Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP.

PURPOSE: The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD. THEORY AND METHODS: Diffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP). RESULTS: We demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings. CONCLUSIONS: AD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.

Elevated Intraindividual Variability in Executive Functions and Associations with White Matter Microstructure in Veterans with Mild Traumatic Brain Injury.

OBJECTIVE: We examined whether intraindividual variability (IIV) across tests of executive functions (EF-IIV) is elevated in Veterans with a history of mild traumatic brain injury (mTBI) relative to military controls (MCs) without a history of mTBI. We also explored relationships among EF-IIV, white matter microstructure, and posttraumatic stress disorder (PTSD) symptoms. METHOD: A total of 77 Veterans (mTBI = 43, MCs = 34) completed neuropsychological testing, diffusion tensor imaging (DTI), and PTSD symptom ratings. EF-IIV was calculated as the standard deviation across six tests of EF, along with an EF-Mean composite. DSI Studio connectometry analysis identified white matter tracts significantly associated with EF-IIV according to generalized fractional anisotropy (GFA). RESULTS: After adjusting for EF-Mean and PTSD symptoms, the mTBI group showed significantly higher EF-IIV than MCs. Groups did not differ on EF-Mean after adjusting for PTSD symptoms. Across groups, PTSD symptoms significantly negatively correlated with EF-Mean, but not with EF-IIV. EF-IIV significantly negatively correlated with GFA in multiple white matter pathways connecting frontal and more posterior regions. CONCLUSIONS: Veterans with mTBI demonstrated significantly greater IIV across EF tests compared to MCs, even after adjusting for mean group differences on those measures as well as PTSD severity. Findings suggest that, in contrast to analyses that explore effects of mean performance across tests, discrepancy analyses may capture unique variance in neuropsychological performance and more sensitively capture cognitive disruption in Veterans with mTBI histories. Importantly, findings show that EF-IIV is negatively associated with the microstructure of white matter pathways interconnecting cortical regions that mediate executive function and attentional processes.

Unemployment Status Is Associated With Greater Cognitive Intraindividual Variability in Veterans With a History of Remote Mild TBI.

OBJECTIVE: To examine the association between employment status and neuropsychological functioning in veterans with a history of remote mild traumatic brain injury (mTBI) using 2 approaches to assess cognitive performance: (a) standard, traditional mean cognitive performance; and (b) across-test intraindividual variability (IIV). SETTING: Outpatient Veterans Affairs (VA) hospital. PARTICIPANTS: Eligibility criteria included veterans with a history of mTBI who performed adequately on performance validity tests. Participants (N = 75; 37 employed, 38 unemployed) were evaluated, on average, about 5.5 years after their most recent mTBI. DESIGN: Observational cohort study; all participants completed a clinical interview and a comprehensive neuropsychological assessment. MAIN MEASURES: Primary outcomes of interest included mean cognitive composite test scores and IIV scores on tasks of memory, attention/processing speed, and executive functioning. RESULTS: Logistic regression models showed that mean cognitive performance was not predictive of employment status; however, IIV indices were ( = 7.88, P = .048) and accounted for 13% of the variance. Greater memory-IIV was significantly associated with being unemployed (ß = -.16, SE = .07, P = .020, Exp(B) = 0.85; 95% CI, 0.74-0.98). CONCLUSION: These findings build upon prior work showing that IIV, or cognitive dispersion, is associated with important functional outcomes following mTBI, including employment status. Future studies are needed to verify these findings, but the present study suggests that IIV indices offer a clinically meaningful marker of cognitive functioning and should be considered when evaluating functional outcomes following head trauma.

Research Letter: PTSD Symptom Severity and Multiple Traumatic Brain Injuries Are Associated With Elevated Memory Complaints in Veterans With Histories of Mild TBI.

OBJECTIVE: The evaluation of memory complaints in mild traumatic brain injury (mTBI) remains an important clinical consideration, especially in the context of comorbid psychiatric symptoms such as posttraumatic stress disorder (PTSD). We compared subjective memory complaints in veterans with and without a history of mTBI, examined ratings between those with single versus multiple mTBIs, and investigated associations between memory complaints and PTSD symptom severity. METHODS: 117 outpatient veterans (mTBI: n = 79 [single mTBI: n = 22, multiple mTBI: n = 57], military controls [MCs]: n = 38) completed a TBI history assessment, the Prospective-Retrospective Memory Questionnaire (PRMQ), and the PTSD Checklist-Military Version (PCL-M). RESULTS: Hierarchical multiple regression showed that greater PCL-M scores significantly predicted elevated PRMQ-Total scores, accounting for 38% of the variance explained (P < .001). mTBI status predicted an additional 5% of variance in memory complaints (P < .01). The multiple-mTBI group endorsed more memory complaints than either MCs (P < .01) or the single-mTBI group (P < .05), who did not differ from MCs (P > .50). CONCLUSIONS: Comorbid PTSD symptoms are an important factor when considering memory complaints in veterans with a reported history of mTBI. However, independent of comorbid PTSD symptoms, mTBI status-particularly in the context of repetitive neurotrauma-uniquely contributes to memory complaints. Findings suggest that veterans with a history of multiple mTBIs may be a particularly vulnerable group in need of specialized interventions and/or psychoeducation.

Fatigue Is Associated With Global and Regional Thalamic Morphometry in Veterans With a History of Mild Traumatic Brain Injury.

OBJECTIVE: Fatigue is a complex, multidimensional phenomenon that commonly occurs following traumatic brain injury (TBI). The thalamus-a structure vulnerable to both primary and secondary injuries in TBI-is thought to play a pivotal role in the manifestation of fatigue. We explored how neuroimaging markers of local and global thalamic morphometry relate to the subjective experience of fatigue post-TBI. METHODS: Sixty-three Veterans with a history of mild TBI underwent structural magnetic resonance imaging and completed questionnaires related to fatigue and psychiatric symptoms. FMRIB's Software (FSL) was utilized to obtain whole brain and thalamic volume estimates, as well as to perform regional thalamic morphometry analyses. RESULTS: Independent of age, sex, intracranial volume, posttraumatic stress disorder, and depressive symptoms, greater levels of self-reported fatigue were significantly associated with decreased right (P = .026) and left (P = .046) thalamic volumes. Regional morphometry analyses revealed that fatigue was significantly associated with reductions in the anterior and dorsomedial aspects of the right thalamic body (P < .05). Similar trends were observed for the left thalamic body (P < .10). CONCLUSIONS: Both global and regional thalamic morphometric changes are associated with the subjective experience of fatigue in Veterans with a history of mild TBI. These findings support a theory in which disruption of thalamocorticostriatal circuitry may result in the manifestation of fatigue in individuals with a history of neurotrauma.

Meta-analyses of clinical neuropsychological tests of executive dysfunction and impulsivity in alcohol use disorder.

BACKGROUND: Promising models for cognitive rehabilitation in alcohol treatment rest on a more nuanced understanding of the associated impairments in the multifaceted domains of executive functioning (EF) and impulsivity. OBJECTIVES: This meta-analysis examined the effects of alcohol on the individual subcomponents of EF and impulsivity in recently detoxified participants, including 1) Inhibition & Self-Regulation, 2) Flexibility & Set Shifting, 3) Planning & Problem Solving, 4) Reasoning & Abstraction, and 5) Verbal Fluency. Impulsivity was further examined through an analysis of motor, cognitive, and decisional subcategories. METHOD: Investigators searched, coded, and calculated effect sizes of impairments demonstrated in a broad range of neuropsychological tests for EF. A total of 77 studies were selected covering 48 years of research with a sample size of 5140. RESULTS: Findings ranged from a Hedges' g effect size of 0.803 for Inhibition to a Hedges' g of 0.359 for Verbal Fluency. Results also varied for the individual subcategories of Inhibition, including a large effect size for decisional impulsivity (g = 0.817) and cognitive impulsivity (0.860), and a moderate effect size for motor impulsivity (g = 0.529). The Hayling Test, Wisconsin Card Sorting Test, and Iowa Gambling Task were the measures most sensitive for alcohol effects. CONCLUSION: Planning, problem solving, and inhibitory abilities are significantly affected by alcohol abuse, with decisional and cognitive forms of impulsivity most impacted. Cognitive remediation targeting these deficits might increase the related functions that mediate the ability to moderate or abstain from alcohol, and so lead to improved treatment results.

Predictors of cognitive and physical fatigue in post-acute mild-moderate traumatic brain injury.

Post-traumatic fatigue (PTF) is a common, disabling, and often chronic symptom following traumatic brain injury (TBI). Yet, the impact of chronic cognitive and physical fatigue and their associations with psychiatric, sleep, cognitive, and psychosocial sequelae in mild-moderate TBI remain poorly understood. Sixty Veterans with a history of mild-moderate TBI and 40 Veteran controls (VC) were administered the Modified Fatigue Impact Scale, a validated measure of TBI-related cognitive and physical fatigue as well as measures of neuropsychiatric, psychosocial, sleep, and objective cognitive functioning. Compared to VC, TBI Veterans endorsed significantly greater levels of cognitive and physical fatigue. In TBI, psychiatric symptoms, sleep disturbance, and post-traumatic amnesia (PTA) were associated with both cognitive and physical fatigue, while loss of consciousness (LOC) and poor attention/processing speed were related to elevations in cognitive fatigue only. In regression analyses, anxiety, sleep disturbance, and LOC significantly predicted cognitive fatigue, while only post-traumatic stress symptoms and PTA contributed to physical fatigue. Cognitive and physical fatigue are problematic symptoms following mild-moderate TBI that are differentially associated with specific injury and psychiatric sequelae. Findings provide potential symptom targets for interventions aimed at ameliorating fatigue, and further underscore the importance of assessing and treating fatigue as a multi-dimensional symptom following TBI.

White Matter Associations With Performance Validity Testing in Veterans With Mild Traumatic Brain Injury: The Utility of Biomarkers in Complicated Assessment.

OBJECTIVE: Failure on performance validity tests (PVTs) is common in Veterans with histories of mild traumatic brain injury (mTBI), leading to questionable validity of clinical presentations. PARTICIPANTS: Using diffusion tensor imaging, we investigated white matter (WM) integrity and cognition in 79 Veterans with history of mTBI who passed PVTs (n = 43; traumatic brain injury [TBI]-passed), history of mTBI who failed at least 1 PVT (n = 13; TBI-failed), and military controls (n = 23; MCs) with no history of TBI. RESULTS: The TBI-failed group demonstrated significantly lower cognitive scores relative to MCs and the TBI-passed group; however, no such differences were observed between MCs and the TBI-passed group. On a global measure of WM integrity (ie, WM burden), the TBI-failed group showed more overall WM abnormalities than the other groups. However, no differences were observed between the MCs and TBI-passed group on WM burden. Interestingly, regional WM analyses revealed abnormalities in the anterior internal capsule and cingulum of both TBI subgroups relative to MCs. Moreover, compared with the TBI-passed group, the TBI-failed group demonstrated significantly decreased WM integrity in the corpus callosum. CONCLUSIONS: Findings revealed that, within our sample, WM abnormalities are evident in those who fail PVTs. This study adds to the burgeoning PVT literature by suggesting that poor PVT performance does not negate the possibility of underlying WM abnormalities in military personnel with history of mTBI.

White Matter Microstructural Compromise Is Associated With Cognition But Not Posttraumatic Stress Disorder Symptoms in Military Veterans With Traumatic Brain Injury.

OBJECTIVE: To investigate white matter microstructure compromise in Veterans with a history of traumatic brain injury (TBI) and its possible contribution to posttraumatic stress disorder (PTSD) symptomatology and neuropsychological functioning via diffusion tensor imaging. PARTICIPANTS AND METHODS: Thirty-eight Veterans with mild (n = 33) and moderate (n = 5) TBI and 17 military control participants without TBI completed neuropsychological testing and psychiatric screening and underwent magnetic resonance imaging an average of 4 years following their TBI event(s). Fractional anisotropy (FA) and diffusivity measures were extracted from 9 white matter tracts. RESULTS: Compared with military control participants, TBI participants reported higher levels of PTSD symptoms and performed worse on measures of memory and psychomotor-processing speed. Traumatic brain injury was associated with lower FA in the genu of the corpus callosum and left cingulum bundle. Fractional anisotropy negatively correlated with processing speed and/or executive functions in 7 of the 8 tracts. Regional FA did not correlate with memory or PTSD symptom ratings. CONCLUSION: Results suggest that current PTSD symptoms are independent of TBI-related white matter alterations, as measured by diffusion tensor imaging. In addition, white matter microstructural compromise may contribute to reduced processing speed in our sample of participants with history of neurotrauma. Findings of the current study add insight into the factors associated with complicated recovery from mild to moderate TBI.

Deep white matter hyperintensities affect verbal memory independent of PTSD symptoms in veterans with mild traumatic brain injury.

OBJECTIVE: Although white matter hyperintensity (WMH) pathology has been observed in the context of traumatic brain injury (TBI), the contribution of this type of macrostructural damage to cognitive and/or post-concussive symptomatology (PCS) remains unclear. METHODS: Sixty-eight Veterans (mTBI = 46, Military Controls [MCs] = 22) with and without history of mild TBI (mTBI) underwent structural MRI and comprehensive cognitive and psychiatric assessment. WMH volume was identified as deep (DWMH) or periventricular (PVWMH) on fluid-attenuated inversion recovery (FLAIR) images. RESULTS: Group analyses revealed that mTBI history was not associated with increased WMH pathology (p's > 0.05). However, after controlling for post-traumatic stress disorder (PTSD) and intracranial volume, DWMH was associated with reduced short-and long-delayed memory performance within the mTBI group (p's < 0.05). Additionally, after adjusting for PTSD and time since injury, regression analyses revealed that WMH was not associated with self-reported ratings of PCS (p's > 0.05) in the mTBI group. CONCLUSIONS: The results demonstrate that, in relatively young Veterans with mTBI, DWMH differentially and negatively affects memory performance above and beyond the effects of PTSD symptoms. The findings may help to clarify prior mixed results as well as offer focused treatment implications for Veterans with history of neurotrauma and evidence of macrostructural white matter damage.

The Relationship Between Postconcussive Symptoms and Quality of Life in Veterans With Mild to Moderate Traumatic Brain Injury.

OBJECTIVE: To assess the relationship between postconcussive symptoms and quality of life (QOL) in Veterans with mild to moderate traumatic brain injury (TBI). METHODS: Sixty-one Operation Enduring Freedom/Operation Iraqi Freedom/Persian Gulf War Veterans with a history of mild or moderate TBI, more than 6 months postinjury, and 21 demographically matched Veteran controls were administered self-report measures of QOL (World Health Organization Quality of Life-BREF) and postconcussive symptom severity (Neurobehavioral Symptom Inventory). RESULTS: Perceived QOL was significantly worse in Veterans with mild-moderate TBI than in controls. In the TBI group, QOL was predominantly associated with affective symptoms, and moderate to strong correlations with fatigue and depression were evident across all QOL areas. Multivariate analyses revealed depression and fatigue to be the best predictors of Psychological, Social, and Environmental QOL, whereas sleep difficulty best predicted Physical QOL in mild-moderate TBI. CONCLUSION: Veterans with post-acute mild-moderate TBI evidence worse QOL than demographically matched Veteran controls. Affective symptoms, and specifically those of fatigue, depression, and sleep difficulty, appear to be the most relevant postconcussive symptoms predicting QOL in this population. These findings underscore the importance of examining specific symptoms as they relate to post-acute TBI QOL and provide guidance for treatment and intervention studies.

White matter integrity in veterans with mild traumatic brain injury: associations with executive function and loss of consciousness.

OBJECTIVE: We investigated using diffusion tensor imaging (DTI) and the association between white matter integrity and executive function (EF) performance in postacute mild traumatic brain injury (mTBI). In addition, we examined whether injury severity, as measured by loss of consciousness (LOC) versus alterations in consciousness (AOC), is related to white matter microstructural alterations and neuropsychological outcome. PARTICIPANTS: Thirty Iraq and Afghanistan War era veterans with a history of mTBI and 15 healthy veteran control participants. RESULTS: There were no significant overall group differences between control and mTBI participants on DTI measures. However, a subgroup of mTBI participants with EF decrements (n = 13) demonstrated significantly decreased fractional anisotropy of prefrontal white matter, corpus callosum, and cingulum bundle structures compared with mTBI participants without EF decrements (n = 17) and control participants. Participants having mTBI with LOC were more likely to evidence reduced EF performances and disrupted ventral prefrontal white matter integrity when compared with either mTBI participants without LOC or control participants. CONCLUSIONS: Findings suggest that altered white matter integrity contributes to reduced EF in subgroups of veterans with a history of mTBI and that LOC may be a risk factor for reduced EF as well as associated changes to ventral prefrontal white matter.

Prospective memory performance in veterans with and without histories of mild traumatic brain injury: effect of the apolipoprotein E (APOE) ε4 genotype.

OBJECTIVE: Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status - particularly possession of the apolipoprotein E (APOE) ε4 allele - can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories. METHODS: 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24-50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4-) on MIST scores. RESULTS: Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay (p=.002, ηp2 =.160), Time Cue (p = .003, ηp2 =.157), and PM Total (p = .016, ηp2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay (p = .011, ηp2 =.113) and PM Total (p = .048, ηp2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale (p = .031, ηp2 = .150). CONCLUSIONS: mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

Early adolescent cortical thinning is related to better neuropsychological performance.

Adolescence is characterized by significant neuromaturation, including extensive cortical thinning, particularly in frontal regions. The goal of this study was to examine the behavioral correlates of neurostructural development in early adolescence. Participants were 185 healthy 12- to 14-year-olds (44% female) recruited from local schools. Participants completed a comprehensive neuropsychological test battery and magnetic resonance imaging session. Cortical surface reconstruction and thickness estimates were performed via FreeSurfer. Age and cortical thickness were negatively correlated in 10 brain regions, 7 of which were in frontal areas (ß = −.15 to −.25, ps ≤ .05). Hierarchical linear regressions examined the influence of cortical thickness on working memory, attention, verbal learning and memory, visuospatial functioning, spatial planning and problem solving, and inhibition, controlling for age and intracranial volume. Thinner parietal cortices predicted better performances on tests of verbal learning and memory, visuospatial functioning, and spatial planning and problem solving (ß = −.14 to −.24, ps ≤ .05). Age, spanning from 12 to 14 years, accounted for up to 6% of cortical thickness, suggesting substantial thinning during early adolescence, with males showing more accelerated thinning than females between ages 12 and 14. For both males and females, thinner parietal association cortices corresponded with better neurocognitive functioning above and beyond age alone.

Subjective memory complaints are associated with decreased cortical thickness in Veterans with histories of mild traumatic brain injury.

Objective: Memory problems are frequently endorsed in Veterans following mild traumatic brain injury (mTBI), but subjective complaints are poorly associated with objective memory performance. Few studies have examined associations between subjective memory complaints and brain morphometry. We investigated whether self-reported memory problems were associated with objective memory performance and cortical thickness in Veterans with a history of mTBI. Methods: 40 Veterans with a history of remote mTBI and 29 Veterans with no history of TBI completed the Prospective-Retrospective Memory Questionnaire (PRMQ), PTSD Checklist (PCL), California Verbal Learning Test-2nd edition (CVLT-II), and 3 T T1 structural magnetic resonance imaging. Cortical thickness was estimated in 14 a priori frontal and temporal regions. Multiple regressions adjusting for age and PCL scores examined associations between PRMQ, CVLT-II scores, and cortical thickness within each Veteran group. Results: Greater subjective memory complaints on the PRMQ were associated with lower cortical thickness in the right middle temporal gyrus (ß = 0.64, q = .004), right inferior temporal gyrus (ß = 0.56, q = .014), right rostral middle frontal gyrus (ß = 0.45, q = .046), and right rostral anterior cingulate gyrus (ß = 0.58, q = .014) in the mTBI group but not the control group (q's > .05). These associations remained significant after adjusting for CVLT-II learning. CVLT-II performance was not associated with PRMQ score or cortical thickness in either group. Conclusions: Subjective memory complaints were associated with lower cortical thickness in right frontal and temporal regions, but not with objective memory performance, in Veterans with histories of mTBI. Subjective complaints post-mTBI may indicate underlying brain morphometry independently of objective cognitive testing.

Sex moderates the association between age and myelin water fraction in the cingulum and fornix among older adults without dementia.

Background: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer's disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52). Methods: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory. Results: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume. Conclusion: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Callosal white matter microstructural recovery in abstinent alcoholics: a longitudinal diffusion tensor imaging study.

BACKGROUND: Previous neuroimaging studies of recently detoxified alcohol-dependent patients (RDA) have found significant loss of white matter integrity associated with the shrinkage of the frontal lobes and thinning of the corpus callosum, especially the genu. The current study hypothesized that, in addition to exhibiting the most microstructural white matter disruption in RDA, the genu will also evidence the most recovery after abstinence. This microstructural recovery will be associated with improvements in executive functioning measures. METHODS: Fifteen RDA were examined approximately 2 weeks after abstinence and again after 1 year of abstinence and compared to 15 age- and education-matched nonalcoholic controls using diffusion tensor imaging (DTI). The effects of group, time, and their interactions on fractional anisotropy, radial diffusivity, and axial diffusivity were evaluated with repeated measures MANOVA; in addition, 2 × 2 ANOVA was used to test changes in measures of executive functioning in the 2 groups. RESULTS: At 2 weeks of abstinence, DTI of RDA showed significantly lower fractional anisotropy and greater radial diffusivity compared to controls in the genu and body of the corpus callosum. Reexamination after 1 year showed significant time by group interaction with fractional anisotropy increasing and radial diffusivity decreasing in RDA but not controls in these 2 regions. A smaller relapsed group did not show improvements between the 2 time points. Abstinent RDA also showed improvement on Digit Span Backward, a measure of working memory, but did not benefit from practice effects on the Halstead Category Test compared to controls. CONCLUSIONS: The results suggest susceptibility of the genu and body of the corpus callosum to the effects of alcohol, and the potential for recovery of both these regions after abstinence, perhaps via mechanisms involving myelin reconstitution.

Elevated Neuropsychological Intraindividual Variability Predicts Poorer Health-Related Quality of Life in Veterans with a History of Mild Traumatic Brain Injury.

We examined the association between cognitive functioning and health-related quality of life (HR-QOL) in military veterans with a history of mild traumatic brain injury (mTBI) using two methods to assess cognition: mean performance on cognitive composite scores and across-test intraindividual variability (IIV). The sample included 73 veterans (84.9% male; age, mean = 32.47 years) who completed neuropsychological testing and self-report questionnaires ∼7 years post-injury. Three cognitive composite scores representing mean performance were computed, including memory, attention/processing speed (A/PS), and executive functioning (EF). Three IIV indices were also calculated reflecting degree of dispersion across the same cognitive domains: memory-IIV, A/PS-IIV, and EF-IIV. The Posttraumatic Stress Disorder (PTSD) Checklist-Military Version (PCL-M) was used to assess current PTSD symptoms, and the World Health Organization Quality of Life Short Version Physical Health domain was used to assess HR-QOL. Hierarchical linear regressions adjusting for PTSD symptoms demonstrated that IIV indices, but not mean cognitive composite scores, significantly predicted HR-QOL. Specifically, memory-IIV, A/PS-IIV, and EF-IIV, when taken together, made an independent and significant contribution to the prediction of HR-QOL. Examination of the standardized coefficients showed that the A/PS-IIV index was uniquely associated with HR-QOL, such that higher A/PS-IIV scores significantly predicted poorer HR-QOL. Our results are the first to show that, in veterans with remote mTBI histories, greater fluctuations in cognitive performance significantly contribute to poorer HR-QOL, even after accounting for PTSD symptom severity. Moreover, findings suggest that, compared to traditional mean cognitive performance scores, measures of IIV may represent more sensitive indicators of clinical outcome and better align with subjective experiences of distress.

Greater Severity and Functional Impact of Post-traumatic Headache in Veterans With Comorbid Neck Pain Following Traumatic Brain Injury.

BACKGROUND: Post-traumatic headache (PTH) is a commonly experienced symptom after mild traumatic brain injury (mTBI). Blast injury- or blunt injury-related mechanisms for mTBI in veterans can also affect musculoskeletal structures in the neck, resulting in comorbid neck pain (NP). However, it is unknown whether the presence of comorbid NP may be associated with a different pattern of headache symptoms, physical functioning, or emotional functioning compared to those without comorbid NP. The purpose of this study is to examine the role of comorbid NP in veterans with mTBI and PTH. DESIGN AND METHODS: This was a cross-sectional investigation of an existing dataset that included 33 veterans who met inclusion criteria for PTH after mTBI. Standardized measures of headache severity and frequency, insomnia, fatigue, mood disorders, and physical and emotional role function were compared between groups with and without comorbid NP. RESULTS: The majority of participants with PTH reported comorbid NP (n = 22/33, 67%). Those with comorbid NP experienced more headache symptoms that were severe or incapacitating, as compared to mild or moderate for those without NP (φ = 0.343, P = .049); however, no differences in headache frequency (φ = 0.231, P = .231) or duration (φ = 0.129, P = .712) were observed. Participants with comorbid NP also reported greater insomnia (d = 1.16, P = .003) and fatigue (d = 0.868, P = .040) as well as lower physical functioning (d = 0.802, P = .036) and greater bodily pain (d = 0.762, P = .012). There were no differences in anxiety, depression, mental health, emotional role limitations, vitality, or social functioning between those with and without comorbid NP (d ≤ 0.656, P ≥ .079). CONCLUSIONS: A majority of veterans with mTBI and PTH in our sample reported comorbid NP that was associated with greater headache symptom severity and physical limitations, but not with mood or emotional limitations. Preliminary findings from this small convenience sample indicate that routine assessment of comorbid NP and associated physical limitations should be considered in veterans with mTBI and PTH.

Decreased myelin content of the fornix predicts poorer memory performance beyond vascular risk, hippocampal volume, and fractional anisotropy in nondemented older adults.

Alterations to cerebral white matter tracts have been associated with cognitive decline in aging and Alzheimer's disease (AD). In particular, the fornix has been implicated as especially vulnerable given that it represents the primary outflow tract of the hippocampus. Despite this, little work has focused on the fornix using a potential early marker of white matter degeneration-myelin water fraction (MWF; an in vivo marker of myelin content). Therefore, we sought to (1) clarify associations between MWF in the fornix and memory functioning, and (2) examine whether fornix MWF relates to memory performance above and beyond hippocampal volume and conventional imaging measures of white matter that may not be as specific to alterations in myelin content. Forty nondemented older adults (mean age = 72.9 years) underwent an MRI exam and neuropsychological assessment. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) was used to quantify fornix MWF and diffusion tensor imaging (DTI) was used to measure fornix fractional anisotropy (FA). Adjusting for age, sex, education, and vascular risk factors, linear regression models revealed that, lower fornix MWF was significantly associated with poorer memory functioning (ß = 0.405, p = .007) across our sample of older adults. Notably, fornix MWF remained a significant predictor of memory functioning (ß = 0.380, p = .015) even after adjusting for fornix DTI FA and hippocampal volume (in addition to the above covariates). Given the observed associations between myelin and memory in older adults without dementia, MWF may be a useful early marker of dementia risk.