Background : Safety efficacy of unilateral VIM Gamma Knife Radiosurgery (VIM GK) has been well demonstrated for Essential tremor. The safety-efficacy of bilateral VIMGK has never been assessed strictly. We conducted a prospective and objective assessed of the changes in cognitive functions (primary criteria), speech, balance in addition to the evaluation of the impact activities of daily living.

Material & method : Between 03/06/2014 & 09/11/2021 have been treated contralaterally by GKS 33 patients presenting with a severe drug-resistant essential tremor previously treated by VIM GK on the dominant side at least 12 months before (monocentric, prospective, non comparative N° EUDRACT : 2013-A01289-36). After frame application stereotactic MR and CTscan imaging a single isocenter of 4mm was positioned at the location of the VIM according to Guiot and adjustment of the target based on a preoperative DTi according to our usual standard technic. Quantitative assessment before, at 6 & 12 months was including neuropsychological testing (MMS, apathy Starkstein scale, Stroop, verbal fluences, similitudes), evaluation of the voice, writing, walk gait (Kinematic gait analysis was performed with the SMART TV image processing system, eMOtion), posture (AMTI force platform), tremor severity (Fahn-Tolosa-Marin rating scale) ADL (Bain Scale) and MRI (volume of T1 contrast enhancement and edema score).). The assessment was perform independently from the neurosurgical team. The results were followed and reviewed by an international independent surveillance committee (MH and PK). Patients acted as their own controls

Results : All the 33 patients have completed the study after the one year follow up (19 male 14 female, 32 right VIM and 1 left). Only one adverse event (expected) was observed (hemi-proprioceptive ataxia & dysarthria due to hyper-response 11 months after VIM GK). The mean age was 71 (55-83). The mean delay between the first and the second GK was 28,7 months. The primary outcome criteria of tolerance on the cognitive functions was altered in none of the patients. The evaluation of speech walk gait and posture (secondary outcome criterion) have shown no worsening. In term of efficacy at 1 year the severity score was improved of 58,5%, the disability score of 84,8% and the functional impact score of 68,6%. Only 4 patients failed to respond but for the 29 remaining the mean improvement was of 74,4% improvement of the tremor on the treated upper limb. No side effect related to the bilaterality of the VIM GKS was found in spite of the independent meticulous prospective assessment.

Conclusion : This is the first prospective trial assessing the safety efficacy of bilateral VIM GK. This trial is demonstrating the excellent safety efficacy of VIM GK of the contralateral side in a subgroup of selected candidates previously treated by VIM GK at least 1 year before with a good response of the first side operated.

Introduction

Despite the dominance of neurostimulation technology, stereotactic lesioning operations play a significant role in the treatment of movement disorders. Bilateral lesioning surgeries  for Parkinson’s disease (PD) facing criticism, because of the high rate of postoperative complications. However, recent advantages in neuroimaging, wide use high-field MRI, and substantial improving software of planning stations allow to accurately identify the anatomical details of the target and create a safe surgical plan. The aim of the study is to evaluate the effectiveness and safety of staged bilateral radiofrequency stereotactic lesioning for PD. 

Material and methods

41 patients with advanced PD, aged from 40 to 72 years (mean 56.6 years) were enrolled in a retrospective study. Stereotactic RF thalamotomy and consecutive contralateral pallidotomy were performed in 29 (71%) patients (group Vim-GPi), thalamotomy and consecutive contralateral lesion of subthalamic nuclei (STN) were performed in 12 (29%) cases (group Vim-STN). Patients who had severe hypokinesia or progressive hypokinesia after unilateral lesioning, were not candidates for staged bilateral stereotactic lesioning. The mean duration of disease before the first surgery was 9.5 years. Mean interval between the two operations was 3.1 years. Operations were provided without microelectrode recording. Neurological and neuropsychological assessments were performed before surgery and one year after second operation.

Results

One year after treatment total UPDRS score in the OFF state improved in group Vim-GPi by 45% and in group Vim-STN by 42%. Slightly more prominent improvement was evident in the motor UPDRS III score, which improved in the OFF state by 52% in group Vim-GPi, and by 61% in group Vim-STN. Overall, levodopa dose was reduced by 41%.  

Regression of motor symptoms allowed to improve general motor activity, functional independence and quality of life, which was confirmed by improvement of mean Schwab & England daily living score from 55% to 71% in group Vim-GPi (29% improvement) and from 59% to 82% in group Vim-STN (39% improvement). Bilateral stereotactic lesioning had no apparent effect on cognitive function. We didn’t note significant changes in UPDRS mentation, behavior and mood subscores after second operation 

Among 82 interventions in 5 (6.1%) cases we performed repositioning of the electrode after intraoperative macrostimulation. There were no adverse effects after the first operation. After the second intervention, neurological complications were observed in 4 (9.8%) cases, among them 1 (2.4%) patient had permanent events, relating to local ischemia after pallidotomy. 

Discussion

In recent years there has been a renewed interest in lesioning interventions has been observing in stereotactic neurosurgery for movement disorders. This can be explained by the significant achievements of neuroradiological, neurophysiological, and stereotactic software technologies. Nevertheless bilateral lesioning surgeries facing criticism, because of the development of postoperative balance or gate problems, speech disturbances, dysphagia and other adverse effects. To eliminate the risk of adverse events, we proposed to create staged asymmetric lesions for advised PD - thalamotomy and consecutive contralateral pallidotomy or thalamotomy and consecutive contralateral subthalamic nucleotomy. 

In the present study, applying of careful patient selection for staged bilateral lesioning allowed to achieve significant improvement. Suppression of the cardinal motor features of PD together with elimination of levodopa-induced dyskinesias  and motor fluctuations played a crucial role in the improvement of UPDRS score one year after second operation. Careful identification and selection of patients for ablative surgery allow to achieve optimal results in the treatment of PD with bilateral symptoms. 

1. Introduction

Essential tremor in the most common movement-disorder and bilateral symptoms are typical.However bilateral surgery has been contraindicated because the incidence of speech disorders in bilateral thalamic coagulation is 40% or higher. In conventional surgery, the target is determined based on the atlas that does not consider individual differences, and the position and extension of the coagulation lesion cannot be confirmed during the surgery, but MRgFUS can monitor the position and progress of the coagulation lesion in real time. In ET, language complications were as low as 13.9% even with bilateral thalamotomy, so we performed staged bilateral thalamotomy at intervals of 1 year or more with sufficient informed consent

2. Methods and Materials

We enrolled９ consecutive patients with refractory essential tremor between September 2016 and June 2022. Patients underwent a second operation at least 1 year after the operation.

For treatment, ExAblate Neuro 4000 　system (Insightec,Haifa,Israel)was used on 1.5 Tesla MRI. The clinical effects was assessed by the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM).

3. Results

Mean patient age was 57.6, and the mean interval between two operations were27.8 months. The second lesion center was superior to the first lesion in all patients.

The baseline CRST score of 63.6 improved significantly to 49.2 after the first surgery and 21.8 after the second surgery. In particular, in Part C of CRST, the baseline of 18.4 improved significantly to 8.2 after the first operation and 2.6 after the second operation.

Adverse events occurred in 6 of 9 patients, one with very mild but permanent dysarthria, while the other two were transient. The patient with permanent sequelae was satisfied with the results because improvement of the tremor.

4. Discussion

It was said that speech disturbance occurred to be 15% in unilateral and 40% in bilateral thalamotomy.Thalamotomy on the dominant hemisphere is said to be three times more risky than on the non-dominant side. On the other hand, the incidence of dysarthria in essential tremor surgery is one-third that of Parkinson's disease.

Therefore, it is considered that safer treatment can be achieved by performing MRgFUS on the dominant hemisphere first, confirming that no adverse event has occurred, and then performing MRgFUS on the non-dominant side after a while.

5. Conclusions

As a treatment method for ET, MRgFUS is comparable to DBS, which has been the golden standard so far, in terms of treatment results and safety.

the improvement of QOL is superior to DBS because it does not require device placement.

6. References

Fukutome K, Hirabayashi H, Osakada Y 4Yoshihiro Kuga Y Ohnishi H: Bilateral Magnetic Resonance Imaging-Guided Focused Ultrasound Thalamotomy for Essential Tremor Stereotact Funct Neurosurg.;1-9.2021 doi: 10.1159/000518662.

Alomar S Nicolas King N Tam J Bari AA, Hamani C Lozano AM:Speech and language adverse effects after thalamotomy and deep brain stimulation in patients with movement disorders: A meta-analysis Mov Disord. ;32(1):53-63. 2017 doi: 10.1002/mds.26924.

Martínez-Fernández R, Mahendran S, Pineda-Pardo JA, Imbach LL, Máñez-Miró JU, Büchele F, Del Álamo M, Rodriguez-Rojas R, Hernández-Fernández F, Werner B, Matarazzo M, Obeso I, Gonzalez-Quarante LH, Deuschl G, Stieglitz L, Baumann CR, Obeso JA.J:Bilateral staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of essential tremor: a case series study. Neurol Neurosurg Psychiatry. ;92(9):927-931.2021 doi: 10.1136/jnnp-2020-325278. Epub 2021 Apr 27.PMID: 33906933

Background: Unilateral MRI-guided focused ultrasound (FUS) has established efficacy in tremor relief. Data regarding the safety and efficacy of bilateral, staged treatments is scarce. 

Objective: To report preliminary results of a clinical trial to evaluate the safety and efficacy of staged bilateral FUS thalamotomy in essential tremor (ET) patients that previously underwent unilateral FUS treatment on the opposite side

Methods: Nine patients that underwent unilateral FUS thalamotomy for medication refractory tremor at least six months before (median 1.7 years) and had severe tremor on the untreated side - underwent FUS treatment to relieve tremor. The target within the VIM was chosen based on the contralateral lesion (as a mirror targeting) and modified based on its clinical effect. The primary outcome was the change in tremor score in the treated hemi-body relative to baseline, using the Clinical Rating Scale for Tremor (CRST). The secondary outcome was the change in quality of life (QOL) in ET (QUEST) score relative to baseline. In addition, an adverse event profile was collected.

Results: Tremor significantly improved following treatment from a median score of 14 at baseline to a median score of 2.5 at 1 month, 3 at 3 months (P=0.001). Quest score improved from a median score of 31 before FUS to 11 at 1 month and 10 at 3 months. All nine patients experienced mild transient ataxia that lasted between 2 days and 4 weeks. Two patients reported tongue sensation abnormalities that did not resolve at 1-month visit. One patient had an ipsilateral minor cerebellar stroke secondary to an antiaggregant medication cessation for the procedure. No speech deficits were noted.

Conclusions: Our preliminary results suggest that staged bilateral magnetic resonance-guided focused ultrasound thalamotomy was effective and safe and improves the tremor and quality of life of patients with ET. Second-side lesions may correlate with a higher rate of ataxia, though probably transient. More extensive studies and longer-term follow-ups are needed to validate these findings. 

Background: Dystonia is a group of disorders characterized by involuntary slow repetitive twisting movements and/or abnormal posture. Surgical options such as neuromodulation through deep brain stimulation and neuroablative procedures are available for patients who do not respond to conservative treatment.

Objective: To present our series of patients with dystonia who were treated with stereotactic combined unilateral radiofrequency lesioning of the motor thalamus, field of Forel, and zona incerta.

Methods: Medical records of 50 patients with dystonia who were treated with unilateral combined lesions were reviewed. Outcomes of the surgical procedure were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (with movement and disability subscales) and Unified Parkinson's Disease Rating Scale-tremor items.

Results: Based on the symptoms, patients were categorized as having generalized dystonia (34%), hemidystonia (30%), and dystonic tremor (DT) (36%). Primary/idiopathic dystonia, primary genetic/hereditary dystonia, and secondary dystonia accounted for 16%, 4%, and 80% of patients, respectively. The mean follow-up duration was 156.2 ± 88.9 mo. The overall improvement in the Burke-Fahn-Marsden Dystonia Rating Scale scores (movement and disability, respectively) was 57.8% and 36.4% in generalized dystonia, 60.0% and 45.8% in hemidystonia, and 65.6% and 56.8% in DT. Patients with DT showed an 83.3% improvement in mean Unified Parkinson's Disease Rating Scale tremor score. Patients with cerebral palsy showed mean improvements of 66.7% in movement scores and 50.8% in disability scores. No mortality or major morbidity was observed postoperatively.

Conclusion: Stereotactic radiofrequency unilateral combined thalamotomy, campotomy, and zona incerta lesions may be an effective surgical alternative for patients with dystonia, especially those with secondary dystonia resistant to deep brain stimulation.

Background: Tremor is an involuntary, rhythmic, and oscillatory movement of a body part. It is a common symptom in movement disorders appearing sometimes in isolation and sometimes in combination with other symptoms. When sufficient relief cannot be achieved with pharmacological treatment, Deep Brain Stimulation (DBS) has proven effective for ET (Essential Tremor) and Parkinson’s Disease tremor. The Vim (Ventromedial Nucleus) has been the main target for tremor DBS surgery. Unfortunately, there is a scarcity of data regarding the effect of Vim DBS on rare tremor syndromes, for some conditions limited to a few case reports and sometimes with conflicting results. The PSA (Posterior Subthalamic Area), is a relatively new target for DBS and  lies in the proximity of Vim, why it is possible to align an electrode to place contacts in both targets (Double target). Double targeting of the VIM and PSA is a rather recent practice, allowing us to stimulate both targets simultaneously or separately. In the current study we decided to apply double targeting to some rare tremor conditions, to decide on the effect and safety of the procedure.

Methods: Between 2019 and 2023, 22 patients with rare tremor syndromes were bilaterally implanted using the double targeting: 7 isolated head tremor, 1 hepatic encephalopathic tremor due to Abernethy Syndrome, 2 voice tremor, 4 dystonic tremor, 8 Holmes tremor (2 MS, 2 cerebellar insult, 4 post-traumatic). The patients’ demographic characteristics, clinical aspects, tremor scores and relevant symptoms are shown in Table 1.

Results: All 22 patients who underwent double targeted DBS surgery demonstrated a remarkable improvement of tremor symptoms. The outcome at 12 month is presented in Table 1, with the items selected in accordance with the patients’ specific condition.

Conclusions: In the current study, double targeting of the Vim and PSA provided a very satisfying degree of tremor reduction in several rare tremor syndromes. Further studies are needed to decide on the relative effectiveness of the two targets in relation to combined targeting, as well as on the role of DBS in various rare tremor conditions.

Introduction

Bilateral deep brain stimulation of the subthalamic nucleus (STN-DBS) is a treatment of choice in Parkinson’s disease (PD) with motor fluctuations. Conventional programming in the ring mode (CP-RM) is used as standard to choose the best therapeutic contact – an exhausting process for patients and caregivers. We instead used guidance software to estimate the patient-specific volume of tissue activated (VTA), facilitating selection of contacts and programming parameters. We aimed to demonstrate similar efficacy between VTA programming and CP-RM.

Methods

Consecutive STN-DBS PD patients (February 2019 to January 2021) were programmed using VTA guidance (VTA group). Their clinical data were retrospectively compared to a historical cohort of STN-DBS PD patients (March 2011 to February 2014) whose stimulation parameters had been determined using CP-RM. Primary outcome: improvement in the Unified Parkinson’s Disease Rating Scale part III score between the preoperative OFF phase and on-stimulation/off-drug condition 1-year postoperatively.

Results

Twenty-six patients were included (VTA n=12; CP-RM n=14; mean age 62.4±7.55 years). There was no significant difference between groups in the primary endpoint (VTA 43.62 vs. CP-RM 41.29). The immediate postoperative length of stay (6.25 vs. 18.93; p<0.0001) and number of hospitalizations post-discharge (1.17 vs. 2.00; p=0.007) were significantly lower in the VTA vs. CP-RM group, respectively.

Discussion

The ability to direct stimulation towards the optimal, patient-specific target has the potential to improve outcomes in PD. However, the increased complexity in programming options has led to conventional programming becoming unwieldy and even more time consuming, placing considerable burden on the patient. Anatomy-based, image-guided visualization software to facilitate the process is essential – but in these relatively early days, the long-term impact of using such software alone to select the optimal contacts and stimulation parameters is uncertain.

Despite the small number of patients, our initial results suggest that use of VTA software alone to choose the optimal contacts for stimulation and subsequently refine therapy does not impair the improvement in motor symptoms over the long term and will reduce both the number of hospitalizations required and the length of the hospital stay. These reductions should help to streamline the care pathway, without compromising therapeutic efficacy. It is our view that VTA software should be used routinely to program patients and at all follow-ups to facilitate individualized patient management and simplify the care pathway. Results must be validated in a larger, multicentric cohort.

Background: Deep Brain Stimulation (DBS) management for Parkinson’s Disease (PD)  can be limited by the burden of traveling to the clinic for care. Patients must travel to the clinic to receive updates to the stimulation, which can be challenging and costly, leading to reduced access. Teleprogramming may reduce the burden of DBS management by enabling DBS device interrogation and programming remotely. The ROAM-DBS trial compares the impact of teleprogramming and in-clinic programming on the time-course of symptom improvement after DBS implant.

Methods: The ROAM-DBS study is a multicenter, prospective randomized controlled trial for PD patients comparing in-clinic DBS programming only with teleprogramming using Abbott’s Neurosphere™ Virtual Clinic platform. After each programming visit, participants are asked to evaluate their symptom improvement using the Patient’s Global Impression of Change (PGI-C), and clinicians rate symptoms using the Clinician’s Global Impression of Change (CGI-C). In addition, participants are asked to complete the PDQ-39 quality of life questionnaire monthly.

Results: 82 patients had enrolled in the ROAM study by March 7, 2023, and 51 had completed the 3-month follow-up. Initial PDQ-39 quality of life scores of 26.8+/-11.8 in the teleprogramming arm are similar to those from the in-clinic arm of 25.8+/-13.6 (p=0.84). After 3-months, most subjects report improvement in PGI-C scores (teleprogramming arm: 23/26; in-clinic arm: 18/25, p=0.41). The teleprogramming arm shows a shorter time to improvement of 34.0+/-16.6 days compared to 46.8+/-19.1 days for the in-clinic arm (p<.05), and 2.8+/-2.4 programming visits compared to 1.25+/-1.1 visits in the clinic arm(p<.01). Similar outcomes are observed with the CGI-C, with 35.9+/-20.1 days to improve 1 point in the teleprogramming arm compared to 51.2+/-16.7 days for the in-clinic arm (p<.01). 2 non-serious, and 2 serious Adverse Events (AE) were reported in the teleprogramming arm, while 3 non-serious and 2 serious AE were reported for the in-clinic arm. 3 of the serious AE were either related to the implant procedure or in 1 case related to cardiac disfunction, and were not the result of programming changes. 

Conclusions: Despite similar baseline symptoms, Parkinson’s patients in the teleprogramming arm improved faster than the in-clinic arm. This suggests that easier access to programming sessions enabled by teleprogramming reduces the time necessary to optimize DBS therapy. Both arms reported similar Adverse Event rates, suggesting that use of teleprogramming does not affect safety of DBS therapy. These early results highlight the potential improvements in DBS care using digital healthcare solutions.

DBS has shown been shown to drastically improve symptoms of movement disorders such as Parkinson’s Disease, Essential Tremor and Dystonia. . High precision in targeting and electrode implantation has been correlated with good clinical outcomes. In the recent years, DBS with segmented leads have not only pioneered novel directional DBS, but also provided innovative approaches in targeting and patient programming. Improvement of imaging, development of intraoperative monitoring research as well as collaboration between biomedical engineers and clinicians has empowered  the development of computer models of DBS as well as their use for computer based DBS programming, either based on probabilistic sweet spots, or more recently, using artificial intelligence (AI). We describe these different approaches and report  our experience in implementing them with local and multicenter clinical data provided by international teams. These approaches facilitate DBS programming and also promote a better understanding of brain networks dysfunctions underlying neurologic and psychiatric disorders.

Objective: To investigate whether motor improvement after STN-DBS can be associated with individual structural connectivity analyzed by Subject sPEcific brain Connectivity display in the Target REgion (SPECTRE).

Methods: Patients from our DBS-Registry with Parkinson’s disease were selected for analysis, if the following was available: (1.) preoperative MedOFF and postoperative follow-up MedOFF StimON values of MDS-UPDRS-III, (2.) preoperative 3T-MRI including dMRI, (3.) Bilateral volumes of activated tissue (VAT, simulated with Brainlab Guide XT) contained STN (segmented with an in-house trained convolutional neural network) at a proportion ≥0.4.

For the generation of SPECTRE maps limbic/motor/associative (green/blue/red) cortical schemes defined in MNI space are warped to subject space, and in a tract weighting approach 500 probabilistic streamlines per voxel are seeded in the VATs to compute their cortical associations (Figure 1). The overall maximum of the motor connectivity (blue) of both VATs (left/right) is used to predict motor performance.

Postoperatively remaining relative motor disability (RRMD) was calculated as the ratio of follow-up divided by preOP UPDRS-values.

Linear regression analysis was calculated to estimate the relation between maximum individual motor connectivity, VAT size and RRMD.

Results: 30 patients were included in the analysis. Regression analysis found a significant effect (F(2, 27)=4.919, p=.015, R²=.27) where individual motor connectivity of the VAT was inversely associated with remaining relative motor disability (t=-2.95, p=0.006, Figure 2) while VAT size was not a significant predictor (t=1.73, p=.095).

Conclusion: SPECTRE imaging can explain treatment effects based on connectivity on a single subject level and has the potential to improve image-based DBS programming and targeting for DBS implantation.

Objectives:  Deep brain stimulation (DBS) targeting the ventral intermediate (Vim) nucleus of the thalamus is an effective treatment for essential tremor (ET).  Yet, it remains unclear which functional connections are most influential in impacting tremor control and/or concomitant gait ataxia. We studied ET patients undergoing DBSto a major input/output tract of the Vim, the dentato-rubro-thalamic tract (DRTt), using resting state functional MRI (rsfMRI) to evaluate connectivity differences between DBS ON and OFF and elucidate significant regions.

Methods: We enrolled fifteen ET patients who had previously undergone DRTt DBS. Anatomical/functional 1.5T MRIs were acquired and replicated for each DBS state. Tremor severity using The Essential Tremor Rating and Assessment Scale (TETRAS) and gait ataxia severity using the Scale for Assessment and Rating of Ataxia (SARA, items 1-3) was scored with DBS ON at optimal stimulation parameters and immediately upon DBS OFF. Regions of interest (ROI) were pre-defined as the bilateral Vim thalamus, pre-central gyrus, superior and inferior parietal lobules (SPL/IPL), dentate nucleus (DN), and cerebellar nodule. Connection strength between each of the 11 ROIs was measured using z-scores of correlation coefficient differences between DBS ON/OFF and correspondent p-value computed by using Fisher’s method, which represents change on individual level.  Effect of DBS treatment at group level was measured by averaging z-scores over all 15 patients between each ROI. Pearson correlation analysis was performed between z-score and tremor duration to see effect of tremor duration on connectivity change. Subgroups of patients with higher SARA scores were also compared. 

Results: All 15 patients had significant differences in tremor between DBS ON/OFF (p<0.001). Group analysis revealed that, with threshold p<0.05,  in DBS ON vs. OFF longer tremor duration was significantly correlated to decrease in connectivity between L SPL and R Vim (R=0.73, p=0.002) and increase in connectivity between R IPL and R pre-central gyrus (R=0.62, p=0.014).  Overall, patients with greater pre-operative ataxia had significantly decreased functional connectivity between multiple ROIs, including DN and cerebellar nodule, when DBS was ON compared to OFF (z-score<4). 

Conclusions: Stimulation of the DRTt and concordant improvement of tremor and ataxia resulted in connectivity decreases seen in multiple regions outside the motor network thought to be involved with tremor pathology. Such functional engagement of the SPL/IPL in tremor and cerebellum in ataxia, when combined with both structural and electrophysiologic connectivity, may help serve as a biomarker to improve DBS targeting and possibly predict outcome.

Background:

DBS of the VIM nucleus is an efficacious treatment for refractory essential tremor, although targeting the intra-thalamic nuclei remains challenging. We developped an AI approach to predict a clinical target for DBS in essential tremor (VIM/PSA). The learning database consisted in clinical and radiological features of patients previously operated on with optimal outcomes. The OPTIVIM trial (NCT03760406) aims to validate this approach.

Patients and Methods:

In this prospective bi-centric (Lyon and Bordeaux), non-comparative, phase-2 clinical trial, we included 22 patients with severe essential tremor despite optimal medical management, aged between 18 and 75 years, with normal MRI, without cognitive impairment (MDRS score ≥ 130) or depression (BDI scale < 20).

The primary endpoint is the efficacy of the procedure on tremor as assessed by the improvement on the Fahn-Tolosa-Marin (FTM) scale between the pre- and post-operative assessments 3 months after surgery. Secondary endpoints are (1) the efficacy of the procedure on tremor as assessed by accelerometry recordings; (2) complications related to surgery and neurostimulation-related side effects, mainly dysarthria and ataxia assessed by the SARA scale (scale for assessment and rating of ataxia); (3) improvement in quality of life’s mPDQ-39 scale between the pre-operative and post-operative assessments; and (4) the stereotactic accuracy was evaluated by calculation of the Euclidian distance between the target and the electrode by co-registration between the marked MRI with the target and the postoperative CT scan. Leads and targeting localisations were studied using leadBDS, Suretune and Guide XT.

The target was planned by OptimDBS RebrAIn software, on a 3D T1 MRI at 1.5 or 3 Tesla. DBS surgery was performed under general anaesthesia, without intra-operative clinical and electrophysiological testing.

Preliminary results:

Twenty-two patients underwent surgery under general anaesthesia with direct insertion of the leads at the target without clinical per-operative evaluation between June 2019 and February 2023 (9M/13F, mean age 63 (+- 11) years old).

The (pre-operative / post-operative) FTM scale means were 51.3/20. The mean improvement of the tremor was 61% on the FTM scale. These scores were confirmed by accelerometry.

The (pre-operative / post-operative) SARA means were 5/3,8. Two patients worsened their SARA.

The (pre-operative / post-operative) mPDQ39 means were 43/21. The mean improvement of quality of life were 50% on the mPDQ39.

The mean distance between the target and the electrode surface was 0,9mm (min 0, max 2.2).

Conclusions:

Asleep DBS for essential tremor using our machine-learning model for targeting the VIM/PSA may be a safe, efficient procedure leading to outcomes comparable to those published in the literature for standard awake DBS surgery.

Objective

Chronic Deep Brain Stimulation of the subthalamic nucleus (STN-DBS) has been shown to improve the motor symptoms of Parkinson’s Disease and reduce levodopa requirement (1). The network topography associated with the therapeutic effects of STN DBS are not well described. FDG PET has been used to study disease and treatment related networks in PD (2, 3). The goal of this study was to identify a network associated with the therapeutic effects of STN DBS

Methods

We studied 13 PD patients with implanted STN-DBS electrodes (24 hemispheres) with FDG PET off medication in the on and off stimulation condition. To derive a brain network, we applied ordinal trend canonical variates analysis (OrT/CVA) to the ON/OFF scan data for each hemisphere (4). Further validation was assessed by quantifying stimulation mediated changes in an independent cohort of 13 STN DBS patients (26 hemispheres) acquired at the San Raffaele Scientific Institute, Italy (5). We assessed relationships between changes in pattern expression and UPDRS motor ratings in the derivation and validation STN DBS samples, and evaluated changes in network pattern in other therapeutic interventions.

Results

We identified a significant hemispheric spatial covariance pattern characterized by stimulation mediated increases in the subthalamic nucleus, ventral thalamus, supplementary motor area and pontine nuclei and decreases in the postcentral gyrus, cerebellar vermis and paravermian region (Fig 1). Subject scores exhibited consistent increases in the ON vs OFF conditions across hemispheres (p < 0.001, permutation test) (Fig 2). Increases in pattern expression across subjects correlated with improvement in UPDRS motor ratings for contralateral limbs (R= 0.6, p < 0.005) (Fig 3(a)). Similar findings were seen in the validation sample, with increased pattern expression in the ON condition (p < 0.05, paired t-test) and significant correlations with motor improvement (R = 0.66, p < 0.05) (Fig 3(b)).
Significant increases in pattern expression were observed with STN stimulation but not Levodopa infusion of comparable efficacy (Fig 4). Less pronounced increases were seen with GPi DBS whereas decreases were present following unilateral subthalamotomy and microlesion (Fig 4). In the absence of treatment, pattern expression was stable in PD patients and healthy controls. Pattern expression from preoperative (R= -0.55, p < 0.05) & OFF (DBS and Levodopa) (R= -0.55, p < 0.005) PET correlated with motor improvements in UPDRS after stimulation (Fig 3(c & d)).

Conclusions

STN-DBS modulates a significant motor related network which correlates with the therapeutic benefit. In contrast to previously characterized PD-related networks, this treatment induced pattern is modulated specifically by STN-DBS but not by other surgical interventions or dopaminergic treatment. Baseline network expression has the potential to predict stimulation associated therapeutic benefit. 

References

1.       1. Bronstein JM, Tagliati M, Alterman RL, Lozano AM, Volkmann J, Stefani A, Horak FB, Okun MS, Foote KD, Krack P, Pahwa R. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Archives of neurology. 2011 Feb 14;68(2):165-.

2.       2. Perovnik M, Rus T, Schindlbeck KA, Eidelberg D. Functional brain networks in the evaluation of patients with neurodegenerative disorders. Nature Reviews Neurology. 2023 Feb;19(2):73-90.

3.       3. Schindlbeck KA, Eidelberg D. Network imaging biomarkers: insights and clinical applications in Parkinson's disease. The Lancet Neurology. 2018 Jul 1;17(7):629-40.

4.      4.Habeck C, Krakauer JW, Ghez C, Sackeim HA, Eidelberg D, Stern Y, Moeller JR. A new approach to spatial covariance modeling of functional brain imaging data: ordinal trend analysis. Neural computation. 2005 Jul 1;17(7):1602-45.

5.      5.Volonté MA, Garibotto V, Spagnolo F, Panzacchi A, Picozzi P, Franzin A, Giovannini E, Leocani L, Cursi M, Comi G, Perani D. Changes in brain glucose metabolism in subthalamic nucleus deep brain stimulation for advanced parkinson's disease. Parkinsonism & Related Disorders. 2012 Jul 1;18(6):770-4.

Background: Tremor is a highly disabling symptom common in both Essential tremor (ET) and Parkinson’s disease (PD), conjugate with the dramatic reduction in quality of life, alongside social exclusion, embarrassment, and immense difficulty in performing routine tasks. Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) is an emerging non-invasive technology that utilizes sound waves energy to induce a focal thermal lesion with sub-millimeter precision to treat patients with tremor. The ventral intermediate nucleus of the thalamus (VIM) is a well-studied target for tremor reduction. However, since the VIM can’t be visualized radiologically, different targeting methods were developed. Indirect targeting is the most common approach for VIM targeting based on patients’ anatomy using the anterior-posterior commissure (AC-PC) as a reference point. However, it is correlated with suboptimal tremor control up to 20%, inconsistency of the treatment’s outcome especially regarding the long-term effect, and side effects such as ataxia, sensory deficits and dysarthria. Moreover, inaccurate targeting causes a longer procedure with excessive sonications that can affect the treatment’s outcome and the adverse events.

Aim: Utilization of advanced analysis methods as a targeting approach for personalized treatment and superior clinical outcomes.

Methods: Pre- and post-operative magnetic resonance imaging (MRI) scans were acquired from 56 patients who underwent MRgFUS. Using the preoperative diffusion tensor imaging (DTI) MRI sequence, three tracts (pyramidal tract [PT], medial lemniscus [ML], and dentatorubrothalamic tract [DRTT]) were located for each patient using tractography. These patients' postoperative T1 weighted images were used for segmentation and volume calculation of the lesion. Geometrical measurements were performed, such as the distance and overlap between the lesion and each of the tracts. To detect the factors affecting the treatment’s outcome, statistical and machine learning tools were applied to find correlations between the postoperative clinical evaluations (up to 2 years followup) and the image analysis.

Results: The overlap of the lesion with a specific region of the DRT, the distance of the lesion from the ML and PT, and the total overlap between the lesion and each tract were shown to have a significant correlation to the treatment’s outcome.

Conclusion:

The optimal treatment target within the VIM can be defined according to the correlations discovered. We suggest an innovative personalized method to detect the “sweet spot” for eliminating tremor using MRgFUS. This technique tailors the target localization to a specific patient based on the patient’s functional anatomy—the spatial locations of the patient’s tracts to improve tremor control and avoid adverse effects.

Background: Deep brain stimulation (DBS) of the nucleus subthalamicus (STN) is an effective surgical treatment for the patients with advanced Parkinson's disease (PD). However, individual improvement (response) after DBS remains variable and average (UPDRS) motor improvement in our  centre for the past ten years has been stable; averaging 46%. The effect of DBS relies on the modulation of malfunctioning brain networks by delivering electrical pulses within the STN. So far, visualizing the multiple brain networks in this small nucleus for DBS surgery has been challenging and prevented electrode placement guided by its cortical (motor) projections. By using structural 7-Tesla MRI (7T MRI) connectivity to visualize (malfunctioning) brain networks, DBS-electrode placement and activation can be individualized and network guided.

Methods: This is a single center prospective observational study. The primary outcome measure is the change in motor symptoms as measured by the disease-specific Unified Parkinson's Disease Rating Scale (UPDRS-III) after six months of DBS. Before DBS surgery, the STN and its cortical connections are visualized using 7T T2-weighted and diffusion weighted imaging. The three major projections of the STN are identified (using probabilistic connectivity): projections connecting to primary and supplementary motor cortex (motor), projections to the prefrontal cortex (associative) and projections to the basofrontal cortex (limbic). Electrode placement is aimed at the motor STN (part of the STN showing highest density of motor projections). 

Results: In 20 PD patients (representing 40 STNs) visualisation of cortical projections originating in the STN using 7T MRI was performed before DBS surgery. The 7T MRI subthalamic network map, showing the (colored) motor STN for each patient, was subsequently imported in de DBS planning software and electrode placement was aimed at this part. Average UPDRS improvement was 57% (range 40% - 83%).

Conclusion: Electrode placement guided by 7T MRI subthalamic network analysis enhanced the effectiveness in DBS for PD. After six months of DBS an average of 57% UPDRS improvement was seen; over 10% more compared to the past 10 years. Variability in motor improvement decreased; all patients had a response (>30% improvement). Current analysis will be extended as enrollment is ongoing and secondary outcome measures (Amsterdam linear disability score, quality of life as measured by PDQ-39, Starkstein apathy scale, motor complication score) will be included.

Background: Deep brain stimulation (DBS) is commonly used practise  for treating various neurological and psychiatric disorders to this day. Stimulation of GPi is an effective treatment for cardinal symptoms of Parkinson Disease, treatment resistant dystonia, dyskinesia, and other hyperkinetic movement disorders. Conventional T1 and T2 weighed MRIs are being used for targeting GPi in general practise but using susceptibility weighted imaging (SWI), proton density (PD) and fast gray matter acquisition T1 inversion recovery (FGATIR) sequences is rather recently debated. In this study, we explored the compatibility of the SWI modality for targeting GPi as we compared the CNR rates of the T2 and SWI acquisitions of the Parkinson patents and used SWI images for preoperative targeting modality for bilateral GPi DBS surgery for one Parkinson patient.

Methods: Between 2019 and 2023, cranial MRI scans and SWI acquisitions of the patients diagnosed with idiopathic PD more than 4 years ago, have collected without them being a candidate for DBS surgery. 20 patients included in the study regarding to their time of diagnosis (mean 4 years) but surgical intervention for treatment augmentation have not been required for 19 patients. Patients’ preoperative T2 weighted MRIs and SWI scans were investigated for detectability of the region of interest (GPi) and adjacent structures were identified for defining the borders. All the GPi structures were identified radiologically as inferior border set to be optic tracts, medial border met by internal capsule, lateral border met by internal lamina and Globus Pallidum externum.

 Results: In T2 and SWI acquisitions, GPi structures harboured different intensities within the same nucleus and both nuclei differed from each other morphologically and radiologically even in the same patient. CNR differences between the structures in T2 and SWI acquisitions revealed that in T2 and SWI, ventral and lateral CNR are similar bur medial border significantly more distinguishable in SWI acquisition. (SWI ventral: 47,25 and lateral :28,5 ;T2 ventral:52 and lateral:31,65)  but medial borders were significantly more distinguishable in SWI acquisition in which CNR scores 59,775 for SWI and 21,3 for T2. One patient operated successfully using SWI sequence as main frame to stereo-planning.

Conclusions: Comparison of the CNR scores of the borders of the GPi between conventional, T2 weighted MR scans and SWI acquisitions favours SWI scans as the contrast between tissues are more significant and visibility values scored higher in SWI scans. Targeting motor subregions of the GPi to achieve best clinical outcome with lower side effect profile is a challenging technique and requires expertise in the field considering the fact that each nucleus has an intensity variation within and each other.

Introduction

Advances in high-resolution intra-operative computed tomography and magnetic resonance neuroimaging technologies have resulted in a shift towards deep brain stimulation (DBS) lead implantation under general anesthesia, termed “Asleep” DBS. Initial studies comparing asleep DBS to traditional implantation techniques using microelectrode recording under light sedation -termed “Awake” DBS - have shown similar outcomes in both lead placement and early clinical response. However, data to date on differences in the patient surgical experience and longer-term outcomes is limited. We present a single center, single surgeon outcomes study, evaluating clinical and patient-reported outcomes after undergoing Awake or Asleep DBS lead placement in STN or GPI.

Methods

We conducted a retrospective review of 92 patients who underwent DBS surgery, either Asleep or Awake, for the treatment of PD and/or dystonia between 2018 and 2022. Surgical targets included globus pallidus internus (GPi) and subthalamic nucleus (STN), with overall cohort breakdowns as follows: 19 patients GPi/Asleep, 19 patients GPi/Awake, 29 patients STN/Asleep, 25 patients STN/Awake. Phone surveys were conducted using a modified quality of life survey (Euro-QoL-5D-5L) to assess patient-reported functional and clinical outcomes following DBS surgery. A chart review was performed to assess for objective differences among Awake and Asleep cohorts in parameters including pre- and post-operative clinical scales and medication dosing.  Six, 12, and 24 month post-operative time points were included as feasible. Comparison between patient-reported outcomes in asleep and awake cohorts, for both surgical targets, were analyzed.

Results

Across stimulation targets there were no significant differences between Awake and Asleep cohorts in the degree which DBS improved quality of life or whether patients would choose to undergo surgery again. The aggregate Asleep and Awake cohorts reported statistically significant improvements in walking, difficulty with activities of daily living, difficulty with performing work/leisure activities, and pain or discomfort due to their symptoms. The Awake cohort also reported significant improvements in anxiety or depression after DBS surgery, whereas the Asleep cohort did not. The Asleep STN had a statistically significant difference in experience of the surgical procedure, consistently reporting a better experience than the Awake STN subgroup.  No significant differences were found in the surgical experience between Awake versus Asleep GPi cohorts.

Conclusion

Asleep and Awake DBS techniques achieve similar outcomes across multiple domains. Asleep STN DBS patients report a more favorable surgical experience. Further studies with larger patient cohorts will continue to delineate patient outcomes differences between these two surgical approaches.

Background

The development of visualization techniques enabled surgeons to target structures for deep brain stimulation directly. However, the number of studies comparing the efficacy of asleep and awake DBS is limited.

Aim

The purpose of the present study was to compare the efficacy and safety of asleep vs awake DBS of the subthalamic nucleus in patients with Parkinson’s disease.

Material and methods

We conducted a randomized controlled trial to assess the efficacy of asleep STN-DBS in patients with Parkinson’s disease. The main group included 20 patients that had been operated on based on direct 3T MRI targeting (T1 SPGR, high-resolution T2, T2-FLAIR, and SWAN sequences) and intraoperative CT, while 20 patients of the control group have been operated on with the implementation of direct 3T MRI targeting, microelectrode recording, and intraoperative stimulation. The primary endpoints were: 1) the difference in motor improvement between the two groups measured as the decrease in the UPDRS III scores postoperatively, and 2) the difference in the rate of serious intra- and postoperative complications. Changes in quality of life, activities of daily living, levodopa therapy-induced complications, levodopa equivalent daily dose, and mild adverse events were chosen as the secondary endpoints. The follow-up period made up for 1 year.

Results

Both groups demonstrated significant improvement in motor function 1 year postoperatively. The UPDRS III OFF score decreased from 53.0 points to 13.5 points in the main group and from 52.5 points to 16.5 points in the control group. In the ON-medication state, these numbers were 16.5 and 10.5 in the main group and 16.5 и 8.0 in the control group. Levodopa-induced dyskinesias and fluctuations were reduced by 6 points in both groups assessed by UPDRS IV. Activities of daily living evaluated by the Schwab-England scale increased from 50 to 80% and from 40 to 70% in the main and control groups, respectively. No significant differences were found between the groups (Mann-Whitney U Test, p>0,05).

There were no serious intra- and postoperative complications in the present study. Stimulation-related complications were presented by stimulation dysarthria, which occurred in 4 patients of the main group and 3 patients of the control group. The noted differences were not significantly relevant (Pearson's chi-squared test, p0671), though the test power wasn't big enough due to a small number of cases.

Conclusion

Asleep deep brain stimulation of the subthalamic nucleus in patients with Parkinson’s disease can be performed with the same efficacy and safety as the standard awake DBS with the use of high-quality 3T MRI and intraoperative CT.

Background: A golden standard surgical method for STN-DBS surgery in Parkinson’s disease includes T2 weighted planar (mostly axial) MRI -based planning, awake multi-trajectory MER, intraoperative test stimulations and implantation of quadripolar electrode with “ring” contacts. Image guided asleep implantation with electronic brain -assisted 3D planning and segmented leads has been proposed as an alternative method. Objective: Here we aimed to compare outcomes between two completely different surgical approaches in a single center in Parkinson’s disease: planar image based awake surgery with MER and ring electrodes (PWMR) (n=65) and 3D electronic brain assisted planning and asleep surgery with segmented leads (EBSS) (n=35). Methods: Motor UPDRS scores (preoperative levodopa-OFF, preoperative levodopa-ON and postoperative levodopa-ON/DBS-ON) and levodopa equivalent doses before and 4-6 months after surgery were collected retrospectively at Tampere University Hospital between 2009 and 2022. PWMR was planned using Elekta Surgiplan / Medtronic S7 software and EBSS using Brainlab Elements software. Deviations from initial surgical trajectory either by selecting another trajectory for final electrode or enabling steering mode programming postoperatively were analyzed. The time spent in operation room (OR) was also compared. Results: Age, time from diagnosis or preoperative motor UPDRS did not differ between PWMR and EBSS groups either in levodopa OFF (38.1±10.4 and 38.1±10.4) or ON (13.0±6.1 and 12.6±8.6) conditions. Significantly lower motor UPDRS in levodopa ON - DBS ON condition was observed after EBSS compared to PWMR (4.5±5.8 and 14.0±8.8; p<0.001, independent samples t-test). Slightly greater reduction in levodopa equivalent dose was observed after PWMR compared to EBSS (59.1±21.2% and 51.7±21.6%), but difference was not statistically significant. The time spent in OR was significantly shorter in EBSS than PWMR (281±34min and 408±57min, p<0.001, independent samples t-test). One of the anterior trajectories (anterolateral, anterior or anteromedial) was chosen in 42.1% of trajectories in PWMR group instead of central trajectory. Current steering was used in 61.8% of the leads in EBSS group. Discussion: According to our experience, electronic brain -assisted delineations suggest slightly more cranial location of STN than comprehended earlier based on T2 axial images alone, where the surgical target was probably placed slightly more inferior and lateral in the area of most prominent low intensity T2 signal. Furthermore, MER might facilitate selection of more anterior trajectory and/or more deep final implantation depths due to MER signal characteristics. Conclusions: Different surgical approaches probably result in slight differences in final DBS lead location, where MER guided implants lie more anterior and inferior with respect to STN while image guided method results in more superficially placed leads in STN. Slightly greater levodopa decrease was observed after MER guided awake surgery, while greater reduction in motor symptoms was observed after image guided asleep surgery with frequently employed current steering possibility. Timewise, asleep surgery was far more effective.

Background: With the improvements in imaging and perioperative techniques of target verification, more Deep Brain Stimulation-surgeries (DBS) are performed with the patient under general anaesthesia (GA). While this is increasingly common regarding DBS in the pallidum and subthalamic nucleus, there are few published works regarding thalamic/subthalamic DBS for tremor in this manner.

Method: A retrospective comparison of the one-year outcome in our last 30 lead implantations targeting caudal Zona incerta (cZi) performed under local anaesthesia (LA) with the first 30 lead implantations under GA.  LA-DBS was performed with visual anatomical targeting on preoperative MRI, followed by intraoperative macrostimulation for target verification. In GA-DBS only visual anatomical targeting was performed. All patients were put under GA for the implantation of the extension cables and IPG. 11 were bilateral procedures but each side was individually evaluated with the other side turned off at follow-up. Postoperative CT-scans were performed for all patients. All patients were evaluated using the Essential Tremor Rating Scale (ETRS) on/off stimulation 1 year after surgery. Friedmans non-parametric test with Wilcoxon signed rank test as a post-hoc analysis was used for within-group analysis. Mann-Whitney U test was used as a between-group test.

Results: In the LA-group, total ETRS improved from a median of 52 at baseline to 20 (62%) on unilateral stimulation 1 year after surgery (table 2). Contralateral (Cl.) tremor and hand function improved from a median of 7 to 0 and 9 to 1, respectively. In the GA-group, total ETRS improved from 48 at baseline to 20 on stimulation 1 year after surgery (58%). Median cl. tremor and hand function improved from 6 to 0 and from 11 to 3, respectively. All within-group improvements were statistically significant and between-group tests did not show any significant differences between the groups.

Most common postoperative adverse events in both groups were transient speech and gait disturbances. One patient began LA-DBS but had to be rescheduled to undergo GA-DBS due to difficulties in mounting the frame because of severe head tremor. One patient in the GA-group developed small pulmonary embolisms after surgery without long-term effects on physical activity. No other serious events were recorded. Three patients in the LA-group had to undergo revision due to straining extension cables/IPG. 6 patients in the LA-group had an additional lead passage due to side effects intraoperatively whilst no leads in the GA-group were moved.   

The mean pulse effective voltage (PEV) and mean frequency (Hz) were lower in the GA-group (p<0.05, table 3). There was a trend towards lower amplitude and pulse width as well (ns).

Location of the active cathode in relation to the midcommissural point (MCP) was 12.4 mm lateral in the LA-group and 12.3mm in the GA-group, 6.7mm posterior in both groups and 1.9mm and 1.6mm inferior, respectively (ns).

Ordinal regression using contralateral tremor as the dependent variable and grouping (LA/GA) and months after first surgery (as a measure of the surgeons increasing experience) as independent variables found no significant odds ratios.

Conclusion: This retrospective comparison of awake and asleep cZi-DBS found no difference in clinical outcome on tremor or mean electrode location.

Objective: Delayed therapy escape is a serious yet frequent condition after thalamic deep brain stimulation (DBS) for essential tremor. It is a complex phenomenon and often associated with ataxia-like symptoms that leads to a significant decrease in quality of life. Due to the gradual evolution of these deficits, early recognition remains difficult. Hence, we aim to identify a diagnostic marker for delayed therapy escape to improve diagnosis and improve patient outcomes.

Methods: 31 patients with bilateral thalamic DBS for essential tremor gave informed consent and were included. Tremor, ataxia, and gait were assessed through operationalized and quantitative analyses including video-based motion capture and Fahn-Tolosa-Marin-Tremor-Rating Scale (FTMTRS) the Scale for the assessment and rating of ataxia (SARA). Examinations were carried out with activated DBS (ON) and directly after deactivation (OFF). We focussed on quantitative tremor analysis from the left arm, as the majority of patients were more affected on the left hand. If available preOP FTMTRS values were obtained. A higher FTMTRS more than 12 months after surgery compared to the score before DBS implantation indicated delayed therapy escape. To identify potential hallmarks of therapy escape, exploratory correlation analyses were conducted using a Pearson’s product-moment correlation coefficient between quantitative tremor features and clinical scores indicating therapy escape and ataxia. Test validity was assessed by computing receiver operating characteristics (ROC) curves. 

Results: PreOP FTMTRS scores were available for 16 patients, among them 5 patients with therapy escape. High values for the ratio of FTMTRS now versus preOP were associated with higher total power of postural tremor at OFF (r=0.779) and lower tremor frequency at OFF (r=-0.625), both on the left side (Fig1). The ratio of these two parameters (Power LOFF/Freq LOFF) yielded the highest pearson’s correlation coefficient (r=0.791) and an area under the curve of 0.89 in the ROC analysis (p=0.0149) (Fig2). Further, it correlated with high SARA values (r=0.694) and decreased step length (r=-0.784) at ON, both signs of ataxia (Fig1).

Conclusion: Frequency of postural tremor at OFF was previously suggested as an indicator of therapy escape (Sajonz et al. 2022). Here a low-frequent and high-power postural tremor at OFF using the ratio of Power LOFF/Freq LOFF was superior for identifying therapy escapers and might be a valuable diagnostic tool in the future. 

REFERENCES

1.     Sajonz, B.E.A., et al. NeuroImage: Clinical, 2022. 36: 103150.

Background

The current focus in thalamic lesioning and deep brain stimulation surgery (DBS) is on brain networks rather than separate nuclei. Understanding these networks is necessary for further unraveling pathophysiology and personalizing treatment in tremor. Long term effect of thalamotomy possibly offers insight in the optimal area for brain network modulation.

Methods

Our electronic database was used to identify tremor patients who underwent thalamotomy between 1990 and 2005 in our centre. Standardized questionnaires and neurological assessments (video recorded) were used for evaluating long term effect on tremor, possible side effects, additional lesioning/DBS surgeries and the use of tremor suppressing medicine.  Long term effect was determined by using the TETRAS (severity scale from 0 to 4); one year after surgery and on the day of the questionnaire.

Results

A total of 171 tremor patients underwent (unilateral) thalamotomy;  24 patients could be reached and were included. These were predominantly Parkinson’s disease and essential tremor patients. Average duration after thalamotomy was 21 years. One year after surgery 21 patients showed improvement in tremor; 19 patients improved ≥ 2 points. Of these 19 patients, 17 patients had a lasting tremor suppressing effect on the day of the questionnaire. In 13 patients adverse effects were seen; most reported (7) was transient dysarthria. Additional lesioning and/or DBS surgery was performed in 14 patients. In the subgroup of patients with Parkinson’s Disease the additional lesioning/or DBS surgery was seen most frequent (6 out of 8).  

Conclusion

This study shows that thalamotomy can have a long lasting tremor suppressing effect; extending up to 30 years. Compared to DBS surgery, lesioning does not entail brain implants and requires less demanding follow up; possibly making this a more accessible treatment for tremor. Currently 7 Tesla MRI scans are performed in a subgroup of the tremor patients in order to perform brain network (probabilistic structural connectivity) analyses. These analyses are used to correlate tremor networks, the location of the lesion within the networks and the long lasting tremor suppressing effect. 

Objective: Optimal target selection is even more essential for the success of thalamotomy for tremor that it is for non-ablative procedures as effect and side-effect persist and may not be influenced after the procedure.

Methods: In a consecutive series of 52 patients with pharmacotherapy resistant tremor disorders treated with magnetic resonance guided high-intensity focused ultrasound (MRgHiFUS) thamalotomy of the contralateral ventral intermediate (Vim) nucleus of the thalamus we switched our targeting practice from a site derived from DBS experience located 2 mm above the anterior-posterior (AC-PC) level to another site exactly at AC-PC level. No other parameters of the treatment were adjusted. The outcome was evaluated using standardized video-documented assessments and safety outcomes at baseline and 6 months after intervention.

Results: We identified a higher incidence of sensory disturbances at 6 months in the patient group treated 2 mm above AC-PC level (25% vs. 11%, p=.007). There were no significant differences regarding gait impairment (24% vs. 11%) and tremor suppression rates were similar (63.6% vs. 60.2%). The general patient satisfaction was high (87% would undergo MRgHiFUS treatment again).

Conclusion: While MRgHiFUS being equally effective regarding tremor control in both treatment groups, the more ventral target at AC-PC level was associated with a better risk-profile. In contrast to the general assumption of a safer target dorsally in the Vim regarding gait disorders we found referring to this no differences in both groups.

Introduction:

This study is a comprehensive analysis of the first 200 cases from a newly established Magnetic Resonance-guided Focused Ultrasound (MRgFUS) program for treating essential tremor (ET) and tremor dominant Parkinson’s disease (tdPD). Despite significant promise, MRgFUS is a relatively new technology and improvement in technique, outcomes, and reduction of complications over time have not been studied. Herein, we review trends in treatments and outcomes over time to assess if there is a positive trend with increased familiarity with MRgFUS.

Methods:

This retrospective study evaluated 200 consecutive unilateral MRgFUS treated patients with the diagnosis of ET and tdPD. Clinical outcomes were assessed at baseline and 6-month follow-up using standardized questionnaires and Clinical Rating Scale for Tremor (CRST) scores of the treated hand. Trends in outcome and treatment parameters over time were assessed. Logistic and linear regressions were utilized to formally assess trends in variables studied.

Results:

The majority of patients were male (67.9%) with an average age of 73 ± 9.0. ET was the dominant diagnosis (80.2%). Mean disease duration was 19.1 ± 15.9 years. Average skull score was 0.53 ± 0.1 with cavitation occurring in 27.8% of the cases. Mean number of sonications was 6.9 ± 1.5. Mean average and peak temperatures were 57.3 ± 2.3 °C and 61.6 ± 3.0 °C, respectively. Mean energy delivered per sonication was 16.8 ± 9.5 kJ. Mean treatment duration was 2.8 ± 0.8 hours. At 6-month follow-up, 89.5% of patients demonstrated greater than 50% reduction in CRST scores of treated hand. Side effects included decreased balance (20.8%), taste changes (7.7%), numbness (6.2%), speech changes (10.0%), and impaired cognition (6.9%). Notably, 51.9% of patients had no side effects.

Logistic regression analyses revealed an increase in reported taste side effects over time. Diagnosis of tdPD was associated with a significantly higher rate of speech (OR 3.95, p = 0.030) and cognitive (OR 4.89, p = 0.027) side effects at 6 months as compared with ET. No association was found between the rostral AC-PC target z-coordinate and side effect profile. Results are summarized in Table 1.

Conclusion:

MRgFUS is effective with an acceptable risk profile. Higher observation of taste changes across treatments is likely secondary to more focused examinations. More rostral targeting may not predict lower likelihood of side effects. tdPD patients are more likely to report post-treatment speech and cognitive changes. 

Objective: The use of magnetic resonance-guided focused ultrasound (MRgFUS) for the treatment of tremor related disorders and other novel indications has been limited by guidelines advocating treatment of patients with a skull density ratio (SDR) above 0.45±0.05 despite reports of successful outcomes in low SDR (LSDR) patients. Our goal was to retrospectively analyze the sonication strategies, adverse effects, clinical and imaging outcomes in patients with SDR below 0.4 treated for tremor with MRgFUS.

Methods: Clinical outcomes and adverse effects were assessed at 3- and 12-months after MRgFUS. Outcomes, lesion location, volume, and shape characteristics (elongation and eccentricity) were compared between the SDR groups.

Results: 102 consecutive patients were included in the analysis, of whom 39 had SDR ≤0.4. No patient was excluded from treatment because of low SDR, with the lowest being 0.22. Lesioning temperatures (>52° C) and therapeutic ablations were achieved in all patients. There was no significant difference in clinical outcome, adverse effects, lesion location and volume between patients with SDR above 0.4 and the LSDR group. The SDR was significantly associated with total energy (rho = -0.459, p < 0.001), heating efficiency (rho = 0.605, p < 0.001), and peak temperature (rho = 0.222, p = 0.025).

Conclusions: Our results show that treatment of tremor in LSDR patients using MRgFUS is technically possible leading to a safe and lasting therapeutic effect. Limiting the number of sonications, adjusting the energy, and duration to achieve the required temperature early during the treatment are suitable strategies in LSDR patients.

Introduction

No prior study has longitudinally assessed Essential Tremor (ET) using passively collected smartphone accelerometer data. Given the ubiquitous nature of smartphones, such a measure could be valuable for clinical care and therapeutic development.

Objective

To measure tremor outcomes in ET patients undergoing MRI-guided focused ultrasound (MRgFUS) thalamotomy using 1) active postural tremor surveys and 2) passive continuously measured smartphone accelerometer data from everyday phone use.

Methods

Patients with ET scheduled for MRgFUS installed the Beiwe application which continuously sampled smartphone accelerometers at 100 Hz. Outcomes per the Clinical Rating Scale for Tremor (CRST) were assessed at enrollment, day before and following MRgFUS, and at 3-month follow-up. Active postural tremor surveys using smartphones were conducted twice per week. Tremor in continuously measured smartphone accelerometer data was detected using a TensorFlow SPICE pitch estimation model. Spectral power was assessed in detected tremor events by evaluating the energy of the fundamental frequency and harmonic overtones.

Results

In a prospective study, 28 patients were included between December 2022 and April 2023, 9 patients have undergone MRgFUS thalamotomy as of abstract submission. Clinically rated postural tremor significantly decreased by 88% from baseline on the day following MRgFUS (p < 0.01). Average spectral power measured during active postural tremor surveys decreased by 90% following MRgFUS (p < 0.01). For tremor detected in passively collected accelerometer data using pitch detection, spectral power decreased by an average 80% following MRgFUS (p < 0.01). Postural tremor (CRST Part A) correlated with spectral power in active postural surveys, and with spectral power in passive data tremor events.

Conclusion

Tremor intensity could be monitored without patient input on a day-by-day basis. Further validation may allow accurate monitoring of tremor severity and treatment response to medications and surgical intervention completely passively.

Introduction

 Medically intractable Essential Tremor (ET) is a challenging condition. Thalamic deep brain stimulation (DBS) is effective, but not all patients are eligible or willing to undergo this procedure. Less invasive neurosurgical procedures such as radiosurgery and MRI-guided focused ultrasound have emerged as second-line options for creating thalamotomy. Recently, a minimally invasive technology called MRI-guided Laser Interstitial Thermal Therapy (MRIg-LITT) has shown promising results in the treatment of epilepsy and tumors. Here, we report a prospective pilot study to investigate the safety and efficacy of unilateral MRIg-LITT thalamotomy in patients with medically intractable ET.

Methods

The procedure involved placing a laser probe in the ventral intermediate nucleus of the thalamus using the ROSA robot system under general anesthesia. Targeting and trajectory planning were established using the ROSANA planning software, which allowed for automatic image fusion between preoperative MRI and CT scan images. Intraoperative guidance was provided by CT scans and microelectrode recording. After placing the probe, a single MRIg-LITT thalamotomy was performed using the Visualase system equipped with a diode laser.

The Fahn-Tolosa-Marin (FTM) scale was used to evaluate improvement of upper limb tremor at 3 and 12 months postoperatively, as assessed blindly by an external expert neurologist. Quality of life was assessed using the Quality of Life in Essential Tremor Questionnaire (QUEST), and cognitive performance was evaluated using the MMSE and the MoCA. Adverse effects were assessed through open-ended questioning and neurological examinations.

Results

Nine patients with medically intractable ET underwent unilateral MRIg-LITT thalamotomy. M age was 68.0±11.67 years, mean duration of tremor was 31.22±18.75 years. The study found significant improvement in tremor in the treated hand, as measured blindly on the FTM, from a mean baseline score of 15.33±2.12 to a score of 4.0±2.50 (p=0.008) at 3 months and 2.56±1.13 (p=0.007) at 12 months. Patients’ perceptions of their quality of life on the QUEST also improved significantly from a mean baseline score of 45.77±11.53 to a score of 16.54±14.88 (p=0.011) at 3 months and 11.79±10.51 (p=0.008) at 12 months. There was no significant difference in cognitive performance, as assessed by the MMSE and the MoCA, before and 12 months after the thalamotomy (p=0.672 and 0.263, respectively). However, dysarthria, proprioceptive disturbances, and gait balance issues were the most frequent adverse events, occurring in 55%, 55%, and 77% of patients, respectively. Nonetheless, these adverse effects were mostly transient and spontaneously resolved in less than a month. No serious adverse effects were reported, and no hospital readmissions were necessary.

Discussion

Unilateral MRIg-LITT thalamotomy seems to be an effective and safe technique to treat upper limb tremor in patients with medically intractable ET who are considered unsuitable or unwilling to undergo DBS surgery. In our opinion, using MRIg-LITT in conjunction with a stereotactic robot and intraoperative electrophysiological testing has multiple advantages over other methods such as DBS, radiosurgery, or MRIg-FUS for creating precise and small lesions like thalamotomies: (1) no hardware is required, (2) no titration is needed, (3) results are obtained quickly, (4) intra-operative patient participation is not required, (5) incisions are minimal, (6) recovery time is minimal, (7) real-time image guidance is available during lesion creation, (8) maximum accuracy is achieved based on the patient's own anatomy rather than an anatomical atlas, (9) head shaving is not required, and (10) there is no interference from skull-density. Additionally, MRIg-LITT thalamotomy seems to have only a few contraindications: (1) patients who cannot receive general anesthesia, (2) patients who are unable to undergo an MRI, and (3) patients who cannot temporarily discontinue anticoagulant or antiplatelet therapy. The preliminary safety and efficacy data presented here lay the foundation for a future trial with a larger cohort and represent an important step towards new treatment possibilities for ET.

Context and purpose: Pharmacoresistant tremors can cause multiple functional handicaps. Thalamotomy by Laser Interstitial Thermal Therapy (LITT) guided and monitored by Magnetic Resonance Imaging (MRI) is one of the recent alternatives to improve the quality of life of these patients. Although practiced since 2019 in the USA and Europe, no study of the spectroscopic and metabolic changes after thalamotomy by LITT has been published. The main objective of this prospective study was to combine MRI and proton Magnetic Resonance Spectroscopy (MRS) to follow up the morphologic, spectroscopic and metabolic features of the treated Ventral intermediate nucleus (VIM) thalamic region after LITT thalamotomy.

Methods: Follow-up from 23 patients, treated by LITT at Amiens-Picardie University Hospital (from March 2019 to date), consisted of MRI (T1, T2 FLAIR, T2*, Diffusion, Perfusion and 3DT1) and MRS (PRESS sequence with 3 Echo Times of 35 ms, 144 ms and 288 ms) data that were collected pre-operatively, at immediate post-operative, at D2/D7 post-operative, at M6 and M12 post-operative. 

Results: MRI results (from 23 patients at immediate postoperative, 21 patients at D2-D7 postoperative, 19 patients at M6 postoperative, and 9 patients at M12 postoperative) were based on the calculation of volumes of FLAIR and Diffusion hypersignals from the VIM region and yielded: the presence of small volumes of hypersignal at immediate postoperative on T2-FLAIR (mean: 0.104 ± 0.062 cm3) and on diffusion (mean: 0.225 ±0.118 cm3) sequences. These hypersignals increased in 100% of patients between D2 and D7 on T2 FLAIR (mean: 3.302 ±1.712 cm3) and on diffusion (mean: 1.455 v 0.806 cm3). These hypersignals then decreased by more than 98% on average in the long term M6-M12 on T2 FLAIR (mean M6: 0.061 ±0.042 cm3, mean M12: 0.026±0.029 cm3) and on diffusion (mean M6: 0.020 ±0.036 cm3, mean M12: 0.016 ±0.032 cm3). MRS results yielded spectroscopic and metabolic changes that were based on the calculation of metabolites ratios from 7/23 patients [Metabolites: Cr: Creatine, NAA: N-acetyl-aspartate, Cho: Choline, mI: Myo-inositol, Lac: Lactate]. We mainly noted that mI/Cr ratio was found to be increased in 100% of patients at immediate postoperative measurements and then tended to progressively decrease. Lac/Cr ratio was increased in 85% of patients at immediate postoperative time and/or at D2-D7, and then continuously decreased, although a persistent residual quantity of lactate was measured at the long term in 71% of patients.

Discussion and conclusion: The present results provide a comprehensive overview of the morphologic, spectroscopic and metabolic changes evolution of the LITT-treated VIM thalamic region. These changes were marked mainly by a fluctuation followed by a stabilization at the long term after (a low-intensity and short-duration LASER parameters) LITT thalamotomy. Thanks to the higher sensivity of MRS (compared to MRI), the strategy of combining MRI and MRS showed an added-value in the evaluation of LITT efficiency then the use of only MRI. Further investigations with a larger data follow-up, as well as an evaluation of the effect of thalamotomy on distant motor regions will be carried out. MRI and MRS features will be also correlated to clinical data in order to improve the implementation, analysis, interpretation and monitoring of this new innovative LITT thalamotomy.

Background: Patient specific targeting of the Ventral intermediate nucleus (Vim) of the thalamus can be acquired based on patterns of cortical and cerebellar connectivity. Although tractography based targeting methods have shown promise in visualising distinct thalamic nuclei, there are several drawbacks. 

Objective: To develop/present a new hybrid, high resolution and high-fidelity imaging modality; and to evaluate its accuracy in Vim-targeting. 

Materials and Methods:  Imaging and outcome data of 35 consecutive refractory tremor patients who had undergone 43 connectivity guided deep brain stimulation (DBS) and/or radiofrequency thermocoagulation (RF-T) between 2013 and 2021 were used. A novel, high fidelity computational MRI map which has both, diffusion and anatomical contrasts was created using individual preoperative connectivity MRI. The map shows intrathalmic contrast for individual thalamic nuclei. Post-hoc analysis was carried out of the degree of overlap between the newly created Vim-target, and the volume of tissue activation (VTA, in case of DBS) or lesion volume (in case of RF-T). This degree of overlap was compared between outcome groups: Outcomes were measured by experts blinded for imaging data at latest follow-up using a Clinical Global Impression-Improvement score (CGI-I), based on a combination of the Fahn-Tolosa-Marin tremor rating scale (FTMTRS) and noted functional tremor improvements, where a CGI-I score of 1-2 (i.e. FTMTRS improvement of ≥50%) was considered favourable.

Results: In 36 of the 43 (84%) performed surgeries (24 DBS and 19 RF-T), direct Vim-targeting was possible using the new hybrid map. For those with a favourable outcome (71% of the patients at a median follow-up of 13 months), the mean amount of overlap between the new Vim-target and the VTA or lesion was 42% (±13), versus only 17% (±15) for patients with an unfavourable outcome (MD 25%, 95% CI 14 – 35, p<0.0001). Retrospective use of this Vim-targeting method used as a tool to predict outcome had a sensitivity of 90%, specificity of 80%, positive predictive value of 90% and negative predictive value of 80%.

Conclusion: We present a new, high resolution and high-fidelity imaging modality, providing a fast and efficacious way of targeting the ventral intermediate nucleus of the thalamus. In this study, this new targeting method was highly accurate in predicting outcomes after deep brain stimulation and radiofrequency thalamotomy when compared to connectivity derived targeting.