DOI: 10.7272/q6rn35sz
title: Changes in brain anatomy during the course of PTSD

description: Longitudinal structural T1-weighted images from middle-aged controls and
 veterans with PTSD (post-traumatic stress disorder). Most patients were
 Vietnam veterans. The goal of this study was to determine whether PTSD was
 associated with an increase in time-related decline in macrostructural
 brain volume and whether these changes were associated with accelerated
 cognitive decline. To quantify brain structure, 3 dimensional T1-weighted
 MRI scans were performed at baseline and again after a minimum of 24
 months in 25 patients with PTSD and 22 controls. Longitudinal changes in
 brain volume were measured using deformation morphometry. For the group as
 a whole PTSD+ patients did not show significant ongoing brain atrophy
 compared to PTSD-. PTSD+ patients were then subgrouped into those with
 decreasing or increasing symptoms. We found little evidence for brain
 markers of accelerated atrophy in PTSD+ veterans whose symptoms improved
 over time, with only a small left parietal region showing greater ongoing
 tissue loss than PTSD-. PTSD patients whose symptoms increased over time
 showed accelerated atrophy throughout the brain, particularly brainstem
 and frontal and temporal lobes. Lastly, for the sample as a whole greater
 rates of brain atrophy were associated with greater rates of decline in
 verbal memory and delayed facial recognition.
description: Participants: After complete description of the study to the subjects,
 written informed consent was obtained to a protocol approved by the review
 boards of both the University of California, San Francisco (UCSF) and the
 San Francisco Veterans Affairs (SFVA) Medical Center. Participants had
 previously participated in one of two earlier studies examining
 neuroimaging and neuropsychological correlates of PTSD (Neylan et al.,
 2004; Samuelson et al., 2006; Schuff et al., 2008; Schuff et al., 2001).
 When initially studied, participants had given consent to be re-contacted
 about future studies. Veterans were contacted a minimum of two years after
 completion of the first assessment. Study procedures included completing a
 neuropsychological test battery and MRI scanning. Participants met the
 following basic inclusion criteria at baseline: veterans 25-65 years of
 age; PTSD+ participants had current PTSD attributable to a traumatic life
 event (e.g., Vietnam or Gulf War combat, experiencing or witnessing
 serious accidents, illnesses, sudden death, physical and sexual assault),
 PTSDparticipants had no current, subthreshold, or lifetime history of
 PTSD. Exclusion criteria at baseline were: diagnosis of drug dependence or
 abuse within the past 6 months, current or lifetime history of any
 psychiatric disorder with psychotic features, current or lifetime history
 of bipolar disorder, history of neurologic or systemic illness affecting
 CNS function, history of head injury with loss of consciousness exceeding
 10 minutes, and history of head injury with any persistent post-injury
 symptoms. Alcohol abuse and dependence were allowable diagnoses for one of
 the original studies. Patients and controls were studied twice, once after
 enrollment (baseline) and again after a minimum of 24 months. Because we
 were interested in the natural course of PTSD, we did not apply
 exclusionary criteria at follow-up. At follow-up, three PTSD+ participants
 met one of the exclusionary baseline diagnoses—two exhibiting psychotic
 symptoms and one exhibiting symptoms of bipolar disorder not otherwise
 specified. These participants did not represent outliers in terms of
 neuropsychological functioning and were included in our previous study of
 longitudinal neuropsychological functioning (Samuelson et al., 2009), and
 were also included in this longitudinal imaging study. This analysis
 included 25 PTSD+ male veterans and 22 PTSDmale veterans that had complete
 longitudinal MRI and neuropsychological datasets. Clinical and cognitive
 testing: Diagnoses of PTSD at baseline and follow-up were made by a
 clinical psychologist using the Clinician Administered PTSD Scale, which
 determines if DSM-IV diagnostic criteria were met (CAPS; (Blake et al.,
 1995)). Individuals with no trauma exposure received a CAPS score of 0.
 The Structured Clinical Interview for DSM-IV Diagnosis (SCID; (First et
 al., 1996)) was used to diagnose comorbid and exclusionary conditions.
 Lifetime alcohol use was obtained using the Lifetime Drinking History
 questionnaire (LDH; (Skinner and Sheu, 1982)). All participants were
 administered a test battery of neuropsychological measures at both
 timepoints, including the California Verbal Learning Test (CVLT; (Delis et
 al., 1987)), Faces I, Faces II, Family Pictures I, Family Pictures II,
 Digit Span and Spatial Span subtests of the Wechsler Memory Scale-Third
 Edition (WMS-III; (Wechsler, 1987)). Samuelson and colleagues previously
 reported on the longitudinal neuropsychological changes observed in this
 dataset (Samuelson et al., 2009), and found a subtle decline in delayed
 facial recognition as indexed by performance on the Faces II subtest. In
 light of this finding and the previous reports of longitudinal changes on
 the CVLT due to PTSD (Yehuda et al., 2006), this study focused only on the
 relationships of longitudinal changes in Faces II, CVLT total (short term
 verbal memory) and CVLT long delay (long term verbal memory) with
 longitudinal measures of brain atrophy. Longitudinal change on these
 neuropsychological tests was defined as (scoretp1-scoretp2)/(test interval
 in yrs). MRI acquisition and processing: T1-weighted images were acquired
 on a clinical 1.5 Tesla MR scanner (Vision, Siemens Medical Systems,
 Iselin NJ) using Magnetization Prepared Rapid Acquisition Gradient Echo
 (TR/TI/TE = 9/300/4 ms, 1x1 mm2 in-plane resolution, 1.5 mm slabs); images
 were acquired orthogonal to the long axis of the hippocampus. Deformation
 based morphometry (DBM) analyses: Robust fluid registration was used to
 nonlinearly register baseline and follow-up scans of each participant to
 create maps of longitudinal atrophy. Each participant's baseline
 image was then registered to an atlas; transformations were combined to
 create maps of longitudinal atrophy in common space as described in
 (Cardenas et al., 2007). The longitudinal atrophy maps were normalized by
 interscan interval and these maps of annualized atrophy rate in common
 space were used in statistical analysis using linear models. ANCOVA at
 each voxel was used to test our first hypothesis that PTSD was associated
 with greater tissue atrophy rates; the maps of longitudinal change were
 the dependent variable, group status (i.e., PTSD+ or PTSD-) was the
 categorical predictor, and age was a covariate. Linear regressions with
 baseline clinical or imaging measures as the independent variable were fit
 at each voxel in order to identify baseline predictors of ongoing atrophy.
 Subsequent analyses compared PTSD+ participants with improving symptoms
 vs. PTSD-, and PTSD+ with worsening symptoms vs. PTSD-, in order to
 determine the relationship between improving mental health and ongoing
 brain atrophy. Using all participants, linear regression with change in
 neuropsychological test score as the independent variable was also fit at
 each voxel, covarying for age, in order to determine the relationship
 between rate of tissue atrophy and cognitive decline. Statistical maps
 were corrected for multiple comparisons by thresholding at uncorrected
 p=0.005, identifying suprathreshold clusters, and using nonstationary
 random field theory (Worsley et al., 2002) to identify clusters with
 corrected p&lt;0.05. Within each cluster with corrected p&lt;0.05, the
 estimated effects (i.e., the voxel-wise beta coefficients from the linear
 model) were averaged to determine the magnitude of the group effects (for
 ANCOVA models) or the slope (for regression models).