Monoaminergic network abnormalities: a marker for multiple sclerosis-related fatigue and depression

Correspondence to Professor Maria A Rocca, Neuroimaging Research Unit, Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan 20132, Italy; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Treatment for multiple sclerosis-associated fatigue and depression aims at increasing monoamine transmission.

• Therefore, monoaminergic functional abnormalities may underpin such symptoms.

WHAT THIS STUDY ADDS

• In 213 patients with multiple sclerosis, we evaluated abnormalities of dopamine, norepinephrine-related and serotonin-related resting state functional connectivity by independent component analysis, constrained to positron emission tomography atlases for dopamine, norepinephrine and serotonin transporters.

• Patients with multiple sclerosis showed abnormalities in all three explored monoaminergic networks, mostly with decreased monoamine-related connectivity in frontal regions and subcortical areas, and increased connectivity in temporo-parieto-occipital areas.

• Fatigue was mostly associated with dopamine network abnormalities, while depression was associated with reduced connectivity of dopamine, serotonin and norepinephrine networks in frontal, precuneal and limbic areas.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Specific patterns of monoaminergic connectivity abnormalities underpin fatigue and depression in multiple sclerosis, providing a marker for such bothersome symptoms.

• Monoamine network functional abnormalities may help clinicians tailor treatment choice for fatigue and depression in multiple sclerosis.

Introduction

Multiple sclerosis (MS) is a disabling condition of the central nervous system, with a wide range of symptoms, including motor disability and cognitive impairment.¹ Fatigue and depression may occur throughout the disease course with a prevalence rate of 35%–95% and aggravate quality of life.^{2 3} Despite the high prevalence, their pathophysiological correlates in MS are not completely unveiled.^{2 3}

MRI correlates of fatigue and depression in patients with MS have been explored with conflicting results concerning the association of these symptoms with global and regional T2-hyperintense lesion burden and grey matter (GM) atrophy.^4–7 On the other hand, task-based and resting state (RS) functional MRI (fMRI) studies showed functional connectivity (FC) abnormalities mostly occurring in the sensorimotor network for fatigue^8–11 and in the executive, salience and default-mode networks for depression.^{12 13}

Symptomatic treatments for depression and fatigue rely on drugs reinforcing monoaminergic synaptic transmission. As such, abnormalities of monoaminergic networks may have a role in determining fatigue and/or depression occurrence. Previous positron emission tomography (PET) studies demonstrated that patients with MS had increased norepinephrine presynaptic transporter concentrations in the limbic structures,¹⁴