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Background: Gait disturbances and balance remain challenging issues in Parkinsonian patients (PD) with deep brain stimulation (DBS). Short pulse deep brain stimulation (spDBS) increases the therapeutic window in PD patients, yet the effect on gait and postural symptoms remains unknown. Objective: We assessed the efficacy of spDBS compared to conventional DBS (cDBS) within the subthalamic nucleus (STN) on Parkinsonian gait. Methods: The study was a single-centre, randomized, double-blind, clinical short-term trial. 20 PD patients were studied postoperatively in three different conditions (DBS stimulation switched off (off DBS), spDBS with 40μs pulse width, cDBS with 60μs pulse width) on regular medication. The primary endpoint was the relative difference of gait velocity at self-paced speed during quantitative gait analysis between stimulation conditions. Secondary endpoints were changes of further measures of quantitative gait analysis, Ziegler course, Berg balance scale, FOG questionnaire, MDS-UPDRS, PDQ-39, and HADS. Mixed-model analysis and post-hoc t-tests were performed. Results: Both spDBS and cDBS improved gait velocity at self-paced speed compared to off DBS, however, there was no significant difference between both stimulation modes. Still, 40% of the patients preferred spDBS over cDBS subjectively. Both stimulation modes were equally effective in improving secondary endpoints of gait, balance, motor and non-motor performances. Conclusion: The use of spDBS and cDBS is equally effective in improving gait and balance in PD and might be beneficial in specified cohorts of PD patients.

Background: Freezing of gait (FOG) is among the most common and disabling symptoms of Parkinson’s disease (PD). Studies show that deep brain stimulation (DBS) of the subthalamic nucleus (STN) can reduce FOG severity. However, there is uncertainty about pathways that need to be modulated to improve FOG. Objective: To investigate whether STN-DBS effectively reduces FOG postoperatively and whether structural connectivity of the stimulated tissue explains variance of outcomes. Methods: We investigated 47 patients with PD and preoperative FOG. Freezing prevalence and severity was primarily assessed using the Freezing of Gait Questionnaire (FOG-Q). In a subset of 18 patients, provoked FOG during a standardized walking course was assessed. Using a publicly available model of basal-ganglia pathways we determined stimulation-dependent connectivity associated with postoperative changes in FOG. A region-of-interest analysis to a priori defined mesencephalic regions was performed using a disease-specific normative connectome. Results: Freezing of gait significantly improved six months postoperatively, marked by reduced frequency and duration of freezing episodes. Optimal stimulation volumes for improving FOG structurally connected to motor areas, the prefrontal cortex and to the globus pallidus. Stimulation of the lenticular fasciculus was associated with worsening of FOG. This connectivity profile was robust in a leave-one-out cross-validation. Subcortically, stimulation of fibers crossing the pedunculopontine nucleus and the substantia nigra correlated with postoperative improvement. Conclusion: STN-DBS can alleviate FOG severity by modulating specific pathways structurally connected to prefrontal and motor cortices. More differentiated FOG assessments may allow to differentiate pathways for specific FOG subtypes in the future.

Significance Prevalence and temporal dynamics of transient oscillations in the beta frequency band (15 to 35 Hz), referred to as β bursts, are correlated with motor performance. Disturbance of these activities is a candidate mechanism for motor impairment in Parkinson’s disease (PD), where the excessively long bursts correlate with symptom severity and are reduced by pharmacological and surgical treatments. Here we describe the changes in action potential firing that take place across multiple nodes of the cortical and basal ganglia circuit as these transient oscillations evolve. These analyses provide fresh insights into the network dynamics of β bursts that can guide novel strategies to interfere with their generation and maintenance in PD., Beta frequency oscillations (15 to 35 Hz) in cortical and basal ganglia circuits become abnormally synchronized in Parkinson’s disease (PD). How excessive beta oscillations emerge in these circuits is unclear. We addressed this issue by defining the firing properties of basal ganglia neurons around the emergence of cortical beta bursts (β bursts), transient (50 to 350 ms) increases in the beta amplitude of cortical signals. In PD patients, the phase locking of background spiking activity in the subthalamic nucleus (STN) to frontal electroencephalograms preceded the onset and followed the temporal profile of cortical β bursts, with conditions of synchronization consistent within and across bursts. Neuronal ensemble recordings in multiple basal ganglia structures of parkinsonian rats revealed that these dynamics were recapitulated in STN, but also in external globus pallidus and striatum. The onset of consistent phase-locking conditions was preceded by abrupt phase slips between cortical and basal ganglia ensemble signals. Single-unit recordings demonstrated that ensemble-level properties of synchronization were not underlain by changes in firing rate but, rather, by the timing of action potentials in relation to cortical oscillation phase. Notably, the preferred angle of phase-locked action potential firing in each basal ganglia structure was shifted during burst initiation, then maintained stable phase relations during the burst. Subthalamic, pallidal, and striatal neurons engaged and disengaged with cortical β bursts to different extents and timings. The temporal evolution of cortical and basal ganglia synchronization is cell type-selective, which could be key for the generation/ maintenance of excessive beta oscillations in parkinsonism.

Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities, inter spike intervals and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Furthermore, inter spike interval frequencies peaked in the same frequencies for which PAC was observed. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinson's disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS. SIGNIFICANCE STATEMENT: Identifying biomarkers for closed-loop deep brain stimulation (DBS) has become an increasingly important issue in Parkinson's Disease (PD) research. Two such biomarkers, phase-amplitude coupling (PAC) and beta-bursts, recorded from the implanted electrodes in subthalamic nucleus in PD patients, correlate with motor impairment. However, the physiological basis of PAC, and it relationship to beta bursts, is unclear. We provide multiple lines of evidence that PAC in the human STN reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with the duration of beta-bursts. This suggests that beta-bursts capture increased subthalamic input/output synchronisation and provides new insights in PD pathology with direct implications for closed-loop DBS therapy strategies.

Introduction The preoperative evaluation of Parkinson’s Disease (PD) patients for subthalamic nucleus deep brain stimulation (STN-DBS) includes the assessment of the neuropsychological status of the patient. A widely used preoperative test is the Mattis Dementia rating scale (MDRS). However, the Montreal cognitive assessment (MoCA) has also been proven to be a sensitive, time-sparing tool with high diagnostic validity in PD. We evaluate the utility of the MoCA as a preoperative screening test for PD patients undergoing bilateral STN-DBS. Methods In this single-centre, retrospective study, we analysed pre- and postoperative assessments of MoCA, MDRS, Movement disorder society-Unified PD Rating Scale-motor examination, PD Questionnaire-39 and levodopa equivalent daily dose. Longitudinal outcome changes were analysed using paired t-test, Pearson’s correlation coefficient, linear regression and CHAID (chi-square automatic interaction detector) regression tree model. Results Clinical motor and cognitive scores of 59 patients (61.05±7.73 years, 24 females) were analysed. The MoCA, but not the MDRS, identified significant postoperative cognitive decline in PD patients undergoing STN-DBS. The preoperative MoCA score correlated with postoperative quality of life improvement, whereas the MDRS did not. PD patients with a MoCA score ≤ 23 points had a significant decline of quality of life after DBS surgery compared to patients > 23 points. Conclusion This study identifies the MoCA as an alternative test within the preoperative evaluation of PD patients for the detection of neuropsychological deficits and prediction of the postoperative improvement of quality of life.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35 Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake human PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In these patients, we demonstrate that a subset of putative STN neurons is strongly and selectively sensitive to magnitude fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to the full range of instantaneous amplitude in the beta-frequency range. In rats, we probed the frequency response of STN neurons in the cortico-basal-ganglia-network more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40 Hz) and constant amplitude. In both healthy and dopamine-depleted rats, only beta-frequency stimulation led to a progressive reduction in the variability of spike timing through the stimulation train. This suggests, that the interval of beta-frequency input provides an optimal window for eliciting the next spike with high fidelity. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input., Highlights • STN-neurons are selectively entrained to cortical beta oscillations in PD patients. • Phase-locking of STN-neurons is linearly dependent on oscillation magnitude. • Beta bursts in LFP/EEG are accompanied by transient synchronisation of STN spiking. • STN neurons are selectively entrained to cortical beta stimulation in rats. • Beta-selectivity of STN neurons is present in control and dopamine-depleted rats.

Parkinson's disease (PD) is a heterogeneous disorder that leads to variable expression of several different motor symptoms. While changes in firing rate, pattern, and oscillation of basal ganglia neurons have been observed in PD patients and experimental animals, there is limited evidence linking them to specific motor symptoms. Here we examined this relationship using extracellular recordings of subthalamic nucleus neurons from 19 PD patients undergoing surgery for deep brain stimulation. For each patient, ≥10 single units and/or multi-units were recorded in the OFF medication state. We correlated the proportion of neurons displaying different activities with preoperative Unified Parkinson's Disease Rating Scale subscores (OFF medication). The mean spectral power at sub-beta frequencies and percentage of units oscillating at beta frequencies were positively correlated with the axial and limb rigidity scores, respectively. The percentage of units oscillating at gamma frequency was negatively correlated with the bradykinesia scores. The mean intraburst rate was positively correlated with both bradykinesia and axial scores, while the related ratio of interspike intervals below/above 10 ms was positively correlated with these symptoms and limb rigidity. None of the activity parameters correlated with tremor. The grand average of all the significantly correlated subthalamic nucleus activities accounted for >60% of the variance of the combined bradykinetic-rigid and axial scores. Our results demonstrate that the occurrence of alterations in the rate and pattern of basal ganglia neurons could partly underlie the variability in parkinsonian phenotype.

Background and objectives The purpose of this study was to assess efficacy and safety of a new patterned theta burst stimulation algorithm of DBS with the aim of expanding the therapeutic window and clinical benefit in PD. Methods In this single-center, randomized, double-blind, clinical short-term trial, unilateral conventional subthalamic DBS was compared with unilateral patterned stimulation algorithms with intraburst high- or low-frequency theta burst stimulation in 17 PD patients. Results There were no serious adverse events with theta burst stimulation. During monopolar review, conventional subthalamic DBS and high-frequency theta burst stimulation were comparable, but low-frequency theta burst stimulation differed by requiring higher stimulation amplitudes for symptom reduction, but a larger therapeutic window. High- and low-frequency theta burst stimulation with adapted stimulation amplitude were effective in PD symptom reduction with differential effects on akinesia and tremor, depending on the theta burst stimulation mode. Conclusions Theta burst stimulation is a safe and effective stimulation mode with potential future application opportunities. © 2020 International Parkinson and Movement Disorder Society.

The goal of the study was to compare the tolerability and the effects of conventional subthalamic nucleus (STN) and combined subthalamic nucleus and substantia nigra (STN+SNr) high-frequency stimulation in regard to neuropsychiatric symptoms in Parkinson’s disease patients. In this single center, randomized, double-blind, cross-over clinical trial, twelve patients with advanced Parkinson’s disease (1 female; age:61.3±7.3years; disease duration:12.3±5.4years; Hoehn and Yahr stage:2.2±0.39) were included. Apathy, fatigue, depression, and impulse control disorder were assessed using a comprehensive set of standardized rating scales and questionnaires such as the Lille Apathy Rating Scale (LARS), Modified Fatigue Impact Scale (MFIS), Becks Depression Inventory (BDI-I), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease Rating Scale (QUIP-RS), and Parkinson’s Disease Questionnaire (PDQ-39). Three patients that were initially assigned to the STN+SNr stimulation mode withdrew from the study within the first week due to discomfort. Statistical comparison of data retrieved from patients who completed the study revealed no significant differences between both stimulation conditions in terms of mean scores of scales measuring apathy, fatigue, depression, impulse control disorder, and quality of life. Individual cases showed an improvement of apathy under combined STN+SNr stimulation. In general, combined STN+SNr stimulation seems to be safe in terms of neuropsychiatric side effects, although careful patient selection and monitoring in the short-term period after changing stimulation settings are recommended.

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson’s disease (PD). It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopamine-depleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (∼20 Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson's disease patients. Computational modeling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here, activity was recorded from 10 awake, parkinsonian patients (6 male, 4 female human subjects) undergoing functional neurosurgery. We demonstrate that stimulation arriving on a particular patient-specific phase of the beta oscillation over consecutive cycles could suppress the amplitude of this pathophysiological activity by up to 40%, while amplification effects were relatively weak. Suppressive effects were accompanied by a reduction in the rhythmic output of subthalamic nucleus (STN) neurons and synchronization with the mesial cortex. While stimulation could alter the spiking pattern of STN neurons, there was no net effect on firing rate, suggesting that reduced beta synchrony was a result of alterations to the relative timing of spiking activity, rather than an overall change in excitability. Together, these results identify a novel intrinsic property of cortico-basal ganglia synchrony that suggests the phase of ongoing neural oscillations could be a viable and effective control signal for the treatment of Parkinson's disease. This work has potential implications for other brain diseases with exaggerated neuronal synchronization and for probing the function of rhythmic activity in the healthy brain.SIGNIFICANCE STATEMENTIn Parkinson's disease (PD), movement impairment is correlated with exaggerated beta frequency oscillations in the cerebral cortex and subthalamic nucleus (STN). Using a novel method of stimulation in PD patients undergoing neurosurgery, we demonstrate that STN beta oscillations can be suppressed when consecutive electrical pulses arrive at a specific phase of the oscillation. This effect is likely because of interrupting the timing of neuronal activity rather than excitability, as stimulation altered the firing pattern of STN spiking without changing overall rate. These findings show the potential of oscillation phase as an input for “closed-loop” stimulation, which could provide a valuable neuromodulation strategy for the treatment of brain disorders and for elucidating the role of neuronal oscillations in the healthy brain.

Prevalence and temporal dynamics of transient oscillations in the beta frequency band (15-35 Hz), referred to as beta bursts, are correlated with motor performance and tactile perception. Disturbance of these activities is a candidate mechanism for motor impairment in Parkinson’s disease (PD), where the excessively long bursts correlate with symptom severity and are reduced by pharmacological and surgical treatments. To date, characterization of beta bursts in PD has been limited to the local field potentials in the subthalamic nucleus (STN) and cortical EEG. Here, we describe the changes that take place in spiking activity across the cortico-basal ganglia circuit, providing a unique insight into the network dynamics of these transient oscillations. Firstly, we demonstrate that rhythmic subthalamic spiking activity emerges at a fixed phase relationship with respect to cortical beta bursts in PD patients. Using multichannel recordings of ensembles of neurons in the 6-OHDA rat model of PD, we then dissect the beta burst dynamics across the sensorimotor cortex and several basal ganglia structures: striatum (Str), globus pallidus externus (GPe) and STN. Each subcortical structure exhibits enhanced rhythmic activity in the beta band locked to the onset of cortical beta bursts and longer cortical bursts lead to stronger subcortical rhythmicity. Crucially, enhanced subcortical rhythmic activity emerges at a fixed phase relationship with respect to the motor cortex, comparable to the relationship observed in PD patients. Striatal beta bursts terminate prior to the recruitment of those in the STN and GPe, suggesting that while they could play an important role in establishing synchrony in the beta band, they do not extensively contribute to its maintenance in other basal ganglia structures. Critically, changes in cortico-subcortical phase coupling precede the onset of a cortical beta burst, supporting the hypothesis that phase alignment across the cortico-basal ganglia network could recruit these structures into synchronous network oscillations. We provide a powerful approach that not only examines pathophysiology of PD across the motor circuit, but also offer insights that could aid in the design of novel neuromodulation strategies to manipulate the state of the motor system before pathological activities emerge.

Objective To compare the effect of simultaneous deep brain stimulation of the subthalamic nucleus and substantia nigra pars reticulata (STN+SNr-DBS) to conventional subthalamic stimulation (STN-DBS) on sleep quality in Parkinson's disease (PD) patients. Methods The study was a single-center, randomized, double-blind, cross-over clinical trial to compare the effect of STN-DBS vs. combined STN+SNr-DBS on subjective measures of sleep quality. Fifteen PD patients (2 female, age 62.5 ± 6.7 years) suffering from moderate idiopathic PD (disease duration: 12.0 ± 5.0 years, Hoehn & Yahr stage: 2.2 ± 0.4 in the MED-ON & STN-DBS-ON condition, Hoehn & Yahr stage: 2.6 ± 0.8 in the MED-OFF condition preoperatively) participated in the study. Sleep quality was evaluated in both stimulation conditions using the PDSS-2 score as a self-rating questionnaire covering several aspects of sleep disturbances. Results PD patients showed mild-moderate sleep disturbances (STN-DBS: PDSS-2 score 17.0 ± 11.0; STN+SNr-DBS: 14.7 ± 9.5) with slight but not significant differences between both stimulation conditions. Considering the different subitems of the PDSS-2, combined STN+SNr stimulation was superior to conventional STN stimulation in improving restless legs symptoms (RLS) at night (STN-DBS = 1.9 ± 2.7 STN+SNr-DBS = 1.0 ± 1.8; W = −2.06, p = 0.039) and immobility at night (STN-DBS = 1.5 ± 1.4 STN+SNr-DBS = 0.6 ± 0.8; W = −2.041, p = 0.041). Conclusion This study demonstrates the safety of STN+SNr-DBS compared to conventional STN-DBS on sleep in general with potential beneficial input on RLS symptoms and akinesia at night.

Stimulation of the subthalamic area (STA) is an effective treatment in essential tremor patients, but limited by stimulation induced adverse effects. The aim of this study was to determine the spatial distribution of stimulus related tremor suppression, ataxia induction and paresthesia of the upper limb in the subthalamic area (STA) of essential tremor patients.We recruited eight patients with essential tremor in a stable postoperative condition (3 months after surgery). Stimulation-induced effects were assessed with suprathreshold stimulation. Tremor severity was assessed with the Fahn-Tolosa-Marin tremor rating scale (TRS) and cerebellar impairment was evaluated using the international cooperative ataxia rating scale (ICARS). Patients rated paresthesia intensity with a visual analog scale. Linear regression analysis was performed to associate stereotactic coordinates with tremor, ataxia and paresthesia.Suprathreshold stimulation significantly decreased tremor and elicited ataxia and paresthesia in all patients (P 0.001). Tremor rating scale (TRS) total score was positively correlated with y-coordinates (r = 0.44, P 0.05), i.e. anterior stimulation sites were more effective to suppress tremor. Concerning adverse effects, ataxia induction was positively correlated with z-coordinates almost reaching statistical significance (r = 0.50, P = 0.07), i.e. inferior stimulation sites elicit stronger ataxia. Furthermore, paresthesia was positively correlated with y-coordinates (r = 0.66; P 0.01) and to a lesser degree with x-coordinates (r = 0.32; P = 0.08), i.e. posterior and lateral stimulation sites within the STA caused more paresthesia.Antero-dorso-medial stimulation site in the STA were associated with less tremor and adverse effects in our small single-center cohort of ET patients with thalamic DBS.

Synchronized oscillations within and between brain areas facilitate normal processing, but are often amplified in disease. A prominent example is the abnormally sustained beta-frequency (~20Hz) oscillations recorded from the cortex and subthalamic nucleus of Parkinson’s Disease patients. Computational modelling suggests that the amplitude of such oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Here we demonstrate in awake, parkinsonian patients undergoing functional neurosurgery, that electrical stimulation arriving on consecutive cycles of a specific phase of the subthalamic oscillation can suppress its amplitude and coupling to cortex. Stimulus-evoked changes in spiking did not have a consistent time course, suggesting that the oscillation was modulated independently of net output. Phase-dependent stimulation could thus be a valuable strategy for treating brain diseases and probing the function of oscillations in the healthy brain.

Zusammenfassung Intraoperative Mikroelektrodenableitungen werden eingesetzt, um die Prazision funktionell-neurochirurgischer Eingriffe zu erhohen. Ihr Haupteinsatzgebiet sind die gezielten Hirnoperationen im Rahmen der Tiefen Hirnstimulation zur Behandlung schwerer Bewegungsstorungen wie Morbus Parkinson, Dystonie oder therapierefraktarer Tremorformen. Dieser Artikel beschreibt die typischen elektrophysiologischen Befunde in den drei wichtigsten subkortikalen Zielgebieten in der funktionellen Neurochirurgie bei Bewegungsstorungen: Nucleus subthalamicus, Globus pallidus internus und Nucleus ventro-intermedius thalami.

Objective While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. Methods Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6 Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5 months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. Results Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. Conclusions This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. Significance STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex.

Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing., Highlights • High density EEG investigation in patients with PD before and after STN-DBS surgery • Resting state EEG: altered spectral composition following STN-DBS • Rhythmic auditory stimulation (RAS): absence of pre-stimulus beta activity in PD • Fast RAS: normalization of beta (13–30 Hz) activities by L-DOPA and STN-DBS • Altered beta modulation profile may contribute to timekeeping deficits in PD.

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.

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.

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.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) reduces akinesia in Parkinson's disease but its impact on fine motor functions was unknown. We assessed the effects of DBS and a levodopa (L-dopa) test on the timing of the precision grip in 18 patients. Improvement on UPDRS-items reflecting hand functions and the shortening of the first phases of the precision grip were more distinct in the L-dopa test than in the pure STN-DBS condition. Other akinesia items and the time for build-up of lifting force were equally improved in both conditions. This suggests that routine STN-DBS might not be equally effective on all aspects of fine motor functions.

For deep brain stimulation (DBS) of the subthalamic nucleus (STN), it would be an advantage if the STN could be visualized with fast acquisition of MR images, allowing direct and individual targeting. We present a protocol for T2-weighted, nonvolumetric fast-acquisition MRI, implemented at 8 centers in 6 countries. Acquisition time varied between 3 min 5 s and 7 min 48 s according to the center, and imaging often provided visualization of the STN on axial and coronal scans. Postoperatively, the same imaging protocol permitted visualization of the target area and DBS electrodes with minimum artifacts. This imaging technique may contribute to a decrease in the number of electrode passes at surgery.

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.

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.

Department of Neurosurgery, Christian-Albrechts-University Kiel, Kiel, GermanyAbstract: In evaluating the success of deep brain stimulation(DBS), the benefit for the patient is the most important criteria.Nevertheless, correct placement of electrodes should also bedetermined in terms of their anatomic position. Therefore, wepropose a suite of different imaging modalities and furtherprocessing, which leads to an exact anatomic and statisticallycomparable documentation of electrode localization. Forty-three consecutive patients with a total of 85 implanted DBSelectrodes were evaluated with respect to postoperative imag-ing. T1-weighted magnetic resonance imaging (T1-MRI) wasperformed in all patients, 34 patients received T2-MRI, in 18patients stereotactic X-ray of the scull was performed in an-teroposterior and lateral projections, whereas 6 patients wereadditionally evaluated by pre- and postoperative MR-imagefusion between T1-data sets and calculation of coordinates forelectrode contacts. In T1-MRI, the artefacts of each electrodecontact could be delineated in relation to anatomic referencestructures, whereas T2-MRI allowed reproducibly for delinea-tion of electrode artefacts within subthalamic nucleus or globuspallidus pars interna. By MR-image fusion it could be shownthat the difference between planned target coordinates and co-ordinates of the active electrode contact ranged below 1 mmexcept for the z axis. The comparison with values obtainedfrom stereotactic X-ray confirmed these results. The sequentialand complementary use of the described imaging modalitiesand further image processing provide clinically reliable andstatistically comparable results to prove the exact anatomicelectrode positioning in DBS in addition to the objective andsubjective improvements of the patients’ symptoms. © 2002Movement Disorder SocietyKey words: DBS; electrode localization; MR-imaging

High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson’s disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.

Objective: To examine the influence of subthalamic nucleus (STN) deep brain stimulation (DBS) on driving in patients with Parkinson disease (PD). Methods: Using a driving simulator setup proven to reflect on-road driving, 2 main analyses were performed: 1) comparison of driving performance among 23 patients with deep brain surgery (DBS patients), 21 patients without surgery (no-DBS patients), and 21 controls; and 2) analysis of the effect of stimulation vs levodopa on driving performance. To this end, 3 tests were run in the medicated DBS patient cohort, with 3 different conditions: “stimulation on” (STIM) (equated to daily treatment), “stimulation off” (OFF), and “stimulation off/levodopa” (LD) (dosage aimed at maintaining motor status). Differences in driving times and errors among conditions were analyzed. Results: Age and cognitive deficits influenced driving performance negatively. The no-DBS patient group performed worse in driving time and driving errors than controls. DBS patients drove slower than controls and no-DBS patients. Driving safety was comparable to controls but higher than in no-DBS patients. Within the DBS patient group, driving was more accurate with STIM than with LD, although motor effects did not differ. Driving with STIM, but not with LD, was superior to driving in the OFF condition. Conclusion: DBS of the STN seems to have a beneficial effect on driving ability in patients with PD, potentially because of nonmotor driving-relevant aspects. Our data suggest that driving permission for DBS-treated patients with PD should not be handled more restrictively than permissions for patients with PD in general. Classification of evidence: This study provides Class IV evidence that STN-DBS in patients with PD is associated with a reduction in driving errors and improvements in driving accuracy in driving simulations.

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson's disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson’s disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a widely used and highly effective treatment for patients with advanced Parkinson's disease (PD). Repetitive TMS (rTMS) applied to motor cortical areas has also been shown to improve symptoms in PD and modulate motor cortical excitability. Here, we compared clinical and neurophysiological effects of STN stimulation with those of 1 Hz rTMS given to the dorsal premotor cortex (PMd) and those following intake of levodopa in a group of PD patients with advanced disease. Ten PD patients were studied on 2 consecutive days before and after surgery. Clinical effects were determined using the UPDRS motor score. Motor thresholds, motor-evoked potential (MEP) amplitudes during slight voluntary contraction, and the cortical silent periods (SP) were measured using TMS. Before surgery effects of levodopa and 1 Hz PMd rTMS and after surgery those of STN stimulation with or without additional levodopa were determined. Levodopa significantly improved clinical symptoms and increased the SP duration. STN stimulation improved clinical symptoms without changing the SP duration. In contrast, 1 Hz PMd rTMS was not effective clinically but normalized the SP duration. Whereas levodopa had widespread effects at different levels of an abnormally active motor network in PD, STN stimulation and PMd rTMS led to either clinical improvement or SP normalization, i.e., only partially reversed abnormal motor network activity.

Here we report a 63-year-old woman with primary cervical dystonia (CD) whose symptoms subsided for more than 30 years following a unilateral stereotactic subthalamotomy contralateral to the overactive left sternocleidomastoid muscle but then gradually recurred over a period of several months. The aim of the present study was to correlate the topography of the stereotactic lesion with the long lasting therapeutic effect. High-resolution magnetic resonance imaging and subsequent stereotactic analysis were performed to determine the anatomical localization of the lesion. The primary coagulation focus comprised the posterior subthalamic white matter in the prelemniscal radiation and field H of Forel. Neighboring structures were implicated to various extents. It is suggested that the posterior subthalamic area, with its abundance of interconnecting fibers and related nuclei, represents an effective target for the neurosurgical treatment of CD that may be explored further with deep brain stimulation.

The ventro-lateral thalamus is the stereotactic target of choice for severe intention tremor. Nevertheless, the optimal target area has remained controversial, and targeting of the subthalamic area has been suggested to be superior.Eleven patients with disabling intention tremor of different etiology (essential tremor (n = 8), multiple sclerosis (n = 2) and one with, spinocerebellar ataxia) were implanted bilaterally with DBS electrodes targeted to the ventro-lateral thalamus using micro-recording and micro-stimulation. Among five tracks explored in parallel optimal tracks were chosen for permanent electrode implantation. Postoperative tremor suppression elicited by individual electrode contacts was quantified using a lateralised tremor rating scale at least 3 months (in most patients1 year) after implantation. The position of electrode contacts was determined retrospectively from stereotactic X-ray exams and by correlation of pre- and postoperative MRI.In all patients, DBS suppressed intention tremor markedly. On average, tremor on the left and right side of the body was improved by 68% (+/-19; standard deviation) and 73% (+/-21), respectively. In most patients, distal electrode contacts located in the subthalamic area proved to be more effective than proximal contacts in the ventro-lateral thalamus. In stereotactic coordinates, the optimal site was located 12.7 mm (+/-1.4; mean +/- standard deviation) lateral, 7.0 (+/-1.6) mm posterior, and 1.5 (+/-2.0) mm ventral to the mid-commissural point. In general, the best contacts could be selected for permanent stimulation. Nevertheless, in some instances, more proximal contacts had to be chosen because of adverse effects (paraesthesiae, dysarthria, gait ataxia) which were more pronounced with bilateral stimulation resulting in slightly less tremor suppression on the left and right side of body (63 +/- 18 and 68 +/- 19%, respectively).Direct comparison of different stimulation sites in individual patients revealed that DBS in the subthalamic area is more effective in suppressing pharmacoresistant intention tremor than the ventro-lateral thalamus proper. Anatomical structures possibly involved in tremor suppression include cerebello-thalamic projections, the prelemniscal radiation, and the zona incerta.

International audience; 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

Deep brain stimulation (DBS) into the subthalamic nucleus (STN) is a highly effective treatment for advanced Parkinson's disease (PD). The consequences of STN stimulation on intracortical and corticospinal excitability have been addressed in a few studies using transcranial magnetic stimulation (TMS). Although excitability measurements were compared between the STN stimulation OFF and ON condition, in these experiments, there are no longitudinal studies examining the impact of electrode implantation per se on motor excitability. Here, we explored the effects of STN electrode implantation on resting motor thresholds (RMT), motor evoked potential (MEP) recruitment curves, and MEP onset latencies on 2 consecutive days before and shortly after STN surgery with the stimulator switched off, thus avoiding the effects of chronic DBS on the motor system, in 8 PD patients not taking any dopaminergic medication. After surgery, RMT and MEP recruitment curves were unchanged. In contrast, MEP onset latencies were significantly shorter when examined in relaxed muscles but were unchanged under preactivation. We hypothesize that postoperatively TMS pulses induced small currents in scalp leads underneath the TMS coil connecting the external stimulator with STN electrodes leading to inadvertent stimulation of fast-conducting descending neural elements in the vicinity of the STN, thereby producing submotor threshold descending volleys. These "conditioning" volleys probably preactivated spinal motor neurons leading to earlier suprathreshold activation by the multiple corticospinal volleys produced by TMS of the motor cortex. These TMS effects need to be considered when interpreting results of excitability measurements in PD patients after implantation of STN electrodes.

Background/Aims: The most effective site for subthalamic nucleus (STN) stimulation has remained unclear. The position of active contacts relative to the dorsal margin of the STN was determined. Methods: Electrodes (n = 49) were implanted following STN mapping by microrecording and microstimulation along five tracks (n = 25 patients). The stereotactic position of active contacts was determined and correlated with microrecordings using an algorithm for direct three-dimensional comparisons (n = 37). Results: Most active contacts were detected within ±1.0 mm from the dorsal margin of the STN as defined by microrecording (32.4%) or farther dorsal in the subthalamic area (37.8%), and only 29.7% were localized to the STN proper. This was consistent with the average stereotactic coordinates of the active contacts in these three groups. Conclusion: Our data suggest that the dorsal border area of the STN is the most effective target. Besides the dorsolateral STN (sensorimotor part) this may include projections from/to STN, the zona incerta, and pallidofugal projections in the fields of Forel.

Background Deep brain stimulation of the subthalamic nucleus (STN) improves motor symptoms of Parkinson disease. Although several studies have assessed cognitive functions before surgery and after long-term STN stimulation, only a few have assessed patients while stimulation is on and off to more specifically address the short-term cognitive effects of STN deep brain stimulation. Objective To examine the short-term effects of STN stimulation on several tests sensitive to executive function and the long-term effects of STN stimulation on a global cognitive scale. Design Twenty-three patients with Parkinson disease were tested 6 to 12 months after surgery with STN stimulation switched on and off in a random order while taking their regular medication. The Unified Parkinson's Disease Rating Scale motor score was also rated in the on and off stimulation condition. The neuropsychological battery included digit span, verbal fluency, Stroop color test, and random number generation in a single- and dual-task condition. Results Short-term stimulation improved the results on the Random Number Generation Task, requiring suppression of habitual responses, but induced more errors in the interference task of the Stroop color test. Digit span, verbal fluency, and dual-task performance results did not change. There was a significant correlation (r= 0.47,P= .02) between improved performance on the Random Number Generation Task and impaired response inhibition in the Stroop interference condition. A preoperative to postoperative comparison showed no changes in global cognitive function with long-term STN deep brain stimulation. Conclusions Short-term STN stimulation improves cognitive flexibility (giving up habitual responses) but impairs response inhibition. Long-term STN stimulation does not change global cognitive function.

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.

Gait analysis was carried out to assess the effects of L-dopa and bilateral subthalamic nucleus stimulation on gait velocity, cadence, stride length, and gait kinematics in nine patients with PD. Substantial effects of bilateral subthalamic nucleus stimulation on gait, with an increase in gait velocity and stride length comparable to that of a suprathreshold L-dopa dose, were found. Interestingly, stride length was more improved by L-dopa and cadence more by subthalamic nucleus stimulation. In two patients with freezing during the "on" period, subthalamic nucleus stimulation failed to reduce this symptom effectively.

Ablative surgery and deep brain stimulation for Parkinson's disease can be performed in the thalamus, the pallidum and the subthalamic nucleus. The efficacy and safety of unilateral pallidotomy is well established. Deep brain stimulation has a lower morbidity and is preferred for bilateral surgery. The subthalamic nucleus presently seems to be the most promising target in advanced stage Parkinson's disease.