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

Abstract

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.

Introduction

In the middle of the 20th century the thalamus was identified as a potential target for stereotactic procedures to alleviate tremor syndromes (Garonzik et al., 2002). In the last twenty years, it became an important target for implantation of Deep Brain Stimulation (DBS) electrodes (Benabid et al., 1991). Although the nomenclature of the thalamus is often used in an inconsistent (and sometimes even confusing) way, nevertheless its lateral parts are now commonly considered the best target for ameliorating different tremor entities. Following Hirai and Jones, the lateral part of the thalamus may be divided into ventral lateral anterior (VLa) and posterior (VLp) nuclei (Hirai and Jones, 1989), with the VLp partially corresponding to Hassler's ventral intermediate nucleus (Vim) (Krack et al., 2002).² This area supposedly receives information predominantly from peripheral somatosensory input and the cerebellum (Asanuma et al., 1983, Macchi and Jones, 1997).

Patients with ET mostly suffer from a disabling postural and action tremor that classically affects the upper extremities with a frequency of 4–8 Hz and ceases typically at rest. Unfortunately, in severely affected patients medication provides insufficient tremor relief. In these cases implantation of DBS electrodes into the VLp is considered an appropriate and effective treatment option to reduce tremor (Blomstedt et al., 2007, Koller et al., 2000, Rehncrona et al., 2003). Patients with a tremor-dominant form of PD may also present with a 4–8 Hz tremor. In contrast to ET patients there is a predominance of resting tremor that emerges after seconds and vanishes with the initiation of a movement. Moreover, in some PD cases an additional postural or kinetic tremor can be observed that might show the same tremor frequency (type I) or a higher frequency (type II) (Deuschl et al., 1998). This tremor may only emerge after up to 10 s of a steady hold-task (i.e. re-emergent tremor). In cases of drug-resistant PD tremor, an improvement can also be achieved by implantation of DBS electrodes in the VLp (Lyons et al., 2001, Rehncrona et al., 2003). However, as akinesia and rigidity are unaffected by the latter treatment, tremor must be the leading symptom for VLp-implantation in PD patients (Hilker et al., 2009). Therefore, this treatment is nowadays only performed on a very limited number of patients. Especially older patients or such being considered as high risk patients are implanted with electrodes at this target point.

A central neuronal oscillator is often assumed to constitute the key pathophysiological process of tremor syndromes. This putative neuronal oscillator is supposed to create a synchronized network at tremor frequency but also at double tremor frequency (first harmonic). This network may comprise cortical and subcortical structures such as the cerebellum or the thalamus (Schnitzler et al., 2009, Timmermann et al., 2003). On a cellular level, such oscillations were demonstrated in single-cell recordings inside VLp for ET (Lenz et al., 1994) and PD (Lenz et al., 1988), and in LFP-recordings for ET and PD but also other tremor entities such as multiple sclerosis (Marsden et al., 2000, Reck et al., 2009b). Additionally, in Parkinsonian tremor electrophysiological recordings revealed pathological oscillations inside the subthalamic nucleus (STN) (Amtage et al., 2008, Florin et al., 2012), each specific for different extremities and antagonistic muscles (Reck et al., 2009a, Reck et al., 2009b). Clinically this segregation of tremor loops had been hypothesized by Raethjen et al. (2000). For the lateral thalamus, a heavily interconnected area of the basal ganglia, it remains to be investigated whether there also exists a functional segregation into subloops or clusters. Clinically this seems conceivable since thalamic DBS in tremor patients leads to a different efficacy of this treatment depending upon the exact location of the stimulation.

We hypothesized that tremor-related activity in the VLp would also be segregated in ‘tremor clusters’ as has been shown for the subthalamic nucleus (Reck et al., 2009b). Furthermore, we investigated whether this putative segregation is disease specific or rather constitutes a more general pathophysiological or organizational principle of tremor activity in the basal–ganglia–thalamus complex. Accordingly, we investigated ET as well as tremordominant PD patients and analyzed their tremor associated LFP activity in the VLp. We accordingly measured intraoperatively thalamic LFPs simultaneously with EMG in 17 patients (12 ET and 5 PD patients) during i) rest, and ii) a simple isometric contraction of the forearm (hold-condition), and analyzed the coherence with extensor and flexor muscles of the contralateral forearm at different heights within the VLp.