Objective - This review analyses the prevalence of painful dystonia in a cohort of children undergoing neuromodulaton. The aim was to better understand the dystonic pain experience and evaluate the improvements one year following deep brain stimulation (DBS).

Background - Dystonic pain is reported as prevalent, however it is yet to be systematically evaluated. There is an overall paucity of literature evaluating the effects of DBS on dystonic pain using validated, reliable methods. The methods that have been used are varied and at times inappropriate for the population being assessed.

Methods - Dystonic pain was assessed in a cohort of children (n= 144) undergoing DBS. Assessment was multi-modal, six different pain assessment methods were used; intendity (proxy - Paediatric Pain profile and self-report - Numerical rating scale-11), parental perception (CPChild Questionnaire), pain frequenct, pain severity and analgesia use. SPSS version 21 was used to analyse the data. Data was analysed on the whole cohort, but also by aetiological sub-classification; inherited DYT positive dystonias (n=8), inherited heredodegenerative dystonias (n=9), acquired dystonias (n= 37) including cerebral palsy (n=21) and idiopathic dystonias (n= 8).

Results - 44.5% (63/144) of this cohort reported dystonic pain. Pain improved after DBS surgery in each group. Clinically significant improvements P<0.001 were noted in whole cohort, using NRS-11 (n=27/63), PPP (n=17/63) and the CPCHILD (n=48/63 assessments. Subjective reductions in frequency and severity were also reported. Very severe pain fell in 9/28 (30%) cases. Constant pain fell from 27/63 to 11/63, a 40.7% reduction and 18/63 (28.6%) became pain free. We found a 40% reduction in children receiving daily analgesia and an increase in 46.1% not requiring any. Whole cohort finds were comparable with the sub-classification except the heredodegenerative group, where subjective improvements were noted only.

Conclusion - This is the first evaluation focussing on the impact of DBS surgery on dystonic pain in children. This unique dataset illustrates the specific improvements from DBS on dystonic pain. Together, intensity, frequency, duration and experience of pain was reportedly improved following DBS, these effects were sustained at one year post surgery. Whilst this sample is small it is actually larger then has been reported internationally elsewhere. Additionally a multi-assessment approach in pain research reduces the risk of bias in an otherwise challenging population. By employing a more thorough and systematic approach to pain assessment and by using both objective (analgesia use) and subjective (self-reort / proxy report) measures results can be considered both clinically and meaningfully important, which is the priority for patients experiencing pain.

Longitudinal data collection and the consideration of a multi-centre research project would improve validity and reliability further. However a reduction in dystonic pain should remain a goal for DBS surgery, particularly given the relationship between pain and poor quality of life, social isolation, self-perception and overall poor health status.

Background: The aim of the present study was to present a case series of 3 patients with longstanding debilitating dystonic tremulous spasmodic torticollis. Pharmacological treatment including benzodiazepines as well botulinum toxin injections failed to adequately control dystonic jerking movements of the head and  neck. The patients were referred for deep brain stimulation (DBS) surgery.

Material and Methods: Two patients underwent bilateral implantation of DBS leads into the posterolateral segment of the globus pallidus internus (GPi). 1 patient received implantation of left lead in the nucleus ventralis intermedius of the thalamus (Vim) and the right DBS lead in the GPi. All surgeries were uneventful. The formal preoperative objective assessment included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and the motor score of Tremor Rating Scale (TRS). The postoperative TWSTRS and TRS assessments were done at 2 months postoperatively and every 6 months up to 36 months after surgery.

Results: At the last follow-up visit, the severity, disability and pain scores of TWSTRS were improved by 50 %, 54 % and 58 % respectively. The TRS improved by 72 % when compared to baseline TRS score.  There were no hardware-related complications over follow-up period.

Conclusion: Our preliminary experience gathered in 3 patients indicates that bilateral DBS can be an effective treatment for disabling tremulous spasmodic torticollis.

Objective: The objective of this device registry entails collecting clinical outcomes, economic value and technical performance of a Deep Brain Stimulation (DBS) system capable of multiple independent current control (MICC) for use in the treatment of dystonia. 

Background: Several studies have now published clinical outcomes using DBS for the treatment of dystonia encompassing a range of dystonic conditions including primary generalized, cervical dystonia, tardive dystonia, and other types of secondary dystonia, and all have reported effective results with use of DBS for the treatment of dystonia.  Here we report the initial outcomes from a multi-center registry of dystonia patients implanted with an MICC-based DBS system.

Methods: This is a prospective, on-label, multi-center, international registry study consisting of up to 200 patients implanted with a DBS system (Vercise, Boston Scientific) for use in the treatment of dystonia followed out to 3 years (post-implant) at up to 40 sites in Europe. Study assessments conducted will be based on dystonia sub-group, classification, and age and include (but not limited) to the following: Burke-Fahn-Marsden Dystonia Rating Scale, Clinical Global Impression of Change, Global Dystonia Scale, SF-36v2 or SF-10v2 Health Survey, and Toronto Western Spasmodic Torticollis Rating Scale. 

Results: Initial results of this on-going registry of DBS outcomes in dystonia patients will be reported. 

Conclusions: Large patient data registries may facilitate insights regarding real-world, clinical use of DBS. This registry represents the first comprehensive, large scale collection of outcomes associated with dystonia patients implanted with a DBS system capable of multiple independent current control (MICC) and will include assessment of economic value and device technical performance.

INTRODUCTION

Dystonia is a rare movement disorder. It is characterized by involuntary patterned sustained or repetitive muscle contractions of opposing muscles, causing, twisting movements and abnormal posturing. Dystonia is typically classifed by age of onset, origine, and affected body region.

When the cause is not defined or unknown, the dystonia is referred to as idiopathique or primary dystonia. Primary dystonia can be familial. Medical treatment rarely relives symptoms. Deep brain stimulation is an effective treatment of generalized dystonia.

MATERIAL AND METHODS

35 patients (20 males and 15 females) underwent this surgical technique.

We have : 27 patients suffering from generalized dystonia, 06 patients with cervical dystonia and 02 patients with hémidystonia.

Etiology : 20 cases : primary dystonia, 15 cases had  secondary dystonia including: 09 cases: Pkan syndrome. 01 cases : posttraumatic dystonia, 02 cases : postneuroleptic dystonia, 01 cases: mitochondrial cytopathy, 02cases post IMC.

Electrodes were bilaterally implanted under stereotactic guidance and connected to neurostimulateur. The varaition of brain impedance and current measurements was activated. Efficacy was evaluated by comparing scores on the clinical and functional Burke-Marsden-Fahn dystonia rating Scales before and after implantation (3 and 6 months and 1 year postopertively). The operation was performed under standard general anesthesia.

RESULTS

Optimal stimulation paramters vary between patients, however, the clinical response varied from patient to patient depending on several factors, including etiology and severity of the dystonia.  After 3 months the improvement of the clinical score was 45%, the functional score was improved by 30%. After that, at 6 months was respectively: clinical: 56% and functional: 41%. Finally at one year : the improvement concerned the clinical score : 80% and the functional score: 85%.

CONCLUSION

Bilateral chronic electrical stimulation can be proposed as first line treatment generalized dystonia.It is conservative,adaptable, reversible and well tolerted by the pediatric population. It must be applied as soon as possible,especially in primary dystonia.Tolerance is excellent and the complication’s rate remains low.The dystonic syndrom partiel contrôle and the significant improvement of pain symptomatology justify this treatment for secondary dystonia in selected patients.

Background:

Beta oscillations (13-30Hz) have been utilized as feedback signal for adaptive Deep Brain Stimulation (aDBS) in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients.¹ In dystonia, low-frequency oscillations (LFO, 4-12Hz) have been found to be correlated with the presence of dystonic symptoms, measured with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), ² making LFO a potencial biomarker for adaptive stimulation. Up to now, the applicability of aDBS in the internal globus pallidus (GPi) using beta oscillations (PD) or LFO (dystonia) is yet to be addressed.

Objective:

To test the safety of aDBS applied in the GPI of a dystonia and a PD patient and its effect in the oscillatory activity used for stimulation feedback.

Materials & Methods:

Bilateral intraoperative local field potentials (LFPs) were recorded in the GPi of one PD patient and one patient with craniocervical dystonia. A 30-second recording segment was used to obtain power spectral density estimates (PSD). LFPs were then filtered around the frequency peak registered in order to make either LFO or beta oscillations evident. Filtered LFPs were rectified and smoothed and stimulation was programmed to respond to increments in amplitude of the selected frequency band. A stimulation segment of approximately 200 seconds per disease was obtained. [Figure1]. Stimulation fractions per condition were calculated by dividing the total duration of the aDBS run into 20 segments. For each segment, the amount of time in which stimulation was turned on was calculated. Correlations between fraction of stimulation and time were conducted using Spearman’s rho.

Results

PSDs revealed a peak around 10 Hz in dystonia and a peak around 18Hz in PD. Stimulation voltages were set according to the voltages used in clinic, being in dystonia 1 V and 2.3 V in PD. GPi-aDBS was well tolerated in both patients and only elicited paresthesias at supraliminal voltages in the extremities contralateral to the stimulation side. aDBS was provided in such a way that it stimulated on average 34% of the time in the dystonia patient and 26.7% of the time in the PD patient. From the beginning to the end of the aDBS condition, despite fixed thresholds, the stimulation fraction dropped significantly, both in PD (ρ = -0.42, p = 0.04) and dystonia (ρ = -0.45, p = 0.04). [Figure2] This implies that the total amount of time that the signal remained above the threshold was progressively reduced by aDBS.

Conclusions

In this proof-of-principle report, aDBS was safely applied in the GPi of both a dystonia and a PD patient. They showed different oscillatory GPi profiles, namely a LFO peak in dystonia and a beta peak in PD. This provides a rationale for formally trialing aDBS in the GPi based on beta (PD) or LFO (dystonia) oscillations.

Bibliography

1.        Beudel, M. & Brown, P. Adaptive deep brain stimulation in Parkinson’s disease. Parkinsonism Relat. Disord. 22 Suppl 1, S123-6 (2016).

2.        Neumann, W.-J. et al. A localized pallidal physiomarker in cervical dystonia. Ann. Neurol. (2017). doi:10.1002/ana.25095

Figure 1.  Example of the application of adaptive DBS based on low-frequency oscillations in dystonia. Upper row: bipolar local field potential (LFP) derived from the internal part of the Globus Pallidus (GPi) filtered between 3 and 37 Hz. Second row: LFP filtered between the peak in low-frequency oscillations ± 3 Hz (i.e. 10 ± 3 Hz). Third row: average low-frequency amplitude envelope over 400ms moving average. The red line depicts the threshold determined for providing stimulation, i.e. when the amplitude is exceeding the red line stimulation is provided. Lower row: Stimulation trigger showing at which moments high frequency stimulation was provided.

Figure 2. A. Relation between the fraction of time that stimulation is turned on (Fraction of Stimulation) and the advancement of the application of aDBS in a dystonia patient and its least square line. B. Similar relation in a PD patient.

Background/Aim: Deep brain stimulation (DBS) has been used successfully in various forms of dystonia. However, there was no clear consensus on whether the globus pallidus interna (GPi) was an effective anatomic structure for secondary dystonia cases. In this study, we reported long-term results of secondary dystonia patients treated with GPi-DBS with microelectrode recording, and the results of our cases compared with the literature results.

Methods: Patients who underwent GPi-DBS for the diagnosis of secondary dystonia between the years of 2011-2017 were evaluated retrospectively. Burke-Fahn-Marsden Dystonia Rating Scale (BFM) scores, clinical improvement rates, follow-up period, stimulation parameters and the need of internal pulse generator replacement were analyzed. The PubMed database was searched carefully for articles describing GPi-DBS only for secondary dystonia. Keywords were ‘dystonia’, ‘deep brain stimulation’, ‘GPi’. In addition, the same database was searched for articles describing STN-DBS only for secondary dystonia. Keywords were ‘dystonia’, ‘deep brain stimulation’, ‘STN’.

Results: A total of 9 secondary dystonia patients (5 male, 4 female) underwent GPi-DBS with microelectrode recording. The mean follow-up period is 30 months. The average BFM score was 58.2 before the surgery, whereas the mean value was 36.5 at the last follow-up of the patients (mean improvement 39%, min: 9%, max: 63%). In the literature review, 63 cases (mean follow-up 18 months) of GPi-DBS treatment were reached in 18 different publications in the presence of microelectrode recording in the case of secondary dystonia. Detailed analysis of BFM scores showed worsening in one case after GPi-DBS, nine had no clinical improvement, and four cases had limited improvement. The number of cases with a 50% ≥ decrease in BFM scores was 21. In the remaining 23 cases, the healing rate was 11-49%.

Conclusion: GPi DBS has long-term efficacy and safety in secondary dystonia patients.

Abstract

In the past few years the occurrence of non- motor symptoms has been increasingly recognized in patients with a variety of movement disorders. Patients with dystonia experience unusual postures and disfigurement which is visible while they move in public. Few reports are available about the self perception of their body and its association with quality of life. The aim of this study was to examine the body concept in relation to quality of life, the severity of dystonia, and mood and anxiety in a series of 20 patients with idiopathic and inherited dystonia prior to deep brain stimulation (generalized, segmental and cervical dystonia). Patients suffered from mood instability and anxiety symptoms except social interaction anxiety. Depression was significantly correlated to the motor scores and to social phobia. Furthermore, impairments of body concept was evident in both cognitive and affective subscores. Mood and body concept negatively influenced the physical and mental domains of quality of life. Deep brain stimulation improved not only dystonia but also associated non-motor symptoms. It is important to recognize such non-motor symptoms in dystonia since they may contribute as well to reduced quality of life.

Background: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) has become an accepted treatment for segmental and generalized dystonia. In severe tremor syndromes the thalamic ventral intermedius nucleus (Vim) is usually the DBS target of choice. Few case reports on thalamic DBS in dystonia have been reported. Patient with dystonic tremor might as well benefit from thalamic DBS.

Objectives: We aimed to evaluate the clinical benefit of Vim DBS in patients with dystonic head tremor.

Methods: Patients with dystonic head tremor were scheduled for Vim DBS. All patients were clinically characterized according to the Burke-Fahn-Marsden (BFM) motor and  disabilityrating scale (BFM-M/BFM-D) and the modified Fahn-Tolosa-Marin Tremor Rating Scale (mFTMTRS) (0-12 point scale for head tremor) pre- and postoperatively. Statistical analysis for significant pre- and postoperative changes in BFM-M/BFM-D and mFTMTRS was performed using the Wilcoxon Rank test for paired variables.

Results: 15 consecutive patients with dystonic head tremor underwent Vim DBS (6 male, mean age at DBS 49.7 +/- 11.8 years). Mean follow-up (FU) duration was 41 months (median 17 months). The mean preoperative BFM-M was 21.8 +/- 11.5, which improved to 12.2 +/- 10.5 at last FU (-44.5%, p<0.05), and the mean preoperative BFM-D was 5.1 +/- 2.9, which improved to 3.4 +/- 4.1 at last FU (-33.3%, p<0.05), while the mean preoperative mFTMTRS was 8.7 +/- 2.5, which improved to 3.5 +/- 2.7 at last FU (-59.8%, p<0.005).

Conclusions: Thalamic DBS should be considered as a primary therapeutic option in patients with segmental dystonia with prominent tremor. Indeed, patients experienced a significant relief of their tremor but also other dystonic symptoms improved significantly as reflected by the BFM.

Introduction

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder, characterized by progressive neurodegeneration associated with brain iron accumulation. Deep brain stimulation (DBS) has been trialed to treat PKAN-associated movement disorders, particularly dystonia. We studied outcome and safety of DBS for PKAN.

Methods

We performed a systematic review and meta-analysis, using independent participant data (n=99) from 38 articles. Primary outcome variables were change in Movement and Disability Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-M and –D) 1 year postoperatively. Secondary outcomes were response rate and complications.

Results

Patients with classic (n=58) and atypical (n=15) PKAN were operated at the median age of 11 and 31 years, respectively (p<.001). Globus pallidus internus (GPi) was primarily targeted (n=88). Mean BFMDRS-M change following GPi-DBS (-26%; 95%CI[-37,-15%]) was more pronounced in atypical vs. classic cases (-45 vs. -15%, respectively, p<0.001). >30% BFMDRS-M improvement at 1 year was observed in 35% of classic vs. 73% of atypical cases (p=0.04). Higher preoperative BFMDRS-M and atypical type were associated with higher BFMDRS-M reduction 1 year after GPi-DBS. Neither age at onset or surgery nor the presence of skeletal deformities and/or muscle contractures predicted outcome. GPi-DBS improved BFMDRS-D only in atypical cases. Longer follow-up suggests benefit decline.

Prevalence of surgical infections (6%) and hardware complications (7%) was similar to other dystonia aetiologies. Two patients died within 3 months. omplication rate was higher when operated in status dystonicus.

Conclusions

This meta-analysis provides level 4 evidence that GPi-DBS reduces BFMDRS in PKAN at 1 year postoperatively; however, this benefit may not be sustained in the long-term.

Introduction

Pallidal deep brain stimulation is an established treatment in patients with dystonia. However, anecdotal evidence suggests that it may lead in some patients to specific parkinsonian symptoms such as freezing of gait, micrographia, and bradykinesia.

Methods

We investigated parkinsonian signs using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale motor score by means of observer-blinded video ratings in a group of 29 patients treated with pallidal stimulation for predominant cervical dystonia and a non-surgical control group of 22 patients with predominant cervical dystonia. Additional assessments included MRI-based models of volume of neural tissue activated to investigate areas of stimulation related to symptom control and those likely to induce parkinsonian signs as well as an EMG analysis to investigate functional vicinity of stimulation fields to the pyramidal tract.

Results

Compared with controls, stimulated patients had significantly higher motor scores (median, 25^th–75^th percentile: 14.0, 8.0–19.5 versus 3.0, 2.0–8.0; p<0.0001), as well as bradykinesia (8.0, 6.0–14.0 versus 2.0, 0.0–3.0; p<0.0001) and axial motor subscores (2.0, 1.0–4.0 versus 0.0, 0.0–1.0; p=0.0002), while rigidity and tremor subscores were not different between groups. Parkinsonian signs were partially reversible upon switching stimulation off for a median of 90 minutes in a subset of 19 patients tolerating this condition. Furthermore, the stimulation group reported more features of freezing of gait on a questionnaire basis. Quality of life was better in stimulated patients compared with control patients, but parkinsonian signs had a significant negative impact on quality of life. In the imaging analysis maximum efficacy for dystonia improvement projected to the posteroventrolateral internal pallidum with overlapping clusters driving severity of bradykinesia and axial motor symptoms. The severities of parkinsonian signs were not correlated with functional vicinity to the pyramidal tract as assessed by EMG. 

Conclusion

Parkinsonian signs, particularly bradykinesia and axial motor signs, due to pallidal stimulation in dystonic patients are frequent and negatively impact on motor functioning and quality of life. Therefore, patients with pallidal stimulation should be monitored closely for such signs both in clinical routine and future clinical trials. Spread of current outside the internal pallidum is an unlikely explanation for this phenomenon, which seems to be caused by stimulation of neural elements within the stimulation target volume.

Internal globus pallidus stimulation (GPi-DBS) is an established therapeutic tool for medically refractory dystonia. However, treatment success predictors and patient satisfaction modulators remain poorly understood. To further study these subjects, we hereby report our single-center experience. We performed a descriptive and inferential retrospective analysis of the GPI-DBS performed at our center. Epidemiological and clinical characteristics were summarized and results were analyzed, according to the Burke-Fahn-Marsden for movement (BFMDRS-M) and dysability (BFMDRS-D) and, additionally, according to a scale of patient/family subjective self-reported benefit.

A total of 8 isolated dystonia cases (5 generalized, 3 cervical), 4 dystonia in neurodegeneration with brain iron accumulation (NBIA), two myoclonic dystonia and one dystonic cerebral palsy case were submitted to GPi-DBS at our institution. Average age at procedure was 36.3 years, ranging from 7 to 65. Average follow-up time was 52±9.8 months. Average pre-operative BFMDRS-M and BFMDRS-D scores were 44.5±8.8 and 12.7±2.4, respectively. On multivariate analysis, older age at procedure, shorter symptom duration before surgery and idiopathic etiology were associated to lower motor and disability scores (p<0.05).  After intervention, a statistically significant decrease of motor and disability scores was observed, with mean absolute reductions of 19.2±5.6 and 5.9±1.7 points, and mean relative reductions of 48.6±8.9% and 54.2±8.6%, on the respective scales at at last follow-up (p<0.05). On multivariate analysis, idiopathic etiology was associated with a decreased absolute motor benefit (p=0.025), but increased proportional benefit relative to pre-operative score (p=0.032). Additionally, higher pre-operative scores were associated to a greater absolute motor ad disability benefit (p=0.033 and p=0.005, respectively). At last follow-up, two thirds of patients/families reported a good or excellent benefit. Subjective benefit was associated to increased relative benefit as measured by BFMDRS-M and BFMDRS-D (p=0.026 and p=0.012), but not to absolute benefit. On multi-variate analysis, NBIA dystonias were associated to higher pre-operative scores (average BFMDRS-M 83.37±25.3 and BFMDRS-D 23.0±9.2); increased absolute benefit at last follow-up (average 36.0±10.2 motor and 10.5±4.1disability benefit); on the other hand, this group achieved lower relative benefits (average 35.63±10% increase for BFMDRS-M and 41.4±12% for BFMDRS-D) and lower subjective benefit (p<0.05).

GPi-DBS is an effective option for improving dystonia patients’ motor and functional performance. Isolated dystonias presented a greater absolute and subjective benefit. The NBIA group might be associated with a greater absolute - but not proportional – benefit, contrasting with isolated dystonia cases. Finally, BFMDRS relative change might be more important than absolute variations for subjective benefit as perceived by the patient and families.

Materials and methods:  32 patients (18 male, 16 female) age from 6 to 64  (mean 27,3) affected by dystonia were treated with DBS GPi. 18 patients were diagnosed with idiopathic general dystonia and with 15 NBIA- related general dystonia. The patients were evaluated with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Unified Dystonia Rating Scale (UDRS) and the SF-36 scale before treatment and 9 and 24 months after the procedure. The permanent electrodes were implanted  to GPi in all patients. The target was identified with direct and indirect method. Intrasurgical macrostimulation and microrecording were used for neurophysiological evaluation of the target.

Findings: No serious morbidity or mortality were reported in the group.  Local chest hematoma was reported at the region, where internal pulse generator was implanted. One patient died at the follow-up period (not related to the DBS procedure or treatment). A significant improvement in all scales were reported in both, generalized dystonia and NBIA. The differences between the groups are presented. Better results were achieved in generalized dystonia group. 

Conclusion: DBS GPi is a safe and effective method of dystonia treatment. Application of this method of treatment in generalized dystonia and dystonia in neurodegeneration with brain iron accumulation is legitimate. The improvement in both functional and quality of life scales were significant in both groups. The response to therapy may depend on clinical diagnosis. DBS GPi improves quality of life in dystonia patients.

Purpose.

It is well known that deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms of Parkinson’s disease (PD). However, the effects of STN-DBS on presynaptic dopaminergic systems are still unclear. The nigrostriatal neuronal degeneration usually continues to progress in PD patients without DBS. Positron emission tomography (PET) with ¹¹C-Labeled 2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane ([¹¹C]CFT) is a marker for loss of presynaptic dopamine transporters in the striatum in PD. Here we used  [¹¹C]CFT PET in order to evaluate binding to the dopamine transporter in PD patients before and after neurosurgical treatment with STN-DBS. Furthermore, we also examined the relationship between CFT binding and motor function before and after STN-DBS.

Methods.

10 patients with PD were examined with [¹¹C]CFT-PET pre-operatively (within one month before surgery), and 12 months after surgery. [¹¹C]CFT binding was evaluated using the region-of interest (ROI) method. ROIs were set bilaterally over the head of the caudate (divided into ventral and dorsal segments at its midpoint), nucleus accumbens, and putamen (divided into anterior-ventral, anterior-dorsal, posterior-ventral, and posterior-dorsal segments at its midpoint). Motor function was also evaluated by the Unified Parkinson’s Disease Rating Scale (UPDRS) part III pre- and post-operatively (at around the same time as the PET study). Spearman’s correlation coefficient by rank tests were used to compare the DBS-induced changes in UPDRS III with DBS-induced changes in [¹¹C]CFT binding.

 Results.

There was a significant reduction in postoperative [¹¹C]CFT uptake in the posterior-dorsal putamen contralateral to the clinically more affected side (to 7.4% of the preoperative mean, p<0.05). However, there was significant increase in [¹¹C]CFT uptake in the contralateral anterior-ventral putamen and ipsilateral ventral caudate (to 4.9% and 10.1% of the preoperative mean, respectively, p<0.05). [¹¹C]CFT uptake was also increased in the ipsilateral anterior-ventral putamen, contralateral ventral caudate and bilateral nucleus accumbens although it did not reach statistical significance. The magnitude of the percentage of reduction in UPDRS III (improvement of the motor function) was significantly correlated with that of increase in [¹¹C]CFT binding in the ipsilateral anterior-ventral putamen and ipsilateral ventral caudate. Although the same tendency was observed in the contralateral ventral caudate and contralateral nucleus accumbens, statistical significance did not reached.

Conclusions.

Our result showed that STN-DBS increases dopamine transporters in the ventral striatum, which is different from natural course of PD. The ventral striatum (anterior-ventral putamen and ventral caudate) ipsilateral to the clinically more affected side was significantly correlated to the the degree of motor improvement after STN-DBS, and contralateral ventral striatum (ventral caudate and nucleus accumbens) showed same tendency although it did not reach statistical significance. This dorsal-to-ventral shift of dopamine transporter density may indicate the compensative and neuroprotective effect of STN-DBS on the presynaptic dopaminergic systems of PD.

Objective: To evaluate the long term follow up of patients in the VANTAGE Study that employed a Deep Brain Stimulation (DBS) system with multiple independent current control (MICC) in the management of symptoms of Parkinson's disease.

Background: We postulated that a multiple source, constant current DBS device (CE marked) permitting a well defined distribution of current would lead to motor improvement in patients with Parkinson's disease (PD). The study demonstrated highly significant improved motor function (p <0.0001) as assessed by UPDRS III "meds off" at 6 months post first lead implant as compared with Baseline "meds off," thereby successfully achieving the study primary endpoint. Here we present the five year, long term results. 

Methods: VANTAGE is a prospective, multicenter, nonrandomized, open label trial sponsored by Boston Scientific. Forty subjects with idiopathic PD were implanted bilaterally with a DBS system (Vercise, Boston Scientific) targeting the subthalamic nucleus and followed up to five years post lead placement. Assessments included UPDRS III scores in the meds off condition, quality of life such as Parkinson's Disease Questionnaire (PDQ39), Modified Schwab and England (SE), etc. Adverse events were collected. 

Results: At four years post lead placement, quality of life as assessed by PDQ39, SE continued to show improvement as compared to baseline. Additionally, the usage of antiparkinsonian medications continued to show a similar trend as reported earlier. This report will present the long term motor outcomes and quality of life results at 5 years post lead placement. 

Conclusions: The collected outcomes from the VANTAGE clinical trial will inform clinicians on use of this system, and its flexibility to manage symptoms of idiopathic PD.

Introduction

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an important advanced therapy for Parkinson’s disease (PD), which alleviates motor symptoms and improves quality of life. However, some individuals develop postoperative neuropsychiatric symptoms such as impulsivity and mood elevation. This is believed to arise from the central role of the STN in cognitive and affective, as well as motor, inhibition. Our group has previously demonstrated that the locus and distribution of subthalamic stimulation is a key determinant of postoperative neuropsychiatric symptoms; here we sought to delineate brain networks responsible for this phenomenon. 

Methods

Forty-five, non-demented persons with PD undertook high-resolution diffusion brain imaging prior to subthalamic DBS. Each participant was assessed with a battery of neuropsychiatric instruments at baseline and at four postoperative intervals up to six-months post-DBS. Participants also played a played a slot-machine in a virtual casino prior to subthalamic DBS (whilst on medication) and three-months postoperatively (whilst on stimulation).  This provided information on gambling behaviour and furnished Bayesian estimates of a participant's confidence in the winning probability and volatility (likelihood that a machine would switch between "hot" and "cold" states) of the slot machine.

Results

We delineated core structural brain networks implicated in cognitive control, response inhibition and reward valuation. At baseline, using multivariate path analysis with partial least squares regression, the connectivity (defined as apparent fibre density) of the STN with cortical regions pre-SMA (supplementary motor area), IFG (inferior frontal gyrus) and ACC (anterior cingulate cortex) was significantly associated with inhibitory errors and ‘double or nothing gambles’ on the slot machine. The connectivity of the ventral striatum (nucleus accumbens) with cortical regions 10-medial, OFC (orbitofrontal cortex) and ACC was significantly associated with impulsive-compulsive behaviours (as rated by the Questionnaire for Impulsive- Compulsive Disorders in PD–Rating Scale), delay aversion (as scored by the delay discounting task), bet size and uncertainty about winning probability on the slot machine. We then generated an individual volume of activated tissue (VAT) for each hemisphere in each participant based upon subthalamic electrode positioning and individualised stimulation parameters. We found that connectivity between the site of stimulation and these cortical targets significantly modulated these behavioural and cognitive measures.

Conclusions

In summary, we identify core subcortical-cortical networks underlying impulsivity and valuation in Parkinson's disease, and demonstrate the interaction between electrode targeting and neuroanatomy in the modulation of post-DBS impulsivity. These data underscore the importance of accurate electrode targeting, contact selection and device programming to reduce postoperative neuropsychiatric impairment. The ability to predict neuropsychiatric symptoms based on subthalamic data may permit anticipation and prevention of these occurrences, improving safety and tolerability.

Objective: This research is a quantitative, exploratory study, which aims to identify the symptoms that patients with Parkinson's disease (PD) expect to improve with deeep brain stimulation (DBS) and whether the expected levels of improvement are met after DBS surgery.

Background: DBS is an effective surgical treatment that improves patient quality of life in advanced PD. It is an essential part of patient care in DBS treatment to identify and manage expectations from the assesment of suitability for DBS to the lifelong care after DBS surgery. The DBS outcome is influenced by patients' varying expectations on how DBS can improve their symptoms after DBS.

Research Methods: 28 participants with advanced PD were recruited and have completed a visual analogue (VAS) questionnaire designed to capture patient's expectations prior to surgery (pre-DBS) and at 6 months to 2 years follow up (post -DBS). 20 patients had subthalamic nucleus (STN) DBS and 8 patients had globus pallidus interna (Gpi) DBS.

Results: For the group as whole, there was a significant reduction in total levodopa equivalent daily dose (mg/day) by 50.45% in the STN group after DBS and the motor symptoms for both STN and Gpi group have improved on the UPDRS III off (p 0.001), mobility (p 0.0048), ADL (p 0.008) and stigma (p 0.014) after DBS. This objective symptomatic improvement was also mirrored in the patients expectations being generally met for the motor symptoms at least. In general expectation of patients in DBS, there was no significant difference (z value (-0.158), two tailed p value 0.875) between the pre-DBS expectation of general improvement in PD symptoms and perceived general improvement 6 months to 2 years after surgery, which confirms that general expectations of  improvement were met after DBS. Most patients reported that expectations of improvement after DBS were met: 64% for motor symptoms, 71% and 83% for quality of life and reductions in medication daily dose (respectively). Only 25% of the expected levels of improvement were met for the non-motor  symptoms and for the social domain. Between STN and Gpi DBS targets, the expectations from DBS were satisfied 6 months to 2 years after the surgery: in Gpi-DBS group, 100% were satisfied in the reduction of dyskinesias, 83.3% for motor symptoms and 66.70% for quality of life. STN-DBS patients were satisfied with the reduction in medication (84.20%), 78.90% for motor symptoms and 73.70% for quality of life.

Conclusions: DBS did meet the perceived expected level of improvement in motor symptoms, quality of life, and reduction in medication within 6 months to 2 years after DBS surgery for the majority of patients which corresponded to the objective clinical outcome. The pre-DBS expected improvement of non-motor symptoms and social domain was not met after surgery. Overall, both STN-DBS and Gpi-DBS patients were satisfied that DBS had met their expectations of surgery.

Objectives: Deep Brain Stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for patients with advanced Parkinson’s disease (PD). The role of the frequency of stimulation is not fully understood. We compared  the effect of 80 Hz and 130 Hz on functions mediated by the associative and oculomotor fronto-striatal loops by assessing several oculomotor tasks and a cognitive test (the Stroop test), in a randomised double blind design.

Methods: After overnight withdrawal of dopaminergic medication, 20 patients received 80Hz and 130 Hz stimulation in a randomised order during 24 hours. The amplitude of stimulation was adjusted to keep the energy delivered stable.  The assessments included:  Unified PD Rating Scale motor score (UPDRS-III), pro-saccade (S) and anti-saccades (AS) task and Stroop test.  Horizontal eye movements were collected using an eye-tracking system consisting of an infrared camera and padded helmet (Mobile EBTH, e(ye)BRAIN. 24 horizontal saccades across 3 visual angles (5°,10°,20°) were registered for both S and AS.

Results: Mean UPDRS-III was not different between the two frequencies (130Hz: 19.2 (9.1), 80Hz: 16.9 (10.5), p=0.2) . Tremor did not deteriorate. The saccade latencies and gain were similar for the two frequencies of stimulation during the S task. However, for AS, the error rate (10.2±6.3 vs. 12.2±5.73, p=0.02) and the latencies (326.0±101.6 ms vs. 381±135 ms, p= 0.03) were higher at 80Hz. The Stroop test revealed less errors in the more complex task at 80Hz (2.5±3.1 vs. 1.1±1.4 p=0.02).

Conclusions: The acute change of frequencies did not affect the clinical benefit measured with UPDRS III. However, antisaccade performance was superior at 130Hz stimulation, while performance on the complex Stroop task was comparatively better at 80Hz. This discrepancy might be related to interference with neural circuits differentially involved in lower-order oculomotor function versus higher-order cognitive tasks.

Objective: To evaluate functional connectivity (FC) of the ventro-lateral thalamus, a common target for drug-resistant essential tremor (ET), resting-state data were analyzed before and 1 year after stereotactic radiosurgical thalamotomy (SRS-T), and compared against healthy controls (HC).

Methods: 17 consecutive patients and 10 HC were enrolled. Tremor network was investigated using ventro-lateral ventral (VLV) nucleus as region-of-interest (ROI), extracted using automated segmentation from pretherapeutic diffusion MRI. Temporal correlations of VLV at whole brain level were evaluated by comparing drug-naïve ET with HC, and longitudinally, 1 year after SRS-T. Thalamotomy volume was always located inside VLV, and did not correlate with any of FC measures (p>0.05). This suggested presence of longitudinal changes in VLV FC independently of thalamotomy volume.

Results: Pretherapeutic ET displayed altered VLV FC with left primary sensory-motor cortex, pedunculopontine nucleus, dorsal anterior cingulate, left visual association and left superior parietal areas. Pretherapeutic negative FC with primary somatosensory cortex and pedunculopontine nucleus correlated with poorer baseline tremor scores (Spearmann=0.04 and 0.01). Longitudinal study displayed changes within right dorsal attention (frontal eye-fields and posterior parietal) and salience (anterior insula) networks, as well as areas involved in hand movement planning or language production.

Conclusion: Our results demonstrated that ET and HC differ in their VLV FC to primary somatosensory and supplementary motor, visual association, or brainstem areas (pedunculopontine nucleus). Longitudinal changes display reorganization of dorsal attention and salience networks after thalamotomy. Beside attentional gateway, they are also known for their major role in facilitating a rapid access to the motor system. 

Objective

The aim of our study was to investigate which cerebral fiber tracts are involved in the alleviation of parkinsonian tremor in deep brain stimulation.

Methods

21 patients with Parkinson´s disease and bilaterally implanted electrodes in the subthalamic nucleus were investigated. In 6 of those patients parkinsonian tremor was present in 11 hemibodies contralateral to the investigated brain-hemispheres. Diffusion weighted images (DWI) with 64 gradient directions were included in the routine preoperative imaging procedure for deep brain stimulation. Post-operative CT scans were fused to the DWI data set and the position of the individual contacts of the electrodes were determined. Probabilistic fiber-tracking was performed with seed regions based on each individual contact of the electrodes and the resulting anatomical fiber tracts were determined. We compared the depicted fiber tracts between contacts, which effectively (<=2V) reduced the tremor (> 50%) with the fiber tracts of contacts that did not.

Results

14 (31.8%) of the 44 contacts achieved a reduction of the contralateral tremor (>50%) with an amplitude <= 2.0V. Effective contacts were significantly more often associated with the fasciculus thalamicus, the ansa and fasciculus lenticularis, the medial and lateral branches of the anterior limb of the internal capsule and fibers passing through the zona incerta (p<0.05) than non-effective contacts. Fibers of the ipsi- and contralateral dentate-rubro-thalamic tract were not depicted differently between effective and non-effective contacts.

Conclusion

As opposed to essential tremor, in parkinsonian tremor the dentate-rubro-thalamic tract does not seem to be the anatomical structure involved in tremor reduction. More likely, stimulated pallido-thalamic and prefrontal-thalamic fibers play the major role concerning the alleviation of parkinsonian tremor.

Background: Despite more than 30 years of applying deep brain stimulation (DBS) for tremor, optimal stimulation parameters remain elusive and clinical outcomes inconsistent. Addressing the individual anatomy and tremor characteristics may be key to deriving the most clinical benefit. In practice, however, the virtually infinite amount of parameter combinations and patient fatigue hinder an individualized, comprehensive exploration of the parameter space. The insufficiently understood relationship between the stimulation parameters (voltage, pulse width and frequency) further emphasizes the need for a robust programming strategy.

Objective: We aimed to test the effect of unexplored DBS settings and hypothesized that applying random combinations of stimulation parameters could lead to improved tremor suppression and reduce side-effects. The main advantage of this approach would be that the DBS parameter space is more thoroughly explored in limited time and the stimulation parameters are independent from each other.

Methods: Ten individual random combinations of stimulation parameters were tested on eleven patients (64 ± 16 y.o.) reporting suboptimal tremor reduction following DBS in the Vim, ZI or GPi for either essential, orthostatic, or Holmes tremor. The effects of the random combinations were documented by means of patient reported outcomes and accelerometer recordings. Clinical follow-up after 6-17 weeks was obtained telephonically.

Results: The experimental paradigm was conducted within 23.8 ± 8.03 minutes per patient and afforded significantly (p = 0.017) improved tremor suppression (.21 ± .12 a.u.) compared to baseline (.93 ± .79 a.u.). Upon medium term follow-up, tremor suppression was retained (p = .01), with prolonged resolution of side-effects in three out of four patients. Noteworthy, optimal titration was achieved with significantly broader pulse widths (Z = -2.81, p = .005) and lower frequencies (Z = -2.14, p = .032) compared to baseline, which is in line with the deleterious effect we observed for maximal stimulation frequencies (U = 486, p = .008).

Conclusion: Random DBS-parameter exploration yielded significant tremor suppression compared to baseline in the short and medium term, with reduced side effects. Our paradigm is a safe, highly effective and time-efficient approach for improving DBS-programming that may provide a basis for closed-loop DBS programming algorithms. Moreover, these findings add to the current understanding of the working mechanisms of DBS and may guide further research.

Introduction: Deep brain stimulation (DBS) in the subthalamic nucleus (STN) region reduces the motor symptoms of Parkinson’s disease (PD). However, symptomatic improvement among patients is variable, perhaps due to inconsistency of the active electrodes location relative to some unknown optimal locus of stimulation. In this study, we mapped the optimal locus of DBS stimulation for bradykinesia, tremor, and rigidity in a mathematically defined and atlas-independent manner.

Methods: In 37 patients treated with STN DBS for PD, we mapped active electrode position to Unified Parkinson’s Disease Rating Scale (UPDRS) improvement, as well as individual scales for tremor, rigidity, and bradykinesia. We then applied a novel computational electrical field model of neuronal activation to provide an independent prediction of optimal lead location for each motor sign across patients.

Results: Using this combined outcomes analysis and our electrophysiological model, we mapped the optimal locus of DBS stimulation to a tightly-defined region 0.49 mm lateral, 0.88 mm posterior, and 2.63 mm dorsal to the anatomical midpoint of the STN. Interestingly, using our atlas-independent computational model, we determined the optimal sties for the 3 hallmark symptoms of PD, and found them to be statistically the same as the overall optimal site of stimulation.

Conclusions: Our results suggest that one locus of stimulation in DBS for PD is in a region dorsal, posterior, and lateral to the anatomical midpoint of the STN optimally improves the overall symptoms of PD as well its major motor components.

Background

In recent years, studies in patients with gait disorders have suggested that Spinal Cord Stimulation might have positive effects on locomotion. Herein, we report the case of a patient with primary progressive freezing of gait who underwent SCS for thirty three years. To the best of our knowledge, it‘s the longest follow-up published for SCS in the treatment of motor disorders.

Case report

In 1987, a 60-year-old woman presented gait disturbance characterized by stepping troubles and motor blocks without pain. She was initially diagnosed as lumbar spinal claudication A SCS test was proposed to improve her symptoms. A trial was positive and a neurostimulation system (Medtronic *) was implanted at T10 spinal level. The gait returned to normal. In 1997, a similar event of severe walking disorders returned, corresponding to a battery depletion. Abnormal gait pattern included shuffling, waddling and freezing of gait. A Parkinson disease (PD) was suspected but neurological examination was normal as DAT SPECT scan and Levodopa was ineffective.The device was replaced and, again, gait troubles vanished. The same events repeated in 2005, 2012 and 2017, occurring at the time of a battery depletion and disappearing following its replacement. SCS parameters based on our experience in lower limbs pain treatment were 80Hz, 300 micros, cycling mode (“off“ 1min, “off“ 2min) and 2.5 v, subthreshold value for paresthesia.

The clinical condition remained stable. She was subjected to an evaluation during the replacement periods, in Off and On stimulation condition including PD scales  (UPDRS III - motor items, Freezing of Gait Questionnaire (FOG-Q), quality of life PDQ 39 and minimental test), a walking test, the SWS Test (“stand-walk-sit“) documented on videotapes and a laboratory analysisto evaluate temporospatial gait parameters.

Results

During this 30 years follow-up period, course of disease was mildly progressive. During “on“ stimulation, patient experienced significant improvement in motor scores and quality of life criteria and the gait parameters were all dramatically improved when compared with Off condition : the completion time was almost four times faster with four times less number of steps and no freezing episodes.

Discussion 

Our patient presented with a pure progressive FOG with shuttling that started 30 years earlier. Otherwise, neurological examination was normal during this time course with no additional signs in keeping with PD or PD plus. This syndrom fit with “Primary Progressive Freezing of Gait“(PPFG) or “Syndrom of Gait Ignition Failure“ (SGIF). The recurrent gait troubles and their recovery by SCS were very similar several years apart. Indeed, the lesion was indolent but sufficient to keep its potential effect. A placebo effect needed to be taken into account.The expectation of clinical improvement which had been found to activate reward mechanisms unlikelysustained at long-term.

On the other hand, directly experiencing the SCS on gait improvement withstimulation-induced paresthesia could establish a learning effect which contributed to the sustained effect.

The mechanisms of SCS efficacy were not elucidated. Trouble originated by a lesion on the gait control pathway whatever the level, resulted in an abnormal modulation on the spinal CPG, that could be reversed by the SCS. Indeed, the SCS could induce supra spinal activation, but the key point was the CPG. Hence, an optimal lead placement at the CPG level seemed crucial for successful stimulation.

Conclusion

SCS remained effective during this very long time without tolerance. Two other cases of PPFG were publishd and two cases of freezing in Supranuclear paralysis. Well Studied in depth cases could disentangled gait disorders in PD. That’s an important point in support of conducting larger randomized studies as new paresthesia free SCS systems are promising.

Disclosure 

The authors have no conflicts of interest relevant to this study. 

Objectives: As a method of measuring the phase difference between two signals, the phase lag index (PLI) of the alpha and beta bands in patients with Parkinson’s disease (PD) was investigated by using magnetoencephalography (MEG).

Methods: 18 PD patients were measured by MEG in the state of overnight withdrawal of Levodopa and after Levodopa treatment; meanwhile, UPDRS III scale was evaluated.

Results: Compared with healthy controls, alpha (8-13 Hz) PLI in the frontal and parietal areas elevated in PD patients, while the elevation was reversed by the Levodopa treatment. The alterations of the UPDRS III total scale (r_s = 0.552, p = 0.013, n = 16) and the changes of akinesia scale (r_s = 0.622, p = 0.005, n = 16) were correlated to the change of beta (13-30 Hz) PLI in the left parietal area. The change of the UPDRS total scale was negatively correlated to duration of disease (r_s = 0.432, p = 0.047, n = 16). There was a negative correlation between the age of PD patients and the change of alpha PLI in the left frontal area (r_s = 0.519, p = 0.020, n = 16). 

Conclusions: PD patients showed a higher Mu PLI in the sensorimotor area relative to the healthy controls. The improvement of motor symptoms of PD patients by levodopa was correlated to the inhibition of beta PLI in the sensorimotor area.

Background: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is routinely proposed to treat Parkinson’s disease (PD) patients with motor fluctuations, its influence on postoperative global impulsivity or impulse control disorders (ICD) is controversial. We studied changes of impulsivity in PD patients treated by DBS-STN, by considering the two dimensions of impulsivity defined by Dickman, namely functional (“physiological”) impulsivity (FI) and dysfunctional (“pathological”) impulsivity (DI).

Methods: We studied retrospectively pre and postoperative data of 33 idiopathic PD patients with levodopa related-motor complications treated by DBS-STN, including UPDRS score, treatment (including dopaminergic agonists intake), cognitive functions (FAB and Mattis scales, apathy inventory), mood (MADRS) and occurrence of ICDs. Impulsivity was assessed using the Dickman scale, who distinguishes two dimensions: the FI that reflects the ability to react quickly when the situation requires it, and the DI who reflects the absence of preliminary reflection in the action, even when the situation requires it. Localization of the stimulating contacts was studied using a deformable histological basal ganglia atlas merged on postoperative MRI. 

Results: Six months after surgery, we observed a significant increase (p<0,001)of DI (mean pre- and post-operative DI scores 9 +/-1,6 and 3,5 +/-2,4) but no change in FI (mean pre- and post-operative FI scores 6,2 +/-2,7 et 5,8 +/-2,6). Factors associated with DI score’s increase >2 were: low preoperative FAB score (p=0,03), high preoperative UPDRS III score (p=0,02) and location of the left electrode in the ventral STN (p=0,012). 

 Conclusion: Our study suggests that DBS-STN might influence differently the two dimensions of impulsivity, by worsening the pathological impulsivity without modifying the physiological impulsivity. Severity of the PD, preoperative impairment of frontal functions and ventral location of the electrode favored worsening of dysfunctional impulsivity. Patients with these contributing factors should beneficiate from a closer psychiatric monitoring. 

Background

Traditionally brain atrophy has been considered a relative contraindication to DBS surgery due to an increased risk of CSF egress, brain shift, targeting error and surgical complications. The aim of this study was to determine the effect of brain atrophy on targeting accuracy and outcome in a cohort of PD patients undergoing DBS surgery using a highly accurate robot-assisted and guide-tube directed method designed to minimised CSF loss and brain shift.

Methods

All surgical procedures were performed using a robot-assisted guide tube-directed method (Renishaw PLC, Gloucs., UK) with on-table fluoroscopic scanning for image-guided targeting verification (O-arm, Medtronic, MN, USA). The drilling process utilised a 1.8mm diameter drill which was intended to minimise the risk of CSF egress and subsequent brain shift. Guide tubes were inserted using a track dilation technique in order to create a pre-formed track. Brain atrophy was quantified by determining the brain parenchymal fraction (BPF) in 113 consecutive PD patients using the MICO method for segmentation of grey matter, white matter and CSF, with a low BPF reflecting increased brain atrophy. Targeting accuracy was determined by comparing the planned guide tube and stylet position with intra-operative fluoroscopic scans following implantation. Vector, radial and depth targeting errors were determined and correlated with BPF using Matlab software (Mathworks, Cambridge, UK) and Spearman's rank correlation analysis. Clinical outcome data was prospectively collected and BPF correlated with UPDRSIII scores at 6 months following surgery. Brain shift was also quantified in a subgroup of 73 patients by comparing the pre-operative and intra-operative position of blood vessels, and correlated with the degree of brain atrophy.

Results

Using the MICO method for brain segmentation, the BPF of PD patients within this cohort ranged from 0.53 to 0.89 (mean 0.78). There was a weakly significant correlation between increased brain atrophy and both radial and vector targeting error, with a trend towards greater error in patients with BPF<0.7. However, the maximum vector and radial targeting error was less than 1.6mm in all patients, with a mean error of 0.78mm. There was no correlation between the degree of brain atrophy and percentage change in UPDRSIII scores at 6 months. No correlation could be found between the degree of brain atrophy and intra-operative brain shift (r=0.18). Two patients suffered brain haemorrhages within this cohort – the BPF in one patient was high (0.82) and lower in the second patient (0.67).       

Conclusions

Using a robot-assisted and guide tube-directed surgical technique designed to minimise CSF egress, targeting remained highly accurate in patients with low BPF and increased brain atrophy, with no correlation found between the degree of atrophy and clinical outcome at 6 months post-operatively. Furthermore, the degree of brain atrophy could not be correlated with intra-operative brain shift in this cohort. Further studies are required to determine whether patients with BPF<0.7 should be counselled for increased risk of targeting error, or whether a “threshold” BPF can be identified which may be used as a selection criterion for patients considered for DBS.  Comparative studies of the effect of brain atrophy on targeting accuracy and outcome when DBS surgery is performed using conventional burr holes with the robot-assisted guide tube-directed method described here are also warranted.

Background: Deep brain stimulation (DBS) is an established treatment for advanced Parkinson’s disease (PD). The most commonly used targets are the subthalamic nucleus, the pallidum and the ventrolateral thalamus. The area below the thalamus, known as the posterior subthalamic area (PSA)/caudal Zona incerta (cZi) has been shown to alleviate PD symptoms such as rigidity and tremor, when subjected to ablation or high-frequency stimulation. The published experience is, however, limited and consists to a large part of unilateral procedures in patients with tremor dominant symptoms.

Aim: To evaluate the effect of bilateral cZi-DBS in a group of patients with PD fulfilling the criteria for bilateral STN-DBS.

Method: The patients in this study were previously included in a randomised blinded trial of cZi DBS versus best medical treatment, with a 6 months follow-up (Blomstedt P, Stenmark Persson R, Hariz G, et al. Deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson’s disease: a randomised blinded evaluation. JNNP 31 January, 2018; Epub ahead of print). In the present study we analysed the results of surgery for the whole cohort at 6 and 12 month after surgery. Main outcomes were differences in motor symptoms (Unified Parkinson’s Disease Rating Scale, UPDRS-III) and in quality of life (Parkinson’s Disease Questionnaire , PDQ-39) between baseline and follow-ups. The patients were evaluated on/off medication at baseline before surgery and on/off medication, on/off stimulation at 6 and 12 months. Preoperative T2-weighted images was used for intensity-based image segmentation and conductivity assignment (ELMA Version 2.4, Department of biomedical engineering, Linköping University, Sweden) based on tabulated conductivity values resulting in a brain model. Patient-specific electrical field simulation of the brain model will be performed using the finite element method (Comsol Multiphysics Ver 5.2, COMSOL AB, Stockholm, Sweden). Friedman’s test was used for statistical evaluation of non-parametric values and the Wilcoxon signed rank test as a post-hoc analysis. Analysis of variance for repeated measurements was used for continuous variables with the Bonferroni correction method as a post hoc test. A p-value ≤0.05 was considered statistically significant.

Results: 
Fifteen patients (4 females) were included. The mean age at surgery was 58.6±2.5 years. Levodopa-equivalent daily dosage (LEDD) were 1248±685 mg at baseline.  The presented results are means ± standard deviation in off-medication state, unless stated otherwise.  
UPDRS-III scores improved from 37.5±11.2 at baseline to 21.2±6.6 (44%) and 22.7±7.5 (40%) on stimulation at 6 and 12 months, respectively (p≤0.0005). Scores of on versus off stimulation showed  an improvement of 49% at 6 months and 47% at 12 months (p≤0.0001).  
Tremor score improved from 9.4±5.4 at baseline to 0.8±1.1 (92%) and 1.2±1.3 (87%) on stim, at 6 and 12 months after surgery (p≤0.0001). Rigidity scores improved from 7.6±2.7 to 5.4±2.7 (29%) and to 5.5±2.5 (28%) (p≤0.005). Akinesia scores improved from 13.0±5.0 to 9.0±4.3 (31%) at 6 months and 9.9±4.8 (24%) at 12 months (p≤0.01). Axial scores improved by 19% at 6 months (p≤0.02) but were no longer significantly changed at 12 months. For PDQ-39, ADL was improved from 28.1±22.2 to 20.8±19.1 (26%, p≤0.05). Stigma improved from 23.4±19.3 to 11.3±15.9 (52%, p≤0.01).

There were no significant changes concerning dyskinesia scores or LEDD. Mean stimulation parameters were 2.3±0.5 V, 66±12.2 µs and 148±13.4 Hz at 6 months and did not change over time. In relation to the midcommissural point, the active contacts were 11.8±1.2 mm lateral, 6.4±1.4 mm posterior and 1.9±1.7 mm inferior.

 
Discussion: The cZi has been suggested as an alternative target for DBS for tremor, including for PD. In this study there was robust effect at one year on tremor, and moderate on akinesia, as well as improvement in ADL and stigma. At 12 months cZi DBS did not affect axial symptoms, dyskinesia scores or LEDD. The cZi as a target for DBS in PD is an addition to the established targets, allowing perhaps to tailor the surgery to the needs of the individual patients. Further analysis in the project will include evaluation of activation volume in reference to the anatomy. Further longer term studies are needed to determine the role of cZi DBS in the surgical therapeutic armamentarium of PD.

Objective

Deep brain stimulation becomes increasingly important in treating the motor symptoms of Parkinson’s disease. To improve target planning in deep brain stimulation, we investigated the connectivity between the stimulated volume and cerebral white matter tracts to find out, which tracts have a positive effect on bradykinesia in Parkinson’s disease.

Methods

This retrospective study was based on 21 patients with Parkinson’s disease who received bilateral deep brain stimulation in the subthalamic nucleus. 18 of these patients initially presented with bradykinesia symptoms existent in 31 hemibodies. Since each lead electrode has four contacts, 124 lead contacts in the associated contralateral brain hemispheres were investigated. The effectiveness in reducing bradykinesia was individually assessed for every lead contact. Furthermore, we performed probabilistic tractography to visualize cerebral fiber-tracts showing connectivity to the stimulated brain volume of each individual electrode contact. Our calculations were carried out using preoperatively acquired diffusion weighted magnetic resonance imaging (64 gradient directions, 12-channel head-coil).

Results

Out of the 124 contacts, 92 (74.2%) showed a reduction of the contralateral bradykinesia symptoms of 50% or more and were therefore considered clinically effective. Clinically effective and ineffective contacts were compared for their connectivity patterns using the computed fiber-tracts. The statistical analysis showed that the effective contacts were significantly (p < 0.05) more often associated with the ipsilateral superior cerebellar peduncle and the ipsilateral dentate nucleus, which partly define the course of the ipsilateral, non-crossing part of the cerebello-thalamo-cortical pathway. Furthermore, the anterolateral fasciculus, the medial forebrain bundle, the zona incerta, the pedunculopontine nucleus and the medial part of the internal capsule’s anterior limb were significantly positively associated. Significant negative correlations existed with the contralateral medial cerebellar peduncle, the central pons and the motor cortex representing the descending cortico-ponto-cerebellar pathway.

Conclusion

A connectivity-based approach may improve target planning in deep brain stimulation. In the case of bradykinesia in Parkinson’s disease, the cortico-cerebellar loop seems to play a key role. Our results showed that a connection to its ascending portion, the ipsilateral cerebello-thalamo-cortical pathway, strongly correlated with the alleviation of bradykinesia, while stimulation of the descending cortico-ponto-cerebellar pathway had no positive influence.

Objective

The need of using multiple trajectories and intraoperative testing in an awake patient during DBS for Parkinson´s disease is discussed controversially. In our department it was done in all cases. We aimed to find out if there is a benefit of such procedure in the clinical outcome.

Methods

We retrospectively analysed all data of patients, who have undergone DBS-surgery for Parkinson`s disease in our department in 2012 and 2014. We recorded the number of microelectrodes, the trajectory of the permanent electrode, the reasons for avoiding the central trajectory and the clinical outcome (UPDRS Part III). The intraoperative effect was defined as the improvement of the rigor estimated in % by a neurologist. The clinical outcome was measured as the difference of the preoperative UPDRS III under L-dopa medication and the postoperative UPDRS III under L-Dopa medication and stimulation. Possible influencing factors on the clinical outcome were estimated with a linear regression model (p<0,05).

Results

In the study period 67 patients were treated with bilateral DBS of the STN because of Parkinson`s disease (134 implantations of permanent electrodes). In 92,88% of the 134 implantations 3 or more trajectories were used for microrecording and intraoperative testing. For implantation of the permanent electrode the central trajectory was used in 58%. In the remaining patients (42%), we used in 56,36% the anterior, in 1,81% the medial and in 41,81% the lateral trajectory. The reason for not using the central trajectory was a better intraoperative effect in 65,38%. Changing the trajectory due to a better intraoperative effect was found to be an independent, significant (p= 0,001) predictor for the clinical outcome with the coefficient factor 8,32 on the right and 9,93 on the left side.

Conclusion

Using multiple trajectories lead to a deviation from the central trajectory in 42 % of the implantations, predominantly due to a better intraoperative effect. This intraoperative testing has turned out to be significantly positively correlated with the clinical outcome (even after controlling for the other variables). This result is in line with the hypothesis that deviating from the central trajectory due to intraoperative testing leads to a better clinical outcome. However, a matched pair analysis between the operation with awake and intubated patients, which would allow to test for a causal relationship, has not been done yet but belongs to our agenda.

Introduction: Deep brain stimulation (DBS) is an established treatment for essential tremor, Parkinson’s disease and dystonia. DBS is also effective in several symptomatic movement disorders, yet, its therapeutic effect on post-encephalitic symptoms has been under-reported.

A case description: A 47–year-old man presented with progressive severe axial and limb tremors for 6 months after resolution of his autoimmune encephalitis. On examination, he showed resting, intentional, and task-related tremors in his trunk and bilateral limbs. He also had dysarthria and moderate torticollis to the right side. His preoperative TETRAS scale score was 44. As the tremors being medically refractory, he underwent bilateral ventral intermediate nucleus (Vim) DBS surgery. The coordinates for Vim were 13.5mm lateral and 5.8mm posterior to the midcommissural point on the anterior and posterior commissural plane. Intraoperative microelectrode recording showed tremor cells from 8.4mm to 2.0mm above the target. The DBS electrodes were implanted to the targets to stimulate these recorded points. After an initial DBS programming, postoperative TETRAS scale score improved to 30.5 by ameliorating his tremor. His dysarthria persisted, yet moderate torticollis disappeared.

Discussion: Bilateral Vim DBS can be an effective treatment for severe post-encephalitic movement disorders.

Introduction: Movement disorders related to hydrocephalus are frequently expressed as Parkinsonism, yet anatomical substrates are fairly unclear. We report here a case of post- hemorrhagic aqueductal stenosis and discuss about the origins of symptoms.  

A case description: A 23–year-old man presented with progressive bradykinesia, ataxia and gait disturbance 1.5 months after acute-phase ventricular drainage treatment for left midbrain hemorrhage ruptured into third ventricle. On examination, he showed masked face, vertical gaze palsy and resting, intentional, and task-related 3-4 Hz tremors in his right upper limb. He also had dysarthria and pyramidal tract sign of right side. His preoperative MDS_UPDRS 3 score was 68. MRI showed triventricular hydrocephalus due to edematous obstruction of aqueduct surrounding ruptured hematoma cavity, which was confirmed endoscopically. Dopamine transporter scan showed decreased uptake in left putamen. After third ventriculostomy, both ventriculomegaly and midbrain edema subsided. His symptoms were alleviated, and MDS_UPDRS 3 score improved to 19 at discharge. Dopaminergic agent was precluded due to its adverse effect. He returned to the work within a year, with residual minimum gaze palsy.

Discussion: Hydrocephalic Parkinsonism is composed of complex symptoms according to affected white matter tracts. In this case, pyramidal tract, medial longitudinal fasciculus, dentate-rubro-thalamic tract and nigrostriatal tract were possibly affected by edema, and their dysfunctions were partially reversible.

Background: The volume of activated tissue (VAT) virtualize the current provide to the DBS lead on brain structures. The objective of the present study was to assess the correlations between the VAT, activation of the corticospinal tract, and the intra-operative side effect (ISE) threshold.

Methods: This double-blind, single-center study was performed between September, 2016, and July, 2017. We identified two groups for statistical analysis: the entire study population, and a subset of patients with additional diffusion tensor imaging (DTI) data for determining the location of the pyramidal tract. We determined the intensity threshold at which the VAT reached the border of the target nucleus (referred to as VATn) and the intensity threshold when the VAT reached the pyramidal tract (referred to as VATndti). In each group of patients, we studied the correlation between the ISE threshold and the VATn or VATndti threshold.

Results: Fifteen patients were included in the study. In both groups, there was a significant correlation between the VAT intensity threshold and the ISE threshold (p=0.018; r=0.31 for VATn in the entire study population). In the subset of patients with valid tractography data, the correlation was stronger (p=0.002; r=0.5 for VATndti).

Conclusion: The present study is the first to show a relationship between the intensity threshold as determined by the use of the VAT and the intra-operative side effect threshold. The correlation between the clinical features and the VAT appear stronger when the model was based on a combination of high-resolution anatomic data and interpretable DTI data.

Background: Directional deep brain stimulation of the subthalamic nucleus for treatment of Parkinson´s disease offers new possibilities of current steering towards clinically effective locations and thereby increasing the therapeutic window. The objective of the current work is to understand the relation between the anatomical stimulation site of directional stimulation and clinical effects.

Methods: Postoperative clinical mapping after 6 months was performed in a prospective, consecutive series of 28 patients. Stimulation effect and side effect thresholds of DBS lead contacts were systematically assessed using the UPDRS motor subscores and compared to baseline in the medication-off state. DBS lead positions and their corresponding volume of tissue activation (VTA) were normalized into the MNI space and integrated into a three-dimensional human brain atlas to construct a stimulation map. Non-parametric statistical tests were applied to test for differences between subgroups.

Results: In 24 of 56 (43%) analysed hemispheres directional stimulation provided a larger therapeutic window compared to omnidirectional stimulation. The mean therapeutic window of the best directional contact was increased by 6.8 ± 60% compared to omnidirectional stimulation whereas it was significantly decreased by 33.2 ± 84% for the worst directional contact (p< 0.001). Clinically effective contacts and their associated VTA projected onto the dorsolateral aspect of the normalized STN. Electrode contacts with a low side effect threshold (< 3.0 mA) projected onto the dorsolateral STN and pointed posterolateral towards the internal capsule.

Conclusion: According to our postoperative mapping results, directional stimulation provides a slightly increased therapeutic window compared to omnidirectional stimulation. The dorsolateral STN seems to be the optimal stimulation site, although stimulation of this subregion is also associated with a low side effect threshold. Follow-up data of chronic stimulation is needed to confirm these preliminary results.

Background: Patients with movement disorders undergoing implantation of deep brain stimulation (DBS) electrodes are typically awake during surgery. Albeit commonly referred to as a highly stressful event, little is hitherto known about how the conscious patient perceives the different stages of awake DBS surgery and which preoperative and perioperative factors shape this intraoperative experience.

Objectives: Here, we set out to identify key factors determining the subjectively perceived intraoperative level of psychological distress in patients with different movement disorders undergoing awake bilateral microelectrode-guided implantation of DBS electrodes at our institution (Department of Neurosurgery, University Medical Center Hamburg-Eppendorf).

Methods: Based on a pre-defined set of constituent surgical phases, patients were asked to report their current level of distress on a verbally administered numerical rating scale from 0 (equal to no stress) to 10 (equal to worst possible stress) throughout the whole surgical procedure. In addition, heart rate and arterial blood pressure were monitored as indices of autonomic stress. A reference group of 67 patients with Parkinson´s disease (PD; mean age, 62 years; mean duration of disease, 12.8 years; average Hoehn & Yahr stage, 2.8) undergoing bilateral DBS of the subthalamic nucleus in the OFF medicated state was compared with 12 essential tremor patients (mean age, 64 years; mean disease duration, 18 years) and 11 dystonia patients (mean age, 56 years; mean disease duration, 15.5 years) undergoing DBS surgery in the ventrointermediate thalamic nucleus and internal globus pallidus, respectively. We employed linear mixed modelling to test for the effects of several preoperative demographic (e.g., gender and age at surgery) and clinical variables (e.g., disease duration and -severity) and perioperative factors (such as surgical phase, duration of surgery, analgosedation) on the dependent variable ‘level of distress’.

Results: Across all patient groups, the average distress score during awake bilateral DBS surgery generally ranged between 4 and 5 on the numerical rating scale from 0 to 10. PD patients reported significantly higher stress levels compared to patients with essential tremor and dystonia (p = 0.012). Subjectively perceived distress levels were critically dependent on surgical phase (p < 0.001), clearly peaking during periods of test stimulation with high frequency (130Hz; pulse width, 60µs). Furthermore, titration of analgosedation with low-dose remifentanil had a significant, time-delayed, effect (p = 0.038). The subjectively perceived distress level did not depend on any other factors including sex, age at surgery, disease duration and duration of surgery (all p > 0.05). The factor ‘disease duration’ was still non-significant (p = 0.081) following separate mixed-effects modelling for the group of parkinsonian patients. However, a median split of the PD sample revealed that patients with longer disease history (>11 years) reported higher distress levels than those with shorter disease duration, presumably paralleling differential motor deterioration following presurgical levodopa withdrawal. Objective stress measures (heart rate, blood pressure) were highly and positively correlated with the reported distress scores.

Conclusions: The verbally administered numerical distress rating scale is a simple and practical tool to monitor the patient´s distress level throughout the course of awake DBS interventions. Our results suggest that distress level is maximal during surgical steps that require the active cooperation of the patient, such as intraoperative test stimulation for unwanted side effects. Furthermore, our results also show that peak stress periods during awake DBS surgery can effectively be countered by careful titration of analgosedation with remifentanil.

Background and Objective     

Deep brain stimulation (DBS) applied with directional leads within the ventrolateral thalamus and subthalamic region may lead to differential effects on tremor suppression, and it may alter the threshold for eliciting paraesthesias.

Methods         

Nine patients suffering from essential tremor (mean age 68,5 yrs, average disease duration 23 yrs) were implanted uni- (1) or bilaterally (8) with directional leads for deep brain stimulation of the ventrolateral thalamus and subthalamic region. Acute effects elicited by stimulation in different directions via bipolar activation of corresponding segments pointing into the same direction (lower segment = cathode) were assessed intraoperatively. Monopolar review (stimulation with 60 usec, 130 Hz) was performed after postoperative microlesioning effects (mean 240 days) had vanished. This involved clinical ratings of tremor suppression, including quantitative accelorometer measurements, and the assessment of the threshold and intensitiy of paraesthesias. The patients and raters were blinded with regard to the direction of stimulation that was chosen in random order and stimulation amplitude.

Results            

None of the patients experienced adverse events related to the surgical procedure or the implanted hardware. All patients exhibited a microlesioning effect and sustained tremor suppression with chronic stimulation. Intraoperative assessments revealed a lower threshold for paraesthesia when stimulation was performed into the posterior (medial and lateral) direction compared to stimulation into the anterior direction. Monopolar review revealed that thresholds for tremor suppression and paraesthesias (all transient) were very variable among patients, and for three electrodes paraesthesia thresholds did not differ between directions. For 73% of the contacts, directional stimulation via segments increased the therapeutic window compared to ring mode stimulation, in particular, if stimulation was applied into the anterior and medial direction. The maximum difference between stimulation amplitudes required for tremor suppression and those eliciting paraesthesias ('therapeutic window') was 2 mA. Based on these assessments, in four patients directional stimulation was commenced and rated superior by the patients at follow-up visits.

Conclusions

The influence of directional DBS on tremor suppression and paraesthesia thresholds is highly variable. Although stimulation in the anterior and medial direction appeared superior in several cases, a uniform pattern among patients could not be observed. Clinical responses may depend on the location of contacts, individual anatomy and biophysical characteristics of directional DBS that required further investigation. 

Objectives:

    In the past few years it has become increasingly acknowledged that large scale oscillatory activity in sensorimotor system plays an important role in physiological brain function as well as pathophysiology of neurological disorders. Thalamic oscillations were commonly reported in Parkinson’s disease (PD). On the other hand, previous studies demonstrated median nerve stimulation evoked potentials in the nucleus ventralis intermedius (Vim) of the thalamusin PD patients (Hanajima R et al, 2004). In fact, the Vim is believed to receive kinesthetic projections including muscle afferent projections (Ohye et al., 1989).

    In the first conventional view, the stimulus presentation evokes new event-related neural activity strictly time-locked to the stimulation which is superimposed on the background activity. And response averaging removes background activity (considered to be noise), whose time course is presumed to be independent of median nerve stimulation. Recently, by contrast, SEP features arise from alterations in the dynamics of ongoing neural synchrony generating thalamic LFP. By these accounts, SEP features are produced through stimulus-induced phase resetting of ongoing field potential oscillations, a phenomenon observed in vitro.

    To address this question, we investigated whether reorganization of background thalamic oscillatory activity contributes to the generation of the evoked potentials in Vim thalamus triggered by median nerve stimulationin patients with essential tremor and Parkinson’s disease.

Methods:

    We recorded mediannerve stimulation-elicited somatosensory evoked potentials (SEPs) from the ventralis intermedius (Vim) thalamus with semi-microelectrodes during stereotactic surgery in 10 patients with Parkinson’s disease (n=3) and essential tremor (n=7). Hilbert transform was used to measure the phase of the thalamic oscillatory SEP responses for each frequency band. Then we here calculated the phase-locking factor (PLF) in order to measure the phase correlation of ongoing local field potentials (LFPs) oscillation across trials for given frequency bands in the generation of the SEPs in Vim thalamus. This measure corresponds to the inter-trial coherence, which indexes the degree of phase synchronization of trials relative to stimulus presentation. The PLF measure takes values between 0 (absence of synchronization) and 1 (perfect synchronization) (Strogatz, 2000). 

Results:

    In about two thirds of thalamic SEPs examined, we found phase-locking of γ frequency band comes first in temporal order, and subsequently that of β band, and followed by phase-locking of slower frequency band (θ and α) of ongoing thalamic LFP oscillation across trials.Transition across trials from uniform to packed phase distribution revealed temporal phase reorganization of given rhythms of thalamic LFP oscillation in relation to stimulation. Otherwise, exclusive slower frequency oscillations such as θ and α band were observed at late period in some SEPs, while no obvious higher frequency band appeared at early period. In some of the surrounding LFPs 3mm apart from those of central electrode, exclusive slower frequency oscillations such as θ and α band were observed at late period, while no obvious higher frequency band was present at early period.

Conclusions:

    The identification of a phase-locking in each rhythm of thalamic SEP trials reinforces the contribution of phase resetting model for somatosensory information processing. This may imply that phase resetting of each ongoing LFP rhythm in an appropriate temporal order at least partly participates in thalamic SEP formation. Understanding characteristic transient responses of neuronal populations to external stimulations may provide us with invaluable clues for investigating how the central nervous system such as thalamic nucleus reacts and adapts to the stimulus perturbations. For the therapeutic applications, however, it is a great challenge to design deep brain stimulation (DBS) techniquesas effective as possible.

Introduction

In Parkinson’s disease (PD) in addition to motor symptoms, nonmotor symptoms and voice and speech disorders can also develop in 90% of PD patients. The aim of our study was to investigate the effects of DBS and different DBS frequencies on speech acoustics of vowels in PD patients.

Methods:

The study included 16 patients who underwent STN-DBS surgery due to PD. The voice recordings for the vowels including [a], [e], [i], and [o] were recorded at frequencies including 230 Hz, 130 Hz, 90 Hz, 60 Hz and off-stimulation. The voice recordings were evaluated by the Praat software and the effects on the first (F1), second (F2), and third formant (F3) frequencies were analyzed.

Results:

A significant difference was found for the F1 value of the vowel [a] at 130 Hz compared to off-stimulation. However, no significant difference was found between the three formant frequencies with regards to the stimulation frequencies and off-stimulation. In addition, though not statistically significant, stimulation at 60 Hz and 230 Hz led to several differences in the formant frequencies of other three vowels (Table-1).

Conclusion:

Our results indicated that STN-DBS stimulation at 130 Hz had a significant positive effect on articulation of [a] compared to off-stimulation. Although there isn’t any statistical significant stimulation at 60 Hz and 230 Hz may also have an effect on the articulation of [e], [i], and [o] but this effect needs to be investigated in future studies with higher numbers of participants.

Background and objectives:

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a proven effective and safe intervention to treat motor symptoms in Parkinson’s disease (PD). Little is known about long-term follow-up (>10 years) after implantation. Our goal is to provide an analysis of motor and cognitive outcome of  PD patients 15 years after surgery for STN-DBS. Additionally, we analysed the burden of the caregiver. To limit the loss to follow-up, patients unable to visit the hospital have been assessed at their homes.

Methods:

In this observational study, we report on the motor/cognitive outcome and caregiver burden in a cohort of 15 PD patients who underwent STN-DBS in the Maastricht University Medical Centre (MUMC+) from January 1999 to December 2003. Motor outcome has been assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) part III and cognition by the Mini-Mental State Examination (MMSE). The caregiver burden was assessed by the Zarit, without assessment before surgery. The UPDRS I and II were used to assess cognition and activities of daily life and the VAS EuroQol (EQ)5D for perception of health.

Results:

Between 1999 and 2003 43 patients were operated of which 15 patients survived follow-up. Motor function (UPDRS III) significantly worsened compared to baseline with antiparkinsonian medication (47.7 vs. 18.3, p=0.005) and was comparable to baseline without antiparkinsonian medication UPDRS III (44.7). Axial symptoms and bradykinesia are most severely affected of all motor symptoms at 15 years after surgery.

At 15 years after surgery, 40% of patients (n=6) met the diagnostic criteria of dementia and PD Mini-mental state examination (MMSE) scores non-significantly declined (baseline 28.0, 15 year FU 22.7). UPDRS II significantly worsened (p<0.01; BWM 10.5, 15 year FU 30.5). UPDRS I significantly declined (p<0.005; BWM 1.46, 15 year FU 6.7)

VAS EQ5D scores were 0.55, EQ-5D scores were 0.43 and 62% (n=8) had signs of mild mood disturbances to severe depression at FU.

A Zarit score above 16, suggestive of clinically significant caregiver burden, was reached by one third (n=5) of caregivers at 15 years after surgery. Mean Zarit scores were 17.9±9.4 and 10±4.9 for caregivers of patients living in their own residence (n=8) and in nursing homes/retirement homes (n=7), respectively, however no significance was found.

Conclusion:

Cognitive and axial symptoms are highly dominating after 15 years of follow-up, whereas tremor and rigidity show less deterioration over time. This has a significant impact on health status, quality of life and caregiver burden.

Introduction

The effect of microelectrode recording (MER) on DBS placement is not well understood.  In order to assess the impact of MER on final DBS lead location in relation to the original anatomical target selected, we compared radial error of DBS lead coordinates in relation to initial target in two groups of hemispheres –Hemispheres whereby the MER resulted in an intentional deviation of DBS placement; versus hemispheres whereby MER did not result in any change in DBS placement location.  

Methods

Hemispheres of patients who underwent DBS surgery with MER at the authors’ institution from 2014-2018 were retrospectively analyzed. Targets consisted of the subthalamic nucleus (STN), ventral intermediate nucleus of the thalamus (VIM), internal globus pallidus (GPi) and zona incerta (ZI). The hemispheres were subdivided into two groups: those in which the initial MER track was chosen for final lead implantation and those where a different track from the initial was chosen. Coordinates of the intended MER-based target and final DBS lead were calculated within the same z-axis plane using intraoperative computed tomography (CT) merged to preoperative magnetic resonance imaging (MRI) studies.  Radial error between MER-based target and final DBS lead was then calculated in both groups and compared using a two-tailed T-test.  

Results

Two hundred forty-seven hemispheres were reviewed (157 STN, 57 VIM, 31 GPi, 2 ZI).  There were 96 hemispheres where the initial MER track was chosen for lead implantation and 151 where a different track was chosen.  Radial error of the DBS lead in hemispheres with lead implantation into the initial MER track was significantly (p<0.05) less than hemispheres where a different track was chosen for lead implantation (0.84±0.07 vs 1.1±0.06 mm).  Radial error broken down by target is shown in Table 1. 

Conclusion

There was a significantly higher radial error of the final DBS lead in hemispheres where a different track from the initial MER track was chosen.  While the difference reached statistical significance, the numerical value of the difference was small.

Corticospinal Tract Activation Threshold Varies in Ring versus Segmented Mode Stimulation in DBS Surgery Using Motor Evoked Potential Measurements

Ryan B. Kochanski MD, Jay Shills, PhD, Gian D. Pal MD MS, Leo Verhagen MD PhD, Sepehr Sani MD

Introduction

The introduction of segmented leads in DBS surgery promises to improve current delivery by directing current in an intended direction and perhaps more importantly, by avoiding current activation of undesired local anatomy.  The extent to which segmented stimulation away from the corticospinal tract (CST) allows for increased side effect threshold as compared to stimulation in ring mode is not well studied. 

Methods

CST activation thresholds were evaluated using motor evoked potentials (MEP).  Electrodes were placed in the contralateral muscles of the face and upper extremity for MEP measurements.  Stimulation (unipolar) was delivered by delivering current to inserted DBS leads (20 hemispheres total; 10 STN, 10 VIM) intra-operatively.  Stimulation parameters included activation of each segment of the middle two contacts followed by ring mode stimulation of all four contact while records MEP thresholds and muscle activated. 

Results

MEP thresholds were obtained from all stimulated segments and rings.  In VIM, the segment with highest threshold was noted at current that was on average 1.1mA above that in ring mode.  The abductor pollicis brevis muscle was the first MEP observed.  In STN stimulation, the results were mixed.  Variable muscle MEPs were seen at threshold stimulation.  Segmented stimulation thresholds were variable when compared to ring mode with the difference in current threshold varying between 0.6 to 1.2mA.  A likely explanation is lack of segment alignment directly opposite of CST along with the curved trajectory of CST superior and lateral to STN.

Conclusion

Segmental DBS stimulation leads to mild increase in CST activation threshold in VIM and STN.  Increased thresholds can be variable in STN likely due to imperfect segmental alignment as well as local anatomy of CST.

Introduction

Deep brain stimulation of the subthalamic nucleus (STN) is an effective therapy for patients with Parkinson’s disease (PD). Different regions within the subthalamic area have been correlated with optimal clinical outcomes. In this work, we correlate the motor outcome in PD patients with the involvement of nigrofugal and pallidofugal pathways by effective stimulation.

Methods:

Fourty-three patients with STN-DBS were included and their clinical and stimulation parameters were recorded at one-year follow-up. Nigrofugal and pallidofugal pathways were obtained using constrained spherical deconvolution probabilistic tractography with imaging data from 43 PD matched subjects from the Parkinson's Progression Markers Initiative connectome. The volume of activated tissue (VAT) for all patients was modelled using finite element method within the LeadDBS software. All VATs were summed and analyzed using generalized linear models in FSL software to obtain statistically significant stimulation clusters correlated with: greater reduction of dopaminergic medication, improvement in Unified Parkinson's Disease Rating Scale (UPDRS) III, bradykinesia, rigidity, and tremor scores. Finally, we calculated the overlap coefficient of these clusters with the nigrofugal or pallidofugal fibers.  Then, these coefficients were compared with the overlap of the significant clusters with the STN.

Results:

Significant reduction of symptoms was obtained with STN-DBS in our patients (p<.05). Nigrofugal and pallidofugal pathways were traced as described in previous anatomical descriptions. Significant clusters associated with the greatest dopaminergic medication reduction, greatest UPDRS improvement overlapped with the nigrofugal fibers (coeff0.50) but not with the STN. Significant clusters associated with greater bradykinesia improvement overlapped with the nigrofugal fibers (coeff 0.55) and with the STN (coeff 0.19). Finally, significant clusters associated with greater rigidity and tremor improvement overlapped with pallidofugal fibers (coeff 0.60) and not with the STN.

Conclussions:

Electrical field involvement of the nigrofugal fibers, more than the STN, appears to produce the most improvement in UPDRS III, bradykinesia, and the most reduction of dopaminergic medications. Similarly, involvement of the pallidofugal fibers and not the STN was associated with greater tremor and rigidity improvement.

Background: Deep brain stimulation (DBS) has been shown to be cost-effective in the treatment of Parkinson's disease. However, it represents a costly burden for national health systems. This situation has been aggravated by the the reduced longevity of newer non-rechargeable batteries, which has led to a rise of battery replacements costs and complications (i.e., device infections), somewhat compromising the sustainability of DBS programs. We hypothesized that investing on rechargeable devices in the short term would result in a reduction of replacements and, hence, of total DBS costs in the middle-to-long term.

Objective: 1) To estimate deep brain stimulation (DBS) material costs for a 6-year-period at our institution considering two scenarios: a conservative one focused on gradual increase of new rechargeable devices; another one with a greater initial investment in rechargeable devices (both new cases and replacements); 2) to compare these estimates to costs of the preceding three years (2014-2016), when devices had higher prices and were mostly non-rechargeable.

Methods: Descriptive analysis of the activity and material costs of DBS at our institution in 2014-2016; estimation of DBS material costs in 2017-2022 based on the aforementioned scenarios; calculation of the shortfall vs. saving resulting from comparison of the different DBS cost estimates to the costs from the 2014-2016 period.

Results: During the 2014-2016 period, the total DBS cost rose from 654.958,14€ in 2014 to 1.023.689,64€ in 2016 (56,30% increase). Regarding the estimates for the 2017-2022 period, the first scenario would benefit initially from devices price-cuts dropping to 907.665,00€ in 2017 (-11,30% compared to 2016, yet +38.58% relative to 2014), but would eventually resume the upwards trend, ending up in 2022 with a total DBS cost of 1.058.541,00€ (+3,40% vs. 2016; +61,62% vs. 2014). Conversely, the second scenario, in spite of greater cost-increase the first 3 years, would eventually lead to a reduction of replacements and subsequently of total DBS costs down to 775.676,00€ in 2022 (-24,03% relative to 2016; only +18,43% compared to 2014).

Conclusion: The cost and saving estimates of increasing the proportion of implanted rechargeable DBS neurostimulators versus primary cell devices (both new cases and replacements) support the notion that this strategy, while costly in the short term, could aid to ensure the sustainability of DBS programs in the long run.

References:

[1]         Eggington S, Valldeoriola F, Chaudhuri KR, et al. The cost-effectiveness of deep brain stimulation in combination with best medical therapy, versus best medical therapy alone, in advanced Parkinson's disease. J Neurol 2014; 261: 106-16.

[2]         Pepper J, Zrinzo L, Mirza B, et al. The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure. Stereotact Funct Neurosurg 2013; 91: 56-65.

Background:Freezing of gait (FoG) in Parkinson’s disease (PD) is an incapacitating transient phenomenon, followed by continuous postural disorders. Spinal cord stimulation (SCS) is a promising intervention for FoG in patients with PD, however its effects on distinct domains of postural control is not well known.Aim:The aim of this study is to assess the effects of SCS on FoG and distinct domains of postural control. Methods:Four patients with FoG were implanted with SCS systems in the upper thoracic spine. Anticipatory postural adjustment (APA), reactive postural responses, gait and FoG were biomechanically assessed. Results:In general, the results showed that SCS improved FoG and APA. However, SCS failed to improve reactive postural responses. SCS seems to influence cortical motor circuits, involving the supplementary motor area. On the other hand, reactive posture control to external perturbation that mainly relies on neuronal circuitries involving the brainstem and spinal cord, is less influenced by SCS. In this short report we provide data suggesting that SCS may affect important measures in anticipation of gait that decreases the chance of FoG in gait initiation. On the other hand, our data provides evidence that SCS failed to improve reactive balance control. We suggest that SCS has distinct effects on specific postural control domains, which is important to develop and improve neuromodulation-based interventions to treat postural and gait disabilities in PD. 

Legends

Figure 1 – (A) Characterization of FoG based on spectral analysis. Schematic representation of a man representing the lumbar accelerometer as a small black box. The curve represents the vertical acceleration acquired during step initiation. The dotted square shows a 7.5s window for the frequency analysis domain (normal gait in blue and freezing in red). (B) Spectral analysis of acceleration showing one band representing the locomotor period (0 - 3Hz) and the FoG band (3 - 8Hz). (C) FoG index showing the clinical threshold (>2=FoG); FoG index is calculated by dividing the FoG band by the locomotor band (blue circle – power peak of normal gait; red circle – power peak of a period with FoG). (D) Representation of the step initiation task, showing the marker on the malleolus to detect the moment that the foot clears the floor. The sequence showed in D and E (1-4) shows: (1) beginning of the task, when the participant is in quiet standing (body weight balanced under the feet), preceding the step. (2) The red arrow shows body weight shifting toward the supporting leg (APA). (3) Once the body weight is shifted contralaterally, the moving leg can be released to take a step and finish the movement (4). The graphs showed in D and E represent the moment that each phase of the sequence (1-4) occurs: 1-quiet standing; 2- peak of APA; 3- step; 4-end of the movement. The red line represents the mediolateral force under the supporting leg, the dotted line is the displacement of the moving foot. The red line in D represents a defective mediolateral displacement of the body weight (APA), showing a relative smaller amplitude and longer APA compared to a normal APA displayed in E.

Figure 2 – Individual and mean values for % change of the outcome variables: time of gait, time of FoG, time of APA, amplitude of APA and the variables that describes reactive postural control - CoPap amplitude and CoMap amplitude. (A) Individual mean curves of the body mediolateral displacement (APA) - thin lines; and the standard deviation (thick and transparent bands) for each stimulation parameter (OFF – gray, 60 Hz – red, 300 Hz – blue). (B) Graphs showing the individual mean values of % of change for each outcome variable in 60 and 300 Hz relative to the off condition. (C) Mean values and standard deviations of % change for each outcome variable (time of gait, time of FoG, time and amplitude of APA, CoP and CoM amplitude. Asterisks highlight significant effects for 60 and 300 Hz as compared to the off condition.