A significant number of people who suffer concussions—estimates range between 10% and 30%—experience a range of physical, cognitive, and emotional symptoms that persist for 4 or more weeks beyond the acute phase of the injury.

Symptoms of what is now called “persisting symptoms after concussion” (PSaC)—formerly called post-concussive syndrome—can be quite impairing. They may include combinations of headache, depression, vestibular dysfunction (disruptions to the inner ear-based balance system), cognitive impairment, and fatigue. These are typically treated, with varying degrees of effectiveness, with a combination of physical therapy, cognitive rehabilitation, drug treatments, and psychological interventions.

Part of the challenge in effectively treating patients with PSaC is the fact that they can differ markedly from one another, owing to differences that include how and where their brain was injured, what symptoms they report, and the duration and perceived severity of these symptoms.

The perpetuation of concussion symptoms is not well understood at the level of underlying brain mechanisms. Researchers, including a team led by 2022 BBRF Young Investigator Sean M. Nestor, M.D., Ph.D., of the Sunnybrook Research Institute and the University of Toronto, Canada, are exploring the possible contributions of large-scale neural networks rendered dysfunctional by concussions. In particular, there is interest in networks involved in sensory processing, attentional control, and cognitive-emotional integration. These include the salience network, the executive control network, the default-mode network, and the somatomotor network.

There are various theories about which of these networks might be centrally involved in generating symptoms associated with PSaC, note Dr. Nestor and colleagues (including three other recipients of BBRF grants) in a new paper appearing in Nature Mental Health. The team describes their multipronged effort to identify a “core neural network” that is associated with PSaC, and to explore whether such a network, if identified, might suggest good locations within the brain’s cerebral cortex that might be targeted by rTMS, or repetitive transcranial magnetic stimulation, a non-invasive method of brain stimulation widely used to treat depression and several other conditions.

The researchers began with the hypothesis that people with a high burden of PSaC symptoms vs. a low burden of symptoms would have different patterns of network disruptions. Leveraging a multifaceted set of neuroimaging analyses across a number of different data sources, the team ultimately was able to identify what it called “the network-based underpinnings of PSaC” and were able to localize an “optimal candidate target” for individualized treatment with rTMS or other brain neuromodulation therapies.

Their method was complex, involving, first, “symptom-activation maps” generated from existing fMRI datasets from past studies of concussion patients. These correlate and attempt to connect specific symptoms within the PSaC cluster with activation of specific brain networks. Spatial coordinates in the brain that were derived from these studies were subjected to a network-based meta-analysis, or combined analysis of multiple such studies (provided they met exacting criteria of acceptability established by the team, and including people with both high and low symptoms burdens).

In individuals within the pool of analyzed studies who had a high burden of PSaC symptoms, all of this data “co-localized” to the brain’s salience network. The salience network identifies and filters internal and external stimuli to guide an individual’s attention and behavior, acting as an interface between cognitive, emotional, and homeostatic systems. The salience network's ability to detect what is important is known to be disrupted in various conditions, including depression and addiction.

In a separate phase of their study, the team mapped the network identified as central in high symptom-burden PSaC patients to data from the Human Connectome Project, a massive undertaking to map the structure and function of the brain. The purpose here was to find targets within the cortex that might provide access to the disrupted salience network. These would be potential brain stimulation targets for PSaC. (Non-invasive methods like rTMS don’t reach deep into the brain, but can affect them indirectly by changing neural activation in shallower regions just beneath the scalp that are connected to regions deeper in the brain.)

In prior attempts to use rTMS to treat PSaC—not especially successful—the targeted region has been that typically employed to treat depression, a large area called the dorsolateral prefrontal cortex (DLPFC). Depression is often reported by people with PSaC, but the team did not want to assume that targets known to alleviate depression would be optimal for the varied non-depressive symptoms of PSaC.

“We used the salience network regions derived from the PSaC symptom-activation analysis to locate connected cortical regions amenable to non-invasive brain stimulation,” the team explained. This led them to a subregion of the DLPFC, one that was most robustly connected to the “regions of interest” within the identified “core” network. This is the potential stimulation target that can now be tested in future research. Compared with the rTMS target in the DLPFC used to treat depression, the team said, this proposed DLPFC target for PSaC has distinct connectivity which “may reflect the broader symptom profile of PSaC which extends beyond mood symptoms to include cognitive, sensory, and somatic [bodily] complaints.”

To be more precise, the new analysis indicated “two broad regions” of the DLPFC within which symptoms and network activation converged “maximally.” These targets may indicate different locations to attempt to treat symptoms by, in one case, using rTMS to increase functional connectivity, and in the other case, to decrease functional connectivity. Finding out which (if either) of these targets and uses of rTMS will alleviate symptoms, and in which patients, will be the subject of upcoming research.

The team also noted that it is not yet clear whether these distinct targets in the DLPFC affect aberrant connectivity that is related to the cause of PSaC symptoms or a compensatory response of the brain to symptoms. Determining whether to use rTMS to stimulate or inhibit neural activity at a particular brain target, will, as is the case in depression treatment, prove critical in developing an actual treatment protocol. Such questions can now be explored in future studies.

The research team included Robin F.H. Cash, Ph.D., 2020 BBRF Young Investigator; Peter Giacobbe, M.D., FRCPC, 2010 BBRF Young Investigator; and Clement Hamani, M.D., Ph.D., 2009 BBRF Young Investigator.