Association of Gene Expression and Tremor Network Structure.

BACKGROUND: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated. OBJECTIVE: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET. METHODS: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55). RESULTS: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006). CONCLUSIONS: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Smaller Cerebellar Lobule VIIb is Associated with Tremor Severity in Parkinson's Disease.

Alterations in the cerebellum's morphology in Parkinson's disease (PD) point to its pathophysiological involvement in this movement disorder. Such abnormalities have previously been attributed to different PD motor subtypes. The aim of the study was to relate volumes of specific cerebellar lobules to motor symptom severity, in particular tremor (TR), bradykinesia/rigidity (BR), and postural instability and gait disorders (PIGD) in PD. We performed a volumetric analysis based on T1-weighted MRI images of 55 participants with PD (22 females, median age 65 years, Hoehn and Yahr stage 2). Multiple regression models were fitted to investigate associations between volumes of cerebellar lobules with clinical symptom severity based on MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score and sub-scores for TR, BR, and PIGD; adjusted for age, sex, disease duration, and intercranial volume as cofactors. Smaller volume of lobule VIIb was associated with higher tremor severity (P = 0.004). No structure-function relationships were detected for other lobules or other motor symptoms. This distinct structural association denotes the involvement of the cerebellum in PD tremor. Characterizing morphological features of the cerebellum leads to a better understanding of its role in the spectrum of motor symptoms in PD and contributes further to identifying potential biological markers.

Cerebellar and cerebral white matter changes in Parkinson's disease with resting tremor.

PURPOSE: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI). METHODS: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed. RESULTS: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR. CONCLUSION: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD.

Histogram analysis of diffusion kurtosis imaging of deep brain nuclei in Parkinson's disease with different motor subtypes.

AIM: To evaluate the diagnostic and differential efficacy of diffusion kurtosis imaging (DKI) histogram analysis for different motor subtypes of Parkinson's disease (PD). MATERIALS AND METHODS: Seventy PD patients including 40 with postural instability and gait disorder (PIGD) and 30 with tremor-dominant (TD) and 36 healthy controls (HC) were enrolled prospectively and underwent MRI examinations. The regions of interest (ROI) in the deep brain nuclei were delineated and features were extracted on the map of mean kurtosis (MK), axial kurtosis (Ka), and radial kurtosis (Kr), respectively. The differences in histogram features between PD patients and HC and between patients with PIGD and TD were compared. The areas under the curve (AUCs) were calculated to evaluate the diagnostic efficacy of all histogram features. The correlations between histogram features and clinical indicators were evaluated. RESULTS: Some DKI histogram features were significantly different between PD patients and HC, and also different between patients with PIGD and TD (all p<0.05). MK of the substantia nigra pars reticulate (SNprkurtosis), Ka of the substantia nigra pars compacta (SNpc) 50 percentile (SNpcP50), and Kr of SNpc 90th percentile showed the highest AUC for distinguishing patients with PIGD from HC. MK-SNpc 10th percentile, Ka-SNpc 25th percentile, and Kr of the head of the caudate nucleus (CN) 90th percentile had the highest AUC for distinguishing patients with TD from HC. MK of the putamen 10th percentile combined with Ka of the bilateral red nucleus RNkurtosis yielded the highest diagnostic performance with an AUC of 0.762 for distinguishing patients with PIGD from TD. Certain DKI histogram features were correlated with Hoehn-Yahr (H&Y) stage, Mini Mental State Examination (MMSE) score, tremor score, and PIGD score (all p<0.05). CONCLUSION: DKI histogram analysis was useful to diagnose and discriminate different motor subtypes of PD. Certain DKI histogram features correlated with clinical indicators.

Initiating a Magnetic Resonance-Guided Focused Ultrasound Program: Comprehensive Workflow and Lessons Learned from the Initial 116 Cases.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) represents an incisionless treatment option for essential or parkinsonian tremor. The incisionless nature of this procedure has garnered interest from both patients and providers. As such, an increasing number of centers are initiating new MRgFUS programs, necessitating development of unique workflows to optimize patient care and safety. Herein, we describe establishment of a multi-disciplinary team, workflow processes, and outcomes for a new MRgFUS program. METHODS: This is a single-academic center retrospective review of 116 consecutive patients treated for hand tremor between 2020 and 2022. MRgFUS team members, treatment workflow, and treatment logistics were reviewed and categorized. Tremor severity and adverse events were evaluated at baseline, 3, 6, and 12 months post-MRgFUS with the Clinical Rating Scale for Tremor Part B (CRST-B). Trends in outcome and treatment parameters over time were assessed. Workflow and technical modifications were noted. RESULTS: The procedure, workflow, and team members remained consistent throughout all treatments. Technique modifications were attempted to reduce adverse events. A significant reduction in CRST-B score was achieved at 3 months (84.5%), 6 months (79.8%), and 12 months (72.2%) post-procedure (p < 0.0001). The most common post-procedure adverse events in the acute period (<1 day) were gait imbalance (61.1%), fatigue and/or lethargy (25.0%), dysarthria (23.2%), headache (20.4%), and lip/hand paresthesia (13.9%). By 12 months, the majority of adverse events had resolved with a residual 17.8% reporting gait imbalance, 2.2% dysarthria, and 8.9% lip/hand paresthesia. No significant trends in treatment parameters were found. CONCLUSIONS: We demonstrate the feasibility of establishing an MRgFUS program with a relatively rapid increase in evaluation and treatment of patients while maintaining high standards of safety and quality. While efficacious and durable, adverse events occur and can be permanent in MRgFUS.

Mapping Pharmacologically Evoked Neurovascular Activation and Its Suppression in a Rat Model of Tremor Using Functional Ultrasound: A Feasibility Study.

Functional ultrasound (fUS), an emerging hemodynamic-based functional neuroimaging technique, is especially suited to probe brain activity and primarily used in animal models. Increasing use of pharmacological models for essential tremor extends new research to the utilization of fUS imaging in such models. Harmaline-induced tremor is an easily provoked model for the development of new therapies for essential tremor (ET). Furthermore, harmaline-induced tremor can be suppressed by the same classic medications used for essential tremor, which leads to the utilization of this model for preclinical testing. However, changes in local cerebral activities under the effect of tremorgenic doses of harmaline have not been completely investigated. In this study, we explored the feasibility of fUS imaging for visualization of cerebral activation and deactivation associated with harmaline-induced tremor and tremor-suppressing effects of propranolol. The spatial resolution of fUS using a high frame rate imaging enabled us to visualize time-locked and site-specific changes in cerebral blood flow associated with harmaline-evoked tremor. Intraperitoneal administration of harmaline generated significant neural activity changes in the primary motor cortex and ventrolateral thalamus (VL Thal) regions during tremor and then gradually returned to baseline level as tremor subsided with time. To the best of our knowledge, this is the first functional ultrasound study to show the neurovascular activation of harmaline-induced tremor and the therapeutic suppression in a rat model. Thus, fUS can be considered a noninvasive imaging method for studying neuronal activities involved in the ET model and its treatment.

Closing the loop: Novel quantitative fMRI approach for manipulation of the sensorimotor loop in tremor.

Tremor is thought to be an effect of oscillatory activity within the sensorimotor network. To date, the underlying pathological brain networks are not fully understood. Disentangling tremor activity from voluntary motor output and sensorimotor feedback systems is challenging. To better understand the intrinsic sensorimotor fingerprint underlying tremor, we aimed to disentangle the sensorimotor system into driving (motor) and feedback/compensatory (sensory) neuronal involvement, and aimed to pinpoint tremor activity in essential tremor (ET) and tremor-dominant Parkinson's disease (PD) with a novel closed-loop approach. Eighteen ET patients, 14 tremor-dominant PD patients, and 18 healthy controls were included. An MR-compatible wrist manipulator was employed during functional MRI (fMRI) while muscle activity during (in)voluntary movements was concurrently recorded using electromyography (EMG). Tremor was quantified based on EMG and correlated to brain activity. Participants performed three tasks: an active wrist motor task, a passive wrist movement task, and rest (no wrist movement). The results in healthy controls proved that our experimental paradigm activated the expected motor and sensory networks separately using the active (motor) and passive (sensory) task. ET patients showed similar patterns of activation within the motor and sensory networks. PD patients had less activity during the active motor task in the cerebellum and basal ganglia compared to ET and healthy controls. EMG showed that in ET, tremor fluctuations correlated positively with activity in the inferior olive region, and that in PD tremor fluctuations correlated positively with cerebellar activity. Our novel approach with an MR-compatible wrist manipulator, allowed to investigate the involvement of the motor and sensory networks separately, and as such to better understand tremor pathophysiology. In ET sensorimotor network function did not differ from healthy controls. PD showed less motor-related activity. Focusing on tremor, our results indicate involvement of the inferior olive in ET tremor modulation, and cerebellar involvement in PD tremor modulation.

Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome in Patients with Cerebellar Ataxia in Japan.

The presence of fragile X mental retardation 1 (FMR1) premutation has been linked to patients with a certain type of cerebellar ataxia, the fragile X-associated tremor/ataxia syndrome (FXTAS). However, its prevalence in Japan has yet to be clarified. The aim of the present study is to determine the prevalence of FXTAS in Japanese patients with cerebellar ataxia and to describe their clinical characteristics. DNA samples were collected from 1328 Japanese patients with cerebellar ataxia, referred for genetic diagnosis. Among them, 995 patients with negative results for the most common spinocerebellar ataxia subtypes were screened for FMR1 premutation. Comprehensive clinical and radiological analyses were performed for the patients harbouring FMR1 premutation. We herein identified FMR1 premutation from one female and two male patients, who satisfied both clinical and radiological criteria of FXTAS (0.3%; 3/995) as well. Both male patients presented with high signal intensity of corticomedullary junction on diffusion-weighted magnetic resonance imaging, a finding comparable to that of neuronal intranuclear inclusion disease. The female patient mimicked multiple system atrophy in the early stages of her disease and developed aseptic meningitis with a suspected immune-mediated mechanism after the onset of FXTAS, which made her unique. Despite the lower prevalence rate in Japan than the previous reports in other countries, the present study emphasises the necessity to consider FXTAS with undiagnosed ataxia, regardless of men or women, particularly for those cases presenting with similar clinical and radiological findings with multiple system atrophy or neuronal intranuclear inclusion disease.

White matter alterations in familial cortical myoclonic tremor with epilepsy type 1.

OBJECTIVE: Although previous imaging studies have reported cerebellar gray matter loss in patients with familial cortical myoclonic tremor with epilepsy (FCMTE), the corresponding white matter alterations remain unknown. We investigated white matter structural changes in FCMTE1 and compared them with clinical and electrophysiological features. METHODS: We enrolled 36 patients carrying heterozygous pathogenic intronic pentanucleotide insertions in the SAMD12 gene and 52 age- and sex-matched healthy controls. Diffusion tensor imaging-derived metrics, including fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated along with white matter voxel-based morphometry (VBM) analysis. We also examined correlations between magnetic resonance metrics and clinical and electrophysiological features. RESULTS: We detected widespread white matter reductions in MD, RD, and AD values in FCMTE1 patients, including in the commissural, projection, and association fibers. VBM analysis revealed that increases in white matter volume predominantly occurred in the right cerebellum and sagittal stratum. MD, RD, AD, and VBM analysis clearly indicated changes in the sagittal stratum. We found a positive correlation between VBM values in the right cerebellum and somatosensory-evoked potential P25-N33 amplitude. Decreased MD and AD values in the right sagittal stratum were detected in patients with versus without photophobia. SIGNIFICANCE: FCMTE is a network disorder involving a wide range of cortical and subcortical structures, including the cerebellum, thalamus, thalamocortical connections, and corticocortical connections. The right sagittal stratum is closely related with visual symptoms, especially photophobia. Our findings indicate that cerebellum and cortical hyperexcitability are closely linked, and emphasize the important role of the cerebellum in the pathophysiological mechanisms of cortical tremor.

Tremor-like grasp phenomenon: case series study.

OBJECTIVE: Tremor-like movements in patients with the grasp phenomenon are reported rarely. METHODS: We clinically and neuroradiologically studied four patients with tremor-like movements related to the grasp phenomenon. RESULTS: All of the patients were women aged between 61 and 98 years. In the present cases, tremor-like movements were observed in the right arm and/or leg. The movements occurred suddenly in three of the patients and chronically in one. The movements were stereotypic, often rhythmical, tremor-like, and accompanied with groping or picking-like movements. All of the patients displayed the grasp phenomenon, including grasp reflex and/or instinctive grasping reaction ipsilateral to the movements. Two patients had a recent broad infarct ipsilateral to the movements. One patient had meningioma contralateral to the movements, which had been surgically resected. The other patient did not have any radiologically proven cerebral lesions, although she had a history of focal seizures contralateral to the movements. CONCLUSIONS: It was suggested that their abnormal movements were closely related to the grasp phenomenon. We concluded that their characteristic tremor-like movements, a "tremor-like grasp phenomenon," was a variation of the grasp phenomenon that was due to hyperexcitation of the frontal lobe contralateral to the movements.

Bilateral ballism as limb-shaking transient ischemic attacks treated with unilateral carotid artery stent placement.

Bilateral limb-shaking transient ischemic attack (LS-TIA) is a rare disease involving carotid artery stenosis, characterized by ballism-like involuntary movements of the arms and legs. We describe the case report of a male patient in his 80s presented with continuous bilateral ballism in the arms and legs and tongue dyskinesia. Magnetic resonance imaging showed no ischemic lesions, while cerebral angiography revealed right internal carotid artery (ICA) occlusion and 80% stenosis of the left ICA. 99mTc-ethyl cysteinate dimer single-photon emission computed tomography demonstrated hypoperfusion in the right cerebral cortex but hyperperfusion in both basal ganglia. Left ICA stenting was performed, and involuntary limb shaking disappeared. This case report highlights the importance of accurate diagnosis and treatment of bilateral ballism as LS-TIA.

[First experience of thalamotomy by focused ultrasound under MR-guided navigation in the treatment of tremor. Neuroimaging follow-up. Case report and literature review]. / Pervyi opyt talamotomii fokusirovannym ul'trazvukom s MRT-navigatsiei pri lechenii tremora. Neirovizualizatsiya v dinamike. Klinicheskoe nablyudenie i obzor literatury.

The authors describe dynamic MRI and clinical data after non-invasive treatment of tremor in the upper extremity. Thalamotomy by high-intensity focused ultrasound under MR-guided navigation was performed. A 57-year-old patient with Parkinson's disease underwent treatment with focused ultrasound. MRI of the brain was performed 1 and 48 hours, 47 days, 3 and 6 months later. Features of natural course of focal brain changes after treatment, data of MR tractography necessary for correction of target zone are described. The authors conclude that MR changes are characterized by presence of a focus in the area of focused exposure. Peak severity is observed on the second day after procedure with subsequent regression. MR-based analysis of predictors is promising to forecast treatment outcomes.

Preserved noradrenergic function in Parkinson's disease patients with rest tremor.

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had 11C-methylreboxetine(11C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline terminal function was relatively preserved in PDT+ compared to PDT-. METHODS: Sixty-five PD patients and 28 healthy controls (HC) were scanned with 11C-MeNER PET. Patients were categorized as PDT+ if subscores in UPDRS-III item 3 or MDS-UPDRS-III item 17 was ≥2; remaining were categorized as PDT-. Simplified reference tissue model 2 distribution volume ratios (DVR) for 11C-MeNER were calculated for thalamus, dorsal and median raphe, locus coeruleus (LC) and red nucleus using time activity curves (TACs) obtained from volumes of interest (VOI). Data were statistically interrogated with a general linear mixed model using 'region', and 'group' as factors and the interaction of 'region x group' was examined. RESULTS: Tremor positive PD patients had a significantly higher mean 11C-MeNER DVR compared to PDT- in LC and thalamus. The PDT+ mean LC DVR was similar to that of HC. PDT+ mean 11C-MeNER DVRs were significantly lower than HC in the dorsal raphe while the PDT- group showed significantly lower mean 11C-MeNER DVR across all regions compared to HC. CONCLUSION: While both PD T+ and PD T- groups showed a significant loss of noradrenaline terminal function compared to controls, noradrenergic neurons were relatively preserved in PDT+ in LC and thalamus. The greater loss of noradrenergic transporters in PDT- in LC and thalamus compared with PDT+ is in line with earlier in-vitro studies and could potentially contribute to their tremor negative phenotype.

Post-stroke palatal tremor as a clinical predictor of dysphagia and its neuroanatomical correlates in patients with midbrain and pontine lesions.

The precise associations between dysphagia and palatal tremor (PT) remain unknown. We aimed to identify the association between PT and dysphagia among patients with midbrain/pontine stroke, compare the characteristics of dysphagia between patients with PT (PT + dysphagia) and without PT (PT- dysphagia), and verify neuroanatomical predictors of PT + dysphagia in this patient population. This retrospective observational study enrolled 40 patients (34 males, 6 females; mean age: 95% confidence interval [CI], 56.6 ± 14.6 years) with first-ever midbrain or pontine stroke exhibiting brain stem lesions admitted to the stroke unit of a single rehabilitation hospital between January 2010 and April 2020. Main outcome measures included dysphagia and aspiration rates and videofluoroscopic swallowing study findings. Lesion localization was stratified according to established vascular territories. Associations between PT and dysphagia and lesion location according to PT and dysphagia were analyzed. Dysphagia and aspiration rates were greater among patients with PT than among those without PT (95% CI, p = 0.030 and p = 0.017, respectively). The proportion of patients exhibiting oral stage impairment (95% CI, p = 0.007) was greater in the PT + dysphagia group than in the PT- dysphagia group. The posterolateral portion of the midbrain and pons (95% CI, p = 0.001 and p < 0.001, respectively) were the lesions more often involved in the PT + dysphagia group. Patients with PT following midbrain/pontine stroke more frequently present with dysphagia than those without PT. Thus, they should be carefully examined for PT and delayed dysphagia, including oral stage impairment, if initial brain images show posterolateral midbrain and pons lesions.

Study on the pathogenesis of Holmes tremor by multimodal 3D medical imaging: case reports of three patients.

BACKGROUND: We examined for the first time the imaging characteristics of Holmes tremor (HT) through multimodal 3D medical imaging. CASE PRESENTATION: Three patients with Holmes tremor who visited the Affiliated Hospital of Chengdu University of TCM from August 2018 to April 2021 were retrospectively investigated to summarize their clinical and imaging data. RESULTS: Holmes tremor in two of the three patients was caused by hypertensive cerebral hemorrhage and in the third patient induced by hemorrhage due to ruptured brain arteriovenous malformations. HT occurred 1 to 24 months after the primary disease onset and manifested as a tremor in the contralateral limb, mostly in the upper portion. Cranial MRI showed that the lesions involved the thalamus in all three patients. The damaged thalamic nuclei included the ventral anterior nucleus, ventral lateral nucleus and ventromedial lateral nucleus, and the damaged nerve fibers included left thalamocortical tracts in one patient. In the other two patients, the damaged thalamic nuclei included the centromedian and dorsomedial nucleus, and the damaged nerve fibers included left cerebellothalamic and thalamocortical tracts. One patient showed significant improvement after treatment with pramipexole while the other two patients exhibited a poor response, one of whom had no response to the treatment with pramipexole and was only significantly relieved by clonazepam. CONCLUSION: We used multimodal 3D medical imaging for the first time to analyze the pathogenesis of HT and found that multiple thalamic nuclei were damaged. The damaged nuclei and nerve fiber tracts of two patients were different from those of the third patient, with different clinical manifestations and therapeutic effects. Therefore, it is speculated that there may be multiple pathogeneses for HT.

The Molecular Neuroimaging of Tremor.

PURPOSE OF REVIEW: Tremor is a hyperkinetic movement disorder most commonly encountered in essential tremor (ET) and Parkinson's disease (PD). The purpose of this review is to summarize molecular neuroimaging studies with major implications on pathophysiological and clinical features of tremor. RECENT FINDINGS: Oscillatory brain activity responsible for tremor manifestation is thought to originate in a cerebello-thalamo-cortical network. Molecular neuroimaging has helped clarify metabolic aspects and neurotransmitter influences on the main tremor network. In ET, recent positron emission tomography (PET) studies are built on previous knowledge and highlighted the possibility of investigating metabolic brain changes after treatments, in the attempt to establish therapeutic biomarkers. In PD, molecular neuroimaging has advanced the knowledge of non-dopaminergic determinants of tremor, providing insights into serotonergic and noradrenergic contributions. Recent advances have greatly extended the knowledge of tremor pathophysiology and it is now necessary to translate such knowledge in more efficacious treatments for this symptom.

Different functional connectivity modes of the right fronto-insular cortex in akinetic-rigid and tremor-dominant Parkinson's disease.

BACKGROUND: Patients with akinetic-rigid Parkinson's disease (AR-PD) are more prone to cognitive decline and depressive symptoms than tremor-dominant PD (TD-PD) patients. The right fronto-insular cortex (rFIC), as a key node of salience network, plays a critical role in the switching between central executive network and default mode network. In this study, we explored the functional connectivity mode of rFIC with triple-brain networks, namely default mode network, salience network, and central executive network, in two motor subtypes of PD. METHODS: We recruited 44 PD patients (including the TD-PD group and AR-PD group) and 18 age-matched healthy controls (HCs). We performed functional connectivity (FC) analysis of resting-state functional MRI. RESULTS: Compared with TD-PD, decreased FC were found in the right insular cortex and bilateral anterior cingulate gyrus in AR-PD. Compared with HCs, decreased FC in the bilateral insula, the anterior cingulate gyrus, the precentral gyrus, and the right medial frontal gyrus were found; therein, the FC value of rFIC-precentral gyrus was positively correlated with the Unified Parkinson's Disease Rating Scale-II score in AR-PD (p = 0.0482, r = 0.4162). While TD-PD showed decreased FC in the left insula as well as bilateral anterior cingulate gyrus when compared with HCs, and the FC value of the rFIC-left insula was positively correlated with its Hamilton Depression Rating Scale score (p = 0.02, r = 0.50). CONCLUSION: The functional connectivity mode of rFIC in AR-PD differed from that in TD-PD. The decreased rFIC FC with the other nodes of salience network might be a potential indicator for AR-PD patients prone to develop cognitive decline and depressive symptoms.

The Brain Connectome after Gamma Knife Radiosurgery of the Ventro-Intermediate Nucleus for Tremor: Marseille-Lausanne Radiobiology Study Protocol.

Essential tremor (ET) is the most common movement disorder. Deep brain stimulation is the current gold standard for drug-resistant tremor, followed by radiofrequency lesioning. Stereotactic radiosurgery by Gamma Knife (GK) is considered as a minimally invasive alternative. The majority of procedures aim at the same target, thalamic ventro-intermediate nucleus (Vim). The primary aim is to assess the clinical response in relationship to neuroimaging changes, both at structural and functional level. All GK treatments are uniformly performed in our center using Guiot's targeting and a radiation dose of 130 Gy. MR neuroimaging protocol includes structural imaging (T1-weighted and diffusion-weighted imaging [DWI]), resting-state functional MRI, and 18F-fluorodeoxyglucose-positron emission tomography. Neuroimaging changes are studied both at the level of the cerebello-thalamo-cortical tract (using the prior hypothesis based upon Vim's circuitry: motor cortex, ipsilateral Vim, and contralateral cerebellar dentate nucleus) and also at global brain level (no prior hypothesis). This protocol aims at using modern neuroimaging techniques for studying Vim GK radiobiology for tremor, in relationship to clinical effects, particularly in ET patients. In perspective, using such an approach, patient selection could be based upon a specific brain connectome profile.

Gamma Knife Thalamotomy for a Medically Refractory Tremors: Longitudinal Evaluation of Clinical Effects and MRI Response Patterns.

OBJECTIVE: The present longitudinal study evaluated the results of Gamma Knife surgery (GKS) for medically refractory tremors. METHODS: The outcome after Gamma Knife thalamotomy targeting the ventral intermediate nucleus (VIM) was analyzed in 17 patients (9 men and 8 women; mean age 72 years) with either Parkinson's disease or an essential tremor, who were followed up for at least 2 years after treatment. Clinical and magnetic resonance imaging (MRI) examinations were done before and every 3 months after GKS. RESULTS: The mean rates of symptom improvement (a decrease in the tremor frequency) were 6%, 39%, 63%, and 64% at 3, 6, 12, and 24 months after treatment, respectively. The defined MRI response patterns included a minimum reaction (in 3 patients), a normal reaction (in 11 patients), and a hyperreaction (in 3 patients). They were not associated with any evaluated pretreatment, radiosurgical, or outcome parameter, although 2 patients with a hyperreaction exhibited mild-to-moderate motor weakness in the contralateral limbs. Linear contrasting of the border between the thalamus and the internal capsule adjacent to the lesion site was noted on follow-up MRI in 13 cases and was associated with a higher symptom improvement rate. CONCLUSION: GKS allows effective and safe management of medically refractory tremors. The treatment is characterized by variable MRI response patterns. Some imaging findings during follow-up may be associated with clinical effects.

Long-Term Outcome and Neuroimaging of Deep Brain Stimulation in Holmes Tremor: A Case Series.

BACKGROUND: Different deep brain stimulation (DBS) targets have been suggested as treatment for patients with pharmacologically refractory Holmes tremor (HT). We report the clinical and quality of life (QoL) long-term (up to nine years) outcome in four patients with HT treated with DBS (in thalamic ventral intermediate nucleus-VIM or in dentato-rubro-thalamic tract-DRTT). MATERIALS AND METHODS: The patients underwent routine clinical evaluations before and after DBS (typically annually). Tremor severity and activities of daily living (ADL) were quantified by the Fahn-Tolosa-Marin Tremor-Rating-Scale (FTMTRS). QoL was assessed using the RAND SF-36-item Health Survey (RAND SF-36). In addition, we computed, in all four patients, the VTA based on the best stimulation settings using heuristic approaches included in the open source toolbox LEAD-DBS. RESULTS: In all patients, tremor and ADL improved significantly at one-year post-DBS follow-up (34-61% improvement in FTMTRS total score compared to baseline). In three out of four patients, the improvement of tremor was sustained no longer than two to three years and only in one patient was sustained up to nine years. In this patient, the largest intersection between VTA and DBS target has been observed. Scores for ADL deteriorated over the course of time, reaching worse levels compared to baseline already during the three-year post-DBS follow-up, in three out of four patients. Physical and mental health component scores of RAND SF-36 had very different outcome between patients and follow-ups and were not associated with tremor-related outcomes. CONCLUSIONS: The benefits of DBS in HT might not be always long lasting. Although QoL slightly improved, this change seemed to be independent of the motor outcome following DBS. The estimation of DBS target and VTA proximity could be a useful tool for DBS clinicians in order to facilitate the DBS programming process and optimize DBS treatment.