Objective: The long-term effectiveness of a Deep Brain Stimulation (DBS) device capable of Multiple Independent Current Control (MICC) is assessed in a prospective, sham-controlled, double-blind randomized controlled trial (RCT) where participants are followed for up to 5-years for the treatment of motor symptoms of Parkinson’s disease (PD).

Background: Subthalamic Nucleus (STN) DBS is an established therapeutic option for managing the motor symptoms of PD, and here we report long-term open-label outcomes (up to 4-years) of a double-blind RCT with sham control using an MICC-based DBS device.

Methods: INTREPID (Clinicaltrials.gov identifier: NCT01839396) is a multi-center, prospective, double-blinded randomized controlled trial (RCT) sponsored by Boston Scientific. Subjects with advanced PD were implanted bilaterally in the STN with a multiple-source, constant-current DBS system (Vercise, Boston Scientific). Subjects were randomized to either receive active versus control settings for 12 weeks. Upon completion of the 12-week blinded period, subjects received their best therapeutic settings in the open-label phase up to 5 years. During long-term follow-up, motor improvement and quality of life was evaluated using UPRDS, PDQ39, and Schwann and England. Adverse events were also collected.

Results: Analysis of the pre-specified primary endpoint demonstrated a mean difference of 3.03 ± 4.52 hours (p<0.001) between active and control groups in ON time without troublesome dyskinesia, with no increase in antiparkinsonian medication, from post-implant baseline to 12-weeks post-randomization. A 49% (p<0.001) improvement in UPDRS III scores (meds off) at 1-year was previously reported and sustained up to 3-year follow-up (46%, p<0.001). Eighty-nine percent of patients at 3-year follow-up reported high satisfaction with their treatment. At 4-year follow-up, improvement in motor function (41%, UPDRSIII scores) and quality of life was sustained.

Conclusions: Long-term follow-up from the INTREPID RCT demonstrates that the use of a multiple-source, constant-current DBS system is safe and effective with sustained improvement in motor function and quality of life up to 4-years post-implant.

Introduction: 

Tremor circuitry has been commonly hypothesized as driven by one or multiple pacemakers within the cerebello-thalamo-cortical pathway, including the cerebellum, contralateral motor thalamus and M1. However, previous studies, using multiple methodologies, have advocated that tremor could be influenced by visual feedback. Furthermore, visual feedback itself would increase tremor and would be accompanied by abnormal changes, spreading outside the cerebello-thalamo-cortical pathway, in the visual system. 

Methods:

The study included 42 participants: 12 HC (group 1), 15 patients with essential tremor (ET) (group 2; right-sided, drug-resistant) before ventro-intermediate ncuelus (Vim) radiosurgery (RS) and the same 15 (group 3) one year after left unilateral Vim RS. Imaging was done on a head-only 3T magnetic resonance imaging (MRI) scanner, SIEMENS SKYRA (Munich, Germany, 32-channel receive-only phased-array head coil). We used blood-oxygenation-level-dependent (BOLD) fMRI during resting state to characterize dynamical interactions of the extrastriate cortex, and compare healthy controls (HC) against ET patients before and 1 year after Vim RS. In particular, we applied the co-activation patterns (CAPs) methodology to extract whole-brain spatial patterns of brain activity that occur dynamically over time. 

Results:

We found that three different patterns are equally occurring in HC and ET and were reminiscent for the “cerebello-visuo-motor” (1), “thalamo-visuo-motor”(including the targeted thalamus, 2), and “basal ganglia and extrastriate” (3) networks. The occurrence of the first one was decreased in pretherapeutic ET as compared to HC, while the other two showed increased occurrences. This suggests a misbalance between the more prominent cerebellar circuitry and the thalamo-visuo-motor and basal ganglia networks. Multiple regression analysis showed that pretherapeutic standard tremor scores negatively correlated with the increased occurrence of the thalamo-visuo-motor network, suggesting a compensatory pathophysiological trait. The clinical improvement after thalamotomy was related to changes of occurrences of the basal ganglia and extrastriate cortex circuitry, which came back to HC values after the intervention, thus suggesting a role of dynamics of the extrastriate cortex in tremor generation and further arrest after the intervention. 

Conclusion:

In sum, we found that resting-state dynamic functional connectivity of the extrastriate cortex can be characterized by three CAPs. These patterns corresponded to (1) a “cerebello-visuo-motor”, (2) a “thalamo-visuo-motor” and (3) a “basal ganglia and extrastriate” network. The first one is decreased in occurrence in pretherapeutic ET as compared to HCs, while the following two rather display increased occurrences. This would suggest a balance between the cerebellar circuitry, and the thalamo-visuo-motor and further basal ganglia ones. The pretherapeutic tremor scores correlated with the abnormal increase in occurrence of the thalamo-visuo-motor network, suggesting a compensatory pathophysiological trait. The improvement in tremor scores after Vim RS is more related to changes within the basal ganglia and extrastriate cortex. All these circuitries aligned to healthy controls after thalamotomy, suggesting a prominent role of the extrastriate cortex and its dynamic connectivity in tremor generation and further arrest after interventional procedures. This opens the discussion for a potential new target for tremor, as we previously advocated in earlier studies, aiming at the extrastriate cortex. These findings support the idea that the visual system plays a prominent role in tremor generation and further arrest after interventional procedures, such as Vim RS.

Background:

DBS of the VIM nucleus is an efficacious treatment for refractory essential tremor, although targeting the intra-thalamic nuclei remains challenging. In a previous work, using machine-learning algorithms, we were able to predict a clinical target for DBS in essential tremor. The learning database consisted in clinical and radiological features of patients previously operated on with optimal outcomes. The OPTI-VIM trial (NCT03760406) is now ongoing to validate this approach.

Patients and Methods:

In this prospective bi-centric (Lyon and Bordeaux), non-comparative, phase-2 clinical trial, we planned to include 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.

The target was planned with the “Optim-DBS” software we developed, 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:

Seven patients underwent surgery under general anaesthesia between June 2019 and January 2020 (4M/3F, mean age 63 years old).

The (pre-operative / post-operative) FTM scale means were 55/23.3. The mean improvement of the tremor was 55% on the FTM scale and 76% for the subscore of upper limb tremor. These scores were confirmed by accelerometry.

The (pre-operative / post-operative) SARA means were 5.9/4.2. Two patients worsened their SARA, the first one significantly worsened his ataxia with a score which increased from 4.5 to 10.5. The second one increased his score non-significantly from 3 to 4.

The (pre-operative / post-operative) PDQ39 means were 42.8/18.5, respectively. The mean improvement of quality of life were 58% on the PDQ39.

There were no surgical or device-related complications during the 3 months of follow-up.

The mean distance between the target and the electrode surface was 0.98mm (min 0, max 2.3).

Conclusions:

Asleep DBS for essential tremor using our machine-learning model for targeting may be a safe, efficient procedure leading to outcomes comparable to those published in the literature for standard awake DBS surgery. The final conclusions will be drawn once the study has been completed.

Objective

To assess the clinical and radiological outcome of 134 patients with esential tremor (ET) and tremor dominant Parkinson’s disease (PD) at 6 month follow up treated by magnetic resonance guided focused ultrasound (MRgFUS).

Background

The efficacy of unilateral Vim (Ventralis Intermedius) thalamotomies by MRgFUS in tremor has been reported. Some authors consider this nucleus as part of the VLp (Ventral Lateralis posterior). It receives projections from the dentato-rubro-thalamic tract (DRT).

MRgFUS is an image-guided, incision-less procedure based on the focalization of high intensity ultrasound beams in a precise area of the brain where it produces a thermal ablation.

The resultant lesion usually presents 3 different areas visible in magnetic resonance (MR): a central necrosis (i) surrounded by cytotoxic (ii) and vasogenic (iii) edema.

Methods

Treatment was performed using MRgFUS equipment (Ex Ablate 4000, InSightec) coupled with a high field MR (3T Skyra, Siemens). Skull density ratio (SDR) was calculated in all patients before treatment. Parameters like intensity and duration of sonications were modulated during the procedure to achieve the target temperature.

Pre-treatment and immediately after treatment 3T MR studies were acquired in all patients. Classic coordinates were used for targeting of the Vim. Probabilistic tractography of the DRT was performed placing the regions of interest (ROIs) in the thalamus, premotor cortex and dentate nucleus (SyngoVia, Siemens).

Volumetry (areas i, ii and iii) and diameter of the lesions were analyzed by manual delineation on 3D T2 SPACE MR sequences with the Iplannet planification software (Brainlab). The volumes were exported as 3D objects and were superimposed onto individualized probabilistic atlas of the thalamic nuclei. Overlapping regions were studied.

Tremor severity was assessed at baseline, 1 (1m), 3 (3m), and 6(6m) month (follow-up using the Clinical Rating Scale for Tremor (CRST) in ET patients and the tremor items of the Unified PD Rating Scale (UPDRS) in PD patients.

Side effects were classified as mild (slight disturbances), moderate (partial impairment of daily activities), or severe (established neurological deficit with any level of disability).

For the statistical analysis, Mann Whitney U and Pearson correlation tests were applied with the STATA statistical tool.

Results

134 patients (87 ET, 47 PD; mean age 72.9 y.o; male 77%) underwent Vim thalamotomy contralateral to the patient´s hand tremor from october 2018 to december 2019. In patients with ET, the contralateral CRST score improved 80,98% (1m, 83 patients), 74% (3m,58 pt), 78% (6m, 34 pt). In PD patients, tremor improvement was 84,78% (1m, 37 pt), 78,84% (3m, 24 pt) and 65,35% (6m,16 pt). 

The most common side effects were gait instability and dysmetria, followed by dysarthria and finger or lip/tongue paresthesias. At 1m, 64% of the patients presented adverse events; 27,5% at 3m and 12,5% at 6m. More than 80-90% were mild, 10-15% were moderate and 0-4% were severe along the 6m period.  

Average volume of the lesions was 11,5 (i); 157,6(ii) and 376,3 (iii) cm3. The average outer volume of the lesions was 404,4 cm3. Mean diameter: 8,9 mm. Larger volumes were directly correlated with a greater number and severity of side effects at 1m, 3 m and 6m (moderate correlation; p<0,05).

Overlapping of individual atlas segmentation and lesions was performed in 47 patients. The mean overlapping percentage of the atlas VLp and the lesion was 70.44% (i), 58,37(ii) and 47,08 (ii). The overlapping region of the necrosis was inferior in those patients whose tremor responded worse to treatment (p<0,01)

Pre-treatment DRT tracts were used as an adjuvant tool during treatment to adjust the targeting coordinates when initial clinical response was poor.

Mean temperature (t) was 58,22º. SDR values were directly correlated with t (r=0,43; p<0,001); i and ii volumes (r=0,28 and 0,37; p<0,001); and inversely correlated with intensity (r=-0,64; p<0,01) and sonication duration( r=- 0,53; p<0,01).

Conclusions

MRgFUS thalamotomy for ET and PD is associated with a great improvement of tremor at 6m follow-up. Although side effects are frequent, the majority are mild. Larger lesions have an impact on its occurrence. SDR values play a role on the treatment outcome.

Objective Deep Brain Stimulation (DBS) of the Posterior Subthalamic Area (PSA) is an emergent target for the treatment of Essential Tremor (ET). Due to the hetereogenous and complex anatomy of the PSA  it remains unclear which specific structures mediate tremor suppression and different sorts of side effects. The objective of the current work was to yield a better understanding of what anatomical structures mediate different clinical effects observed during directional DBS of the PSA.

Methods We analysed a consecutive series of 12 ET patients. Imaging analysis and systematic clinical testing performed 4-6 months postoperatively yielded location, clinical efficacy and corresponding therapeutic windows for 160 directional contacts. Overlap ratios between individual stimulation activation volumes (VTA) and neighbouring thalamic and subthalamic nuclei as well as individual fiber tracts were calculated. Further, we generated stimulation heatmaps to assess the area of activity and structures stimulated during tremor suppression and occurrence of side effects.

Results Stimulation of the Dentato-Rubrothalamic Tract (DRTT) and the Zona incerta (Zi) was most consistently correlated with tremor suppression. Both individual and group analysis demonstrated a similar pattern of activation for tremor suppression and different sorts of side-effects. Unlike current clinical concepts, induction of spasms and paresthesia were not correlated with stimulation of the corticospinal tract and the medial lemniscus.  Furthermore, we noticed a significant difference in the therapeutic window between the best and worst directional contacts while the best directional contacts did not provide significantly larger windows than omnidirectional stimulation at the same level.

Conclusion PSA DBS is effective in suppressing all aspects of ET but can be associated with concomitant side effects limiting the therapeutic window. Activation patterns for tremor suppression and side effects were similar and predominantly involved the DRTT and the Zi. We found no different activation patterns between different types of side effects and no clear correlation between structure and function. Future studies with use of more sophisticated VTA modelling taking into account fiber heterogeneity and orientation may eventually better delineate these different clusters, which may allow for a refined targeting and programming within this area.

INTRODUCTION

High-frequency deep brain stimulation of the subthalamic nucleus is the preferred surgical treatment for advanced Parkinson's disease. A recent innovation in this technique is the advent of directional leads allowing for current steering, which can increase the stimulation threshold for adverse effects and widen the therapeutic window. However, selecting programming settings is time consuming as it entails a thorough monopolar clinical review. To overcome this, directional stimulation programming may be guided by intraoperatively recording local field potential beta oscillations (13-35Hz) from the implanted leads.

OBJECTIVE

Objective of this study is first, to evaluate whether the power of beta oscillations intraoperatively recorded from directional local field potentials can predict the clinically most effective contacts; and second, to assess the clinical impact of beta-based programming of directional deep brain stimulation at long term follow-up.

MATERIAL AND METHODS

We conducted a non-randomized, open-label, prospective study with 24 Parkinson`s Disease patients (mean age 55.8 years, 66.7% male), divided in two groups. In the group A (14 patients, 2016-2018), we investigated whether beta activity in the directional contacts correlated with clinical efficacy (defined by clinical monopolar review, blinded to beta activity). Stimulating parameters were selected according to the clinical monopolar review, assessed with a mean follow-up of 27 months (15-38 months). In the group B (10 patients, 2018-2019), stimulating parameters were selected according to beta activity and assessed with a mean follow-up of 14 months (6-21 months).

RESULTS

Neurophysiological results showed that the strongest correlation between beta activity and clinical efficacy was obtained with the low-beta sub-band (13-20Hz) rather than with total beta activity (13-35 Hz). Contacts with highest beta peaks increased the threshold window by 25%. Selecting the two contacts with highest beta peaks provided 82% probability of selecting the best clinical contact. Clinical results showed similar improvement of motor features with reduced need of dopaminergic medication in both groups.  In group A (stimulation parameters based on clinical monopolar review), showed a 78% UDPRS-III reduction and 60% LEDD reduction. In group B (stimulation parameters based on beta peak power), showed a 75% UDPRS-III reduction and 62% LEDD reduction. Importantly, this clinical improvement was maintained at long-term follow up.

CONCLUSION

Our results demonstrate the clinical efficacy of directional stimulation over 3 years of follow up and validate the use of intraoperative local field potentials beta oscillations to guide the initial programming of long-term directional deep brain stimulation in Parkinson`s disease. Local field potential-guided programming provides a unique opportunity to adjust the stimulation for each individual patient, and the combination of physiological guidance with directionality will allow us to shape activation volumes tailored to patient needs  

Background:Subthalamic nucleus (STN) deep brain stimulation (DBS) can ameliorate motor symptoms in Parkinson’s disease (PD), however, its utility as well as mechanism in reducing comorbid major depression remained uncertain. Here, we shed light on the neural mechanism of STN-DBS in managing comorbid treatment-resistant depression (TRD) in PD.

Objective:To assess motor symptoms, depressive symptoms, quality of life, and regional cerebral glucose metabolism before and after STN-DBS in PD patients with TRD.

Method:We prospectively studied 18 PD patients with TRD (d-PD) who underwent bilateral STN-DBS and an age- and sex-matched group containing 16 health controls. Clinical assessments were performed before and after STN-DBSat approximately 1-year follow-up. Cerebral regional glucose metabolism was assessed by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) before and after STN-DBS.

Results:After STN-DBS, the d-PD patients presented a substantial reductionon both motor and depressive symptoms. Improvement was also observed in their daily functioning and quality of life, whereas cognitive functioning was not significantly modified. Compared to controls, d-PD patients had widespread abnormalities in cerebral regional glucose metabolism before surgery  which were partially restored after STN-DBS. Moreover, improvement in depressive symptoms were associated with metabolic patternrestoration in brain regions implicated in emotional regulation (i.e., right inferior frontal gyrus, right orbitofrontal cortex and right lingual gyrus.).

Conclusion:STN-DBS may offer additional benefits in d-PD patients. The antidepressant effects appears to be associated with the restoration of abnormal glucose metabolism in widely distributed networks involved in emotion, motivation, and attention.

Introduction: Magnetic Resonance-guided focused ultrasound thalamotomy (MRgFUS) is an effective treatment for tremor, however, side effects may occur. The purpose of the present study was to investigate the spatial relationship between thalamotomies and specific sensory side effects as well as their functional connectivity with somatosensory cortex and relationship to the medial lemniscus (ML).

Methods: Of 103 patients treated with MRgFUS for tremor, 17 developed sensory side effects after thalamotomy persisting 3 months after the procedure. These side effects were categorized into four groups based on the location of the disturbance: face/mouth/tongue numbness/paresthesia, hand-only paresthesia, hemi-body/limb paresthesia, and dysgeusia. Then, areas of significant risk (ASR) for each category were defined using voxel-wise mass univariate analysis and overlaid on corresponding odds ratio maps. The ASR area associated with the maximum risk was used as a region-of-interest in a normative functional connectome to determine side-effect specific functional connectivity. Finally, each ASR was overlaid on the medial lemniscus derived from normative template.

Results: Thalamotomies producing sensory side effects extended posteriorly into the principle sensory nucleus of the thalamus. Thalamic regions associated with significant risk of the specific sensory side effects were distributed according to the somatotopy of the sensory thalamus, with the dysguesia ASR being located the most medial. ML fibers touched by ASRs were found to be organized according to the known somatotopic organization of the ML below the thalamus and at the level of the midbrain. Positive functional connectivity was found between each of the sensory-specific thalamic seeds and the primary somatosensory cortex and insular cortex.

Discussion: Distinct regions in the sensory thalamus may give rise to specific side effects when included in a thalamotomy lesion. These findings demonstrate the relationship between the sensory thalamus, ML, and bilateral sensory cortex. The functional connectivity patterns found between the sensory-specific thalamic seed regions and the insular cortex support the role of the insula in primary processing of gustatory information and also in multi-sensory integration.
 

Objective:

In this retrospective study we analyzed the surgery‐ and hardware‐related morbidity of deep brain stimulation within 30 days after surgery.

Methods:

600 functional stereotactic operations (DBS electrode implantation or radiofrequency lesioning) were performed from 1997 to 2018. All procedures were performed or supervised by the senior neurosurgeon in three different centers using the same technique. The target was determined with CT-stereotactic surgery supplemented by MR imaging and approached via a guiding cannula. MER was performed in 2/3 of the cases via a single channel technique, supplemented by additional trajectories if decided necessary. Surgery was performed while patient was awake in 531 instances. Postoperative CT scans obtained within 24 hours after surgery were searched for haemorrhage of any size at any site. Hardware- or other surgery-related complications within 30 days after surgery were documented.

Results:

A total of 251 women and 349 men with a median age of 55 years were operated. The majority of patients underwent DBS (580), while a subset had radiofrequency lesioning procedures (20). Overall in 19 (3.25 %) procedures an intracranial haemorrhage was detected, which was asymptomatic in all patients except in 1 patient (0,16 %), who had a persistent mild hemiparesis on the right side. Early infections were noticed in 3 patients (0,53 %), 1 at the site of the IPG, 2 at the site of the cranial skin incision. Four patient (0,7 %)  had an intraoperative seizure, and 2 (0,3 %) had a seizure one day after surgery. Three patients (0,53 %) had clinically relevant intraoperative air embolism, and in 1 patient (0,16 %) pulmonary embolism occurred. One patient (0,16 %) had an acute coronary syndrome during IPG implantation, in four patients (0,7 %) surgery terminated because of cardiac coronary syndromes were suspected, which however, weren’t confirmed later.

Conclusions:

Stereotactic functional surgery is a generally safe procedure with low morbidity and no mortality when performed by an experienced team. Intraoperative haemorrhage constitutes the highest surgically related complication. Awake surgery is tolerated without relevant problems by the majority of patients. Infections within 30 days after surgery are rare.

Objective: Camptocormia is a common and often debilitating postural deformity in Parkinson's disease (PD). Few treatments are currently effective. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) shows potential in treating camptocormia, but evidence remian limited to case reports. We here report the effect of GPi-DBS in the treatment of camptocormia in a retrospective cohort of PD patients.

Methods: Video recordings of patients who recieved GPi-DBS were retrospectively reviewed. The total and upper camptocormia angles (TCC angle and UCC angle), were used to compare camptocormia alterations. The Unified Parkinson’s Disease RatingAssessment Scale Part III (UPDRS-III) was used to assess the patients’ motor symptoms.

Results: Thirty-six consecutive patients with advanced PD who underwent GPi-DBS were reviewed. Twelve patients manifested per-operative camptocormia: eight had lower camptocormia (TCC >30°; TCC-camptocormia), four had upper camptocormia (UCC >45°; UCC-camptocormia). Mean follow-up time was 7.3 ± 3.3 months. GPi-DBS improved TCC-camptocormia by 40.4% (angle from 39.1° ± 10.1° to 23.3° ± 8.1°, p=0.017) and UCC-camptocormia by 22.8% (angle from 50.5° ± 2.6° to 39.0° ± 6.7°, p=0.012) (Fig.1).Larger improvement was seen in patients with a larger pre-surgical TCC angle. No significant outliers among the leads were identified through the location analysis (Fig.2).

Conclusion: Our study demonstrates the potential effectiveness of GPi-DBS for treating camptocormia in PD patients. Controlled studies with larger numbers of unselected camptocormia patients should extend our findings.

Figure Legends

Fig. 1. Pre- and post-surgical total- (A) and upper (B) camptocormia angles (TCC/UCC angles) in patients with lower camptocormia (blue symbols and lines), upper camptocormia (red symbols and lines) and without camptocormia (green symbols and lines). *p < 0.05; ns: not significant. 

Fig. 2. The DBS leads of all patients with TCC-camptocormia (A) and UCC-camptorcormia (B) were merged on the T2-weighted (upper) and T1-weighted (lower) Montreal Neurological Institute (MNI) templates, with active contacts marked in red. Masses with yellow described the location of the STN, red for the red nucleus, green for the GPi, blue for the globus pallidus externus (GPe).

Impairments of gait and balance are amongst the most disabling and least well-understood symptoms of Parkinson's disease (PD). Well-established neuromodulation therapies for PD are highly effective for the treatment of upper-limb motor symptoms such as tremor or bradykinesia. However, these approaches exhibit modest results for alleviating locomotor deficits, presumably because the control of gait involves additional pathways governed by different neural dynamics.

A key limitation holding back the design of novel therapies is the lack of mechanistic readouts that may help understand and capture pathological neural activity patterns related to leg dysfunction. Here, we sought to identify the cortical and subcortical neural signatures underlying leg movements in PD. We recorded the local field potentials from deep brain stimulation electrodes implanted in the subthalamic nucleus (STN) in conjunction with 64-channel cortical electroencephalographic (EEG) in patients with advanced Parkinson's disease, as they performed a well-controlled leg motor task requiring single-joint modulations of force (high and low force).

We found distinct modulations in STN and EEG frequency bands that strongly correlate with leg motor effort, predominantly in the low beta (~13-20Hz), high beta (~20-35Hz) and gamma (35-90Hz) bands. In particular, high beta desynchronization was time-locked to leg muscle recruitment and maintained throughout force production with amplitudes that correlated with effort, both in STN and EEG (predominantly central sensorimotor electrodes) signals. Low beta and low gamma (35-50Hz) bands also exhibited modulations with leg movements, but with behaviors that differed across patients and between EEG and STN. Interestingly, force-related correlates were identified in STN and EEG regardless of the mobilized leg joint (ankle or knee) or of the direction of movement (flexion or extension), although power differences across force levels varied for each condition.

Our results highlight clear neural patterns underlying effort-related leg movements, both in STN and EEG signals, which hold promises to help clarify the role of such networks during adaptations in gait, initiation and turning, or during episodes of shuffling steps or freezing. Our results additionally emphasize differences across patients in specific frequency bands, which may be related to the pathology of each subject, and which may critically need to be accounted for when developing therapies that address leg-related disorders in PD.

Most patients with advanced Parkinson's disease (PD) suffer from disturbances of gait and balance, which severely affect their everyday mobility, independence and quality of life. Unlike upper-limb motor symptoms, these deficits respond poorly to commonly available therapies. A key limitation holding back the design of better focused, evidence-based therapies stems from the lack of biomarkers that correlate pathological neural activity patterns and leg dysfunction during gait. However, this identification is contingent on technologies, concepts and methodologies allowing to simultaneously record and link brain states to whole-body biomechanical features representative of gait deficits.

Here we employed a whole-body gait monitoring platform, operating wirelessly and in real-time, to map the activity of the subthalamic nucleus onto kinematic and muscle activity patterns while patients executed a range of locomotor activities. We contrasted the neural correlates underlying basic walking, turning and precision locomotion in order to uncover the STN involvement in locomotor tasks requiring different levels of muscle recruitment and effort.

Similarly to our previous observations during a single-joint leg motor effort task, we found that STN activity patterns exhibit distinct modulations in low beta (~13-20 Hz), high beta (~20-35 Hz) and low-gamma (~35-50 Hz) power during gait, which were aligned to the recruitment of well-defined leg muscle groups (synergies) during each phase of gait, initiation and turning. Although STN patterns displayed significant differences across patients, they all exhibited clear monotonic modulations with effort that correlated in time with increases in muscle synergy activations related to propulsion. We additionally identified specific modulations in patients suffering from freezing of gait.

These results reinforce the link between STN activity patterns and the modulation of vigor in locomotor networks, and may help predict the signatures that underlie propulsion-related deficits of gait and balance in PD, such as asymmetry, shuffling steps or eventually freezing of gait. Our results additionally emphasize particularities in individuals that exhibit freezing, which may critically need to be accounted for when developing therapies that address leg-related disorders in PD.

Cognitive outcomes following deep brain stimulation (DBS) in Parkinson’s disease (PD) have gained much attention with particular concern for verbal fluency. Current stimulation paradigms utilize high (gamma) frequency stimulation for optimal motor benefits; however, little work has been done to optimize stimulation parameters for cognition. Recent evidence implicates a role of subthalamic nucleus (STN) low (theta) frequency oscillations in executive function and suggests that theta frequency stimulation could improve executive function in PD. The aim of this study was to evaluate the acute on/off effects of bilateral gamma frequency STN stimulation on verbal fluency and executive function in PD and compare with the effects of theta frequency stimulation.

Twelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized neuropsychological evaluation during stimulation at (1) 130-135Hz (gamma, baseline), (2) 10Hz (theta) and (3) off. Processing speed, verbal fluency, and executive functions were evaluated using a verbal fluency task (phonemic, episodic, nonepisodic, and switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects. Preoperative (mean 4.7 months) scores were compared with postoperative (mean 11 months) scores.

Theta frequency stimulation significantly improved  compared to gamma frequency stimulation (p=0.02), but not compared to off (p>0.05). There were no significant differences between stimulation frequencies in phonemic or nonepisodic verbal fluency, color-word interference or random number generation (p>0.05). Comparing preoperative to postoperative scores, there were no differences in verbal fluency or color-word interference (p>.05).

Our study is the first to show improved episodic verbal fluency during theta versus gamma frequency stimulation, corroborating a role of theta oscillations in cognition. Further work is needed to explore if theta frequency stimulation can be interleaved with gamma frequency stimulation to concomitantly improve both motor and cognitive outcomes.

Background/ Aims: Deep brain stimulation (DBS) has demonstrated pronounced benefit in treating dystonic conditions, however adverse events (AE) related to the procedure might impact the outcome. DBS-related AEs have been reported in literature; nevertheless, one unanswered question relates to whether the rate of complications is higher in patients with severe dystonia when compared to patients with less severe forms. 

The aim of this study was to first, determine which features explain the best dystonia severity at baseline and second, whether the frequency of DBS AEs was related to symptom severity.

Methods: A total of 80 patients treated with DBS for dystonia in a single center over 20 years were evaluated. We considered the occurrence of dystonic storm (DS) prior to DBS as a criterion for dystonia severity. We performed a case-control study in order to compare 40 patients who developed at least one DS episode (group 0) with a reference group who did not (group 1), matched for sex, age at first DBS and clinical phenotype. 

Related to DBS complications, we considered infection, hemorrhage, lead fracture, extension cable fracture or tension requesting surgical replacement and skin erosion. All patients were treated for dystonia with initial bilateral pallidal stimulation. 

First, we aimed to explain dystonia severity as expressed by the Burke Fahn Marsden dystonia rating scale (motor section) at baseline previous to DBS administration, based on the following variables: gender, family history, age at symptom onset, type of movement disorders, other neurologic or systemic manifestations, etiology, age at worsening with functional disability, number of SD episodes pre-DBS, disease duration pre-DBS, symptom distribution at onset, abnormal movements and postures at onset, duration of ICU stay pre-DBS, distribution of MRI abnormalities. 

Analysis was performed for n=37 subjects from group 0 and n=32 from group 1, for whom all the variables were available. Several machine learning algorithms have been used such as linear regression as well as models based on decision trees (Random Forest and Xgboost). We tested parameters and hyperparameters to obtain the combination providing the best accuracy. To validate model accuracy, mean absolute error (MAE) and root mean square error (RMSE) have been applied and cross-validation for each algorithm and for each group. 

Second, we assessed complications following DBS surgery for n=35 subjects from group 0, for whom 64 features were available and studied. Machine learning algorithms have been applied with use of Random Forest Classifier and XGBoost Classifier. 

Results: Generalized symptom distribution at disease onset was the most frequent presentation among group 0 (42.5%), vs. focal symptom distribution in group 1 (43.6%), p<0.005. Among group 0, 75% patients presented disability at disease onset (gait disturbance, hand movement or sitting abnormalities, dysarthria, dysphagia or dyspnea) vs. 20.5% of patients in group 1, p<0.005. An independent-sample t-test was conducted to compare the preoperative M-BFMDRS scores for both groups. There was a significant difference in scores for DS-patients (mean 85.15 ± 19.92) and non-DS patients (mean 57.80 ± 19.03), p<0.005.

Surgical revision was performed in 37,5% of subjects from group 0 vs. 25% from group 1 (p>0,05). Infections occurred in 20% of the subjects from group 0 vs. 11,1% from group 1. Lead fracture occurred in 20% vs. 17,1% in groups 0 and 1, respectively. No bleeding occurred in both groups. Revision of lead position was more frequent in group 1.

Based on the correlation matrix and models applied, the main features explaining the dystonia severity scores at baseline for group 0 were the following: age at worsening with functional disability and age at symptom onset, symptom distribution at onset, etiology, disease duration before DBS and MRI abnormalities of cortical distribution and for group 1, disease duration pre-DBS, symptom distribution at onset and age at worsening with functional disability.

The main features explaining hardware related complications were etiology, age and symptom distribution at dystonia onset.

Conclusion: DS prior DBS, generalized symptom distribution and disability at disease onset seem to be surrogates for dystonia severity. DBS-related AEs appear to be higher in severe dystonia, which could be due to the fact that these patients have a poorer clinical condition and hence are more prone to surgical complications.

Background: Deep Brain Stimulation (DBS) is an established therapy for medication-refractory Essential Tremor (ET). However, predictors of outcome and the optimal stimulation site remain a matter of controversy.

Objective: The objective of this study was to collect clinical and neuroimaging data of a large cohort of patients with DBS for ET from different European centers to identify predictors of outcome and to construct a probabilistic stimulation map and identify an optimal stimulation site.

Methods: This study enrolled 119 ET patients treated chronically with unilateral or bilateral DBS operated at five different European DBS centres for retrospective analysis of data on baseline covariates, pre- and postoperative clinical tremor scores (12-month) as well as individual imaging data to obtain individual electrode positions and stimulation volumes.  We calculated a stimulation map using voxel-wise statistical analysis. We used multiple regression analysis to estimate predictors of tremor reduction.

Results: The mean tremor reduction per patient across all centers was 59.3 % (55.7 – 62.9%, 95% CI). Preoperative tremor severity was the only baseline clinical characteristic that was significantly associated with outcome (r² = 0.05, p= 0.03). We identified an area of optimal stimulation that extended from the posterior part of the PSA to the Vim and coincided with the area of highest likelihood to contain the DRTT. The anatomical location of stimulation was the overall best predictor of outcome.

Conclusions: Our multicentre ET probabilistic stimulation map identified an area of optimal stimulation along the course of the DRTT. This target may be used to guide surgical planning and for computer-assisted planning and programming of deep brain stimulation to in the future.

Introduction, objective

It is unknown if there is a difference in outcome in asleep versus awake deep brain stimulation (DBS) of the subthalamic nucleus for advanced Parinson’s disease.

Objective: We hypothesized that there would be a difference in adverse effects concerning cognition, mood and behavior between awake and asleep DBS favoring the asleep arm of the study. We further hypothesized that the motor outcomes would be identical between the groups.

Methods

The study was a single-center prospective randomized open-label blinded end-point trial. There were 187 persons with Parkinson’s disease referred for DBS between May 2015 to March 2019 and of those 110 were eligible for participation in the study. The primary outcome follow-up visit was conducted six months following DBS.

Bilateral subthalamic nucleus DBS was performed asleep (under general anesthesia) or awake without sedation. Both arms of the study used a frame-based intraoperative microelectrode recording technique for placement of the DBS leads.

The primary outcome variable was the between group difference in cognitive, mood and behavioral adverse effects as measured by a composite score. The secondary outcomes included the Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), the patient assessment of surgical burden and operative time.

Results

The participants were randomized to awake (local anesthesia) (N=56, mean age 60.0 years (SD7.4), 40 male (71%)) or to asleep (general anesthesia) (N=54, mean age 61.3 years (SD7.9), 38 male (70%)) DBS surgery. The six months follow-up visit was completed by 103 participants. The proportion of patients with adverse cognitive, mood and behavioral effects on the composite score was 15 of 52 (29%) after awake and 11 of 51 (22%) after asleep DBS (odds ratio 0.7 (95% CI 0·3-1·7)). There was no difference in improvement in the off-medication MDS-UPDRS Motor Examination scores between groups (local anesthesia -27·3±17·5 points, general anesthesia -25·3±14·3 points, mean difference -2·0 (95% CI -8·1 to 4·2)). Asleep surgery was experienced as less burdensome by the patients and was 26 minutes shorter than awake surgery. 

Conclusion

There was no difference in the primary outcome of asleep versus awake DBS. Future large randomized studies should examine some of the newer asleep based DBS technologies as this study was limited to frame-based microelectrode guided procedures.

Introduction 

Since the first implantation of a deep brain stimulation system carried out by Pollack and Benabid in essential tremor, it became the gold standard treatment in the 30 years in movement disorders. Today, accurate planning and electrophysiological mapping of the target region is still essential to achieve successful results. Since 2017, the introduction of diffusion tensor imaging, tractography and their routine use in our department, the technique provided a valuable tool to non-invasively map and pinpoint the stereotactic target in 42 Parkinson’s disease, 8 dystonia, and 19 tremor patients. This trend steers us further away from awake surgeries even in tremor DBS, where anatomical boundaries of the ventral intermediate nucleus, mainly the closeness of the sensory thalamic nuclei can result in unwanted sensations under stimulation. 

Materials and methods

16 patients were enrolled in this study. Each patient underwent a preoperative MRI session under general anesthesia, T1, T2, contrast enhanced T1, and DTI images have been acquired in two different centers (10 patients - Philips Achieva - 32 directions, b0=800; 7 patients - Siemens Magnetom Verio 64 directions, b0=1000). Preoperative DTI analysis and fiber tracking has been carried out using tools available in FSL 6.0 (FMRIB) and Freesurfer 6.0 (Martinos Center for Biomedical Imaging). Reconstruction of diffusion tensors, probabilistic fiber tracking, and visualization of the results has been carried out on a Titan XP GPU based system. Connectivity segmentation of thalamus, to visualize the sensory nuclei and the Vim, the traversing lemniscal and dentate-rubro-thalamic pathways were done preoperatively, results were integrated into a Medtronic Cranial Planning Station. Implantation of DBS leads has been carried out using a Leksell stereotactic G frame and a ROSA stereotactic robot system. Intraoperative electrophysiological mapping and macrosimulation were done to control the imaging results.

Results

Of the 32 implanted electrodes patients 29 were within a 1 mm close range of the DRT, 65,63% was placed within the tract. The remaining 3 electrodes were within a 2 mm range. Sufficient tremor control was achieved in all of the implanted patients, no sensory side effect has been observed under implantation or postoperative programming, chronic stimulation. Optimal tremor control was found near the thalamic entry of the DRT. 

Discussion

Visualization of the DRT, the sensory nuclei, and the lemniscal pathways provide a patient specific implementation of DBS surgery. Relying only on standard stereotactic coordinates might result in unwanted side effects, sensory activation during stimulation. The described method is not only sufficient to achieve tremor control but can also minimize the possibility of suboptimal lead placement, thus might reduce the requirement of intraoperative electrophysiology and awake surgery.

Background:

Deep brain stimulation (DBS) of the Pedunculopontine nucleus (PPN) has been investigated for the treatment of levodopa-refractory gait dysfunction in Parkinsonian disorders, with equivocal results so far.

Objectives:

To summarise the clinical outcomes of PPN-DBS treated patients at our centre and elicit any patterns that may guide future research.

Materials and Methods:

Pre- and post-operative objective overall motor and gait subsection scores as well as patient-reported outcomes were recorded for six PPN-DBS treated patients; three with Parkinson’s disease (PD) and three with Progressive supranuclear palsy (PSP). Electrodes were implanted unilaterally in the first three patients and bilaterally in the latter three, using an MRI-guided MRI-verified technique. Stimulation was initiated at 20-30Hz and optimised in an iterative manner.

Results:

Unilaterally treated patients did not demonstrate significant improvements in gait questionnaires, UPDRS-III or PSPRS scores or their respective gait subsections. This contrasted with at least an initial response in bilaterally treated patients. Diurnal cycling of stimulation in a PD patient with habituation to the initial benefit reproduced substantial improvements in FOG 3 years post-operatively. Among the PSP patients, one with a Parkinsonian subtype had a sustained improvement in FOG while another with Richardson syndrome (PSP-RS) did not benefit.

Conclusions:

PPN-DBS remains an investigational treatment for levodopa-refractory FOG. This series corroborates some previously reported findings: bilateral stimulation may be more effective than unilateral stimulation, the response in PSP patients may depend on the disease subtype, and diurnal cycling of stimulation to overcome habituation merits further investigation.

Deep brain stimulation (DBS) of the subthalamus nucleus (STN) is a highly effective surgical technique for providing relief to patients suffering from Parkinson’s disease (PD). The ventral intermediate nucleus of the thalamus (VIM) target is also very effective for treating essential tremor (ET) with DBS or lesion. Nevertheless, targeting procedures remain controversial and variable. Two main techniques are used to identify the target: (i) the indirect technique, which transforms or wraps atlas or statistical information in a patient-specific space; (ii) the direct technique, which creates direct visualisation of the target on pre-operative magnetic resonance imaging (MR) with the multiplication of complex MR sequences.

With the help of the ESSFN, we wanted to interview European centres for functional and stereotactic neurosurgery to assess the reality of heterogeneous targeting and the difficulties encountered by surgeons.

Method:

Two surveys on STN and VIM targeting were sent to ESSFN members and the French centres of functional and stereotactic neurosurgery.

The first part of the survey focused on targeting, and the second part on difficulties encountered by centres during targeting.

Results: Forty-seven centres responded to the survey (about 40% of the 120 European centres of stereotactic and functional neurosurgery) with 1,548 targeting procedures having been conducted (STN 1000, VIM 548) in 18 countries in 2019.

All STN targeting was performed for DBS. 39% of centres targeted STN for diseases other than PD but these represent only 0.7% of STN targeting.

VIM targeting was performed by centres which practice DBS only (46%), DBS and lesion (31%) or lesion only (23%). VIM targeting was performed for tremors other than ET by 59% of centres, accounting for 18% of VIM targeting procedures.

Centres perform a mean of 26 STN targeting procedures per year with a median of 15, and a mean of 13 VIM targeting procedures per year with a median of 8. A significant number of centres carry out less than 10 VIM or STN targeting procedures per year.

Direct STN targeting was performed by 15 centres for 32% of STN targeting procedures without using statistical coordinates. Only 6 centres conducting 17% of targeting procedures did not use per-operative evaluations. Direct VIM targeting was used by 3 centres for 4% of VIM targeting procedures without using statistical coordinates and 10 centres (35% of targeting) did not use per-operative evaluations.

The mean targeting duration was 1 h 40 for STN (median of 2 h) and 1 h 25 for VIM (median of 1 h 00). Targeting is always performed by a neurosurgeon who is sometimes assisted by a neurologist or radiologist.

The two main problems noted by neurosurgeons are the complexity and heterogeneity of practices, followed by the duration of targeting and intra-operative evaluation, and the invasive nature of the latter.

Conclusions

More VIM targeting procedures are carried out than expected. Per-operative evaluation remains the reference method. Some lesion centres have significant VIM activities. STN targeting for indications other than PD is anecdotal, and the complexity and lack of homogeneity of practices are the main problems encountered by neurosurgeons.

Introduction
Unlike primary dystonias where the results of deep brain stimulation (DBS) can be responsible for an improvement of 70 to 90%, the benefit in secondary dystonias is less significant, on average 30%.
We present our cohort of implanted secondary dystonias, comparing our results to the literature data in terms of efficacy, complications and prognostic factors.

Patients & Methods
Among all the dystonic children implanted in our centre since 2015 (n=42), 18 patients (8-16 years old) with secondary dystonia (8 cerebral palsy, 4 PKAN, 1 glutaric aciduria, 5 without etiology), were implanted in the internal pallidum (GPi) bilateral implantation; One patient received a multi-targeted implantation (4 electrodes > GPI+STN).
All implantations were performed under general anaesthesia with electrophysiological control. Validation of the position of the electrodes was carried out intraoperatively by scanner and then again by scanner at 10 days postoperatively. The target chosen was the ventral posterolateral part of the GPi corrected according to the anatomical variability associated with the pallidal lesions induced by the pathology.
All indications were validated in RCP or Multidisciplinary Consultation for paediatric movement disorders. The expected benefits of DBS ranged from a reduction in painful attacks to functional improvement, depending on the initial pathology.

Results
The results are very heterogeneous, ranging from a spectacular improvement for a progressive, unlabelled disease to a lack of efficacy for 2 children with Cerebral Palsy. There were no additional postoperative complications compared to primary dystonias, including infectious dystonias (2/2 cases).

Discussion
We currently have few prognostic means to evaluate good candidates. Precise electrode placement in the GPi is crucial despite the possible lesions of the GP. Other targets than GPi or multi targets schemes can be a alernative surgical option. Early implantation would ensure better results. 
Patient selection and definition of expectations regarding the benefit to be expected from DBS are particularly important in this population.
DBS may be useful in secondary dystonias, particularly in dyskinetic, painful, and malignant forms. It should be discussed on a case-by-case basis with clear goals to be achieved, as functional gain may not always be the primary goal of DBS in this population.

Background: Dentato-rubro-thalamic tract (DRT) deep brain stimulation  (DBS) suppresses tremor in essential tremor (ET) patients. However, DRT depiction through tractography can vary depending on the included brain regions. Moreover, it is unclear which section of the DRT is optimal for DBS.

Objective: Evaluating  deterministic DRT tractography and tremor control in DBS for ET.

Methods: After DBS surgery, DRT tractography was conducted in 37 trajectories (20 ET patients). Per trajectory, 5 different DRT depictions with various regions of interest (ROI) were constructed. Comparison resulted in an DRT depiction with highest correspondence to intraoperative tremor control. This DRT depiction was subsequently used for evaluation of short term postoperative adverse and beneficial effects.

Results: Postoperative optimized DRT tractography employing the ROIs motor cortex, posterior subthalamic area and ipsilateral superior cerebellar peduncle and dentate nucleus best corresponded with intraoperative trajectories (92%) and active DBS contacts (93%) showing optimal tremor control. DRT tractography employing a red nucleus or ventral intermediate nucleus of the thalamus ROI often resulted in a more medial course. Optimal stimulation was located in the section between VIM and PSA.

Conclusion: This optimized deterministic DRT tractography determination strongly correlates with optimal tremor control and shows limited side-effects. This technique is readily implementable for DBS target planning in ET. 

Figure legend

The panels A to G show the different possible depictions of DRTs which are used for comparison. The above panel shows an axial, the bottom a coronal view on a 3-Tesla T2 MRI of the thalamic and subthalamic area (commissural aligned imaging). The green DRT is depicted with ROIs in the ipsilateral motor area, ipsilateral PSA, ipsilateral cerebellar peduncle and dentate nucleus (DRT-PSA). The DRT-VIM (purple) is depicted after adding VIM (depicted by the software) as a ROI. The DRT-RN (orange) is depicted with ROIs in ipsilateral motor area, ipsilateral red nucleus, ipsilateral cerebellar peduncle and dentate nucleus (DRT-RN). The crossing DRT-RN (red) crosses the midline at the level of the red nucleus, and is depicted with ROIs in the ipsilateral motor area, and RN, contralateral cerebellar peduncle and dentate nucleus. The definite DBS electrode (yellow) is displayed. Panel A is located 2 mm above the commissural line, panel B at the commissural line, panel C is located 2 mm below the commissural line, panel D is located 4 mm below, panel E is located 6 mm below, panel F is located 8 mm below and panel G is located 10 mm below.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective surgical treatment for patients with advanced Parkinson’s disease (PD). Combining 7.0-Tesla (7T)  T2 and diffusion weighted (DWI) sequences allows for segmenting the motor part of the STN and possible optimisation of DBS.

Methods: 7T T2 and DWI sequences were obtained and probabilistic segmentation of motor, associative and limbic STN subdivisions was performed. Left and right sided motor outcome (MDS-UPDRS) scores were used for evaluating the correspondence between segmented location of stimulation and DBS effect. The Bejjani line was reviewed for crossing of segments.

Results: A total of 50 STNs were segmented in 25 patients. Due to the high resolution of the sequences, segmentation was well feasible using 7T T2 and DWI. Although the highest density of motor connections was situated in the dorsolateral STN for all, exact partitioning of subdivisions differed considerably. For all the active electrode contacts situated within the predominantly motor-connected segment of the STN, the average hemi-body UPDRS motor improvement was 80%, outside this segment 52%. The Bejjani line was situated in the motor segment for 32 STNs.  

Conclusion: The implementation of 7T T2 and DWI for STN segmentation in DBS for PD is feasible and offers insight in location of the motor segment. Segment guided electrode placement, instead of classical targeting, is likely to further improve motor response in DBS for PD. However, for full exploitation commercially available DBS software would have to allow for post-processing imaging.  

Background: Subthalamic deep brain stimulation (DBS STN) became established as an effective treatment for advanced Parkinson's disease (PD). A new era in DBS appeared to be the introduction of segmented electrodes, which allow steering electric field in a certain direction horizontally. In view of ongoing discussion about the optimal stimulation spot within the STN in individual patients, directionality seems to be particularly relevant. Experimental modeling of directional stimulation suggests a possibility to increase the therapeutic window, reduce the appearance of stimulation-induced side effects, and enhance the efficiency of DBS. However, growing complexity of postoperative programming and patient management should be considered. There is still insufficient clinical data on eventual benefits of using segmented electrodes for outcome.

Objective: To assess efficacy and programming features of DBS STN using segmented directional electrodes compared to conventional omnidirectional leads in PD-patients with motor fluctuations.

Patients and methods: The study included 40 patients with advanced PD who underwent bilateral DBS STN surgery at our center in the last 3 years. In 20 patients (40 DBS-leads), segmented 8-contact electrodes were implanted (mean age at surgery 54.9±9.5 years, disease duration 13.2±4.3 years, Hoehn&Yahr stage 3.2±0.5). In the other 20 patients operated in the same timeframe (40 leads implanted), conventional 4-contact electrodes were used (mean age at surgery 57.4±9.0 years, disease duration 11.4±4.7 years, Hoehn&Yahr stage 3.2 ± 0.5). Groups did not differ significantly in baseline characteristics. All patients were operated by the same surgeon according to the uniform surgical technique including intraoperative microelectrode recording of neural activity (MER) and test stimulation. Neurological examination was standardized and performed preoperatively and at the 6-month follow-up in OFF- and ON-medication conditions (UPDRS, Schwab&England scale, PDQ39, levodopa equivalent daily doze/LEDD scoring). We analyzed intraoperative strategy, primary and following adjustments of the settings, and clinical outcome in each patient.

Results: Final trajectory of electrode implantation confirmed by MER and intraoperative stimulation coincided with central image-calculated trajectory in 67.5% of cases. In 32.5% of electrodes, correction of trajectory was performed (mainly in the medial direction). For MER, 1 to 3 microelectrodes were used (mean 1.5).

At the time of 6 months following continuous DBS STN, all patients experienced amelioration of parkinsonian symptoms and daily life activity in OFF-medication state with no significant difference between two groups. In patients with segmented leads implanted, mean OFF-state UPDRS-3 decreased from 51.3 to 16.7 points (66.3%) and UPDRS-2 from 23.0 to 8.7 (59.8%) compared to from 50.5 to 12.3 (73.9%) and from 22.9 to 9.8 (55.7%), respectively, in patients with conventional electrodes. In both groups, motor symptoms in ON-state also improved (mean UPDRS-3 changed from 13.0 to 7.9). Mean LEDD reduced from 1700 to 735 mg and from 1759 to 581 mg, respectively (p>0.05). Quality of life improvement comprised 19.3% for the whole group.

During initial setup, all leads were carefully screened for the best stimulation level, and then segmented ones were checked for the best direction of stimulation. Directional stimulation was preferentially used if better efficacy or minimization of DBS-induced side effects could be achieved. At the 3-month follow-up, in patients with segmented electrodes, directionality was employed in 9 patients (45%, 15 leads), To the 6-month follow-up, 14 leads were programmed directionally (9 patients). In 7 cases (17.5%), the most efficient electrode contact appeared to be outside the segmented level.

Conclusion: According to our data, efficacy of DBS STN via segmented electrodes is comparable to traditional omnipolar stimulation in short-term follow-up. Directional stimulation provides additional possibilities for programming and optimizing the clinical outcome of DBS STN. At the same time, high precision electrode placement is still required. Considering the increased complexity and time of selecting individual stimulation settings, systematic approach and development of new automated programming algorithms are desirable. We need studies in a larger patient population with long-term follow-up in order to evaluate potential benefits of directional DBS STN.

Objective: To characterize electrical features of long-term DBS settings for PD and ET patients, and how these features impact primary cell internal pulse generator (IPG) longevity derived from a global, multi-center registry.

Background: Several recent articles have been published on the impact of programmed settings and impedance on total electrical energy delivered (TEED) and consequently, battery longevity in DBS patients implanted with Activa PC have been compared with predecessor Kinetra IPGs.^1-2 However, Activa PC contains hardware and programming capabilities that expand features beyond those available with Kinetra to provide physicians with more choices and greater flexibility in managing patient symptoms. The difference in battery longevity between Activa PC and Kinetra may be due to a number of design improvements which include size reduction for patient comfort and additional device features valuable in therapy optimization. In addition, sample size, diagnosis and duration of disease, stimulation settings including longitudinal impedance changes, and length of follow-up vary widely in these studies. The effect of these electrical parameters is better understood when a standardized approach across diverse centers and patient populations is used, such as a global registry.

Methods: The Product Surveillance Registry (PSR) was established in 2009, as a prospective long-term, multi-center global registry to monitor the reliability and safety of DBS systems. The stimulation settings were analyzed for 612 patients at 35 centers in 11 countries; 452 were first-time implanted IPGs and 215 were replacement IPGs. Electrical parameters were noted after stable programmed settings were achieved (6 months in de novo patients, 1 month in replacement patients). IPG longevity was estimated as the time to replacement due to battery depletion.  TEED (µJ) per lead was estimated from the actual device reported stimulation parameters and impedances over the lifetime of the battery. Statistical analysis was completed using Cox Proportional Hazards regression and Kaplan-Meier methods. 

Results:  The median IPG longevity for first-time implanted devices was 4.7 and 4.5 years, in PD and ET patients, respectively and device longevity was significantly longer in the first-time implanted group compared to the IPG replacement group. The IPG replacement group had higher TEED per lead for both PD and ET patients resulting in reduced battery life (Table 1), likely due to higher stimulation settings. Therapy impedance was significantly higher in first-time IPG devices compared to replacement devices in PD patients (p<0.0001); but not in ET patients (p=0.174).  Also, monopolar stimulation was used more frequently (78 % in PD vs 70% in ET) and 82% of devices had lead placed in STN target site in PD patients. The analysis of different stimulation targets revealed significant reduction of TEED in STN-DBS compared to GPi-DBS in first-time implanted PD patients (p<0.0001).

TEED increased significantly over time in PD patients (p<0.0001 in first-time implanted IPGs, but change was not significant in ET patients (p=0.386). With respect to therapy impedance, there was  evidence of significant downward trend in first-time implanted  PD and ET patients (p<0.0001, Figure 1). Overall, a significant inverse correlation was observed between IPG longevity and TEED in both PD (HR=1.009, p<0.0001) and ET (HR=1.011, p<0.0001) patients. 

Conclusion: The present analyses represent battery longevity from a real-world global patient population and reflect standard practice patterns at most DBS centers without protocol constraints regarding the management of these patients.  IPG longevity was quite similar in PD and ET patients but shorter in replacement IPGs, likely due to  higher energy demand in replacement IPGs compared to first-time implanted systems. The increase in TEED over time and higher TEED in replacement IPG may reflect changes in stimulation settings, usage patterns, or local tissue impedance fluctuations. Overall this analysis demonstrated the expected performance of 3-5 years of primary cell battery longevity for DBS therapy from a multi-center global registry in PD and ET patients.

References

1.              Helmers AK, Lubbing I, Deuschl G, et al. Neuromodulation. 2018;21(6):593-596.

2.              Niemann M, Schneider GH, Kuhn A, Vajkoczy P, Faust K. Neuromodulation. 2018;21(6):597-603.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has demonstrated major improvement of motor and non-motor manifestations and quality of life in Parkinson"s disease (PD) despite various surgical approaches. This single-center study aims to compare clinical outcomes and electrode placement accuracy in patients who underwent robot-assisted versus conventional frame-based stereotactic STN DBS surgery for PD.

Methods

This retrospective study included 48 PD patients, enrolled between October 2016 and December 2018 in the University hospital of Neurology and Neurosurgery of Lyon. They underwent either robot-assisted surgery (RAS) (Neuromate®, Renishaw) (n=20) or conventional frame-based stereotactic surgery (FSS) (n=28) with the same principles of STN targeting on MRI. ES performed RAS surgery, while GP performed FSS. Patients were evaluated before and 1 year after surgery. Electrode contacts within the STN was determined using merge of post-operative CT- and pre-op MRI with Brainlab® GUIDE™ XT software (Fig1).

Results

Median age at surgery was the same (62.5 years old) in both groups. 1 year after surgery, with stimulation on and pharmaceutical treatment, there was no difference in the evolution of MDS-UPDRS III (p=0.29) and IV (p=0,80) between groups, the evolution of the quality of life (p=0.25), the evolution of levodopa treatment (p=0.94). The rate of complications was not different between both groups (p=0.99). Surgery duration was significantly longer in the RAS group (479 min, Q1-Q3: 460— 490) cmpared to the FSS group (351 min, Q1-Q3 317-392) (p=0.0001). There was no difference in electrode placement accuracy in both groups (table1).

Discussion

This is the first study comparing clinical outcomes between robot-assisted and conventional surgery for DBS in PD in the same surgical center. We showed no difference in motor results, quality of life improvement, evolution of Levodopa treatment, complications of the surgery or electrode placement accuracy. The duration of surgery was increased in the RAS group. Prospective randomized study including a larger sample is required to determine best surgical approach, keeping in mind that the most important remains surgeon’s experience with the technique used.

Fig.1 : electrode placement accuracy 

Table 1: Results 

Optimization of the stimulation parameters settings of directional leads with a patient-specific imaging software in implanted parkinsonian patients

Gustavo Touzet MD³, Anne-Sophie Rolland PhD ¹, Nicolas Carrière MD², Bastien Gouges³, Luc Defebvre MD PhD², David Devos MD PhD^1,2, Caroline Moreau MD PhD², Nicolas Reyns MD PhD³

¹Department of Medical Pharmacology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France; ²Department of Neurology, Lille University, INSERM UMRS_1171, University Hospital Center, LICEND COEN Center, Lille, France; ³Department of Neurosurgery, CHU LILLE University Hospital, France

Objectives: Deep brain stimulation in the subthalamic nucleus (STN) is routinely proposed to parkinsonian patients. Introduction of directional leads offers more flexibility for programming but may also increase the complexity and duration of the procedure. Here we assess whether Guide XT^R, a new patient-specific imaging software, is helpful to refine stimulation parameters and to simplify the time consuming programming process.

Background: Clinical examination of the stimulation effect for each contact is the empirical method to set up stimulation parameters. Guide XT^R models the volume of activated tissue and provides semi-automatic lead localization and segmentation of deep brain structures in order to visualize leads position and anatomical structures relative to putative stimulation fields.

Methods: We evaluated all parkinsonian patients who were implanted with bilateral directional leads in the STN. After surgery, patients were programmed and followed by the neurological team while blinded from anatomical data. All parameters were reviewed (ring or directional mode) and optimized based on standard clinical evaluation. After surgery, Guide XT was used to analyze imaging data by the neurosurgical team to choose the best stimulation configuration and parameters blinded from clinical data. Clinically determined parameters were then compared to imaging-based parameters.

Results: Twenty-eight patients were included in the study (19 males, 9 females, 59.1 ± 5.5 years old, disease duration 12.3 ± 7.4 years). The stimulation depth was similar between imaging and clinical settings in 75% of cases. Stimulation direction was similar between imaging and clinical settings in 18.75% of cases. Ring mode was selected in 62.5% with the clinical procedure and in 25% with the imaging procedure.

Conclusion: Predicted depth of stimulation using imaging data and empirically determined stimulation using clinical effects showed good concordance. Clinician used mainly ring mode stimulation despite imaging data suggesting a potentially better stimulation configuration using directional mode, possibly due to the complexity of the clinical evaluation. Imaging-guided parameters settings refined with clinical evaluation could therefore help to optimize parameters and limit non-motor side effects and need to be further evaluated.

Keywords: Parkinson’s disease, stimulation parameters, directional leads

Trials based on individual parallel designs have demonstrated that deep brain stimulation (DBS) treatments targeting either the subthalamic nucleus (STN) or globus pallidus interna (GPi) are both effective for the motor symptoms of Parkinson’s disease. However, few studies have compared the motor effects of STN and GPi DBS in individual patients. We compared the acute effects of unilateral STN and unilateral GPi DBS on motor function in individual patients with Parkinson’s disease treated with continuous DBS of both unilateral targets.

This prospective, double-blind, randomized crossover study assessed eight patients with idiopathic Parkinson’s disease who had been treated with continuous DBS of the unilateral STN and contralateral GPi for 2 years. Motor symptom severity, quantified by the Movement Disorder Society-Unified Parkinson Disease Rating Scale part III (MDS UPDRS-III), was assessed preoperatively and at 2-year follow-up in four randomized, double-blinded conditions: 1) Med−STN+GPi−, 2) Med−STN−GPi+, 3) Med+STN+GPi−, and 4) Med+STN−GPi+. The MDS UPDRS-III total score and subscale scores, including scores for axial and bilateral limb symptoms, served as the dependent variables.

Of the eight participants, seven completed the assessments in all four conditions, while one missed two postsurgical Med+ conditions. At the 2-year follow-up, compared with the preoperative Med− state, in the Med−STN+GPi− condition, the cardinal symptoms in both limbs were all improved, although the axial symptoms had deteriorated, except in the context of arising from a chair. In the Med−STN−GPi+ state, symptoms of the GPi-stim limb were improved significantly, while only tremor was improved on the ipsilateral side. The axial symptoms in the Med−STN−GPi+ state significantly worsened, and all sub-scores showed aggravation. Compared with the preoperative Med+ state, in the Med+STN+GPi− state, cardinal symptoms were improved on both sides, except for the tremor on the STN-stim side. The axial symptoms were more serious and the only improved axial symptom was arising from a chair. In the Med+STN−GPi+ state, the overall motor symptoms were aggravated, and the treatment effect was only reflected in the symptoms of tremor and rigidity on the GPi-stim side. The axial symptoms of the Med+ states were all worsened, except in the context of arising from a chair.

In conclusion, improvement of motor symptoms was significantly increased in all sub-scores favoring STN, except for the worsening degree of gait, in which Med+STN−GPi+ was slightly lower than Med+STN+GPi−. We also noted the effects of STN+ acting on both limbs, in contrast to the effects of GPi+, which mainly acted on the contralateral side. 

Objective – To investigate the use of biphasic anode-first pulses on the therapeutic window in essential tremor (ET) patients treated with ventral intermediate nucleus deep brain stimulation (DBS). Figure 1.

Background – Since the inception of DBS, cathodic pulses have been used¹. Modelling studies suggest that biphasic pulses may influence the therapeutic window².

Methods – Stimulation was delivered on the most ventral contact, unless this elicited unbearable paresthesias. In that case, one level more dorsally was stimulated. The non-tested hemisphere was turned OFF. Three thresholds were acutely defined for both cathodic and biphasic anode-first pulses: lowest amplitude inducing tremor arrest while performing a finger-to-nose test contralaterally (LowerTW),  lowest amplitude inducing upper limb ataxia contralaterally (AtaxicTW) and lowest amplitude causing non-transient stimulation-induced side effects contralaterally, other than limb ataxia (UpperTW). The thresholds were defined twice in all hemispheres and average results per hemisphere were analyzed. Wilcoxon signed rank test was used to compare the thresholds.

Results – Four ET patients (8 hemispheres) participated in this study. LowerTW was not significantly different between cathode versus biphasic pulse (1.82 ± 0.69 mA versus 2.11 ± 0.62 mA, p = 0.25). The amplitude that elicited limb ataxia was however significantly higher in the biphasic anode-first pulse (2.74 ± 0.96 mA versus 3.75 ± 1.41 mA, p = 0.0078). Also, non-ataxic side effect was only evoked at higher stimulation amplitudes when compared to biphasic pulses (3.69 ± 1.84 mA versus 4.78 ± 1.97 mA, p = 0.0078). Figure 2.

Conclusions – Biphasic pulses elicit stimulation-induced side effects at higher amplitudes, therefore increasing the therapeutic window. Further work is needed to determine if these pulses can bring clinical benefit compared to standard cathodic pulses.

References

1.          Benabid AL, Pollak P, Hoffmann D, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet. 1991;337(8738):403-406. doi:10.1016/0140-6736(91)91175-T

2.          Wongsarnpigoon A, Grill W. Energy-efficient waveform shapes for neural stimulation revealed with a genetic algorithm. J Neural Eng. 2010;7(4):1-20. doi:10.1088/1741-2560/7/4/046009.Energy-efficient

Directional subthalamic nucleus deep brain stimulation in Parkinson’s disease allows for a better therapeutic window, with increased motor effects and less stimulation side effects. In our study, we aimed to determine the preferred type of stimulation (omnidirectional or directional) on last-follow-up in patients who were all implanted with directional leads. We then correlated the results of choice of type of stimulation with the anatomical electrode position in the subthalamic nucleus.

From April 2018 to August 2020, 17 patients received directional leads (Boston Scientific) for severe Parkinson’s disease implanted bilaterally into the subthalamic nucleus. The neurologists of the team had all freedom to change the mode of stimulation, but were at that time blinded to the exact lead position of the contacts as revealed by the guide XT software. DBS stimulation status (omnidirectional vs directional) and its evolution was compared post-operatively (when the patient was discharged) and at last follow-up with at least 1 year of follow up.  This mode of stimulation was then correlated to the evolution of the MDS UPDRS scores, to the side effects and to the anatomical position of the implanted electrodes. 1 patient was followed in another centre and data were not available.

6 and 10 patients were stimulated with directional (37%) or omnidirectional mode (63%) respectively at discharge. At last follow up, 11 out of 16 (69%) had a directional mode of stimulation, 7 switching from omnidirectional to directional mode, and 2 switching from directional to omnidirectional mode. Reasons for change included better efficacy and the need to reduce the side-effects. Anatomical correlations will be discussed according to those findings.

In conclusion, there was a great tendency to stimulate preferentially a majority of patients using directional mode for different reasons discussed in the paper.

Doparesistant Freezing of gait (FOG) and falls represent the dominant motor disabilities in advanced  Parkinson’s disease (PD). Their pathophysiology is poorly understood, but imaging and post-mortem studies suggest a causal role of cholinergic dysfunction within the pedunculopontine nucleus (PPN), located in the mesencephalic locomotor region (MLR), also including the cuneiform nucleus (CuN) dorsally. We herein investigate the effects of deep brain stimulation (DBS) of the PPN and CuN nuclei, for treating gait and balance disorders in Parkinson’s disease (PD) patients in a randomized double-blind cross-over clinical trial. Six PD patients with dopa-resistant freezing of gait (FOG) and/or falls were included and operated for bilateral MLR-DBS. Patients each received three DBS conditions, PPN, CuN or sham, in a randomized order for 2-months each, followed by an open-label phase. The primary outcome was the change in anteroposterior anticipatory postural adjustments (APAs) during gait initiation on a force platform at the end of each DBS condition. Secondary outcomes included safety and differences in gait kinetics, and clinical gait, cognitive and quality of life scales between DBS conditions. During the randomized period, we found that the anteroposterior APA were not significantly different between the DBS conditions (median displacement [1^st_3^rd quartile] of 3.07 [3.12_4.62] mm with sham-DBS, 1.95 [2.29_3.85] mm with PPN-DBS and 2.78 [1.66_4.04] mm with CuN-DBS; p=0.25). Step length and velocity were significantly higher with CuN-DBS vs both sham-DBS and PPN-DBS. Conversely, step length and velocity were lower with PPN-DBS vs sham-DBS, with greater double stance and gait initiation durations. One year after surgery, step length was significantly lower with PPN-DBS vs inclusion. We also found no significant differences in the clinical scales including  the parkinsonian disability, gait and balance scales, and assessment of cognition or psychiatric troubles. Lastly, we observed 3 serious adverse events with one electrode displacement in one patient, one patient had a subdural hematoma following recurrent falls that did not necessitated surgery. Our study suggests a better effect of CuN-DBS relative to PPN-DBS on walking ability in advanced PD patients. However, the absence of significant clinical benefit with 2 months of DBS with no aggravation in FOG or falls one year after surgery would suggest that optimized DBS and for longer period might be beneficial. Further research is needed to better understand the role of the MLR in gait and balance control in humans using new imaging or neurophysiological approaches.

Objetive:

Deep brain stimulation (DBS) has been shown to be effective and safe for treating the cardinal symptoms of Parkinson's disease.

Some aspects of the disease, such as gait disorders, respond worse to DBS. Various publications suggest the efficacy of combined DBS in the subthalamic nucleus (STN) and the substantia nigra (SN) for refractory gait disorder in PD. The objectives of our study are to confirm these previous findings. Material and methods:We present data from our randomized, crossover, double-blind, single-center study conducted in 10 patients with advanced PD.
Octopolar deep brain stimulation electrodes were placed bilaterally at STN, leaving the most distal contacts at SN. To perform the quantitative gait analysis, the Step 32 system was used. Clinical and neurophysiological parameters were compared after 4 weeks of STN stimulation versus 4 weeks of combined STN and SN stimulation. Side effects and patient preferences were reported. Results:
There were no complications associated with surgery Postoperative improvement was observed in the cardinal symptoms of PD and in gait parameters. The number of normal gait cycles increased significantly after surgery in both forms of stimulation.
The greatest increase in normal gait cycles occurred in combined STN and SN stimulation (0.57 preoperative, 0.71 STN, 0.79 STN + SN). Coclusion: The combined STN and SN DBS is a safe and effective technique to improve the axial motor disorders of PD, such as gait blocks and postural instability. Studies with a larger number of patients and long-term follow-up would be very useful to confirm the evidence of our work.

Background: Both the FDA, under 21 CFR 1271.15(b), and the EU, under Art 2§2(a) and Preamble 8 of Dir. 2004/23/EC, allow for a Same Surgical Procedure Exemption for the grafting of autologous tissue during a same surgical procedure. With a goal of providing support to sick or dying cells, we have previously used this Exemption to deliver autologous injury-activated peripheral nerve graft tissue (APNG) to the substantia nigra in patients with Parkinson’s disease who are undergoing deep brain stimulation (DBS) surgery (van Horne et al. 2018). Following injury, the peripheral nervous system, activates a reparative response that generates a host of neurotrophic and cell-survival factors.

Objective: As part of an open-label Phase I clinical trial (NCT02369003) to expand the utility of this approach and examine dose escalation, we unilaterally implanted APNG to the substantia nigra under two different dosing regimens: a single deployment of APNG or two deployments of APNG.

Methods: As part of the standard of care, participants underwent a two-staged DBS procedure. At the time of stage I, the sural nerve was transected and the incision was closed. Later (3 to 14 days later) at stage II, the injured sural nerve was identified, and an about 1 cm section was excised. The fascicles were identified, diced, and deposited in the substantia nigra with one deployment or a deployment both to the anterior and to the posterior substantia nigra. Participants were followed for 12 months and the motor component of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) was used to assess for changes in Parkinson’s disease severity.

Results: Across our previous trial (van Horne et al. 2018) and this one, a total of 37 participants have received only unilateral grafts to the substantia nigra with a mean age of 62 years (95% Confidence Interval: 60 to 65 years). Adverse event profiles were comparable to standard DBS with the most common study-related events being paresthesias of the lateral foot distal to the sural nerve tissue harvest site.  For the single deployment, off-state motor MDS-UPDRS mean scores were 45.3 points (40.2 to 50.5; n=28) at screening and 36.6 points (30.5 to 42.7; n=24) at 12 months. For participants receiving two deployments: 42.8 points (30.7 to 54.9; n=9) at screening and 35.8 points (21.5 to 50.0; n=8) at 12 months. Overall for unilateral APNG delivery, pooling both groups, the mean decrease in scores at 12 months was -8.4 points (-4.1 to -12.6; n=32). When we analyzed the lateral components of the MDS-UPDRS, the mean difference in scores at 12 months for the body side contralateral to the APNG deployment was -4.6 points (-2.8 to -6.6) and for the side ipsilateral to the APNG deployment it was -0.8 (-2.0 to + 0.5).

Conclusions: Further examination of the approach is merited to further establish the safety profile for this procedure and to investigate the potential for this strategy for disease modification.

Introduction

Essential tremor (ET) is one of the most common neurological disorders with a prevalence of 4.6% in people aged 65 years or older. Medical management is generally initiated when the tremor begins to interfere with the patient’s ability to undertake daily activities, but the effectiveness of drugs for this disorder is limited.

Stereotactic radiofrequency (RF) thalamotomy and deep brain stimulation (DBS), targeted to the ventralis intermedius nucleus of the thalamus (Vim), have proven effective for treating ET and other tremors. These interventions, although highly effective, have risks associated with an open neurosurgical operation.  Radiosurgical Vim thalamotomy with Gamma Knife has been used as a non-invasive alternative treatment. However, the lack of immediate clinical improvement and the possibility of extension of the lesion beyond the initially targeted region over time inducing permanent neurological deficits have limited the use of this technique.1

For the last decade, MRgFUS has been raising a lot of interest, as an incisionless and low-risk therapeutic option. This type of treatment creates a coagulation lesion via high-intensity ultrasound beams that converge in a selected target, with great accuracy and with neither need of incising the skin nor opening the skull. Vim-MRgFUS has been used to treat tremor associated with Parkinson´s disease, Essential Tremor, Multiple Sclerosis and Fragile X-associated ataxia.

In the present study, the durability of tremor relief in patients followed for 6 months after MRgFUS thalamotomy was evaluated to confirm the durability of efficacy and safety of MRgFUS thalamotomy for the treatment of medically refractory ET.

Methods

One hundred twenty-three ET patients treated with unilateral MRgFUS VIM between 2018 and 2021 were evaluated using the Clinical Rating Scale for Tremor (CRST) score at month, three months, and 6 months. Lesion characteristics were assessed on routine MRI sequences at 6 months in 44 patients. Relationships between imaging appearance in Brainlab Sotware (BrainLAB AG, Munich, Alemania), details of thalamotomy procedure (Insightec Inc, Tirat Carmel, Israel) and clinical outcome were investigated.

Results

Mean hand tremor score section A and B at baseline (20.77 ± 5.81; 123 patients) improved by 83.33% ± 22.10% (Section A), 73.51% ± 28.40% (Section B) and 75.74% ± 33.53% (Section C;) at 6 months. This improvements difference was significant (p= 0.05). Paresthesias and gait disturbances were the most common adverse effects at 1 months and at 6 months only 28% patients presented soft adverse effects.

On T2-weighted images the most lesion was hyperintense, the mean relative volume at 6 months was 0,037 ± 0.026cm3 (IQR 0.31– 0.058cm3), some lesions were no longer discernable in T2-weighted images. Mean AC-PC line length was 25.98 ± 1.87 mm (IQR 24.63– 27.45mm). Clinically determined centers of Vim lesion placement differed from the assumed position of the nucleus as suggested in the literature. On the right-left axis, mean lesion position was 14.33 ± 1.95 mm (range 13.37 – 14.93mm) from third wall and 6.75 ± 1.19mm (IQR 5.76 ± 7.45mm) distance from the posterior commissure on the AC-PC line, what represents 26.01 ± 4.21% (IQR 23.55- 27.76%) of AC-PC line. On the dorso- ventral axis, mean lesion position was 3.01 ± 1.21mm (IQR 2.13-3.75). The mean of III ventricle measured on T2-weighted images was 6.81 ± 2.02 mm (IQR 5.63 – 8.35mm). The median patient SDR was 0.52 (IQR 0.44 -0.57). MRgFUS thalamotomies were performed using a median of 3.4 ± 1.4 sonications over maximal mean temperature of 55°C (IQR 2-4), delivering a median of 16243 ± 8640 joules (IQR 8655- 24154). The median of seconds over 55° was 29.85 ± 12.5 seconds (IQR 21 -37.5 seconds). The median median maximal mean temperature of 58 ± 2.14°C (IQR 57-60°C). There was no significant correlation between lesion volume at 6 months and clinical improvement (p =0.13) for tremor reduction on the treated side. The technical parameters were no significant correlation with clinical improvement, nevertheless, III ventricle size was significant correlation with tremor reduction (p=0,046), the greater ventricular size the clinical improvement decrease. 

Conclusion

MRgFUS thalamotomy for ET is an effective and safe procedure that provides long-term tremor relief and improvement in quality of life even in patients with medication-resistant disabling tremor.