German registry of paediatric deep brain stimulation in patients with childhood-onset dystonia (GEPESTIM).

BACKGROUND: Data on paediatric deep brain stimulation (DBS) is limited, especially for long-term outcomes, because of small numbers in single center series and lack of systematic multi-center trials. OBJECTIVES: We seek to systematically evaluate the clinical outcome of paediatric patients undergoing DBS. METHODS: A German registry on paediatric DBS (GEPESTIM) was created to collect data of patients with dystonia undergoing DBS up to the age of 18 years. Patients were divided into three groups according to etiology (group 1 inherited, group 2 acquired, and group 3 idiopathic dystonia). RESULTS: Data of 44 patients with a mean age of 12.8 years at time of operation provided by 6 German centers could be documented in the registry so far (group 1 n = 18, group 2 n = 16, group 3 n = 10). Average absolute improvement after implantation was 15.5 ± 18.0 for 27 patients with pre- and postoperative Burke-Fahn-Marsden Dystonia Rating scale movement scores available (p < 0.001) (group 1: 19.6 ± 19.7, n = 12; group 2: 7.0 ± 8.9, n = 8; group 3: 19.2 ± 20.7, n = 7). Infection was the main reason for hardware removal (n = 6). 20 IPG replacements due to battery expiry were necessary in 15 patients at 3.7 ± 1.8 years after last implantation. DISCUSSION: Pre- and postoperative data on paediatric DBS are very heterogeneous and incomplete but corroborate the positive effects of DBS on inherited and acquired dystonia. Adverse events including relatively frequent IPG replacements due to battery expiry seem to be a prominent feature of children with dystonia undergoing DBS. The registry enables collaborative research on DBS treatment in the paediatric population and to create standardized management algorithms in the future.

Globus pallidus internus neuronal activity: a comparative study of linear and non-linear features in patients with dystonia or Parkinson's disease.

Movement disorders such as Parkinson's disease (PD) and dystonia are associated with alterations of basal ganglia motor circuits and abnormal neuronal activity in the output nucleus, the globus pallidus internus (GPi). This study aims to compare the electrophysiological hallmarks for PD and dystonia in the linear and non-linear time stamp domains in patients who underwent microelectrode recordings during functional stereotactic surgery for deep brain stimulation (DBS) or pallidotomy. We analyzed single-unit neuronal activity in the posteroventral lateral region of the GPi in awake patients prior to pallidotomy or the implantation of DBS electrodes in 29 patients with PD (N = 83 neurons) and 13 patients with dystonia (N = 41 neurons) under comparable conditions. The discharge rate and the instantaneous frequency of the GPi in dystonia patients were significantly lower than in PD patients (P < 0.001), while the total number of bursts, the percentage of spikes in bursts and the mean duration of bursts were higher (P < 0.001). Further, non-linear analysis revealed higher irregularity or entropy in the data streams of GPi neurons of PD patients compared to the dystonia patients group (P < 0.001). This study indicates that both linear and non-linear features of neuronal activity in the human GPi differ between PD and dystonia. Our results may serve as the basis for future studies on linear and non-linear analysis of neuronal firing patterns in various movement disorders.

GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia.

OBJECTIVES: Stimulation-induced hypokinetic gait disorders with freezing of gait (FOG) have been reported only recently as adverse effects of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in patients with dystonia. The aim of this work was to determine the frequency and the nature of this GPi-DBS-induced phenomenon. METHODS: We retrospectively screened our database of patients with dystonia who underwent DBS. Patients with focal, segmental, or generalized dystonia of primary or tardive origin and no gait disorder due to lower limb dystonia before DBS, bilateral pallidal stimulation, and a follow-up for more than 6 months were included. Reports of adverse events were analyzed, and gait abnormalities were scored by comparing preoperative and postoperative video recordings using Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) items 3.10 (gait) and 3.11 (FOG). To assess the role of GPi-DBS in gait abnormalities, DBS was paused for 24 hours. Gait and FOG were assessed 30 minutes, 2 hours, and 24 hours after restarting DBS. Finally, a standardized adjustment algorithm was performed trying to eliminate the gait disorder. RESULTS: Of a collective of 71 patients with dystonia, 6 presented with a new gait disorder (8.5%; 2 men, 4 women, mean age 61.3 years [48-69 years], 2 craniocervical, 1 DYT-1 segmental, 1 truncal, 2 tardive dystonia). GPi-DBS improved Burke-Fahn-Marsden Dystonia Rating Scale motor score by 54% and disability score by 52%. MDS-UPDRS item 3.10 worsened from 0.5 (±0.8) to 2.0 (±0.9) and item 3.11 from 0 to 2.5 (±0.5). The gait disorder displayed shuffling steps and difficulties with gait initiation and turning. Increasing voltages improved dystonia but triggered FOG, sometimes worsening over a period of a few hours. It vanished within minutes after ceasing DBS. Electrode misplacement was ruled out. In all but one patient, no optimal configuration was found despite extensive testing of settings (monopolar, bipolar, pulse width 60-210 µs, frequency 60-180 Hz). Nevertheless, a compromise between optimal stimulation for dystonia and eliciting FOG was achieved in each case. CONCLUSIONS: A hypokinetic gait disorder with FOG can be a complication of GPi-DBS.

Human hypothalamus shows differential responses to basic motivational stimuli--an invasive electrophysiology study.

The hypothalamus supports basic motivational behaviours such as mating and feeding. Recording directly from the posterior inferior hypothalamus in a male patient receiving a deep brain stimulation (DBS) electrode for the alleviation of cluster headache, we tested the hypothalamic response to different classes of motivational stimuli (sexually relevant: pictures of dressed and undressed women; pictures of food) and pictures of common objects as control. Averaged local field potentials (LFP) to sexually relevant stimuli were characterized by a biphasic significantly enhanced response (relative to objects; bootstrapping statistics) with a first phase starting at around 200 ms and a second phase peaking at around 600 ms. Sexually relevant stimuli also showed a greatly enhanced positivity relative to other stimulus classes in surface event-related potentials in a group of 11 male control participants. It is suggested that the hypothalamus is involved in the recruitment of attentional resources by sexually relevant stimuli reflected in this surface positivity. In a second session, the response to food stimuli relative to objects was tested in two states: after fasting for 14 h, LFPs to food and object stimuli showed significant differences in between 300 and 850 ms, which disappeared after a full high-calorie meal, thus replicating classic studies in monkeys [Rolls et al., Brain Res (1976) 111:53-66]. The current data are the first to demonstrate hypothalamic responses to the sight of motivational stimuli in man and thus shows that recording from DBS electrodes might provide important information about the cognitive functions of subcortical structures.

Classical and molecular cytogenetics of the pufferfish Tetraodon nigroviridis.

Because of its highly compact genome, the pufferfish has become an important animal model in genome research. Although the small chromosome size renders chromosome analysis difficult, we have established both classical and molecular cytogenetics in the freshwater pufferfish Tetraodon nigroviridis (TNI). The karyotype of T. nigroviridis consists of 2n = 42 biarmed chromosomes, in contrast to the known 2n = 44 chromosomes of the Japanese pufferfish Fugu rubripes (FRU). RBA banding can identify homologous chromosomes in both species. TNI 1 corresponds to two smaller FRU chromosomes, explaining the difference in chromosome number. TNI 2 is homologous to FRU 1. Fluorescence in-situ hybridization (FISH) allows one to map single-copy sequences, i.e. the Huntingtin gene, on chromosomes of the species of origin and also on chromosomes of the heterologous pufferfish species. Hybridization of total genomic DNA shows large blocks of (species-specific) repetitive sequences in the pericentromeric region of all TNI and FRU chromosomes. Hybridization with cloned human rDNA and classical silver staining reveal two large and actively transcribed rRNA gene clusters. Similar to the situation in mammals, the highly compact pufferfish genome is endowed with considerable amounts of localized repeat DNAs.