Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Bilateral staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of essential tremor: a case series study.

BACKGROUND: Unilateral magnetic resonance-guided focused ultrasound (FUS) thalamotomy is efficacious for the treatment of medically refractory essential tremor (ET). Viability of bilateral FUS ablation is unexplored. METHODS: Patients diagnosed with medically refractory ET and previously treated with unilateral FUS thalamotomy at least 5 months before underwent bilateral treatment. The timepoints were baseline (before first thalamotomy) and FUS1 and FUS2 (4 weeks before and 6 months after second thalamotomy, respectively). The primary endpoint was safety. Efficacy was assessed through the Clinical Rating Scale for Tremor (CRST), which includes subscales for tremor examination (part A), task performance (part B) and tremor-related disability (part C). RESULTS: Nine patients were treated. No permanent adverse events were registered. Six patients presented mild gait instability and one dysarthria, all resolving within the first few weeks. Three patients reported perioral hypoesthesia, resolving in one case. Total CRST score improved by 71% from baseline to FUS2 (from 52.3±12 to 15.5±9.4, p<0.001), conveying a 67% reduction in bilateral upper limb A+B (from 32.3±7.8 to 10.8±7.3, p=0.001). Part C decreased by 81% (from 16.4±3.6 to 3.1±2.9, p<0.001). Reduction in head and voice tremor was 66% (from 1.2±0.44 to 0.4±0.54, p=0.01) and 45% (from 1.8±1.1 to 1±0.8, p=0.02), respectively. CONCLUSION: Bilateral staged FUS thalamotomy for ET is feasible and might be safe and effective. Voice and head tremor might also improve. A controlled study is warranted.

MDS evidence-based review of treatments for essential tremor.

BACKGROUND: Essential tremor is one of the most prevalent movement disorders. Many treatments for essential tremor have been reported in clinical practice, but it is uncertain which options have the most robust evidence. The International Parkinson and Movement Disorder Society commissioned a task force on tremor to review clinical studies of treatments for essential tremor. OBJECTIVES: To conduct an evidence-based review of current pharmacological and surgical treatments for essential tremor, using standardized criteria defined a priori by the International Parkinson and Movement Disorder Society. METHODS: We followed the recommendations of the International Parkinson and Movement Disorder Society Evidence Based Medicine Committee. RESULTS: Sixty-four studies of pharmacological and surgical interventions were included in the review. Propranolol and primidone were classified as clinically useful, similar to Topiramate, but only for doses higher than 200 mg/day. Alprazolam and botulinum toxin type A were classified as possibly useful. Unilateral Ventralis intermedius thalamic DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy were considered possibly useful. All the above recommendations were made for limb tremor in essential tremor. There was insufficient evidence for voice and head tremor as well as for the remaining interventions. CONCLUSION: Propranolol, primidone, and topiramate (>200 mg/day) are the pharmacological interventions in which the data reviewed robustly supported efficacy. Their safety profile and patient preference may guide the prioritization of these interventions in clinical practice. MRI-guided focused ultrasound thalamotomy was, for the first time, assessed and was considered to be possibly useful. There is a need to improve study design in essential tremor and overcome the limitation of small sample sizes, cross-over studies, short-term follow-up studies, and use of nonvalidated clinical scales. © 2019 International Parkinson and Movement Disorder Society.

Movement disorders in multiple sclerosis and their treatment.

Hyperkinetic movement disorders such as tremors are not uncommon in patients with multiple sclerosis (MS). The classical feature is intention tremor, whereas rest tremors appear not to occur. Treatment is mainly invasive, with options of Gamma Knife surgery, thalamotomy or deep brain stimulation depending on individual circumstances. Deep brain stimulation is the only option for patients who require a bilateral intervention. All treatment recommendations have only low evidence. Tremors can also be cured spontaneously by a subsequent strategic MS lesion. Paroxysmal dyskinesias are rarer than tremors. The rarest MS movement disorder is symptomatic paroxysmal choreoathetosis, tonic spasms or 'brain stem fits'; attacks are short but frequent, up to 200 per day and generally respond well to carbamazepine.

Cost-effectiveness of neurostimulation in Parkinson's disease with early motor complications.

BACKGROUND: Recent research efforts have focused on the effects of deep brain stimulation of the subthalamic nucleus (STN DBS) for selected patients with mild-to-moderate PD experiencing motor complications. OBJECTIVES: We assessed the cost utility of subthalamic DBS compared with the best medical treatment for German patients below the age of 61 with early motor complications of PD. METHODS: We applied a previously published Markov model that integrated health utilities based on EuroQoL and direct costs over patients' lifetime adjusted to the German health care payer perspective (year of costing: 2013). Effectiveness was evaluated using the Parkinson's Disease Questionnaire 39 summary index. We performed sensitivity analyses to assess uncertainty. RESULTS: In the base-case analysis, the incremental cost-utility ratio for STN DBS compared to best medical treatment was 22,700 Euros per quality-adjusted life year gained. The time to, and costs for, battery exchange had a major effect on the incremental cost-utility ratios, but never exceeded a threshold of 50,000 Euros per quality-adjusted life year. CONCLUSIONS: Our decision analysis supports the fact that STN DBS at earlier stages of the disease is cost-effective in patients below the age of 61 when compared with the best medical treatment in the German health care system. This finding was supported by detailed sensitivity analyses reporting robust results. Whereas the EARLYSTIM study has shown STN DBS to be superior to medical therapy with respect to quality of life for patients with early motor complications, this further analysis has shown its cost-effectiveness. © 2016 International Parkinson and Movement Disorder Society.

The pathophysiology of essential tremor and Parkinson's tremor.

We review recent evidence about the pathophysiology of essential tremor and tremor in Parkinson's disease. We believe that a network perspective is necessary to understand this common neurological symptom, and that knowledge of cerebral network dysfunction in tremor disorders will help to develop new therapies. Both essential tremor and Parkinson's tremor are associated with increased activity in the cerebellothalamocortical circuit. However, different pathophysiological mechanisms lead to tremulous activity within this circuit. In Parkinson's disease, evidence suggests that dopaminergic dysfunction of the pallidum triggers increased activity in the cerebellothalamocortical circuit. In essential tremor, GABAergic dysfunction of the cerebellar dentate nucleus and brain stem, possibly caused by neurodegeneration in these regions, may lead to tremulous activity within the cerebellothalamocortical circuit. In both disorders, network parameters such as the strength and directionality of interregional coupling are crucially altered. Exciting new research uses these network parameters to develop network-based therapies, such as closed-loop deep brain stimulation and transcranial magnetic or direct current stimulation.

Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: concept and standards of the EARLYSTIM-study.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson's disease (PD) with disabling motor complications. However, stimulation may be beneficial at an earlier stage of PD when motor fluctuations and dyskinesia are only mild and psychosocial competence is still maintained. The EARLYSTIM trial was conducted in patients with recent onset of levodopa-induced motor complications (≤ 3 years) whose social and occupational functioning remained preserved. This is called 'early' here. The study was a randomized, multicenter, bi-national pivotal trial with a 2 year observation period. Quality of life was the main outcome measure, and a video-based motor score was a blinded secondary outcome of the study. Motor, neuropsychological, psychiatric and psychosocial aspects were captured by established scales and questionnaires. The patient group randomized here is the earliest in the disease course and the youngest recruited in controlled DBS trials so far. The methodological innovation for DBS-studies of this study lies in novel procedures developed and used for monitoring best medical treatment, neurosurgical consistency, best management of stimulation programming, blinded video assessment of motor disability, and prevention of suicidal behaviors.

Subcortical substrates of TMS induced modulation of the cortico-cortical connectivity.

BACKGROUND: Transcranial magnetic stimulation (TMS) can modulate transiently the physiological brain oscillations, e.g. the alpha rhythm. It has been hypothesized that this effect is not limited to the stimulated region but involves subcortical and distant cortical areas. METHODS: We applied single pulse TMS to the primary motor cortex (M1) of healthy subjects to interfere the cortical oscillatory activity recorded by simultaneous EEG and calculated the cortico-cortical coherence and power in the alpha and beta band. To study the structural substrate of the functional connectivity we performed diffusion tensor imaging and fractional anisotropy analysis (FA). To capture the pathways involved we applied probabilistic tractography to reconstruct the entire network. RESULTS: Suprathreshold TMS of M1 induced a consistent enhancement of interhemispheric cortico-cortical alpha band coherence that lasted ca. 175 ms. after the pulse has been applied. The changes were confined to the interhemispheric central EEG electrodes (i.e. C3-C4). There were no consistent changes in the beta band. Power analysis revealed a longer lasting increase in the beta band after TMS pulses. A cluster in the contralateral thalamus showed a linear relationship between regional FA and TMS induced change in alpha band coherence. Probabilistic tractography presents the transcallosal and the contralateral thalamocortical pathways as essential for the observed oscillatory synchronisation. CONCLUSION: TMS induces an enhancement of oscillatory interaction between corresponding central regions of both hemispheres in the alpha band. The contralateral thalamus, transcallosal fibres and the contralateral thalamocortical pathways may constitute critical brain structures mediating the TMS induced change in oscillatory coupling.

Lower limb joints kinematics in essential tremor and the effect of thalamic stimulation.

Following the hypothesis that thalamic deep brain stimulation improves ataxia in patients with essential tremor by modulating the cerebello-thalamo-cortical pathway, we examined the joint kinematics of lower limbs during uninterrupted gait in eleven patients who have been treated with bilateral thalamic stimulation for 24.7±20.3 months. Patients were assessed under routine chronic stimulation, supra-therapeutic amplitude, and off stimulation by means of an infrared movement analysis system while walking on a treadmill. Chronic thalamic DBS normalized the highly variable excursion throughout the gait cycle that characterized the subgroup of patients with longest disease duration. Supratherapeutic thalamic DBS amplitude did not reproduce such improvements while, more importantly, it induced ataxic changes of joint excursion. The normalization of kinematic abnormalities argues against the hypothesis of a cerebellar neurodegeneration in ET. Moreover, these results suggest that the beneficial effect of thalamic DBS on ataxic symptoms is limited to a narrow therapeutic window.

Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?

Tremor in Parkinson's disease has several mysterious features. Clinically, tremor is seen in only three out of four patients with Parkinson's disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion in Parkinson's disease, and the cerebello-thalamo-cortical circuit, which is also involved in many other tremors. The purpose of this review is to integrate these clinical and pathophysiological features of tremor in Parkinson's disease. We first describe clinical and pathological differences between tremor-dominant and non-tremor Parkinson's disease subtypes, and then summarize recent studies on the pathophysiology of tremor. We also discuss a newly proposed 'dimmer-switch model' that explains tremor as resulting from the combined actions of two circuits: the basal ganglia that trigger tremor episodes and the cerebello-thalamo-cortical circuit that produces the tremor. Finally, we address several important open questions: why resting tremor stops during voluntary movements, why it has a variable response to dopaminergic treatment, why it indicates a benign Parkinson's disease subtype and why its expression decreases with disease progression.

White matter microstructural changes of thalamocortical networks in photosensitivity and idiopathic generalized epilepsy.

PURPOSE: Photosensitivity or photoparoxysmal response (PPR) is an electroencephalography trait that is highly associated with idiopathic generalized epilepsies (IGEs) and characterized by changes in cortical excitability in response to photic stimulation. Studying functional and structural changes of PPR might provide important insights into the pathogenesis of IGE. Recent studies revealed a functional network consisting of occipital, parietal, and precentral areas that might be implicated in PPR. Herein, we investigate the microstructural changes associated with PPR. METHODS: Twelve healthy subjects with PPR, nine patients with IGE and PPR (IGE-PPR group), and 18 healthy controls were studied with diffusion magnetic resonance imaging. Tract-based spatial statistics were used to test for regional differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity between groups. KEY FINDINGS: Subjects with PPR exhibited higher FA in the right precentral juxtacortical white matter and higher MD in lateral occipital areas relative to controls. Patients with IGE-patients showed additional increases in regional FA in the thalamus and juxtacortical precentral and parietal areas. Both subjects with PPR and patients with IGE-PPR presented axial and radial diffusivity changes in the occipital regions. SIGNIFICANCE: Our results show that PPR is associated with subcortical microstructural changes in precentral, parietal, and occipital regions. The coexistence of PPR and IGE is associated with white matter abnormalities in the thalamus and precuneus. PPR and epilepsy share similar functional and structural networks in widespread cortical and subcortical areas.

The oscillating central network of Essential tremor.

Essential tremor (ET) is a centrally driven tremor. It is meanwhile well established that it does not emerge from one single oscillator but an oscillatory network comprising most parts of the physiological central motor network. Several lines of evidence hint at the olivocerebellar system and the thalamus as key structures within this network whereas the cortical motor regions are only intermittently entrained in the tremor rhythm in thalamocortical loops. Dynamic changes in network composition and the interaction in symmetric loops seem to be specific to the generation of tremor. The same network in voluntary motor control is more fixed and subcortico-cortical interactions are preferentially via thalamocortical relays. Thus it is not primarily the network topography but the dynamics and interaction within the network that determines whether involuntary tremor or voluntary movements emerge. And this may be the basis for the selective effect of deep brain stimulation on tremor.

Gait ataxia in essential tremor is differentially modulated by thalamic stimulation.

Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 ± 3.9 years; disease duration 24.4 ± 11.2 years; follow-up after surgery 24.7 ± 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra-therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra-therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation).

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

Involvement of the mitochondrial ATP-sensitive potassium channel in the neuroprotective effect of hyperbaric oxygenation after cerebral ischemia.

In the present study, we investigated whether activation of mitochondrial ATP-sensitive potassium channel is involved in the neuroprotective effect offered by early hyperbaric oxygenation after cerebral ischemia. The selective mitochondrial ATP-sensitive potassium channel antagonist 5-hydroxydecanoate was infused intracerebroventricularly before hyperbaric oxygenation treatment initiated 3 h after middle cerebral artery occlusion for 90 min. Neurological status was evaluated and brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis 24 h after middle cerebral artery occlusion. Early hyperbaric oxygenation treatment improved neurologic deficits and reduced infarct volume, while these effects were reversed by the administration of 5-hydroxydecanoate. Furthermore, early hyperbaric oxygenation significantly decreased the number of apoptotic cells in the peri-infarct cortex 24 h after ischemic insult and this effect was also blocked by 5-hydroxydecanoate. The present findings suggest that early hyperbaric oxygenation therapy prevents apoptosis and promotes neurologic functional recovery after focal cerebral ischemia, and the opening of mitochondrial ATP-sensitive potassium channel plays a role in this antiapoptotic effect of early hyperbaric oxygenation.

Most effective stimulation site in subthalamic deep brain stimulation for Parkinson's disease.

The optimal stimulation site in subthalamic deep brain stimulation (STN-DBS) was evaluated by correlation of the stereotactic position of the stimulation electrode with the electrophysiologically specified dorsal STN border. In a series of 25 electrodes, best clinical results with least energy consumption were found in contacts located in the dorsolateral border zone, whereas contacts within the subthalamic white matter, e.g., zona incerta, were significantly less effective. We suggest that the dorsolateral STN border should be covered by STN-DBS.

Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease.

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

Therapeutic window for use of hyperbaric oxygenation in focal transient ischemia in rats.

BACKGROUND AND PURPOSE: Hyperbaric oxygenation (HBO) is an attractive procedure that has been used frequently in cerebral ischemia. However, depending on the model of cerebral ischemia and HBO protocol, different and conflicting results were obtained in the past. This study was undertaken to reevaluate the effects of single administration of HBO in 2 models of acute cerebral ischemia: transient or permanent focal ischemia in rats. A comparison of the 2 ischemia models was undertaken to search for a putative therapeutic window. METHODS: The intraluminal middle cerebral artery occlusion model (MCAO) was used. The effect of single HBO therapy (3 atm absolute, 60 minutes) on transient or permanent focal ischemia, when applied at different times (3, 6, or 12 hours) after MCAO, was investigated; infarct volume and neurological deficits were assessed at 24 hours and up to 7 days. RESULTS: HBO had neuroprotective effects on transient MCAO when HBO was initiated within the first 6 hours, while it aggravated the ischemic injury histologically and clinically when initiated 12 hours after MCAO. In permanent MCAO, HBO did not reduce tissue damage regardless of the timing of therapy. CONCLUSIONS: HBO is highly efficient in reducing infarct volume and improving neurobehavioral outcome in transient MCAO within the first 6 hours. HBO at later time points (>or=12 hours) is harmful by increasing infarct volume. In permanent MCAO, HBO failed to improve infarct volume and clinical outcome.