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A preliminary study of transient confusional states following bilateral subthalamic stimulation for Parkinson's disease.

Transient postoperative confusion (POC) occurs in 5-25% of patients following bilateral subthalamic nucleus stimulation. We retrospectively reviewed data on 96 patients who underwent bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease. Nine percent of patients developed POC. There was no significant correlation between age/perioperative factors and POC. The POC group had a significantly higher incidence of depression and frontal-subcortical dysfunction on preoperative evaluation than patients without POC. Postoperative neuropsychological evaluations revealed declines on measures of general cognitive function and memory in the POC group. We provide preliminary evidence that patients with depression and frontal-subcortical dysfunction are more likely to develop POC, and that POC is more often associated with cognitive decline following surgery.

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Clinical correlates and cognitive underpinnings of verbal fluency impairment after chronic subthalamic stimulation in Parkinson's disease.

A decline in verbal fluency is the most consistent neuropsychological sequela of deep brain stimulation (DBS) for Parkinson's disease. We assessed clinical correlates and switching and clustering subcomponents in 26 parkinsonians undergoing subthalamic DBS. Post-surgical motor improvement was accompanied by worsening at both letter and category fluency tasks. Total number of words and switches decreased, while average cluster size was unchanged. Worsening tended to be prominent in patients with baseline poorer cognitive status and more depressed mood. Impairment of shifting suggests prefrontal dysfunction, possibly due to disruption of fronto-striatal circuits along the surgical trajectory and/or to high frequency stimulation itself.

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Reduction in voice tremor under thalamic stimulation.

We studied the effect of deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus on voice symptoms in seven patients with essential tremor. All had undergone DBS for management of hand tremor. Five of the patients had received unilateral implants; two were treated bilaterally. Each reported improvement in hand tremor with thalamic stimulation (a 1-to-3-point change on a 5-point severity scale). Voice tremor was evaluated with and without stimulation using patient and clinician severity ratings, and acoustic measures (rate and amplitude). Four of the seven patients showed reductions in voice symptoms in at least two of these measures, although degree of change differed (e.g., from 1 to 3 points on the 5-point severity scale). Voice gains typically were restricted to those patients with the more severe symptoms and did not parallel improvements in the upper extremities. It appears that reduced voice tremor may be an additional benefit of DBS for some individuals.

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Effects of internal globus pallidus stimulation on motor cortex excitability.

BACKGROUND: Deep brain stimulation is a promising treatment for PD, but its physiologic effects and mechanisms of action remain poorly understood. Magnetic stimulation studies have revealed abnormalities in several different excitatory and inhibitory circuits in the motor cortex in PD. METHODS: The physiologic effects of internal globus pallidus (GPi) stimulation in seven patients with PD and seven age-matched healthy volunteers were studied. The stimulators were set at the optimal parameters (ON), at half the optimal amplitude (Half-Amp), or switched off (OFF) in random order. Patients were taking their usual medications. Magnetic stimulation was applied to the motor cortex, and motor evoked potentials (MEP) were recorded from the contralateral first dorsal interosseous muscle. Several excitatory and inhibitory pathways that have been found to be abnormal in PD were tested. RESULTS: The motor threshold (MT), MEP recruitment curve (stimulus intensities from 100 to 150% of MT), short and long interval intracortical inhibition, and intracortical facilitation were similar in the three stimulator conditions tested both at rest and during voluntary contraction. The silent period (SP) was longer in the OFF and Half-Amp conditions than in normal control subjects. In the stimulator ON condition, the SP was significantly reduced compared with the OFF condition and became similar to that in normal control subjects. CONCLUSIONS: GPi stimulation while on dopaminergic medications reduced the SP following magnetic stimulation but did not change corticospinal excitability or other measures of intracortical inhibition and facilitation. The reduction of SP may be related to the antidyskinetic and levodopa-blocking effects of ventral GPi stimulation.

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Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability.

BACKGROUND: Deep brain stimulation of the internal global pallidus (GPi) and the subthalamic nucleus (STN) has become a treatment alternative in advanced PD. Although the effects of GPi stimulation have been examined recently, little is known about STN stimulation effects on motor cortex excitability. METHODS: The effects of STN stimulation were studied in eight patients with advanced PD using paired-pulse transcranial magnetic stimulation (TMS) in comparison with healthy control subjects. Motor evoked potentials following paired-pulse TMS (interstimulus interval 3 ms to test for corticocortical inhibition vs 13 ms for facilitation) have been recorded from the extensor carpi radialis and its functional antagonist, the flexor carpi radialis muscle. Silent period (SP) was also determined. Patients were examined under four conditions: medication "off"/stimulator "off" vs medication "on"/stimulator "off" vs medication "off"/stimulator "on" vs medication "on"/stimulator "on." RESULTS: Although the mean values for intracortical inhibition (ICI) were not significantly different, data variation was smaller and levels of significance higher with the STN stimulator switched "on," suggesting that ICI was more consistent. SP during stimulator "on"/medication "on" was longer than during stimulator "off"/medication "off." Motor performance as indicated by a finger-tapping test and Unified PD Rating Scale III was significantly better with dopaminergic medication and further improved with stimulator "on." CONCLUSIONS: Results suggest an effect of subthalamic nucleus stimulation on intracortical inhibitory mechanisms. This hypothesis could at least partially explain a more consistent depression of motor evoked potentials following inhibiting paired-pulse transcranial magnetic stimulation, a longer silent period (under stimulator "on"/medication "on"), and a reduction of akinesia and rigidity leading to a better motor performance in subthalamic nucleus-stimulated patients.

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The impact on Parkinson's disease of electrical parameter settings in STN stimulation.

BACKGROUND: The main advantage of deep brain stimulation (DBS) in the treatment of PD is that the electrical settings can be adjusted to optimize benefits and minimize adverse effects. The main objective of this study was to discover how varying these electrical parameters impacted on parkinsonian motor signs. METHODS: Twelve patients with PD with chronic bilateral subthalamic nucleus (STN) stimulation were selected. The authors evaluated the effects of a variation in the voltages, frequencies, and pulse widths on tremor, bradykinesia, and rigidity using two different paradigms: one in which the total electrical energy delivered was held constant, and one in which this was varied. Up to 26 parameter conditions were tested under double blind randomized conditions. RESULTS: Voltages >or=3 V and frequencies >or=130 Hz led to the greatest improvement in all three parkinsonian signs. A rate of 5 Hz significantly worsened akinesia. The combination of the highest voltage with the narrowest pulse width was most effective. CONCLUSIONS: This study confirms that the most beneficial effects induced by STN stimulation are obtained at high frequencies and that voltage is the most critical factor to obtain adequate alteration in STN activity. The mechanisms by which STN DBS improves parkinsonism remain speculative.

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Biochemical and electrophysiological changes of substantia nigra pars reticulata driven by subthalamic stimulation in patients with Parkinson's disease.

To understand the events underlying the clinical efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN), electrophysiological recordings and microdialysis evaluations were carried out in the substantia nigra pars reticulata (SNr), one of the two basal ganglia (BG) nuclei targeted by STN output, in patients with Parkinson's disease (PD). Clinically effective STN-DBS caused a significant increase of the SNr firing rate. The poststimulus histogram (PSTH) showed an excitation peak at 1.92-3.85 ms after the STN stimulus. The spontaneous discharge of SNr neurons was driven at the frequency of the stimulation (130 Hz), as shown in the autocorrelograms (AutoCrl). The fast Fourier transform (FFT) analysis showed a peak at 130 Hz, and a less pronounced second one at 260 Hz. Accordingly, in the distribution of the interspike intervals (ISIs), the mode was earlier, and skewness more asymmetric. Biochemically, the increased excitatory driving from the STN was reflected by a clear-cut increase in cyclic guanosine 3',5'-monophosphate (cGMP) levels in the SNr. These results indicate that the beneficial effect of DBS in PD patients is paralleled with a stimulus-synchronized activation of the STN target, SNr. Our findings suggest that, during STN-DBS, a critical change towards a high-frequency oscillatory discharge occurs.

Action Potentials↗

Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson's disease: target related effect or selection bias?

BACKGROUND: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. OBJECTIVE: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. METHODS: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). RESULTS: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. CONCLUSION: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.

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Subthalamic stimulation activates internal pallidus: evidence from cGMP microdialysis in PD patients.

Parkinson's disease patients benefit from deep brain stimulation (DBS) in subthalamic nucleus (STN), but the basis for this effect is still disputed. In this intraoperative microdialysis study, we found elevated cGMP extracellular concentrations in the internal segment of the globus pallidus, despite negligible changes in glutamate levels, during a clinically effective STN-DBS. This supports the view that a clinically beneficial effect of STN-DBS is paralleled by an augmentation (and not an inactivation) of the STN output onto the GPi.

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Nonpharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities.

Until recently, a review of nonpharmacological, somatic treatments of psychiatric disorders would have included only electroconvulsive therapy (ECT). This situation is now changing very substantially. Although ECT remains the only modality in widespread clinical use, several new techniques are under investigation. Their principal indication in the psychiatric context is the treatment of major depression, but other applications are also being studied. All the novel treatments involve brain stimulation, which is achieved by different technological methods. The treatment closest to the threshold of clinical acceptability is transcranial magnetic stimulation (TMS). Although TMS is safe and relatively easy to administer, its efficacy has still to be definitively established. Other modalities, at various stages of research development, include magnetic seizure therapy (MST), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). We briefly review the development and technical aspects of these treatments, their potential role in the treatment of major depression, adverse effects, and putative mechanism of action. As the only one of these treatment modalities that is in widespread clinical use, more extended consideration is given to ECT Although more than half a century has elapsed since ECT was first introduced, it remains the most effective treatment for major depression, with efficacy in patients refractory to antidepressant drugs and an acceptable safety profile. Although they hold considerable promise, the novel brain stimulation techniques reviewed here will be need to be further developed before they achieve clinical acceptability.

Brain↗

Effective desynchronization by nonlinear delayed feedback.

We show that nonlinear delayed feedback opens up novel means for the control of synchronization. In particular, we propose a demand-controlled method for powerful desynchronization, which does not require any time-consuming calibration. Our technique distinguishes itself by its robustness against variations of system parameters, even in strongly coupled ensembles of oscillators. We suggest our method for mild and effective deep brain stimulation in neurological diseases characterized by pathological cerebral synchronization.

Deep Brain Stimulation↗

Freezing of gait after bilateral subthalamic nucleus stimulation for Parkinson's disease.

OBJECTIVE: To determine the long-term effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on freezing of gait in Parkinson's disease patients. PATIENTS AND METHODS: Sixty-seven patients were followed 12 months after bilateral STN DBS and 32 patients were followed 24 months post-surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) with medications on and off at baseline and again in both conditions with stimulation on at follow-up. Specific attention was paid to the freezing item of the ADL section. RESULTS: Freezing scores in the medication off state improved significantly with stimulation at 1 and 2 years. In the medication on state there were no significant improvements in freezing. CONCLUSION: Off period freezing of gait is significantly improved with STN DBS up to 24 months; however, on period freezing is not affected by STN DBS.

Adult↗

Long-term outcomes of bilateral subthalamic nucleus stimulation in patients with advanced Parkinson's disease.

BACKGROUND: In patients with advanced Parkinson's disease (PD), deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to improve motor function and decrease medication requirements in the short term. However, the long-term benefits of DBS are not yet established. OBJECTIVE: It was the aim of this study to evaluate long-term outcomes of patients with PD treated with bilateral DBS of the STN. DESIGN AND METHODS: Thirty-three subjects who had bilateral STN DBS were followed prospectively after surgery. We evaluated subjects, using the Unified Parkinson's Disease Rating Scale (UPDRS), preoperatively, 12 months after surgery and at a long-term follow-up visit. Ratings were performed on and off dopaminergic medications. We compared postoperative UPDRS scores, dyskinesia ratings and medication dosages with preoperative values. RESULTS: Twenty-seven subjects had evaluations beyond 18 months (median 33.7 months). Total UPDRS scores in the 'medication-off' state were improved by 37% (p < 0.001) at 12 months and 17.7% (p = 0.0051) at the long-term evaluation. Medication-off state UPDRS part III scores were significantly improved at both 1 year and at the last evaluation (37.6 and 29.3%; p < 0.001). Dopaminergic medication requirements were decreased by 35.3% (p < 0.001) during the first postoperative year and remained below preoperative levels at the long-term evaluation. Average duration of 'off' time remained decreased by about 40% at both 1 year and at the time of last evaluation. Subjects had a sustained reduction in dyskinesia severity (88.6% at 1 year and 68.8% at last evaluation). CONCLUSIONS: In this cohort of subjects with advanced PD, bilateral STN stimulation improved 'off' medication motor function, reduced time spent in the medication-off state and reduced medication requirements for up to 4 years after surgery. We conclude that STN DBS is an effective long-term therapy for selected patients with advanced PD.

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Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease.

The authors systematically studied the emergence of restless legs syndrome (RLS) after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Postoperatively, 11 of 195 patients with STN DBS reported new problematic symptoms of RLS. The mean reduction in antiparkinsonian medication was 74%. The mean RLS score at diagnosis was 15 (+/-5.9) of a possible 24 points and after symptomatic drug therapy 4.3 (+/-3.1) points. Reduction of antiparkinsonian medication during STN DBS may unmask symptoms of RLS and complicate therapy of both RLS and PD.

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Neural prostheses in clinical applications--trends from precision mechanics towards biomedical microsystems in neurological rehabilitation.

Neural prostheses partially restore body functions by technical nerve excitation after trauma or neurological diseases. External devices and implants have been developed since the early 1960s for many applications. Several systems have reached nowadays clinical practice: Cochlea implants help the deaf to hear, micturition is induced by bladder stimulators in paralyzed persons and deep brain stimulation helps patients with Parkinson's disease to participate in daily life again. So far, clinical neural prostheses are fabricated with means of precision mechanics. Since microsystem technology opens the opportunity to design and develop complex systems with a high number of electrodes to interface with the nervous systems, the opportunity for selective stimulation and complex implant scenarios seems to be feasible in the near future. The potentials and limitations with regard to biomedical microdevices are introduced and discussed in this paper. Target specifications are derived from existing implants and are discussed on selected applications that has been investigated in experimental research: a micromachined implant to interface a nerve stump with a sieve electrode, cuff electrodes with integrated electronics, and an epiretinal vision prosthesis.

Biomechanical Phenomena↗

Assessment of Surgical Salvage Outcomes for Exposed Cranial Neuromodulating Devices.

OBJECTIVES: Implanted neuromodulating devices (NMDs) such as cochlear implants (CIs) and deep brain stimulators (DBSs) are commonly used in modern medicine. Rarely, complications arise post-operatively, including hardware exposure. Traditional teaching suggests that these devices require removal if exposed; however, surgical salvage is a high risk, high reward alternative. We review our single institution experience managing NMD exposure with surgical salvage. METHODS: Retrospective chart review was performed on individuals who had a NMD implanted and underwent an attempt at surgical salvage for exposure during the study period (January 01, 2021 through December 31, 2023). Study outcome success was defined as maintaining a functional NMD 1&#x2009;year after salvage was attempted. Surgical techniques associated with successful salvage were compared. RESULTS: Nine of 729 patients (1.2%) implanted with NMDs experienced hardware exposure during this 2-year study period. Nine subjects were referred for NMD salvage; however, only 6 of 9 subjects (66.7%, CI&#x2009;=&#x2009;3; DBS&#x2009;=&#x2009;3) underwent NMD salvage attempts. Four of the subjects had successful salvage demonstrated successful salvage with a functioning NMD and without wound healing concerns 1&#x2009;year after their salvage procedure. CONCLUSIONS: Classic teaching states that exposed NMDs require explantation. However, this approach necessarily imposes time without benefit from the NMD between explantation and reimplantation. Our experience demonstrates that surgical salvage can be a successful alternative for the majority (66.7%) of individuals.

Humans↗

Behavioural changes after bilateral subthalamic stimulation in advanced Parkinson disease: a systematic review.

INTRODUCTION: The long-lasting beneficial effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on motor function have now largely been acknowledged. Whereas behavioural changes have been demonstrated in certain case reports and small case series, some authors have not observed behavioural changes at all. The extent to which these changes occur has not yet been established. The aim of the present study was to systematically analyse behavioural changes of bilateral STN DBS. MATERIALS AND METHODS: A structured Medline search was conducted using previously described methods. Studies were selected according to specific in- and exclusion criteria. Data on patients, surgical technique, outcome and complications were collected and pooled. RESULTS: In total 1,398 patients who underwent bilateral STN DBS were included. The total cumulative follow-up period was 1,480 patient-years. Cognitive problems were seen in 41%, depression in 8%, and (hypo)mania in 4% of the patients. Anxiety disorders were observed in less than 2%, and personality changes, hypersexuality, apathy, anxiety, and aggressiveness were observed in less than 0.5% of the group studied. About half of the patients did not experience behavioural changes. CONCLUSION: Caregivers should be aware of the extent of these behavioural changes and a risk/benefit evaluation should be performed for individual patients.

Adult↗

Motor fluctuations in Parkinson's disease.

Parkinson's disease is characterized by progressive slowness in activities of daily living and is the most common cause of parkinsonism, whose symptoms include resting tremor, cogwheel rigidity, and bradykinesia. The introduction of levodopa and its positive effect on motor dysfunction in Parkinson's disease has allowed neurologists to focus on motor fluctuations. "End-of-dose wearing-off" and "morning akinesia" are terms to describe the transition between a patient's relatively normal motor performance when levodopa is effective and when it has transiently lost its effect on motor responses and parkinsonian symptoms reemerge. The choices available to alleviate these motor fluctuations range from altering the patient's levodopa/carbidopa dosing schedule to the addition of other agents to the regimen, including dopamine receptor agonists, catechol-O-methyltransferase inhibitors, monoamine oxidase inhibitors, and amantadine, as well as implementing dietary changes. Therapeutic decisions can be difficult because older agents have not been compared in head-to-head trials to determine which drugs are better than others and the order in which they should be tried or added to the levodopa regimen; however, all of the available treatments provide a good possibility of benefit to the patient. Deep brain stimulation surgery is an option for patients with medically intractable severe motor fluctuations.

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