European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part IV: deep brain stimulation.

In 2011 the European Society for the Study of Tourette Syndrome (ESSTS) published its first European clinical guidelines for the treatment of Tourette Syndrome (TS) with part IV on deep brain stimulation (DBS). Here, we present a revised version of these guidelines with updated recommendations based on the current literature covering the last decade as well as a survey among ESSTS experts. Currently, data from the International Tourette DBS Registry and Database, two meta-analyses, and eight randomized controlled trials (RCTs) are available. Interpretation of outcomes is limited by small sample sizes and short follow-up periods. Compared to open uncontrolled case studies, RCTs report less favorable outcomes with conflicting results. This could be related to several different aspects including methodological issues, but also substantial placebo effects. These guidelines, therefore, not only present currently available data from open and controlled studies, but also include expert knowledge. Although the overall database has increased in size since 2011, definite conclusions regarding the efficacy and tolerability of DBS in TS are still open to debate. Therefore, we continue to consider DBS for TS as an experimental treatment that should be used only in carefully selected, severely affected and otherwise treatment-resistant patients.

Bilateral double beta peaks in a PD patient with STN electrodes.

Subthalamic local field potentials in the beta band are considered as potential biomarkers for closed-loop deep brain stimulation. To investigate the subthalamic beta band peak amplitudes in a Parkinson's disease patient over an extended period of time by using a novel and commercially available neurostimulator with permanent sensing capability. We recorded local field potentials of the subthalamic nucleus using the Medtronic Percept™ implantable neurostimulator at rest and during physical activity (gait) with and in response to deep brain stimulation. We found a double-peaked beta activity on both sides. Increasing stimulation and physical activity resulted in a decreased beta band amplitude, but was accompanied by the appearance of a second, and previously unrecognized peak at 13 Hz in the right hemisphere. Our results will support the investigation of distinct different peaks in the beta band and their relevance and usefulness as closed-loop biomarkers.

[Trigeminal neuralgia : Modern diagnostic workup and treatment]. / Trigeminusneuralgie : Moderne Diagnostik und Therapie.

The present article gives an update of relevant aspects in the diagnosis and therapy of trigeminal neuralgia from the neurological, neuroradiological and neurosurgical point of view. The diagnosis of trigeminal neuralgia is clinical, but high-quality imaging is mandatory to identify secondary causes and a neurovascular contact. New methods such as DTI (diffusion tensor imaging) allow a more differentiated assessment of the consequences of a vascular contact on the trigeminal nerve. Carbamazepine and oxcarbazepine continue to be first choice for the medical treatment, but have been supplemented by additional options such as pregabaline, lamotrigine, and onabotulinumtoxin A. In patients insufficiently responding to medical treatment, there are neurosurgical treatment options giving very good results. The best long-term results have been described for microvascular decompression, but percutaneous and radiosurgical treatments also are good options, especially in patients with an increased surgical risk profile, in secondary trigeminal neuralgia, and in case of recurrence after microvascular decompression.

Inhibition of mitophagy decreases survival of Caenorhabditis elegans by increasing protein aggregation.

Autophagy of mitochondria, i.e., mitophagy, plays a crucial role in coping with stressors in the aging process, metabolic disturbances, and neurological disorders. Impairments of the process might consequently lead to enhanced accumulation of aged and aggregated proteins and reduced cellular integrity in response to stress. In the present study, we used the stress-sensitive mutant mev-1 of Caenorhabditis elegans to assess the effects of the knockdown of mitophagy relevant genes on survival under heat stress, the amount of autophagosomes, and on protein aggregation. RNA interference for dct-1, drp-1, eat-3, fis-1, fzo1, glb-1, pink-1, and pgam-5 all resulted in a significant reduction of survival time at 37 °C. These effects were associated with a decrease in autophagosomal flux of proteins, as indicated by increased accumulation of GFP-tagged SQST-1, and a reduced amount of lysosomes demonstrating that autophagy was hampered. Moreover, the gene knockdowns led to increased levels of reactive oxygen species in mitochondria and an enhanced protein aggregation. In conclusion, our studies show that mitophagy is of central importance to keep mitochondria functional in order to prevent production of excess reactive oxygen species and protein aggregation and finally a reduction of survival under heat stress.

Subthalamic stimulation, oscillatory activity and connectivity reveal functional role of STN and network mechanisms during decision making under conflict.

Inhibitory control is an important executive function that is necessary to suppress premature actions and to block interference from irrelevant stimuli. Current experimental studies and models highlight proactive and reactive mechanisms and claim several cortical and subcortical structures to be involved in response inhibition. However, the involved structures, network mechanisms and the behavioral relevance of the underlying neural activity remain debated. We report cortical EEG and invasive subthalamic local field potential recordings from a fully implanted sensing neurostimulator in Parkinson's patients during a stimulus- and response conflict task with and without deep brain stimulation (DBS). DBS made reaction times faster overall while leaving the effects of conflict intact: this lack of any effect on conflict may have been inherent to our task encouraging a high level of proactive inhibition. Drift diffusion modelling hints that DBS influences decision thresholds and drift rates are modulated by stimulus conflict. Both cortical EEG and subthalamic (STN) LFP oscillations reflected reaction times (RT). With these results, we provide a different interpretation of previously conflict-related oscillations in the STN and suggest that the STN implements a general task-specific decision threshold. The timecourse and topography of subthalamic-cortical oscillatory connectivity suggest the involvement of motor, frontal midline and posterior regions in a larger network with complementary functionality, oscillatory mechanisms and structures. While beta oscillations are functionally associated with motor cortical-subthalamic connectivity, low frequency oscillations reveal a subthalamic-frontal-posterior network. With our results, we suggest that proactive as well as reactive mechanisms and structures are involved in implementing a task-related dynamic inhibitory signal. We propose that motor and executive control networks with complementary oscillatory mechanisms are tonically active, react to stimuli and release inhibition at the response when uncertainty is resolved and return to their default state afterwards.

The role of the pallidothalamic fibre tracts in deep brain stimulation for dystonia: A diffusion MRI tractography study.

BACKGROUND: Deep Brain Stimulation (DBS) of the Globus pallidus internus (GPi) is gold standard treatment in medically refractory dystonia. Recent evidence indicates that stimulation effects are also due to axonal modulation and affection of a fibre network. For the GPi, the pallidothalamic tracts are known to be the major motor efferent pathways. The aim of this study is to explore the anatomic vicinity of these tracts and DBS electrodes in dystonia applying diffusion tractography. METHODS: Diffusion MRI was acquired in ten patients presenting for DBS for dystonia. We applied both a conventionally used probabilistic tractography algorithm (FSL) as well as a probabilistic streamline tracking approach, based on constrained spherical deconvolution and particle filtering with anatomic priors, to the datasets. DBS electrodes were coregistered to the diffusion datasets. RESULTS: We were able to delineate the pallidothalamic tracts in all patients. Using the streamline approach, we were able to distinguish between the two sub-components of the tracts, the ansa lenticularis and the fasciculus lenticularis. Clinically efficient DBS electrodes displayed a close anatomic vicinity pathway of the pallidothalamic tracts, and their course was consistent with previous tracer labelling studies. Although we present only anatomic data, we interpret these findings as evidence of the possible involvement of fibre tracts to the clinical effect in DBS. Electrophysiological intraoperative recordings would be needed to complement our findings. In the future, a clear and individual delineation of the pallidothalamic tracts could optimize the stereotactic process of optimal electrode localization. Hum Brain Mapp 38:1224-1232, 2017. © 2016 Wiley Periodicals, Inc.

Connectivity patterns of pallidal DBS electrodes in focal dystonia: a diffusion tensor tractography study.

Deep brain stimulation (DBS) of the internal pallidal segment (GPi: globus pallidus internus) is gold standard treatment for medically intractable dystonia, but detailed knowledge of mechanisms of action is still not available. There is evidence that stimulation of ventral and dorsal GPi produces opposite motor effects. The aim of this study was to analyse connectivity profiles of ventral and dorsal GPi. Probabilistic tractography was initiated from DBS electrode contacts in 8 patients with focal dystonia and connectivity patterns compared. We found a considerable difference in anterior-posterior distribution of fibres along the mesial cortical sensorimotor areas between the ventral and dorsal GPi connectivity. This finding of distinct GPi connectivity profiles further confirms the clinical evidence that the ventral and dorsal GPi belong to different functional and anatomic motor subsystems. Their involvement could play an important role in promoting clinical DBS effects in dystonia.

Onset latency of segmental dystonia after deep brain stimulation cessation: a randomized, double-blind crossover trial.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is an effective treatment for cervical dystonia (CD). Interestingly, the onset of initial DBS effects is significantly prolonged compared with that in other diseases, such as Parkinson's disease. The return of symptoms after cessation of DBS could be delayed as well, but this has not been studied systematically. METHODS: In patients who were treated for CD using DBS and had a good treatment effect, we compared interruption of DBS with sham-OFF in a randomized, double-blind crossover trial. RESULTS: We observed that dystonic features appeared within a few minutes at almost full intensity in all patients after the cessation of DBS. CONCLUSIONS: The almost immediate onset of dystonic features in our sample seems to exclude mechanisms with long time constants from the pathophysiology of dystonia. Thus, it is likely that, in these patients, an aberrant pattern of neural activity representing an inappropriate set point value for the position of the head is responsible for dystonia.

Early cranioplasty may improve outcome in neurological patients with decompressive craniectomy.

PRIMARY OBJECTIVE: Decompressive craniectomy is an effective therapy to relieve intractable intracranial hypertension following acute brain injury. However, little is known about the optimal timing for cranioplasties in the sub-acute phase. The objective of the present study was to analyse the effect of cranioplasty timing on neurological outcomes. RESEARCH DESIGN: Single-centre observational study. METHODS AND PROCEDURES: One hundred and forty-seven consecutive patients with decompressive craniectomy and cranioplasty during the course of inpatient neurorehabilitation were identified by means of a retrospective hospital database search. This database contains the following prospectively-entered weekly scores: Barthel-Index (BI), Functional Independence Measure (FIM) and Coma Remission Scale (CRS). Additional clinical data were taken retrospectively from patient charts. Regression analysis was used to identify factors that influenced the end-of-rehabilitation outcome. MAIN OUTCOMES AND RESULTS: Patients with shorter delays to cranioplasty (<86 days) had a better functional outcome than patients with longer delays of >85 days (60 ± 29.5 versus 25 ± 24.1 BI points; p < 0.01, respectively). Age, pre-operative BI and CRS scores were additional independent outcome factors. Complication rates were not different between early and late cranioplasty groups. CONCLUSIONS: Patients with decompressive craniectomy for management of intracranial hypertension may benefit from early cranioplasty.

Subthalamic oscillatory activity during normal and impaired speech.

OBJECTIVE: We studied the relationship between oscillatory activity in the subthalamic nucleus (STN) and speech production in order to better understand the functional role of the STN. METHODS: We simultaneously recorded subthalamic local field potentials and audio recordings from 5 patients with Parkinson's disease while they performed verbal fluency tasks. We then analyzed the oscillatory signals present in the subthalamic nucleus during these tasks. RESULTS: We report that normal speech leads to a suppression of subthalamic alpha and beta power. Contrarily, a patient with motor blocks during speech initiation showed a low beta power increase. We also report an increase in error rates in the phonemic non-alternating verbal fluency task during deep brain stimulation (DBS). CONCLUSIONS: We confirm previous findings that intact speech leads to desynchronization in the beta range in the STN. The speech related narrowband beta power increase in a patient with speech problems suggests that exaggerated synchronization in this frequency band is associated with motor blocks during speech initiation. The increased number of errors in verbal fluency tasks during DBS might be caused by an impairment of the response inhibition network caused by stimulation of the STN. SIGNIFICANCE: We suggest that the inability to attenuate beta activity during motor processes is associated with motor freezing across motor behaviours such as speech and gait, as previously shown for freezing of gait.

Movement kinematic after deep brain stimulation associated microlesions.

BACKGROUNDS: Deep brain stimulation is widely used for the treatment of movement disorders such as Parkinson's disease and dystonia. After the implantation of electrodes an immediate improvement of clinical symptoms has been described. It is unclear, whether movement kinematics are also changed by this 'microlesion effect'. METHODS: To gain further insight into these mechanisms, we studied arm, hand and finger movements preoperatively and immediately after the implantation of deep brain stimulation electrodes in patients with Parkinson's disease and dystonia. RESULTS: After implantation and without stimulation there was a clear reduction of clinical symptoms in both groups, as has been described previously. However, movement velocity was affected differently. Parkinsonian patients showed increased movement velocity postoperatively, whereas dystonic patients were significantly slower after electrode implantation. CONCLUSIONS: Lesioning and stimulation of these structures have the same beneficial clinical effects. Furthermore we suggest that globus pallidus internum lesions act by inhibiting a system which mainly acts upon muscular tone and limb posture whereas subthalamic stimulation or lesion causes a more unspecific disinhibition of movements.

Evidence of a non-motor microlesion effect following deep brain surgery: a case report.

We report the case of a patient who developed acute transient psychosis after implantation, but not activation of pallidal deep brain electrodes for generalised dystonia. Psychotic symptoms coincided temporally with postoperative motor improvement induced by the microlesion effect after electode implantation. This finding suggests that the microlesion effect may not be confined to motor improvement, but also comprises non-motor symptoms. In our case, affection of adjacent dopaminergic fibres of passages has to be assumed.

The human thalamus orchestrates neocortical oscillations during NREM sleep.

A hallmark of non-rapid eye movement sleep is the coordinated interplay of slow oscillations (SOs) and sleep spindles. Traditionally, a cortico-thalamo-cortical loop is suggested to coordinate these rhythms: neocortically-generated SOs trigger spindles in the thalamus that are projected back to neocortex. Here, we used intrathalamic recordings from human epilepsy patients to test this canonical interplay. We show that SOs in the anterior thalamus precede neocortical SOs (peak -50 ms), whereas concurrently-recorded SOs in the mediodorsal thalamus are led by neocortical SOs (peak +50 ms). Sleep spindles, detected in both thalamic nuclei, preceded their neocortical counterparts (peak -100 ms) and were initiated during early phases of thalamic SOs. Our findings indicate an active role of the anterior thalamus in organizing sleep rhythms in the neocortex and highlight the functional diversity of thalamic nuclei in humans. The thalamic coordination of sleep oscillations could have broad implications for the mechanisms underlying memory consolidation.

Peaks in the beta band of the human subthalamic nucleus: a case for low beta and high beta activity.

OBJECTIVE: Peaks in the beta band of local field potentials (LFPs) may serve as a biological feedback signal for closed-loop deep brain stimulation (DBS) in Parkinson's disease (PD). However, the specific frequency of such peaks and their response to DBS and to different types of movement remains uncertain. In the present study, the authors examined the abundance of discernible peaks in the beta band and the effect of different types of movement and DBS on these peaks. METHODS: Subthalamic nucleus LFPs were analyzed from 38 patients with PD in a frequency range between 10 and 35 Hz, as well as the impact of movement (gait, hand movements) and electrical stimulation on these peaks. The position of the electrode segments from which LFPs were recorded was computed. RESULTS: The authors found a bimodal distribution of peaks in the beta band with discernible high- (27 Hz) and low-frequency (15 Hz) peaks. Movement of either hand had no significant effect on these peaks, whereas walking significantly reduced high-frequency beta peaks but not the peaks in the low beta band. Stimulation caused an amplitude-dependent suppression of both peaks. CONCLUSIONS: DBS suppresses LFP beta peaks of different frequencies, whereas beta suppression caused by movement is dependent on the type of movement and frequency of the peak. These results will support the investigation of distinct LFP spectra for the application of closed-loop DBS.

Alpha frequency modulation in the human basal ganglia is dependent on motor task.

Depth recordings from the basal ganglia of patients suffering from Parkinson's disease (PD) or dystonia have revealed local field potential (LFP) activity in specific frequency bands. Depth recordings also allow us to study LFP power spectra during different types of limb movements, thus helping to elucidate the role of the basal ganglia in specific motor tasks. Accordingly, we recorded bilateral LFP activity from the subthalamic nucleus (STN) of patients with PD (n=9) and from the globus pallidus internum (GPi) of patients with dystonia (n=8). Recordings were taken during the performance of repetitive passive, active and ballistic fast extensions and flexions of the elbow joint and during rest. The first result was that the frequency spectra varied task-specifically in a similar fashion in GPi and STN. The amplitude of the alpha frequency on the contralateral side was significantly higher in ballistic fast movements compared with rest, passive and active performance in both STN and GPi. In conclusion, ballistic fast movements cause synchronized basal ganglia activity in the alpha range. Because this was seen in both patient groups (PD and dystonia) we consider this activity as task-specific rather than disease-related.

Trigeminal neuralgia due to neurovascular compression: high-spatial-resolution diffusion-tensor imaging reveals microstructural neural changes.

PURPOSE: To preoperatively detect, by using diffusion-tensor imaging coregistered with anatomic magnetic resonance (MR) imaging, suspected microstructural tissue changes of the trigeminal nerves in patients with trigeminal neuralgia (TN) resulting from neurovascular compression. MATERIALS AND METHODS: The study was approved by the institutional review board, and written informed consent was obtained from all patients. Twenty patients (mean age, 51.3 years) with TN and evidence of neurovascular contact were examined with use of a 3.0-T MR unit combined with an eight-channel head coil before undergoing surgical decompression. A single-shot diffusion-tensor echo-planar sequence was used along 15 different diffusion directions, with a b value of 1000 sec/mm(2) and a section thickness of 2 mm. For anatomic correlation, 0.6-mm isotropic three-dimensional fast imaging employing steady-state images were acquired for coregistration with the functional diffusion-tensor maps. After region of interest placement, mean fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were calculated for each nerve by using the paired-sample two-tailed t test (with P < .005 indicating significance) and compared with surgical findings. RESULTS: FA was significantly lower (P = .004) on the trigeminal neuralgia-affected side (mean FA, 0.203) than on the contralateral side (mean FA, 0.239). ADCs were nearly identical between the normal and TN-affected nerve tissues. CONCLUSION: These findings suggest that diffusion-tensor imaging enables the identification and quantification of anisotropic changes between normal nerve tissue and TN-affected trigeminal nerves. Coregistration of anatomic three-dimensional fast imaging employing steady-state imaging and diffusion-tensor imaging facilitates excellent delineation of the cisternal segments of the trigeminal nerves.

Long-term results of electroconvulsive therapy in severe Gilles de la Tourette syndrome.

To avoid chronic distress and increasing social isolation, patients with severe, medication-resistant Gilles de la Tourette syndrome (GTS) require treatment alternatives. Electroconvulsive therapy (ECT) is such an alternative treatment, which, however, is rarely mentioned in the literature: a Pubmed search revealed only 7 reports on GTS and ECT, and there were no long-term data on continuously applied maintenance ECT in GTS. This report is the first to document a 5-year-long, full remission from severe GTS after long-term ECT.

Microvascular decompression for trigeminal neuralgia in the elderly: efficacy and safety.

OBJECTIVE: The safety and efficacy of surgical microvascular decompression (MVD) in elderly patients with trigeminal neuralgia (TN) is controversially discussed in the literature. A widespread reluctance to expose this cohort to major intracranial surgery persists. Our aim was to compare the efficacy and safety between older and younger patients with TN. METHODS: In this cross-sectional study, 139 MVD procedures (103 patients < 70 and 36 patients ≥ 70) were included. Surgical fitness was assessed by the American Society of Anesthesiology (ASA) grade. The pain-free interval was evaluated using Kaplan-Meier analysis only in patients with a recent follow-up visit. Independent risk factors for recurrence in patients with a minimum 12-month follow-up were determined. RESULTS: Patients ≥ 70 showed a significantly higher number of comorbidities. Pain intensity, affection of trigeminal branches and symptom duration was similar between groups. No significant difference in treatment associated complications and permanent neurological deficits was shown. There was no treatment-related mortality. A tendency towards a lower recurrence rate in patients < 70 did not reach statistical significance (17.6% vs. 28.6%, P = 0.274). Pain-free interval was not different between both cohorts (78.7 vs. 73.5 months, P = 0.391). CONCLUSION: Despite a higher prevalence of comorbidities in elderly patients, complication rates and neurological deficits after MVD were comparable to younger patients. Rates of immediate and long-term pain relief compared favorably to previous studies and were similar between elderly and younger patients. These data endorse MVD as a safe and effective first-line surgical procedure for elderly patients with TN and neurovascular conflict on MRI.

Long-term effect of bilateral STN-DBS on non-motor symptoms in Parkinson's disease: A four-year observational, prospective study.

BACKGROUND: Several studies have shown beneficial effects of bilateral stimulation of the subthalamic nucleus (STN-DBS) on motor as well as on non-motor symptoms (NMS) up to 36 months post-surgery in advanced Parkinson's disease (PD) patients. We set to explore the long-term effect of STN-DBS on NMS in a four-year follow-up, prospective, observational study. METHODS: Forty patients were enrolled and assessed at baseline. Twenty-eight were followed-up at 6, 12, 24, 36 and 48 months after the operation. The effect of post-operative time on NMS was analyzed by six-level repeated measures ANOVA. In a post-hoc analysis the follow-up scores were compared to baseline using a paired t-test. RESULTS: The following scores stayed improved up to 24 months after surgery, presented as baseline/24 months, p-value (t-test): total Non-Motor Symptoms Scale score (54.0 ± 5.6/44.9 ± 5.0, p = 0.029), Hamilton Anxiety Scale (14.3 ± 1.3/11.3 ± 1.2, p = 0.019) and PDQ39 (53.4 ± 4.5/40.2 ± 2.9, p = 0.012). PD Sleep Scale 2 remained improved throughout the study (17.4 ± 2.0/12.8 ± 1.3 at 48 months, p = 0.032), while Beck Depression Inventory only at six months post-surgery (9.5 ± 1.2/6.7 ± 0.7 at 6 months, p = 0.006). Montreal Cognitive Assessment remained stable up to 24 months and then declined at 36 months (26.3 ± 0.5/25.4 ± 0.5 at 36 months, p = 0.003), Starkstein Apathy Scale deteriorated throughout the study (7.6 ± 0.7/12.7 ± 0.9 at 48 months, p = 0.006). CONCLUSIONS: We observed beneficial effect of STN-DBS in several but not all domains of NMS at least up to 24 months post-op in advanced PD. Further long-term studies on larger cohorts of PD patients and longer follow-up need to be conducted to better understand the long-term effect of STN-DBS on NMS.

What have we learned from 8 years of deep brain stimulation of the anterior thalamic nucleus? Experiences and insights of a single center.

OBJECTIVE: In the absence of a standard or guideline for the treatment of epilepsy patients with deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT), systematic single-center investigations are essential to establish effective approaches. Here, the authors report on the long-term results of one of the largest single-center ANT DBS cohorts. METHODS: The outcome data of 23 consecutive patients with transventricularly implanted electrodes were retrospectively analyzed with regard to adverse events, lead placement, stimulation-related side effects, and changes in seizure frequency. Depression and quality-of-life scores were collected in a subgroup of 9 patients. RESULTS: All but 2 patients initially underwent bilateral implantation, and 84.4% of all DBS leads were successfully located within the ANT. The mean follow-up time was 46.57 ± 23.20 months. A seizure reduction > 50% was documented in 73.9% of patients, and 34.6% achieved an Engel class I outcome. In 3 patients, clinical response was achieved by switching the electrode contact or changing from the monopolar to bipolar stimulation mode. Unilateral implantation seemed ineffective, whereas bilateral stimulation with successful ANT implantation only on one side led to a clinical response. Double stimulation with additional vagus nerve stimulation was safe. Changes in cycling mode or stimulation amplitude influenced therapy tolerability and, only to a lesser extent, seizure frequency. Side effects were rare and typically vanished by lowering the stimulation amplitude or changing the active electrode contact. Furthermore, depression and aspects of quality of life significantly improved with ANT DBS treatment. CONCLUSIONS: The transventricular approach as well as double stimulation proved safe. The anteroventral ANT appeared to be the most efficacious stimulation site. This systematic investigation with reluctant medication changes allowed for the development of a better idea of the association between parameter changes and outcome in ANT DBS patients, but larger samples are still needed to assess the potential of bipolar stimulation and distinct cycling frequencies. Furthermore, more multifaceted and objective assessments of treatment outcome are needed to fully assess the effects of ANT DBS treatment.