Marlieke Scholten

Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial

Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial.

Long-term outcome of deep brain stimulation in fragile X-associated tremor/ataxia syndrome

INTRODUCTION Fragile X-associated tremor/ataxia syndrome (FXTAS) presents as complex movement disorder including tremor and cerebellar ataxia. The efficacy and safety of deep brain stimulation of the nucleus ventralis intermedius of the thalamus in atypical tremor syndromes like FXTAS remains to be determined. METHODS Here, we report the long-term outcome of three male genetically confirmed FXTAS patients treated with bilateral neurostimulation of the nucleus ventralis intermedius for up to four years. RESULTS All patients demonstrated sustained improvement of both tremor and ataxia - the latter included improvement of intention tremor and axial tremor. Kinematic gait analyses further demonstrated a regularization of the gait cycle. Initial improvements of hand functional disability were not sustained and reached the preoperative level of impairment within one to two years from surgery. CONCLUSION Our data on patients with a genetic cause of tremor show favorable outcome and may contribute to improved patient stratification for neurostimulation therapy in the future.

Cortical correlates of susceptibility to upper limb freezing in Parkinson's disease.

OBJECTIVE Freezing behavior is an unmet symptom in Parkinsons disease (PD), which reflects its complex pathophysiology. Freezing behavior can emerge when attentional capacity is reduced, i.e. under dual task interference. In this study, we characterized the cortical network signatures underlying the susceptibility to freezing during continuous finger tapping. METHODS Fourteen PD patients with STN-DBS and thirteen age- and gender-matched healthy controls performed continuous tapping with the index finger as single motor task and during dual tasking. Synchronized EEG and mechanogram of the finger tapping were recorded. Subsequently, we analyzed cortical activity and cortico-cortical phase synchronization. We correlated these spectral measures with the biomechanically confirmed numbers of freezing episodes during finger tapping. RESULTS During dual tasking compared to the single motor task, PD patients showed an increase of cortico-cortical phase synchronization over the left prefrontal area from 13 to 30Hz. This correlated with increased occurrence of freezing episodes. Interestingly, PD patients lacked the increase of prefrontal cortico-cortical synchronization from 4 to 7Hz during dual tasking as observed in healthy controls. CONCLUSION Dual task interference led to an increase of left prefrontal beta band synchronization (13-30Hz) in PD and this increment predicted the number of freezing episodes. This increment may underscore the relevance of prefrontal executive dysfunction in freezing susceptibility. SIGNIFICANCE These findings enhance our understanding of the pathological network mechanisms behind increased susceptibility to freezing behavior.

Long-Term Effect of GPi-DBS in a Patient With Generalized Dystonia Due to GLUT1 Deficiency Syndrome

Treatment outcomes from pallidal deep brain stimulation are highly heterogeneous reflecting the phenotypic and etiologic spectrum of dystonia. Treatment stratification to neurostimulation therapy primarily relies on the phenotypic motor presentation; however, etiology including genetic factors are increasingly recognized as modifiers of treatment outcomes. Here, we describe a 53 year-old female patient with a progressive generalized dystonia since age 25. The patient underwent deep brain stimulation of the globus pallidus internus (GPi-DBS) at age 44. Since the clinical phenotype included mobile choreo-dystonic features, we expected favorable therapeutic outcome from GPi-DBS. Although mobile dystonia components were slightly improved in the long-term outcome from GPi-DBS the overall therapeutic response 9 years from implantation was limited when comparing “stimulation off” and “stimulation on” despite of proper electrode localization and sufficient stimulation programming. In order to further understand the reason for this limited motor symptom response, we aimed to clarify the etiology of generalized dystonia in this patient. Genetic testing identified a novel heterozygous pathogenic SLC2A1 mutation as cause of glucose transporter type 1 deficiency syndrome (GLUT1-DS). This case report presents the first outcome of GPi-DBS in a patient with GLUT1-DS, and suggests that genotype relations may increasingly complement phenotype-based therapy stratification of GPi-DBS in dystonia.

P106. Anodal tDCS over the left sensorimotor area improves motor symptoms and modulates corticocortical coherence in Parkinson’s disease

Network activity in the beta range is correlated with motor symptoms in Parkinson’s disease (PD). Anodal transcranial direct current stimulation (atDCS) over the sensorimotor area modulates cortical excitability and may alleviate motor symptoms in PD. In this study, we aimed to explore the effect of atDCS over the left sensorimotor area on clinical motor outcome, right hand fine motor performance and cortical motor network connectivity. In this double-blind randomized sham-controlled combined EEG and tDCS study, we investigated ten pharmacologically treated idiopathic PD patients after overnight withdrawal of dopaminergic medication and eleven healthy controls during an isometric precision grip task of the right hand before and after stimulation. Participants were studied and crossed-over in two sessions on different days with either ‘verum’ or ‘sham’ stimulation of atDCS (20 min; 1 mA; electrodes placed over left ‘C3’ (anode) and right ‘Fp2’ (cathode)). Cortical connectivity was expressed as corticocortical imaginary coherence in the high beta band (22–27 Hz) between ‘C3’ and all other EEG-channels; the topographic distribution was obtained from 25 cortical EEG channels placed according to the 10–20 system. Fine motor performance was expressed as accuracy error during the precision grip task with lower accuracy error indicating higher motor precision. Clinical motor outcome was measured using the UPDRS III motor score. PD patients with ‘verum’ stimulation showed an increase of corticocortical imaginary coherence in the high beta band from ‘C3’ to the right motor area 30 min after stimulation. This was paralleled by a significant decrease in the UPDRS III motor score. There was no similar modulation in PD ‘sham’ stimulation and in healthy controls in both ‘verum’ and ‘sham’ conditions. However, interestingly, HC showed beta band coupling prior to stimulation directed from ‘C3’ to the right hemisphere. Both groups showed no significant change regarding the accuracy error after stimulation. AtDCS of ‘C3’ entrains beta band coupling between ‘C3’ and the right sensorimotor area with ‘C3’ leading right hemispheric beta band oscillations in the temporal domain. We speculate that this could represent a mechanism to tone down inhibitory influences of the right hemisphere ipsilateral to the right hand, given that increased beta synchrony is associated with increasing motor inhibition in previous studies.

Effects of Subthalamic and Nigral Stimulation on Gait Kinematics in Parkinson's Disease

Conventional subthalamic deep brain stimulation for Parkinson’s disease (PD) presumably modulates the spatial component of gait. However, temporal dysregulation of gait is one of the factors that is tightly associated with freezing of gait (FOG). Temporal locomotor integration may be modulated differentially at distinct levels of the basal ganglia. Owing to its specific descending brainstem projections, stimulation of the substantia nigra pars reticulata (SNr) area might modulate spatial and temporal parameters of gait differentially compared to standard subthalamic nucleus (STN) stimulation. Here, we aimed to characterize the differential effect of STN or SNr stimulation on kinematic gait parameters. We analyzed biomechanical parameters during unconstrained over ground walking in 12 PD patients with subthalamic deep brain stimulation and FOG. Patients performed walking in three therapeutic conditions: (i) Off stimulation, (ii) STN stimulation (alone), and (iii) SNr stimulation (alone). SNr stimulation was achieved by stimulating the most caudal contact of the electrode. We recorded gait using three sensors (each containing a tri-axial accelerometer, gyroscope, and magnetometer) attached on both left and right ankle, and to the lumbar spine. STN stimulation improved both the spatial features (stride length, stride length variability) and the temporal parameters of gait. SNr stimulation improved temporal parameters of gait (swing time asymmetry). Correlation analysis suggested that patients with more medial localization of the SNr contact associated with a stronger regularization of gait. These results suggest that SNr stimulation might support temporal regularization of gait integration.

P137. Nigral and subthalamic neurostimulation modulate intermuscular coherence in Parkinson’s disease

Introduction Combined nigral and subthalamic stimulation is under consideration to modulate otherwise resistant axial motor symptoms, namely freezing of gait in idiopathic Parkinson’s disease (PD). The impact of subthalamic or nigral stimulation on neuromuscular motor integration however needs further characterization. Methods We used fully mobile EEG and EMG recordings, wireless kinematic sensors and video documentation to record patients during a gait cycle. Seven patients with deep brain stimulation were examined both during walking and standing after overnight withdrawal of dopaminergic medications. Recordings in different therapeutic conditions were obtained, i.e. ‘stimulation off’ (StimOff), ‘subthalamic stimulation on’ (STNOn), and ‘nigral stimulation on’ (SNrOn). Results The main finding was an increase of intermuscular coherence in the alpha and low beta bands during ‘walking’ in both STNOn and SNrOn. During ‘standing’ there was increased coherence in theta and alpha bands (‘STNOn’) and in the alpha and low beta bands (‘SNrOn’). Discussion Subthalamic and nigral stimulation increase intermuscular beta band coherence. Intermuscular beta band coherence may reflect increased corticospinal motor control from corticospinal beta drives to the spinal motor unit pool (Marsden et al., 2001; Weiss et al., 2012).