Mental health symptoms are common after traumatic brain injury (TBI), including mild TBI, or concussion. Depression, anxiety, irritability, emotional changes, sleep disruption, and posttraumatic stress symptoms can occur after injury, often alongside persistent cognitive and physical symptoms. A 2022 review in Biological Psychiatry described psychiatric and neurobehavioral consequences across the spectrum of TBI and noted that even mild TBI can be associated with new or worsening psychiatric symptoms, including depression and posttraumatic stress disorder.
A 2025 umbrella review in Nature Mental Health synthesized 24 systematic reviews and meta-analyses involving more than 31 million participants and found that TBI was associated with increased risk across multiple mental and physical health outcomes.
While a concussion begins with mechanical force, its effects extend well beyond the initial impact. The injury can initiate alterations in inflammation, oxidative balance, energy metabolism, mitochondrial function, neurotransmission, and other aspects of cellular signaling—processes that unfold within the context of one’s pre-existing physiological and psychological health.
From Impact to Biological Response
Following TBI, the brain undergoes changes in cerebral metabolism, mitochondrial function, oxidative balance, and neuroinflammatory activity. Inflammation is part of the normal response to injury and contributes to repair. When inflammatory signaling becomes excessive or prolonged, however, it can contribute to ongoing cellular stress.
Changes in brain energy metabolism are also important. A 2024 review in the Journal of Neuroinflammation described alterations in glucose utilization, mitochondrial metabolism, lipid oxidation, and ketone metabolism following TBI.
Fatigue, brain fog, headaches, sleep disturbance, irritability, anxiety, low mood, and difficulty with attention or emotional regulation can therefore have multiple contributors.
Recovery does not occur in isolation. Physiological and psychological factors present before, during, and after an injury can compound its effects and contribute to persistent symptoms. These may include anxiety, depression, sleep disturbance, chronic stress, nutritional insufficiency, metabolic dysregulation, and other physiological stressors
A 2025 systematic review and meta-analysis in JAMA Network Open examined 15 studies involving more than 592,000 adults with mild TBI. The factors most consistently associated with persistent symptoms, included acute cognitive difficulties, a history of anxiety, depression or sleep disorders, and clinical signs such as loss of consciousness or amnesia. These findings suggest that both the acute response to injury and an individual’s pre-existing clinical history may be relevant to the course of recovery.
Adverse childhood experiences may also be relevant to the broader context of injury. A 2019 scoping review found an association between ACE exposure and TBI occurrence. A 2025 systematic review and meta-analysis similarly found an association between ACE scores and TBI occurrence.
These findings illustrate how multiple biological, physiological and psychological factors can intersect with injury and contribute to persistent symptoms.
When Trauma & Hyperarousal Add Another Layer
The circumstances surrounding a head injury can also influence the biological response to it. A concussion resulting from a frightening accident, interpersonal violence, military exposure, sporting event, or another traumatic event may involve both the neurological effects of head injury and activation of the stress response.
Hyperarousal can affect sleep, autonomic regulation, attention, mood, and perception of physical symptoms. These effects can overlap substantially with post-concussion symptoms, making it difficult to determine which processes are contributing most to an individual’s presentation.
Neurological injury and persistent stress activation may also compound one another. Poor sleep can increase physiological stress and worsen cognitive and emotional symptoms, while ongoing hyperarousal may make it more difficult to recover from the neurological and metabolic consequences of injury.
Anxiety, irritability, insomnia, and difficulty concentrating therefore may have multiple contributors. Understanding these contributors matters as addressing the relevant physiology can help to modulate and mitigate symptom burden, supporting recovery.
The HILL Model: Head Impact, Inflammation, Low-Dose Lithium
The HILL model—Head Impact, Inflammation, Low-Dose Lithium—proposes a framework for understanding how biological response following a head injury may evolve beyond the initial mechanical insult.
Published in Trends Open in 2026, the model describes a proposed sequence in which head impact initiates an inflammatory response that may contribute to downstream changes in oxidative balance, mitochondrial function, cellular signaling, metabolism, and neuronal function. It further proposes that low-dose lithium may have modulatory effects on these processes.
In this framework, the initial injury is followed by a biological response that can extend beyond the site of initial impact, with inflammatory and metabolic alterations influencing multiple interconnected processes. The model also considers downstream effects involving intestinal permeability, the gut microbiome, systemic inflammation, and neuroinflammation—reflecting the bidirectional relationship between the brain and peripheral physiology. .
Why Nutritional Lithium?
Lithium is a naturally occurring trace element found in soil, food, and drinking water with exposure varying according to geography and diet.
Although lithium is best known as a pharmaceutical treatment in psychiatry, lower levels of lithium exposure have been studied for broader biological effects. Research on nutritional or low-dose lithium has examined cellular signaling, neuroprotection, inflammatory pathways, oxidative stress, and processes involved in neuronal resilience.
The HILL model proposes that some of these biological effects may be relevant to the response following head injury, including the inflammatory and cellular processes that develop following the initial impact.
Nutritional or low-dose lithium is distinct from pharmaceutical lithium, which is administered at therapeutic doses and requires clinical monitoring.
Assessing Factors That Shape Recovery
A concussion diagnosis identifies the injury, but it does not explain every factor that may influence recovery or contribute to persistent symptoms.
Depending on the presentation, assessment may consider:
- Inflammatory and immune signaling
- Cellular energy and mitochondrial function
- Oxidative stress and redox balance
- Sleep and circadian regulation
- Nutritional status and dietary intake
- Metabolic and vascular factors
- Autonomic regulation and hyperarousal
- Pre-existing psychological and physiological factors
- New or worsened changes that emerged after the injury
Symptoms can reflect several interacting processes. Fatigue, for example, may occur in the context of altered energy metabolism, inadequate sleep, nutritional insufficiency, or increased physiological demand. Cognitive difficulties may reflect the neurological effects of injury alongside sleep disruption, inflammation, stress physiology, or metabolic dysfunction. Irritability and anxiety may similarly involve neurological changes, heightened stress physiology, or both.
The clinical question, therefore, is not simply which symptom is present, but what factors may be contributing to it and whether those factors are modifiable.
Assessment can then help shape a more individualized approach to recovery—one that considers the physiology underlying the person’s presentation rather than relying on the concussion diagnosis alone.
Putting Biology Into Context
Concussion recovery involves more than the initial mechanical injury. The biological response that follows can affect inflammatory signaling, energy metabolism, oxidative balance, mitochondrial function, sleep, autonomic regulation, and other aspects of physiology. Pre-existing factors may further influence how an individual responds, while new changes that develop after the injury can introduce additional challenges to recovery.
The HILL model offers one emerging framework for understanding the relationship between head impact, inflammation, downstream biological effects, and the potential modulatory role of low-dose lithium. Nutritional and targeted interventions provide another area of investigation, particularly approaches that address pathways involved in inflammation, oxidative balance, mitochondrial function, and cellular resilience.
For individuals with persistent symptoms, these considerations provide a basis for looking beyond the diagnosis itself: identifying the physiological factors most relevant to the individual’s presentation, addressing those that are modifiable, and reassessing as recovery progresses.
References
- Howlett JR, Nelson LD, Stein MB. Mental Health Consequences of Traumatic Brain Injury. Biol Psychiatry. 2022 Mar 1;91(5):413-420. doi: 10.1016/j.biopsych.2021.09.024. Epub 2021 Oct 2. PMID: 34893317; PMCID: PMC8849136.
- Ogonah MGT, Botchway S, Yu R, Schofield PW, Fazel S. An umbrella review of health outcomes following traumatic brain injury. Nat Ment Health. 2025;3(1):83-91. doi: 10.1038/s44220-024-00356-5. Epub 2025 Jan 3. PMID: 39802934; PMCID: PMC11717692.
- Oft HC, Simon DW, Sun D. New insights into metabolism dysregulation after TBI. J Neuroinflammation. 2024 Jul 29;21(1):184. doi: 10.1186/s12974-024-03177-6. PMID: 39075578; PMCID: PMC11288120.
- McIntosh SJ, Vergeer MH, Galarneau JM, Eliason PH, Debert CT. Factors Associated With Persisting Symptoms After Concussion in Adults With Mild TBI: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025 Jun 2;8(6):e2516619. doi: 10.1001/jamanetworkopen.2025.16619. PMID: 40531530; PMCID: PMC12177663.
- Zhu J, MacIsaac-Jones MAC, Jenkins S, Yeates KO, Madigan S. Association Between Adverse Childhood Experiences Score and Traumatic Brain Injury Occurrence: A Systematic Review and Meta-Analysis. J Neurotrauma. 2025 Nov;42(21-22):1907-1917. doi: 10.1177/08977151251372608. Epub 2025 Sep 2. PMID: 40892488.
- Ma Z, Bayley MT, Perrier L, Dhir P, Dépatie L, Comper P, Ruttan L, Lay C, Munce SEP. The association between adverse childhood experiences and adult traumatic brain injury/concussion: a scoping review. Disabil Rehabil. 2019 Jun;41(11):1360-1366. doi: 10.1080/09638288.2018.1424957. Epub 2018 Jan 12. PMID: 29327631.
- Gadh S, Spuch C. HILL model: head impact, inflammation, low-dose lithium. Trends Open. 2026;1(2):199-213. doi:10.1016/j.treopn.2026.05.010.
