Martin M. Reich

Parkinson's disease in GTP cyclohydrolase 1 mutation carriers

Mutations in the gene encoding the dopamine-synthetic enzyme GTP cyclohydrolase-1 (GCH1) cause DOPA-responsive dystonia (DRD). Mencacci et al. demonstrate that GCH1 variants are associated with an increased risk of Parkinsons disease in both DRD pedigrees and in patients with Parkinsons disease but without a family history of DRD.

Short pulse width widens the therapeutic window of subthalamic neurostimulation

We explored the impact of pulse durations <60 μsec on the therapeutic window of subthalamic neurostimulation in Parkinsons disease. Current thresholds for full rigidity control and first muscle contractions were evaluated at pulse durations between 20 and 120 μsec during a monopolar review session in four patients. The average therapeutic window was 2.16 mA at 60 μsec, which proportionally increased by 182% at 30 μsec, while decreasing by 46% at 120 μsec. Measured chronaxies and model data suggest, that pulse durations <60 μsec lead to a focusing of the neurostimulation effect on smaller diameter axons close to the electrode while avoiding stimulation of distant pyramidal tract fibers.

Connectivity Predicts deep brain stimulation outcome in Parkinson disease

The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort.

Differential effect of dopa and subthalamic stimulation on vestibular activity in Parkinson's disease.

Postural disturbances in advanced Parkinsons disease are less responsive to therapy than other cardinal motor signs. The vestibulocollic reflex represents one brain‐stem neuronal circuit involved in postural adjustments. The objective of this study was to investigate the vestibulocollic reflex in parkinsonian patients and the effects of subthalamic stimulation and dopa by recording vestibular‐evoked myogenic potentials. After overnight withdrawal of medication, 20 patients with Parkinsons disease with (6 men, 4 women; mean age, 64.4 ± 2.2 years) or without (8 men, 2 women; mean age, 62.7 ± 3.9 years) implanted subthalamic electrodes in different treatment conditions were compared with 10 age‐matched controls (5 men, 5 women; mean age, 59.6 ± 2.4 years). Vestibular‐evoked myogenic potentials were recorded by electromyographic surface electrodes applied to both sternocleidomastoid muscles (band‐pass filter, 8–1600 Hz; sampling rate, 5 kHz) and averaged in response to bilateral auditory tone bursts (120 dB SPL; sine waves, 7 ms; 1000 Hz) applied through earphones. Adjusted vestibular‐evoked myogenic potential amplitudes were significantly smaller in parkinsonian patients than in controls, in particular in patients without surgery. Administration of dopa, but not subthalamic stimulation, significantly increased amplitudes. Onset latencies were similar for all groups and treatment conditions. Decreased vestibular‐evoked myogenic potential amplitudes in parkinsonian patients suggest reduced vestibular nuclei excitability within the brain stem, which is modulated by dopa but not by subthalamic stimulation. This suggests different pathways for the action of both treatment modalities in Parkinsons disease and may explain clinical differences in terms of postural disturbances.

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Pulse duration settings in subthalamic stimulation for Parkinson's disease: Pulse Duration in DBS

Stimulation parameters in deep brain stimulation (DBS) of the subthalamic nucleus for Parkinsons disease (PD) are rarely tested in double‐blind conditions. Evidence‐based recommendations on optimal stimulator settings are needed. Results from the CUSTOM‐DBS study are reported, comparing 2 pulse durations.

Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson’s Disease

Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson’s disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta-suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross-hemispheric coupling, thus allowing fine-tuning of movement.

The Pirouette Test to Evaluate Asymmetry in Parkinsonian Gait Freezing

Freezing of gait (FOG) is one of the most challenging motor symptoms of Parkinson’s disease (PD) because it limits mobility and causes falls. It is characterized by brief episodes of inability to move forward, despite the intention to walk, which typically occur on initiating gait, when passing obstacles, or on turning. Normally, FOG is overcome after a couple of seconds, sometimes with the help of cueing maneuvers, but episodes can exceed 30 seconds. Medication, DBS, and rehabilitation techniques are helpful in controlling FOG in some patients, but FOG remains one of the most challenging motor symptoms to treat in advanced PD. A particular problem is de novo FOG after otherwise successful STN-DBS. When occurring early after surgery during the adjustment phase of neurostimulation, it cannot be ascribed to disease progression, but is rather provoked by the necessary reduction of dopaminergic medication in combination with inappropriate programming for the control of gait symptoms. Several recent studies have suggested special stimulation parameter settings to control FOG, which address impaired rhythmicity, symmetry, or bilateral coordination associated with FOG episodes, including lower-frequency stimulation with 60 to 80 Hz, reduction of amplitude on the side with longer stride length, and an interleaving stimulation of the distal contact in the SNr. Nevertheless, it remains enigmatic as to who responds or may be especially suited for which option. FOG can be asymmetric, affecting mainly one foot, which then triggers a generalized freezing episode. Assessing gait asymmetry can be challenging for the clinician, because it may not be obvious during normal walking or standard challenge tests. We found forced clockwise or counterclockwise turning most useful in determining the more affected leg, which we termed the “pirouette test.” In the French ballet glossary, “pirouette” refers to “spinning around.” In practice, the patient is asked to perform a full 360-degree circle on the spot by moving one leg around a standing leg. The outer leg walking the circle is more prone to freezing and indicates the dominant symptomatic side, when the pirouette is preformed in both directions (see Video 1; Fig. 1). The pirouette test may be repeatedly performed during DBS parameter adjustments until symmetric clockwise and counterclockwise turning is achieved. Here, we illustrate the usefulness of this approach in a 60year-old man suffering from PD for the past 6 years. He was considered for STN-DBS at our institution because of severe motor fluctuations, including end-of-dose akinesia, painful offperiod dystonia and peak-dose dyskinesia. In the preoperative levodopa challenge test, the patient scored 56 points on the UPDRS-III in the practically defined “off” and 9 points after a suprathreshold dosage of L-dopa. Interestingly, FOG was observed preoperatively only in a minimal degree in the medication (MED) OFF condition (score of 1 point in item III.11). Because of the excellent L-dopa response and a lack of contraindications, the patient was implanted bilaterally in the STN during June 2013. He opted for a novel rechargeable DBS system (Vercise; Boston Scientific, Valencia, CA). After relief of the microlesioning effect, the initial stimulation settings (right STN: case +, contact 11-, 2.4 mA, 60 ls, 130 Hz; left STN: case +, contact 2and 3(50% each), 1.6 mA, 60 ls, 130 Hz) was very satisfactory, resulting in an UPDRS-III score of 12 points in the MED OFF/stimulation (STIM) ON condition. Therefore, an almost complete withdrawal of dopaminergic drugs was possible. A few weeks later, the patient started to complain about gait freezing, particularly when crossing confined spaces, impairing his professional and social activities and causing two falls. On clinical examination, the patient exhibited mild and brief freezing and festinations during gait initiation, which could not be clearly assigned to one side (total UPDRS III: 20 points; item gait: 5 points). By performing the pirouette test, freezing became obvious for the left leg only (see Video 1). Therefore, we tried to optimize efficacy of right STN stimulation by increasing amplitude (>3.5 mA with 130 Hz) and shifting current to the adjacent contacts (proximal and distal current steering). This could not achieve satisfactory control of FOG, despite an excellent improvement of bradykinesia and rigidity in

Intraoperative Thresholds for Capsular Stimulation Are Reliable for Chronic Pallidal Deep Brain Stimulation in Dystonia.

Background: The threshold current for inducing muscle contractions by stimulation of pyramidal tract fibres adjacent to the globus pallidus internus (GPi) is, besides microelectrode recordings for the determination of nuclear boundaries, currently the only neurophysiological marker for intraoperative refinement of the anatomically planned target point for pallidal deep brain stimulation (GPi-DBS) in dystonia. Objectives: To determine the relationship between intraoperative thresholds for muscle contractions under general anaesthesia and postoperative thresholds in GPi-DBS. Methods: Intraoperatively, current amplitude thresholds (120 µs, 130 Hz) were determined in 6 dystonic patients under general anaesthesia (through the uninsulated tip of the microelectrode guide tube). Postoperative localization of chronic stimulation electrodes by MRI and image fusion with the stereotactic planning determined the stimulation contact for comparing thresholds with intraoperative values. Results: Current thresholds were 3.3 ± 0.8 mA intraoperatively (follow-up 0, FU0; n = 12), 2.9 ± 1.2 mA within 1 week after surgery (FU1; n = 12), and 3.5 ± 1.6 mA after 6-17 months (FU2; n = 8). FU0 and FU1 differed by trend, and FU1 and FU2 were significantly different (Friedman test, p = 0.0048; post hoc Dunn multiple comparison test, p < 0.05). FU0 and FU2 were not different. Discussion: The threshold amplitude to induce tonic muscular contractions may constitute a valid approach of functionally refining the anatomically guided electrode placement in GPi-DBS for dystonia, because intraoperative values are predictive for postoperative thresholds with the chronically implanted neurostimulation system.

Young-onset multiple system atrophy: Clinical and pathological features: Young-Onset Msa

Background: The onset of multiple system atrophy (MSA) before age 40 years is referred to as “young‐onset MSA.” We identified clinical and pathological characteristics that might help with its early diagnosis and distinction from young‐onset Parkinsons disease and late‐onset MSA.