Computational Modeling of Ultrasonic Subthalamic Nucleus Stimulation.

OBJECTIVE: To explore the potential of ultrasonic modulation of plateau-potential generating subthalamic nucleus neurons (STN), by modeling their interaction with continuous and pulsed ultrasonic waves. METHODS: A computational model for ultrasonic stimulation of the STN is created by combining the Otsuka-model with the bilayer sonophore model. The neuronal response to continuous and pulsed ultrasonic waves is computed in parallel for a range of frequencies, duty cycles, pulse repetition frequencies, and intensities. RESULTS: Ultrasonic intensity in continuous-wave stimulation determines the firing pattern of the STN. Three observed spiking modes in order of increasing intensity are low frequency spiking, high frequency spiking with significant spike-frequency and spike-amplitude adaptation, and a silenced mode. Continuous-wave stimulation has little capability to manipulate the saturated spiking rate in the high frequency spiking mode. In contrast, STN firing rates induced by pulsed ultrasound insonication will saturate to the pulse repetition frequency with short latencies, for sufficiently large intensity and repetition frequency. CONCLUSION: Computational results show that the activity of plateau-potential generating STN can be modulated by selection of the stimulus parameters. Low intensities result in repetitive firing, while higher intensities silence the STN. Pulsed ultrasonic stimulation results in a shorter saturation latency and is able to modulate spiking rates. SIGNIFICANCE: Stimulation or suppresion of the STN is important in the treatment of Parkinson's disease, e.g., in deep brain stimulation. This explorative study on ultrasonic modulation of the STN, could be a step in the direction of minimally invasive alternatives to conventional deep brain stimulation.

Remotely Programmed Deep Brain Stimulation of the Bilateral Subthalamic Nucleus for the Treatment of Primary Parkinson Disease: A Randomized Controlled Trial Investigating the Safety and Efficacy of a Novel Deep Brain Stimulation System.

BACKGROUND: Deep brain stimulation (DBS) is the most commonly performed surgery for the debilitating symptoms of Parkinson disease (PD). However, DBS systems remain largely unaffordable to patients in developing countries, warranting the development of a safe, economically viable, and functionally comparable alternative. OBJECTIVE: To investigate the efficacy and safety of wirelessly programmed DBS of bilateral subthalamic nucleus (STN) in patients with primary PD. METHODS: Sixty-four patients with primary PD were randomly divided into test and control groups (1:1), where DBS was initiated at either 1 month or 3 months, respectively, after surgery. Safety and efficacy of the treatment were compared between on- and off-medication states 3 months after surgery. Outcome measures included analysis of Unified Parkinson's Disease Rating Scale (UPDRS) scores, duration of "on" periods, and daily equivalent doses of levodopa. All patients were followed up both 6 and 12 months after surgery. RESULTS: Three months after surgery, significant decrease in the UPDRS motor scores were observed for the test group in the off-medication state (25.08 ± 1.00) versus the control group (4.20 ± 1.99). CONCLUSIONS: Bilateral wireless programming STN-DBS is safe and effective for patients with primary PD in whom medical management has failed to restore motor function.

STN-DBS activates the target area in Parkinson disease: an FDG-PET study.

OBJECTIVE: The immediate effects of deep brain stimulation (DBS) on subcortical neurons of its target region are controversial. METHODS: We measured the regional normalized resting cerebral metabolic rate of glucose (nCMRGlc) with 18-fluorodeoxyglucose (FDG) and PET in 12 patients with Parkinson disease (PD) and bilateral DBS of the subthalamic nucleus (STN) compared to 10 age-matched controls. PET was performed before surgery and 6 months after electrode implantation in DBS off- and on-conditions. Stereotactic coordinates of active STN electrode poles were determined with intraoperative skull x-ray and transferred to preoperative MR images. Subsequently, volumes of interest (VOIs) were placed around active electrode contacts, in the STN and in the globus pallidus. DBS induced changes of nCMRGlc values were determined in each VOI after PET and MRI coregistration. RESULTS: Electrode placement without stimulation led to significant FDG uptake reduction in the electrode region and in the STN (microlesional effect). Under active DBS, the local nCMRGlc significantly increased in all VOIs under investigation. CONCLUSIONS: The data demonstrate that deep brain stimulation (DBS) induced metabolic activation of the subthalamic region and the directly connected globus pallidus which is in line with local and remote excitation of neurons by high frequency stimulation. These PET findings most likely reflect tonic driving of the DBS target area and its projection sites via ortho- and antidromic fiber conduction. We conclude that subthalamic nucleus DBS has predominant excitatory properties and does, therefore, fundamentally differ from lesional neurosurgery.

The effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) on cognition in Parkinson disease.

The effects of subthalamic nucleus (STN) stimulation on cognition and mood have not been well established. The authors estimated cognitive and mood effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) at 6 months and 1 year postoperatively. Forty-six patients were recruited from the Movement Disorder Center at Seoul National University Hospital. Neuropsychologic tests were performed three times, before, 6 months after, and 1 year after surgery. Mean patient age was 58 and mean education duration 8 years. Eighteen of the 46 patients were men. The instruments used for assessing cognitive functions were; the Mini-Mental Status Examination (MMSE), the Trail Making Test (TMT), the Korean Boston Naming Test (K-BNT), the Rey-Kim Memory Battery, the Grooved pegboard test, the Stroop test, a fluency test, the Wisconsin Card Sorting test (WCST), and the Beck depression inventory (BDI). Of these tests, the verbal memory test, the Stroop test, and the fluency test showed statistically significant changes. The verbal memory test using the Rey-Kim memory battery showed a decline in delayed recall and recognition at 6 months and 1 year postoperatively, whereas nonverbal memory showed no meaningful change. In terms of frontal lobe function tests, Stroop test and fluency test findings were found to be aggravated at 6 months and this continued at 1 year postoperatively. Previous studies have consistently reported a reduction in verbal fluency and improvements in self-reported symptoms of depression after STN DBS. However, in the present study, Beck depression inventory (B.D.I.) was not significantly changed. Other tests, namely, MMSE, TMT, K-BNT, Grooved pegboard test, and the WCST also failed to show significant changes. Of the baseline characteristics, age at onset, number of years in full-time education, and L-dopa equivalent dosage were found to be correlated with a postoperative decline in neuropsychological test results. The correlation of motor improvement and cognitive deterioration was not significant, which suggests that the stimulation effect is rather confined to the motor-related part in the STN. In conclusion, bilateral STN DBS in Parkinson's disease did not lead to a significant global deterioration in cognitive function. However, our findings suggest that it has minor detrimental long-term impacts on memory and frontal lobe function.

Emotion recognition impairment and apathy after subthalamic nucleus stimulation in Parkinson's disease have separate neural substrates.

OBJECTIVE: To test the hypothesis that emotion recognition and apathy share the same functional circuit involving the subthalamic nucleus (STN). METHODS: A consecutive series of 17 patients with advanced Parkinson's disease (PD) was assessed 3 months before (M-3) and 3 months (M+3) after STN deep brain stimulation (DBS). Mean (+/-S.D.) age at surgery was 56.9 (8.7) years. Mean disease duration at surgery was 11.8 (2.6) years. Apathy was measured using the Apathy Evaluation Scale (AES) at both M-3 and M3. Patients were also assessed using a computerised paradigm of facial emotion recognition [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto: Consulting Psychologist Press] before and after STN DBS. Prior to this, the Benton Facial Recognition Test was used to check that the ability to perceive faces was intact. RESULTS: Apathy had significantly worsened at M3 (42.5+/-8.9, p=0.006) after STN-DBS, in relation to the preoperative assessment (37.2+/-5.5). There was also a significant reduction in recognition percentages for facial expressions of fear (43.1%+/-22.9 vs. 61.6%+/-21.4, p=0.022) and sadness (52.7%+/-19.1 vs. 67.6%+/-22.8, p=0.031) after STN DBS. However, the postoperative worsening of apathy and emotion recognition impairment were not correlated. CONCLUSIONS: Our results confirm that the STN is involved in both the apathy and emotion recognition networks. However, the absence of any correlation between apathy and emotion recognition impairment suggests that the worsening of apathy following surgery could not be explained by a lack of facial emotion recognition and that its behavioural and cognitive components should therefore also be taken into consideration.

Effects of subthalamic nucleus stimulation on striatal dopaminergic transmission in patients with Parkinson's disease within one-year follow-up.

The mechanisms by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) leads to clinical benefit in Parkinson's disease (PD), especially with regard to dopaminergic transmission, remain unclear. Therefore, the objective of our study was to evaluate alterations of synaptic dopaminergic signaling following bilateral STN-DBS in advanced PD within a one-year follow-up. We used [(123)I]FP-CIT single-photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) availability and [(123)I]IBZM SPECT to assess dopamine D(2) receptor (D2R) availability (stimulator ON condition).Patients (n=18) showed a tendency towards a better suppression of symptoms after STN-DBS (Unified Parkinson's Disease Rating Scale motor score with medication decreased from 24.1+/-16.1 to 15.4+/-7.45; p=0. 002) while medication was strongly reduced (61% reduction of levodopa equivalent units; p<0. 0001). No changes of striatal [(123)I]FP-CIT binding and an increase of [(123)I]IBZM binding up to 16% (p<0. 05) between pre-surgery and follow-up investigations were noticed. These data show that clinical improvement and reduction of dopaminergic drugs in patients with advanced PD undergoing bilateral STN-DBS are paralleled by stable DAT and recovery of striatal D2R availability 12 months after surgery.

Deep brain stimulation for Parkinson's disease: prevalence of adverse events and need for standardized reporting.

Deep brain stimulation (DBS) has assumed a prominent role in the treatment of Parkinson's disease (PD). In this manuscript, we attempt to estimate the prevalence and categorize adverse events (AEs) of DBS in PD, based on efficacy studies published over the last decade. We conclude that reliable categorization and quantification of AEs based on available data poses many challenges and argue that a standardized scheme for reporting AEs should be created. This would provide a foundation for a meaningful risk/benefit analysis, for comparison of results between centers and, ultimately, for a well informed decision by physicians and patients as to whether surgery should be pursued.

Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus.

OBJECTIVE: To evaluate motor and nonmotor symptoms in patients with Parkinson's disease undergoing bilateral deep brain stimulation of the subthalamic nucleus (STN DBS). METHODS: Thirty-six consecutive patients receiving bilateral STN stimulation implants were evaluated preoperatively as well as 12 and 24 months after surgery. Motor symptoms were assessed through the Unified Parkinson's Disease Rating Scale (UPDRS). Data concerning nonmotor symptoms were collected from items of the UPDRS and 2 additional questions from clinical charts regarding constipation and urological dysfunction. RESULTS: STN DBS was effective in controlling motor symptoms; concerning nonmotor symptoms, sleep quality and constipation improved after surgery as compared to baseline. Salivation, swallowing and sensory complaints were ameliorated to a comparable degree by the medication on state, whether preoperatively or postoperatively. With a lower dose of dopaminergic medication, however, the medication on state appeared to be a much larger percentage of the day postoperatively. No significant variations were detected in intellectual impairment, depression, thought disorders, motivation, falling unrelated to freezing, nausea, orthostatic hypotension and urological dysfunction. CONCLUSIONS: STN DBS effectively controls motor symptoms, while nonmotor features of advanced Parkinson's disease patients are mostly unchanged after surgery, even though some specific aspects, notably sleep complaints and constipation, are ameliorated.

Lexical-semantic inhibitory mechanisms in Parkinson's disease as a function of subthalamic stimulation.

Inhibitory control may be affected by Parkinson's disease (PD) due to impairment within the non-motor basal ganglia-thalamocortical circuits. The present study aimed to identify the effects of chronic stimulation of the subthalamic nucleus (STN) on lexical-semantic inhibitory control. Eighteen participants with PD who had undergone surgery for deep brain stimulation (DBS) of the STN, completed a picture-word interference (PWI) task and the Hayling test in on and off stimulation conditions. The results of PD participants were compared with 21 non-neurologically impaired control participants. PD participants performed no differently from controls on the PWI task, and no significant differences between on and off stimulation conditions were revealed, therefore suggesting that PD participants are not impaired in lexical-semantic interference control. In contrast, in the off stimulation condition, PD participants had significantly delayed reaction times and increased errors on the inhibition section of the Hayling test compared with the STN stimulation condition and control participants. These results suggest that PD patients are impaired in aspects of inhibitory control that are dependent on behavioural inhibition (such as the suppression of prepotent responses) and selection from competing alternatives without the presence of external cues. Furthermore, STN stimulation acts to restore these behavioural inhibitory processes.

Effects of chronic subthalamic stimulation on nonmotor fluctuations in Parkinson's disease.

The aim of this study was to assess the outcome of nonmotor fluctuations (NMF) after chronic Subthalamic nucleus (STN) Deep Brain Stimulation (DBS) in Parkinson's disease(PD). Chronic stimulation of the STN has proved to be an effective treatment for advanced PD with motor complications. The outcome of NMF, which are also disabling, remains unknown. Forty-patients underwent bilateral STN stimulation. Each patient was interviewed before and after 1 yr of STN DBS with a structured questionnaire about their NMF. After 1 yr of chronic stimulation, the improvement in the motor score (UPDRS III) and dyskinesia amounted respectively to 67.4 and 76.3%. The decrease in motor fluctuations (MF) was 59% and 13 patients reported that their MF had disappeared. Comparatively, a reduction of the total number of NMF was also observed (mean number preoperatively: 15.6 per patient, postoperatively: 6.6). Most of the nonmotor fluctuating symptoms occurred in the "off" state preoperatively and no longer depended on the patient's motor state after surgery. The improvement in NMF was not identical for the different categories: pain/sensory fluctuations showed the best response to STN DBS (84.2%). Dysautonomic and cognitive fluctuations were also markedly improved (>60%) while psychic fluctuations remained the most frequent postoperative NMF observed. Some incapacitating manifestations such as drenching sweats and akathisia showed a remarkably good response to STN stimulation. In conclusion STN DBS alleviates NMF. It has strikingly successful effects on sensory, dysautonomic and cognitive fluctuations. However, psychic fluctuations respond less consistently to this treatment.

Impact of chronic subthalamic high-frequency stimulation on metabolic basal ganglia activity: a 2-deoxyglucose uptake and cytochrome oxidase mRNA study in a macaque model of Parkinson's disease.

The mechanisms of action of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) remain only partially understood. Hitherto, experimental studies have suggested that STN-HFS reduces the activity of STN neurons. However, some recent reports have challenged this view, showing that STN-HFS might also increase the activity of globus pallidus internalis (GPi) neurons that are under strong excitatory drive of the STN. In addition, most results emanate from studies applying acute STN-HFS, while parkinsonian patients receive chronic stimulation. Thus, the present study was designed to assess the effect of chronic (10 days) STN-HFS in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate. For this purpose, 2-deoxyglucose (2-DG) uptake, a measure of global synaptic activity, was assessed in the basal ganglia and the motor thalamus after chronic unilateral STN-HFS. Cytochrome oxidase subunit 1 (COI) mRNA expression, a marker of efferent metabolic activity, was additionally assessed in the globus pallidus. Chronic STN-HFS (i) reversed abnormally decreased 2-DG uptake in the STN of parkinsonian nonhuman primates, (ii) reversed abnormally increased 2-DG accumulation in the GPi while COI mRNA expression was increased, suggesting global activation of GPi neurons, and (iii) reversed abnormally increased 2-DG uptake in the ventrolateral motor thalamus nucleus. The simultaneous decrease in 2-DG uptake and increase in COI mRNA expression are difficult to reconcile with the current model of basal ganglia function and suggest that the mechanisms by which STN-HFS exerts its clinical benefits are more complex than a simple reversal of abnormal activity in the STN and its targets.

Long-term cognitive profile and incidence of dementia after STN-DBS in Parkinson's disease.

An effect of subthalamic nucleus deep brain stimulation (STN-DBS) on cognition has been suspected but long-term observations are lacking. The aim of this study was to evaluate the long-term cognitive profile and the incidence of dementia in a cohort of Parkinson's disease (PD) patients treated by STN-DBS. 57 consecutive patients were prospectively assessed by the mean of a neuropsychological battery over 3 years after surgery. Dementia (DSM-IV) and UPDRS I to IV were recorded. 24.5% of patients converted to dementia over 3 years (incidence of 89 of 1,000 per year). This group of patients cognitively continuously worsened over 3 years up to fulfilling dementia criteria (PDD). The rest of the cohort remained cognitively stable (PD) over the whole follow-up. Preoperative differences between PDD and PD included older age (69.2 +/- 5.8 years; 62.6 +/- 8 years), presence of hallucinations and poorer executive score (10.1 +/- 5.9; 5.5 +/- 4.4). The incidence of dementia over 3 years after STN-DBS is similar to the one reported in medically treated patients. The PDD presented preoperative risk factors of developing dementia similar to those described in medically treated patients. These observations suggest dementia being secondary to the natural evolution of PD rather than a direct effect of STN-DBS.

Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation.

Pathological gambling (PG) related to dopaminergic treatment in Parkinson's disease (PD) is part of a spectrum of behavioral disorders called the dopamine dysregulation syndrome (DDS). We describe a series of PD patients with preoperative active PG due to dopaminergic treatment from a total of 598 patients who have undergone surgery for subthalamic nucleus stimulation for disabling motor fluctuations. The patients had systematic open assessment of behavioral symptoms and standardized assessments of motor symptoms, mood, and apathy. Seven patients (6 men, 1 woman; age, 54 +/- 9 years; levodopa equivalent dose, 1,390 +/- 350 mg/day) had preoperative PG over a mean of 7 years, intolerant to reduction in medication. Six had nonmotor fluctuations and four had other behavioral symptoms consistent with a diagnosis of the DDS. After surgery, motor symptoms improved, allowing for 74% reduction of dopaminergic treatment, below the dosage of gambling onset. In all patients, PG resolved postoperatively after 18 months on average (range, 0-48), although transient worsening occurred in two. Improvement paralleled the time course and degree of reduction in dopaminergic treatment. Nonmotor fluctuations, off period dysphoria, and other symptoms of the DDS improved. Two patients developed persistent apathy. In conclusion, PG and other symptoms of the DDS-associated dopaminergic treatment improved in our patients following surgery. Dopaminergic dysregulation commonly attributed to pulsatile overstimulation of the limbic dopaminergic system may be subject to desensitization on chronic subthalamic stimulation, which has a relative motor selectivity and allows for decrease in dopaminergic treatment.

Side-effects of subthalamic stimulation in Parkinson's disease: clinical evolution and predictive factors.

Chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) is an alternative treatment for disabling forms of Parkinson's disease when on-off fluctuations and levodopa-induced dyskinesias compromise patients' quality of life. The aim of this study was to assess the evolution of side-effects during the first year of follow-up and search for clinical predictive factors accounting for their occurrence. We compared the frequency of side-effects at 3 and 12 months after surgery in a cohort of 44 patients. The off-medication scores of Unified Parkinson's Disease Rating Scale (UPDRS) II, III, axial symptoms, disease duration and age at surgery were retained for correlation analysis. Dysarthria/hypophonia, weight gain and postural instability were the most frequent chronic side-effects. Whereas dysarthria/hypophonia remained stable over time, weight gain and postural instability increased during the first year post-op. High axial and UPDRS II scores at surgery were predictive of dysarthria/hypophonia. Age and axial score at surgery were positively correlated with postural instability. Despite the occurrence of side-effects, the benefit/side-effects ratio of STN stimulation was largely positive during the first year of follow-up. Age, intensity of axial symptoms and UDPRS II off-medication score before surgery are predictive factors of dysarthria/hypophonia and postural instability after surgery.

Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN DBS) is an increasingly common treatment for Parkinson's disease. Qualitative reviews have concluded that diminished verbal fluency is common after STN DBS, but that changes in global cognitive abilities, attention, executive functions, and memory are only inconsistently observed and, when present, often nominal or transient. We did a quantitative meta-analysis to improve understanding of the variability and clinical significance of cognitive dysfunction after STN DBS. METHODS: We searched MedLine, PsycLIT, and ISI Web of Science electronic databases for articles published between 1990 and 2006, and extracted information about number of patients, exclusion criteria, confirmation of target by microelectrode recording, verification of electrode placement via radiographic means, stimulation parameters, assessment time points, assessment measures, whether patients were on levodopa or dopaminomimetics, and summary statistics needed for computation of effect sizes. We used the random-effects meta-analytical model to assess continuous outcomes before and after STN DBS. FINDINGS: Of 40 neuropsychological studies identified, 28 cohort studies (including 612 patients) were eligible for inclusion in the meta-analysis. After adjusting for heterogeneity of variance in study effect sizes, the random effects meta-analysis revealed significant, albeit small, declines in executive functions and verbal learning and memory. Moderate declines were only reported in semantic (Cohen's d 0.73) and phonemic verbal fluency (0.51). Changes in verbal fluency were not related to patient age, disease duration, stimulation parameters, or change in dopaminomimetic dose after surgery. INTERPRETATION: STN DBS, in selected patients, seems relatively safe from a cognitive standpoint. However, difficulty in identification of factors underlying changes in verbal fluency draws attention to the need for uniform and detailed reporting of patient selection, demographic, disease, treatment, surgical, stimulation, and clinical outcome parameters.

Deep brain stimulation of the subthalamic nucleus affects resting EEG and visual evoked potentials in Parkinson's disease.

OBJECTIVE: We studied changes of the EEG spectral power induced by deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease (PD). Also analyzed were changes of visual evoked potentials (VEP) with DBS on and off. METHODS: Eleven patients with advanced PD treated with bilateral DBS STN were examined after an overnight withdrawal of L-DOPA and 2 h after switching off the neurostimulators. All underwent clinical examination followed by resting EEG and VEP recordings, a procedure repeated after DBS STN was switched on. RESULTS: With DBS switched on, the dominant EEG frequency increased from 9.44+/-1.3 to 9.71+/-1.3 Hz (P<0.01) while its relative spectral power dropped by 11% on average (P<0.05). Switching on the neurostimulators caused a decrease in the N70/P100 amplitude of the VEP (P<0.01), which inversely correlated with the intensity of DBS (black-and-white pattern: P<0.01; color pattern: P<0.05). CONCLUSIONS: Despite artifacts generated by neurostimulators, the VEP and resting EEG were suitable for the detection of effects related to DBS STN. The acceleration of dominant frequency in the alpha band may be evidence of DBS STN influence on speeding up of intracortical oscillations. The spectral power decrease, seen mainly in the fronto-central region, might reflect a desynchronization in the premotor and motor circuits, though no movement was executed. Similarly, desynchronization of the cortical activity recorded posteriorly may by responsible for the VEP amplitude decrease implying DBS STN-related influence even on the visual system. SIGNIFICANCE: Changes in idling EEG activity observed diffusely over scalp together with involvement of the VEP suggest that the effects of DBS STN reach far beyond the motor system influencing the basic mechanisms of rhythmic cortical oscillations.

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

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

Evolution of Parkinson's disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus.

Patients with advanced Parkinson's disease (PD) and motor complications can obtain significant symptom improvement by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Very little is published, however, about long-term effect and disease evolution during DBS. We performed a 4-year prospective study of the first 22 consecutive patients treated with STN DBS. The patients were evaluated with Unified Parkinson's Disease Rating Scale Part II to VI and a patient diary concerning on-off periods and dyskinesia. Patients were scored before surgery on medication and off medication for 10 to 12 hours and in four conditions 1 and 4 years after surgery: off medication+/-stimulation and on medication+/-stimulation. In advanced PD, a significant reduction of dyskinesia and off periods was present 4 years (90%/67%) after the operation. Total motor function on stimulation alone improved 55% at 4 years, compared with baseline and activities of daily living (42%). On stimulation, significant worsening of axial symptoms and speech was present from 1 to 4 years. To evaluate disease evolution, motor symptoms were assessed off stimulation and medication for 12 hours and were found not to worsen compared with baseline, which is remarkable in an otherwise progressive disorder. Five patients developed dementia. Severe adverse events were not observed.

Psychiatric symptoms following surgery for Parkinson's disease with an emphasis on subthalamic stimulation.

Bilateral subthalamic stimulation is a very effective neurosurgical treatment for advanced Parkinson's disease. Despite the range and frequency of psychiatric symptoms occurring in the postoperative state, most of these symptoms are transient and manageable. In clinical practice, preoperative psychiatric vulnerability, as with that of preoperative cognitive status, takes on an important role. Psychiatric assessment and active preoperative and postoperative intervention can potentially modify psychiatric outcomes. These psychiatric and psychological issues will take on greater importance, particularly with the rapid expansion of the number of neurosurgical sites and the need for adequate assessment and optimal management of patients. The paucity of the literature underscores the need for well-designed studies on psychiatric issues investigating both pathophysiology and clinical outcomes.

Movement-related changes in oscillatory activity in the human subthalamic nucleus: ipsilateral vs. contralateral movements.

A voluntary movement is accompanied by a series of changes in neuronal oscillatory activity in the subthalamic nucleus (STN). These changes can be recorded through electrodes implanted for deep brain stimulation to treat Parkinson's disease in the time interval between the surgery and the internalization of the connections to the batteries. Both baseline activity and movement-related changes are different in the 'on' and 'off' medication motor states. In the 'off' state a low frequency activity in the alpha-beta range (8-25 Hz) that dominates the spectrum is interrupted during the movement, while in the 'on' state baseline frequencies are higher and a peri-movement gamma increase (70-80 Hz) is usually observed. Similar changes have been described with electrocorticographic recordings over the primary motor cortex but the gamma increase was only present during contralateral movements. We compared ipsi- and contralateral movement-related changes in STN activity, using a time-frequency analysis of the recordings obtained simultaneously in both STN and the scalp (electroencephalography) during right and left hand movements. The movement-related changes observed in the STN in the 'on' and the 'off' states were similar to those described previously in terms of predominant frequency bands, but we found bilateral changes in the STN during movements of either hand. A contralateral earlier start of the beta STN changes was mostly observed when the moving hand corresponded to the less-affected side, irrespective of hand dominance. These results suggest that movement-related activity in the STN has, by and large, a bilateral representation and probably reflects cortical input.