New Insights into Post-Concussion Syndrome: Targeting the Salience Network for Treatment

A significant portion of individuals who experience concussions continue to suffer from a variety of physical, cognitive, and emotional challenges for an extended period beyond the initial injury. This condition, previously known as post-concussive syndrome and now referred to as “persisting symptoms after concussion” (PSaC), can be profoundly debilitating. Symptoms often include chronic headaches, mood disturbances, balance issues, cognitive impairments, and persistent fatigue. Current therapeutic approaches, encompassing physical therapy, cognitive rehabilitation, pharmacological interventions, and psychological support, yield varying degrees of success in managing these complex symptoms. The challenge in treating PSaC effectively stems from the highly individualized nature of the condition, influenced by factors such as the injury mechanism, specific symptom presentation, and the duration and severity of these symptoms. Understanding the underlying brain mechanisms responsible for the persistence of these symptoms remains a critical area of research, with a growing focus on the role of dysfunctional large-scale neural networks.

Researchers, including a team spearheaded by Dr. Sean M. Nestor from the Sunnybrook Research Institute and the University of Toronto, have been delving into the contributions of neural networks to PSaC. Their investigations specifically target networks involved in sensory processing, attentional regulation, and cognitive-emotional integration, such as the salience network, executive control network, default-mode network, and somatomotor network. The team's recent publication in Nature Mental Health highlights their multipronged strategy to pinpoint a core neural network associated with PSaC. This endeavor aims to identify optimal cerebral cortex locations that could be targeted by repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique widely used for treating depression and other neurological conditions. The ultimate goal is to develop more precise and effective treatments for the lingering effects of concussions.

The study commenced with the premise that individuals experiencing a high burden of PSaC symptoms would exhibit distinct patterns of network disruptions compared to those with a lower symptom burden. Employing a sophisticated array of neuroimaging analyses across diverse data sources, the research team successfully uncovered what they termed the “network-based underpinnings of PSaC.” This breakthrough allowed them to pinpoint an “optimal candidate target” for personalized treatment using rTMS or other neuromodulation therapies. Their methodology involved generating "symptom-activation maps" from existing fMRI datasets of past concussion studies, which aimed to correlate specific PSaC symptoms with the activation of particular brain networks. Spatial coordinates derived from these studies were then subjected to a rigorous network-based meta-analysis, incorporating data from individuals with both high and low symptom burdens, provided they met strict acceptability criteria.

Remarkably, the data from individuals with a high burden of PSaC symptoms consistently co-localized to the brain's salience network. The salience network plays a crucial role in identifying and filtering internal and external stimuli, thereby guiding an individual's attention and behavior. It acts as an interface between cognitive, emotional, and homeostatic systems. Disruptions in the salience network's ability to detect salient information are known to be implicated in various conditions, including depression and addiction. In a subsequent phase of their investigation, the team mapped this identified network, central to high symptom-burden PSaC patients, onto data from the Human Connectome Project. This extensive project aims to comprehensively map the brain's structure and function. The objective was to locate cortical targets that could provide access to the disrupted salience network, thus serving as potential brain stimulation sites for PSaC. Non-invasive methods like rTMS do not penetrate deep into the brain but can indirectly influence deeper regions by altering neural activation in shallower areas connected to them.

Previous attempts to treat PSaC with rTMS, which had limited success, typically targeted the dorsolateral prefrontal cortex (DLPFC), a large area commonly stimulated for depression. While depression is frequently reported by individuals with PSaC, the research team recognized that targets effective for depression might not be optimal for the varied non-depressive symptoms of PSaC. Consequently, they utilized regions of the salience network, identified through their symptom-activation analysis, to locate connected cortical regions amenable to non-invasive brain stimulation. This led them to a specific subregion within the DLPFC, which showed the most robust connectivity to the “regions of interest” within their identified “core” network. This subregion now represents a promising stimulation target for future research. The team emphasized that this proposed DLPFC target for PSaC possesses distinct connectivity compared to the rTMS target used for depression, suggesting it may better address the broader symptom profile of PSaC, which extends beyond mood disturbances to include cognitive, sensory, and bodily complaints.

More precisely, the new analysis revealed two broad regions within the DLPFC where symptom presentation and network activation converged maximally. These targets suggest different approaches for treatment: one potentially involves using rTMS to enhance functional connectivity, while the other aims to decrease it. Future research will explore which of these targets, or both, and which application of rTMS, will alleviate symptoms and in which patient populations. Furthermore, it remains unclear whether these distinct DLPFC targets influence aberrant connectivity that directly causes PSaC symptoms or if they represent a compensatory brain response. Determining whether to stimulate or inhibit neural activity at a specific brain target, similar to depression treatment, will be crucial in developing an effective treatment protocol. These questions are now ripe for exploration in upcoming studies, promising to refine our understanding and treatment strategies for persisting symptoms after concussion.