Abstract
Background
The impact of comorbid post-traumatic stress disorder (PTSD) and depression on cognitive outcomes after traumatic brain injury (TBI) is not well understood.
Objective
To investigate associations of PTSD and depression with cognitive performance over the first year post-injury.
Methods
1550 participants with Glasgow Coma Scale 13–15 TBI from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Study were included. Participants underwent in-person assessments at 2 weeks, 6 months and 1 year post-injury. Meeting screening criteria for PTSD was determined using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders. Meeting screening criteria for depression was determined using the Patient Health Questionnaire–9. Cognition was assessed using a five-test battery. Linear mixed effects models were used to examine associations of PTSD and depression with cognition after TBI.
Findings
Participants had a mean age of 41 years, 34% were female, 65% did not meet screening criteria for PTSD or depression, 3% met screening criteria for depression only, 16% met screening criteria for PTSD only and 16% met screening criteria for both depression and PTSD in the first year post-TBI. Mean performance on all cognitive tests improved at a similar rate over the first year post-injury in all PTSD/depression groups, but cognitive test performance was consistently worse among individuals with concurrent PTSD and/or depression compared with individuals with neither.
Conclusions
Individuals with TBI meeting screening criteria for PTSD and/or depression have consistently worse cognitive performance over the first year post-injury compared with individuals without psychiatric comorbidities, but the average rate of cognitive improvement over the first year was similar regardless of PTSD/depression status.
Clinical implications
Further work is warranted to determine if cognitive and psychiatric-focused interventions may improve rates of cognitive improvement post-injury among individuals with comorbid PTSD and/or depression so that these individuals may ultimately achieve levels of cognition comparable to individuals without psychiatric comorbidities.
Keywords: Depression; Stress Disorders, Traumatic; Neurocognitive Disorders
WHAT IS ALREADY KNOWN ON THIS TOPIC
The impact of comorbid post-traumatic stress disorder (PTSD) and depression on cognitive outcomes after traumatic brain injury (TBI) is not well understood.
WHAT THIS STUDY ADDS
This study provides evidence that individuals who sustain a TBI and meet screening criteria for PTSD and depression have consistently worse cognitive performance over the first year post-injury compared with individuals without psychiatric comorbidities. However, the average rate of cognitive improvement over the first year is similar regardless of PTSD/depression status.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Meeting screening criteria for PTSD and/or depression may not impact the rate at which an individual improves cognitively post-TBI, but individuals meeting screening criteria for PTSD and depression have consistently worse cognitive performance after injury. Further work is warranted to determine if cognitive and psychiatric-focused interventions may improve rates of cognitive improvement post-injury among individuals with comorbid PTSD and/or depression so that these individuals may ultimately achieve levels of cognition comparable to individuals without psychiatric comorbidities.
Introduction
Traumatic brain injury (TBI) presenting with a Glasgow Coma Scale (GCS) score of 13–15 is the most common form of TBI.1 Prior studies provide evidence that a subset of individuals who have a TBI with GCS 13–15 may experience long-term symptomatology.2 Indeed, TBI is associated with reduced cognitive ability in the immediate post-injury period that is followed by gradual but sometimes incomplete recovery, contributing to functional dependence and disability.1,3 TBI is highly co-occurring with both post-traumatic stress disorder (PTSD) and depression, with 14%–44% of individuals presenting with GCS 13–15 TBI subsequently meeting screening criteria for PTSD and 9%–43% subsequently meeting screening criteria for depression.4,7 Psychiatric conditions such as PTSD and depression have a strong, bidirectional relationship with TBI and overlapping symptoms of emotional dysregulation and cognitive impairment.8 Presence of premorbid depression, PTSD or other psychiatric conditions is associated with worse clinical recovery after TBI,9 and similarly, prior work has reported worsening of PTSD and depressive symptoms years after TBI.10 Both PTSD and depression are also independently associated with cognitive dysfunction,11 12 but the joint implications of comorbid PTSD and depression for cognitive outcomes after GCS 13–15 TBI are not well understood.
Leveraging data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study, our objective was to investigate associations of PTSD and depression with changes in cognition over the first year after a GCS 13–15 TBI. We hypothesised that participants meeting screening criteria for PTSD and depression post-injury would have lower 2-week post-injury cognitive performance and less cognitive recovery over the first year post-injury compared with participants not meeting screening criteria for PTSD or depression and compared with individuals meeting screening criteria for either PTSD alone or depression alone.
Methods
Study design and population
The TRACK-TBI Study is a prospective cohort of patients with acute TBI who presented to one of eighteen level 1 trauma centres in the USA.13 Patients were eligible for enrolment if they presented with one or more of the American Congress of Rehabilitation Medicine clinical criteria for TBI: loss of consciousness, post-traumatic amnesia, alteration of mental status or other acute neurologic signs associated with TBI (eg, seizure, focal neurologic deficit) and received a clinically-indicated head CT within 24-hours of injury.13 Participants were enrolled between 26 February 2014 and 8 July 2018 and attended in-person follow-up visits at 2 weeks, 6 months and 1 year post-injury.13 TRACK-TBI Study data were collected in accordance with the National Institutes of Health-National Institute of Neurological Disorders and Stroke TBI common data elements.13
Of the 2000 TRACK-TBI Study participants aged ≥17 years with an emergency department arrival GCS score of 13–15, we excluded 428 without cognitive data at any timepoint and 22 without PTSD and depression data at any timepoint, leaving 1550 participants included in our analyses (figure 1).
Figure 1. Participant inclusion/exclusion diagram. GCS, Glasgow Coma Scale; TRACK-TBI, Transforming Research and Clinical Knowledge in traumatic brain injury.
Ethics approval
The TRACK-TBI Study was approved by the institutional review board at each enrolling site, with the University of California, San Francisco (UCSF) as the coordinating centre (UCSF Committee on Human Research, Study #10–00011). All participants (or their legally authorised representatives) provided written informed consent.
PTSD and depression
PTSD symptoms were assessed using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5; score range 0–80). Consistent with prior studies,6 a PCL-5 score ≥33 was used as the threshold to classify a participant as meeting screening criteria for PTSD. The PCL-5 was administered at 2 weeks, 6 months and 1 year post-injury.
Depression symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9; score range 0–27). Consistent with prior work,6 a PHQ-9 score ≥15 was used as the threshold to classify a participant as meeting screening criteria for depression. The PHQ-9 was administered at 2 weeks, 6 months and 1 year post-injury.
In primary analyses, a 4-level time-varying exposure variable was used: no PTSD and no depression, PTSD only, depression only and both PTSD and depression. In secondary analyses, time-varying PTSD (yes; no) and time-varying depression (yes; no) were evaluated separately. In additional secondary analyses, we separately considered time-varying continuous PCL-5 scores (modelled per 10-point increase in score) and PHQ-9 scores (modelled per 5-point increase in score).
Cognitive outcomes
Participants underwent in-person cognitive assessments at 2 weeks, 6 months and 1 year post-injury. Cognitive assessments included the Rey Auditory Verbal Learning Test (RAVLT)14 immediate (trials 1–5 total score) and delayed recall (test of verbal episodic memory; higher scores reflect better performance), the Trail Making Test (TMT) parts A and B15 (test of executive function; higher scaled score reflects better performance) and the Wechsler Adult Intelligence Scale—Fourth Edition Processing Speed Index16 (WAIS-IV PSI; higher score reflects better performance). A global cognitive factor score was created by performing confirmatory factor analysis to test the fit of a 1-factor model comprising the five cognitive outcomes (RAVLT immediate recall, RAVLT delayed recall, TMT A, TMT B and WAIS-IV-PSI).17 One model was fit for each follow-up time-point (2 weeks, 6 months, 1 year), and correlated residuals were allowed between the two RAVLT items and between the two TMT items. Longitudinal measurement invariance model fit was adequate (based on the delta root mean square error of approximation and the delta comparative fit index) to consider the global cognitive factor reasonably invariant to time (ie, that the global cognitive factor reflects the same construct from 2 weeks to 1 year post-injury), and estimated global cognitive factor scores were extracted from the strict invariance model for use in analyses.17
For statistical modelling, the global cognitive factor score and all individual test scores were transformed to Z-scores standardised to the 2-week post-TBI timepoint. The primary outcome was the global cognitive factor Z-score, and secondary outcomes included each cognitive test Z-score individually.
Statistical analyses
To examine associations of PTSD and/or depression with cognitive function, we used linear mixed effects models with random intercepts. These models are relatively robust to missing data as they leverage the repeated measurements over time in the same individuals,18 allowing the model to incorporate information from available data points to partially compensate for missing outcome observations (available cognitive data: 93.9% at 2 weeks, 84.7% at 6 months and 77.7% at 1 year). Each model included the main time-varying exposure of PTSD and/or depression, timepoint, and interaction between PTSD and/or depression and timepoint. Each model was additionally adjusted for the following covariates: age, sex, race/ethnicity, education, the National Institute of Health (NIH) Toolbox–Picture Vocabulary Test score, insurance, injury severity, alcohol use, smoking, illicit drug use and day-1 post-injury glial fibrillar acid protein (GFAP) (online supplemental eMethods). In our primary analyses examining associations of the 4-level time-varying exposure variable (no PTSD and no depression, PTSD only, depression only and both PTSD and depression) with cognition, we performed comparisons of the 2-week test scores and of the slopes between each timepoint (2 week to 1 year, 2 weeks to 6 months and 6 months to 1 year post-injury) between groups using linear contrasts that are presented both unadjusted (two-sided p value <0.05 a priori defined as statistically significant) and adjusted for multiple comparisons using the Benjamini-Hochberg method with a 5% false-discovery rate. Results of secondary analyses (associations of time-varying PTSD and PCL-5 scores and time-varying depression and PHQ-9 scores with cognitive outcomes) are shown unadjusted for multiple comparisons. We additionally performed three supplemental analyses examining associations of the 4-level time-varying exposure variable with cognition: (1) using non-z-score transformed cognitive test scores (to facilitate clinical interpretability), (2) excluding 343 participants who failed an embedded performance validity test (defined as TMT-A raw score >62, WAIS-IV PSI coding scaled score <6, or WAIS-IV PSI symbol search scaled score <6)19 and (3) excluding 351 participants with a history of psychiatric disease at baseline/enrolment (self-reported, yes; no). For all analyses, we used multiple imputation by chained equations with 20 sets of imputations to account for missing covariate data (online supplemental eMethods).
Multiple imputation by chained equations was performed using SPSS V.26 (Chicago, Illinois), and all other statistical analyses were performed using SAS V.9.4 (Cary, North Carolina).
Results
Overall, the 1550 included participants had a mean age of 41 years (SD=17.2), 33.9% were female, 57.3% were Non-Hispanic White and 52.4% had an initial GCS score of 15 and CT negative for radiologic signs of intracranial injury (table 1). The majority (65.2%) of participants did not meet screening criteria for either PTSD or depression at any visit timepoint (2 weeks, 6 months, 1 year) over the first year post-injury, 3.1% met screening criteria for depression only, 16.1% met screening criteria for PTSD only and 15.5% met screening criteria for both depression and PTSD. Compared with participants who never met screening criteria for PTSD or depression, participants who met screening criteria for both PTSD and depression were slightly younger (39.7 vs 42.5 years), more likely to be female (44.8% vs 30.2%), more likely to have a history of pre-injury psychiatric disease (41.9% vs 16.7%), less likely to have an initial GCS score of 13–14 (20.2% vs 24.8%) and had lower median day-1 post-injury GFAP levels (138 vs 335 pg/mL). Participants who met screening criteria for both PTSD and depression had similar injury severity and median day-1 post-injury GFAP levels as participants who met screening criteria for PTSD only, but were less likely to have an initial GCS score of 13–14 and had lower median day-1 post-injury GFAP levels compared with participants who met screening criteria for depression only. Compared with participants included in the analysis, participants excluded from the analysis (n=450) were older and more likely to have a TBI of greater severity (ie, GCS 13–14) (online supplemental eTable-1).
Table 1. Participant characteristics overall and stratified by ever PTSD and depression in the first year post-TBI.
| Total population (n=1550) | Stratified by ever PTSD and depression in first year post-TBI | ||||
|---|---|---|---|---|---|
| No PTSD and no depression (n=1011) | Depression only (n=48) |
PTSD only (n=250) |
Both PTSD and depression (n=241) |
||
| Age (years), mean (SD) | 41.0 (17.2) | 42.5 (18.1) | 42.0 (16.4) | 35.8 (14.9) | 39.7 (14.4) |
| Sex, n (%) | |||||
| Female | 525 (33.9) | 305 (30.2) | 20 (41.7) | 92 (36.8) | 108 (44.8) |
| Male | 1025 (66.1) | 706 (69.8) | 28 (58.3) | 158 (63.2) | 133 (55.2) |
| Race/ethnicity, n (%) | |||||
| Non-Hispanic White | 884 (57.3) | 628 (62.4) | 29 (60.4) | 106 (42.7) | 121 (50.2) |
| Non-Hispanic Black | 270 (17.5) | 133 (13.2) | 3 (6.3) | 68 (27.4) | 66 (27.4) |
| Hispanic | 303 (19.6) | 179 (17.8) | 14 (29.2) | 62 (25.0) | 48 (19.9) |
| Other | 86 (5.6) | 66 (6.6) | 2 (4.2) | 12 (4.8) | 6 (2.5) |
| Education (years), mean (SD) | 13.6 (2.9) | 14.0 (2.9) | 13.6 (2.4) | 12.9 (2.4) | 12.7 (2.6) |
| Insurance, n (%) | |||||
| Private | 997 (65.9) | 698 (70.5) | 31 (64.6) | 131 (54.1) | 137 (58.8) |
| Medicaid | 160 (10.6) | 83 (8.4) | 5 (10.4) | 27 (11.2) | 45 (19.3) |
| Self-pay | 307 (20.3) | 176 (17.8) | 8 (16.7) | 78 (32.2) | 45 (19.3) |
| Other | 49 (3.2) | 33 (3.3) | 4 (8.3) | 6 (2.5) | 6 (2.6) |
| Injury severity, n (%) | |||||
| GCS 13–14 | 357 (23.5) | 246 (24.8) | 13 (27.7) | 50 (20.5) | 48 (20.2) |
| GCS 15 and CT positive | 366 (24.1) | 265 (26.7) | 13 (27.7) | 45 (18.4) | 43 (18.1) |
| GCS 15 and CT negative | 797 (52.4) | 480 (48.4) | 21 (44.7) | 149 (61.1) | 147 (61.8) |
| Witnessed loss of consciousness, n (%) | 1278 (86.6) | 828 (85.4) | 41 (87.2) | 209 (88.2) | 200 (90.1) |
| Post-traumatic amnesia, n (%) | 1153 (81.9) | 746 (81.3) | 36 (90.0) | 183 (79.9) | 188 (85.5) |
| Injury cause, n (%) | |||||
| Motor vehicle crash, occupant | 487 (31.4) | 276 (27.3) | 13 (27.1) | 99 (39.6) | 99 (41.1) |
| Motorcycle crash | 126 (8.1) | 80 (7.9) | 6 (12.5) | 19 (7.6) | 21 (8.7) |
| Motor vehicle crash, cyclist/pedestrian | 262 (16.9) | 201 (19.9) | 9 (18.8) | 32 (12.8) | 20 (8.3) |
| Fall | 399 (25.7) | 290 (28.7) | 13 (27.1) | 39 (15.6) | 57 (23.7) |
| Assault | 103 (6.6) | 46 (4.5) | 0 (0.0) | 38 (15.2) | 19 (7.9) |
| Other/unknown | 173 (11.2) | 118 (11.7) | 7 (14.6) | 23 (9.2) | 25 (10.4) |
| Highest level of care, n (%) | |||||
| Emergency department discharge | 435 (28.1) | 277 (27.4) | 11 (22.9) | 79 (31.6) | 68 (28.2) |
| Hospital admission without ICU level care | 680 (43.9) | 433 (42.8) | 21 (43.8) | 116 (46.4) | 110 (45.6) |
| Hospital admission with ICU level care | 435 (28.1) | 301 (29.8) | 16 (33.3) | 55 (22.0) | 63 (26.1) |
| Length of hospital stay (days), median (IQR)* | 2.2 (1.3–4.0) | 2.3 (1.3–3.2) | 2.8 (1.8–4.9) | 2.2 (1.4–3.8) | 1.8 (1.2–3.5) |
| Day 1 GFAP (pg/mL), median (IQR) | 276 (69–794) | 335 (98–941) | 399 (61–1251) | 177 (35–618) | 138 (20–505) |
| History of psychiatric disease, n (%) | 351 (22.7) | 169 (16.7) | 13 (27.1) | 68 (27.3) | 101 (41.9) |
| Alcohol use (AUDIT-C score), mean (SD) | 3.0 (2.5) | 3.0 (2.5) | 2.8 (2.3) | 3.2 (2.6) | 2.6 (2.5) |
| Smoking in year prior to injury, n (%) | 400 (27.2) | 221 (22.9) | 8 (17.8) | 80 (34.2) | 91 (39.4) |
| Illicit or non-prescription drug use in the year prior to injury, n (%) | 387 (25.6) | 216 (21.9) | 12 (26.1) | 90 (36.7) | 69 (29.4) |
| NIH Toolbox–Picture Vocabulary Test score, mean (SD) | 116 (12) | 119 (12) | 118 (11) | 112 (11) | 112 (10) |
Note: The following variables contained missing data: race/ethnicity (n=7), education (n=30), insurance (n=37), injury severity (n=30), loss of consciousness (n=74), post-traumatic amnesia (n=143), day 1 GFAP (n=62), psychiatric disease (n=1), alcohol use (n=33), smoking in year prior to injury (n=77), illicit/non-prescription drug use in year prior to injury (n=37) and NIH Toolbox–Picture Vocabulary Test (n=386).
Length of hospital stay shown for participants who were admitted to the hospital either with or without ICU level care (does not include participants who were discharged from the emergency department).
AUDIT-C, Alcohol Use Disorders Identification Test-C; GCS, Glasgow Coma Scale; GFAP, glial fibrillar acid protein; ICU, intensive care unit; IQR, interquartile range; NIH, National Institute of Health; PTSD, post-traumatic stress disorder; TBI, traumatic brain injury.
Unadjusted mean performance on all cognitive tests improved at a similar rate over the first year post-injury, but was consistently worse (at 2 weeks, 6 months and 1 year post-injury) among individuals who met screening criteria for both PTSD and depression compared with individuals who did not meet screening criteria for either PTSD or depression (figure 2). Mean performance for individuals who met screening criteria for either depression only or PTSD only was similar, and point estimates were intermediate between point estimates for individuals who met screening criteria for both PTSD and depression and individuals who did not meet screening criteria for either PTSD or depression.
Figure 2. Mean (SE) cognitive test performance at 2 weeks, 6 months and 1 year post-TBI by time-varying PTSD and depression status. PTSD, post-traumatic stress disorder; RAVLT, Rey Auditory Verbal Learning Test; TBI, traumatic brain injury; WAIS-PSI, Wechsler Adult Intelligence Scale—Fourth Edition Processing Speed Index.
In adjusted models, compared with participants not meeting screening criteria for PTSD or depression, participants meeting screening criteria for both conditions had lower 2-week scores globally (difference in 2-week global cognitive factor Z-score=−0.11, 95% CI −0.15 to –0.07) and on the RAVLT immediate and delayed recall, TMT-A and WAIS-PSI; these differences remained statistically significant after correction for multiple comparisons (table 2). Compared with participants not meeting screening criteria for PTSD or depression, participants meeting screening criteria for depression had lower 2 week scores on the RAVLT delayed recall and the WAIS-PSI; these differences remained statistically significant after correction for multiple comparisons. Participants meeting screening criteria for PTSD only had similar 2 week cognitive performance compared with participants not meeting screening criteria for PTSD or depression.
Table 2. Adjusted associations of time-varying PTSD and depression with cognition in the first year post-injury.
| Time-varying PTSD and depression in first year post-TBI | ||||
|---|---|---|---|---|
| No PTSD and no depression B (95% CI) |
Depression only B (95% CI) |
PTSD Only B (95% CI) |
Both PTSD and depression B (95% CI) |
|
| Global cognitive factor | ||||
| Difference in 2-week Z-score | Ref(Zmean=0.07)*†# | −0.06 (−0.13 to 0.00)* | −0.03 (−0.07 to 0.00) | −0.11 (−0.15 to 0.07) †# |
| Change in Z-score from 2 weeks to 1 year | 0.56 (0.54 to 0.57) | 0.62 (0.49 to 0.75) | 0.53 (0.48 to 0.58) | 0.56 (0.51 to 0.62) |
| Change in Z-score from 2 weeks to 6 months | 0.32 (0.31 to 0.34)‡ | 0.37 (0.27 to 0.48) | 0.32 (0.28 to 0.37) | 0.39 (0.34 to 0.44)‡ |
| Change in Z-score from 6 months to 1 year | 0.23 (0.22 to 0.25) | 0.25 (0.11 to 0.38) | 0.21 (0.16 to 0.25) | 0.17 (0.11 to 0.23) |
| RAVLT immediate recall | ||||
| Difference in 2-week Z-score | Ref(Zmean=0.08)§# | −0.20 (−0.42 to 0.01) | −0.01 (−0.13 to 0.10) | −0.19 (−0.33 to 0.06)§# |
| Change in Z-score from 2 weeks to 1 year | 0.37 (0.32 to 0.43)¶** | 0.19 (−0.24 to 0.62) | 0.14 (−0.02 to 0.30)¶ | 0.16 (−0.03 to 0.36)** |
| Change in Z-score from 2 weeks to 6 months | 0.03 (−0.03 to 0.08)†† | 0.11 (−0.24 to 0.45) | −0.13 (−0.27 to 0.02)†† | −0.09 (−0.26 to 0.09) |
| Change in Z-score from 6 months to 1 year | 0.35 (0.29 to 0.40) | 0.08 (−0.37 to 0.53) | 0.27 (0.11 to 0.43) | 0.25 (0.05 to 0.45) |
| RAVLT delayed recall | ||||
| Difference in 2-week Z-score | Ref(Zmean=0.06)‡‡#§§# | −0.27 (−0.49 to 0.04) hour‡‡# | −0.08 (−0.20 to 0.05) | −0.23 (−0.37 to 0.09) §§# |
| Change in Z-score from 2 weeks to 1 year | 0.26 (0.20 to 0.32) | 0.42 (−0.04 to 0.88) | 0.18 (0.01 to 0.35) | 0.13 (−0.08 to 0.33) |
| Change in Z-score from 2 weeks to 6 months | 0.07 (0.01 to 0.12) | 0.08 (−0.29 to 0.44) | 0.04 (0.12 to 0.19) | 0.05 (−0.14 to 0.23) |
| Change in Z-score from 6 months to 1 year | 0.20 (0.14 to 0.26) | 0.35 (−0.13 to 0.83) | 0.15 (−0.03 to 0.32) | 0.08 (−0.14 to 0.29) |
| TMT A (scaled score) | ||||
| Difference in 2-week Z-score | Ref(Zmean=0.07)¶¶# | −0.06 (−0.25 to 0.13) | −0.09 (−0.20 to 0.01) | −0.21 (−0.33 to 0.08) ¶¶# |
| Change in Z-score from 2 weeks to 1 year | 0.42 (0.37 to 0.47) | 0.40 (0.00 to 0.80) | 0.47 (0.33 to 0.62) | 0.42 (0.23 to 0.60) |
| Change in Z-score from 2 weeks to 6 months | 0.29 (0.24 to 0.34) | 0.25 (−0.07 to 0.57) | 0.34 (0.20 to 0.47) | 0.42 (0.26 to 0.58) |
| Change in Z-score from 6 months to 1 year | 0.13 (0.08 to 0.19) | 0.14 (−0.27 to 0.56) | 0.14 (−0.01 to 0.29) | −0.01 (−0.19 to 0.18) |
| TMT B (scaled score) | ||||
| Difference in 2-week Z-score | Ref(Zmean=0.06) | −0.02 (−0.21 to 0.16) | −0.02 (−0.12 to 0.09) | −0.11 (−0.23 to 0.01) |
| Change in Z-score from 2 weeks to 1 year | 0.33 (0.28 to 0.38) | 0.67 (0.28 to 1.06) | 0.23 (0.09 to 0.38) | 0.26 (0.09 to 0.44) |
| Change in Z-score from 2 weeks to 6 months | 0.23 (0.18 to 0.28)*** | 0.21 (−0.10 to 0.52) | 0.07 (−0.06 to 0.20)*** | 0.22 (0.07 to 0.38) |
| Change in Z-score from 6 months to 1 year | 0.10 (0.05 to 0.15) | 0.46 (0.06 to 0.86) | 0.16 (0.02 to 0.31) | 0.04 (−0.14 to 0.22) |
| WAIS-PSI | ||||
| Difference in 2-week Z-score | Ref(Zmean=0.09)†††#‡‡‡# | −0.21 (−0.38 to 0.04) †††# | −0.05 (−0.14 to 0.04) | −0.25 (−0.36 to 0.14) ‡‡‡# |
| Change in Z-score from 2 weeks to 1 year | 0.59 (0.54 to 0.63)§§§ | 0.73 (0.39 to 1.08) | 0.44 (0.32 to 0.57)§§§ | 0.54 (0.38 to 0.69) |
| Change in Z-score from 2 weeks to 6 months | 0.38 (0.34 to 0.43) | 0.45 (0.17 to 0.74) | 0.33 (0.21 to 0.44) | 0.39 (0.25 to 0.53) |
| Change in Z-score from 6 months to 1 year | 0.21 (0.16 to 0.25) | 0.28 (−0.08 to 0.64) | 0.12 (−0.01 to 0.25) | 0.14 (−0.01 to 0.30) |
Linear mixed effects regression models with random intercepts were adjusted for fixed-effect covariates (age, sex, race/ethnicity, education, NIH Toolbox–Picture Vocabulary Test score, insurance, GCS, alcohol use, smoking, drug use, day-1 GFAP). Multiple imputation is used to account for missing covariate values.
#Group comparison remained statistically significant after adjustment for multiple comparisons using the Benjamini-Hochberg method with a 5% false-discovery rate.
p=0.049 comparing depression only group to no PTSD and no depression group for 2-week global cognitive factor Z-score.
p<0.001# comparing both PTSD and depression group to no PTSD and no depression group for 2-week global cognitive factor Z-score.
p=0.020 comparing both PTSD and depression group to no PTSD and no depression group for 2 weeks to 6 months global cognitive factor Z-score.
p=0.004# comparing both PTSD and depression group to no PTSD and no depression group for 2-week RAVLT immediate recall Z-score.
p=0.008 comparing PTSD only group to no PTSD and no depression group for 2 weeks to 1 year RAVLT immediate recall Z-score.
p=0.043 comparing both PTSD and depression group to no PTSD and no depression group for 2 weeks to 1 year RAVLT immediate recall Z-score.
p=0.050 comparing PTSD only group to no PTSD and no depression group for 2 weeks to 6 months RAVLT immediate recall Z-score.
p=0.019# comparing PTSD only group to no PTSD and no depression group for 2-week RAVLT delayed recall Z-score.
p=0.001# comparing both PTSD and depression group to no PTSD and no depression group for 2-week RAVLT delayed recall Z-score.
p=0.001# comparing both PTSD and depression group to no PTSD and no depression group for 2-week TMT A (scaled score) Z-score.
p=0.026 comparing PTSD only group to no PTSD and no depression group for 2 weeks to 6 months TMT B (scaled score) Z-score.
p=0.015# comparing depression only group to no PTSD and no depression group for 2-week WAIS-PSI Z-score.
p<0.001# comparing both PTSD and depression group to no PTSD and no depression group for 2-week WAIS-PSI Z-score.
p=0.037 comparing PTSD only group to no PTSD and no depression group for 2 weeks to 1 year WAIS-PSI Z-score.
GCS, Glasgow Coma Scale; GFAP, glial fibrillar acid protein; NIH, National Institutes of Health; PTSD, post-traumatic stress disorder; RAVLT, Rey Auditory Verbal Learning Test; TBI, traumatic brain injury; TMT, Trail Making Test; WAIS-PSI, Wechsler Adult Intelligence Scale—Fourth Edition Processing Speed Index.
In adjusted analyses evaluating change in cognition over time, compared with participants not meeting screening criteria for PTSD or depression, participants meeting screening criteria for both PTSD and depression had greater global improvement between 2 weeks and 6 months (B=0.32, 95% CI 0.31 to 0.34 vs B=0.39, 95% CI 0.34 to 0.44, p=0.020), but less improvement on the RAVLT immediate recall between 2 weeks and 1 year (B=0.37, 95% CI 0.31 to 0.43 vs B=0.16, 95% CI −0.03 to 0.36, p=0.043) (table 2). Neither of these two between-group comparisons was statistically significant after correction for multiple comparisons. Participants meeting screening criteria for PTSD only had less improvement on the RAVLT immediate recall, TMT-B and WAIS-PSI (not statistically significant after correction for multiple comparisons), while participants meeting screening criteria for depression only performed similarly to participants not meeting screening criteria for PTSD or depression.
Supplemental analyses using non-Z-score transformed cognitive test scores (online supplemental eTable-2) and excluding participants with a history of psychiatric disease at baseline/enrolment (online supplemental eTable-3) were similar to the primary analyses. Supplemental analyses excluding participants who failed an embedded performance validity test were also largely similar to the primary analyses, but results were attenuated (online supplemental eTable-4).
In secondary analyses, time-varying PTSD and time-varying depression were evaluated separately. Characteristics of the analytic population stratified by PTSD status are shown in online supplemental eTable-5. Compared with participants never meeting screening criteria for PTSD, participants meeting screening criteria for PTSD were younger (37.7 vs 42.5 years), more likely to be female (40.7% vs 30.7%), less likely to have an initial GCS score of 13–14 (20.3% vs 25.0%) and had lower median day-1 GFAP (154 vs 335 pg/mL). The unadjusted mean performance on all cognitive tests improved over the first year post-injury, but was consistently worse (at 2 weeks, 6 months and 1 year post-injury) among individuals who met screening criteria for PTSD compared with individuals who did not meet screening criteria for PTSD (online supplemental eFigure-1). In adjusted models, compared with participants not meeting screening criteria for PTSD, participants meeting screening criteria had lower 2-week scores globally (difference in 2-week global cognitive factor Z-score=−0.06, 95% CI −0.09 to –0.03) and performed worse on the RAVLT delayed recall, TMT A and WAIS-PSI. Participants meeting screening criteria for PTSD improved less than participants not meeting screening criteria for PTSD globally (6 months to 1 year difference in global cognitive factor Z-score=−0.04, 95% CI −0.08 to 0.00) on the RAVLT immediate recall (2 weeks to 1 year difference in RAVLT immediate recall Z-score=−0.23, 95% CI −0.36 to –0.09 and 2 weeks to 6 months difference in RAVLT immediate recall Z-score=−0.14, 95% CI −0.27 to –0.02) (online supplemental eTable-6). Associations with cognition over time were consistent when the PCL-5 score was modelled as a continuous variable.
Compared with participants never meeting screening criteria for depression, participants meeting screening criteria for depression were of similar age (40.1 vs 41.2 years), more likely to be female (44.3% vs 31.5%), less likely to have an initial GCS score of 13–14 (21.4% vs 24.0%) and had a lower median day-1 GFAP (150 vs 294 pg/mL) (online supplemental eTable-5). The unadjusted mean performance on all cognitive tests improved over the first year post-injury but was consistently worse at all follow-up time points among individuals who met screening criteria for depression compared with individuals who did not meet screening criteria for depression (online supplemental eFigure-2). Compared with participants not meeting screening criteria for depression, participants meeting screening criteria had lower adjusted 2-week scores globally (difference in 2-week global cognitive factor Z-score=−0.10, 95% CI −0.13 to –0.06) and performed worse on the RAVLT immediate and delayed recall, the TMT A and the WAIS-PSI. Participants meeting screening criteria for depression improved more than participants not meeting screening criteria for depression globally between 2 weeks and 6 months post-injury and on the RAVLT immediate recall between 2 weeks and 1 year post-injury, but other adjusted changes in cognitive performance over time were similar by depression status (online supplemental eTable-7). Associations with cognition over time were consistent when the PHQ-9 score was modelled as a continuous variable.
Discussion
In this study of individuals with TBI and initial GCS of 13–15, meeting screening criteria for the psychiatric conditions of PTSD and depression were common over the first year post-injury, affecting 35% of the cohort. Individuals meeting screening criteria for PTSD and/or depression performed consistently worse on cognitive assessments at 2 weeks, 6 months and 1 year post-injury compared with individuals with neither, though the magnitudes of associations were small. The rate of change in cognition over time, however, was similar between groups. These results suggest that individuals with psychiatric comorbidities such as PTSD and depression may have worse immediate post-injury cognitive function, but further work is warranted to determine if these patients may benefit (ie, experience faster rates of cognitive improvement and achieve levels of cognition comparable to those without psychiatric comorbidities) from intensive cognitive rehabilitation and/or psychiatric-focused interventions in the immediate post-injury period.
Our work expands the extant literature on TBI-related cognitive impairment. First, we evaluated both the individual and joint implications of comorbid PTSD and depression on cognitive function following TBI. Prior studies investigating associations of TBI with cognition have considered comorbid PTSD and comorbid depression separately.20,22 Further, the majority of prior studies were cross-sectional, investigating cognitive status at one point in time.20,23 Consistent with these cross-sectional studies,20,23 we observed that individuals with TBI with comorbid PTSD and/or depression performed worse (small effect sizes) on measures of cognition globally and in processing speed, memory and executive functioning at each time-point compared with individuals with TBI without these comorbidities. However, it is important to consider that the group-level effect sizes in our study do not meet the threshold for a minimal clinically important difference, which other studies have suggested to be 0.4–0.5 SD using a distribution-based approach.24 Our study also extends the observation of consistently lower cognition among individuals presenting with TBI and comorbid PTSD and/or depression to level 1 trauma centres for care. Indeed, most prior studies of patients with TBI that have considered PTSD and depression in association with cognition have been performed in active-duty military or veteran populations.22 23 25 26
By tracking cognitive function over time, our longitudinal results not only demonstrate small post-injury differences in cognition among individuals who meet versus do not meet screening criteria for depression and/or PTSD, but also provide evidence that the rates of change in cognition are similar regardless of PTSD and depression status. Taken together, these findings have implications for post-TBI management with regard to timing, intensity and approach to therapy. Prior studies have suggested that individuals with TBI and psychiatric comorbidities benefit from cognitive rehabilitation after injury,25 26 with improvements observed in executive functioning after a rehabilitation programme that combined mindfulness-based attention and individualised goal management strategies.26 Further work is needed to determine the optimal timing and intensity of cognitive rehabilitation and mental health treatment after injury to improve the consistently lower cognitive functioning observed among individuals with TBI and comorbid PTSD and/or depression. Additional research incorporating clinical assessment is necessary to determine the most effective focus for treatment/rehabilitation: cognitive symptoms, post-traumatic or depressive symptoms or a combination.
These results should be interpreted in the context of certain limitations. First, the study population includes individuals with GCS 13–15 TBI who presented to level 1 trauma centres in the USA and who completed at least one assessment of cognition, PTSD symptoms and depression symptoms. Thus, results do not generalise to individuals with more severe injuries and may not generalise to individuals presenting to community hospitals, outpatient clinics or who did not seek medical care. It is possible that a subset of included TBI patients with GCS 15 and CT negative for radiologic signs of intracranial injury may be misclassified (ie, they may have endorsed clinical signs such as post-traumatic amnesia or altered mental status that were due to an acute trauma response rather than a TBI). It is further possible that this misclassification may be differential by PTSD status. Consistent with prior work,27 we found that individuals with PTSD were more likely to have normal GCS (ie, score of 15), a CT negative for radiologic signs of intracranial injury and lower day 1 GFAP values. Second, PTSD and probable were determined using the PCL-5 and PHQ-9, respectively. Although these measures are standardised and validated,28 29 these patient-reported questionnaires are used as screening tools rather than confirmatory diagnostic testing. We also were not able to incorporate information on medication use over time into our PTSD and depression variables as TRACK-TBI does not collect data on medications after baseline/enrolment. Third, the TRACK-TBI Study does not have separate measures of cognitive performance validity, so it is possible that there was differential engagement/effort on cognitive testing by group. However, in our sensitivity analysis excluding individuals who failed an embedded performance validity test, results were similar but slightly attenuated compared with our main analysis. There is also the possibility that improvements on cognitive testing over time are related to practice effects. However, the TRACK-TBI Study uses different versions of the RAVLT, decreasing the impact of practice effects. Fourth, because TRACK-TBI participants are enrolled at the time of TBI, we do not have pre-injury measurements of cognitive performance. However, in our analysis, we adjusted for performance on the NIH Toolbox–Picture Vocabulary test, which is a measure of crystallised intelligence (ie, premorbid/pre-injury cognitive ability), suggesting that our results are potentially independent of pre-injury differences in cognition. Our study also does not allow us to determine whether individuals with psychiatric comorbidities have lower cognitive performance prior to the TBI event compared with individuals without psychiatric comorbidities or if individuals with psychiatric comorbidities are more susceptible to the cognitive effects of the injury, resulting in a greater post-injury decrease in cognition. However, results from our sensitivity analysis excluding participants with psychiatric diagnoses at baseline/enrolment were similar to our main analyses. Alternatively, it is also possible that individuals who suffer greater cognitive deficits after TBI are more likely to later have PTSD and/or depression.
In conclusion, this study provides evidence that individuals with TBI presenting with an initial GCS score of 13–15 and meeting screening criteria for PTSD and/or depression have consistently worse cognitive performance over the first year post-injury (though the magnitudes of associations were small). However, the average rate of cognitive improvement over the first year was similar regardless of PTSD and/or depression status, suggesting that these conditions do not impact capacity for improved cognitive performance post-injury. Further work is warranted to determine if cognitive and psychiatric-focused interventions may improve rates of cognitive improvement post-injury among individuals with comorbid PTSD and/or depression so that these individuals may ultimately achieve levels of cognition comparable to individuals without psychiatric comorbidities.
Supplementary material
Footnotes
Funding: The TRACK-TBI study was funded by the US National Institute for Neurological Disorders and Stroke (NINDS) (grant number U01NS1365885). Dr Nelson was supported by NINDS (grant number R01NS110856). Dr. Scott was supported by the US VA ORD (grant numbers I01RX002699 and I21RX004627). Dr. Schneider was supported by the US Department of Defense (grant number W81XWH-21-1-0590 and NINDS grant number K23NS123340).
Provenance and peer review: Not commissioned; externally peer-reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study involved human participants. The TRACK-TBI Study was approved by the institutional review board at each enrolling site, with the University of California, San Francisco (UCSF) as the coordinating centre (UCSF Committee on Human Research, Study #10-00011). All participants (or their legally authorised representatives) provided written informed consent to participate in the study before taking part.
Data availability free text: Data from the TRACK-TBI study are available through the Federal Interagency Traumatic Brain Injury Research (FITBIR) Informatics System at doi: 10.23718/FITBIR/1518881. Qualified researchers may request access to data stored in FITBIR which requires obtaining data access privileges outlined by FITBIR. TRACK-TBI Study protocols and data collection forms are available at https://tracktbi.ucsf.edu/researchers. Investigators interested in investigating specific data elements may submit a Data Collaboration Request (https://tracktbi.ucsf.edu/collaboration-opportunities) to the TRACK-TBI Executive Committee. Analytic code used to conduct the analyses in this study is not available in a public repository and may be made available upon email request to the corresponding author. TRACK-TBI Study protocols, informed consent forms, data collection forms and data dictionaries are available for public access at https://tracktbi.ucsf.edu/researchers.
Collaborators: THE TRACK-TBI Study investigators: Ann-Christine Duhaime, MD, MassGeneral Hospital for Children; Shawn Eagle, PhD, University of Pittsburgh; Ramesh Grandhi, MD MS, University of Utah; C. Dirk Keene, MD PhD, University of Washington; Frederick K. Korley, MD, PhD, University of Michigan; Vijay Krishnamoorthy, MD, Duke University; Christine MacDonald, PhD, University of Washington; Michael McCrea, PhD, Medical College of Wisconsin; Randall Merchant, PhD, Virginia Commonwealth University; Laura B. Ngwenya, MD, PhD, University of Cincinnati; David Okonkwo, MD PhD, University of Pittsburgh; Ava Puccio, PhD, University of Pittsburgh; David Schnyer, PhD, UT Austin; Sabrina R. Taylor, PhD, University of California, San Francisco; John K. Yue, MD, University of California, San Francisco; Ross Zafonte, DO, Harvard Medical School.
Contributor Information
TRACK-TBI Investigators:
Ann-Christine Duhaime, Shawn Eagle, Ramesh Grandhi, C Dirk Keene, Frederick K Korley, Vijay Krishnamoorthy, Christine MacDonald, Michael McCrea, Randall Merchant, Laura B. Ngwenya, David Okonkwo, Ava Puccio, David Schnyer, Sabrina R Taylor, John K Yue, and Ross Zafonte
Data availability statement
Data are available in a public, open access repository.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data are available in a public, open access repository.