Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease.

Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico-cortical coherence in the beta band was significantly attenuated over the bilateral sensorimotor areas. Similarly, the global cortico-cortical phase synchronization was attenuated, and the topographic differentiation revealed stronger desynchronization over the (ipsilateral) right-hemispheric prefrontal, premotor and sensorimotor areas compared to 'stimulation off'. We further demonstrated that the cortico-cortical phase synchronization was largely dominated by genuine neuronal coupling. The clinical improvement with 'stimulation on' compared to 'stimulation off' could be predicted from this cortical decoupling with multiple regressions, and the reduction of synchronization over the right prefrontal area showed a linear univariate correlation with clinical improvement. Our study demonstrates wide-spread activity and synchronization modulations of the cortical motor network, and highlights subthalamic stimulation as a network-modulating therapy. Accordingly, subthalamic stimulation may release bilateral cortical computational resources by facilitating movement-related desynchronization. Moreover, the subthalamic nucleus is critical to balance inhibitory and facilitatory cortical players within the motor program.

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.

Clinical and Kinematic Correlates of Favorable Gait Outcomes From Subthalamic Stimulation.

Objective: Gait and freezing of gait (FoG) are highly relevant to the outcomes of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). Previous studies pointed to variable response to combined dopaminergic and STN-DBS treatment. Here, we performed a prospective exploratory study on associations of preoperative clinical and kinematic gait measures with quantitative gait and FoG outcomes after STN-DBS implantation. Methods: We characterized 18 consecutive PD patients (13 freezers) before and after STN-DBS implantation. The patients received preoperative levodopa challenges (MedOff vs. MedOn) and a postoperative reassessment at 6 months from surgery in MedOn/StimOn condition. We correlated the FoG outcome, calculated as improvement of Freezing of Gait Assessment Course (FoG-AC) from baseline MedOff to 6-month follow-up MedOn/StimOn, with the levodopa response of preoperative clinical and kinematic gait measures. We considered measures with significant correlations for a multiple regression model. Results: We found that the postoperative gait and FoG outcomes were associated with the preoperative levodopa response of clinical and kinematic gait measures. In particular, preoperative levodopa sensitivity of FoG showed high correlation with a favorable quantitative FoG outcome. Among kinematic measures, preoperative levodopa response of stride length and range of motion showed high correlation with favorable FoG outcome. In addition, the preoperative levodopa sensitivity of FoG predicted postoperative FoG outcome with high accuracy (R 2 = 0.952; 95% CI: 0.95-1.29; P < 0.001). Conclusions: Preoperative clinical and kinematic measures correlated with favorable postoperative gait and FoG outcomes. The findings should be reproduced in larger and independent cohorts to verify their predictive value.

Transitions between repetitive tapping and upper limb freezing show impaired movement-related beta band modulation.

OBJECTIVE: Freezing phenomena in idiopathic Parkinson's disease (PD) constitute an important unaddressed therapeutic need. Changes in cortical neurophysiological signatures may precede a single freezing episode and indicate the evolution of abnormal motor network processes. Here, we hypothesize that the movement-related power modulation in the beta-band observed during regular finger tapping, deteriorates in the transition period before upper limb freezing (ULF). METHODS: We analyzed a 36-channel EEG of 13 patients with PD during self-paced repetitive tapping of the right index finger. In offline analysis, we compared the transition period immediately before ULF ('transition') with regular tapping regarding movement-related power modulation and interregional phase synchronization. RESULTS: From time-frequency analyses, we observed that the tap cycle related beta-band power modulation over the left sensorimotor area was diminished in the transition period before ULF. Furthermore, increased beta-band power was observed in the transition period compared to regular tapping centered over the left centro-parietal and right frontal areas. Phase synchronization between the left fronto-parietal areas and the left sensorimotor area was elevated during transition compared to regular tapping. CONCLUSION: Together, these results indicate that diminished beta band power modulation and increased phase synchronization precede ULF. SIGNIFICANCE: We demonstrate that pathological cortical motor processing is present in the transition phase from regular tapping to an ULF episode.

Anodal tDCS modulates cortical activity and synchronization in Parkinson's disease depending on motor processing.

BACKGROUND: Transcranial direct current stimulation (tDCS) may alleviate motor symptoms in Parkinson's disease (PD). However, the neurophysiological effects of tDCS on cortical activation, synchronization, and the relation to clinical motor symptoms and motor integration need characterization. OBJECTIVE: We aimed to explore the effect of tDCS over the left sensorimotor area on clinical motor outcome, right hand fine motor performance as well as cortical activity and synchronization in the high beta range. METHODS: In this double-blind randomized sham-controlled clinico-neurophysiological study we investigated ten idiopathic PD patients and eleven matched healthy controls (HC) on two days during an isometric precision grip task and at rest before and after 'verum' and 'sham' anodal tDCS (20 min; 1 mA; anode [C3], cathode [Fp2]). We measured clinical outcome, fine motor performance, and analysed both cortical frequency domain activity and corticocortical imaginary coherence. RESULTS: tDCS improved PD motor symptoms. Neurophysiological features indicated a motor-task-specific modulation of activity and coherence from 22 to 27 Hz after 'verum' stimulation in PD. Activity was significantly reduced over the left sensorimotor and right frontotemporal area. Before stimulation, PD patients showed reduced coherence over the left sensorimotor area during motor task compared to HC, and this increased after 'verum' stimulation in the motor task. The activity and synchronization modulation were neither observed at rest, after sham stimulation nor in healthy controls. CONCLUSION: Verum tDCS modulated the PD cortical network specifically during fine motor integration. Cortical oscillatory features were not in general deregulated in PD, but depended on motor processing.

Anticipatory postural adjustments are modulated by substantia nigra stimulation in people with Parkinson's disease and freezing of gait.

BACKGROUND: A precise understanding of the neuronal circuits involved in the control of anticipatory postural adjustments (APAs) for gait initiation is missing. Neurostimulation in Parkinson's disease (PD) provides a method of modulating APAs to gain insight into the underlying circuitry. OBJECTIVE: Our objective was to investigate if APA kinematics for step initiation could be modulated by high frequency stimulation of the subthalamic nucleus (STN) or substantia nigra pars reticulata (SNr) in people with PD and freezing of gait (FoG). METHODS: We studied 14 people with PD and FoG using neurostimulation of the STN and SNr areas after overnight withdrawal of dopaminergic medication on the instrumented stand and walk test. We tested patients in the following randomized conditions: 'off stimulation', 'STN' stimulation (only), and 'SNr' stimulation (only). Patients were blinded to the stimulation condition. The APAs were recorded with inertial sensors and processed offline. Moreover, we assessed clinical scores with respect to motor symptoms, non-motor symptoms, executive function, and FoG. RESULTS: SNr but not STN stimulation modulated the anterio-posterior size of APA. The SNr modulation of APA was associated with the stimulation effect on FoG (trend; r = 0.580, P = 0.102). The APA modulation was not correlated with any other cognitive or clinical measures. CONCLUSION: Neuromodulation of the SNr but not of the STN modulated APAs in PD patients with FoG. The different effects of STN or SNr on the kinematic parameters of APA support the concept of segregate targets in order to address diverse kinematic components of PD gait.

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.

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.

Neuromuscular correlates of subthalamic stimulation and upper limb freezing in Parkinson's disease.

OBJECTIVE: The pathophysiology of deep brain stimulation mechanisms and resistant freezing phenomena in idiopathic Parkinson's disease (iPD) remains incompletely understood. Further studies on the neuromuscular substrates are needed. METHODS: We analyzed 16 patients with advanced iPD and bilateral subthalamic nucleus stimulation, and 13 age- and gender-matched healthy controls. Patients were tested after overnight withdrawal of medication with 'stimulation off' (StimOff) and 'stimulation on' (StimOn). Subjects performed continuous tapping of the right index finger with simultaneous recordings of biomechanical registration, EMG of finger flexors and extensors, and EEG. First, we analyzed EEG and EMG spectral measures comparing StimOff with healthy controls and StimOff with StimOn (irrespective of freezing). Second, we contrasted 'regular (unimpaired) tapping' and 'freezing' resistant to subthalamic neurostimulation as obtained in StimOn. RESULTS: iPD showed increased intermuscular coherence around 8Hz in StimOff that was reduced in StimOn. This 8Hz muscular activity was not coherent to cortical activity. 'Freezing' episodes showed increased muscle activity of finger flexors and extensors at 6-9Hz, and increased cortical activity at 7-11Hz. During transition from regular tapping to 'freezing' the cortical activity first increased over the left sensorimotor area followed by a spread to the left frontal and right parietal areas. CONCLUSIONS: We identified neuromuscular motor network features of subthalamic neurostimulation therapy and resistant upper limb freezing that point to increased low-frequency muscular and cortical activity. SIGNIFICANCE: Together, our findings demonstrate several motor network abnormalities associated with upper limb freezing that may translate into future research on freezing of gait in iPD.

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

OBJECTIVE: Freezing behavior is an unmet symptom in Parkinson's 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 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.