Abstract: We report two patients, in whom stuttering evolved as an adverse effect of pallidal deep brain stimulation for treating dystonia. Speech dysfluency was observed under conditions that optimally suppressed dystonic symptoms without inducing other extrinsic stimulation effects. This emphasizes a role of the sensorimotor part of the internal globus pallidus in regulating speech fluency.

Abstract: Medical treatment of dystonia, particularly generalised forms of the disorder, is often not satisfactory or causes intolerable side effects. In focal dystonia, a reasonable treatment option with botulinum toxin exists but some patients either do not respond well or develop neutralising antibodies with secondary therapy failure. Deep brain stimulation (DBS) of the globus pallidus internus has been shown to be effective in both generalised and focal dystonia. This paper gives recommendations regarding the use of DBS in different forms of dystonia based on the currently available scientific data as well as the longstanding personal experience of the authors. The inclusion criteria for DBS candidates as well as the peri- and postoperative patient management are addressed. These recommendations were developed in a consensus procedure in the German Deep Brain Stimulation Association.

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Abstract: BACKGROUND: Tremor is one of the cardinal symptoms in Parkinson's disease, but only few clinical studies have focussed on its therapy as the primary endpoint. One reason is the substantial fluctuation of tremor severity over time, which is difficult to capture and may render momentary clinical assessments unreliable. METHODS: We evaluated the usefulness of a novel wrist-worn actigraph allowing long-term recordings of tremor in a pilot study, in which we assessed the therapeutic effect of cabergoline on tremor in 10 patients with tremor-dominant Parkinson's disease. Clinical data were obtained by using the Unified Parkinson's Disease Rating Scale (UPDRS Part III, item 20) and simultaneously a patient's tremor diary. RESULTS: We found a significant reduction in UPDRS motor and tremor scores, in tremor duration and tremor amplitude by actigraphy and diaries. Furthermore, we found significant correlations between actigraphy measurements and patient ratings of tremor intensity and occurrence in diaries. CONCLUSION: Long-term actigraphy is a reliable method to assess tremor occurrence and severity and may be used to document antitremor effects in clinical studies.

Abstract: Deep brain stimulation (DBS) has been shown to be effective for levodopa-responsive symptoms and tremor in Parkinson's disease (PD). The subthalamic nucleus (STN) is the preferred target for most patients suffering from late stage motor complications of the disorder. STN DBS is superior to best medical treatment concerning the control of motor fluctuations and the increase of on-time without dyskinesias. In contrast to DBS of the internal pallidum (GPi), STN stimulation also permits a reduction of the dopaminergic medication. Long-term data demonstrated sustained effectiveness of STN DBS despite progressive disease. DBS of the thalamic ventral intermediate nucleus (VIM) is an alternative target in older PD patients with severe PD tremor refractory to medication. In order to minimize potential risks and side effects, the use of DBS needs careful adherence to inclusion and exclusion criteria for eligible PD patients. This paper summarizes the current consensus recommendations of the German Deep Brain Stimulation Association for DBS in PD.

Abstract: In Germany, deep brain stimulation (DBS) of the thalamic ventralis intermedius nucleus (VIM) is licensed for treatment of essential tremor in cases unresponsive to pharmacotherapy. Especially a bothersome hand tremor interfering with activities of daily living will improve, whereas head, tongue or vocal tremor shows less response. DBS was proven to be superior to lesional thalamotomy with better functional outcome and less adverse effects. The consensus statement presented here reflects the current recommendations of the German Deep Brain Stimulation Study Group for inclusion and exclusion criteria as well as for peri-, intra- and postoperative neurological management.

Abstract: OBJECTIVE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is an effective treatment for medically refractory primary dystonia. We present our technique for direct preoperative visualization of the target using a fast spin-echo inversion-recovery (FSE-IR) sequence. METHODS: Twenty-three consecutive patients (mean age 41 years, range 9-68 years, male to female ratio 11:12) with severe dystonia were operated using a combination of FSE-IR imaging for direct visualization of the globus pallidus internus with stereotactic, gadolinium-enhanced T1-MPRage images. The complete procedure, including stereotactic MRI, was performed under general anesthesia with propofol and remifentanyl. We used multichannel microdrive systems (Medtronic; Alpha-Omega) to introduce up to five parallel microelectrodes for microelectrode recordings (MER) and test stimulation with the central trajectory directed at the anatomically predefined target. The initial standard coordinates in relation to the mid-commissural point (mid-AC-PC) were as follows: lateral 21 mm, anterior 3 mm, and inferior 2 mm, which were then adapted to the individual case based on direct visualization of the target area and further refined by the intraoperative neurophysiology. RESULTS: In ten patients (43%) atlas-based standard coordinates were modified based on the direct visualization of the GPi in the FSE-IR images (bilaterally in seven patients, unilaterally in three). The modified targets ranged from 18.5 to 23.5 mm (mean 20.76 mm) laterally, 1-7 mm (mean 2.75 mm) anteriorly and 1-2 mm (mean 1.95 mm) inferiorly to the mid-AC-PC. We implanted the permanent electrode based on the results of MER and intraoperative stimulation performed to determine the threshold for pyramidal tract responses on the central trajectory in 67%, medially in 16%, anteriorly in 11%, laterally in 4%, dorsally in 2%. The procedure resulted in excellent clinical benefits (average reduction of the Burke-Fahn-Marsden Dystonia Rating Score (BFMDRS) or the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) were respectively 65.9%, range 20.9-91.4%) within the first year after surgery. Safety was demonstrated by the absence of intracranial bleeding or other surgical complications causing neurological morbidity. CONCLUSION: Inversion recovery sequences are an excellent tool for direct visualization of the GPi. These images can be fused to stereotactic MRI or CCT and may help to improve anatomical targeting of the GPi for the implantation of DBS electrodes.

Abstract: OBJECTIVE: Deep brain stimulation (DBS) has become a standard procedure for movement disorders such as Parkinson's disease, essential tremor or dystonia. Recently, deep brain stimulation of the posterior hypothalamus has been shown to be effective in the treatment of drug-resistant chronic cluster headache. METHODS: DBS of the posterior inferior hypothalamus was performed on two patients with chronic cluster headaches, one 55-year-old man with medically intractable chronic cluster headache since 1996, and one 31-year-old woman with a chronic form since 2002. Both patients showed continuous worsening headaches in the last years despite high dose medical treatment. The patients fulfilled the published criteria for DBS in chronic cluster headaches. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to the published coordinates (2 mm lateral, 3 mm posterior, 5 mm inferior) referenced to the mid-AC-PC line. RESULTS: The intra- and postoperative course was uneventful and postoperative MRI control documented regular position of the DBS electrodes. The current stimulation parameters were at 12 months postoperatively 0 neg., G pos.; 5.5 V; 60 micros; 180 Hz (Case 1) and 0 neg., G pos.; 3.0 V; 60 micros; 185 Hz, at 3 months postoperatively (Case 2). Surgery- or stimulation-related side effects were not observed. Both patients showed initial pain reduction in the first days whereas 12 respectively 3 month follow-up did not show a significant reduction in attack frequency or intensity. CONCLUSION: Deep brain stimulation of the posterior inferior hypothalamus is an experimental procedure and should be restricted to selected therapy-refractory patients and should be performed in centers experienced in patient selection and performance of DBS as well as postoperative pain treatment. A prospective multi-centre study is necessary to evaluate its effectiveness.

Abstract: OFF-period dyskinesias have been reported as a consequence of fetal nigral transplantation for Parkinson's disease. This type of dyskinesias may appear in patients even in the prolonged absence of antiparkinson medication and be aggravated by levodopa. Therefore, pharmacological therapeutic approaches in these patients are limited. Here we report two patients with bilateral fetal nigral grafts in the caudate and putamen subjected to deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN). Clinical assessment was performed according to UPDRS and the clinical dyskinesia rating scale. In both patients, we found significant improvement in OFF-period symptoms as well as levodopa-induced dyskinesias. However, only GPi-DBS led to a significant reduction of OFF-period dyskinesias whereas STN-DBS did not influence dyskinesias unrelated to external dopaminergic application. These findings, based on two case reports, highlight the pivotal role of the GPi in mediating dyskinesia-related neural activity within the basal ganglia loop.

Abstract: BACKGROUND: Axial symptoms of Parkinson disease (PD) may result from dysfunctional basal ganglia-brainstem connections. In this study, we assessed whether modulation of basal ganglia activity by high-frequency stimulation of the subthalamic nucleus (STN-HFS) in PD had an impact on the brainstem-controlled startle system. METHODS: We assessed auditory startle responses (recorded from right orbicularis oculi, masseter, sternocleidomastoid, biceps brachii, and soleus muscle) and audiospinal facilitation (startle conditioned soleus H-reflexes at interstimulus intervals of 0-250 msec) in 24 patients with PD with chronically implanted, bilateral STN electrodes in the stimulation on (STIM ON) and off condition (STIM OFF) and 20 healthy controls. RESULTS: The mixed linear analysis of variance model revealed a significant effect for the startle onset latency in the orbicularis oculi muscle for the factors GROUP (patients with PD vs controls; p < 0.0001, F = 44.66) and STIM (nested within GROUP) (p = 0.0034, F = 8.79). Audiospinal facilitation was modulated by STN-HFS as shown by highly significant effects for STIM [GROUP] (p < 0.0001, F = 15.9), ISI [GROUP] (p < 0.0001, F = 3.5), and the interaction of ISI x STIM [GROUP] (p = 0.0085, F = 2.65) in the mixed linear model. CONCLUSION: High-frequency stimulation of the subthalamic nucleus alters the excitability of the brainstem startle system in Parkinson disease, most likely by releasing the reticular motor system from abnormal descending input of the basal ganglia via pallidotegmental pathways.

Abstract: The pathophysiology of Parkinson's disease is marked by the loss of dopaminergic neurons, which leads to striatal dopaminergic deficiency. This causes resting tremor, hypokinesia, rigidity, bradykinesia, and loss of postural reflexes. Most current treatments for Parkinson's disease aim to restore striatal dopamine signaling by increasing the supply of dopamine with oral levodopa (L-dopa), stimulating dopamine receptors directly using dopamine agonists, or inhibiting the reuptake of endogenous dopamine. L-dopa is standard therapy for patients with Parkinson's disease. However, with continued treatment and disease progression, the response to oral dopaminergic drugs becomes unstable and motor fluctuations emerge, including off periods and dyskinesia. Direct duodenal-administered infusible L-dopa/carbidopa is effective for the management of refractory motor fluctuations in some patient populations. However, enteral infusions cannot mimic the function of the normal dopaminergic brain, and around-the-clock constant-rate administration carries the risk of causing refractory off periods associated with severe immobility and hyperpyrexia. Subthalamic nucleus (STN) deep brain stimulation (DBS) is also a promising treatment. DBS passes a high-frequency electrical current into the target area, mimicking the effect of lesioning the stimulated area. However, this treatment requires invasive surgery and is appropriate for a limited segment of the patient population. This supplement provides a rationale for the use of continuous dopaminergic receptor stimulation and offers guidelines on the individualization of treatment decisions, with special focus on continuous L-dopa infusion and STN DBS. Erik Wolters, MD, PhD, offers an introduction to the impact of continuous L-dopa infusion. Andrew J. Lees, MD, FRCP, provides an overview of the physiologic response to L-dopa and reviews clinical pharmacologic studies of intravenous and intraduodenal L-dopa. Jens Volkmann, MD, discusses selection criteria for STN DBS and duodenal L-dopa/carbidopa infusion. Teus van Laar, MD, PhD, and Ad Hovestadt, MD, discuss the first data from a Dutch cohort study of duodenal L-dopa/carbidopa.

Abstract: As part of the first randomized, sham-stimulation controlled trial on deep brain stimulation (DBS) in primary segmental or generalized dystonia, health-related quality of life (HRQoL) was assessed by SF-36. After the 3-month sham-controlled phase, significant HRQoL improvement occurred only in the active-stimulation group. The open-label extension phase resulted in a significant improvement in all SF-36 domains following 6 months of neurostimulation. These results demonstrate a favorable impact of DBS on HRQoL in primary dystonia.

Abstract: BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces motor symptoms in patients with Parkinson's disease (PD) and improves their quality of life; however, the effect of DBS on cognitive functions and its psychiatric side-effects are still controversial. To assess the neuropsychiatric consequences of DBS in patients with PD we did an ancillary protocol as part of a randomised study that compared DBS with the best medical treatment. METHODS: 156 patients with advanced Parkinson's disease and motor fluctuations were randomly assigned to have DBS of the STN or the best medical treatment for PD according to the German Society of Neurology guidelines. 123 patients had neuropsychological and psychiatric examinations to assess the changes between baseline and after 6 months. The primary outcome was the comparison of the effect of DBS with the best medical treatment on overall cognitive functioning (Mattis dementia rating scale). Secondary outcomes were the effects on executive function, depression, anxiety, psychiatric status, manic symptoms, and quality of life. Analysis was per protocol. The study is registered at ClinicalTrials.gov, number NCT00196911. FINDINGS: 60 patients were randomly assigned to receive STN-DBS and 63 patients to have best medical treatment. After 6 months, impairments were seen in executive function (difference of changes [DBS-best medical treatment] in verbal fluency [semantic] -4.50 points, 95% CI -8.07 to -0.93, Cohen's d=-;0.4; verbal fluency [phonemic] -3.06 points, -5.50 to -0.62, -0.5; Stroop 2 naming colour error rate -0.37 points, -0.73 to 0.00, -0.4; Stroop 3 word reading time -5.17 s, -8.82 to -1.52, -0.5; Stroop 4 colour naming time -13.00 s, -25.12 to -0.89, -0.4), irrespective of the improvement in quality of life (difference of changes in PDQ-39 10.16 points, 5.45 to 14.87, 0.6; SF-36 physical 16.55 points, 10.89 to 22.21, 0.9; SF-36 psychological 9.74 points, 2.18 to 17.29, 0.5). Anxiety was reduced in the DBS group compared with the medication group (difference of changes in Beck anxiety inventory 10.43 points, 6.08 to 14.78, 0.8). Ten patients in the DBS group and eight patients in the best medical treatment group had severe psychiatric adverse events. INTERPRETATION: DBS of the STN does not reduce overall cognition or affectivity, although there is a selective decrease in frontal cognitive functions and an improvement in anxiety in patients after the treatment. These changes do not affect improvements in quality of life. DBS of the STN is safe with respect to neuropsychological and psychiatric effects in carefully selected patients during a 6-month follow-up period. FUNDING: German Federal Ministry of Education and Research (01GI0201).

Abstract: In addition to motor symptoms, patients with Parkinson's disease (PD) show deficits in sensory processing. These deficits are thought to result from deficient gating of sensory information due to basal ganglia dysfunction in PD. Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been shown to improve sensory deficits in PD, e.g. STN-DBS normalizes the perception of urinary bladder filling in patients with PD. This study aimed at investigating how STN-DBS modulates the processing of urinary bladder information to elucidate the (patho-)physiology of sensory gating mechanisms in PD. Nine PD patients with bilateral STN-DBS switched on (STN-DBS ON) or off (STN-DBS OFF) were studied during dynamic bladder filling and an empty bladder condition (for control), while changes in regional cerebral blood flow (rCBF) were measured by PET. Urinary bladder filling led to an increased rCBF in the periaqueductal grey (PAG), the posterior thalamus, the insular cortex as well as in the right frontal cortex and the cerebellum bilaterally. A significant interaction between bladder condition and STN-DBS was observed in the posterior thalamus and the insular cortex, with enhanced modulation of these areas during STN-DBS ON compared to STN-DBS OFF. Furthermore, regression analyses revealed a modulation of the neural activity in the thalamus and the insular cortex by the PAG activity during STN-DBS ON only. Thus, STN-DBS led to a significant enhancement of afferent urinary bladder information processing. The data suggest that STN-DBS facilitates the discrimination of different bodily states by supporting sensory perception and the underlying neural mechanisms. Furthermore, this is the first imaging study, which shows an effect of STN-DBS on sensory gating in PD patients and its neural basis.

Abstract: Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

Abstract: Deep brain stimulation (DBS) of the posterior hypothalamus was found to be effective in the treatment of drug-resistant chronic cluster headache. We report the results of a multicentre case series of six patients with chronic cluster headache in whom a DBS in the posterior hypothalamus was performed. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to published coordinates 2 mm lateral, 3 mm posterior and 5 mm inferior referenced to the mid-AC-PC line. Microelectrode recordings at the target revealed single unit activity with a mean discharge rate of 17 Hz (range 13-35 Hz, n = 4). Out of six patients, four showed a profound decrease of their attack frequency and pain intensity on the visual analogue scale during the first 6 months. Of these, one patient was attack free for 6 months under neurostimulation before returning to the baseline which led to abortion of the DBS. Two patients had experienced only a marginal, non-significant decrease within the first weeks under neurostimulation before returning to their former attack frequency. After a mean follow-up of 17 months, three patients are almost completely attack free, whereas three patients can be considered as treatment failures. The stimulation was well tolerated and stimulation-related side-effects were not observed on long term. DBS of the posterior inferior hypothalamus is an effective therapeutic option in a subset of patients. Future controlled multicentre trials will need to confirm this open-label experience and should help to better define predictive factors for non-responders.

Abstract: OBJECTIVES: To study the frequency of different gene mutations in patients with early-onset parkinsonism and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and the short- and long-term surgical outcome in mutation-positive (MUT+) and -negative (MUT-) patients. METHODS: Eighty patients with disease onset at age <or= 45 years and bilateral STN-DBS were screened for mutations in the Parkin gene and PINK1 gene and for the recurrent p.G2019S mutation in the LRRK2 gene. The Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (H-Y) scale were used to compare the on- and off-medication conditions preoperatively and in the off-medication/on-stimulation condition postoperatively. RESULTS: We identified 12 mutation carriers (11 Parkin [6 with 2 mutated alleles, 5 with 1 mutated allele], 1 homozygous PINK1). There were no clinical differences between the MUT- and MUT+ patients preoperatively, except for more severe H-Y stage and postural and gait scores in the on-medication state in the MUT+ group. During the first year after surgery, MUT- patients showed better clinical improvement (56% motor UPDRS improvement) compared with MUT+ patients (36%). However, in the long-term follow-up (3-6 years), both groups presented with the same degree of clinical improvement (MUT-: 44% vs MUT+: 42%). Although the MUT+ group showed more severe axial signs preoperatively, MUT- patients developed levodopa- and deep brain stimulation-resistant axial signs within the first 3 to 6 years postoperatively, which diminished the initial benefit soon after surgery. CONCLUSIONS: Patients with Parkin or PINK1 mutations benefit from subthalamic nucleus deep brain stimulation. However, the clinical response is not superior to non-mutation carriers and might be limited by more advanced axial motor symptoms at a relatively early disease stage.

Abstract: Deep brain stimulation (DBS) has gained increasing attention as a therapy for movement disorders. Neuropsychological alterations can accompany the disease evolution and medical therapy of PD. Also, interfering abruptly with the biological balance by means of a surgical intervention into complex circuits with motor but also cognitive and limbic functions, could potentially cause severe problems. Because cognitive or emotional impairments may have an even stronger impact on quality of life, than motor symptoms, care must be taken to perform surgery in the safest possible way to exclude adverse effects in these domains. Detailed neuropsychological evaluations may become helpful to further understand the mechanisms underlying some aspects of the clinical pictures both pre- and postoperatively and to define risk populations, that should be excluded from this intervention.

Abstract: We have previously shown that in patients with Parkinson's disease (PD), high-frequency stimulation (HFS) of the subthalamic nucleus (STN) modifies spinal excitability via subcortical reticulospinal routes. To investigate whether STN-HFS also modifies spinal excitability via transcortical routes in PD, 10 patients with PD (9 men, 1 woman; 58.3 +/- 8.3 years) were investigated in the medical OFF-state with or without STN-HFS. The H-reflex of the right soleus muscle was recorded during slight plantar flexion at 20% of maximum force. A conditioning transcranial stimulus was applied at 95% of active motor threshold to the contralateral primary motor leg area (M1) 0-5 ms after eliciting the H-reflex. The same paradigm was applied to 8 healthy individuals (5 men, 3 women; 50.8 +/- 3.0 years). Transcranial magnetic stimulation (TMS) facilitated the H-reflex amplitude in healthy controls. A facilitatory effect of the corticospinal input on the H-reflex was also found in patients with PD, but only with STN-HFS switched on. When STN-HFS was discontinued, the H-reflex was no longer facilitated by the TMS pulse. Accordingly, analysis of variance showed a main effect of stimulation (F = 11.15; P = 0.005), ISI (F = 6.1; P = 0.003), and an interaction between stimulation and group (PD vs. control) (F = 8.9; P = 0.01). STN-HFS restores the normal facilitatory drive of a transcranially evoked motor cortical response to the spinal motoneuron pool. In addition to subcortical routes, STN-DBS also alters spinal excitability via transcortical pathways.

Abstract: We recorded resting-state neuronal activity from the human subthalamic nucleus (STN) during functional stereotactic surgeries. By inserting up to five parallel microelectrodes for single- or multiunit recordings and applying statistical spike-sorting methods, we were able to isolate a total of 351 single units in 65 patients with Parkinson's disease (PD) and 33 single units in 9 patients suffering from essential tremor (ET). Among these were 93 pairs of simultaneously recorded neurons in PD and 17 in ET, which were detected either by the same (n = 30) or neighboring microelectrodes (n = 80). Essential tremor is a movement disorder without any known basal ganglia pathology and with normal dopaminergic brain function. By comparing the neuronal activity of the STN in patients suffering from PD and ET we intended to characterize, for the first time, changes of basal ganglia activity in the human disease state that had previously been described in animal models of Parkinson's disease. We found a significant increase in the mean firing rate of STN neurons in PD and a relatively larger fraction of neurons exhibiting burstlike activity compared with ET. The overall proportion of neurons exhibiting intrinsic oscillations or interneuronal synchronization as defined by significant spectral peaks in the auto- or cross-correlations functions did not differ between PD and ET when considering the entire frequency range of 1-100 Hz. The distribution of significant oscillations across the theta (1-8 Hz), alpha (8-12 Hz), beta (12-35 Hz), and gamma band (>35 Hz), however, was uneven in ET and PD, as indicated by a trend in Fisher's exact test (P = 0.05). Oscillations and pairwise synchronizations within the 12- to 35-Hz band were a unique feature of PD. Our results confirm the predictions of the rate model of Parkinson's disease. In addition, they emphasize abnormalities in the patterning and dynamics of neuronal discharges in the parkinsonian STN, which support current concepts of abnormal motor loop oscillations in Parkinson's disease.

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Abstract: OBJECTIVE: Postoperative monitoring of the electrode position is important to evaluate the best stimulation site in deep brain stimulation. MR imaging is excellent for ruling out postoperative complications e.g. haemorrhage, but its accuracy in electrode localisation is still controversial. The reasons for this are the size of the artefact around the electrode and its unclear relation to the electrode position (concentric or eccentric). The goal of this study was to determine the relation and size of these artefacts to the electrodes by comparing the position of the electrodes in postoperative MR and CT imaging. MATERIAL AND METHODS: Five patients underwent deep brain stimulation of the subthalamic nucleus due to levodopa-induced motor complications in Parkinson's disease. A stereotactic CT and a non-stereotactic MR were performed for postoperative localisation of the electrode position. The stereotactic MR for planning of the trajectories and targets was done under general anaesthesia. The latter two were fused to the stereotactic MR and the position of the DBS electrode contacts was determined on CT and MRI. The size of the artefact was measured at the level of each contact in two directions, anterior to posterior (AP) and lateral. Altogether 40 contacts were evaluated. RESULTS: Mean size of the CT-artefact was 2.6 mm AP (range, 2.0-3.2 mm) and 2.6 mm laterally (range, 2.0-3.8 mm). In comparison, mean size on the MRI was 3.5 mm AP (range, 2.9-5.3 mm) and 3.8 mm laterally (range, 2.9-4.8 mm). A trajectory with a 1.2 mm diameter (size of the DBS electrode) was centred on the electrodes' artefact of the CT and the MRI. The difference between the contact coordinates was calculated as deviation of the artefact around the electrode on the MR. Mean deviation was 0.2 mm on the x-axis (range, 0-0.5 mm), 0.5 mm on the y-axis (range, 0-1.1 mm) and 0.3 mm on the z-axis (range, 0-0.7 mm). There were no significant differences (t-test, p > 0.4). CONCLUSION: The size of the electrodes' artefact was smaller on CT compared to MR. Furthermore, the position was not precisely concentric around the electrode. Nevertheless, the mean deviation after measuring the contact position in both CT and MR was less than 1 mm in all three planes. Both techniques are eligible for postoperative localisation of DBS electrodes, with a small imprecision of the non-stereotactic MR compared to the stereotactic CT. This might be compensated by the fact that postoperative MR can rule out asymptomatic postoperative complications e.g. haemorrhages or infarctions, without radiation exposure of the patient.

Abstract: Dysfunctions of the autonomic nervous system (ANS) are common in Parkinson's disease (PD). Regarding motor disability, deep brain stimulation of the subthalamic nucleus (STN) is an effective treatment option in long lasting PD. The aims of this study were to examine whether STN stimulation has an influence on functions of the ANS and to compare these effects to those induced by levodopa. Blood pressure (BP) and heart rate (HR) during rest and orthostatic conditions, HR variability (HRV) and breathing-induced cutaneous sympathetic vasoconstriction (CVC) were tested in 14 PD patients treated with STN stimulation during "ON" and "OFF" condition of the stimulator. The effects of a single dose of levodopa on ANS were tested in 15 PD patients without DBS. STN stimulation had no influence on cardiovascular ANS functions, whereas CVC was significantly increased. In contrast, levodopa significantly lowered BP and HR at rest and enhanced orthostatic hypotension. Further, HRV, skin perfusion and temperature increased after administration of levodopa. Our results suggest that in contrast to levodopa, STN stimulation has only minor effects on autonomic functions. Since less pharmacotherapy is needed after STN stimulation, reduced levodopa intake results in relative improvement of autonomic function in deep brain stimulated PD patients.

Abstract: Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

Abstract: Chronic high-frequency stimulation of the subthalamic nucleus has evolved into a routine treatment for motor fluctuations, dyskinesia and medically refractory tremor in Parkinson's disease. The most important predictors for surgical benefit include excellent responsiveness of akinetic-rigid and axial motor symptoms to levodopa, a normal cognitive status and younger age. Current evidence suggests that for patients fulfilling these selection criteria deep brain stimulation of the subthalamic nucleus is superior to standard oral drug therapy in maintaining a good level of health-related quality of life.

Abstract: PURPOSE OF REVIEW: The clinical effectiveness and limitations of subthalamic nucleus deep brain stimulation for Parkinson's disease are summarized and recent developments concerning alternative brain targets for deep brain stimulation or restorative surgical therapies are discussed. RECENT FINDINGS: In a controlled study subthalamic nucleus deep brain stimulation was superior to best medical management in improving quality of life of patients with advanced Parkinson's disease. The benefits of the procedure on levodopa-sensitive motor symptoms are sustained for up to 5 years, but it does not halt disease progression. Cognitive decline and worsening of axial motor symptoms may limit the overall benefit. Age at the time of surgery is an important factor for long-term stability and safety. Psychosocial aspects of Parkinson's disease can profoundly impact on the ability of a patient to reintegrate after surgery and have to be considered in patient selection. Stimulation of the pedunculopontine nucleus may have an additive effect on postural and gait symptoms, which do not respond to levodopa or subthalamic nucleus deep brain stimulation. SUMMARY: Deep brain stimulation is emerging from an empirical to an evidence based therapy. The safety and efficacy of the procedure may legitimize surgery at a younger age before social maladjustment prevents reintegration of the patient into a normal life.

Abstract: In general, expressing emotions is beneficial and withholding emotions has personal and social costs. Yet, to serve social functions there are situations when emotions are withheld strategically. We examined whether social anxiety influenced when and how emotion expressiveness influences interpersonal closeness in existing romantic relationships. For people with greater social anxiety, withholding the expression of negative emotions was proposed to preserve romantic relationships and their benefits. We examined whether social anxiety and emotion expressiveness interacted to predict prospective changes in romantic relationship closeness over a 12-week period. For people with less social anxiety, relationship closeness was enhanced over time when negative emotions were openly expressed whereas relationship deterioration was found for those more likely to withhold emotions. The reverse pattern was found for people with greater social anxiety such that relationship closeness was enhanced over time for those more likely to withhold negative emotions. Related social anxiety findings were found for discrepancies between desired and actual feelings of closeness over time. Findings were not attributable to depressive symptoms. These results suggest that the costs and benefits of emotion expression are influenced by a person's degree of social anxiety.

Abstract: Rarely, the postoperative management of patients with subthalamic deep brain stimulation (STN-DBS) is complicated by pharmacologically intractable dyskinesias. Here we report that in three of these patients additional stimulation of a proximal contact located within the subthalamic white matter may lead to a significant reduction of dyskinesias associated with STN-DBS. We propose that pallidofugal fiber tracts play a major role in the etiopathology of dyskinesias and their blockade through DBS may explain our observations.

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Abstract: Numerous factors need to be taken into account when managing a patient with Parkinson's disease (PD) after deep brain stimulation (DBS). Questions such as when to begin programming, how to conduct a programming screen, how to assess the effects of programming, and how to titrate stimulation and medication for each of the targeted sites need to be addressed. Follow-up care should be determined, including patient adjustments of stimulation, timing of follow-up visits and telephone contact with the patient, and stimulation and medication conditions during the follow-up assessments. A management plan for problems that can arise after DBS such as weight gain, dyskinesia, axial symptoms, speech dysfunction, muscle contractions, paresthesia, eyelid, ocular and visual disturbances, and behavioral and cognitive problems should be developed. Long-term complications such as infection or erosion, loss of effect, intermittent stimulation, tolerance, and pain or discomfort can develop and need to be managed. Other factors that need consideration are social and job-related factors, development of dementia, general medical issues, and lifestyle changes. This report from the Consensus on Deep Brain Stimulation for Parkinson's Disease, a project commissioned by the Congress of Neurological Surgeons and the Movement Disorder Society, outlines answers to a series of questions developed to address all aspects of DBS postoperative management and decision-making with a systematic overview of the literature (until mid-2004) and by the expert opinion of the authors. The report has been endorsed by the Scientific Issues Committee of the Movement Disorder Society and the American Society of Stereotactic and Functional Neurosurgery.

Abstract: This study investigates the ability to use foreknowledge in preparation of cognitive processes in young and older participants and in PD patients. Additionally, we test the hypothesis that age-associated cognitive deficits in task switching reflect a dopaminergic dysfunction that accompanies healthy aging. To this end, we use a task-switching paradigm that (i) is known to be highly sensitive for dopaminergic dysfunction in the frontostriatal loops and (ii) can be applied with predictable and unpredictable switch and non-switch trials to assess the effect of task foreknowledge. Our results show that young participants benefit from foreknowledge and are thus able to prepare for predictable cognitive processes. Older participants have lost their ability to benefit from foreknowledge, which seems to be an effect of healthy aging. In predictable trials, the performance of PD patients did not differ from that of controls. Thus, PD patients do not show an additional deficit in the preparation of predictable cognitive switches. However, PD patients are specifically impaired in unpredictable trials compared to controls. We suggest that this result can be explained by the uncertainty about the next task in the unpredictable condition which prevents an automatic process and demands more attention. Furthermore, our results of older participants do not resemble the deficits seen in PD patients in task-switching behavior. This argues for different mechanisms that underlie the changes in task-switching behavior in healthy aging and PD.

Abstract: The clinical success of deep brain stimulation (DBS) for treating Parkinson's disease (PD) critically depends on the quality of postoperative neurological management. Movement disorder specialists becoming involved with this therapy need to acquire new skills to adapt optimally stimulation parameters and medication after implantation of a DBS system. At first glance, the infinite number of theoretically possible parameter combinations seems to make programming a complex and time-consuming art. This article outlines a stepwise and standardized approach, reducing the possible parameter settings in DBS to a few relevant combinations. The basic programming algorithms for thalamic, subthalamic, and pallidal stimulation in PD are explained and summarized in flowcharts.

Abstract: 3,4-Diaminopyridine (3,4-DAP) is a potassium channel blocker that has recently demonstrated an antioscillatory effect in humans by significantly reducing downbeat nystagmus. Based on the presumed role of intrinsic oscillations in the pathophysiology of essential tremor (ET), the authors conducted a double-blind, placebo-controlled crossover study assessing the antitremor effect of a single dose of 3,4-DAP in 19 patients with ET. They did not find any significant change in tremor severity as measured by clinical ratings or accelerometry.

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Abstract: Mutations in LRRK2 (leucine-rich repeat kinase 2) have been associated with autosomal dominant Parkinson's disease (PD) and cluster in several 3' exons of the gene. The majority of mutations have been detected in late-onset cases (age at onset >50 years). We screened 5 of the 51 exons of LRRK2 that previously have been reported to harbor mutations in 98 early-onset and 42 late-onset PD patients. We identified two mutations (c.4321C>T, c.6055G>A) in three early-onset patients. Screening of an additional 220 early-onset PD patients for these mutations revealed another mutation carrier. In conclusion, LRRK2 mutations need to be considered also in early-onset PD.

Abstract: Implicit memory and learning mechanisms are composed of multiple processes and systems. Previous studies demonstrated a basal ganglia involvement in purely cognitive tasks that form stimulus response habits by reinforcement learning such as implicit classification learning. We will test the basal ganglia influence on two cognitive implicit tasks previously described by Berry and Broadbent, the sugar production task and the personal interaction task. Furthermore, we will investigate the relationship between certain aspects of an executive dysfunction and implicit learning. To this end, we have tested 22 Parkinsonian patients and 22 age-matched controls on two implicit cognitive tasks, in which participants learned to control a complex system. They interacted with the system by choosing an input value and obtaining an output that was related in a complex manner to the input. The objective was to reach and maintain a specific target value across trials (dynamic system learning). The two tasks followed the same underlying complex rule but had different surface appearances. Subsequently, participants performed an executive test battery including the Stroop test, verbal fluency and the Wisconsin card sorting test (WCST). The results demonstrate intact implicit learning in patients, despite an executive dysfunction in the Parkinsonian group. They lead to the conclusion that the basal ganglia system affected in Parkinson's disease does not contribute to the implicit acquisition of a new cognitive skill. Furthermore, the Parkinsonian patients were able to reach a specific goal in an implicit learning context despite impaired goal directed behaviour in the WCST, a classic test of executive functions. These results demonstrate a functional independence of implicit cognitive skill learning and certain aspects of executive functions.

Abstract: BACKGROUND: Neurostimulation of the subthalamic nucleus reduces levodopa-related motor complications in advanced Parkinson's disease. We compared this treatment plus medication with medical management. METHODS: In this randomized-pairs trial, we enrolled 156 patients with advanced Parkinson's disease and severe motor symptoms. The primary end points were the changes from baseline to six months in the quality of life, as assessed by the Parkinson's Disease Questionnaire (PDQ-39), and the severity of symptoms without medication, according to the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III). RESULTS: Pairwise comparisons showed that neurostimulation, as compared with medication alone, caused greater improvements from baseline to six months in the PDQ-39 (50 of 78 pairs, P=0.02) and the UPDRS-III (55 of 78, P<0.001), with mean improvements of 9.5 and 19.6 points, respectively. Neurostimulation resulted in improvements of 24 to 38 percent in the PDQ-39 subscales for mobility, activities of daily living, emotional well-being, stigma, and bodily discomfort. Serious adverse events were more common with neurostimulation than with medication alone (13 percent vs. 4 percent, P<0.04) and included a fatal intracerebral hemorrhage. The overall frequency of adverse events was higher in the medication group (64 percent vs. 50 percent, P=0.08). CONCLUSIONS: In this six-month study of patients under 75 years of age with severe motor complications of Parkinson's disease, neurostimulation of the subthalamic nucleus was more effective than medical management alone. (ClinicalTrials.gov number, NCT00196911 [ClinicalTrials.gov].).

Abstract: Patients with Parkinson's disease frequently have mild to moderate depression and exhibit low hedonic tone. The authors investigate the impact of a single L-dopa challenge and the acute effects of electric stimulation of the subthalamic nucleus (STN) on symptoms of depression and hedonic tone. Depressive symptoms improved with L-dopa and STN stimulation to the same extent. However, hedonic tone improved only with L-dopa. Most of the emotional changes did not correlate with changes in motor performance, indicating they were not just reactive but specific to the treatment. These results demonstrate a single dissociation of depressive symptoms and anhedonia in response to an acute L-dopa and STN-stimulation challenge.

Abstract: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with onset in childhood and rapid progression. There is no causative and insufficient symptomatic drug therapy. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been reported to improve motor function. Most case reports, however, are limited to short observational periods. The impact of DBS on the progression and life expectancy in PKAN is unknown. We present a 5-year outcome and video documentation of bilateral GPi-DBS of an adolescent patient suffering from genetically defined PKAN.

Abstract: BACKGROUND: Neurostimulation of the internal globus pallidus has been shown to be effective in reducing symptoms of primary dystonia. We compared this surgical treatment with sham stimulation in a randomized, controlled clinical trial. METHODS: Forty patients with primary segmental or generalized dystonia received an implanted device for deep-brain stimulation and were randomly assigned to receive either neurostimulation or sham stimulation for 3 months. The primary end point was the change from baseline to 3 months in the severity of symptoms, according to the movement subscore on the Burke-Fahn-Marsden Dystonia Rating Scale (range, 0 to 120, with higher scores indicating greater impairment). Two investigators who were unaware of treatment status assessed the severity of dystonia by reviewing videotaped sessions. Subsequently, all patients received open-label neurostimulation; blinded assessment was repeated after 6 months of active treatment. RESULTS: Three months after randomization, the change from baseline in the mean (+/-SD) movement score was significantly greater in the neurostimulation group (-15.8+/-14.1 points) than in the sham-stimulation group (-1.4+/-3.8 points, P<0.001). During the open-label extension period, this improvement was sustained among patients originally assigned to the neurostimulation group, and patients in the sham-stimulation group had a similar benefit when they switched to active treatment. The combined analysis of the entire cohort after 6 months of neurostimulation revealed substantial improvement in all movement symptoms (except speech and swallowing), the level of disability, and quality of life, as compared with baseline scores. A total of 22 adverse events occurred in 19 patients, including 4 infections at the stimulator site and 1 lead dislodgment. The most frequent adverse event was dysarthria. CONCLUSIONS: Bilateral pallidal neurostimulation for 3 months was more effective than sham stimulation in patients with primary generalized or segmental dystonia. (ClinicalTrials.gov number, NCT00142259 [ClinicalTrials.gov].).

Abstract: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for off-period motor symptoms and dyskinesias in advanced Parkinson's disease. Clinical studies have shown that STN-DBS also ameliorates urinary bladder function in Parkinson's disease patients by delaying the first desire to void and increasing bladder capacity. This study aimed at investigating the effect of STN-DBS on the neural mechanisms underlying cerebral bladder control. Using PET to measure changes in regional cerebral blood flow (rCBF), 11 patients with bilateral STN-DBS were studied during urodynamic bladder filling in STN-DBS ON and OFF condition. A filled bladder led to a significant increase of rCBF in the anterior cingulate cortex, which was further enhanced during STN-DBS OFF. A significant interaction between bladder state and STN-DBS was observed in lateral frontal cortex with increased rCBF when the bladder was filled during STN-DBS OFF. The data suggest that STN-DBS ameliorates bladder dysfunction and that this modulation may result from facilitated processing of afferent bladder information.

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Abstract: Premutations in the FMR1 gene may be associated with some cases of parkinsonism. To test this hypothesis, we determined the CGG repeat number in FMR1 in 673 individuals with and without parkinsonism and detected 3 premutation carriers (2 patients, 1 control). Of note, 1 of the affected premutation carriers had a heterozygous Parkin mutation.

Abstract: We report on an unusual presentation of a task-specific focal oromandibular dystonia in a 47-year-old man of Turkish descent. His speech was affected exclusively while reciting Islamic prayers in Arabic language, which he otherwise did not speak.

Abstract: In five patients with medically refractory tardive dystonia, continuous bilateral high-frequency stimulation of the globus pallidus internus was associated with a rapid (within 12 to 72 hours) and substantial (mean 87%, 10.7 SD of the motor part of the Burke-Fahn-Marsden Dystonia Rating Scale) improvement of dystonia and functional disability without adverse events.

Abstract: During the last few years, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as a promising therapy, alleviating major motor symptoms of Parkinson's disease (PD). However, in times of growing budgetary limitations, medical decisions are no longer merely based on clinical efficacy, but also on cost-effectiveness. Here we assess treatment costs (i. e. costs for conservative pharmacological treatment and all in-patient admissions) of 46 PD patients for one year before and two years after STN-DBS. The present data show that total treatment costs were increased by 32% for the first year and decreased by 54% for the second year of STN-DBS in comparison with preoperative values while the Unified Parkinson's Disease Rating Scale (UPDRS III) was significantly improved. The increase for the first year after surgery was mainly due to the implantation of the STN electrodes and the stimulation device. Taken together, STNDBS pays off from the second year of stimulation while motor symptoms are significantly improved. The present study provides first data of an important number of patients on clinical effectiveness and expenses in relation to STNDBS.

Abstract: Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

Abstract: We present the results of continuous microelectrode recordings from individual pallidal neurons in patients with idiopathic torsion dystonia under different levels of propofol anesthesia. Neither the estimated plasma concentration of propofol nor the level of consciousness had a consistent effect on abnormally low neuronal firing rates. Our data support the pathophysiological model of a decreased basal ganglia output in dystonia and argue against a possible pharmacological artifact.

Abstract: Deep brain stimulation has gained increasing interest in the treatment of movement disorders. Presenting our clinical series of 179 patients operated upon since 1999, the indications, risks and benefits for the patients are discussed in order to further improve the techniques and their applications.

Abstract: OBJECTIVE: To study the effect of ethanol on gait in patients with essential tremor (ET). METHODS: Using a three-dimensional opto-electronic gait analysis system, the authors analyzed gait at free-speed walking, at a given velocity, and during tandem gait. Patients with ET with advanced disease were examined before and after a small oral dose of ethanol. The results of the patients with ET were compared with those from age-matched healthy controls (HCs). The primary outcome criteria were the number of missteps and the ataxia score during tandem gait. RESULTS: Before alcohol, patients with ET had more missteps and an abnormal ataxia score compared with HCs. The ingestion of alcohol with a mean blood level of 0.45% led to a significant improvement of the ataxia score and the number of missteps. HCs showed a worsening of the ataxia score and an increase of the number of missteps after alcohol, which failed to reach significance. CONCLUSIONS: Orally administered ethanol improved gait ataxia in patients with essential tremor (ET). This may reflect a reversible effect of ethanol on receptors being involved in the pathology of ET. Ethanol may act via an influence of the inferior olive or directly on alcohol-sensitive gamma-aminobutyric acid receptors within the cerebellum.

Abstract: OBJECTIVE: High-frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a new and promising treatment option for severe dystonia. Yet only few studies have been published to date regarding this treatment. We present the results of DBS of the GPi in 17 patients with severe dystonia of different causes. METHODS: In our study, we included 10 patients with primary generalized dystonia, six patients with secondary generalized dystonia, and one patient with a severe dystonic cervical tremor. In all patients, DBS electrodes were implanted bilaterally within the GPi. Mean follow-up time was 36 months (range, 12-66 mo). Preoperative and postoperative evaluations (at least annually) were performed using the Burk-Fahn-Marsden scale. RESULTS: The best improvement was achieved in patients with DYT1-positive dystonia. Patients with DYT1-negative generalized dystonia showed inhomogeneous results. There was no significant change in patients with tardive dystonia. One case of Hallervorden-Spatz disease improved dramatically within the first 2 years. The improvement in the cervical dystonic tremor was disappointing, however. Three years after DBS implantation, we found a secondary worsening of symptoms in one patient with a DYT1-positive dystonia and in the patient with Hallervorden-Spatz disease. CONCLUSION: DBS of the GPi is a new and promising treatment option for dystonia. Secondary worsening may limit this therapy.

Abstract: BACKGROUND: Recent animal experiments suggest an important role of descending input from basal ganglia to brainstem and via the reticulospinal tract (RST) to spinal cord in the genesis of motor symptoms in Parkinson disease (PD). In humans, a marker for RST activity is Ib mediated autogenic inhibition, which is reduced in PD patients. The authors investigated the effect of high frequency stimulation of the subthalamic nucleus (STN-HFS) on autogenic inhibition in PD. METHODS: In 10 controls and 10 PD patients with chronically implanted STN electrodes, the soleus H-reflex conditioned by gastrocnemius nerve stimulation (interstimulus interval 2 to 10 msec) was used to examine the effect of STN-HFS on the activity of Ib spinal interneurons. RESULTS: STN-HFS was able to restore the abnormally reduced autogenic inhibition. The H-reflex changes during STN-HFS significantly correlated with the clinical improvement of gait and posture. CONCLUSIONS: Observed changes in spinal autogenic inhibition may allow measurement of the contribution of subcortical routes to the STN-HFS induced motor benefit in PD.

Abstract: BACKGROUND: The pathophysiologic mechanism underlying psychogenic tremor is not clear. Continuous voluntary production of tremor may be uncovered by a positive entrainment of tremor in different limbs. But some patients have tremor ongoing during their waking time which is unlikely to be produced voluntarily. Therefore, nonvoluntary physiologic oscillatory mechanisms must be considered. METHODS: Fifteen patients with psychogenic tremor manifesting in both hands, who were diagnosed using established criteria, were examined. Postural tremor was recorded with accelerometry and electromyography (EMG) while the hands were held against gravity. Power spectral peak frequencies and accelerometric total power as a measure of amplitude were determined. Coherency spectra between the EMG signals from the right and left arm were calculated. RESULTS: Seven of 15 patients showed a significant coherency between the two hands; the remaining 8 patients maintained independent oscillations. Clinical presentation, tremor frequencies, and amplitudes were not significantly different between the two groups. CONCLUSIONS: Two different pathogenetic mechanisms may play a role in psychogenic tremor. Bilateral voluntary movements are typically coherent. Thus, coherent psychogenic tremor would be in keeping with voluntarily produced oscillations. Absent coherence is an indication of another, possibly nonvoluntary mechanism like clonus or enhanced physiologic tremor.

Abstract: OBJECTIVES: Sporadic (SSP) and hereditary spastic paraplegias (HSP) are clinically and genetically heterogeneous disorders, which are characterised by a slowly progressive spastic paraparesis. Initial symptoms and the rate of progression are variable even among members of the same family. Spastic paraparesis is the major and most disabling clinical symptom and was assessed with gait analysis using a three-dimensional infrared movement analysis system. METHODS AND RESULTS: 22 patients with clinically and/or genetically confirmed SSP/HSP were compared with age-matched control subjects. Significantly lower values were found for gait velocity, stride length, step height and the range of motion of the knee-angle. The gait pattern is characterised by a severe spasticity of both legs with only mild paresis. The balance-related gait parameters show a broad-based gait without inwardly rotated feet. No correlation was found between disease duration and the severity of the gait disorder and the central motor conduction time to the leg muscles and the abnormal gait parameters. The gait pattern did not differ between the 7 SSP cases and the 15 HSP cases. CONCLUSIONS: We conclude that three-dimensional gait analysis can uncover specific features of such rare gait disorders, and may be used as an objective tool to quantify the impairment of gait parameters in patients with SSP/HSP and thus can be used to monitor disease progression and the effect of therapeutic interventions.

Abstract: The optimal stimulation site in subthalamic deep brain stimulation (STN-DBS) was evaluated by correlation of the stereotactic position of the stimulation electrode with the electrophysiologically specified dorsal STN border. In a series of 25 electrodes, best clinical results with least energy consumption were found in contacts located in the dorsolateral border zone, whereas contacts within the subthalamic white matter, e.g., zona incerta, were significantly less effective. We suggest that the dorsolateral STN border should be covered by STN-DBS.

Abstract: Depression occurs in approximately 45% of all patients with Parkinson's disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.

Abstract: Detrusor hyperreflexia is a relevant clinical symptom for patients suffering from Parkinson's disease. In a series of 16 patients, we demonstrated that subthalamic deep brain stimulation has a significant and urodynamically recordable effect leading to a normalization of pathologically increased bladder sensibility.

Abstract: Approximately 25% of patients with idiopathic Parkinson's disease (IPD) later develop dementia, with the typical characteristics as detailed in ICD-10 and DSM-IV. Differential diagnosis has to exclude dementia due to Lewy bodies, subcortical vascular encephalopathy and subcortical dementia due to progressive supranuclear paralysis or corticobasal degeneration. Several studies showed promising results for cholinesterase inhibitors such as donepezile, rivastigmine and galantamine. The demented Parkinsonian patients then present with improvement in cognitive function while motor skills do not deteriorate.

Abstract: We followed up 11 patients for up to 5 years after bilateral pallidal deep brain stimulation for advanced Parkinson's disease. Dyskinesias remained significantly reduced until the last assessment. The initial improvement of off-period motor symptoms and fluctuations, however, was not sustained and gradually declined. Beneficial effects of pallidal deep brain stimulation on activities of daily living in the on- and off-period were lost after the first year. Replacement of pallidal electrodes into the subthalamic nucleus in four patients could restore the initial benefit of deep brain stimulation and allowed a significant reduction of dopaminergic drug therapy.

Abstract: Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.

Abstract: BACKGROUND: The subthalamic nucleus is the preferred target for deep brain stimulation in patients with advanced Parkinson's disease. The site of permanent stimulation is the subject of ongoing debate, as stimulation both within and adjacent to the subthalamic nucleus may be effective. OBJECTIVE: To assess the position of active electrode contacts in relation to the dorsal margin of the subthalamic nucleus as determined by intraoperative microrecordings and magnetic resonance imaging (MRI). METHODS: In 25 patients suffering from severe levodopa sensitive parkinsonism, deep brain stimulating electrodes (n = 49) were implanted following mapping of the subthalamic nucleus by microrecording and microstimulation along five parallel tracks. Postoperative stereotactic radiography and fusion of pre- and postoperative MRI studies were used to determine the stereotactic position relative to the midcommissural point of the most effective electrode contacts selected for permanent stimulation (n = 49). Intraoperative microrecordings were analysed retrospectively to define the dorsal margin of the subthalamic nucleus. In cases where the dorsal margin could be defined in at least three microrecording tracks (n = 37) it was correlated with the position of the active contact using an algorithm developed for direct three dimensional comparisons. RESULTS: Stimulation of the subthalamic nucleus resulted in marked improvement in levodopa sensitive parkinsonian symptoms and levodopa induced dyskinesias, with significant improvement in UPDRS III scores. In several instances, projection of the electrode artefacts onto the T2 weighted MRI visualised subthalamic nucleus of individual patients suggested that the electrodes had passed through the subthalamic nucleus. When the actual position of active electrode contacts (n = 35) was correlated with the dorsal margin of the subthalamic nucleus as defined neurophysiologically, most contacts were located either in proximity (+/- 1.0 mm) to the dorsal border of the subthalamic nucleus (32.4%) or further dorsal within the subthalamic region (37.8%). The other active contacts (29.7%) were detected within the dorsal (sensorimotor) subthalamic nucleus. The average position of all active contacts (n = 49) was 12.8 mm (+/- 1.0) lateral, 1.9 mm (+/- 1.4) posterior, and 1.6 mm (+/- 2.1) ventral to the midcommissural point. CONCLUSIONS: Subthalamic nucleus stimulation appears to be most effective in the border area between the upper subthalamic nucleus (sensorimotor part) and the subthalamic area containing the zona incerta, fields of Forel, and subthalamic nucleus projections.

Abstract: BACKGROUND: High-frequency electrical stimulation of the subthalamic nucleus is a new and highly effective therapy for complications of long-term levodopa therapy and motor symptoms in advanced Parkinson disease (PD). Clinical observations indicate additional influence on emotional behavior. METHODS: Electrical stimulation of deep brain nuclei with pulse rates above 100 Hz provokes a reversible, lesioning-like effect. Here, the effect of deep brain stimulation of the subthalamic nucleus on emotional, cognitive, and motor performance in patients with PD (n = 12) was examined. The results were compared with the effects of a suprathreshold dose of levodopa intended to transiently restore striatal dopamine deficiency. Patients were tested during medication off/stimulation off (STIM OFF), medication off/stimulation on (STIM ON), and during the best motor state after taking levodopa without deep brain stimulation (MED). RESULTS: More positive self-reported mood and an enhanced mood induction effect as well as improvement in emotional memory during STIM ON were observed, while during STIM OFF, patients revealed reduced emotional performance. Comparable effects were revealed by STIM ON and MED. Cognitive performance was not affected by the different conditions and treatments. CONCLUSIONS: Deep brain stimulation of the subthalamic nucleus selectively enhanced affective processing and subjective well-being and seemed to be antidepressive. Levodopa and deep brain stimulation had similar effects on emotion. This finding may provide new clues about the neurobiologic bases of emotion and mood disorders, and it illustrates the important role of the basal ganglia and the dopaminergic system in emotional processing in addition to the well-known motor and cognitive functions.

Abstract: DBS of the STN is one of the most promising new therapies for the treatment of PD. However - like many other therapies for PD - the present stage of the scientific assessment does not yet suffice the rigid criteria of evidence-based medicine. Further studies should specifically address the questions of efficacy and side effects as well as the impact on quality of life.

Abstract: We studied 48 patients after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) who were evaluated 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS) in a standardized levodopa test. Additional follow-up was available in 32 patients after 12 months and in 20 patients after 24 months. At 6 months follow-up, STN-DBS reduced the UPDRS motor score by 50.9% compared to baseline. This improvement remained constant at 12 months with 57.5% and at 24 months with 57.3%. Relevant side effects after STN-DBS included intraoperative subdural hematoma without neurological sequelae (n = 1), minor intracerebral bleeding with slight transient hemiparesis (n = 1), dislocation of impulse generator (n = 2), transient perioperative confusional symptoms (n = 7), psychotic symptoms (n = 2), depression (n = 5), hypomanic behaviour (n = 2), and transient manic psychosis (n = 1). One patient died because of heart failure during the first postoperative year. The current series demonstrates efficacy and safety of STN-DBS beyond the first year after surgical procedure. Complications of STN-DBS comprise a wide range of psychiatric adverse events which, however, were temporary.

Abstract: Data from experiments in MPTP monkeys as well as from invasive and non-invasive recordings in patients with Parkinson's disease suggest an abnormal synchronization of neuronal activity in the generation of resting tremor in Parkinson's disease. In six patients with tremor-dominant idiopathic Parkinson's disease, we recorded simultaneously surface electromyograms (EMGs) of hand muscles, and brain activity with a whole-head magnetoencephalography (MEG) system. Using a recently developed analysis tool (Dynamic Imaging of Coherent Sources; DICS), we determined cerebro-muscular and cerebro-cerebral coherence as well as the partial coherence between cerebral areas and muscle, and localized coherent sources within the individual MRI scans. The phase lag between the EMG and cerebral activity was determined by means of a Hilbert transform of both signals. After overnight withdrawal from medication, patients showed typical Parkinson's disease resting tremor (4-6 Hz). This tremor was associated with strong coherence between the EMG of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Phase lags between M1 activity and EMG were between 15 and 25 ms (M1 activity leading) at single, but also at double tremor frequency, corresponding well to the corticomuscular conduction time. Furthermore, significant coherence was observed between M1 and medial wall areas (cingulate/supplementary motor area; CMA/SMA), lateral premotor cortex (PM), diencephalon, secondary somatosensory cortex (SII), posterior parietal cortex (PPC) and the contralateral cerebellum at single tremor and, even stronger at double tremor frequency. Spectra of coherence between thalamic activity and cerebellum as well as several brain areas revealed additional broad peaks around 20 Hz. Power spectral analysis of activity in all central areas indicated the strongest frequency components at double tremor frequency. Partial coherence analysis and the calculation of phase shifts revealed a strong bidirectional coupling between the EMG and diencephalic activity and a direct afferent coupling between the EMG and SII and the PPC. In contrast, the cerebellum, SMA/CMA and PM show little evidence for direct coupling with the peripheral EMG but seem to be connected with the periphery via other cerebral areas (e.g. M1). In summary, our results demonstrate tremor-related oscillatory activity within a cerebral network, with abnormal coupling in a cerebello-diencephalic-cortical loop and cortical motor (M1, SMA/CMA, PM) and sensory (SII, PPC) areas contralateral to the tremor hand. The main frequency of cerebro-cerebral coupling corresponds to double the tremor frequency.

Abstract: OBJECTIVE: To assess the effects on motor functioning, health status and direct medical costs of high-frequency stimulation of the subthalamic nucleus (DBS-STN) in patients with idiopathic Parkinson's disease (PD). In addition, the cost-effectiveness of DBS-STN vs. drug treatment was investigated. METHODS: 16 consecutive patients with PD from two centers (Düsseldorf/Cologne; Kiel) treated by DBS-STN were prospectively evaluated. Clinical evaluations were done at baseline and 1, 3, 6, 12 months following surgery by means of the Unified Parkinson's disease Rating Scale (UPDRS). Health status of PD patients was assessed using the Sickness Impact Profile (SIP) at baseline and 6 months following surgery. Relevant economic data were taken from the medical records and costs (1999) were derived from different German medical economic resources. Costs were determined from the perspective of the health care provider. RESULTS: Following DBS-STN UPDRS scores (subscores and sum score) as well as health status improved considerably in PD patients. The overall SIP score and the physical dimension score (p < 0.009) were significantly different (p < 0.01) six month after surgery compared with baseline values. Mean costs of DM 40,020 (US dollars 20,810, EURO 20,410, GB pounds 12,810) per patient were spent during the 12 month observation period for in-patient and out-patient care. These expenses included already the costs for the electronic device for bilateral stimulation. Following DBS-STN medication was considerably reduced. Mean daily drug costs at baseline were DM 46.7+/-21.8 (US dollars 24, EURO 24, GB pounds 15) and DM 18.3+/-17.7 (US dollars 10, EURO 9, GB pounds 6) at 12 months following DBS-STN. Accounting for the decreased drug consumption, total annual costs amounted to DM 31,400 (US dollars 16,330, EURO 16,010, GB pounds 10,050). Further, we estimated the incremental cost effectiveness as DBS-STN had higher costs but was more effective than baseline treatment. The incremental total cost-effectiveness ratio for DBS-STN was DM 1.800 (US dollars 940, EURO 920, GB pounds 580) for one point decrease of the UPDRS. CONCLUSION: DBS-STN is an effective treatment that considerably alleviates the severity of signs and symptoms and improves the health status of patients with PD. Compared with drug treatment, however, the expenditures associated with DBS-STN are increased when only direct medical costs are considered in a one year horizon. However, on a long-term basis costs will decrease considerably because of the reduction of the drug expenditure and improved functioning in all activities of daily living. To adequately evaluate the cost-effectiveness of DBS-STN compared with standard drug regimen for PD it is necessary to include direct, indirect and intangible costs on a long-term basis and under standardized circumstances.

Abstract: Deep brain stimulation (DBS) has developed into an established therapy for the treatment of movement disorders, most commonly Parkinson's disease and tremor of different etiology. The subthalamic nucleus (STN) has evolved as the preferred target for DBS in patients with idiopathic Parkinson's disease. The principal target for DBS in tremor patients is the ventrolateral thalamus which has been explored for ablative procedures (thalamotomy) for some decades. Detailed information about the exact site of chronic stimulation, i.e. the location of the active electrode contacts, are important to map the actual subcortical structures modulating the therapeutic effects of DBS. We compared two different methods not requiring intra-operative teleradiography to determine the stereotactic coordinates of single electrode contacts, (i) correlation of pre- and post-operative MRI, and (ii) post-operative stereotactic skull x-ray. For seven patients implanted bilateral with quadripolar DBS electrodes the coordinates for each contact were determined by both approaches. This revealed for a total of 56 electrode contacts a median euclidean 3D-difference between both methods of 1.18 mm (range 0.42 to 1.93 mm). These data suggest that both approaches may be used to determine the position of single electrode contacts.

Abstract: Basal ganglia-thalamocortical circuits play an important role in movement preparation and execution. Tracer, single-cell, and lesion studies in monkeys suggest the existence of topologically segregated motor and nonmotor basal ganglia cortical circuits. In this study we used deep brain stimulation (DBS) of the posteroventrolateral globus pallidus internus (GPi) in patients with Parkinson's disease to elucidate the function of the GPi in human sensorimotor behavior. This question was investigated by comparing the influence of DBS on patients' performance in various reaction-time tasks that differed with respect to cognitive but not motor requirements. As a main result, DBS improved performance on the different tasks independently of the complexity of the involved cognitive processing functions. Furthermore, the observed effects did not depend on the modality of the processed information. These results suggest that the functional state of the posteroventrolateral GPi selectively affects the motor stage in simple sensorimotor acts, because this stage was the only stage involved in all investigated tasks. In addition to DBS, we manipulated the levodopa medication state of the PD patients. In contrast to DBS, levodopa effects on reaction times were less consistent. Levodopa improved reaction times in choice reaction tasks significantly, while affecting reaction times in a simple reaction task to a lesser extent. Error analysis revealed that the medication-dependent reaction-time improvement in the choice reaction tasks was accompanied by an increase in errors, suggesting a shift of the speed-accuracy criteria of the patients. A similar pattern of results was not observed for the DBS effects. Taken together, our data are in agreement with recent findings in monkeys that indicate a topological organization of the GPi in which motor functions are localized in posterolateral regions apart from cognitive regions. Furthermore, our data show a way to uncover the subcortical-cortical circuitry serving human sensorimotor behavior.

Abstract: The clinical success of deep brain stimulation (DBS) for treating Parkinson's disease, tremor, or dystonia critically depends on the quality of postoperative neurologic management. Movement disorder specialists becoming involved with this therapy need to acquire new skills to optimally adapt stimulation parameters and medication after implantation of a DBS system. In clinical practice, the infinite number of possible parameter settings in DBS can be reduced to few relevant combinations. In this article, the authors describe a general scheme of selecting stimulation parameters in DBS and provide clinical and neurophysiological arguments for such a standardized algorithm. They also describe noninvasive technical trouble shooting by using programming features of the commercially available neurostimulation devices.

Abstract: Deep brain stimulation (DBS) for dystonia still needs to be considered investigational, because there are no controlled studies for this indication, the optimal target point is uncertain, and long-term effects are unknown. The striking improvement of levodopa-induced dyskinesias in Parkinson's disease by deep brain stimulation of the internal pallidum has encouraged the use of this therapy for generalized and severe segmental dystonia in children and adults. Single case and small cohort studies have reported impressive efficacy of pallidal DBS in patients with primary dystonia, especially DYT1 mutation carriers, but results in secondary dystonia are less conclusive. This article discusses the different factors influencing patient selection for surgical treatment and describes standardized methods and the caveats for clinical documentation of treatment results in dystonia.

Abstract: The two principle targets for deep brain stimulation or lesioning in patients with Parkinson's disease, the subthalamic nucleus (STN) and the globus pallidus internus (GPi), reveal a high degree of individual variability which is relevant to the planning of stereotactic operations. Both nuclei can clearly be delineated in T2WI spin echo MRI which was acquired under stereotactic conditions in general anesthesia before surgery. Such images of 35 patients served for retrospective morphometric analysis of different basal ganglia nuclei (STN, GP, red nucleus, and substantia nigra) and several anatomical landmarks (anterior and posterior commissure, maximum width of third ventricle, brain length and width). The average AC-PC distance was 25.74 mm (range 21 to 29 mm) and is in agreement with previous studies. On average, the center of the STN was located 12.65 mm (+/-1.3) lateral from the midline as determined 3 mm ventral to the intercommissural plane. The average width of the third ventricle was 7.05 mm (+/-2.41). The width of the third ventricle correlated with the laterality of the STN (r(right)=.78; r(left)=.83) and GP (r(right)=.76; r(left)=.68). Although to a lesser extent, significant correlations were also observed between the laterality of the STN and brain width, improving prediction of STN laterality by multiple linear regression analysis (r(right)=.82; r(left)=.87). Similarly, the laterality of GP correlated with brain width. In addition, gender-specific differences were detected. The STN and GP was located farther lateral in males which may be due to overall brain anatomy as gender-specific differences were also observed for brain width and length and AC-PC distance. MRI-based in vivo-localization of different basal ganglia nuclei extend statistical information from common histological brain atlases which are based on a limited number of brains. The correlations observed between different basal ganglia nuclei, i.e. the STN and GPi, and anatomical landmarks may be useful for surgical planning.

Abstract: OBJECT: The goal of this study was to relate the degree of clinical improvement and that of energy consumption to the anatomical position of electrode poles used for long-term stimulation. METHODS: The authors conducted a retrospective analysis of 15 consecutive patients in whom targeting of the subthalamic nucleus (STN) had been performed using ventriculography, three-dimensional (3D) magnetic resonance (MR) imaging, and 3D computerized tomography, together with macrostimulation and teleradiographic control of the electrode position. In these patients the follow-up period ranged from 6 to 12 months. Postoperative improvement in contralateral motor symptoms, which was assessed by assigning a lateralized motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRS), and stimulus intensity required for optimal treatment results were correlated with the intracerebral position of the active electrode pole. Bilateral high-frequency stimulation of the STN improved the UPDRS motor score during the medication-off period by an average of 60.5% compared with that at baseline. Repeated transfer of stereotactic coordinates from postoperative teleradiography to treatment-planning MR images documented the proper localization of the most distal electrode pole (pole 0) in the targeted STN. Nevertheless, in most cases the best clinical improvement was achieved using electrode poles that were located several millimeters above the electrode tip. If the relative improvement in motor symptoms was correlated with the required electrical energy for chronic stimulation, the best coefficient was observed for active electrode poles projecting onto white matter dorsal to the STN. CONCLUSIONS: This observation makes blocking or activation of large fiber connections arising in the STN or running nearby more likely than electrical interference with cell bodies inside the STN. Anatomical correlates may be the pallidothalamic bundle (including Field H of Forel and the thalamic fascicle), the pallidosubthalamic tract, and/or the zona incerta.

Abstract: Deep brain simulation (DBS) is a powerful new therapeutic approach for patients with Parkinson's disease. However, patient selection is critical for a valuable therapeutic result. Dopa sensitivity of the target symptoms, severe disability and low neurosurgical risks are among the major criteria for this indication. Other criteria like age or cognition must still be addressed in future prospective studies. The preferred target for DBS in PD is the subthalamic nucleus for various good reasons. However, prospective studies for this procedure are lacking and some clinical problems may be more easily solved with targeting the internal pallidum or the thalamus. Despite major progress in this field, much work remains to be done.

Abstract: Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Abstract: With a growing number of patients treated with deep brain stimulation (DBS) operations for both hardware-related complications and routine replacements of impulse generators will be performed more frequently. Failure of DBS systems have to be analyzed thoroughly as this thwarts the enormous efforts required for proper electrode implantation and operative revisions increase the morbidity associated with DBS. A female patient implanted with DBS electrodes for advanced Parkinson's disease presented with straining of the right extension lead and deteriorating gait because of electrode migration. This was due to a malpositioned set screw connector adapting the electrode lead to the extension wire which had been placed below the mastoid process. Following surgical revision with implantation of a new electrode into the STN, electrode dislocation recurred requiring another surgical revision. This was due to renewed connector migration from its parietal position into the cervical region. Straining of extension leads should be recognized as a warning sign for (imminent) electrode dislocation or lead fracture. This may just be the case with connectors located below the mastoid process or in the cervical region, a risk which appears to be increased further with reduced-length extensions. Renewed dislocation of revised extensions may be prevented by securing the position of the connector (e.g. with manipulates).

Abstract: We report the failure of bilateral globus pallidus internus deep brain stimulation to improve chorea in a patient with chorea-acanthocytosis. Prior to this surgery the patient had experienced a striking but short lived amelioration of symptoms with clozapine therapy.

Abstract: Bilateral high-frequency stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) both alleviate akinesia, rigidity, and tremor in idiopathic Parkinson's disease. To test the specific effect of these procedures on gait, we used quantitative gait analysis in addition to relevant subscores of the Unified Parkinson's Disease Rating Scale in a group of 10 patients with advanced Parkinson's disease treated by GPi stimulation and eight patients treated by STN stimulation. Patients were assessed before and 3 months after surgery. Thirty age-matched healthy subjects served as controls. The non-random selection allowed a descriptive but no direct statistical comparison of the respective procedure. Gait analysis showed significant stimulation-induced improvements of spatiotemporal gait and step parameters in both patient groups. Moreover, the effects on step length and cadence suggested a differential effect of both basal ganglia targets. Hence, the increase in gait velocity in the STN group was almost exclusively due to a significant increase in step length, while in the GPi group statistically non-significant increases in both step length and cadence contributed.

Abstract: The authors retrospectively compared 1-year results of bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN; n = 16) and internal pallidum (GPi) (n = 11) in advanced PD and found about equal improvements in "off" period motor symptoms, dyskinesias, and fluctuations. STN stimulation reduced medication requirements by 65% and required significantly less electrical power. These advantages contrasted with a need for more intensive postoperative monitoring and a higher incidence of adverse events related to levodopa withdrawal.

Abstract: OBJECTIVE: To investigate the cerebral metabolic and functional patterns during recovery from cortical blindness. DESIGN: Follow-up study with serial clinical, metabolic, and functional imaging and visual evoked potentials. CASE PRESENTATION: A 24-year-old woman suffered from cortical blindness after cardiac arrest and recovered over a 6-month period. During recovery, she experienced complex visual hallucinations that could be initiated by visual imagery. RESULTS: Initially, the regional cerebral metabolic rate of glucose was severely reduced in the visual and parieto-occipital cortex bilaterally but recovered almost completely. Visual hallucinations led to significant increases of the regional cerebral blood flow in the initially severely hypometabolic parieto-occipital and temporo-lateral cortex. CONCLUSIONS: Recovery of vision was related to normalization of the postlesionally dysfunctional cortex. Visual hallucinations appeared as the clinical correlate of the electrophysiological hyperexcitability of the recovering partially damaged visual cortex.

Abstract: We investigated the neuromagnetic responses to mechanical stimulation of the oesophagus. In six healthy right-handed volunteers (mean age 31.6 years) the proximal and distal oesophagus were stimulated by electronically controlled pump-inflation of a silicone balloon once every 4.5-5.5 sec (dwell time 145 msec). The balloon volume was adjusted to induce different sensation levels (i) just above threshold of perception, (ii) strong sensation and (iii) painful sensation. Evoked magnetic brain responses were recorded time-locked to stimulus onset with a Neuromag-122TM whole-head neuromagnetometer and modelled as equivalent current diploe (ECD) sources. ECDs were superimposed on individual magnetic resonance imaging (MRI) scans. Magnetic brain responses following distal oesophageal stimulation were adequately explained by a time-varying 2-4 dipole model with unilateral or bilateral sources in second somatosensory cortex and later sources in the frontal cortex. With increasing stimulus intensities, latencies of the sources decreased and amplitudes increased. Proximal oesophageal stimulation led to activation of source areas spatially similar to those of distal oesophageal stimulation but with shorter response latencies. Both painful and nonpainful mechanical stimulation of the oesophagus activate the second somatosensory cortex (SII). Evidence for topographic organization of oesophageal afferents in SII is poor.

Abstract: Sensory stimuli from the visceral domain exhibit perceptual characteristics different from stimuli applied to the body surface. Compared with somatosensation there is not much known about the cortical projection and functional organization of visceral sensation in humans. In this study, we determined the cortical areas activated by non-painful electrical stimulation of visceral afferents in the distal oesophagus, and somatosensory afferents in the median nerve and the lip in seven healthy volunteers using whole-head magnetoencephalography. Stimulation of somatosensory afferents elicited short-latency responses (approximately 20-60 ms) in the primary somatosensory cortex (SI) contralateral (median nerve) or bilateral (lip) to the stimulated side, and long-latency responses (approximately 60-160 ms) bilaterally in the second somatosensory cortex (SII). In contrast, stimulation of visceral oesophageal afferents did not evoke discernible responses in SI but well reproducible bilateral SII responses (approximately 70-190 ms) in close vicinity to long-latency SII responses following median nerve and lip stimuli. Psychophysically, temporal discrimination of successive stimuli became worse with increasing stimulus repetition rates (0.25 Hz, 0.5 Hz, 1 Hz, 2 Hz) only for visceral oesophageal, but not for somatosensory median nerve stimuli. Correspondingly, amplitudes of the first cortical response to oesophageal stimulation emerging in the SII cortex declined with increasing stimulus repetition rates whereas the earliest cortical response elicited by median nerve stimuli (20 ms SI response) remained unaffected by the stimulus frequency. Our results indicate that visceral afferents from the oesophagus primarily project to the SII cortex and, unlike somatosensory afferents, lack a significant SI representation. We propose that this cortical projection pattern forms the neurophysiological basis of the low temporal and spatial resolution of conscious visceral sensation.

Abstract: Neurons in the human brain, especially in thalamic nuclei and the cerebral cortex, exhibit intrinsic membrane oscillations, which may be synchronized into network oscillations and form the macroscopic rhythms detectable with electroencephalography (EEG) and magnetoencephalography (MEG). Recent data also suggest that certain neurologic disorders may be associated with the occurrence of pathologically synchronized oscillatory brain activity. Human tremors may be the behavioral correlate of such abnormal brain rhythms. This article summarizes the current literature about sensorimotor oscillatory activity in people recorded by MEG and discusses the possible functional significance of the findings for motor control in health and disease.

Abstract: In the past decade there has been a resurgence of interest in neurosurgical interventions for the treatment of medically intractable Parkinson's disease. The reasons for this development include improved surgical techniques, a better understanding of the pathophysiology of Parkinson's disease providing the scientific rationale for such interventions, and the clinical problems of long-term levodopa treatment. Among the modern stereotactic procedures that are now available for the treatment of patients with advanced Parkinson's disease and levodopa-induced side effects, the effects of pallidotomy are best studied. More recently, chronic high-frequency stimulation of the internal pallidum and subthalamic nucleus have been proposed as surgical alternatives. This article reviews the most recent reports concerning the indication and results of stereotactic surgery for the treatment of advanced Parkinson's disease.

Abstract: We report here the results of an open prospective study in 9 patients suffering from severe Parkinson's disease with on/off fluctuations and restricted off-period mobility, who underwent bilateral implantation of stimulating electrodes in the internal pallidum. At 3-month follow-up, the total Unified Parkinson's Disease Rating Scale (UPDRS) motor score in the medication-off state was reduced from 54.1+/-14.8 to 23.9+/-11.7 (44.2%) when stimulation was turned on. Comparison of UPDRS subscores revealed significant improvements for tremor, rigidity, bradykinesia, gait and posture, and dyskinesias. The results of the clinical scoring could be confirmed by significant changes in the quantitative assessment of hand function and walking. Bilateral pallidal stimulation reduced the amount and severity of on/off fluctuations. Additional follow-up at 6 months (n=6), 9 months (n=6), and 12 months (n=4) did not show a decline in effectiveness of stimulation. There was no permanent morbidity associated with the procedure. A subtle reduction of verbal fluency, which was not evident to the patients, was the only cognitive side effect of the procedure in neuropsychological testing. Chronic bilateral high-frequency stimulation of the internal pallidum seems to be a neurologically safe and highly effective treatment for "off" symptoms, dyskinesias, and motor fluctuations in advanced stages of Parkinson's disease.

Abstract: The cortical representation of five simple hand and finger movements in the human motor cortex was determined in left- and right-handed people with whole-head magnetoencephalography. Different movements were found to be represented by spatially segregated dipolar sources in primary motor cortex. The spatial arrangement of neuronal sources for digit and wrist movements was nonsomatotopic and varied greatly between subjects. As an estimator of hand area size in primary motor cortex, we determined the smallest cuboid volume enclosing the five dipole sources within the left and right hemisphere of each subject. Interhemispheric comparison revealed a significant increase of this volume in primary motor cortex opposite to the preferred hand. This asymmetry was due to a greater spatial segregation of neuronal dipole generators subserving different hand and finger actions in the dominant hemisphere. Mean Euclidean distances between dipole sources for different movements were 10.7 +/- 3.5 mm in the dominant and 9.4 +/- 3.5 mm in the nondominant hemisphere (mean +/- SD; P = 0. 01, two-tailed t-test). The expansion of hand representation in primary motor cortex could not simply be attributed to a greater number of pyramidal cells devoted to each particular movement as inferred from current source amplitudes. The degree of hemispheric asymmetry of hand area size in the primary motor cortex was correlated highly with the asymmetry of hand performance in a standardized handedness test (r = -0.76, P < 0.01). These results demonstrate for the first time a biological correlate of handedness in human motor cortex. The expansion of hand motor cortex in the dominant hemisphere may provide extra space for the cortical encoding of a greater motor skill repertoire of the preferred hand.

Abstract: The dipole sources of interictal spike activity were localized and the myoclonus activity back-averaged by combined magnetoencephalography and surface electromyographic measurements in a child who had epilepsia partialis continua without a structural brain lesion. Dipole sources were matched with metabolic information obtained from interictal 5-fluoro-D-glucose positron emission tomography (PET) and superimposed onto high-resolution magnetic resonance images. Dipole sources of interictal epileptic discharges clustered within the inferior parietal cortex, which also showed a regional hypermetabolism on PET scans. The dipole sources of reafferent activity following myocloni in the postcentral gyrus were associated with a local hypometabolism Although there was no obvious phase relationship between interictal spikes and myoclonic jerks, the myocloni were initiated from within the interictal spike area in the extrarolandic cortex. The data demonstrate that motor symptoms may be a remote effect of epileptic activity within functional brain circuits.

Abstract: A variety of clinical and experimental findings suggest that parkinsonian resting tremor results from the involuntary activation of a central mechanism normally used for the production of rapid voluntary alternating movements. However, such central motor loop oscillations have never been directly demonstrated in parkinsonian patients. Using magnetoencephalography, we recorded synchronized and tremor-related neuromagnetic activity over wide areas of the frontal and parietal cortex. The spatial and temporal organization of this activity was studied in seven patients suffering from early-stage idiopathic Parkinson's disease (PD). Single equivalent current dipole (ECD) analysis and fully three-dimensional distributed source solutions (magnetic field tomography, MFT) were used in this analysis. ECD and MFT solutions were superimposed on high-resolution MRI. The findings indicate that 3 to 6 Hz tremor in PD is accompanied by rhythmic subsequent electrical activation at the diencephalic level and in lateral premotor, somatomotor, and somatosensory cortex. Tremor-evoked magnetic activity can be attributed to source generators that were previously described for voluntary movements. The interference of such slow central motor loop oscillations with voluntary motor activity may therefore constitute a pathophysiologic link between tremor and bradykinesia in PD.

Abstract: Microelectrode recordings in adult mammals have clearly demonstrated that somatosensory cortical maps reorganize following peripheral nerve injuries and functional modifications; however, such reorganization has never been directly demonstrated in humans. Using magnetoencephalography, we have been able to demonstrate the somatotopic organization of the hand area in normal humans with high spatial precision. Somatosensory cortical plasticity was detected in two adults who were studied before and after surgical separation of webbed fingers (syndactyly). The presurgical maps displayed shrunken and nonsomatotopic hand representations. Within weeks following surgery, cortical reorganization occurring over distances of 3-9 mm was evident, correlating with the new functional status of their separated digits. In contrast, no modification of the somatosensory map was observed months following transfer of a neurovascular skin island flap for sensory reconstruction of the thumb in two subjects in whom sensory transfer failed to occur.

Abstract: We performed high-resolution magnetic resonance morphometry of the total midsagittal area and seven midsagittal subareas of the corpus callosum in healthy young adult dextrals and sinistrals (N = 52). There was no influence of handedness on these anatomic measurements. However, an effect of sex emerged, with women (N = 26) having a larger proportional isthmus segment of the callosum. This may reflect a sex-specific difference in the interhemispheric connectivity and functional organization of the temporoparietal association cortex.

Abstract: Auditory lateralization was investigated in 26 right-handed and 26 left-handed, normal subjects using seven different dichotic listening tests in each proband (free recall of digit lists, free recall of consonant-vowel (CV) syllables, four different CV syllable monitoring paradigms, and free recall of Morse codes). Reliabilities calculated with the formula of Spearman-Brown were low for digit recall (0.29, corrected for test length: 0.50), but good for CV recall (0.83), CV monitoring (0.75-0.88), and Morse code recall (0.50, corrected for test length: 0.88). Nevertheless, interest correlations were low, both for right- and left-handers (negative correlations ranging from -0.44 to -0.05, positive correlations ranging from 0.01 to 0.51). Only 38-77% of the right-handed and left-handed subjects retained one direction of ear advantage across any combination of two tests. The data suggest that different dichotic tests reveal different results. This may be due to psychometric, procedural, or phonetic properties. We conclude that individual predictions of language dominance are not justified using the dichotic tests evaluated in the present study.

Abstract: Absolute and relative speech timing were examined in patients suffering from Parkinson's, Huntington's, and Wilson's disease. The task was to speak a standard sentence 10 times, first slowly, and then successively faster up to maximum rate. All patient groups had low maximal speech rates and showed decreased variability of speech rate. The duration of pauses between words was the same as in normals and the relative time structure of the test sentence was basically preserved. For comparison, two cases with nonfluent aphasia had even slower speech rates, large increases in pause duration, and major changes in relative speech timing. The results show the same type of alterations of the temporal organization of speech as those characteristic for rapid alternating limb movements in such patients. They support the view that the speech and skeletomotor systems share common neural control modes despite fundamental biomechanical differences. The common denominator between the speech and the skeletomotor disturbances in basal ganglia diseases may be the undamping and slowing of a fast central oscillator.

Abstract: Asymmetry of the planum temporale, a language-related intrasylvian area on the superior temporal gyrus, is the most remarkable anatomical left-right asymmetry of the human brain. The in vivo application of magnetic resonance morphometry in 52 healthy volunteers (26 dextrals and 26 sinistrals) revealed that planum temporale asymmetry is correlated with hand dominance. Left-handers had a significantly lesser degree of leftward planum temporale asymmetry than right-handers. Thus, a structural-functional relation exists in cerebral asymmetry. The correlation is likely to reflect language representation. Because familial sinistrality influenced the anatomical pattern in left-handers and planum temporale asymmetry is already present in the newborn, prenatal factors must play an important role in the development of functional laterality.