Neuromodulation Mechanism Of MRgFUS Thalamotomy For The Treatment Of Tremor-related Disorders

Objective:Tremor is a common and very disabling symptom in essential tremor(ET)patients and Parkinson’s disease(PD)patients.Transcranial magnetic resonance imaging-guided focused ultrasound thalamotomy of the ventral intermediate nucleus(VIM-MRgFUS)is a novel minimally invasive treatment for medically-refractory tremor.This study aimed to(1)assess the clinical efficacy of unilateral VIM-MRgFUS in the treatment of ET and tremor-dominant PD,and analyze the characterization of radiological and volumetric aspects of the MRgFUS thalamic lesion;(2)evaluate the effects of VIM-MRgFUS on local fluctuations in neuronal activity as measured by the fractional amplitude of low-frequency fluctuations(fALFF)in patients with PD;(3)explore the accuracy and the predictive value of T-VIM by combining tractography and resting-state functional connectivity techniques in VIM-MRgFUS in treating Parkinson’s disease(PD);(4)establish a disease-specific network associated with the therapeutic effects of VIM-MRgFUS on ET and investigate its regional characteristics and genetic signatures to gain insights into the neurobiological mechanism of ET and MRgFUS thalamotomy.Methods:A total of 25 patients with ET and 10 patients with tremor-dominant PD were prospectively and consecutively included in this study,who underwent unilateral VIMMRgFUS in Chinese PLA general hospital from January 2019 to August 2021,and finished a postoperative follow up for 6 months and 1 year,respectively.Clinical assessments were performed before treatment,and 1 month,3 months,6 months,and 1 year after treatment using the clinical rating scale for tremor(CRST).Multimodal neuroimaging data were acquired before treatment,and 24 hours,1 week,1 month,3 months,6 months,and 1 year after treatment,including T2 weighted images(T2WI),diffusion weighted images(DWI),susceptibility weighted imaging(SWI),high-resolution three-dimensional T1 weighted images(T1WI),resting-state functional MRI images(rs-fMRI)and diffusion tensor images(DTI).For the purpose(1),methods are as follows:we analyzed the tremor scores before and after treatment using Wilcoxon signed-rank tests,and investigated the relationship between skull density ratio(SDR)and therapeutic parameters using spearman rank correlation.T2WI,DWI and SWI acquired at multiple time points were used to observe the radiological and volumetric aspects of the MRgFUS thalamic lesion.For the purpose(2),methods are as follows:rs-fMRI data of PD patients were processed using fALFF approach.A whole-brain voxel wise paired t-test was used to identify significant changes in fALFF at 12 months after treatment compared to baseline.Then fALFF in the regions with significant differences were extracted from fALFF maps of patients for further one-way repeated-measures ANOVA to investigate its dynamic alterations.The association between fALFF changes induced by thalamotomy and tremor improvement were evaluated using the nonparametric Spearman rank test.For the purpose(3),methods are as follows:T-VIM and Surgical VIM(S-VIM)were defined on preoperative DTI and the post 24-hour T1WI,respectively.The overlapping volume and center distance between S-VIM and T-VIM were measured to determine their correlation with postoperative 12-month tremor improvement.Then,the pretherapeutic functional connectivity of T-VIM or S-VIM based on region-of-interest connectivity and whole-brain seed-to-voxel connectivity were measured by the resting-state functional connectivity technique to investigate their correlation with tremor improvement.For the purpose(4),methods are as follows:rs-fMRI data of ET patients at baseline and postoperative 6-month was processed to measure fALFF.Ordinal trends canonical variates analysis(OrT/CVA)was performed on the within-subject fALFF data to identify a distinct ET-related network.Regional characteristics analyses were performed based on atlasand voxel-wise approaches.Genetic functional enrichment analysis was conducted to study the genetic signatures using brain-wide gene expression data,and further clarified using in vivo nuclear imaging derived neurotransmitter data.Results:All 35 patients experienced significant tremor improvement immediately following VIM-MRgFUS.Among the 10 patients with PD,one patient lost follow up after 1 week,the remaining 9 PD patients had a median treated hand tremor score of 3.00,4.00,3.00 at 1 month,3 months and 1 year after treatment,respectively.Compared to the preoperative score,the treated hand tremor was improved by a median of 14.00(P<0.01)at 1 month,14.00 at 3 months(P<0.05),and 13.00 at 1 year(P<0.01).Tremor score in the treated hand of ET patients at baseline(median 20.00;25 patients)improved by a median of 18.50 at 1 month(24 patients;P<0.001),18.00 at 3 months(22 patients;P<0.001),and 16.00 at 6 months(25 patients;P<0.001).No persistent severe adverse events were reported after unilateral VIMMRgFUS.The most common adverse events after treatment were balance disturbance and paresthesia.SDR was significantly negatively correlated with the average maximum delivered energy(Spearman Rho=-0.70,P<0.001),the average measured power(Spearman Rho=0.66,P<0.001),and the duration for each sonication(Spearman Rho=-0.63,P<0.001),but positively correlated with the temperature rise per unit energy(Spearman Rho=0.70,P<0.001).Within 24 hours after surgery,T2WI showed three concentric zones at the site of the focal spot,DWI showed a ring-like high signal or a punctate or circular high signal in the lesioning site.At 1 week after treatment,all thalamic lesions enlarged.After that,thalamic lesions gradually shrunk.At 6 months,most thalamic lesions were no longer detectable on T2WI,but still can be identified as a low signal point on DWI.At 6 months and 1 year after treatment,all lesions can be identified on SWI.Volumetric analysis showed that the lesion reached a maximum volume at 1 week after treatment,then shrank after that.Whole-brain voxel-based analysis on the fALFF of PD patients showed that fALFF in the left occipital cortex(Brodmann area 17,BA17)significantly decreased at 12 months after thalamotomy compared to baseline(voxel P<0.001,cluster P<0.05 FWE corrected).At baseline,fALFF in the left occipital BA17 in PD patients was elevated compared with that in age-and gender-matched healthy subjects(P<0.05).Longitudinal analysis displayed the dynamic changes of fALFF in this region(F(5,40)=3.61,P=0.009).There was a significant positive correlation between the falling trend in fALFF in the left occipital BA17 and PD tremor improvement after treatment over time points(Spearman Rho=0.44,P=0.02).Both overlapping volume and center distance between T-VIM and SVIM were significantly correlated with PD tremor improvement(overlapping volume:r=0.79,P=0.012;center distance:r=-0.70,P=0.037).The seed-to voxel functional connectivity analysis revealed that pretherapeutic functional connectivity of T-VIM with visual area of PD patients was significantly correlated with tremor improvement(voxel P<0.001,cluster P<0.05 FWE corrected).The region of interest-based functional connectivity analysis further showed that pretherapeutic functional connectivity between T-VIM and ipsilateral sensorimotor cortex(r=0.88,P=0.002)or subthalamic nucleus(r=0.70,P=0.036),and pretherapeutic functional connectivity between S-VIM and ipsilateral sensorimotor cortex(r=0.75,P=0.019)were positively correlated with tremor improvement.OrT/CVA analysis revealed a significant ET-related network for which expression showed consistent increases in subject after surgery.Treatment-induced increases in subject expression were significantly correlated with concurrent tremor improvement.This network was characterized by increased activity in the sensorimotor cortex and decreased activity in the posterior cingulate cortex.This network was correlated with an expression map of a weighted combination genes enriched for serotoninmitochondria relevant ontology terms,which was further validated by emission computed tomography data.Conclusion:This pilot study provided the preliminary evidence about the effectiveness and safety of VIM-MRgFUS for the treatment of medication-refractory disabling tremor in essential tremor and Parkinson’s disease,which offers an important basis for the national clinical promotion.The findings about the impact of SDR on treatment parameters gives vital reference about the parameters setting for VIM-MRgFUS.The T2WI and DWI are the sequences of choice to observe lesions within 3 months after treatment.SWI is recommended to identify lesions after 6 months.The visual area is reported as relevant to tremor improvement in PD after VIM-MRgFUS,suggesting a distant effect of MRgFUS thalamotomy and the involvement of specific visuomotor networks in tremor control in PD.The tractography-based direct targeting of VIM may improve the clinical application of VIM-MRgFUS to treat PD.The pretherapeutic functional connectivity of T-VIM with ipsilateral sensorimotor cortex,subthalamic nucleus and visual area might predict PD tremor responses after VIM-MRgFUS.The therapeutic effects of VIM-MRgFUS on ET is associated with modulating a distinct ETrelated network which may be driven by serotonin-mitochondria relevant neurobiological mechanism.Quantification of treatment-induced modulation on the ET-related network can provide an objective marker for evaluating the efficacy of VIM-MRgFUS.