Link Between Neuroinflammation and Anhedonic Symptoms in MS

Functional and structural disruption in the mesocorticolimbic pathways associated with dysfunctional reward processing may play a key role in the pathophysiology of fatigue, depression, and pain, in patients with multiple sclerosis (MS), according to a review published in Multiple Sclerosis Journal.

Previous studies have shown that among patients with MS, fatigue, depression, and pain, are highly prevalent, and frequently co-occur as a symptom cluster. These symptoms create a substantial burden and have been labeled as the anhedonic symptom triad. Fatigue, depression, and pain are associated with several structural and functional changes of the brain in patients with MS, especially in the prefrontal cortex, the basal ganglia, and the limbic system.

The objective of the current review was to summarize the neuroimaging and neuroimmunological data suggesting that altered reward pathways may play an important role in the development of this triad.

Neuroimaging Findings

Among patients with MS, fatigue and depression have been associated with higher lesion load, more severe cortical atrophy in the prefrontal cortex, gray matter atrophy in the basal ganglia, along with white matter tract abnormalities in fronto-striatal and fronto-limbic pathways. In line with these structural changes, functional studies reported decreased glucose metabolism in the prefrontal cortex and the basal ganglia. Fatigue has been associated with decreased functional connectivity between the ventral striatum and the prefrontal cortex, while depression was linked to a disconnection of cortical and subcortical areas of the limbic system.

Pain has been associated with gray matter atrophy in the basal ganglia and the limbic system. Functional studies have shown a decreased connectivity between the caudate and the accumbens nuclei.

These structural and functional changes suggest that in patients with MS, fatigue, depression, and pain, are associated with alterations that may result in degeneration of the mesocorticolimbic pathway.

Neuroimmunological Findings

Disruption of the neural function secondary to neuroinflammation may result in fatigue, depression and pain. Previous studies in patients with MS have suggested that increased serum levels of tumor necrosis factor alpha and interferon-gamma, as well as higher cerebrospinal fluid levels of interleukin-6, are associated with increased fatigue and depression.

Pro-inflammatory cytokines may disrupt the monoamines dopamine and serotonin and alter monoaminergic neurotransmission. These changes may impair the function and structure of mesocorticolimbic pathways and brain areas and may ultimately lead to degeneration of pathways important for valence and reward processing and cause fatigue, depression, and pain in patients with MS. Microglial activation and demyelinating lesions with excess glutamate levels may have a key role in the neurodegeneration of brain structures involved in the reward processing.

Therapeutic Implications

This framework of how neuroinflammation might translate into symptoms of fatigue, pain, and depression has potential therapeutic implications.

Pharmacologically, medications that may enhance monoamine neurotransmission may improve these anhedonic symptoms in patients with MS. These include selective serotonin and noradrenaline reuptake inhibitors, psychostimulants with dopaminergic effects, drugs that increase dopamine synthesis such as L-methylfolate and L-DOPA, and medications with beneficial effects on excess glutamatergic neurotransmission.

Anti-inflammatory therapy may also be useful for treatment. One such medication, minocycline, stabilizes glia function and may improve anhedonic symptoms. Antibodies that target tumor necrosis factor-alpha and the interleukin-6 receptor were reported to improve symptoms of fatigue, pain, and depression in other immune-mediated diseases. They may, however, induce relapses in patients with MS. Additionally, disease-modifying treatments may have an important effect on anhedonic symptoms in this patient population.

Non-pharmacologically, behavioral and biopsychosocial intervention, including cognitive-behavioral therapy, may counteract the anhedonic symptom triad. Non-invasive brain stimulation techniques may improve cortico-subcortical network functioning and provide symptomatic relief.

“[I]nterventional studies are needed to probe the effectiveness of the different pharmacological and non-pharmacological therapeutic approaches in MS patients. These steps might help to better understand and treat anhedonic symptoms in MS and beyond”, concluded the study researchers.

Reference

Heitmann H, Andlauer TFM, Korn T, et al. Fatigue, depression, and pain in multiple sclerosis: How neuroinflammation translates into dysfunctional reward processing and anhedonic symptoms. Mult Scler. Published online November 12, 2020). doi:10.1177/1352458520972279