Relationships between Serotonin Transporter Binding in the Raphe Nuclei, Basal Ganglia, and Hippocampus with Clinical Symptoms in Cervical Dystonia: A [11C]DASB Positron Emission Tomography Study.

Marenka Smit,Jan Booij,Marina A Tijssen,Anna L Bartels,Rudi A Dierckx,Erik F De Vries,David Vállez García,Antoon T Willemsen,Bauke M De Jong,Evelien Zoons

doi:10.3389/fneur.2018.00088

Abstract

Alterations of the central serotonergic system have been implicated in the pathophysiology of dystonia. In this molecular imaging study, we assessed whether altered presynaptic serotonin transporter (SERT) binding contributes to the pathophysiology of cervical dystonia (CD), concerning both motor and non-motor symptoms (NMS). We assessed the non-displaceable binding potential (BPND) using the selective SERT tracer [11C]DASB and positron emission tomography (PET) in 14 CD patients and 12 age- and gender-matched controls. Severity of motor symptoms was scored using the Toronto Western Spasmodic Torticollis Rating Scale and Clinical Global Impression jerks/tremor scale. NMS for depressive symptoms, anxiety, fatigue, and sleep disturbances were assessed with quantitative rating scales. The relationship between SERT binding and clinical patient characteristics was analyzed with the Spearman's rho test and multiple regression. When comparing the CD patients with controls, no significant differences in BPND were found. Higher BPND in the dorsal raphe nucleus was statistically significantly correlated (p < 0.001) with motor symptom severity (rs = 0.65), pain (rs = 0.73), and sleep disturbances (rs = 0.73), with motor symptom severity being the most important predictor of SERT binding. Furthermore, fatigue was negatively associated with the BPND in the medial raphe nucleus (rs = -0.61, p = 0.045), and sleep disorders were positively associated with the BPND in the caudate nucleus (rs = 0.58, p = 0.03) and the hippocampus (rs = 0.56, p = 0.02). Motor symptoms, as well as pain, sleep disturbances, and fatigue in CD showed a significant relationship with SERT binding in the raphe nuclei. Moreover, fatigue showed a significant relationship with the medial raphe nucleus and sleep disorders with the caudate nucleus and hippocampus. These findings suggest that an altered serotonergic signaling in different brain areas in CD is related to different motor as well as NMS, which will further stimulate research on the role of serotonin in the pathogenesis of dystonia.

Highlights

Cervical dystonia (CD) is a movement disorder characterized by involuntary abnormal muscle contractions of the neck
Further evidence that alterations of the serotonergic system may play a role in the pathogenesis of dystonia, including CD, can be inferred from case reports describing dystonia induced by selective serotonin reuptake inhibitors
Fatigue was negatively associated with the BPND in the median raphe nucleus (mRN), while the domain sleep disorders was positively associated with the BPND in the caudate nucleus and the hippocampus. In this functional brain imaging study, we demonstrated, to the best of our knowledge for the first time, statistically significant positive correlations between [11C]DASB BPND in the dorsal raphe nucleus (dRN) of CD patients and the severity of dystonic motor symptoms, pain scores, and sleep disturbances, but not with psychiatric comorbidity

Summary

Introduction

Cervical dystonia (CD) is a movement disorder characterized by involuntary abnormal muscle contractions of the neck. The pathogenesis of CD is largely unknown, alterations of the serotonergic system have been suggested to play a major role in both motor symptoms and NMS in dystonia [for review, see Ref. The GPi plays a key role in the network underlying the pathophysiology of dystonia [3, 4], a contribution supported by the therapeutic effect of GPi deep brain stimulation for dystonia [3]. Further evidence that alterations of the serotonergic system may play a role in the pathogenesis of dystonia, including CD, can be inferred from case reports describing dystonia induced by selective serotonin reuptake inhibitors. In children with dopa-responsive dystonia as well as in adults with idiopathic adult-onset dystonia decreased levels of serotonin metabolites in cerebrospinal fluid have been reported [5]

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