The effect of subthalamic deep brain stimulation on motor learning in Parkinson’s disease

Deep brain stimulation (DBS) of the subthalamic nucleus is an effective and adjustable treatment for Parkinson’s disease patients with (early) motor complications and has been shown to elicit changes in motor and non-motor cortico-basal ganglia circuits through modulation of distributed neural networks. Recent findings on subcortical basal ganglia - cerebellar anatomy have revealed projections from the subthalamic nucleus to cerebellar hemispheres, which might be modulated by subthalamic DBS. Both the basal ganglia and the cerebellum are known to be involved in motor learning and Parkinson’s disease. This study aimed at investigating the effect of subthalamic DBS on motor learning in Parkinson’s disease (PD) and characterizing underlying neural networks. To this end, 20 Parkinson’s disease patients undergoing subthalamic DBS and 20 age-matched healthy controls performed a visuomotor task. Motor learning was assessed as reduction in movement times from beginning to end of task for each group. DBS electrodes were localized and projected to a publicly available normative connectome (1000 healthy subjects) and a connectivity map for DBS induced improvement in motor learning was calculated. Region of interest analysis was performed to assess the role of connectivity to motor cortex (M1) and cerebellar hemispheres in DBS induced learning. Permutation tests and multiple regressions were conducted for the main statistical analyses; for significant regression models and correlations leave one out cross validation (LOOCV) was performed. Motor learning was impaired in Parkinson’s disease patients off DBS comparing with healthy controls (PD off DBS: 12.2±5.4% from 1311±160ms to 1089±118ms; mean ± standard error of mean; healthy controls: 33.48±3.6% from 729±63ms to 473±42ms; off DBS vs. healthy controls P=0.002). STN-DBS led to a statistically significant improvement in motor learning (PD on DBS: 27.7±6.1% from 940±120ms to 615±84ms; on vs. off DBS P=0.01). There was no statistically significant difference between patients on DBS and healthy controls (P=0.4). DBS induced improvement in motor learning was not correlated with improvement in motor deficits (R=-0.02, P=0.5). A specific connectivity profile including the right cerebellar hemisphere was associated with improved motor learning through DBS (R²=0.33, P=0.01; LOOCV: R=0.43, P=0.028). Region of interest analysis revealed the ipsilateral cerebellum to be the best predictor of DBS induced motor learning (R2=0.34, P=0.008; LOOCV: R=0.045, P=0.02). Here, connectivity to the STN was higher than to M1, suggesting a putative role of the recently discovered basal ganglia - cerebellar circuit bypassing the cortex. This study extends current knowledge on motor learning in Parkinson’s disease and highlights the notion of network modulation in DBS.Die Tiefe Hirnstimulation (THS) des Nucleus subthalamicus ist eine effektive Therapiealternative für Patienten mit idiopathischem Parkinson Syndrom (IPS) und (frühen) motorischen Komplikationen, welche zu verschiedenen motorischen und nicht-motorischen Effekten in der Kortex-Basalganglienschleife führt. Es ist lange bekannt, dass die Basalganglien und das Kleinhirn sowohl beim IPS als auch beim motorischen Lernen eine Rolle spielen. Neue anatomische Studien zeigten eine disynaptische subkortikale Verbindung zwischen den Nucleus subthalamicus und den Kleinhirnhemisphären mit bisher unklarer funktioneller Bedeutung. Die vorliegende Studie untersucht den Effekt subthalamischer THS auf motorisches Lernen beim idiopathischen Parkinson Syndrom mit dem Ziel, zugrundeliegende neuronale Netzwerke zu charakterisieren. Hierfür führten 20 Patienten mit IPS unter THS und 20 altersgepaarte gesunde Probanden eine visuomotorische Reaktionszeitaufgabe durch. Motorisches Lernen wurde als Verbesserung der Bewegungszeiten durch Wiederholung der Aufgabe definiert. THS Elektroden wurden lokalisiert und auf ein öffentlich verfügbares normatives funktionelles MRT Konnektom projiziert (1000 gesunde Probanden). Das optimale Konnektivitätsprofil für THS induziertes motorisches Lernen wurde berechnet. Zusätzlich wurde eine Konnektivitätsanalyse durchgeführt, um die Rolle der Verbindung von aktiven THS Kontakten zum motorischen Kortex und zu den Kleinhirnhemisphären für THS induziertes Lernen zu untersuchen. Die statistische Auswertung der Hauptergebnisse erfolgte durch Monte Carlo Permutation und multiple Regressionen; statistisch signifikante Regressionsmodelle und Korrelationen wurden mittels der „Leave one out“ Methode kreuzvalidiert. Patienten mit IPS und ausgeschalteter THS zeigten ein signifikant beeinträchtigtes motorisches Lernen im Vergleich zu gesunden Kontrollen (IPS mit THS OFF: 12.2±5.4%, von 1311±160ms auf 1089±118ms; gesunde Kontrollen: 33.48±3.6%, von 729±63ms auf 473±42ms; P=0.002). Die subthalamische THS führte zu einer statistisch signifikanten Verbesserung des motorischen Lernens in Patienten mit IPS (IPS mit THS ON: 27.7±6.1%, von 940±120ms auf 615±84ms; P=0.01). Es ergab sich kein signifikanter Unterschied zwischen Patienten mit eingeschalteter THS und gesunden Kontrollen (P=0.4). THS induziertes motorisches Lernen korrelierte nicht mit Linderung motorischer Symptome (R=-0.02, P=0.5). Es konnte ein spezifisches fMRT Konnektivitätsprofil von den aktiven THS Kontakten definiert werden, welches prädiktiv für den Effekt der THS auf motorisches Lernen war (R²=0.33, P=0.01; LOOCV: R=0.43, P=0.028). Eine weiterführende Analyse ergab einen gesonderten Einfluss der rechten Kleinhirnhemisphäre als bester Prädiktor für THS induziertes motorisches Lernen (R2=0.34, P=0.008; LOOCV: R=0.045, P=0.02). In diesen Voxels war funktionelle Konnektivität zum Nucleus subthalamicus höher als zum motorischen Kortex, hinweisend auf eine relevante Rolle der beschriebenen direkten Verbindung vom Nucleus subthalamicus zu den Kleinhirnhemisphären. Diese Studie liefert neue Erkenntnisse über den Zusammenhang von motorischem Lernen und der Neuromodulation motorischer Netzwerke beim idiopathischen Parkinson Syndrom und erweitert das Konzept der Netzwerkmodulation als mechanistisches Modell zur Wirksamkeit der THS

Deep brain stimulation reduces (nocturnal) dyskinetic exacerbations in patients with ADCY5 mutation: a case series

Mutations in the ADCY5 gene can cause a complex hyperkinetic movement disorder. Episodic exacerbations of dyskinesia are a particularly disturbing symptom as they occur predominantly during night and interrupt sleep. We present the clinical short- and long-term effects of pallidal deep brain stimulation (DBS) in three patients with a confirmed pathogenic ADCY5 mutation. Patients were implanted with bilateral pallidal DBS at the age of 34, 20 and 13 years. Medical records were reviewed for clinical history. Pre- and postoperative video files were assessed using the “Abnormal Involuntary Movement Scale” (AIMS) as well as the motor part of the “Burke Fahn Marsden Dystonia Rating Scale” (BFMDRS). All patients reported subjective general improvement ranging from 40 to 60%, especially the reduction of nocturnal episodic dyskinesias (80–90%). Objective scales revealed only a mild decrease of involuntary movements in all and reduced dystonia in one patient. DBS-induced effects were sustained up to 13 years after implantation. We demonstrate that treatment with pallidal DBS was effective in reducing nocturnal dyskinetic exacerbations in patients with ADCY5-related movement disorder, which was sustained over the long term

Hypertrophic Pachymeningitis with Persistent Intrathecal Inflammation Secondary to Neurosarcoidosis Treated with Intraventricular Chemotherapy: A Case Report

Hypertrophic pachymeningitis (HP) is a rare immune-mediated disease characterized by thickening of the dura mater with consecutive cranial neuropathy. While HP is usually treated with systemic immunotherapies, response to therapy is variable and may be limited by insufficient drug concentrations in the brain. We report on a 57-year-old patient with HP manifesting with vision and hearing loss who had sustained clinical progression despite various systemic immunotherapies. Intraventricular chemotherapy with methotrexate, cytarabine, and dexamethasone was initiated. We present clinical, imaging and cerebrospinal fluid (CSF) findings, including cytokine levels before and after intraventricular treatment: rapid decrease of cell count, lactate and profibrotic cytokine levels in the CSF following intraventricular chemotherapy was paralleled by a mild reduction of dura thickness in MRI. The already severely impaired visual acuity and hearing loss did not progress further. Treatment was complicated by exacerbation of previously subtle psychiatric symptoms. Follow-up was terminated after 6 months as the patient suffered from a fatal ischemic stroke. Autopsy revealed neurosarcoidosis as the underlying cause of HP. This case report suggests that intrathecal chemotherapy can reduce the inflammatory milieu in the CNS and should be considered for treatment-refractory HP before irreversible damage of cranial nerves has occurred