Sage Journals: Discover world-class research

Abstract

Objective

To complete a systematic review of the literature examining neuroimaging findings unique to co-occurring syndromal depression in the setting of TBI.

Methods

A PRISMA compliant literature search was conducted in PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases for articles published prior to April of 2022. The database query yielded 4447 unique articles. These articles were narrowed based on specific inclusion criteria (e.g., clear TBI definition, clear depression construct commenting on the syndrome of major depressive disorder, conducted empirical analyses comparing neuroimaging correlates in TBI subjects with depression versus TBI subjects without depression, controlled for the time interval between TBI occurrence and acquisition of neuroimaging).

Results

A final cohort of 10 articles resulted, comprising the findings from 423 civilians with brain injury, 129 of which developed post-TBI depression. Four articles studied mild TBI, three mild/moderate, one moderate/severe, and two all-comers, with nine articles focusing on single TBI and one including both single and recurrent injuries. Spatially convergent structural abnormalities in individuals with TBI and co-occurring syndromal depression were identified primarily in bilateral frontal regions, particularly in those with damage to the left frontal lobe and prefrontal cortices, as well as temporal regions including bilateral temporal lobes, the left superior temporal gyrus, and bilateral hippocampi. Various parietal regions and the nucleus accumbens were also implicated. EEG studies showed supporting evidence of functional changes in frontal regions.

Conclusion

Additional inquiry with attention to TBI without depression control groups, consistent TBI definitions, previous TBI, clinically diagnosed syndromal depression, imaging timing post-injury, acute prospective design, functional neuroimaging, and well-defined neuroanatomical regions of interest is crucial to extrapolating finer discrepancies between primary and TBI-related depression.

Keywords

Traumatic brain injury depression neuroimaging neuropsychiatric symptoms

Introduction

The conceptualization of traumatic brain injury (TBI) as a disease process with potential for consequential downstream effects, rather than a singular isolated event, is becoming an increasingly validated viewpoint amongst clinical scientists.¹ TBI is an incompletely understood precursor to often under-reported neuropsychiatric disruption. It has been linked to a variety of new-onset psychiatric complications and is a risk factor for decompensation of previously well-controlled conditions. There may be utility in ascertaining how the clinical expression of psychiatric disorders in the context of TBI might compare to their idiopathic counterparts, especially as it relates to neuroanatomical underpinnings. Such ideas represent the premise of the current systematic review, which has the objective of synthesizing the existing literature that examines neuroimaging findings related to co-occurring syndromal depression in the setting of TBI.

Prevalence of depression following traumatic brain injury is quite common. It has been shown that 17−53% of TBI patients experience depressive symptoms during the first year post-injury.^2–6 Studies have also found that 27 − 29% of TBI patients meet criteria for major depressive disorder.^7–9 Studies that have followed individuals with TBI for one year or more post-injury found depression and anxiety to be the most commonly reported neuropsychiatric symptoms.^10–12 There is also evidence that depression portends worse TBI recovery trajectories.^13,14

Mood-related neuropsychiatric symptoms (NPS), including symptoms of depression, have not traditionally been at the center of TBI outcomes research. Instead, cognition-related NPS and functional ability have been the primary investigational foci. Despite this, NPS have a variety of characteristics that warrant their study in the setting of TBI. For example, the clinical profile of depression that occurs in patients with TBI is distinct from that of idiopathic depression. Individuals with TBI are at greater risk for developing more isolated depressive symptoms⁸ characterized by increased apathy and irritability,¹⁵ as well as greater social isolation, hostility, and more cognitive deficits.¹⁶ The tendency for brain injury to manifest phenotypic expressions in a more isolated manner could provide key insights into the brain networks implicated in depression. TBI supplies an etiology, a key component of the disease triad, which is largely missing in idiopathic depression.

Neuroimaging studies on idiopathic depression have broadly suggested frontal lobe involvement including functional hypoactivation in the left dorsolateral PFC,¹⁷ functional hyperactivity of the ventromedial PFC,^18,19 and decreased volume in the PFC, hippocampi, amygdala, and basal ganglia.²⁰ Imaging correlates of idiopathic depression have received ample research attention, producing a multitude of systematic reviews and meta-analytic studies, with some even focusing on a single imaging modality.^21–27 Imaging correlates of TBI-related depression, however, have not achieved such large-scale focus. Existing systematic reviews on post-TBI depression do not primarily focus on imaging findings.^3,7,28–31

This systematic review summarizes the neuroimaging literature investigating syndromal depressive disorder in TBI. The aim of this review is to determine if there an area of the brain which when damaged, as demonstrated by neuroimaging, seems to be associated with the diagnosis of a depressive disorder after TBI. We posit that this effort may prove useful for future work regarding TBI screening and surveillance, bolstering preventative research efforts in neuropsychiatry, distinguishing specifiers in heterogeneous populations, and identifying neuroimaging markers for improvement in TBI patients.

Methods

Search strategy

A structured literature search strategy was designed to garner articles with neuroimaging and syndromal depression components in human TBI samples. Articles published up to April, 2022 were extracted from PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases. Boolean searches were kept broad in the interest of reflecting all neuroimaging modalities and in order to capture broad domains of neuropsychiatric symptomatology. A more general approach was also necessitated by the current state of the TBI literature, which comprises many disparate approaches to definition, severity, population, and timing of assessment. We employed 41 imaging-, 35 neuropsychiatric symptom-, and 15 TBI-related keywords. Exact search phrases and MeSH search field qualifiers are outlined in Appendix 1.

Review protocol

This review adhered to PRISMA³² guidelines for implementation and reporting of systematic reviews. A summary of the review protocol, including the number of articles included and excluded in each step, can be found in Figure 1. In the first level of the screening process, titles and abstracts were reviewed in parallel for determination of inclusion or exclusion. Individuals in dyads, each with at least one senior TBI researcher, were blind to each other's determinations. An identical data extraction sheet was utilized by all reviewers (authors LNR, BRB, AK, MJCB, TP, SJ, NTT, JA, MBJ, AB, DAS, CR, ELG, LM, EBA, AP, DJL, ML, MEP). Discrepancies and cases in which a reviewer was unsure were routed to a third-party reviewer for a final decision. All included articles were then subjected to a full-text review by dyads, again followed by a reappraisal if necessary. The resulting article cohort was then split up into six neuropsychiatric domains: depression, anxiety, post-traumatic stress disorder, sleep disturbance, behavior/personality change, and psychosis. The present review focuses on syndromal depression. A series of subsequent reviews focused on the other neuropsychiatric domains will be published from these same efforts.

Figure 1.

Article selection process

Inclusion and exclusion criteria

For both title/abstract and full-text reviews, a standardized set of inclusion and exclusion criteria were applied. Articles were excluded if they: (1) Lacked any one of the three key elements (i.e., neuroimaging, NPS, and TBI); (2) Were of an undesirable study type (i.e., case reports/case series with n < 5, editorials, commentary letters, replies to editor, book reviews, non-peer-reviewed articles, conference proceedings, poster abstracts, dissertations); (3) Were not written in English; and/or (4) The study population had no human subjects or adult data (≤18 years). Articles were not excluded on the basis of TBI severity, singularity or reoccurrence of TBI, acuity or chronicity of neuropsychiatric symptoms, neuroimaging modality, or if neuroimaging was conducted in the acute (≤ 48 h), sub-acute (2 days − 2 weeks), intermediate (2 weeks − 6 months), or chronic (> 6 months) time-span post-TBI. This information was, however, collected on all articles.

Final articles selected for the present syndromal depression-centric review include those that met all of the following additional criteria: (1) Conducted empirical analyses comparing neuroimaging correlates in TBI subjects with depression versus TBI subjects without depression; (2) Had a clear TBI definition for participants included in the study (i.e., formalized or study-specific criteria with any combination of Glasgow Coma Scale score, loss/alteration in consciousness, and/or post-traumatic amnesia); (3) TBI was clinician diagnosed, (e.g., a hospitalization-requiring injury that yielded confirmatory medical records and was not based on self-report); (4) Quantified and controlled for the time interval between TBI occurrence and acquisition of neuroimaging; (5) Had a clear depression construct (i.e., used DSM criteria/a structured diagnostic interview to comment on syndromal depressive disorder, not only depressive symptoms; was not broadly studying “affect”, which could include mood pathology other than depression, such as anxiety or mania).

Article quality review

Included articles were reviewed for methodological quality and sources of potential bias (Supplemental Figures 1a and 1b) using the Newcastle-Ottawa Scale.³³ Broadly, this scale evaluates the risk of selection bias, comparability of comparison groups (e.g., risk of potential confounds), and the validity of outcome/exposure ascertainment for observational, non-randomized investigations (including distinct evaluation criteria for case-control and cohort studies). Articles were sorted based on the appropriate study type (i.e., case-control or cohort), and the corresponding Newcastle-Ottawa schematic was applied. Articles were determined to be case-control or cohort based on the outcome of interest to the systematic review, not necessarily the articles’ primary outcome. Each article was analyzed by a dyad of reviewers (LNR & BRB or AK & MJCB) followed by a consensus process, during which any discrepancies were addressed. Quality assessment data are presented, however, articles were not excluded from the systematic review based on quality outcomes.

Brain mapping

Approximate regions of interest (ROIs) reported by each study as having statistically significant associations with depression were extracted from a brain parcellation map in the Montreal National Institute (MNI) space³⁴ (JHU MNI Type II)³⁵ using MATLAB³⁶ (MATLAB R2021b, The MathWorks). In JHU MNI type II parcellation map, the entire gray matter and the white matter are parcellated. Color overlays of segmented brain structures were displayed on a representative T1-weighted MP-RAGE image (Figure 2(a)) using MRIcron visualization³⁷ software. Subsequently, a statistical analysis tool in MRIcron was used to extract region overlaps across studies. Finally, color overlays representing the extracted overlaps of 2 and 3 studies were displayed on a T1-weighted MP-RAGE image (Figure 2(b)).

Figure 2a.

Brain mapping by article of approximate structural ROI overlays implicated in TBI-related depression.

Figure 2b.

Brain map representing the approximate locations of replicated structural neuroimaging findings in TBI-related depression.

Results

Application of inclusion and exclusion criteria produced a final cohort of 10 articles (Table 2). Not including duplicate sample populations, these articles comprised the findings of 129 civilian subjects who developed post-TBI depression, and 294 who did not develop post-TBI depression. No studies with military or sport populations survived to the final article cohort. Two articles did not exclude for pre-TBI depressive disorders,^12,38 three articles did not exclude for co-occurring anxiety disorders,^39–41 and two articles excluded for previous TBIs.^39,42 Only one article conducted a formal power analysis⁴³ and three studies reported effect size statistics.^43–45 For details regarding article population, TBI severity, TBI occurrence, timing of imaging post-TBI, and neuroimaging modality, refer to Table 1. For limitations of the literature base and recommendations based on these limitations, refer to Table 3. For technical data on imaging parameters, see Supplemental Table 1.

Table 1.

Summary of article characteristics (n = 10)

Variable	Number of Articles
Population
Civilian	10
Military	0
Sport	0
TBI Severity
Mild	4
Mild & Moderate	3
Moderate & Severe	1
All-comers	2
TBI Occurrence
Single	9
Single & Recurrent	1
Imaging Timing Post-TBI *
Acute	0
Acute & Subacute	1
Intermediate	3
Intermediate & Chronic	5
Chronic	1
Neuroimaging Modality**
MRI	4
DTI	3
EEG	3
PET	1
Neuroimaging Analysis
ROI	5
Whole Brain	5

Note: ^* Acute ≤ 48 h, subacute 2 days − 2 weeks, intermediate 2 weeks − 6 months, and chronic > 6 months. ** Numbers do not summate to 10 because an article had more than one imaging modality.. MRI = magnetic resonance imaging, CT = computed tomography, DTI = diffusion tensor imaging, EEG = electroencephalogram, PET = positron emission tomography, ROI = region of interest

Table 2.

Articles with neuroimaging findings comparing traumatic brain injury patients with and without syndromal depression (n = 10)

Article	Sample Size*	Population	TBI Diagnostic Criteria **	TBI Severity; Occurrence	Timing of Neuroimaging Since TBI	Neuroimaging Modality	Neuropsychiatric Outcome Measure(s) and Description of Depression Construct	Findings Comparing TBI Patients With Depression and TBI Patients Without Depression***
Alhilali et al., 2015⁴³	n = 65 (TBI-D = 13, TBI + D = 32)	Civilian	LOC < 1 min, PTA < 30 min, unremarkable CT	Mild; Single, recurrent	Median = 20 days, Range = 0–506 days	DTI	DSM-V criteria for a depressive disorder due to another medical condition (mTBI). History of a neuropsychiatric illness prior to TBI was an exclusion criterion.	Significantly decreased fractional anisotropy within the right nucleus accumbens, right anterior limb of the internal capsule, and right superior longitudinal fasciculus in TBI subjects with depression compared to TBI subjects without depression.
Bailey et al., 2014⁴⁰	n = 35 (TBI-D = 20, TBI + D = 15)	Civilian	LOC ≥ 1 min, PTA ≥ 30 min, neuroradiological evidence suggesting TBI. Severity determined by GCS (mild = 13–15, moderate = 9–12 or 12–15 with intracranial surgery/focal lesions, severe = 3–8).	Mild, moderate; Single	≥ 6 weeks	EEG	MDD diagnosis assessed by the MINI for DSM-IV. Severity was assessed with the BDI-II and MDARS. Participants with comorbid axis 1 psychiatric disorders were excluded, with the exception of anxiety. Anti-depressant medications were continued during the study. Depression prior to the TBI was an exclusion criterion.	TBI subjects with depression had significantly less fronto-central negativity, less N2 global field power, and an altered N2b window compared to TBI subjects without depressionduring an inhibition task.
Bailey et al., 2015³⁹^†	n = 28 (TBI-D = 16, TBI + D = 12)	Civilian	GCS ≥ 9 and PTA or LOC > 10 min, but less than 24 h	Mild, moderate; Single	≥ 6 weeks (TBI-D mean = 32.63 months, TBI + D mean = 188.05 months)	EEG	Current depressive episode assessed with the MINI for DSM-IV. Excluded if met criteria for any axis 1 psychiatric disorder (with the exception of depression and generalized anxiety disorder). Depression severity had to be in the moderate to severe range (>20) on the MDARS to be included. Those taking a single anti-depressant medication were allowed in the study. Depression prior to the TBI was an exclusion criterion.	TBI subjects with depression had an altered topographical distribution of activity during the Pe window, with reduced frontal positivity compared to TBI subjects without depression.. TBI subjects with depression showed a more posterior distribution of positivity compared to TBI subjects without depression. Topographical ANOVA showed a significant difference between TBI subjects with and without depression for averaged activity during the Pe window. There were no significant differences in neural response strength.
Bailey et al., 2017⁴¹^†	n = 35 (TBI-D = 20, TBI + D = 15)	Civilian	Mild/moderate injury severity was determined by LOC < 24 h and an initial GCS > 9. To ensure injuries were at least mild, a LOC or PTA ≥ 10 min. or an initial GCS of < 15 was required.	Mild, moderate; Single	≥ 6 weeks (TBI only mean = 22.89 months, TBI + D mean = 176.77 months)	EEG	MDD diagnosis assessed with the MINI for DSM-IV. Included if MDD was deemed to be causally related to the TBI by the study psychiatrist Severity assessed with BDI-II and MDARS (>19 to be included, which is moderate to severe). Comorbid psychiatric diagnoses detected with the MINI were excluded (with the exception of anxiety disorder). Depression prior to TBI was an exclusion criterion.	TBI subjects without depression showed increased left temporal/inferior frontal to right parieto-occipital and fronto-central connectivity whereas TBI subjects with depression showed increased bilateral temporal to parieto-occipital connectivity.
Jolly et al., 2019⁴⁶	n = 12 (TBI-D = 6, TBI + D = 6)	Civilian	Moderate-severe severity was determined using the Mayo TBI Severity Classification System (one or more of the following criteria apply:1. death due to TBI, 2. LOC ≥ 30 min., 3. anterograde PTA ≥ 24 h, 4. Worst 24 h GCS ≤ 13, 5. One or more traumatic neuroimaging finding).	Moderate, severe; Single	Median = 44 months, Range = 15–372 months	PET, DTI	MDD diagnosis made by a qualified psychiatrist using the SCID for DSM-IV-TR Axis I disorders. Severity of depressive symptoms assessed with the BDI. Depression prior to TBI, having other current DSM-IV diagnoses, and being on medication known to affect dopaminergic function were exclusion criteria.	There were no significant differences in [¹¹C]PHNO BP_ND binding in the amygdala, nucleus accumbens, caudate, hypothalamus, pallidum, putamen, thalamus, or substantia nigra between TBI subjects with depression and TBI subjects without depression. There were no significant differences in fractional anisotropy in the uncinate fasciculus and cingulum between TBI subjects with depression and TBI subjects without depression.
Jorge et al., 2004¹²	n = 91 (TBI-D = 61, TBI + D = 30)	Civilian	Mild = GCS 13–15, moderate = 9–12, severe = 3–8. GCS of 12–15 with focal lesions were considered moderate.	All; Single	3 months	MRI	MDD diagnosed using two semi-structured interviews, the PSE and SCID for DSM-IV. Depression severity assessed with the HAM-D.	Decreased frontal grey matter volume with decreased left frontal gray matter in TBI subjects with depression as opposed to TBI subjects without depression. TBI subjects with depression had significantly decreased cortical volume in the dorsolateral and ventrolateral PFC, and middle/superior/ inferior gyri. Total brain volume, white matter volume, and grey matter volume did not significantly differ between groups. Occipital and temporal grey matter volume was not associated with depression. There was no volume-depression association for the parietal lobe, lateral frontal lobe, orbitofrontal, or medial frontal PFC.
Jorge et al., 2007³⁸	n = 37 (TBI-D = 18, TBI + D = 19)	Civilian	Mild = GCS 13–15, moderate = 9–12, severe = 3–8. Patients with a GCS 13–15 with a history of intracranial surgery or focal lesions greater than 15 cc were considered moderate.	All; Single	3 months	MRI	Mood disorders due to TBI with major depressed or mixed features assessed with the PSE and SCID for DSM-IV. Depression severity assessed with the HAM-D.	Left frontal grey matter volume decrease in TBI subjects with depression as opposed to TBI subjects without depression. Decreased bilateral hippocampal volume in TBI plus depression group as opposed to TBI only group, most amplified in moderate/severe TBI. There was no difference between groups in frontal lobe lesion frequency or whole/left/right volume. Total brain volume and frequency of focal lesions did not significantly differ between groups.
Maller et al., 2014⁴⁴	n = 26 (TBI-D = 12, TBI + D = 14)	Civilian	Field GCS = 13–14, LOC 15 min. to 2 h, PTA 0 min to 48 h	Mild; Single	CT in acute phase, MRI range = 6 weeks to 12 months	MRI	MDD diagnosis made by a treating psychiatrist and confirmed with the MINI for DSM-IV as well as a score of at least 16 on the MADRS. TBI patients were required to have no history of pre-TBI depression. TBI-related major depression patients were required to have developed MDD between 6 weeks and 12 months post-TBI.	TBI subjects with depression had reduced volume in temporal, left inferior parietal, and right lingual regions compared to TBI subjects without depression. The left and right nucleus accumbens were also decreased in size. Higher depression severity in those with TBI and major depression significantly correlated with reduced volume in anterior cingulate, bilateral entorhinal cortex, left hippocampus, right insula, right temporal gyrus, and temporal lobe (not significant after multiple corrections).
Rao et al., 2012⁴⁵	n = 14 (TBI-D = 10, TBI + D = 4)	Civilian	GCS ≥ 13, ACRM criteria	Mild; Single	≤ 1 month	DTI	Mood Disorder Due to General Medical Condition assessed by the SCID for DSM-IV with subtypes of 1) major depressive-like episode (if the full criteria for a major depressive episode were met); or 2) depressive features (prominent depressed mood but full criteria for a major depressive episode were not met). The HAM-D was used to assess the severity of depression. Those with history of previous major depression/other psychiatric disorders or previous brain injury were excluded.	TBI subjects with depression had significantly decreased fractional anisotropy in the left superior temporal gyrus compared to TBI subjects without depression. There were no significant differences between the two groups in fractional anisotropy of the right superior temporal gyrus/white matter, left/right temporal middle/inferior temporal gyrus/white matter, left/right superior/middle/inferior frontal gyrus and white matter, left/right caudate nucleus, putamen, globus pallidus, or thalamus. Increased mean diffusivity in the temporal and inferior frontal lobes was associated with increased depression over time. Lower fractional anisotropy in superior/middle temporal gyri associated with depression level at baseline and predictive of higher depressive symptoms over time. Higher mean diffusivity score in the right superior longitudinal fasciculus, inferior frontal white matter, and superior temporal white matter was predictive of increasing HAM-D scores. Higher mean diffusivity in the left side of the superior longitudinal fasciculus was associated with lower Ham-D scores. Mean diffusivity/fractional anisotropy of varied frontal and subcortical regions with respect to depression at multiple time points did not differ.
Wang et al., 2014⁴²	n = 200 (TBI-D = 172, TBI + D = 28)	Civilian	GCS 13–15, PTA < 24 h, unremarkable CT and MRI	Mild; Single	Range = 2 h to 3 days	MRI (SWI)	As per DSM-IV-TR criteria utilizing the SCID, depressive disorders after TBI were grouped as ‘Mood Disorder Due to General Medical Condition’ (MDD-GMC), with subtypes of (1) major depressive-like episode (if the full criteria for a major depressive episode were met); or (2) depressive features (prominent depressed mood but full criteria for a major depressive episode were not met). Only those who met criteria for ‘Mood Disorder Due to General Medical Condition’ major depressive-like episode subtype for at least one follow-up visit within 1 year were considered as major depression after TBI. History of depression prior to TBI (having reported depression diagnosis, treatment for depression, depression-related counseling, or a suicide attempt) was an exclusion criterion.	Patients who had a major depressive episode within one year after TBI had a significantly higher rate of abnormality (microbleeds) at the whole-brain level than those without a major depressive episode after TBI. Number and volume of microbleed lesions in frontal, temporal, and parietal lobes was significantly higher in the depressed TBI subjects with depression than TBI subjects without depression.

Note: * Sample size has been adjusted to reflect only participants with TBI + depression and TBI-depression and does not include other groups such as depression only and normal controls.

** All TBI was diagnosed by a clinician.

*** The findings listed in this table only focus on analyses comparing TBI with depression and TBI without depression. Some articles conducted additional analyses comparing TBI subjects to other groups, such as normal controls or depression only controls.

† Denotes duplicate samples that were not included in the overall N's calculated by this review

TBI + D = traumatic brain injury with depression, TBI-D = traumatic brain injury without depression, GCS = Glasgow Coma Scale, LOC = loss of consciousness, AOC = alteration of consciousness, PTA = post-traumatic amnesia, ACRM = American Congress of Rehabilitation Medicine, MRI = magnetic resonance imaging, SWI = susceptibility-weighted imaging, DTI = diffusion tensor imaging, EEG = electroencephalogram, PET = positron emission tomography, PSE = Present State Examination, DSM-V = Diagnostic and Statistical Manual of Mental Disorders 5^th Edition, DSM-IV = Diagnostic and Statistical Manual of Mental Disorders 4^th Edition, DSM-IV-TR = Diagnostic and Statistical Manual of Mental Disorders 4^th Edition Text Revision, MINI for DSM-IV = Mini-international Neuropsychiatric Interview, BDI = Beck Depression Inventory, BDI II = Beck Depression Inventory Version 2, MADRS = Montgomery–Åsberg Depression Rating Scale, SCID = Structured Clinical Interview for DSM-5, HAM-D = Hamilton Depression Rating Scale, HRS-D = Hamilton Rating Scale for Depression, CES-D = Center for Epidemiologic Studies Depression Scale, MDD = major depressive disorder, PFC = prefrontal cortex.

Table 3.

Limitations existing among the included studies in the current systematic review and recommendations for future research

Limitations	Recommendations for Future Research
Sample- / Study-related
Sample heterogeneity (e.g., TBI severity, TBI definition, depressive syndrome definition, time since injury)	In addition to below, more selective inclusion criteria (e.g., mild TBI, subacute TBI, new onset depression only).
Insufficient sample sizes	Seeing as how nine out of ten articles did not conduct a formal power analysis, fully-powered and longitudinal cohort studies are a glaring gap in the field, which will be needed for causality and directionality determination. Effect size statistics should be reported to enable future work to be appropriately powered. Future systematic reviews separated by TBI severity, timing of neuroimaging since injury, etc. and a quantifiable meta-analysis should be considered once the literature base in this area is more developed.
High level of bias regarding the comparability of cohorts/cases on the basis of design or analysis	Exposed and non-exposed individuals in cohort studies and cases/controls in case-control studies must be matched in design and/or confounders must be adjusted for in the analysis (e.g., making statements of no differences between groups or that differences were not statistically significant).
Difficulty isolating the direct connections between neuroimaging findings and TBI-associated depressive syndromes	Ensure that studies are properly designed to isolate the neuroimaging findings specific to TBI-related depressive syndromes, such as comparison groups with TBI only and idiopathic depression only.
Lack of acute prospective studies	Design of future studies with initial data/imaging collection in the acute phase of TBI and multiple follow-up data/imaging collection points across time.
TBI-related
Inconsistent TBI definitions	Clearly quantify and report on the established National Institute of Neurological Disorders and Stroke common data elements for TBI ⁵⁴ (e.g., loss of consciousness and post-traumatic amnesia duration, Glasgow Coma Scale score). Utilize established TBI criteria (e.g., Veterans Affairs/Department of Defense, American Congress of Rehabilitation Medicine) rather than study-specific criteria.
No solely severe TBI samples	Future inquiry into the neuroimaging correlates of post-TBI depression in patients with severe TBI. Some articles in this review looked at participants with multiple severities of TBI (including severe) combined into one sample, however, there were no distinct severe TBI groups.
Lack of military- and sports-related TBI	Although these populations should be considered separately from general civilian populations, they do warrant focused study (exclusion occurred largely due to lack of clinician confirmation of TBI diagnosis).
Not considering the potential impact of post-concussive syndrome and other post-TBI complications on depression	Post-concussive syndrome and other post-TBI complications (e.g., headache, vestibular disorders) may act as a trigger for developing depression after a brain injury. To overcome this potential confound, future studies should consider choosing TBI control subjects that have similar medical comorbidities.
Depression-related
Largely reported data on depressive symptoms as opposed to clinically diagnosed syndromal depressive disorders	Use a structured diagnostic interview tool administered by a clinician, (e.g., SCID for DSM-V, MINI for DSM-V) instead of or in addition to screeners noting depressive symptoms (e.g., PHQ-9, Beck Depression Inventory).
Ability to confirm that post-TBI depression is new onset vs. a recurrence of a pre-injury depressive illness	Report and statistically adjust for data on pre-TBI depression history or exclude for pre-injury depressive disorders as post-TBI depression can be a recurrence of a pre-injury depressive illness ^5,6.
Retention of participants with TBI-related depression who also have co-occurring anxiety disorders	Conduct analyses comparing participants with and without co-morbid anxiety disorders to examine for any potential differences.
Depression just one of multiple neuropsychiatric symptoms examined per study	Focus studies on depressive syndrome specifically rather than affective disorders more broadly
Neuroimaging-related
Neuroanatomical regions of interest on imaging generally broad and not well-defined	More in-depth description of the neuroanatomical boundaries of regions of interest
Unclear time interval between the TBI and neuroimaging, as well as the onset of depressive symptoms and neuroimaging	Quantify timing of TBI, depressive symptom onset, and neuroimaging collection. Time interval between TBI occurrence and neuroimaging collection should be adjusted for. Special attention should be given to DTI studies due to the potential for non-linear brain changes to be detected on measures of connectivity, which is an important confound to consider.
Lack of CT and functional MRI studies meeting inclusion criteria	Additional attention to TBI and depressive syndrome definition when designing studies utilizing functional neuroimaging techniques and structural whole brain analyses

Findings by imaging modality

MRI volumetrics

Structural findings visualized by neuroanatomical region of interest (ROI) via brain mapping are displayed in Figure 2(a) and 2(b). Of the three articles with structural findings related to MRI volumetrics, all had significant findings associating onset of depression with decreased volume/cortical thinning in subjects who developed post-TBI depression compared to TBI subjects who did not.^12,38,44 Areas implicated were left frontal grey matter, dorsolateral PFC, ventrolateral PFC, middle/superior/inferior gyri,¹² left frontal grey matter, bilateral hippocampal volume,³⁸ temporal, left inferior parietal, and right lingual regions as well as left and right nucleus accumbens.⁴⁴

Susceptibility-weighted imaging

There was one article that utilized susceptibility-weighted imaging⁴² which found the number and volume of microbleed lesions to be higher in the depressed TBI group when compared to the non-depressed TBI group referencing the frontal lobe, temporal lobe, parietal lobe, and whole brain.¹⁶

Diffuse tensor imaging (DTI)

Three articles conducted diffusion tensor imaging (DTI) analyses. Two of these articles found decreased fractional anisotropy to be associated with presence of depression in subjects with mild TBI when compared to mild TBI with absence of depression.^43,45 These findings corresponded to the right nucleus accumbens, right anterior limb of the internal capsule and right superior longitudinal fasciculus, as well as the left superior temporal gyrus. The third article did not find significant differences in fractional anisotropy of the uncinate fasciculus and cingulum between TBI subjects with depression and TBI subjects without depression.⁴⁶

Positron emission tomography (PET)

One article featured the PET modality, specifically focusing on dopamine D2/D3 receptor availability following TBI.⁴⁶ There were no significant differences in [¹¹C]PHNO BP_ND binding in the amygdala, nucleus accumbens, caudate, hypothalamus, pallidum, putamen, thalamus, or substantia nigra between TBI subjects with depression and TBI subjects without depression.

Electroencephalography (EEG)

Three articles contained EEG analyses, all of which were in the chronic/intermediate time frame for when imaging was conducted relative to injury occurrence. Two studies focused on frontal regions and found less fronto-central negativity, less N2 global field power, an altered N2b window, reduced frontal positivity, a more posterior distribution of positivity, and an altered pattern of averaged activity during the Pe window in depressed TBI subjects compared to non-depressed TBI subjects.^39,40 The third study found that TBI subjects without depression showed increased left temporal/inferior frontal to right parieto-occipital and fronto-central connectivity whereas TBI subjects with depression showed increased bilateral temporal to parieto-occipital connectivity.⁴¹ All three of the EEG modality articles were out of the same research group.

Article quality

Bias amongst cohort studies (n = 3) solely resulted from comparability of cohorts on the basis of design or analysis (Supplemental Figure 1a). Bias in case-control studies (n = 7) was mainly due to definition of controls, comparability of cases and controls on the basis of design or analysis, representativeness of the cases, and to a lesser degree selection of controls (Supplemental Figure 1b). Additionally, assessment of article quality revealed a widespread absence of methodologically controlling for previous TBI(s).

Discussion

This systematic review summarized the neuroimaging literature reporting on structural and functional changes associated with syndromal depressive disorder in the setting of TBI. Existing systematic reviews address the imaging correlates of idiopathic depression, and separately the imaging correlates of TBI, however this review aimed to synthesize the imaging findings that integrate depression and TBI. From a final cohort of 10 articles representing the findings from 423 total participants with TBI, we ascertained that syndromal depression developed after a TBI is generally associated with decreased volume or cortical thinning,^12,38,44 decreased functional connectivity,^39–41 decreases in white matter fractional anisotropy,^43,45 and higher number/volume of microbleeds⁴² when compared to TBI subjects who did not develop depression. Regionally, TBI-related depression was associated with a variety of bilateral frontal regions,^12,39,40,42 particularly in those with damage to the left frontal gray matter,^12,38 including the dorsolateral and ventrolateral prefrontal cortex, and middle/superior/inferior gyri..¹² Temporal regions were also well-represented, including bilateral temporal lobes,^41,42,44 the left superior temporal gyrus,⁴⁵ and bilateral hippocampi.³⁸ Other regions were the parietal lobes (bilateral, left inferior lobe, lingual gyrus)^41,42,44 and nucleus accumbens.^43,44 Taken together, these findings suggest that TBI-related depression is associated with diffuse changes throughout the brain, accompanied by a host of specific, regional alterations.

The findings reviewed herein identified spatially convergent structural abnormalities in individuals with chronic TBI and co-occurring syndromal depression in the bilateral frontal regions, particularly in those with damage to the left frontal lobe, including the prefrontal, orbitofrontal, and anterior cingulate cortices. Functional findings from EEG studies in this review further supported the beforementioned structural emphasis on frontal regions. Those regions have been consistently reported to be part of the biological pathways underpinning heterogeneous mental disorders like major depression.^26,47,48 Nevertheless, TBI is more likely to affect frontal areas due to the anatomy of the brain within the skull in the context of TBI mechanics.⁴⁹ Thus, there is a degree of uncertainty regarding the precise pathways which could be influenced by those structural products with relevance to the underlying neurobiology of subsets of individuals who develop depression following TBI. More likely, it cannot be fully attributed to a specific frontal brain lesion but should be related to the whole frontal cortex and its interconnections.

Localized frontal lobe findings could be categorized into the three frontal-subcortical circuits implicated in TBI: the dorsolateral prefrontal circuit, orbitomedial frontal circuit, and anterior cingulate circuit.⁵⁰ These circuits are implicated in corresponding clinical syndromes (i.e., dysexecutive, disinhibition, and apathy syndrome, respectively).⁵¹ In the current review, regarding differences between TBI subjects with and without depression, the two circuits that were most implicated were the dorsolateral prefrontal circuit (see Jorge et al., 2004 regarding the dorsolateral prefrontal cortex¹²) and orbitomedial frontal circuit (see Maller et al., 2014 and Alhilali et al., 2015, which both involve the nucleus accumbens^43,44). The anterior cingulate circuit did not have as many findings when comparing TBI subjects with and without depression, though Maller et al., 2014 found that higher depression severity in those with TBI and depression significantly correlated with reduced volume in the anterior cingulate.⁴⁴ Many articles in the current review focused on functional activity of the frontal lobes more globally,^40,41 volumetrics of total frontal white/gray matter,¹² and microbleeds in frontal regions.⁴²

Amongst the included articles, frontal regions were a main focus and temporal regions were also well represented. The parietal lobes, including occipital/lingual regions, and right nucleus accumbens, are also worthy of mention. Regions of lesser emphasis were the right anterior limb of the internal capsule and right superior longitudinal fasciculus. Global volumetric brain analyses on MRI did not reach significance, which is consistent with systematic review results in idiopathic depression.²⁴ In contrast, significant findings from whole-brain analyses have been identified in a systematic review of TBI alone.⁵² It is therefore possible that some of the less consistent findings in this review are related to TBI itself rather than the co-presenting depressive syndrome.

Regarding imaging modality, amongst articles finding significant differences between TBI patients with and without depression, there were four articles on structural MRI concerned with cortical findings (one susceptibility weighted), three articles on DTI concerned with white matter and subcortical findings, and three articles that focused on connectivity with EEG. A recent systematic review was conducted on the characterization of chronic traumatic encephalopathy/TBI using various imaging modalities.⁵² By comparison, there was a far greater proportion of articles in the chronic traumatic encephalopathy/TBI review focused on structural imaging (21 of 25 articles) and fewer that utilized functional imaging (6 of 25 articles). This may suggest discordant approaches to studying emotional syndromes (focus on brain function) vs. brain trauma itself (focus on structure).

It is also an important confound to consider that certain connectivity measures, namely those used in DTI, have demonstrated non-linear brain changes over time post-injury. Two of the three DTI articles included in this review found significantly decreased fractional anisotropy in acute and subacute TBI compared to controls,^43,45 which is consistent with the literature regarding connectivity measures in TBI longitudinally.⁵³ The third article in this review, which looked at chronic TBI, did not note significant differences in fractional anisotropy.⁴⁶

This review identified notable limitations in the literature base and areas of focus for future research, which are displayed in Table 3. There are also several methodological limitations to consider with the reported findings of this review. The timing of a patient's depression as it related to their TBI, as well as the timing of imaging data acquisition, was variable across articles and therefore not restricted. Also included in this review were several articles by the same authors that utilized some of the same participants in both studies. This issue of duplicate samples was factored in when calculating the sample size of this review. Three EEG articles were included in this review; the conclusions we can draw from those articles and the comparisons that can be made to MRI, DTI, and PET studies are limited by the spatial localization limitations that are inherent to the EEG modality. Additionally, because publication dates of the final article cohort ranged from 2004 to 2019, articles used both DSM-IV and DSM-5 criteria with their respective structured clinical interviews.

A systematic review was performed to examine neuroimaging correlates of co-occurring syndromal depression in TBI with the aim of utilizing neuropsychiatric illness to improve our understanding of what neuroanatomy to investigate in idiopathic depression. Research examining the nexus of TBI and depression represents an emerging field; additional inquiry with attention to TBI-only control groups, consistent TBI definitions, previous TBI, clinically diagnosed syndromal depression, co-occurring anxiety disorders, imaging timing post-injury, acute prospective design, functional neuroimaging, and well-defined neuroanatomical regions of interest is crucial to extrapolating finer discrepancies between the pathophysiology of idiopathic and TBI-related depression. The impact of TBI on brain abnormalities in individuals with depression requires further study, with continued research focus on structural, functional, and metabolic correlates of the prefrontal cortex, anterior cingulate, and other selected regions.

Supplemental Material

sj-jpg-1-ccn-10.1177_20597002221133183 - Supplemental material for Neuroimaging correlates of syndromal depression following traumatic brain injury: A systematic review of the literature

Supplemental material, sj-jpg-1-ccn-10.1177_20597002221133183 for Neuroimaging correlates of syndromal depression following traumatic brain injury: A systematic review of the literature by Lisa N. Richey, Barry R. Bryant, Akshay Krieg, Michael J. C. Bray, Aaron I. Esagoff, Tejus Pradeep, Sahar Jahed, Licia P. Luna, Nicholas T. Trapp, Jaxon Adkins, Melissa B. Jones, Andrew Bledsoe, Daniel A. Stevens, Carrie Roper, Eric L. Goldwaser, LiAnn Morris, Emily Berich-Anastasio, Alexandra Pletnikova, Katie Lobner, Daniel J. Lee, Margo Lauterbach, Simon Ducharme, Haris I. Sair and Matthew E. Peters in Journal of Concussion

Supplemental Material

sj-jpg-2-ccn-10.1177_20597002221133183 - Supplemental material for Neuroimaging correlates of syndromal depression following traumatic brain injury: A systematic review of the literature

Supplemental material, sj-jpg-2-ccn-10.1177_20597002221133183 for Neuroimaging correlates of syndromal depression following traumatic brain injury: A systematic review of the literature by Lisa N. Richey, Barry R. Bryant, Akshay Krieg, Michael J. C. Bray, Aaron I. Esagoff, Tejus Pradeep, Sahar Jahed, Licia P. Luna, Nicholas T. Trapp, Jaxon Adkins, Melissa B. Jones, Andrew Bledsoe, Daniel A. Stevens, Carrie Roper, Eric L. Goldwaser, LiAnn Morris, Emily Berich-Anastasio, Alexandra Pletnikova, Katie Lobner, Daniel J. Lee, Margo Lauterbach, Simon Ducharme, Haris I. Sair and Matthew E. Peters in Journal of Concussion

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article

Ethical approval

Not applicable. This study is exempt from IRB review.

ORCID iDs

Lisa N. Richey

Michael J. C. Bray

Aaron I. Esagoff

Daniel A. Stevens

Supplemental material

Supplemental material for this article is available online.

Appendix

References

Corrigan

Hammond

. Traumatic brain injury as a chronic health condition. Arch Phys Med Rehabil 2013; 94: 1199–1201.

Guillamondegui

Montgomery

Phibbs

, et al. Traumatic Brain Injury and Depression. Comparative Effectiveness Review No. 25. Rockville, MD, www.ahrq.gov (April 2011, accessed 26 March 2020).

Scholten

Haagsma

Cnossen

, et al. Prevalence of and risk factors for anxiety and depressive disorders after traumatic brain injury: a systematic review. J Neurotrauma 2016; 33: 1969–1994.

Bryant

O’Donnell

Creamer

, et al. The psychiatric sequelae of traumatic injury. Am J Psychiatry 2010; 167: 312–320.

Bombardier

Fann

Temkin

, et al. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA 2010; 303: 1938–1945.

Gould

Ponsford

Johnston

, et al. Relationship between psychiatric disorders and 1-year psychosocial outcome following traumatic brain injury. Journal of Head Trauma Rehabilitation 2011; 26: 79–89.

Osborn

Mathias

Fairweather-Schmidt

. Depression following adult, non-penetrating traumatic brain injury: a meta-analysis examining methodological variables and sample characteristics. Neurosci Biobehav Rev 2014; 47: 1–15.

Seel

Kreutzer

Rosenthal

, et al. Depression after traumatic brain injury: a national institute on disability and rehabilitation research model systems multicenter investigation. Arch Phys Med Rehabil 2003; 84: 177–184.

Kreutzer

Seel

Gourley

. The prevalence and symptom rates of depression after traumatic brain injury: a comprehensive examination. Brain Inj 2001; 15: 563–576.

10.

Whelan-Goodinson

Ponsford

Johnston

, et al. Psychiatric disorders following traumatic brain injury: their nature and frequency. Journal of Head Trauma Rehabilitation 2009; 24: 324–332.

11.

Hart

Hoffman

Pretz

, et al. A longitudinal study of major and minor depression following traumatic brain injury. Arch Phys Med Rehabil 2012; 93: 1343–1349.

12.

Jorge

Robinson

Moser

, et al. Major depression following traumatic brain injury. Arch Gen Psychiatry 2004; 61: 42–50.

13.

Guskiewicz

Marshall

Bailes

, et al. Recurrent concussion and risk of depression in retired professional football players. Med Sci Sports Exerc 2007; 39: 903–909.

14.

Mooney

Speed

. The association between mild traumatic brain injury and psychiatric conditions. Brain Inj 2001; 15: 865–877.

15.

Stéfan

Mathé

Dhenain

, et al. What are the disruptive symptoms of behavioral disorders after traumatic brain injury? A systematic review leading to recommendations for good practices. Ann Phys Rehabil Med 2016; 59(1): 5–17. https://doi.org/10.1016/j.rehab.2015.11.002

16.

Mauri

Paletta

Colasanti

, et al. Clinical and neuropsychological correlates of major depression following post-traumatic brain injury, a prospective study. Asian J Psychiatr 2014; 12: 118–124.

17.

Biver

Goldman

Delvenne

, et al. Frontal and parietal metabolic disturbances in unipolar depression. Biol Psychiatry 1994; 36: 381–388.

18.

Drevets

Videen

Price

, et al. A functional anatomical study of unipolar depression. J Neurosci 1992; 12: 3628–3641.

19.

Koenigs

Grafman

. The functional neuroanatomy of depression: distinct roles for ventromedial and dorsolateral prefrontal cortex. Behav Brain Res 2009; 201: 239–243.

20.

Sheline

. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry 2003; 54: 338–352.

21.

Herrmann

le Masurier

Ebmeier

. White matter hyperintensities in late life depression: a systematic review. J Neurol Neurosurg Psychiatry 2008; 79: 619–624.

22.

Bora

Fornito

Pantelis

, et al. Gray matter abnormalities in Major depressive disorder: a meta-analysis of voxel based morphometry studies. J Affect Disord 2012; 138: 9–18.

23.

Chen

, et al. Disorganization of white matter architecture in major depressive disorder: a meta-analysis of diffusion tensor imaging with tract-based spatial statistics. Sci Rep 2016; 6: 21825.

24.

Arnone

McIntosh

Ebmeier

, et al. Magnetic resonance imaging studies in unipolar depression: systematic review and meta-regression analyses. Eur Neuropsychopharmacol 2012; 22: 1–16.

25.

Koolschijn

PCMP

van Haren

NEM

Lensvelt-Mulders

GJLM

, et al. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp 2009; 30: 3719–3735.

26.

Sexton

Mackay

Ebmeier

. A systematic review and meta-analysis of magnetic resonance imaging studies in late-life depression. Am J Geriatr Psychiatry 2013; 21: 184–195.

27.

Wang

Leonards

Sterzer

, et al. White matter lesions and depression: a systematic review and meta-analysis. J Psychiatr Res 2014; 56: 56–64.

28.

Cnossen

Scholten

Lingsma

, et al. Predictors of Major depression and posttraumatic stress disorder following traumatic brain injury: a systematic review and meta-analysis. J Neuropsychiatry Clin Neurosci 2017; 29: 206–224.

29.

Fann

Hart

Schomer

. Treatment for depression after traumatic brain injury: a systematic review. J Neurotrauma 2009; 26: 2383–2402.

30.

Barker-Collo

Starkey

Theadom

. Treatment for depression following mild traumatic brain injury in adults: a meta-analysis. Brain Inj 2013; 27: 1124–1133.

31.

Menzel

. Depression in the elderly after traumatic brain injury: a systematic review. Brain Inj 2008; 22: 375–380.

32.

Moher

Shamseer

Clarke

, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015; 4: 1.

33.

Wells

Shea

O’Connell

, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa, ON, http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (2003, accessed 14 June 2020).

34.

Evans

Collins

Millst

, et al. 3D Statistical neuroanatomical models from 305 MRI volumes. Proc IEEE nucl sci symp med imaging conf 1993; 1813–1817.

35.

Oishi

Faria

Jiang

, et al. Atlas-based whole brain white matter analysis using large deformation diffeomorphic metric mapping: application to normal elderly and Alzheimer’s disease participants. Neuroimage 2009; 46: 486.

36.

MATLAB, https://www.mathworks.com/products/matlab.html (2022).

37.

NITRC: MRIcron, https://www.nitrc.org/projects/mricron (2019, accessed 2 June 2022).

38.

Jorge

Acion

Starkstein

, et al. Hippocampal volume and mood disorders after traumatic brain injury. Biol Psychiatry 2007; 62: 332–338.

39.

Bailey

Hoy

Maller

, et al. Neural evidence that conscious awareness of errors is reduced in depression following a traumatic brain injury. Biol Psychol 2015; 106: 1–10.

40.

Bailey

Hoy

Maller

, et al. An exploratory analysis of go/Nogo event-related potentials in major depression and depression following traumatic brain injury. Psychiatry Res 2014; 224: 324–334.

41.

Bailey

Rogasch

Hoy

, et al. Increased gamma connectivity during working memory retention following traumatic brain injury. Brain Inj 2017; 31: 379–389.

42.

Wang

Wei

X-E

M-H

, et al. Microbleeds on susceptibility-weighted MRI in depressive and non-depressive patients after mild traumatic brain injury. Neurol Sci 2014; 35: 1533–1539.

43.

Alhilali

Delic

Gumus

, et al. Evaluation of white matter injury patterns underlying neuropsychiatric symptoms after mild traumatic brain injury. Radiology 2015; 277: 793–800.

44.

Maller

Thomson

RHS

Pannek

, et al. Volumetrics relate to the development of depression after traumatic brain injury. Behav Brain Res 2014; 271: 147–153.

45.

Rao

Mielke

, et al. Diffusion tensor imaging atlas-based analyses in major depression after mild traumatic brain injury. J Neuropsychiatry Clin Neurosci 2012; 24: 309–315.

46.

Jolly

Raymont

Cole

, et al. Dopamine D2/D3 receptor abnormalities after traumatic brain injury and their relationship to post-traumatic depression. Neuroimage Clin 2019; 24: 101950.

47.

Kempton

Salvador

Munafò

, et al. Structural neuroimaging studies in major depressive disorder: meta-analysis and comparison with bipolar disorder. Arch Gen Psychiatry 2011; 68: 675–690.

48.

Gray

Müller

Eickhoff

, et al. Multimodal abnormalities of brain structure and function in Major depressive disorder: a meta-analysis of neuroimaging studies. Am J Psychiatry 2020; 177: 422–434.

49.

Irimia

van Horn

. Functional neuroimaging of traumatic brain injury: advances and clinical utility. Neuropsychiatr Dis Treat 2015; 11: 2355–2365.

50.

Mega

Cummings

. Frontal-subcortical circuits and neuropsychiatric disorders. Journal of Neuropsychiatry and Clinical Neurosciences 1994; 6: 358–370.

51.

Peters

Moussawi

Rao

. Teaching clinical reasoning with an example mnemonic for the neuropsychiatric syndromes of traumatic brain injury. Acad Psychiatry 2018; 42: 686–689.

52.

Ruprecht

Scheurer

Lenz

. Systematic review on the characterization of chronic traumatic encephalopathy by MRI and MRS. J Magn Reson Imaging 2019; 49: 212–228.

53.

Sidaros

Engberg

Sidaros

, et al. Diffusion tensor imaging during recovery from severe traumatic brain injury and relation to clinical outcome: a longitudinal study. Brain 2008; 131: 559–572.

54.

van de Vyvere

de La Rosa

Wilms

, et al. Prognostic validation of the NINDS common data elements for the radiologic reporting of acute traumatic brain injuries: a CENTER-TBI study. J Neurotrauma 2020; 37: 1269–1282.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.08 MB