'Depression Circuit' Identified in MS Patients

Batya Swift Yasgur, MA, LSW

January 31, 2023

The common coexistence of multiple sclerosis (MS) and depression may be explained in part by MS lesions occurring along a specific "depression circuit" in the brain, new research suggests.

In an analysis of almost 300 participants with MS, investigators estimated whole-brain connectivity of each person's white matter lesion locations. Results showed that functional connectivity between MS lesion locations and their depression circuit was correlated with depression severity in MS and was specific to depression as compared with other symptoms of MS.

The peak of this circuit was located in the ventral midbrain, which is the source of dopamine in the brain's reward system.

"Depression in MS is an organic structural disease, not just a complication of overall disability," lead author Shan Siddiqi, MD, assistant professor of psychiatry, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

"We now have evidence to say that focal brain stimulation and dopamine-targeted antidepressants, such as bupropion, might be better for these patients," said Siddiqi, who is also director of psychiatric neuromodulation research at Brigham and Women's Center for Brain Circuit Therapeutics in Boston.

The findings were published online January 19 in Nature Mental Health.

Long-Standing Debate

MS can "cause focal/sometimes reversible lesions to specific brain regions, and these patients are at particularly high risk for depression," Siddiqi said.

"There has been a long-standing debate about whether the location of damage is related to depression, but nobody has ever been able to prove it one way or the other," he noted, adding that he was motivated to "to settle that debate."

More broadly, the "key motivator" in most of his research is to identify treatment targets, because "depression is a debilitating complication of MS, and these patients are less responsive to conventional treatments," said Siddiqi.

He noted that newer treatments, such as focal brain stimulation, can be effective for depression, but only if clinicians know the correct brain region to target. "By mapping lesions that can cause a symptom, we can also find targets to relieve the same symptom," he said.

"When lesions causing a specific symptom do not consistently localize to a specific region, they may still localize to a specific distributed brain circuit," the investigators write.

"These brain circuits can be identified using lesion network mapping, a technique that uses a normative connectome database...to compare the functional connectivity of brain lesions, rather than just their location," they add.

Recently, the researchers conducted a study of depression associated with focal lesions caused by stroke and penetrating head trauma. They found that gray matter lesions that cause depression "are functionally connected to a common brain circuit."

Moreover, depression improved after transmagnetic stimulation (TMS) was delivered to the positive parts of this circuit or deep brain stimulation (DBS) was delivered to the negative parts. This suggests that "lesion-derived circuits can be effective targets for therapeutic brain stimulation," the investigators write.

They had identified a "convergent neuro-anatomical substrate for depression across 14 datasets of lesions, TMS sites, and DBS sites."

In the current study, they drew on data from a longitudinal clinical and radiologic database of patients with MS (n = 281). Complete MRI data, depression scores, and overall disability scores were available for all participants at baseline.

Best Targets

Lesions were distributed throughout the white matter, with "high density" in periventricular regions. The researchers used these data to conduct lesion network mapping and spatial correlation analyses using their a priori circuit.

They estimated whole-brain connectivity for each participant's lesion location, using a "normative connectome database," and then assessed the similarity of each lesion's connectivity profile to their depression circuit, using spatial correlations. They then compared spatial correlations with depression scores.

"Participants with MS whose lesions were more connected to our a priori depression circuit had higher depression scores, independent of the effect of age, sex, overall disability, and total lesion volume (r = .15; P = .013)," the investigators report.

Moreover, this relationship was "specific to depression," as compared with 11 other metrics and overall disability (P = .0058; 25,000 permutations).

The findings remained consistent after further adjustment for fatigue and cognitive symptoms (r = 0.16; P = .0075).

The next step was to derive a brain network for MS depression by "comparing lesion connectivity profile with depression severity across all participants."

The topography of this MS circuit revealed a "high spatial correlation" with the topography of the previous convergent depression circuit (spatial r = 0.63), with permutation testing confirming that the relationship was "stronger than chance" (P = .015; 25,000 permutations).

The ventral midbrain, including the ventral tegmental area, was most implicated in this circuit (familywise-error-corrected P < .05).

"Mapping the circuitry helps us detect relationships that we couldn't find by just looking at lesion locations," Siddiqi said. "We found that lesions connected to a specific 'depression circuit' is what distinguished lesions associated with depression vs those not associated with depression."

The researchers "found that the best target for brain stimulation is probably the same as for other causes of depression, while the best target for antidepressant drugs in MS might be the dopamine system," he added.

Siddiqi noted that neither of these approaches has yet been tested in a clinical trial, "so our study may justify this type of clinical trial."

Paving the Way

Commenting for Medscape Medical News, Theodore Satterthwaite, MD, associate professor of psychiatry and director at Penn Lifespan Informatics and Neuroimaging Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, called the study "important."

Patients with MS "frequently develop depression, but it is pretty unclear why this is the case. This study shows that MS impacts a brain network that has been linked to depression in many other situations," said Satterthwaite, who was not involved with the research.

He noted that the study "also suggests that injury to brain networks may provide a common pathway to depression."

This could "pave the way for new approaches for brain stimulation therapies for depression in many contexts ― in MS and beyond," Satterthwaite said.

The SysteMS study was funded by Verily Life Sciences. The current analysis was supported by the Brain and Behavior Research Foundation, the Baszucki Family Foundation, and the National Institute of Mental Health. Siddiqi is a scientific consultant for Magnus Medical and a clinical consultant for Acacia Mental Health, Kaizen Brain Center, and Boston Precision Neurotherapeutics. He and one of his co-authors have jointly received investigator-initiated research funding from Neuronetics, and he has served as a speaker for Brainsway and PsychU.org (unbranded, sponsored by Otsuka). Siddiqi also owns intellectual property involving the use of functional connectivity to target TMS. The other authors' disclosures are listed in the original article. Satterthwaite reports no relevant financial relationships.

Nat Ment Health. Published online. Full article

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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