Effects Of Subthalamic Nucleus Stimulation Research Articles

Effect of subthalamic nucleus stimulation on penicillin induced focal motor seizures in primate.

Drug-resistant motor epilepsies are particularly incapacitating for the patients. In a primate model of focal motor seizures induced by intracortical injection of penicillin, we recently showed that seizures propagated from the motor cortex towards the basal ganglia. Using the same animal model here, we hypothesized that disruption of subthalamic nucleus (STN) activity by chronic high frequency stimulation (HFS) could modify pathological excessive cortical synchronisation occurring during focal motor seizures, and therefore could reduce seizure activity. Two monkeys were chronically implanted with one electrode positioned into the STN. In each experiment, seizures were induced during 6 hours by injecting penicillin into the motor cortex. During stimulation sessions, HFS-STN was applied at the beginning of penicillin injection. Our results indicate that HFS-STN improved focal motor seizures by delaying the occurrence of the first seizure, by decreasing the number of seizures by 47% and therefore the total time spent seizing by 53% compared to control. These results argue for a therapeutic use of HFS-STN in motor seizures because they were obtained in a very severe primate model of motor status similar to that seen in human. Furthermore, HFS-STN was much more efficient than direct cortical HFS of the epileptic focus, which we already tested in the same primate model. The present study suggests that HFS-STN could be used as an experimental therapy when other therapeutic strategies are not possible or have failed in humans suffering from motor epilepsy but the present study still warrants controlled studies in humans.

The effects of subthalamic nucleus stimulation on semantic and syntactic performance in spontaneous language production in people with Parkinson's disease

Abstract Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an established therapeutic option for advanced Parkinson's disease (PD). In this study, the effects of unilateral and bilateral STN stimulation on spontaneous language production are explored, by comparing linguistic performance in different stimulation conditions with normative data of healthy subjects. Language samples of ten PD patients with DBS of the STN were obtained in four stimulation conditions: bilateral stimulation on, bilateral stimulation off, stimulation of the left STN only and stimulation of the right STN only. The spontaneous language production differed from the normative data in all four stimulation conditions. Especially morphosyntactic elements of spontaneous language production were altered. Despite these linguistic differences with normal controls no significant differences between stimulation conditions were found. These results emphasize that the effects of STN stimulation on spontaneous language production reflect a complex interplay of multiple factors.

No evidence for disease-modifying or neuroprotective effects of subthalamic nucleus stimulation in PD

No evidence for disease-modifying or neuroprotective effects of subthalamic nucleus stimulation in PD

Deep Brain Stimulation of the Rat Subthalamic Nucleus Induced Inhibition of Median Raphe Serotonergic and Dopaminergic Neurotransmission.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) relieves motor dysfunction in advanced Parkinson's disease (PD). However, STN DBS treated patients can experience unpleasant and debilitating psychiatric side effects such as depression and impulsivity. The neural basis of these psychiatric effects has been linked to a dysfunction of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission. STN DBS inhibited activity of 5-HT cell bodies in the dorsal raphe nucleus (DRN). Another important 5-HT source is located in the median raphe nucleus (MRN), which also contains a population of dopamine neurons. The effects of STN DBS on the MRN are unknown. Here, we test the hypothesis that STN DBS reduces 5-HT and dopaminergic function in the MRN, which may contribute to the psychiatric side effects of STN stimulation. Bilateral STN DBS was applied in a freely moving rat model. Following STN DBS, rats were sacrificed and the brains were processed for c-Fos, 5-HT and tyrosine hydroxylase (TH) immunohistochemistry. We found that STN DBS significantly lowered c-Fos expression compared to non-stimulated controls indicating reduced neuronal activity. Moreover, the mean optical density values of 5-HT and TH cells in the MRN was significantly lower compared to controls. These results show that STN DBS inhibits 5-HT and dopamine neurotransmission in the MRN.

Effect of Subthalamic Nucleus Stimulation during Exercise on the Mesolimbocortical Dopaminergic Region in Parkinson'S Disease: A Positron Emission Tomography Study

To elucidate the dynamic effects of deep brain stimulation (DBS) in the subthalamic nucleus (STN) during activity on the dopaminergic system, 12 PD patients who had STN-DBS operations at least 1 month prior, underwent two positron emission tomography scans during right-foot movement in DBS-off and DBS-on conditions. To quantify motor performance changes, the motion speed and mobility angle of the foot at the ankle were measured twice. Estimations of the binding potential of [(11)C]raclopride (BP(ND)) were based on the Logan plot method. Significant motor recovery was found in the DBS-on condition. The STN-DBS during exercise significantly reduced the [(11)C]raclopride BP(ND) in the caudate and the nucleus accumbens (NA), but not in the dorsal or ventral putamen. The magnitude of dopamine release in the NA correlated negatively with the magnitude of motor load, indicating that STN-DBS facilitated motor behavior more smoothly and at less expense to dopamine neurons in the region. The lack of dopamine release in the putamen and the significant dopamine release in the ventromedial striatum by STN-DBS during exercise indicated dopaminergic activation occurring in the motivational circuit during action, suggesting a compensatory functional activation of the motor loop from the nonmotor to the motor loop system.

Impulsivity, impulse control disorders, and subthalamic stimulation in Parkinson’s disease

Subthalamic nucleus (STN) stimulation in advanced Parkinson’s disease is a very powerful treatment for a highly selected group of patients. However, behavioral problems after neurosurgery have frequently been reported and may hamper the therapeutic success. In particular, impulsivity and impulse control disorders are often discussed as adverse effects of STN stimulation, and there is an ongoing debate whether stimulation causes or improves behavioral problems. We here point out that behavior after surgery for STN stimulation depends on five interacting factors: (1) impulsivity as an effect of STN stimulation, (2) hypo- and hyperdopaminergic behaviors as a result of changes of dopaminergic medication, (3) individually different mesolimbic denervation, (4) exact location of the electrode within the STN, and (5) reactive psychosocial changes. The complex interplay of these factors has so far not been taken into account appropriately to understand the postoperative behavioral events. We here propose a two axes model that may help clinicians understand the effects of treatment changes after neurosurgery and provide a basis for optimization of stimulation parameter programming and adjustment of dopaminergic medication.

Cognitive Effects of Subthalamic Nucleus Stimulation in Parkinson’s Disease: A Controlled Study

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor function in selected patients with Parkinson’s disease (PD) but can be associated with variable changes in cognitive functions. Methods: We studied 21 patients selected for STN-DBS and compared 6-month clinical and neuropsychological outcomes between those who underwent surgery (n = 9) and those who voluntarily refused it (n = 12). Results: Motor and quality of life outcomes were markedly superior in the STN-DBS group versus controls. A wide neuropsychological battery was administered, and the whole sample showed a statistically significant worsening in phonemic verbal fluency, time to perform the Trail Making Test part B, Digit Symbol score of WAIS-III and color-naming score of the Stroop Test. In comparison to controls, a trend to a slightly worse deterioration in phonemic verbal fluency was observed in the STN-DBS patients and was significantly correlated with reductions in the <smlcap>l</smlcap>-dopa-equivalent daily dose (r = 0.850, p = 0.007). Conclusion: Our study confirms the safety of STN-DBS from a cognitive standpoint; a reduction in verbal fluency at 6 months after surgery can also be related to PD progression and medication reduction.

P1‐329: Long‐term effects of subthalamic nucleus stimulation on cognition

Background: At present there is no cure for the common causes of dementia: Alzheimer’sand cerebrovascular-disease. Dementia may be preventable in up to 50% of cases by regular participation in multimodal physical-, socialand cognitive-activity programmes; however, most adults are not active enough. Common barriers to increased activities have been identified and may be overcome by specific psychological motivational techniques whilst the benefits from the activities can be maximised through evidence based activity design. Furthermore, activity interventions can be provided for patients with mild cognitive impairment (MCI) that are at increased risk of dementia. The ThinkingFit programme was designed to study the success of engaging patients with MCI in regular physical-, socialand cognitive-activities by making the activities fun and easily accessible. Methods: MCI participants were recruited from memory clinics and received the 12-week activity programme. The physical activity involved walking from home at an intensity of 65-75% of maximum predicted effort, 3 times a week for 30 minutes. Participants were supervised on 7 out of the expected 36 walks. The social activity took place weekly at a local facility and involved arts and crafts. Groups consisted of 8 participants to promote reinforcing group dynamics. For cognitive stimulation, participants complete 90 min/week of computer based cognitive training (www.lumosity. com). To include participants unable to travel to community centers due to disability or poor local transport, a home-based version of the activity program was provided using video teleconferencing. Results: To date, out of 193 patients screened, 78 were recruited and 74 completed the programme. High activity completion rates were recorded and responses from participants have been overwhelmingly positive: the majority would like to continue the programme in the long-term. Conclusions: High rates of recruitment can be achieved for MCI patients into intensive multimodal activity programmes, and the application of targeted motivational techniques result in high activity compliance rates. Extended periods of activity participation will be required to study the effects on dementia progression, and our results suggest it may be achievable through provision of specifically designed programmes.

Deep brain stimulation of the subthalamic nucleus improves sense of well‐being in parkinson's disease

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the motor symptoms of Parkinson's disease. Although a range of psychiatric and behavioral problems have been documented following deep brain stimulation, the short-term effects of subthalamic nucleus stimulation on patients' mood have only been investigated in a few studies. Our aim was to compare self-reported mood in Parkinson's patients with deep brain stimulation of the subthalamic nucleus ON versus OFF. Twenty-three Parkinson's patients with bilateral deep brain stimulation of the subthalamic nucleus and 11 unoperated Parkinson's patients completed a mood visual analogue scale twice. Operated patients were tested with deep brain stimulation of the subthalamic nucleus both ON and OFF. All were assessed on medication. The operated Parkinson's group reported feeling significantly better coordinated, stronger, and more contented with deep brain stimulation ON compared to OFF. Fourteen of the 16 mood scales changed in a positive direction when deep brain stimulation of the subthalamic nucleus was ON. When changes in motor scores were taken into account, the operated patients still reported feeling better-coordinated, but also less gregarious with stimulation ON. Unoperated Parkinson's patients showed no differences on any of these measures between their 2 ratings. Short-term changes in deep brain stimulation of the subthalamic nucleus have a small and mostly positive effect on mood, which may be partly related to improvements in motor symptoms. The implications for day-to-day management of patients with deep brain stimulation of the subthalamic nucleus are discussed.

9. Effects of subthalamic nucleus stimulation to electroencephalograms: Comparison between early phase and 12 months after surgery

9. Effects of subthalamic nucleus stimulation to electroencephalograms: Comparison between early phase and 12 months after surgery

P6.17 Voluntary, spontaneous, and reflex blinking in Parkinson's disease: the effects of subthalamic nucleus stimulation

P6.17 Voluntary, spontaneous, and reflex blinking in Parkinson's disease: the effects of subthalamic nucleus stimulation

Effects of Subthalamic Nucleus Stimulation on Emotional Prosody Comprehension in Parkinson's Disease

BackgroundAlthough impaired decoding of emotional prosody has frequently been associated with Parkinson's disease (PD), to date only few reports have sought to explore the effect of Parkinson's treatment on disturbances of prosody decoding. In particular, little is known about how surgical treatment approaches such as high frequency deep brain stimulation (DBS) affect emotional speech perception in patients with PD. Accordingly, the objective of this study was to evaluate the effect of subthalamic nucleus (STN) stimulation on prosody processing.Methodology/Principal FindingsTo this end the performance of 13 PD patients on three tasks requiring the decoding of emotional speech was assessed and subsequently compared to the performance of healthy control individuals. To delineate the effect of STN-DBS, all patients were tested with stimulators turned on as well as with stimulators turned off. Results revealed that irrespective of whether assessments were made “on” or “off” stimulation, patients' performance was less accurate as compared to healthy control participants on all tasks employed in this study. However, while accuracy appeared to be unaffected by stimulator status, a facilitation of reactions specific to highly conflicting emotional stimulus material (i.e. stimulus material presenting contradicting emotional messages on a verbal and non-verbal prosodic level) was observed during “on” stimulation assessments.ConclusionIn sum, presented results suggest that the processing of emotional speech is indeed modulated by STN-DBS. Observed alterations might, on the one hand, reflect a more efficient processing of highly conflicting stimulus material following DBS. However, on the other hand, given the lack of an improvement in accuracy, increased impulsivity associated with STN stimulation needs to be taken into consideration.

Analysis of the Time Course of the Effect of Subthalamic Nucleus Stimulation upon Hand Function in Parkinson’s Patients

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) as treatment for Parkinson’s disease has been in use for more than a decade, yet the immediate effect of stimulation upon movement parameters is not well characterized. Objective: The goal of the current study is the identification of the best time point to test hand function after programming DBS devices. Methods: Reaction time, movement time and velocity were measured at multiple time points with a movement-sensitive glove after the deep brain stimulator had been turned on or off, during ‘off medication’ conditions. Results: Velocity, movement time and reaction time worsened significantly in the first 20 min after the deep brain stimulator had been turned off. A ‘plateau effect’ after 20 min was not observed. Initiation of stimulation led to immediate significant increases in movement time and velocity and to a lesser degree a decrease in reaction time. Patients performed more inconsistently over time after onset of stimulation compared to stimulation withdrawal. Intraoperative testing showed an immediate improvement in velocity after placement of the STN deep brain stimulator. Conclusion: Movement time and velocity already reach their peak changes within 20 min after the deep brain stimulator has been reprogrammed, and therefore, this time point may be used to test the maximal clinical effect of stimulation.

Deep Brain Stimulation of the Subthalamic Nucleus Improves Reward-Based Decision-Learning in Parkinson's Disease

Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinson's disease (PD). We determined computational measures of outcome evaluation and reward prediction from PD patients who performed a probabilistic reward-based decision-learning task. In previous work, these measures covaried with activation in the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that stimulation of the STN motor regions in PD patients served to improve reward-based decision-learning, probably through its effect on activity in frontostriatal motor loops (prominently involving the putamen and, hence, reward prediction). In a subset of relatively younger patients with relatively shorter disease duration, the effects of DBS appeared to spread to more cognitive regions of the STN, benefiting loops that connect the caudate to various prefrontal areas importantfor outcome evaluation. These results highlight positive effects of STN stimulation on cognitive functions that may benefit PD patients in daily-life association-learning situations.

Metabolic activity of the subthalamic nucleus in a primate model of L-Dopa-unresponsive parkinsonism

Increased activity of the subthalamic nucleus (STN) is critical in mediating motor symptoms of Parkinson's disease. To determine if altered STN activity also occurs in levodopa (L-Dopa)-unresponsive parkinsonism due to a combined nigral and striatal degeneration, metabolic activity of the STN was assessed using cytochrome oxidase (CO) histochemistry in monkeys with nigral, striatal, or nigral+striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and/or 3-nitropropionic acid (3NP). MPTP- and MPTP+3NP-treated monkeys had a similar parkinsonian score and were clinically indistinguishable. However, CO activity in the STN was significantly increased in MPTP-induced parkinsonism but not in MPTP+3NP-induced striatonigral degeneration. These results indicate that metabolic activity of the STN is normal following a combined nigral+striatal degeneration and may help to understand the lack of effect of STN stimulation in L-Dopa-unresponsive parkinsonism.

Subthalamic nucleus stimulation influences expression and suppression of impulsive behaviour in Parkinson’s disease

Past studies show beneficial as well as detrimental effects of subthalamic nucleus deep-brain stimulation on impulsive behaviour. We address this paradox by investigating individuals with Parkinson's disease treated with subthalamic nucleus stimulation (n = 17) and healthy controls without Parkinson's disease (n = 17) on performance in a Simon task. In this reaction time task, conflict between premature response impulses and goal-directed action selection is manipulated. We applied distributional analytic methods to separate the strength of the initial response impulse from the proficiency of inhibitory control engaged subsequently to suppress the impulse. Patients with Parkinson's disease were tested when stimulation was either turned on or off. Mean conflict interference effects did not differ between controls and patients, or within patients when stimulation was on versus off. In contrast, distributional analyses revealed two dissociable effects of subthalamic nucleus stimulation. Fast response errors indicated that stimulation increased impulsive, premature responding in high conflict situations. Later in the reaction process, however, stimulation improved the proficiency with which inhibitory control was engaged to suppress these impulses selectively, thereby facilitating selection of the correct action. This temporal dissociation supports a conceptual framework for resolving past paradoxical findings and further highlights that dynamic aspects of impulse and inhibitory control underlying goal-directed behaviour rely in part on neural circuitry inclusive of the subthalamic nucleus.

A video clinical global impression scale (CGI) in obsessive compulsive disorder

The Clinical Global Impression scale (CGI) is frequently used in clinical research because of its face validity and ease of use but data on its reliability are scarce. Our goal was to estimate the reliability of the scale and compare reliability between face-to-face and video scoring. We analyzed 50 different video interviews recorded during 5 visits of a crossover trial to study the effect of subthalamic nucleus stimulation. Six specialized clinicians rated the CGI using these videos, providing 300 different ratings. The intraclass correlation was lower at inclusion (0.30 [0.13–0.50]) than at later visits (0.68 [0.61–0.80]). Reliability was not influenced by the patients' stimulation status. The mean of at least two independent evaluations of the video is needed to achieve an ICC greater than 0.8. The video CGI is a valid clinical outcome measure suitable for clinical trials (ClinicalTrials.gov number, NCT00169377).

Effects of STN stimulation on the initiation and inhibition of saccade in Parkinson disease

The basal ganglia (BG) play an important role in controlling saccades. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used as a treatment of Parkinson disease (PD) by altering the function of the BG. Nevertheless, the effects of STN DBS on saccade performance are not fully clarified in a systematic manner. In this study, we examined the effects of bilateral STN DBS on both the initiation and inhibition of saccades in PD. Thirty-two patients with PD performed 4 oculomotor tasks. Two tasks (visually guided saccades and gap saccades) were reflexive and 2 (memory-guided saccades [MGS] and antisaccades) were volitional. While taking their regular doses of antiparkinsonian drugs, patients performed these tasks under 2 conditions: during DBS (DBS-on condition) and without DBS (DBS-off condition). Fifty-one age-matched subjects served as controls. In the DBS-on condition, parameters of saccade initiation were improved in all tasks, with shorter latencies and increased amplitudes, except for MGS latency. STN DBS improved the ability to suppress unwanted saccades to the cue stimulus in the MGS task. However, it did not suppress prosaccades during the antisaccade task. These results suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects the neural pathway common to both reflexive and volitional saccades, possibly by acting on the STN-substantia nigra pars reticulata-superior colliculi pathway. STN DBS may set the functional level of the superior colliculi appropriate for both saccade initiation and inhibition through this pathway. These findings provide novel insights into the pathophysiology of Parkinson disease and may yield better treatment strategies.

A positive correlation between fractional white matter volume and the response of Parkinson disease patients to subthalamic stimulation

Since optimal patient selection is essential for the success of subthalamic nucleus (STN) stimulation, the identification of reliable outcome predictors is important. The purpose of this study was to identify new imaging characteristics sufficiently reliable to predict treatment results. Using preoperative magnetic resonance imaging studies of 21 Parkinson disease (PD) patients treated by STN stimulation, we performed whole brain-based analysis of voxel-based morphometry (VBM) data. Intracranial structures segmented into the gray matter fraction (GMF), white matter fraction (WMF), and cerebrospinal fluid fraction (CSFF) were subjected to univariate and multivariate analysis of the correlation between fractional volumes and postoperative improvement rates using the Unified PD Rating Scale (UPDRS). At 3 months after surgery, the WMF was significantly correlated with improvement rated on the total UPDRS (p = 0.006), UPDRS part II (activities of daily living; p = 0.008), UPDRS part III (motor; p = 0.005). In contrast, there was no significant correlation between the effect of STN stimulation and GMF or the effect of stimulation and CSFF. The WMF also showed a significant correlation with postoperative scores in the "on" drug and "on" stimulation state (total UPDRS, p = 0.027; UPDRS part II, p = 0.019; UPDRS part III, p = 0.034). Our data indicate that patients with a larger white matter volume benefited from STN stimulation whereas the volume of other brain structures was not correlated with its effect. We posit that preserved connectivity between components of the basal ganglia-thalamocortical circuit may be required for the effectiveness of electrical stimulation. VBM may represent a powerful tool to predict the response of patients with advanced PD to STN stimulation.

Impact of Subthalamic Nucleus Stimulation on Young-Onset Parkinson’s Disease

Objective. To clarify the efficacy of subthalamic nucleus (STN) stimulation in young-onset Parkinson's disease (PD), we compared the effects of STN stimulation on the motor symptoms between young-onset PD (YOPD) and late-onset PD (LOPD). Methods. We analyzed the effects of STN stimulation on motor function and motor fluctuations in 15 patients with YOPD, and 113 patients with LOPD who underwent STN stimulation during the same period. The Unified Parkinson's Disease Rating Scale (UPDRS) was evaluated during the on-period and off-period, which are defined as the times at which the motor symptoms are the best and worst during the daily active time with sustaining anti-parkinsonian drugs. The dyskinesia severity rating scale (DSRS) also was employed to assess the severity of peak-dose dyskinesia. We analyzed the changes in levodopa equivalent daily dose (LED), motor fluctuations, DSRS, and UPDRS part 3 score after STN stimulation, and compared the changes in each score between the two groups (YOPD vs. LOPD). Results. The LED was reduced, and the on-off motor fluctuation index, dyskinesia rating scale score (on-period), and UPDRS part 3 score (on- and off-periods) were improved in both the YOPD and LOPD groups. The improvement rates of the UPDRS part 3 scores in both the on- and off-periods in the YOPD group were superior to those in the LOPD group. The results of multivariate logistic regression analysis demonstrated that YOPD itself is the best responder to STN stimulation. Conclusions. STN stimulation can reduce the LED and improve motor fluctuations in patients with YOPD. The effects of STN stimulation on the motor symptoms of YOPD patients are superior to those in LOPD. The present findings suggest that YOPD patients suffering from several problems related to pharmacological therapy are probably good candidates for STN stimulation.