Stephen Tisch

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinsons disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease.

Excessive synchronization of neuronal activity at around 20 Hz is a common finding in the basal ganglia of patients with untreated Parkinsons disease (PD). Correlative evidence suggests, but does not prove, that this spontaneous activity may contribute to slowness of movement in this condition. Here we investigate whether externally imposed synchronization through direct stimulation of the region of the subthalamic nucleus at 20 Hz can slow motor performance in a simple unimanual tapping task and whether this effect is frequency selective. Tapping rates were recorded on 42 sides in 22 patients with PD after overnight withdrawal of medication. Tapping was performed without stimulation and during bilateral stimulation at 20 Hz, 50 Hz and 130 Hz. We found that tapping rates were slowed by 8.2+/-3.2% (p=0.014) during 20-Hz stimulation in subjects with relatively preserved baseline function in the task. This effect was frequency selective. The current data provide proof of the principle that excessive beta synchrony within the basal ganglia-cortical loop may contribute to the slowing of movements in Parkinsons disease.

Effect of electrode contact location on clinical efficacy of pallidal deep brain stimulation in primary generalised dystonia.

Objectives: To determine the effect of electrode contact location on efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for primary generalised dystonia (PGD). Subjects and methods: A consecutive series of 15 patients with PGD (10 females, mean age 42 years, seven DYT1) who underwent bilateral GPi DBS, were assessed using the Burke–Fahn–Marsden (BFM) dystonia scale before and 6 months after surgery. The position of the stimulated electrode contact(s) was determined from the postoperative stereotactic MRI. Contralateral limb and total axial BFM subscores were compared with the location of the stimulated contact(s) within the GPi. Results: The mean total BFM score decreased from 38.9 preoperatively to 11.9 at 6 months, an improvement of 69.5% (p<0.00001). Cluster analysis of the stimulated contact coordinates identified two groups, distributed along an anterodorsal to posteroventral axis. Clinical improvement was greater for posteroventral than anterodorsal stimulation for the arm (86% vs 52%; p<0.05) and trunk (96% vs 65%; p<0.05) and inversely correlated with the y coordinate. For the leg, posteroventral and anterodorsal stimulation were of equivalent efficacy. Overall clinical improvement was maximal with posteroventral stimulation (89% vs 67%; p<0.05) and inversely correlated with the y (A-P) coordinate (r = −0.62, p<0.05). Conclusion: GPi DBS is effective for PGD but outcome is dependent on contact location. Posteroventral GPi stimulation provides the best overall effect and is superior for the arm and trunk. These results may be explained by the functional anatomy of GPi and its outflow tracts.

Dystonia in neurodegeneration with brain iron accumulation: outcome of bilateral pallidal stimulation.

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale—Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale—Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2–6 and 9–15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2–6 months and 25.7% at 9–15 months. At 9–15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9–15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2–6 months; this failed to reach significance at 9–15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson's disease surgery

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinsons disease (PD). However, therapeutic efficacy is limited by difficulties in consistently and correctly targeting this nucleus. Increasing evidence suggests that there is abnormal synchronization of beta frequency band activity (approximately 20 Hz) in the STN of PD patients, as reflected in the oscillatory nature of the local field potential (LFP). We hypothesized that an increase in the power of the LFP beta activity may provide intra-operative confirmation of STN targeting in patients undergoing STN implantation for the treatment of advanced PD. Accordingly, we recorded LFPs from the four contacts of DBS electrodes as the latter were advanced in 2 mm steps from a point 4-6 mm above the intended surgical target point in the STN, to a point 4 mm below this. Contacts were configured to give three bipolar recordings of LFPs. These were analyzed on 16 sides in 9 patients. The power in the 13-35 Hz band recorded at the lowest contact pair underwent a steep but focal increase during electrode descent. The depth of the peak beta activity showed excellent agreement with the level of the intra-operative clinical stun effect (k coefficient = 0.792). The depth of peak beta activity also showed 100% specificity and 100% sensitivity for placement within STN in comparison to pre- and Post-operative stereotactic MRI. Functional physiological localization of STN by the on-line spectral analysis of LFPs is quick to perform and may provide information directly relevant to the position of the electrode contact actually used for DBS.

Stereotactic localization of the human pedunculopontine nucleus: atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization

The pedunculopontine nucleus (PPN) is a promising new target for deep brain stimulation (DBS) in parkinsonian patients with gait disturbance and postural instability refractory to other treatment modalities. This region of the brain is unfamiliar territory to most functional neurosurgeons. This paper reviews the anatomy of the human PPN and describes novel, clinically relevant methods for the atlas-based and MRI-based localization of the nucleus. These two methods of PPN localization are evaluated and compared on stereotactic MRI data acquired from a diverse group of 12 patients undergoing implantation of deep brain electrodes at sites other than the PPN. Atlas-based coordinates of the rostral and caudal PPN poles in relation to fourth ventricular landmarks were established by amalgamating information sourced from two published human brain atlases. These landmarks were identified on acquired T1 images and atlas-derived coordinates used to plot the predicted PPN location on all 24 sides. Images acquired using a specifically modified, proton-density MRI protocol were available for each patient and were spatially fused to the T1 images. This widely available and rapid protocol provided excellent definition between gray and white matter within the region of interest. Together with an understanding of the regional anatomy, direct localization of the PPN was possible on all 24 sides. The coordinates for each directly localized nucleus were measured in relation to third and fourth ventricular landmarks. The mean (SD) of the directly localized PPN midpoints was 6.4 mm (0.5) lateral, 3.5 mm (1.0) posterior and 11.4 mm (1.2) caudal to the posterior commissure in the anterior commissure-posterior commissure plane. For the directly localized nucleus, there was similar concordance for the rostral pole of the PPN in relation to third and fourth ventricular landmarks (P>0.05). For the caudal PPN pole, fourth ventricular landmarks provided greater concordance with reference to the anteroposterior coordinate (P<0.001). There was a significant difference between localization of the PPN poles as predicted by atlas-based coordinates and direct MRI localization. This difference affected mainly the rostrocaudal coordinates; the mean lateral and anteroposterior coordinates of the directly localized PPN poles were within 0.5 mm of the atlas-based predicted values. Our findings provide simple, rapid and precise methods that are of clinical relevance to the atlas-based and direct stereotactic localization of the human PPN. Direct MRI localization may allow greater individual accuracy than that afforded by atlas-based coordinates when localizing the human PPN and may be relevant to groups evaluating the clinical role of PPN DBS.

Severe tongue protrusion dystonia Clinical syndromes and possible treatment

We describe intermittent or sustained severe involuntary tongue protrusion in patients with a dystonic syndrome. Speech, swallowing, and breathing difficulties can be severe enough to be life threatening. Causes include neuroacanthocytosis, pantothenate kinase–associated neurodegeneration, Lesch–Nyhan syndrome, and postanoxic and tardive dystonia. The pathophysiology of intermittent severe tongue protrusion remains unknown. Tongue protrusion dystonia is often unresponsive to oral drugs but may benefit from botulinum toxin injections into the genioglossus muscle. Bilateral deep brain pallidal stimulation was beneficial in two cases.

Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor

To evaluate the posterior subthalamic area (PSA) as a target for deep brain stimulation (DBS) in the treatment of essential tremor (ET). The ventral intermediate nucleus of the thalamus is the traditional target for DBS in the treatment of ET. Recent studies have presented beneficial effects of DBS in the PSA in the treatment of tremor. Twenty‐one patients with ET were included in this study. All patients were evaluated before and 1 year after surgery, on and off stimulation, using the essential tremor rating scale (ETRS). A marked microlesional effect was noticed in 83%, in some cases obviating the need for electrical stimulation for many months. The total ETRS was reduced from 46.2 at baseline to 18.7 (60%). Item 5/6 (tremor of the upper extremity) was improved from 6.2 to 0.3 (95%), and items 11 to 14 (hand function) from 9.7 to 1.3 (87%) concerning the contralateral hand. Activities of daily living were improved by 66%. No severe complication occurred. Eight patients presented a postoperative mild dysphasia that regressed within days to weeks. DBS in the PSA resulted in a marked reduction of tremor.

Effects of contact location and voltage amplitude on speech and movement in bilateral subthalamic nucleus deep brain stimulation.

Subthalamic nucleus deep brain stimulation (STN‐DBS) is particularly effective in improving limb symptoms in Parkinsons disease. However, speech shows a variable response. Contact site and amplitude of stimulation have been suggested as possible factors influencing speech. In this double blind study, we assessed 14 patients post bilateral STN‐DBS, without medication. Six conditions were studied in random order as follows: stimulation inside the STN at low voltage (2 V) and at high voltage (4 V); above the STN at 2 V and at 4 V, at usual clinical parameters, and off‐stimulation. The site of stimulation was defined on the postoperative stereotactic MRI data. Speech protocol consisted of the assessment of intelligibility of the dysarthric speech, maximum sustained phonation, and a 1‐minute monologue. Movement was assessed using the UPDRS‐III. Stimulation at 4 V significantly reduced the speech intelligibility (P = 0.004) independently from the site of stimulation. Stimulation at 4 V significantly improved the motor function. Stimulation inside the nucleus was significantly more effective than outside the nucleus (P = 0.0006). The significant improvement in movement coupled with significant deterioration in speech intelligibility when patients are stimulated inside the nucleus at high voltage indicates a critical role for electrical stimulation parameters in speech motor control.

Activation of the subthalamic region during emotional processing in Parkinson disease.

Objective: To elucidate the involvement of the human subthalamic nucleus (STN) region in the processing or transmission of emotional information. Methods: Local field potentials (LFPs) were recorded from this region in 10 patients with Parkinson disease (PD) undergoing bilateral implantation of the STN for high-frequency stimulation. LFP recordings were made while patients viewed pleasant and unpleasant emotionally arousing and neutral pictures. Results: A significant decrease (event-related desynchronization [ERD]) in the local alpha power (8 to 12 Hz) was found for all stimulus categories starting at about 0.5 seconds after stimulus presentation. However, 1 to 2 seconds poststimulus, the ERD was larger in trials of pleasant (mean ERD: 21.6 ± 2.8%; p < 0.009) and unpleasant (mean ERD: 15.0 ± 4.2%; p = 0.018) stimuli compared with neutral stimuli (mean ERD: 4.4 ± 4.2%). Conclusion: The delayed modulation of alpha activity recorded from the area of the subthalamic nucleus in PD may reflect the processing or transmission of information related to emotional stimuli. “Limbic” activation in the region of the subthalamic nucleus may explain why high-frequency stimulation of the subthalamic nucleus alters affect in some patients with PD.