Outcomes and Mechanisms Associated With Selective Thalamic Neuronal Loss in Chronic Traumatic Brain Injury

Abstract

Importance: The chronic neuronal burden of traumatic brain injury (TBI) is not fully characterized by routine imaging, limiting understanding of the role of neuronal substrates in adverse outcomes.

Objective: To determine whether tissues that appear healthy on routine imaging can be investigated for selective neuronal loss using [11C]flumazenil (FMZ) positron emission tomography (PET) and to examine whether this neuronal loss is associated with long-term outcomes.

Design, setting, and participants: In this cross-sectional study, data were collected prospectively from 2 centers (University of Cambridge in the UK and Weill Cornell Medicine in the US) between September 1, 2004, and May 31, 2021. Patients with TBI (>6 months postinjury) were compared with healthy control participants (all aged >18 years). Individuals with neurological disease, benzodiazepine use, or contraindication to magnetic resonance imaging were excluded. Data were retrospectively collated with nonconsecutive recruitment, owing to convenience and scanner or PET ligand availability. Data were analyzed between February 1 and September 30, 2023.

Exposure: Flumazenil voxelwise binding potential relative to nondisplaceable binding potential (BPND).

Main outcomes and measures: Selective neuronal loss identified with FMZ PET was compared between groups on voxelwise and regional scales, and its association with functional, cognitive, and psychological outcomes was examined using Glasgow Outcome Scale (GOS) scores, measures of sustained executive attention (animal and sustained fluency), and 36-Item Short Form Health Survey (SF-36) scores. Diffusion tensor imaging was used to assess structural connectivity of regions of cortical damage, and its association with thalamic selective neuronal loss.

Results: In this study, 24 patients with chronic TBI (mean [SD] age, 39.2 [12.3] years; 18 men [75.0%]) and 33 healthy control participants (mean [SD] age, 47.6 [20.5] years; 23 men [69.7%]) underwent FMZ PET. Patients with TBI had a median time of 29 (range, 7-95) months from injury to scan. They displayed selective neuronal loss in thalamic nuclei, over and above gross volume loss in the left thalamus, and bilateral central, mediodorsal, ventral-lateral dorsal, anterior, and ventral anterior thalamic nuclei, across a wide range of injury severities. Neuronal loss was associated with worse functional outcome using GOS scores (left thalamus, left ventral anterior, and bilateral central, mediodorsal, and anterior nuclei), worse cognitive outcome on measures of sustained executive attention (left thalamus, bilateral central, and right mediodorsal nuclei), and worse emotional outcome using SF-36 scores (right central thalamic nucleus). Chronic thalamic neuronal loss partially mirrored the location of primary cortical contusions, which may indicate secondary injury mechanisms of transneuronal degeneration.

Conclusions and relevance: The findings of this study suggest that selective thalamic vulnerability may have chronic neuronal consequences with relevance to long-term outcome, suggesting the evolving and potentially lifelong thalamic neuronal consequences of TBI. FMZ PET is a more sensitive marker of the burden of neuronal injury than routine imaging; therefore, it could inform outcome prognostication and may lead to the development of individualized precision medicine approaches.

Figure 1.. [¹¹C]Flumazenil (FMZ) Nondisplaceable Binding Potential Relative to Nondisplaceable Distribution Volume (BP_ND) Reduction in Chronic Traumatic Brain Injury (TBI)

A, Voxelwise comparisons of FMZ BP_ND between the control and TBI groups, with all patients included (n = 24). The color bar shows t values surviving significance thresholds of P < .001 (uncorrected, voxel level) and P < .05 (familywise error, cluster level). B and C, Region of interest (ROI)-level comparisons between control participants and patients with TBI, with statistically significant differences surviving false-discovery rate correction indicated with P values. The y-axis of mean FMZ BP_ND is adjusted for covariates. Panel B presents comparisons when including covariates of age, sex, and research site. Panel C demonstrates the remaining statistically significant differences when normalized ROI volume is additionally included as a covariate in the linear model. Patients with TBI were excluded from each comparison in panels B and C if they presented a contusion within that region (n = 3 excluded for thalamic ROIs and n = 11 excluded in frontal ROIs). L indicates left; m, medio; R, right; vl, ventral-lateral.

Figure 2.. Association Between [¹¹C]Flumazenil (FMZ) Nondisplaceable Binding Potential Relative to Nondisplaceable Distribution Volume (BP_ND) and Chronic Outcome

A and B, Statistically significant correlations between mean FMZ BP_ND within a region of interest (ROI) and outcome for Glasgow Outcome Scale (GOS) score (A) and animal fluency in 60 to 90 seconds (B). Full test results are presented in the Results. The y-axis of mean FMZ BP_ND is adjusted for covariates of age, sex, research site, and normalized ROI volume. Each test included patients with nonthalamic contusions (n = 15) with that outcome available (n = 2 patients did not complete animal fluency due to fatigue). Corresponding thalamic view highlights associated nuclei in panels A and B, respectively. L indicates left; m, medio; R, right; v, ventral.

Figure 3.. Association Between [¹¹C]Flumazenil (FMZ) Nondisplaceable Binding Potential Relative to Nondisplaceable Distribution Volume (BP_ND) and Contusion Structural Connectivity

A, Traumatic contusion masks summed across the group with traumatic brain injury. Values indicate the number of patients with a contusion in that region (ie, a value of 4 indicates 4 patients exhibit contusions at this location). B, Statistically significant negative correlations between FMZ BP_ND and structural connectivity probability, where each point is an individual. Individuals were included if they did not present a thalamic lesion with contusion mask (n = 15) and were successful at producing some tracts between the respective thalamic nucleus and their contusion mask. Results indicate a mirroring effect between cortical damage and chronic thalamic neuronal loss. The x-axis of mean FMZ BP_ND is adjusted for covariates. Prefix m indicates medio; v, ventral.