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Depression after TBI could be new clinical disorder – US study

A recent study has suggested that depression after a traumatic brain injury (TBI) could actually be a clinically distinct disorder rather than a traditional major depressive order, which would have implications for patient treatment, said the researchers.

The findings, said corresponding author Dr Shan Siddiqi, from Brigham and Women’s Hospital and a founding member of the Mass General Brigham health care system, “help explain how the physical trauma to specific brain circuits can lead to development of depression”.

“If we’re right, it means we should be treating depression after TBI like a distinct disease.”

Siddiqi, of the Brigham’s Department of Psychiatry and Centre for Brain Circuit Therapeutics, said many clinicians have suspected that this is a clinically distinct disorder with a unique pattern of symptoms and unique treatment response, including poor response to conventional antidepressants.

“But until now, we didn’t have clear physiological evidence to prove this.”

Siddiqi collaborated with researchers from Washington University, Duke University School of Medicine, the University of Padua, and the Uniformed Services University of the Health Sciences on the study.

The findings are published in Science Translational Medicine.

The work started as a side project seven years ago when Siddiqi was motivated by a patient he shared with Dr David Brody, a co-author on the study and a neurologist at Uniformed Services University. The two started a small clinical trial that used personalised brain mapping to target brain stimulation as a treatment for TBI patients with depression.

In the process, they noticed a specific pattern of abnormalities in these patients’ brain maps.

The current study included 273 adults with TBI, usually from sports injuries, military injuries, or car accidents. People in this group were compared with other groups who did not have a TBI or depression, people with depression without TBI, and people with post-traumatic stress disorder.

Study participants went through a resting-state functional connectivity MRI, a brain scan that looks at how oxygen is moving in the brain. These scans gave information about oxygenation in up to 200 000 points in the brain at about 1 000 different points in time, leading to about 200m data points in each person.

Based on this information, a machine learning algorithm was used to generate an individualised map of each person’s brain.

The location of the brain circuit involved in depression was the same among people with TBI as people without TBI, but the nature of the abnormalities was different. Connectivity in this circuit was decreased in depression without TBI and was increased in TBI-associated depression.

This implies that TBI-associated depression may be a different disease process, leading the study authors to propose a new name: “TBI affective syndrome”.

“I’ve always suspected it isn’t the same as regular major depressive disorder or other mental health conditions that are not related to traumatic brain injury,” said Brody.

“There’s still a lot we don’t understand, but we’re starting to make progress.”

One limitation of the trial is that with so much data, the researchers were not able to do detailed assessments of each patient beyond brain mapping.

As a future step, investigators would like to assess participants’ behaviour in a more sophisticated way and potentially define different kinds of TBI-associated neuropsychiatric syndromes.

Siddiqi and Brody are also using this approach to develop personalised treatments.

Originally, they set out to design a new treatment in which they used this brain mapping technology to target a specific brain region for people with TBI and depression, using transcranial magnetic stimulation (TMS).

They enrolled 15 people in the pilot and saw success with the treatment.

Since then, they have received funding to replicate the study in a multi-centre military trial.

“We hope our discovery guides a precision medicine approach to managing depression and mild TBI, and perhaps even intervene in neuro-vulnerable trauma survivors before the onset of chronic symptoms,” said

Dr Rajendra Morey, a professor of psychiatry at Duke University School of Medicine, and co-author on the study.

Study details

Precision functional MRI mapping reveals distinct connectivity patterns for depression associated with traumatic brain injury

Shan Siddiqi, Sridhar Kandala, Carl Hacker, Heather Bouchard, David Brody.

Published in Science Translational Medicine on 5 July 2023


Depression associated with traumatic brain injury (TBI) is believed to be clinically distinct from primary major depressive disorder (MDD) and may be less responsive to conventional treatments. Brain connectivity differences between the dorsal attention network (DAN), default mode network (DMN), and sub-genual cingulate have been implicated in TBI and MDD. To characterise these distinctions, we applied precision functional mapping of brain network connectivity to resting-state functional magnetic resonance imaging data from five published patient cohorts, four discovery cohorts (n = 93), and one replication cohort (n = 180). We identified a distinct brain connectivity profile in TBI-associated depression that was independent of TBI, MDD, posttraumatic stress disorder (PTSD), depression severity, and cohort. TBI-associated depression was independently associated with decreased DAN–sub-genual cingulate connectivity, increased DAN-DMN connectivity, and the combined effect of both. This effect was stronger when using precision functional mapping relative to group-level network maps. Our results support the possibility of a physiologically distinct “TBI affective syndrome,” which may benefit from individualised neuro-modulation approaches to target its distinct neural circuitry.


Science Translational Medicine article – Precision functional MRI mapping reveals distinct connectivity patterns for depression associated with traumatic brain injury (Open access)


MedicalXPress article – Study suggests depression after traumatic brain injury could represent a new, distinct disease (Open access)


See more from MedicalBrief archives:


UCT: Grant for under-researched field of traumatic brain injury research


Severe traumatic brain injury: Don’t be too hasty in pulling the plug


Widely available drug reduces head injury deaths by up to 20% — large trial



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