Hippocampal atrophy is associated with psychotic symptom severity following traumatic brain injury

Abstract

Psychosis is a rare, but particularly serious sequela of traumatic brain injury. However, little is known as to the neurobiological processes that may contribute to its onset. Early evidence suggests that psychotic symptom development after traumatic brain injury may co-occur with hippocampal degeneration, invoking the possibility of a relationship. Particularly regarding the hippocampal head, these degenerative changes may lead to dysregulation in dopaminergic circuits, as is reported in psychoses due to schizophrenia, resulting in the positive symptom profile typically seen in post-injury psychosis. The objective of this study was to examine change in hippocampal volume and psychotic symptoms across time in a sample of moderate-to-severe traumatic brain injury patients. We hypothesized that hippocampal volume loss would be associated with increased psychotic symptom severity. From a database of n = 137 adult patients with prospectively collected, longitudinal imaging and neuropsychiatric outcomes, n = 24 had complete data at time points of interest (5- and 12-months post-traumatic brain injury) and showed increasing psychotic symptom severity on the Personality Assessment Inventory psychotic experiences subscale of the schizophrenia clinical scale across time. Secondary analysis employing stepwise regression with hippocampal volume change (independent variable) and Personality Assessment Inventory psychotic symptom change (dependent variable) from 5 to 12 months post-injury was conducted including age, sex, marijuana use, family history of schizophrenia, years of education, and injury severity as control variables. Total right hippocampal volume loss predicted an increase on the Personality Assessment Inventory psychotic experiences subscale (F(1, 22)=5.396, adj.R2=0.161, p=0.030; β =-0.017, 95%CI=-0.018,-0.016) as did volume of the right hippocampal head (F(1, 22)=5.764, adj.R2=0.172, p=0.025; β=-0.019, 95% CI=-0.021,-0.017). Final model goodness of fit was confirmed using k-fold (k = 5) cross validation. Consistent with our hypotheses, the current findings suggest that hippocampal degeneration in the chronic stages of moderate-to-severe traumatic brain injury may play a role in the delayed onset of psychotic symptoms after traumatic brain injury. These findings localized to the right hippocampal head are supportive of a proposed etiological mechanism whereby atrophy of the hippocampal head may lead to dysregulation of dopaminergic networks following traumatic brain injury; possibly accounting for observed clinical features of psychotic disorder after traumatic brain injury (including prolonged latency period to symptom onset and predominance of positive symptoms). If further validated, these findings may bear important clinical implications for neurorehabilitative therapies following traumatic brain injury.

Effect of traumatic brain injury on mild behavioral impairment domains prior to all‐cause dementia diagnosis and throughout disease progression

“…This domain broadly encompasses NPS associated with positive psychotic symptoms. Interestingly, emerging literature has suggested that, in the chronic stages of moderate–severe TBI, progressive hippocampal atrophy may dysregulate amplitude of dopaminergic firing in mesolimbic circuits, increasing risk of positive psychotic symptoms in the years post‐injury 19,46 . After moderate–severe TBI, hippocampal volumetric decrements have been observed and may continue to progress for years after the injury event 47,48 .…”

“…19,46 After moderate-severe TBI, hippocampal volumetric decrements have been observed and may continue to progress for years after the injury event. 47,48 In the context of dementia, TBI may introduce vulnerabilities to hippocampal neurodegeneration, such as vascular dysfunction, 49 thereby increasing risk of these NPS by similar mechanisms as have been proposed outside the context of dementia (see Bray et al 19 and Grace 46 ). The present study found that risk of this MBI domain was increased solely in the more severe group and that increased risk appeared to be more pronounced later in dementia progression; while these are in line with this possible explanation, evidence in support of this proposed mechanism is preliminary and further study is required.…”

“…[42][43][44][45] Characterization of decreased motivation risk may lead to better firing in mesolimbic circuits, increasing risk of positive psychotic symptoms in the years post-injury. 19,46 After moderate-severe TBI, hippocampal volumetric decrements have been observed and may continue to progress for years after the injury event. 47,48 In the context of dementia, TBI may introduce vulnerabilities to hippocampal neurodegeneration, such as vascular dysfunction, 49 thereby increasing risk of these NPS by similar mechanisms as have been proposed outside the context of dementia (see Bray et al 19 and Grace 46 ).…”

“… 16 , 18 Additionally, emerging evidence suggests that hippocampal atrophy secondary to moderate–severe TBI may contribute to dysregulation of downstream mesolimbic dopaminergic circuits, increasing risk of hallucinations and delusions. 19 TBI may damage and/or introduce vulnerability in one or more of these neural circuits, perhaps contributing to the altered NPS phenotypes observed in post‐TBI dementia.…”

“…Anterior cingulate circuits (comprising the anterior cingulate cortex, caudate nucleus, and putamen) are responsible for motivation and reward‐related behaviors and, when damaged, lead to apathy with restricted emotional responses and difficulty initiating volitional behaviors 16,18 . Additionally, emerging evidence suggests that hippocampal atrophy secondary to moderate–severe TBI may contribute to dysregulation of downstream mesolimbic dopaminergic circuits, increasing risk of hallucinations and delusions 19 . TBI may damage and/or introduce vulnerability in one or more of these neural circuits, perhaps contributing to the altered NPS phenotypes observed in post‐TBI dementia.…”