Elsevier

World Neurosurgery

Volume 113, May 2018, Pages e453-e464
World Neurosurgery

Original Article
Ventrolateral Motor Thalamus Abnormal Connectivity in Essential Tremor Before and After Thalamotomy: A Resting-State Functional Magnetic Resonance Imaging Study

https://doi.org/10.1016/j.wneu.2018.02.055Get rights and content

Highlights

  • Pretherapeutic ET altered motor thalamus FC with left primary somatosensory cortex.

  • Pretherapeutic ET altered motor thalamus FC with pedunculopontine nucleus.

  • Changes in motor thalamus FC after thalamotomy: right dorsal attention network.

  • Changes in motor thalamus FC after thalamotomy: salience networks.

  • Changes in motor thalamus FC after thalamotomy: hand movement planning areas.

Objective

To evaluate functional connectivity (FC) of the ventrolateral thalamus, a common target for drug-resistant essential tremor (ET), resting-state data were analyzed before and 1 year after stereotactic radiosurgical thalamotomy and compared against healthy controls (HCs).

Methods

In total, 17 consecutive patients with ET and 10 HCs were enrolled. Tremor network was investigated using the ventrolateral ventral (VLV) thalamic nucleus as the region of interest, extracted with automated segmentation from pretherapeutic diffusion magnetic resonance imaging. Temporal correlations of VLV at whole brain level were evaluated by comparing drug-naïve patients with ET with HCs, and longitudinally, 1 year after stereotactic radiosurgical thalamotomy. 1 year thalamotomy MR signature was always located inside VLV and did not correlate with any of FC measures (P > 0.05). This suggested presence of longitudinal changes in VLV FC independently of the MR signature volume.

Results

Pretherapeutic ET displayed altered VLV FC with left primary sensory-motor cortex, pedunculopontine nucleus, dorsal anterior cingulate, left visual association, and left superior parietal areas. Pretherapeutic negative FC with primary somatosensory cortex and pedunculopontine nucleus correlated with poorer baseline tremor scores (Spearman = 0.04 and 0.01). Longitudinal study displayed changes within right dorsal attention (frontal eye-fields and posterior parietal) and salience (anterior insula) networks, as well as areas involved in hand movement planning or language production.

Conclusions

Our results demonstrated that patients with ET and HCs differ in their left VLV FC to primary somatosensory and supplementary motor, visual association, or brainstem areas (pedunculopontine nucleus). Longitudinal changes display reorganization of dorsal attention and salience networks after thalamotomy. Beside attentional gateway, they are also known for their major role in facilitating a rapid access to the motor system.

Introduction

Essential tremor (ET) is the most prevalent movement disorder in the adult population.1, 2, 3 Initially regarded as an individual illness, it is nowadays suggested as a family of diseases.4 The pathophysiology is still poorly understood.3, 5

One hypothesis for tremor generation suggests a central role of the inferior olivary nucleus (ION).6 In addition, recent findings using resting-state functional magnetic resonance imaging (fMRI) showed that pretherapeutic interconnectivity strength between the ION and bilateral motor cortex is predictive for tremor arrest after thalamotomy.7 This hypothesis is based on the fact that ION would produce an abnormal rhythmic output, affecting synchronization of Purkinje cell firing,8 propagated through the cerebellothalamic tract,9, 10 tuning motor activity.11 Independently of the tremor origin (ION vs. cerebellum), the abnormal rhythmic output travels from dentate cerebellar nucleus to the contralateral M1 area, passing through the ventrointermediate nucleus (Vim) (e.g., “tremor ax”).12 In fact, the Vim has been successfully targeted in tremor since the pioneering thermocoagulation performed by Hassler,13 further continuing with the stereotactic radiofrequency thalamotomy14 and more recently deep-brain stimulation (DBS),15, 16 the standard of care.

An alternative to open surgical procedures, radiosurgery (RS), which aims at the same target (e.g., Vim), has a high level of evidence.17, 18, 19 Unlike radiofrequency thalamotomy and DBS, RS does not have the possibility of intraoperative confirmation and induces a delayed clinical and radiologic effect, up to 1 year after the procedure.17 More recently, high-focused ultrasound (HIFU), which produces a controlled thermocoagulation, has demonstrated its safety and efficacy, with an immediate clinical and radiologic effect.20

fMRI is a valuable, noninvasive technique, that allows exploring brain networks in healthy and pathologic conditions, including ET.21, 22, 23, 24 Resting-state fMRI, in particular, evaluates interactions between segregated brain areas in the absence of an explicit task. Resting-state activity is observed through changes in spontaneous fluctuations of blood-oxygen-level-dependent signal.25 The former can be acquired with minimal patient compliance, which unlocks new possibilities for application in the clinical realm.26

Here, we used resting-state fMRI to describe the anterolateral motor thalamus temporal correlations at the whole brain level (seed-to-voxel analysis). Function connectivity (FC) derived from resting-state fMRI time-courses was analyzed pretherapeutically, before stereotactic radiosurgical thalamotomy (SRS-T, as compared with healthy controls [HCs]) and 1 year later. The studied region-of-interest seed was the ventrolateral ventral nucleus (VLV; nomenclature form Morel et al.27), as Vim is not directly visible on current 1.5- and 3-Tesla magnetic resonance imaging (MRI) acquisitions. The VLV was obtained by using a newly automated, robust, and reproducible method for thalamus clustering published by our group.28 This method exclusively explores local thalamic diffusion properties across both HCs and patients with ET (pretherapeutic data).28

Our primary aims in this study were 1) to compare VLV FC in HCs versus pretherapeutic ET; and 2) to evaluate longitudinal changes 1 year after SRS-T (as compared with pretherapeutic), to account for the delayed clinical effect.29

Our first hypothesis was that pretherapeutically FC is impaired within the previously described tremor network, based on recent fMRI studies and existing physiopathologic theories.1, 22, 23 However, in addition to the main role of Vim in tremor propagation and its altered thalamocortical connectivity in ET,23 recent studies have specified an increased FC of sensory-motor and salience networks in patients with ET compared with HCs.30 Our second hypothesis was that SRS-T would not only generate changes within the thalamocortical network but also produce a functional reorganization of salience networks.

Section snippets

Participants

We included 17 consecutive patients (right-handed, drug-resistant, drug-naïve during study neuroimaging protocol) treated only with left unilateral SRS-T between September 2014 and August 2015 at Marseille University Hospital, Marseille, France. All were referred by a neurologist specialized in movement disorders (T.W.). Clinical diagnosis was ET in all cases.

Only patients meeting inclusion criteria analyzed here were included: confirmed diagnosis of ET, able to give formal approval,

Results

We evaluated the impact of age, disease duration, or volume lesion, and we report no statistically significant correlation (Spearman > 0.05) with FC values. Furthermore, no statistically significant differences in FC between left and right VLV nucleus were found.

Discussion

In the present study, we evaluated the tremor network using a seed-to-voxel approach on resting-state fMRI data, as functional imaging had been widely used as an alternative for evaluating segregated brain processes.38, 39, 40 We focus on FC of the most commonly used surgical target for tremor, the ventrolateral motor thalamus. With regard to HCs versus pretherapeutic ET FC, we report as statistically significant: primary somatosensory, visual association, and anterior cingulate cortex, as well

Acknowledgments

We acknowledge the important contribution of Axelle Cretol, from Marseille University Hospital (CHU Timone), Marseille, France, who, as research assistant, kept the database up-to-date.

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  • Cited by (0)

    Conflict of interest statement: The work was supported in part by the Swiss National Science Foundation (SNSF-205321–157040), in part by the Centre d'Imagerie BioMédicale (CIBM) of the University of Lausanne (UNIL), the Swiss Federal Institute of Technology Lausanne (EPFL), the University of Geneva (UniGe), the Centre Hospitalier Universitaire Vaudois (CHUV), the Hôpitaux Universitaires de Genève (HUG), and the Leenaards and Jeantet Foundations and in part by the CHU Timone, Marseille, France.

    Elena Najdenovska and Jean Régis are co–first authors.

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