10\u003csup\u003e(α/N)*ΔR\u003c/sup\u003e \u0026ndash; 1). Hereby, T is a function of the change in tremor ratings ΔR, α is a coefficient for the 0\u0026ndash;4 scale and equals to 0.5, and N is the number of items included in the scale.\u003c/p\u003e \u003cp\u003eIn DBS and MRgFUS, tremor improvement of the contralateral extremity ranges between 40\u0026ndash;80%, given different rating methods and study protocols\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. In our cohort the mean tremor reduction after 6 months was 76%. We tried various grouping methods (50%, 60% and 70% of tremor improvement); however, only the categorization using 70% resulted in a sufficiently large group size. Therefore, we categorized patients into the higher TI group with T\u0026thinsp;\u0026ge;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;50) and the lower TI group with T\u0026thinsp;\u0026lt;\u0026thinsp;0.7 (n\u0026thinsp;=\u0026thinsp;18) according to the CRST\u003csub\u003etreated\u003c/sub\u003e score after six months (T2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eImage acquisition and analysis\u003c/h2\u003e \u003cp\u003eStandardized MR imaging according to a clinical protocol was acquired at T0 and T2 using a clinical 3-Tesla scanner (Philips Achieva TX, Best, The Netherlands) equipped with an eight-channel head coil. The protocol comprised a 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) sequence acquired with isotropic resolution of 1mm and the following parameters: TR\u0026thinsp;=\u0026thinsp;7.286ms, TE\u0026thinsp;=\u0026thinsp;3.93ms, matrix\u0026thinsp;=\u0026thinsp;256x256mm, 180 slices in total, scan time\u0026thinsp;=\u0026thinsp;4.66min.\u003c/p\u003e \u003cp\u003eAn automated artificial-intelligence (AI)-based software was used to determine quantitative analyses of the volume of different brain areas in ml. This commercially licensed MRI post-processing software named \"mdbrain\" (v4.4.1 and higher) is provided by mediaire GmbH, Berlin, Germany, which is an approved medical device manufacturer according to the European Medical Device Directive 93/42/EEC and is certified according to DIN EN ISO 13485:2016. The \"mdbrain\" software is approved as a Conformit\u0026eacute; Europ\u0026eacute;enne (CE)-marked medical device and performs automatic brain volumetry of different brain regions using native 3D T1-weighted sequences to allow quantitative statements based on an extensive population-based normative database. The algorithm and embedded normative database are trained nationwide, not limited to the experience of a single centre, and have been validated for accuracy\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The system leverages a custom deep learning segmentation model based on the U-Net architecture to perform a highly accurate side- and region-specific (e.g. lobes) rapid brain volumetry, which was trained on a heterogeneous dataset of 3D T1w images (n\u0026thinsp;=\u0026thinsp;2869, balanced m/f). Augmentation techniques (augmentation of contrast, resolution, rotation, elastic deformation) have been used to maximize the model\u0026rsquo;s applicability in daily routine. The volumetrized structures were the total brain volume (TBV), gray (GM) and white matter (WM), cortical gray matter (cGM), and the cerebellar cortex. Several cortical and subcortical brain areas were additionally assessed for each side separately as follows: frontal lobe, parietal lobe, occipital lobe, temporal lobe, caudate nucleus, putamen, pallidum and thalamus.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was carried out using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, N.Y., USA). Shapiro-Wilk test was used to evaluate the normal distribution of the data and parametric or non-parametric tests were applied according to the results. Group differences of demographical and clinical data were evaluated with the χ 2 test (sex, handedness) and the Mann-Whitney-U test or student\u0026rsquo;s t-test (age, age of onset, disease duration, total CRST score and subscores).\u003c/p\u003e \u003cp\u003eFor volumetric analysis, all acquired brain volumes were normalized to the intracranial volume (ICV) of each subject. To determine the estimated ICV, the TBV and total ventricle volume were summed up. The Wilcoxon signed-rank test or paired t-test was used to assess significant changes of brain volumes after six months. Brain volume differences between ET and PD as well as the higher and lower TI group were examined using the analysis of covariance (ANCOVA) and adjusting for age and sex. For all patients, a hierarchical multiple linear regression was used to determine the contribution of disease duration and tremor severity (clinical scores) on volumetric measurements while controlling for age and sex. Therefore, age and sex were entered in the first block. Next, disease duration and the CRST score were added as predictors. P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation and categorial variables as frequency and proportions.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eDemographical and clinical characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean age in ET (70.6 \u0026plusmn; 11.1 years) and PD (63.5 \u0026plusmn; 12.0 years) patients differed significantly (p=0.012). No statistically significant difference was found in the other demographic characteristics (i.e., sex and handedness). ET patients reported a significant younger age of onset (p=0.004) and more prolonged disease duration (p\u0026lt;0.001). Total CRST score (T0: p\u0026lt;0.001, T1: p\u0026lt;0.001, T2: p\u0026lt;0.001) and subscores (treated extremity: T0: p=0.002, T1: p=0.03; untreated extremity: T0: p\u0026lt;0.001, T1: p\u0026lt;0.001, T2: p\u0026lt;0.001) were significantly higher in ET patients, except of post-6 months subscores for the treated extremity (Fig. 1A).\u003c/p\u003e\n\u003cp\u003e39 (80%) ET patients and 11 (58%) PD patients still had a considerable TI after six months. Comparing the high and low TI group in both diseases, demographical characteristics did not differ significantly. Furthermore, CRST scores did not differ significantly except of a significant higher subscore for the treated extremity six months after MRgFUS treatment in ET patients with poor tremor response (p\u0026lt;0.001). In PD patients, the total CRST score (p=0.04) and the subscore for the treated extremity at baseline (p\u0026lt;0.001) showed significant higher values in the high TI group whereas no significant differences could be found after six months (Fig. B). Detailed demographical and clinical characteristics are given in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContribution of disease-related factors to brain volumes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHierarchical linear regression was used to determine whether disease duration or clinical scores contributed to the volumetric measurements, while controlling for sex and age. In both, ET and PD patients, no statistically significant association of the single brain volumes with disease-related factors could be detected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVolumetric Results in ET and PD patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo significant volume differences were found between ET and PD patients at baseline and after six months. Relative brain volume changes in ET and PD patients are reported in Table 2.\u003c/p\u003e\n\u003cp\u003eIn both ET and PD, the most evident reduction six months after MRgFUS treatment was present in the treated thalamus (ET: -3%, PD: -4%). The most evident increase occurred within the occipital lobe contralateral to the treated hemisphere (ET: +3%, PD: +5%). Moreover, PD patients showed a considerable reduction in the caudate nucleus volume contralateral to the treated hemisphere (-4%).\u003c/p\u003e\n\u003cp\u003eIn ET patients, we found additional significant but minor (\u0026lt; \u0026plusmn;3%) volume differences of the TBV, WM, GM, cGM, both frontal and parietal lobes, as well as the putamen and pallidum ipsilateral to the treated hemisphere six months after MRgFUS treatment. In PD, the TBV, cGM volumes as well as the parietal lobe ipsilateral and the frontal and temporal lobe contralateral to the treated hemisphere differed significantly. Furthermore, significant volume reduction was observed within the putamen of the ipsilateral hemisphere.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVolumetric Results according to TI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eET patients:\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn the higher and lower TI group, significant volume differences after six months could be found within the GM and thalamus ipsilateral to the treated hemisphere.\u003c/p\u003e\n\u003cp\u003ePatients with higher TI showed significant decreases of the ipsilateral frontal lobe, the ipsilateral pallidum and the contralateral putamen but increases in both occipital lobes. In contrast, patients with low TI showed significant volume loss of the cGM and the contralateral frontal and parietal lobe.\u003c/p\u003e\n\u003cp\u003eA considerable reduction was observed within the thalamus ipsilateral to the treated hemisphere in both subgroups (high TI: -3%, low TI: -3%). In contrast, the occipital lobe contralateral to the treated hemisphere showed significant enlargement only in the high TI subgroup (+3%) (Fig.2A, Suppl. Tbl. S1).\u003c/p\u003e\n\u003cp\u003eCompared to the high TI subgroup, significant larger volumes were found in the contralateral occipital lobe at baseline (mean difference (MD)= -0.002, p=0.02) and after six months (MD= -0.002, p=0.02) in the low TI subgroup.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePD patients:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn PD patients \u0026ndash; regardless of tremor outcome \u0026ndash; significant reductions were found in the frontal lobe contralateral to the treated hemisphere, the ipsilateral putamen and ipsilateral thalamus. The high TI group showed additional significant volume reductions of the ipsilateral parietal lobe, the contralateral temporal lobe and the contralateral pallidum. Patients with poor tremor outcome had further significant reductions of the cGM. Considerable volume reductions occurred in the ipsilateral thalamus in both groups (high TI: -3%, low TI: -4%). In the high TI group significant volume reductions were found in the ipsilateral parietal lobe (-3%), ipsilateral putamen (-3%) and contralateral pallidum (-3%). The contralateral occipital lobe showed enlargement \u0026gt;5% in both groups, but did not reach statistical significance (Fig. 2B, Suppl. Tbl. S2).\u003c/p\u003e\n\u003cp\u003eAt baseline, the higher TI group had significant smaller volumes of the ipsilateral occipital lobe (MD= -0.002, p=0.02) and ipsilateral thalamus (MD= -0.0003, p=0.03) while larger volumes were evident in the ipsilateral caudate nucleus (MD= 0.0002, p=0.02) and contralateral putamen (MD= 0.0002, p=0.04). After six months, significant differences were found only in the contralateral occipital lobe (MD= -0.002, p=0.02) and contralateral caudate nucleus (MD= 0.0001, p=0.03).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eMRgFUS is a newly developed method to treat drug-refractory tremor syndromes by selective thermal lesions of defined structures in the central nervous system. The safety and efficacy has been demonstrated in several case series and randomized trials \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Moreover, lesion characterization, the association with VIM overlap, tract disruption and clinical outcome has been investigated across numerous previous studies \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Nevertheless, to date less is known about possible whole brain volumes changes after MRgFUS thalamotomy. Bruno et al. were the first to examine brain volume changes after 12 months in 16 patients with disabling ET and 15 patients with tdPD using the same fully-automated AI-based volumetry approach as in our study: significant volume reductions of the treated thalamus and ipsilateral basal ganglia structures were noted in ET patients. Furthermore, the authors observed a significant reduction in cerebellar volumes in ET patients and raised the question whether the observed reductions could be attributed to the treatment itself or to pathological atrophy. No significant volume differences could be found in PD patients or in association with age or tremor score. With the mere of a larger caudate nucleus in ET patients, no differences were observed comparing ET and PD patients \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn line with these recently published findings, we also observed significant reductions of the treated thalamus and ipsilateral basal ganglia, which were present not only in the ET but also in the PD cohort. Although the underlying pathophysiological mechanisms in ET and PD are different, recent findings also point to certain common features involving basal ganglia and cerebellar circuits \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Besides the widely known role of the basal ganglia in the pathomechanism of PD, previous research has provided evidence of basal ganglia network hyperactivity caused by an increased excitatory output from the motor cortex (receiving increased excitatory input from the thalamus) also in ET \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. MRgFUS thalamotomy could therefore explain downregulation and subsequent volume reduction not only of the thalamus but also of basal ganglia structures.\u003c/p\u003e \u003cp\u003eIn the case of deep brain stimulation (DBS), only a few studies have also investigated structural brain volume changes after DBS. Volume reductions were observed in the caudate nucleus, pallidum, putamen, and thalamus ipsilateral to the implanted hemisphere \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In contrast, another study analyzed the brain volumes of 8 PD patients after a mean interval of 15 months following unilateral DBS implantation. This reported significant hippocampal atrophy as well as an increase in volume of the contralateral putamen and a tendency for the contralateral caudate nucleus to enlarge \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. It should be noted that the aforementioned studies had several methodological differences, such as cohort size and timing of MRI acquisition. Although the previous studies yielded divergent results, they suggest that DBS may contribute to progressive brain volume changes (especially within the basal ganglia), possibly as a result of chronic neuromodulation or Wallerian degeneration \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Nevertheless, DBS surgery was performed in PD patients regardless of their clinical phenotype (e.g., tremor dominance) and targeted the subthalamic nucleus, thus limiting comparisons with VIM-MRgFUS in tremor syndromes.\u003c/p\u003e \u003cp\u003eIn contrast to Bruno et al. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, we found no changes in cerebellar volumes. The cerebellum is thought to drive tremor activity in ET, and previous studies have reported volume losses in specific cerebellar regions such as the vermis or in ET patients with head tremor only, suggesting a heterogenous or more advanced pathological course \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. However, Bruno et al. did not provide information on the duration or severity of the disease. Less advanced disease progression could therefore be a possible reason for the differing results. Furthermore, in contrast to the reported study, we used relative volumes to investigate volume changes after MRgFUS treatment. This form of normalization to ICV has the substantial advantage of reducing interindividual variation or image distortions in serial imaging measurements. Thus, it can be assumed that the validity and comparability of the normalized whole-brain volumes obtained in our study is substantially increased.\u003c/p\u003e \u003cp\u003eInterestingly, we observed a significant increase in volumes of the contralateral occipital lobe, which was particularly significant in ET patients with higher TI. Visual association areas have been reported to be involved in tremor modulation. Tuleasca and colleagues reported several findings in structural and functional network studies supporting a link of visual association areas with tremor generation or arrest after thalamotomy. In a voxel-based morphometry analysis 1 year after left VIM radiosurgery, they reported decreased GM density in a large occipital cluster ipsilateral to the treated VIM correlating with higher TI \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Furthermore, pretherapeutic GM density levels in the right Brodmann area 18 (visual association area V2) was found to predict TI of the right treated hand \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Investigating functional changes after VIM radiosurgery, the same group observed a widespread visually-sensitive functional network in ET. Moreover, network interconnectivity strength with right visual Brodmann area 19 was found to be related with tremor arrest \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Comparisons with healthy controls also suggest normalization of interconnectivity in visual areas after radiosurgery, with patients with pretherapeutic higher functional interconnectivity within these areas showing larger benefits \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Another study investigating functional changes in ET after MRgFUS treatment reported significant lower functional connectivity in visual associated areas compared to healthy controls with partially restoration after the treatment \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Consistent with these findings, our group observed negative correlations between tremor severity and several bilateral visual processing areas in 22 patients with severe ET undergoing MRgFUS treatment (Kindler et al., manuscript under review). Furthermore, increased functional connectivity could be detected in all visual clusters six months after thalamotomy (Kindler et al., manuscript under review). Similarly, previous work suggest an involvement of visual areas in PD as well, but has often been primarily linked to visual problems in PD \u003csup\u003e\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Comparing PD patients with different phenotypes, a previous study found hyper-connectivity between the basal ganglia and visual cortex in tdPD patients suggesting a possible relation with tremor \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Supporting this thesis, an \u003csup\u003e18\u003c/sup\u003eF-FDG-PET/MRI study revealed an increased metabolic activity in the calcarine cortex after MRgFUS subthalamotomy \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Likewise, in another study spontaneous neural activity in the left occipital cortex significantly decreased in nine tdPD patients 12 months after MRgFUS thalamotomy \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Although numerous studies indicate an involvement of visual association areas in tremor modulation, the role of visual association areas is still poorly understood. One explanation is the involvement of visual areas in the sensory guidance of movements; herein, contralateral visual areas are found to be connected with the ipsilateral thalamus and motor cortex \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Another hypothesis, supported by fMRI studies in ET patients, proposes that the cerebellum acts as a mediator between visual and somatosensory/motor information \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo our knowledge, we investigated for the first time the changes in brain volume after MRgFUS thalamotomy in relation to tremor response. Our study relied on a fully automated, quantitative, and thus objective assessment of spatial clusters of brain volume abnormalities. This approach detected visually inconspicuous findings and potentially demonstrated the impact of MRgFUS on brain integrity, unlike most previous imaging studies. Both ET and PD patients with high and low TI showed decreased volumes of the ipsilateral thalamus six months after thalamotomy. In addition, enlargement of the contralateral occipital lobe was found, but reached significance only in ET patients with high TI. In PD patients with high TI, significant reductions were also observed in the basal ganglia structures (putamen, pallidum). Comparing the volumes in patients with high and poor TI, the differences within the occipital lobes as well as in the thalamus and basal ganglia at baseline and after six months might reflect a complex basal ganglia-thalamo-visuo-cortical network involved in tremor generation. Nevertheless, the volume differences did not exceed 5%. Although no contribution of tremor severity and duration was found, the observed changes could also be related to disease progression. Larger controlled studies are needed to gain further insight into the effects of MRgFUS treatment and TI on changes in subcortical and cortical brain volume.\u003c/p\u003e \u003cp\u003eSeveral limitations of this exploratory study should be noted. Brain volume changes were assessed six months after MRgFUS treatment. Therefore, further effects of possible restoration might not have been evident yet. In view of the initial volume changes shown here after only 6 months, further studies with longer follow-up periods would be of great interest. The outcome of tremor depends mainly on the size and location of the thalamotomy performed, which we did not consider separately in our analysis. Possible (partial) lesioning of adjacent networks, such as the medial lemniscus, may also cause alterations particularly in cortical structures. The aim of our study was to generally investigate potential brain volume changes after a standardized clinical MRgFUS procedure in a relatively large cohort of ET and tremor-dominant PD patients; in this respect, the observation of specific spatial patterns of brain volumetric alterations made here supports the use of brain volumetry despite possibly small interindividual differences in the ablation cavities. However, for this reason, differences in brain volumes should be interpreted with caution as pre-therapeutic prognostic factors. Although we used a fully automated segmentation approach that is approved for clinical use in accordance with CE certification, technical limitations and possible confounding factors such as slice thickness, MRI noise level, MRI orientation, field strength, and anatomic boundary criteria \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e may generally affect the results. However, the initial and follow-up MRI scans were acquired at the same MR scanner according to a standardized imaging protocol, which largely eliminates the influence of these common confounding factors mentioned above. Lastly, the categorization of patients into a lower and higher TI group using a pre-specified cut-off of 70% improvement was arbitrary and therefore may have introduced some interindividual selection bias.\u003c/p\u003e \u003cp\u003eIn conclusion, our results indicate that TI achieved by MRgFUS thalamotomy affects a complex basal ganglia-thalamo-visuo-cortical network in patients with ET and tdPD. We identified a consistent spatial pattern of brain volume changes, particularly occipital lobe enlargement contralateral to the thalamotomy side, strongly suggesting possible restorative/reshaping effects after TI. Further studies, including a dedicated control group and a longer follow-up period, would be desirable to further explore cortical changes and long-term neurological trajectories after TI. In addition, diffusion tensor imaging or functional imaging could provide additional insights into tremor generation and modulation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAC-PC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Anterior commissure to posterior commissure\u003c/p\u003e\n\u003cp\u003eAI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Artificial-intelligence\u003c/p\u003e\n\u003cp\u003eANCOVA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Analysis of covariance\u003c/p\u003e\n\u003cp\u003eCE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Conformit\u0026eacute; Europ\u0026eacute;enne\u003c/p\u003e\n\u003cp\u003ecGM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cortical gray matter\u003c/p\u003e\n\u003cp\u003eCRST \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Clinical Rating Scale for Tremor\u003c/p\u003e\n\u003cp\u003eDBS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Deep brain stimulation\u003c/p\u003e\n\u003cp\u003eET\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Essential tremor\u003c/p\u003e\n\u003cp\u003eGM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Gray matter\u003c/p\u003e\n\u003cp\u003eICV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Intracranial volume\u003c/p\u003e\n\u003cp\u003eMD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mean difference\u003c/p\u003e\n\u003cp\u003eMPRAGE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Magnetization-prepared rapid gradient-echo\u003c/p\u003e\n\u003cp\u003eMRgFUS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;MRI-guided focused ultrasound\u003c/p\u003e\n\u003cp\u003ePD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Parkinson\u0026rsquo;s disease\u003c/p\u003e\n\u003cp\u003eTBV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Total brain volume\u003c/p\u003e\n\u003cp\u003eTdPD\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Tremor dominant Parkinson\u0026rsquo;s disease\u003c/p\u003e\n\u003cp\u003eTI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Tremor improvement\u003c/p\u003e\n\u003cp\u003eUPDRS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;MDS-Unified Parkinson\u0026rsquo;s Disease Rating Scale\u003c/p\u003e\n\u003cp\u003eVIM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Ventral intermediate nucleus\u003c/p\u003e\n\u003cp\u003eWM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; White matter\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge Karolina Makowski, clinical study team assistant at University hospital of Bonn, for her support in organisation and data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHORS\u0026rsquo; ROLES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVP contributed to conception and design, data acquisition, data analysis and interpretation, drafted the manuscript and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eEP contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eVB contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eHB contributed to conception and design and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eDP contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eMS\u0026nbsp;contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eSZ\u0026nbsp;contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eAR contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eUW contributed to data acquisition and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eFCS contributed to conception and design, data acquisition, data analysis and interpretation and critically revised the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors gave their final approval and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING SOURCES AND CONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe MRgFUS system was in part funded by the German Research Foundation (INST 1172/64-1) and the University of Bonn\u0026rsquo;s Faculty of Medicine.\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest relevant to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFINANCIAL DISCLOSURES OF ALL AUTHORS (for the previous 12 months)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUW served as consultant and lecturer and on advisory boards for Bayer AG, STADA Pharm and Zambon; he received grant from the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG) and the Deutsche Parkinson Vereinigung e.V..\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChandran V, Pal PK. 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The cerebellum communicates with the basal ganglia. Nat Neurosci 2005; 8(11):1491\u0026ndash;93. https://doi.org/10.1038/nn1544.\u003c/li\u003e\n\u003cli\u003ePrasad S, Shah A, Bhalsing KS, Ingalhalikar M, Saini J, Pal PK. Clinical correlates of abnormal subcortical volumes in Essential Tremor. J Neural Transm (Vienna) 2019; 126(5):569\u0026ndash;76. https://doi.org/10.1007/s00702-019-02004-0.\u003c/li\u003e\n\u003cli\u003eTuleasca C, Najdenovska E, R\u0026eacute;gis J, et al. Clinical response to Vim\u0026apos;s thalamic stereotactic radiosurgery for essential tremor is associated with distinctive functional connectivity patterns. Acta Neurochir (Wien) 2018; 160(3):611\u0026ndash;24. https://doi.org/10.1007/s00701-017-3456-x.\u003c/li\u003e\n\u003cli\u003eKern DS, Uy D, Rhoades R, Ojemann S, Abosch A, Thompson JA. Discrete changes in brain volume after deep brain stimulation in patients with Parkinson\u0026apos;s disease. J Neurol Neurosurg Psychiatry 2020; 91(9):928\u0026ndash;37. https://doi.org/10.1136/jnnp-2019-322688.\u003c/li\u003e\n\u003cli\u003eSankar T, Li SX, Obuchi T, et al. Structural brain changes following subthalamic nucleus deep brain stimulation in Parkinson\u0026apos;s disease. Mov Disord 2016; 31(9):1423\u0026ndash;25. https://doi.org/10.1002/mds.26707.\u003c/li\u003e\n\u003cli\u003eChoi S-M, Kim BC, Chang J, et al. Comparison of the Brain Volume in Essential Tremor and Parkinson\u0026apos;s Disease Tremor Using an Automated Segmentation Method. Eur Neurol 2015; 73(5-6):303\u0026ndash;09. https://doi.org/10.1159/000381708.\u003c/li\u003e\n\u003cli\u003eShin H, Lee D-K, Lee J-M, et al. Atrophy of the Cerebellar Vermis in Essential Tremor: Segmental Volumetric MRI Analysis. Cerebellum 2016; 15(2):174\u0026ndash;81. https://doi.org/10.1007/s12311-015-0682-8.\u003c/li\u003e\n\u003cli\u003eTuleasca C, Witjas T, Najdenovska E, et al. Assessing the clinical outcome of Vim radiosurgery with voxel-based morphometry: visual areas are linked with tremor arrest! Acta Neurochir (Wien) 2017; 159(11):2139\u0026ndash;44. https://doi.org/10.1007/s00701-017-3317-7.\u003c/li\u003e\n\u003cli\u003eTuleasca C, Witjas T, van de Ville D, et al. Right Brodmann area 18 predicts tremor arrest after Vim radiosurgery: a voxel-based morphometry study. Acta Neurochir (Wien) 2018; 160(3):603\u0026ndash;09. https://doi.org/10.1007/s00701-017-3391-x.\u003c/li\u003e\n\u003cli\u003eTuleasca C, Bolton TAW, R\u0026eacute;gis J, et al. Normalization of aberrant pretherapeutic dynamic functional connectivity of extrastriate visual system in patients who underwent thalamotomy with stereotactic radiosurgery for essential tremor: a resting-state functional MRI study. J Neurosurg 2019; 132(6):1792\u0026ndash;801. https://doi.org/10.3171/2019.2.JNS183454.\u003c/li\u003e\n\u003cli\u003eTuleasca C, Najdenovska E, R\u0026eacute;gis J, et al. Ventrolateral Motor Thalamus Abnormal Connectivity in Essential Tremor Before and After Thalamotomy: A Resting-State Functional Magnetic Resonance Imaging Study. World Neurosurg 2018; 113:e453-e464. https://doi.org/10.1016/j.wneu.2018.02.055.\u003c/li\u003e\n\u003cli\u003eKato S, Maesawa S, Bagarinao E, et al. Magnetic resonance-guided focused ultrasound thalamotomy restored distinctive resting-state networks in patients with essential tremor. J Neurosurg 2023; 138(2):306\u0026ndash;17. https://doi.org/10.3171/2022.5.JNS22411.\u003c/li\u003e\n\u003cli\u003eG\u0026ouml;ttlich M, M\u0026uuml;nte TF, Heldmann M, Kasten M, Hagenah J, Kr\u0026auml;mer UM. Altered resting state brain networks in Parkinson\u0026apos;s disease. PLoS One 2013; 8(10):e77336. https://doi.org/10.1371/journal.pone.0077336.\u003c/li\u003e\n\u003cli\u003eZhang D, Liu X, Chen J, Liu B. Distinguishing Patients with Parkinson\u0026apos;s Disease Subtypes from Normal Controls Based on Functional Network Regional Efficiencies. PLoS One 2014; 9(12):e115131. https://doi.org/10.1371/journal.pone.0115131.\u003c/li\u003e\n\u003cli\u003eZhang D, Liu X, Chen J, Liu B, Wang J. Widespread increase of functional connectivity in Parkinson\u0026apos;s disease with tremor: a resting-state FMRI study. Front Aging Neurosci 2015; 7:6. https://doi.org/10.3389/fnagi.2015.00006.\u003c/li\u003e\n\u003cli\u003eHou Y, Ou R, Yang J, Song W, Gong Q, Shang H. Patterns of striatal and cerebellar functional connectivity in early-stage drug-na\u0026iuml;ve patients with Parkinson\u0026apos;s disease subtypes. Neuroradiology 2018; 60(12):1323\u0026ndash;33. https://doi.org/10.1007/s00234-018-2101-6.\u003c/li\u003e\n\u003cli\u003eRodriguez-Rojas R, Pineda-Pardo JA, Martinez-Fernandez R, et al. Functional impact of subthalamotomy by magnetic resonance-guided focused ultrasound in Parkinson\u0026apos;s disease: a hybrid PET/MR study of resting-state brain metabolism. Eur J Nucl Med Mol Imaging 2020; 47(2):425\u0026ndash;36. https://doi.org/10.1007/s00259-019-04497-z.\u003c/li\u003e\n\u003cli\u003eXiong Y, Han D, He J, et al. Correlation of visual area with tremor improvement after MRgFUS thalamotomy in Parkinson\u0026apos;s disease. J Neurosurg 2022; 136(3):681\u0026ndash;88. https://doi.org/10.3171/2021.3.JNS204329.\u003c/li\u003e\n\u003cli\u003eGlickstein M. How are visual areas of the brain connected to motor areas for the sensory guidance of movement? Trends Neurosci 2000; 23(12):613\u0026ndash;17. https://doi.org/10.1016/s0166-2236(00)01681-7.\u003c/li\u003e\n\u003cli\u003eArcher DB, Coombes SA, Chu WT, et al. A widespread visually-sensitive functional network relates to symptoms in essential tremor. Brain 2018; 141(2):472\u0026ndash;85. https://doi.org/10.1093/brain/awx338.\u003c/li\u003e\n\u003cli\u003eTuleasca C, R\u0026eacute;gis J, Najdenovska E, et al. Visually-sensitive networks in essential tremor: evidence from structural and functional imaging. Brain 2018; 141(6):e47. https://doi.org/10.1093/brain/awy094.\u003c/li\u003e\n\u003cli\u003eCerasa A, Messina D, Nicoletti G, et al. Cerebellar atrophy in essential tremor using an automated segmentation method. AJNR Am J Neuroradiol 2009; 30(6):1240\u0026ndash;43. https://doi.org/10.3174/ajnr.A1544.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"tremor, thalamotomy, brain volumes, MRgFUS","lastPublishedDoi":"10.21203/rs.3.rs-3716028/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3716028/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMagnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy is a recently developed technique for treatment of severe tremor syndromes. Less is known about potential cortical and subcortical structural changes after ablation of the ventral intermediate nucleus and how these are potentially related to tremor relief.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eUsing an automated artificial-intelligence based approach, cortical and subcortical brain volume changes were investigated in 49 patients with essential tremor (ET) and 19 patients with tremor-dominant Parkinson\u0026rsquo;s disease (tdPD) before and six months after MRgFUS. Clinical outcome was assessed using the Clinical Rating Scale for Tremor. To evaluate differences in brain volumes, patients were further categorized into a high and low tremor improvement (TI) group.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBrain volumes did not differ significantly between ET and tdPD patients at baseline. In both entities, significant volume reductions were found in the thalamus treated with thalamotomy along with volume increases in the occipital lobe contralateral to the MRgFUS lesion. Furthermore, significant differences between high and low TI groups were found in the contralateral occipital lobe in both entities, and in the contralateral caudate nucleus in tdPD patients. A significant volume reduction was found in tdPD patients with high TI in ipsilateral parietal lobe, ipsilateral putamen, and contralateral pallidum.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOur results indicate that TI achieved by MRgFUS thalamotomy affects a complex basal ganglia-thalamo-visuo-cortical network in patients with ET and tdPD. We identified a consistent spatial pattern of brain volume changes, particularly occipital lobe enlargement contralateral to the thalamotomy side, strongly suggesting possible restorative/reshaping effects after TI.\u003c/p\u003e","manuscriptTitle":"Brain volume changes after MR-guided focused ultrasound thalamotomy in patients with essential tremor and Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 19:57:59","doi":"10.21203/rs.3.rs-3716028/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2ea67041-2bc7-4098-aaa3-3e3ee50f9bdf","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":27802346,"name":"Health sciences/Neurology/Neurological disorders/Movement disorders/Parkinson's disease"},{"id":27802347,"name":"Biological sciences/Neuroscience/Computational neuroscience/Learning algorithms"},{"id":27802348,"name":"Health sciences/Diseases/Neurological disorders/Neurodegenerative diseases/Parkinson's disease"},{"id":27802349,"name":"Health sciences/Medical research/Outcomes research"}],"tags":[],"updatedAt":"2024-03-21T05:21:13+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-02 19:57:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3716028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3716028","identity":"rs-3716028","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}