Non-lesional treatment options for tremor in idiopathic Parkinson syndrome: a protocol for a systematic literature review.

INTRODUCTION: Idiopathic Parkinson syndrome (iPS) is one of the most common neurodegenerative disorders characterised by the triad of bradykinesia, rigidity and tremor. Tremor at rest predominantly at one side is often perceived by patients as severely disabling and yet ranges among the most difficult symptoms to treat. In medically refractory cases, lesional approaches have proven to be effective alternatives. However, to date, there is no comprehensive analysis of non-surgical therapies to manage iPS-patients' tremor. We therefore present a detailed study protocol for a systematic literature review assessing efficacy/effectiveness and safety of non-lesional treatments for tremor in iPS. METHODS AND ANALYSIS: We will search three electronic databases (MEDLINE, EMBASE and PsycINFO) using a combination of title/abstract keywords. Additionally, hand-searched reference and citation lists of key reviews identified through the search strategy will be screened. Eligible studies should investigate the efficacy/effectiveness and safety of therapeutic options for tremor in iPS excluding lesional interventions. Publications will be independently assessed for inclusion criteria by two investigators and study information summarised using a standardised template including quality assessment according to the QualSyst tool. We will provide a narrative synthesis of results and conduct a meta-analysis whenever possible. ETHICS AND DISSEMINATION: We commit to present contemporary evidence on the efficacy/effectiveness and safety of non-lesional interventions for tremor in iPS in a future publication. We aim to compile rich data of published studies to inform healthcare professionals in order to ultimately improve patient outcomes. PROSPERO REGISTRATION NUMBER: CRD42020202911).

A functional micro-electrode mapping of ventral thalamus in essential tremor.

Deep brain stimulation enables the delivery of therapeutic interventions to otherwise inaccessible areas of the brain while, at the same time, offering the unique opportunity to record from these same regions in awake patients. The posterior ventrolateral thalamus has become a reliable deep brain stimulation target for medically-refractory patients suffering from essential tremor. However, the contribution of the thalamus in essential tremor, and even whether posterior ventrolateral thalamus is the optimal target, remains a matter of ongoing debate. There are several lines of evidence supporting clusters of activity within the posterior ventrolateral thalamus that are important for tremor emergence. In this study we sought to map the functional properties of these clusters through microelectrode recordings during deep brain stimulation surgery. Data were obtained from 10 severely affected patients with essential tremor (12 hemispheres) undergoing deep brain stimulation surgery. Our results demonstrate power and coherence maxima located in the inferior posterior ventrolateral thalamus and immediate ventral region. Moreover, we identified distinct yet overlapping clusters of predominantly efferent (driving) and afferent (feedback) activity, with a preference for more efferent contributors, consistent with a net role in the driving of tremor output. Finally, we demonstrate that resolvable thalamic spiking activity directly relates to background activity and that the strength of tremor may be dictated by phase relationships between efferent and afferent pockets in the posterior ventrolateral thalamus. Taken together, these results provide important evidence for the role of the inferior posterior ventrolateral thalamus and its border region in essential tremor pathophysiology. Such results progress our mechanistic understanding and promote the adoption of next-generation therapies such as high resolution segregated deep brain stimulation electrodes.

Stimulating at the right time: phase-specific deep brain stimulation.

SEE MOLL AND ENGEL DOI101093/AWW308 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Brain regions dynamically engage and disengage with one another to execute everyday actions from movement to decision making. Pathologies such as Parkinson's disease and tremor emerge when brain regions controlling movement cannot readily decouple, compromising motor function. Here, we propose a novel stimulation strategy that selectively regulates neural synchrony through phase-specific stimulation. We demonstrate for the first time the therapeutic potential of such a stimulation strategy for the treatment of patients with pathological tremor. Symptom suppression is achieved by delivering stimulation to the ventrolateral thalamus, timed according to the patient's tremor rhythm. Sustained locking of deep brain stimulation to a particular phase of tremor afforded clinically significant tremor relief (up to 87% tremor suppression) in selected patients with essential tremor despite delivering less than half the energy of conventional high frequency stimulation. Phase-specific stimulation efficacy depended on the resonant characteristics of the underlying tremor network. Selective regulation of neural synchrony through phase-locked stimulation has the potential to both increase the efficiency of therapy and to minimize stimulation-induced side effects.

Thalamomuscular coherence in essential tremor: hen or egg in the emergence of tremor?

Thalamomuscular coherence in essential tremor (ET) has consistently been detected in numerous neurophysiological studies. Thereby, spatial properties of coherence indicate a differentiated, somatotopic organization; so far, however, little attention has been paid to temporal aspects of this interdependency. Further insight into the relationship between tremor onset and the onset of coherence could pave the way to more efficient deep brain stimulation (DBS) algorithms for tremor. We studied 10 severely affected ET patients (six females, four males) during surgery for DBS-electrode implantation and simultaneously recorded local field potentials (LFPs) and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm during its elevation. The temporal relationship between the onset of significant wavelet cross spectrum (WCS) and tremor onset was determined. Moreover, we examined the influence of electrode location within one recording depth on this latency and the coincidence of coherence and tremor for depths with strong overall coherence ("tremor clusters") and those without. Data analysis revealed tremor onset occurring 220 ± 460 ms before the start of significant LFP-EMG coherence. Furthermore, we could detect an anterolateral gradient of WCS onset within one recording depth. Finally, the coincidence of tremor and coherence was significantly higher in tremor clusters. We conclude that tremor onset precedes the beginning of coherence. Besides, within one recording depth there is a spread of the tremor signal. This reflects the importance of somatosensory feedback for ET and questions the suitability of thalamomuscular coherence as a biomarker for "closed-loop" DBS systems to prevent tremor emergence.

Verbal fluency in essential tremor patients: the effects of deep brain stimulation.

OBJECTIVE: To assess the effects of different frequencies of thalamic Deep-Brain-Stimulation (DBS) on cognitive performance of patients suffering from Essential Tremor (ET). METHODS: In 17 ET-patients with thalamic-DBS, Tremor-Rating-Scale (TRS), standardized phonemic and semantic verbal fluency (VF), Stroop-Color-Word-Test and Digit-span-test were investigated in three randomized stimulation-settings: i) high-frequency stimulation (HFS), ii) low-frequency stimulation (LFS) and iii) OFF-stimulation (DBS-OFF). Paired-samples t-test for TRS and one-way repeated measures analysis of variance for cognitive performance were calculated. RESULTS: Tremor was reduced during HFS (MeanTRS-HFS = 12.9 ± 9.6) compared to DBS-OFF (MeanTRS-OFF = 44.4 ± 19.8, P < .001) and to LFS (MeanTRS-10 Hz = 50.0 ± 24.2; P < .001). While performance of Stroop-task and digit-span remained unaffected by stimulation-settings (P > .05), phonemic and semantic VF differed significantly between the three conditions (FPvf = 5.28, FSvf = 3.41, both P < .05). Post-hoc comparisons revealed significant differences for both phonemic and semantic VF between LFS (MeanPvf-10 Hz = 54.6 ± 9.2, MeanSvf-10 Hz = 56.4 ± 7.9) and HFS (MeanPvf-ON = 48.3 ± 11.4, MeanSvf-ON = 51.1 ± 11.0, both P < .05), while DBS-OFF (MeanPvf-OFF = 51.2 ± 9.3, MeanSvf-OFF = 53.6 ± 12.9) and HFS and DBS-OFF and LFS did not differ significantly (P > .05). CONCLUSIONS: HFS compared to LFS or DBS-OFF significantly reduced tremor but simultaneously worsened VF while working memory and cognitive inhibition remained unaffected. In contrast, LFS enhanced VF but did not ameliorate tremor. The data emphasize the relevance of thalamocortical loops for verbal fluency but also suggest that more sophisticated DBS-regimes in ET may improve both motor and cognitive performance.

Effects of low-frequency thalamic deep brain stimulation in essential tremor patients.

BACKGROUND: Essential tremor (ET) patients may present with postural and/or intentional tremor. But despite high-frequency thalamic deep brain stimulation (DBS) effectively suppressing both, the emergence of intentional tremor has been attributed to a higher extent to cerebellar dysfunction. Therefore, we hypothesized thalamic 10 Hz-stimulation, which is known to worsen motor functions, having more impact on intentional tremor than on postural tremor. METHODS: In sixteen ET-patients with bilateral thalamic-DBS, tremor rating scale (TRS) and ultrasound-based tremor-amplitude measurements were analyzed by sequentially applying three DBS-settings in a randomized order: i) low-frequency stimulation (LFS), ii) DBS being turned off (DBS-OFF) and iii) high-frequency stimulation (HFS). Repeated measures analyses of variance for TRS and for the quotients of tremor-amplitudes during DBS-OFF and LFS for intentional (q(int)) and postural tasks (q(post)) were calculated. Finally, electrode localization and the abovementioned quotients were put into relation by Pearson's correlation coefficient. RESULTS: HFS reduced TRS significantly compared to DBS-OFF and LFS (ps<.001), while the latter two also differed significantly with TRS being the worst during LFS (p<.05). Additionally, intentional tremor-amplitude appeared to be strongly influenced by LFS than postural tremor-amplitude (p<.05). Furthermore, a lower placement of the electrodes caused worse intentional tremor-amplitude during LFS (r=.517, p>.05), while postural tremor-amplitude was unrelated to electrode localization (ps<.05). CONCLUSIONS: During LFS in ET-patients, there is a more severe exacerbation of intentional tremor compared to postural tremor. Possibly, there are two different mechanisms responsible for both tremor entities, making more refined stimulation regimes feasible in the future.

Essential tremor and tremor in Parkinson's disease are associated with distinct 'tremor clusters' in the ventral thalamus.

Different tremor entities such as Essential Tremor (ET) or tremor in Parkinson's disease (PD) can be ameliorated by the implantation of electrodes in the ventral thalamus for Deep Brain Stimulation (DBS). The exact neural mechanisms underlying this treatment, as well as the specific pathophysiology of the tremor in both diseases to date remain elusive. Since tremor-related local field potentials (LFP) have been shown to cluster with a somatotopic representation in the subthalamic nucleus, we here investigated the neurophysiological correlates of tremor in the ventral thalamus in ET and PD using power and coherence analysis. Local field potentials (LFPs) at different recording depths and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm were recorded simultaneously in twelve ET and five PD patients. Data analysis revealed individual electrophysiological patterns of LFP-EMG coherence at single and double tremor frequency for each patient. Patterns observed varied in their spatial distribution within the Ventral lateral posterior nucleus of the thalamus (VLp), revealing a specific topography of 'tremor clusters' for PD and ET. The data strongly suggest that within VLp individual tremor-related electrophysiological signatures exist in ET and PD tremor.