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Effects of bilateral subthalamic nucleus stimulation on resting-state cerebral glucose metabolism in advanced Parkinson's disease.

BACKGROUND: The major neuropathological symptoms of Parkinson's disease (PD) consist of a loss of pigmented dopaminergic neurons in the substantia nigra and the presence of Lewy bodies. This study was to investigate the effects of bilateral subthalamic nucleus (STN) stimulation on resting-state cerebral glucose metabolism in advanced PD, and investigate the mechanism of deep brain stimulation (DBS). METHODS: Seven consecutive advanced PD patients (4 men and 3 women, mean age 64 +/- 4 years, mean H-Y disability rating 4.4 +/- 0.65) receiving bilateral STN DBS underwent 18F-fluorodeoxyglucose (18F-FDG)/positron-emission tomography (PET) examinations at rest both preoperatively and one month postoperatively, with STN stimulation still on. The unified PD rating scale was used to evaluate the clinical state under each condition. Statistical parametric mapping (SPM) was used to investigate the regional cerebral metabolic rates of glucose (rCMRGlu) during STN stimulation, and to compare these values to rCMRGlu preoperation. RESULTS: STN stimulation clearly improved clinical symptoms in all patients. A significant increase in rCMRGlu was found in the bilateral lentiform nucleus, brainstem (midbrain and pons), bilateral premotor area (BA6), parietal-occipital cortex, and anterior cingulated cortex, and a marked decrease in rCMRGlu was noted in the left limbic lobe and bilateral inferior frontal cortex (P < 0.05). CONCLUSION: Bilateral STN stimulation may activate the projection axon from the STN, improving clinical symptoms in advanced PD patients by improving both ascending and descending pathways from the basal ganglia and increasing the metabolism of higher-order motor control in the frontal cortex.

Brain↗

Effects of subthalamic nucleus stimulation on characteristics of EMG activity underlying reaction time in Parkinson's disease.

We examined the effects of high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS) on characteristics of electromyographic (EMG) activity of the agonist muscle in 8 patients with Parkinson's disease (PD). Patients were examined during STN-DBS (ON), and 30 minutes after switching off both stimulators (OFF). They were asked to make a ballistic movement in paradigms of simple reaction time (SRT) and choice reaction time (CRT) tasks. Onset of movement (MOVonset) was measured as the latency of the initial displacement from baseline of the signal from an accelerometer attached to the dorsum of the hand. In the associated EMG activity, recorded from wrist extensor muscles, we measured onset latency (EMGonset), size of the first EMG burst (EMGsize), and number of EMG bursts (EMGbursts) counted between EMGonset and task execution. MOVonset and EMGonset were significantly shorter in ON than in OFF conditions in CRT. EMGsize was larger, EMGbursts were reduced, and peak of the acceleration profile was larger in ON compared with OFF conditions in both SRT and CRT. Our results indicate that STN-DBS induces a significant improvement in motor performance of reaction time tasks in PD patients. Such improvement is associated with a change in features of the EMG activity suggesting an increase in the excitability of the motor pathways engaged in ballistic movements.

Aged↗

Thalamic stimulation for tremor. Subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect.

The aim of this study was to investigate the impact of unilateral deep brain stimulation (DBS) of the ventrointermediate (Vim) thalamic nucleus on neuropsychological functioning comparing stimulation-on with stimulation-off conditions. Nine patients [five patients with Parkinson's Disease (PD), two patients with essential tremor (ET) and 2 patients with multiple sclerosis (MS)] underwent comprehensive neuropsychological testing for cognitive functions, including general mental impairment, aphasia, agnosia, executive and constructional abilities, learning, memory, cognitive processing speed and attention as well as depression. The neuropsychological assessments were performed at least 6 months postoperatively (mean 9 months). Testing in the stimulation-on and stimulation-off condition was obtained within a period of 3 to 4 weeks. Unilateral DBS resulted in improvement of tremor in all patients. There were no significant differences between the stimulation-on and the stimulation-off condition with the exception of a decrement of word-recall in the short delay free-recall subtest of the Rey Auditory-Verbal Learning Test (RAVLT). Subgroup analysis indicated that the impairment in word-recall was related to left-sided thalamic stimulation. Our study confirms that chronic unilateral DBS is a safe method with regard to cognitive function. The subtle changes in episodic memory are related to stimulation per se and not to a microthalamotomy effect.

Aged↗

Stimulation of the posterior hypothalamus for treatment of chronic intractable cluster headaches: first reported series.

OBJECTIVE: To describe the results of deep brain stimulation of the ipsilateral posterior hypothalamus for the treatment of drug-resistant chronic cluster headaches (CHs). A technique for electrode placement is reported. METHODS: Because recent functional studies suggested hypothalamic dysfunction as the cause of CH bouts, we explored the therapeutic effectiveness of posterior hypothalamic stimulation for the treatment of CHs. Five patients with intractable chronic CHs were treated with long-term, high-frequency, electrical stimulation of the posterior hypothalamus. Electrodes were stereotactically implanted in the following position: 3 mm behind the midcommissural point, 5 mm below the midcommissural point, and 2 mm lateral to the midline. RESULTS: Since this treatment, all five patients continue to be pain-free after 2 to 22 months of follow-up monitoring. Two of the five patients have remained pain-free without any medication, whereas three of the five required low doses of methysergide (two patients) or verapamil (one patient). No adverse side effects of chronic, high-frequency, hypothalamic stimulation have been observed, and we have not encountered any acute complications resulting from the implant procedure. There have been no tolerance phenomena. CONCLUSION: These preliminary results indicate a role for posterior hypothalamic stimulation, which was demonstrated to be safe and effective, in the treatment of drug-resistant chronic CHs. These data point to a central pathogenesis for chronic CHs.

Adult↗

Cognitive changes following subthalamic nucleus stimulation in two patients with Parkinson disease.

The limits of a drug therapy in severe forms of Parkinson disease have led to refining neurosurgery on the basal ganglia. Deep brain stimulation of the subthalamic nucleus has been recognized as one of the most promising techniques to decrease "off" motor symptoms and motor fluctuations, allowing a reduction of drug therapy and limiting side effects of the drugs. There is still open debate on the possible consequences of chronic subthalamic stimulation in other ways, apart from motor symptoms, of general cognitive performance. We examined and followed two patients with Parkinson disease for 9 mo. after surgery for deep stimulation, studying their cognitive performances. There is a general amelioration of cognitive performances, in particular as far as linguistic capabilities is concerned. We discuss the possible significance of these results, reminding strenuously that only two patients were involved, so the potential for generalization is seriously limited.

Aged↗

Neuropsychological and quality of life outcomes 12 months after unilateral thalamic stimulation for essential tremor.

OBJECTIVES: To evaluate the one year cognitive, mood state, and quality of life (QoL) outcomes of unilateral thalamic deep brain stimulation (DBS) for essential tremor (ET). METHODS: 40 patients diagnosed with ET completed comprehensive neuropsychological assessments about one month before and three and 12 months after DBS electrode implantation. Data were subjected to multivariate analyses, and significant results were further analysed using univariate techniques. RESULTS: Analyses revealed statistically significant improvements on a cognitive screening measure and in aspects of fine visuomotor and visuoperceptual functions, verbal memory, mood state, and QoL. No group-wise declines in cognition were observed, but more patients showed declines than improvements on language and visual memory tests. Semantic verbal fluency declined significantly in four (10%) of the patients. In these four patients, diminished lexical verbal fluency was present at baseline. CONCLUSION: Cognitive, mood, and QoL outcomes after one year of DBS for ET are favourable; there were no overall deleterious effects on cognition, and DBS was accompanied by a significant reduction in anxiety and improvements in quality of life. However, preoperative verbal fluency diminution may predispose to further fluency declines after DBS.

Aged↗

[Deep cerebral stimulation in the management of deafferentation pain].

The authors studied the clinical records of 42 patients with deafferentation who were treated with deep brain stimulation and electrodes placed in the ventral basal complex of the thalamus and/or in the central grey matter by the stereotactic method used in the University of Toronto. They describe the selection criteria, the surgical technique used and the results obtained, including the complications and successful outcomes. This procedure is usually the only alternative for patients who have undergone diverse medical and surgical therapies, and it is not a destructive method, as are other surgical techniques.

Adult↗

Repetitive transcranial magnetic stimulation (rTMS): insights into the treatment of Parkinson's disease by cortical stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a potent tool that can be used to modify activity of targeted cortical areas. Significant clinical effects have been obtained in patients with Parkinson's disease (PD) by stimulating different cortical regions with rTMS at inhibitory (low) or excitatory (high) frequency. These effects were thought to result from plastic changes in motor cortical networks. Actually cortical dysfunction has been documented in PD by neuroimaging and neurophysiologic studies showing either hypo- or hyper-activation of various brain areas. In addition, cortical excitability studies using transcranial magnetic stimulation disclosed significant alterations in intracortical facilitatory or inhibitory processes according to the resting state or to phases of movement preparation or execution. These observations clearly support the therapeutic potential of cortical neuromodulation in PD. Motor cortex stimulation could impact on any station within the cortico-basal ganglia-thalamo-cortical loops that are involved in motor control, providing alleviation of parkinsonian symptoms. Depending on the target, cortical stimulation might improve motor performance or other symptoms associated with PD, like depression. Clinical application of rTMS to treat PD patients is limited by the short duration of the effects beyond the time of stimulation, even if long-lasting improvements have been observed after repeated rTMS sessions. In any case, the place of cortical stimulation in the therapeutic management of PD patients remains to be determined, as an alternative or a complementary technique to deep brain stimulation. The rTMS technique could be used to better define the targets and the parameters of stimulation subsequently applied in chronic epidural stimulation.

Cerebral Cortex↗

Extradural motor cortex stimulation in Parkinson's disease.

Extradural motor cortex stimulation (EMCS) is a surgical procedure proposed for patients with advanced Parkinson's disease (PD) who cannot undergo deep brain stimulation (DBS). Five PD patients with motor fluctuations and dyskinesia underwent EMCS of the left hemisphere. All fulfilled CAPSIT criteria for DBS, with the exception of age > 70 years. Patients were assessed preoperatively and 6 months after surgery on and off medications, with stimulator on, and 2 weeks later with stimulator off. Outcome measures included changes in mean medication dosage (levodopa and dopamine agonists), Unified Parkinson's Disease Rating Scale (UPDRS Parts II-III and Item 39), and dyskinesias (Abnormal Involuntary Movements Scale [AIMS]). We found no significant mean changes following EMCS. However, there was a trend for a reduction of mean daily medication intake (-30%) and AIMS (-19%). There were 3 patients who reported reduced OFF time (UPDRS Item 39) and 4 of 5 who felt a subjective benefit in stability and gait. In our PD cohort, EMCS induced no objective benefit, although some subjective improvement was reported mostly on axial symptoms.

Aged↗

Comparison of motor effects following subcortical electrical stimulation through electrodes in the globus pallidus internus and cortical transcranial magnetic stimulation.

Current concepts of transcranial magnetic stimulation (TMS) over the primary motor cortex are still under debate as to whether inhibitory motor effects are exclusively of cortical origin. To further elucidate a potential subcortical influence on motor effects, we combined TMS and unilateral subcortical electrical stimulation (SES) of the corticospinal tract. SES was performed through implanted depth electrodes in eight patients treated with deep brain stimulation (DBS) for severe dystonia. Chronaxie, conduction velocity (CV) of the stimulated fibres and poststimulus time histograms of single motor unit recordings were calculated to provide evidence of an activation of large diameter myelinated fibres by SES. Excitatory and inhibitory motor effects recorded bilaterally from the first dorsal interosseus muscle were measured after SES and focal TMS of the motor cortex. This allowed us to compare motor effects of subcortical (direct) and cortical (mainly indirect) activation of corticospinal neurons. SES activated a fast conducting monosynaptic pathway to the alpha motoneuron. Motor responses elicited by SES had significantly shorter onset latency and shorter duration of the contralateral silent period compared to TMS induced motor effects. Spinal excitability as assessed by H-reflex was significantly reduced during the silent period after SES. No ipsilateral motor effects could be elicited by SES while TMS was followed by an ipsilateral inhibition. The results suggest that SES activated the corticospinal neurons at the level of the internal capsule. Comparison of SES and TMS induced motor effects reveals that the first part of the TMS induced contralateral silent period should be of spinal origin while its later part is due to cortical inhibitory mechanisms. Furthermore, the present results suggest that the ipsilateral inhibition is predominantly mediated via transcallosal pathways.

Adolescent↗

Effective desynchronization with bipolar double-pulse stimulation.

This paper is devoted to the desynchronizing effects of bipolar stimuli on a synchronized cluster of globally coupled phase oscillators. The bipolar pulses considered here are symmetrical and consist of a positive and a negative monopolar pulse. A bipolar single pulse with the right intensity and duration desynchronizes a synchronized cluster provided the stimulus is administered at a vulnerable initial phase of the cluster's order parameter. A considerably more effective desynchronization is achieved with a bipolar double pulse consisting of two qualitatively different bipolar pulses. The first bipolar pulse is stronger and resets the cluster, so that the second bipolar pulse, which follows after a constant delay, hits the cluster in a vulnerable state and desynchronizes it. A bipolar double pulse desynchronizes the cluster independently of the cluster's dynamical state at the beginning of the stimulation. The dynamics of the order parameter during a bipolar single pulse or a bipolar double pulse is different from the dynamics during a monopolar single pulse or a monopolar double pulse. Nevertheless, concerning their desynchronizing effects the monopolar and the bipolar stimuli are comparable, respectively. This is significant for applications where bipolar stimulation is required. For example, in medicine and physiology charge-balanced stimulation is typically necessary in order to avoid tissue damage. Based on the results presented here, demand-controlled bipolar double-pulse stimulation is suggested as a milder and more efficient therapy compared to the standard permanent high-frequency deep brain stimulation in neurological patients.

Journal Article↗

Parkinson's disease: aetiology, diagnosis, and management.

OBJECTIVE: To review the aetiology, diagnosis, and management of Parkinson's disease, with a local perspective. DATA SOURCES: Medline from 1966 onwards, and all major neurological journals and movement disorder journals were searched for evidence on the aetiology, diagnosis, and management of Parkinson's disease. STUDY SELECTION: Key words for the literature search were "Parkinson's disease" and "Chinese" or "Hong Kong". DATA EXTRACTION: All relevant articles in English were reviewed. DATA SYNTHESIS: The number of promising genes for familial Parkinson's disease is still expanding rapidly and there has been a wealth of studies on susceptibility genes for Parkinson's disease. Potential treatment choices include the use of agents thought to be neuroprotective, symptomatic treatment with drugs or surgery, and non-pharmacological treatments. Pharmacological treatment using a dopa-sparing strategy and continuous dopaminergic stimulation is now gaining support to address the issue of long-term motor complications. Surgical treatment with deep brain stimulation is safe and effective for refractory cases and has been increasingly utilised locally. CONCLUSIONS: Medical therapy remains the mainstay of treatment and newer agents and treatment approaches are emerging, which will hopefully address the issue of neuroprotection and provide symptomatic treatment with fewer motor complications.

Antiparkinson Agents↗

Stimulation of the subthalamic nucleus in Parkinson's disease: cognitive and affective changes are not linked to the motor outcome.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN0 DBS) is a widely performed surgical treatment in PD. However, the relationship between motor results and cognitive/behavioural modifications is unclear. OBJECTIVE: This study investigated the correlation patterns of the motor, cognitive and behavioural consequences of STN DBS with respect to positioning of the active contact. METHODS: Fifty-eight consecutive PD patients having undergone STN DBS were assessed pre-operatively and 12 months after surgery. RESULTS: Motor, cognitive and behavioural results were neither correlated to each other nor linked to the position of the active contact. Three patients with a history of pre-operative, dopaminergic psychosis or post-surgical confusion became demented. Age and a distant history of depression were associated with the occurrence of post-surgical depression. CONCLUSION: Correct screening of patients for STN DBS remains an important issue, since the current implantation procedure is not able to take account of potential functional heterogeneity within the target.

Affect↗

Deactivation of thalamocortical activity is responsible for suppression of parkinsonian tremor by thalamic stimulation: a 99mTc-ECD SPECT study.

Four patients with Parkinson's disease (PD) achieved excellent improvement of their unilateral tremor by chronic deep brain stimulation (DBS) of the contralateral ventral intermediate (Vim) nucleus of the thalamus. Repeated measurements of cerebral blood flow were obtained 14 days apart off and on stimulation using 99mTc-ECD SPECT. Subjects were scanned at rest and the data were compared with those of normal healthy volunteers. During stimulation, there were highly significant deactivations in the motor area and supplementary motor area on the electrode side and in the prefrontal area and the anterior cingulum bilaterally. No cerebellar deactivation was detected. We conclude that the mechanism responsible for suppression of parkinsonian tremor by thalamic stimulation is deactivation of thalamocortical activity.

Aged↗

Comparison of pallidal and subthalamic stimulation on force control in patient's with Parkinson's disease.

The aim of this study was to determine the effects of unilateral deep brain stimulation (DBS) on the control and coordination of grasping forces produced by Parkinson's disease (PD) patients. Ten advanced PD patients with unilateral DBS in the globus pallidus (GPi) or the subthalamic nucleus (STN) (5 patients in each group) performed a functional bimanual dexterous manipulation task. Experiments were performed in the "Off" medication state with DBS "On" and "Off. " DBS resulted in (a) significant clinical improvements, (b) greater maximum grip force for both limbs, (c) reduced movement time, and (d) bilateral coupling of grasping forces. There were no significant differences between the GPi and STN groups for any clinical or kinematic measures. DBS of the GPi and STN leads to an improvement in the motor functioning of advanced PD patients. Improvement in force-timing specification during DBS might allow PD patients to employ a feedforward method of force control.

Adult↗

Tolerance and tremor rebound following long-term chronic thalamic stimulation for Parkinsonian and essential tremor.

Fifty-eight patients, 36 with essential tremor (ET) and 22 with Parkinson's disease (PD), received deep brain stimulation (DBS) in the thalamic ventral intermediate (Vim) nucleus. The mean follow-up was 17 months for ET and 21 months for PD patients. Stimulation parameters were adjusted as needed, at various intervals after surgery. Results were assessed using routine clinical evaluation and established outcome scales. All patients needed incremental increase in stimulation parameters at various intervals during the first 6-12 months after surgery. The mean voltage 1 week postoperatively was 1. 45 V in PD patients, and 1.37 V in ET patients. Twelve months later, the figures were 2.14 V in PD and 2.25 V in ET patients. At 1 year, the Essential Tremor Rating Scale (ETRS) improved from 54 to 28 (p < 0.0001). The motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) improved from 37 to 26 (p < 0.01). Tremor items of the UPDRS improved more markedly (p < 0.0001). One week postoperatively 90% of PD, and 89% of ET patients were tremor free. One year later, 70% of PD and 60% of ET patients remained mostly tremor free. Upon switching off stimulation, there was a clear tendency for tremor rebound (p = 0.07) in the PD group, requiring continuous 24-hour stimulation in some patients. Permanent non-adjustable ataxia was induced by stimulation in 2 PD patients.

Electric Stimulation Therapy↗

Stimulation of the subthalamic nucleus compared with the globus pallidus internus in patients with Parkinson disease.

OBJECT: The authors compared the effects of deep brain stimulation (DBS) in the globus pallidus internus (GPi) with those in the subthalamic nucleus (STN) in patients with Parkinson disease (PD) in whom electrodes had been bilaterally implanted in both targets. METHODS: Eight of 14 patients with advanced PD in whom electrodes had been implanted bilaterally in both the GPi and STN for DBS were selected on the basis of optimal DBS effects and were studied 2 months postsurgery in off- and on-stimulus conditions and after at least 1 month of pharmacological withdrawal. Subcutaneous administration of an apomorphine test dose (0.04 mg/kg) was also performed in both conditions. Compared with the off status, the results showed less reduction in the Unified PD Rating Scale Section III scores during DBS in the GPi (43.1%) than during DBS of the STN (54.5%) or DBS of both the STN and GPi (57.1%). The difference between the effects of DBS in the GPi compared with that in the STN or simultaneous DBS was statistically significant (p < 0.01). In contrast, no statistical difference was found between DBS in the STN and simultaneous DBS in the STN and GPi (p < 0.9). The improvement induced by adding apomorphine administration to DBS was similar in all three stimulus modalities. The abnormal involuntary movements (AIMs) induced by apomorphine were almost abolished by DBS of the GPi, but were not affected by stimulation of the STN. The simultaneous stimulation of STN and GPi produced both antiparkinsonian and anti-AIM effects. CONCLUSIONS: The improvement of parkinsonian symptoms during stimulation of the GPi, STN, and both nuclei simultaneously may indicate a similar DBS mechanism for both nuclei in inducing antiparkinsonian effects, although STN is more effective. The antidyskinetic effects produced only by DBS of the GPi, with or without STN, may indicate different mechanisms for the antidyskinetic and antiparkinsonian activity related to DBS of the GPi or an additional mechanism in the GPi. These findings indicate that implantation of double electrodes for DBS should not be proposed as a routine procedure, but could be considered as a possible subsequent choice if electrode implantation for DBS of the STN does not control AIMs.

Adult↗

Electrophysiology of sensory and sensorimotor processing in mice under general anesthesia.

Like many other complex biological phenomena, sensory processing is starting to be studied at the level of the gene. Whereas the mouse is the standard organism for molecular neurobiology, somatosensation and pain are mainly investigated in the rat. The in-vitro electrophysiological technique is well established in mice. The effect of manipulations of the mouse genome on neuronal systems and networks has to be investigated under in-vivo conditions. Thus, the step from the rat to the smaller mouse seems to be important in terms of progress in molecular neurobiology. So far, there is no published study of sensory processing by electrophysiological means in mice under controlled general anesthesia. In this paper we describe a technique for electrophysiological recordings of sensory and sensorimotor processing in anesthetized mice. The mouse is anesthetized by continuous administration of the short-acting general anesthetic methohexital sodium salt via the jugular vein and artificially ventilated via a tracheotomy. The electrocardiogram and the carotid artery blood pressure are monitored. The sensorimotor jaw-opening reflex and the hindpaw withdrawal reflex are elicited by electric stimulation of the tongue and the sole of the hindpaw, respectively. The jaw-opening reflex is inhibited by deep brain stimulation of the rostral ventromedial medulla. On- and off-cells of the rostral ventromedial medulla and sensory neurons of the spinal trigeminal nucleus are extracellularly recorded by tungsten electrodes. General anesthesia can be reliably induced, maintained and sufficiently controlled in mice. Under this condition, studies can be performed on sensory processing in mice.

Action Potentials↗