Neurobiological Mechanisms Underlying Psychological Dysfunction After Brain Injuries

Figures

• 

  Figure 1. Therapeutic efficacy of psychological dysfunction in non-injured versus injured populations. While symptomatology is comparable, the therapeutic efficacy for psychological dysfunction is notably diminished in brain-injured populations compared to non-injured individuals. (Created with Biorender.com).

• 

  Figure 2. Different types of brain injury are associated with varying prevalences of psychological dysfunction. Psychological dysfunction is more prevalent in populations with brain injury, with each injury type exhibiting distinct rates and prevalences of psychological symptoms. Notably, vascular cognitive impairment and dementia (VCID), despite showing minimal overt damage (highlighted in red), exhibit the highest prevalence of psychological dysfunction. (Created with Biorender.com) (ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; TBI: traumatic brain injury).

• 

  Figure 3. Psychological dysfunction is associated with alterations in specific brain regions responsible for emotional regulation, with each region contributing to distinct pathogenic cascades that collectively intensify psychological dysfunction. An analysis of studies on psychological dysfunction suggests that the brain sub-regions examined are not dependent on the location, severity, or presence of the primary injury. The primary regions investigated in relation to psychological dysfunction following brain injury include (A) the hippocampus, (B) the cortex, (C) the amygdala, (D) the hypothalamus, (E) white matter, (F) the striatum, and (G) the ventral tegmental area. Notably, the hippocampus, cortex, and amygdala are the main regions studied, while other areas involved in psychological regulation remain comparatively underexplored. (White boxes = depression, gray boxes = anxiety, gradient boxes = anxiety and depression) (Created with Biorender.com) (CCH: chronic cerebral hypoperfusion; ICH: intracerebral hemorrhage; SAH: subarachnoid hemorrhage; TBI: traumatic brain injury).

• 

  Figure 4. Therapeutic interventions targeting neurobiological mechanisms underlying psychological dysfunction in injury-related contexts. Eleven overarching categories of neurobiological mechanisms have been identified as contributing to psychological dysfunction in the context of brain injury. While there is considerable overlap across different types of brain injury, not all mechanisms have been evaluated in every form of brain injury. Additionally, among the assessed mechanisms, only a subset has been specifically targeted with the aim of influencing psychological function (solid, double-headed arrows = identified mechanisms that have been targeted, others have not been targeted at all for therapeutic intervention (dashed, single-headed arrows (see: Table 3, greyed out rows)).

• 

  Figure 5. Nrf2 emerges as a promising upstream target for therapeutic intervention in psychological dysfunction associated with brain injury. To effectively address the multiple underlying mechanisms contributing to psychological dysfunction following brain injury, targeting upstream pathways may offer a promising direction for future research. Given its ability to simultaneously modulate neurotransmission, neuroinflammation, oxidative stress, and apoptosis, Nrf2 stands out as a potential target for therapeutic intervention. (Created with Biorender.com).

• 

  Figure 6. The potential of neuropeptides as promising upstream targets for therapeutic intervention in injury-dependent psychological dysfunction. Neuropeptides function as multifaceted molecules that regulate several processes within the nervous system, including neurotransmission, neuroinflammation, oxidative stress, apoptosis, synaptic plasticity, cerebral blood flow (CBF), and stress responses. These pathways are integral to the development of injury-dependent psychological dysfunction, highlighting the significant potential of neuropeptides as a target for therapeutic intervention. (Each mechanism is annotated with the corresponding neuropeptides that influence it, represented by specific icons: CGRP (square), angiotensin (circle), NPY (pentagon), substance P (star), and CCK (triangle)). (Created with Biorender.com).

• 

  Figure 7. Non-pharmacological interventions as potential therapeutic strategies for alleviating psychological dysfunction following brain injury. Non-pharmacological interventions are inherently multi-mechanistic, enabling them to influence a broad array of factors that contribute to the onset of psychological dysfunction following brain injury. These factors include neurotransmission, neuroinflammation, oxidative stress, apoptosis, synaptic plasticity, cerebral blood flow (CBF), and stress responses, thereby targeting a significant portion of the pathways involved in the development of psychological distress. (Each mechanism is annotated with the interventions known to influence it, represented by specific icons: physical exercise (square), neuromodulation (circle), and an enriched environment (triangle)). (Created with Biorender.com).