Volume In Posttraumatic Stress Disorder Research Articles

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Smaller Total and Subregional Cerebellar Volumes in Posttraumatic Stress Disorder: A Mega-Analysis by the ENIGMA-PGC PTSD Workgroup

Smaller Total and Subregional Cerebellar Volumes in Posttraumatic Stress Disorder: A Mega-Analysis by the ENIGMA-PGC PTSD Workgroup

P657. Cerebellum Structural Covariance Networks in PTSD and Depression

The cerebellum has an important role in sensorimotor function, cognition, and emotion. Neuroimaging studies have reported altered cerebellum activation, functional connectivity, and volume in posttraumatic stress disorder and depression. The aim of the study was to identify the structural covariance networks of the cerebellum in PTSD and depression using neuroimaging meta-analysis.

The environment contributes more than genetics to smaller hippocampal volume in Posttraumatic Stress Disorder (PTSD)

BackgroundStudies using structural magnetic resonance imaging (MRI) volumetrics showed smaller hippocampal volume in patients with post-traumatic stress disorder (PTSD). These studies were cross-sectional and did not address whether smaller volume is secondary to stress-induced damage, or whether pre-existing factors account for the findings. The purpose of this study was to use a co-twin case control design to assess the relative contribution of genetic and environmental factors to hippocampal volume in PTSD. MethodsMonozygotic (N = 13 pairs) and dizygotic (N = 21 pairs) twins with a history of Vietnam Era military service, where one brother went to Vietnam and developed PTSD, while his brother did not go to Vietnam or develop PTSD, underwent MR imaging of the brain. Structural MRI scans were used to manually outline the left and right hippocampus on multiple coronal slices, add the areas and adjust for slice thickness to determine hippocampal volume. ResultsTwins with Vietnam combat-related PTSD had a mean 11% smaller right hippocampal volume in comparison to their twin brothers without combat exposure or PTSD (p < .05). There was no significant interaction by zygosity, suggesting that this was not a predisposing risk factor or genetic effect. ConclusionsThese findings are consistent with smaller hippocampal volume in PTSD, and suggest that the effects are primarily due to environmental effects such as the stress of combat.

Brain Volume in Veterans: Relationship to Posttraumatic Stress Disorder and Mild Traumatic Brain Injury.

Clarify associations between diagnosis of posttraumatic stress disorder (PTSD) and deployment traumatic brain injury (TBI) on salient regional brain volumes in returning combat veterans. Iraq and Afghanistan era combat veterans, N = 163, 86.5% male. Clinician-administered PTSD Scale (CAPS-5), Mid-Atlantic MIRECC Assessment of TBI (MMA-TBI), magnetic resonance imaging. Hierarchical regression analyses evaluated associations and interactions between current and lifetime PTSD diagnosis, deployment TBI, and bilateral volume of hippocampus, anterior cingulate cortex, amygdala, orbitofrontal cortex, precuneus, and insula. Deployment TBI was associated with lower bilateral hippocampal volume (P = .007-.032) and right medial orbitofrontal cortex volume (P = .006). Neither current nor lifetime PTSD diagnosis was associated with volumetric outcomes beyond covariates and deployment TBI. History of deployment TBI is independently associated with lower volumes in hippocampus and medial orbitofrontal cortex. These results support TBI as a potential contributing factor to consider in reduced cortical volume in PTSD.

Right temporal pole volume reduction in PTSD

Previous magnetic resonance imaging studies of post-traumatic stress disorder (PTSD) have reported cortical volume alterations in the parahippocampal, anterior cingulate cortex, and temporal pole. It is unclear, however, if these cortical regions are specifically associated with PTSD or associated with common comorbidities. Here, we present the result of cortical volume differences between PTSD and healthy and psychiatric controls. In this study, healthy controls (n = 67) were matched for demographic characteristics (age, sex, race) and psychiatric controls (n = 67) were matched for demographic characteristics plus all other psychiatric diagnoses (past and current) to a group of PTSD patients (N = 67). We assessed group differences of 34 bilateral cortical structure volumes using statistically defined brain regions-of-interest from FreeSurfer between PTSD patients and healthy controls. We found 10 regions to be significantly different between PTSD and healthy controls and analyzed the group differences between PTSD and psychiatric controls within these regions. The right temporal pole volume in PTSD was found to be significantly smaller than both healthy and psychiatry controls. Our finding suggests only right temporal pole volume reduction is specifically associated with PTSD, and also highlights the need for using appropriate controls in psychiatry research.

Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia

BackgroundMany studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. MethodsWe analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. ResultsIn a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p = .00054), and smaller amygdalae (d = −0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). ConclusionsOur study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.

Evidence for smaller right amygdala volumes in posttraumatic stress disorder following childhood trauma

Hippocampus and amygdala volumes in posttraumatic stress disorder (PTSD) related to childhood trauma are relatively understudied, albeit the potential importance to the disorder. Whereas some studies reported smaller hippocampal volumes, little evidence was found for abnormal amygdala volumes. Here we investigated hippocampus and amygdala volumes and shapes in an adult sample of PTSD patients related to childhood trauma. T1-weighted MR images were acquired from 12 female PTSD patients with trauma related to physical, sexual, and/or emotional abuse before age 18, and from 12 matched controls. Hippocampus and amygdala were segmented, and volumes were calculated and corrected for the total intracranial volume. Additionally, a shape analysis was done on the surface of the structures to explore abnormalities in specific subnuclei. Smaller right amygdala volumes were found in PTSD patients as compared with the controls. This difference appeared to be located specifically in the basolateral and superficial nuclei groups. Severity of sexual abuse during childhood was negatively correlated with the size of the amygdala. No difference in hippocampal volumes was found. Although our results are not conclusive, traumatic events in childhood might impede normal development of the amygdala, which could render a person more vulnerable to develop PTSD later in life.

Reduced hippocampal volume is associated with overgeneralization of negative context in individuals with PTSD.

Previous studies demonstrated reduced hippocampal volume in individuals with posttraumatic stress disorder (PTSD). However, the functional role the hippocampus plays in PTSD symptomatology is still unclear. The aim of the present study was to explore generalization learning and its connection to hippocampal volume in individuals with and without PTSD. Animal and human models argue that hippocampal deficit may result in failure to process contextual information. Therefore we predicted associations between reduced hippocampal volume and overgeneralization of context in individuals with PTSD. We conducted MRI scans of bilateral hippocampal and amygdala formations as well as intracranial and total brain volumes. Generalization was measured using a novel-learning paradigm, which separately evaluates generalization of cue and context in conditions of negative and positive outcomes. As expected, MRI scans indicated reduced hippocampal volume in PTSD compared to non-PTSD participants. Behavioral results revealed a selective deficit in context generalization learning in individuals with PTSD, F(1, 43) = 8.27, p < .01, η(p)² = .16. Specifically, as predicted, while generalization of cue was spared in both groups, individuals with PTSD showed overgeneralization of negative context. Hence, they could not learn that a previously negative context is later associated with a positive outcome, F(1, 43) = 7.33, p = .01, η(p)² = .15. Most importantly, overgeneralization of negative context significantly correlated with right and left hippocampal volume (r = .61, p = .000; r = .5, p = .000). Finally, bilateral hippocampal volume provided the strongest prediction of overgeneralization of negative context. Reduced hippocampal volume may account for the difficulty of individuals with PTSD to differentiate negative and novel conditions and hence may facilitate reexperiencing symptoms.

Amygdala Volume Changes in Posttraumatic Stress Disorder in a Large Case-Controlled Veterans Group

Smaller hippocampal volumes are well established in posttraumatic stress disorder (PTSD), but the relatively few studies of amygdala volume in PTSD have produced equivocal results. To assess a large cohort of recent military veterans with PTSD and trauma-exposed control subjects, with sufficient power to perform a definitive assessment of the effect of PTSD on volumetric changes in the amygdala and hippocampus and of the contribution of illness duration, trauma load, and depressive symptoms. Case-controlled design with structural magnetic resonance imaging and clinical diagnostic assessments. We controlled statistically for the important potential confounds of alcohol use, depression, and medication use. Durham Veterans Affairs Medical Center, which is located in proximity to major military bases. Ambulatory patients (n = 200) recruited from a registry of military service members and veterans serving after September 11, 2001, including a group with current PTSD (n = 99) and a trauma-exposed comparison group without PTSD (n = 101). Amygdala and hippocampal volumes computed from automated segmentation of high-resolution structural 3-T magnetic resonance imaging. Smaller volume was demonstrated in the PTSD group compared with the non-PTSD group for the left amygdala (P = .002), right amygdala (P = .01), and left hippocampus (P = .02) but not for the right hippocampus (P = .25). Amygdala volumes were not associated with PTSD chronicity, trauma load, or severity of depressive symptoms. These results provide clear evidence of an association between a smaller amygdala volume and PTSD. The lack of correlation between trauma load or illness chronicity and amygdala volume suggests that a smaller amygdala represents a vulnerability to developing PTSD or the lack of a dose-response relationship with amygdala volume. Our results may trigger a renewed impetus for investigating structural differences in the amygdala, its genetic determinants, its environmental modulators, and the possibility that it reflects an intrinsic vulnerability to PTSD.

Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans

Prior studies have examined differences in brain volume between patients with post-traumatic stress disorder (PTSD) and control subjects. Convergent findings include smaller hippocampus and medial prefrontal cortex volumes in PTSD. However, post-traumatic stress symptoms (PTSS) exist on a spectrum, and neural changes may occur beyond the diagnostic threshold of PTSD. We examined the relationship between PTSS and gray matter among combat-exposed U.S. military veterans. Structural brain magnetic resonance imaging (MRI) was obtained on 28 combat veterans from Operations Enduring and Iraqi Freedom. PTSS were assessed using the Clinician-Administered PTSD Scale (CAPS). Thirteen subjects met criteria for PTSD. Subjects were unmedicated, and free of major comorbid psychiatric disorders. Images were analyzed using voxel-based morphometry, and regressed against the total CAPS score and trauma load. Images were subsequently analyzed by diagnosis of PTSD vs. non-PTSD. CAPS scores were inversely correlated with volumes of the subgenual cingulate (sgACC), caudate, hypothalamus, insula, and left middle temporal gyrus (MTG). Group contrast revealed smaller sgACC, caudate, hypothalamus, left insula, left MTG, and right MFG in the PTSD group. PTSS are associated with abnormalities in limbic structures that may underlie the pathophysiology of PTSD. These abnormalities exist on a continuum with PTSS, beyond a diagnosis of PTSD.

Habenula volume in post-traumatic stress disorder measured with high-resolution MRI

BackgroundThe habenula plays an important role in regulating behavioral responses to stress and shows increased cerebral blood flow and decreased gray matter volume in patients with mood disorders. Here, we compare the volume of the habenula in unmedicated patients with post-traumatic stress disorder (PTSD) and healthy controls (HC) using MRI.FindingsHigh-resolution images (resolution of approximately 0.4 mm3) were acquired using a 3T scanner and a pulse sequence optimized for tissue contrast resolution. The habenula was manually segmented by one rater blind to diagnosis. PTSD and HC participants did not differ significantly in absolute or normalized habenula volume. Post hoc analyses controlling for the effects of comorbid major depressive disorder (MDD) and type and age of trauma exposure were not significant. Further, there was no association between PTSD severity and habenula volume.ConclusionsOur data suggest that PTSD is not associated with robust structural changes in the habenula. The modest size of the PTSD sample may have reduced statistical power thereby accounting for the negative results obtained.

EMDR Treatment for Posttraumatic Stress Disorder, With Focus on Hippocampal Volumes: A Pilot Study

EMDR Treatment for Posttraumatic Stress Disorder, With Focus on Hippocampal Volumes: A Pilot Study

Alcohol use and hippocampal volume deficits in adults with posttraumatic stress disorder: A meta-analysis

Posttraumatic stress disorder (PTSD) is associated with hippocampal volume deficits, but the effects of alcohol use on hippocampal volume in PTSD are unclear. We meta-analytically examined the relationship between alcohol use, PTSD, and hippocampal volume deficits. Studies were initially searched through electronic databases. Twelve studies reporting data for the right hippocampal volume and 11 studies with data for the left hippocampal volume met initial inclusion criteria. In the meta-analysis of the studies in which subjects had no lifetime history of alcoholism, both the left and right hippocampal volumes were smaller in PTSD subjects compared to controls. Meta-regression using a continuous trial-level covariate showed that a lifetime history of alcoholism further moderates left and right hippocampal volume in PTSD. PTSD is associated with hippocampal volume deficits independent of a lifetime history of alcoholism, but alcoholism further contributes to the hippocampal volume deficits associated with PTSD.

Memory and Posttraumatic Stress Disorder

In this issue of the Zeitschrift fur Psychologie / Journal of Psychology we have assembled a number of articles and comments that deal with the relationship of trauma and memory, with an emphasis on the role of memory mechanisms in posttraumatic stress disorder (PTSD). There is uniformity in the assumption that memory is severely altered by traumatic events, but memory deficits may also contribute to the development of stress-related disorders. Although there is agreement that in PTSD memory mechanisms are at the core of the disorder, there is disagreement on the nature of the pathology and to what extent additional factors such as appraisal of the deficit are of importance. As Ehlers (2010) notes, there is clear evidence of a preponderance of emotional memories that are often sensory, fast, tied to very aversive moments of the traumatic experience, experienced as immediate rather than past, and related to non-declarative learning processes such as Pavlovian conditioning and priming. Whereas these memories seem to predominate, generalize (see Lissek & Grillon, 2010), and fail to extinguish (Wessa & Flor, 2007), episodic memories of the trauma and life in general seem to be affected, be it by fragmentation (Brewin, 2007), lack of connectedness (Michael, Ehlers, Halligan, & Clark, 2005), or overgeneralization (Schonfeld, Ehlers, Bollinghaus, & Rief, 2007). Early theories about memory mechanisms in PTSD suggested that the documented reduction of hippocampal volume in PTSD might lead to a dissociation of declarative and non-declarative memories (Elzinga & Bremner, 2002). However, these alterations are not as straightforward as it might seem since it could be shown that recall of trauma-related materials is similar in traumatized persons with and without PTSD (Wessa, Jatzko, & Flor, 2006). Retrieval-induced forgetting is also not significantly different in PTSD versus non-PTSD subjects as shown by Koessler and colleagues (2010). Diener, Flor, and Wessa (2010) demonstrate a specific deficit in encoding but not retrieval of episodic memory that is associated with hyperarousal symptoms. This suggests that a very thorough analysis of memory mechanisms is needed and that categories such as declarative/non-declarative or episodic versus semantic need to be further differentiated and specific aspects of these memory processes – such as elaboration, connectedness, or trauma-relevance – need to be considered. For example, the reduced hippocampal volumes could also lead to reduced context conditioning, which is also a form of emotional associative learning, whereas cue conditioning, which is more amygdala-dependent, seems to be enhanced. We (Lang et al., 2009) and others (Alvarez, Biggs, Chen, Pine, & Grillon, 2008; Marschner, Kalisch, Vervliet, Vansteenwegen, & Buchel, 2008) have shown that the hippocampus is involved in context conditioning in human beings and we have preliminary data that indicate impaired context conditioning in persons with small hippocampal volumes (Pohlack, Liebscher, Ridder, Lipinski, & Flor, 2009). A detailed examination of contextual memory in PTSD seems therefore warranted. Context is also important for extinction learning where the organism has to learn to associate the conditioned stimuli with a certain context, no longer with a danger. Bouton and colleagues (2006) and others have emphasized the important role of context for extinction. Disordered context conditioning might therefore not only contribute to the feeling of ‘‘nowness’’ that characterizes the intrusions of PTSD patients and to the inability to feel safe (since safe and dangerous contexts cannot be properly differentiated) but may also impair the extinction of the cue-conditioned fear response since the extinction context has not been associated to the cues. This reasoning is in line with the proposal by Schauer and Elbert (2010), who argue that it is important to consider the peritraumatic defense processes that are activated and that subgroups of patients can be identified that are at different positions in the defense cascade. They specifically emphasize that memory processes are substantially different if persons are putting on a peritraumatic sympathetic activation versus those who went down the entire defense cascade where a parasympathetic dominance and dissociation prevail. This depends on the type of trauma and possibilities of the organism for optimal response. Extinction learning is especially hampered by dissociative

Antidepressants, age, and neuroprogenitors

New neurons are generated in the granule cell layer of the dentate gyrus (DG) of the hippocampus in adult humans (Eriksson et al, 1998). Our knowledge of adult neurogenesis in humans is quite limited and it could differ from adult neurogenesis in lower mammals. In rodents, neurogenesis is necessary for learning, and some antidepressant effects are lost in the absence of adult neurogenesis, which increases with environmental enrichment and exercise (Olson et al, 2006), as well as with antidepressant treatment (Couillard-Despres et al, 2009). We reported (Boldrini et al, 2009) that selective serotonin reuptake inhibitors and tricyclic antidepressants increase dividing and neural progenitor cells (NPCs) in the DG of depressed subjects (MDD), compared with untreated MDD patients or controls. In humans, antidepressants increase the number of mitotic cells of all phenotypes in the DG, regardless of age. On the other hand, replication of NPCs, as in lower mammals, decreases with age (Couillard-Despres et al, 2009). This might explain why there is a poor antidepressant response in the elderly. The functional relevance of the enhancement of neurogenesis by antidepressants needs to be ascertained by determining whether increased cell proliferation is associated with improvement of symptoms in MDD. In our study (Boldrini et al, 2009), a significant proportion of subjects died by suicide, which would argue against the benefits of antidepressant-induced cell proliferation, as opposed to the potential benefits of cell maturation, survival, and integration into functional neural networks, which should have a greater role in the potential beneficial impact of adult neurogenesis. Exposure to enriched environments, learning, and neurotrophins improve the survival and differentiation of newborn cells. Factors regulating cell survival and integration should be considered when examining the role of adult neurogenesis for antidepressant efficacy. Another open question is the role of neurogenesis in the pathogenesis of MDD. Adult neurogenesis decreases with stress in rodents and is enhanced by environmental enrichment, exercise, and antidepressants. However, blunted cell replication alone does not induce depression-like behavior in mice. Growth factors, which affect neurogenesis, are decreased in MDD. Therefore, impaired hippocampal plasticity may be involved in the pathogenesis of MDD, not merely because of impaired cell replication but also because of impaired cell connectivity and functional integration into brain circuits that regulate emotional responses to the environment. In our study, the antidepressant-induced increase in NPCs and dividing cells was associated with a larger volume of DG. Antidepressant treatment is known to increase hippocampal volume in posttraumatic stress disorder (Bossini et al, 2007), but no similar data are available in depression, although patients with MDD have a smaller hippocampus. The volume increase could be related to a restoration of cell number or neuropil, as antidepressants reverse dendritic shrinkage and improve cell survival, activating the antiapoptotic protein Bcl-2 and brain-derived neurotrophic factor expression in mammals. Future studies must determine whether antidepressant response is linked to increased neurogenesis, but assessing adult neurogenesis in vivo is challenging. In a recent study, magnetic resonance spectroscopy was proposed as a possible method, but the specificity of the molecule used to identify NPCs was questioned and the results have not been replicated. Positron emission tomography has the limitation of low resolution and the unknown consequences of radiolabeling newborn cells. Cerebral blood volume, which correlates with angiogenesis, may prove to be a viable method for detecting neurogenesis in vivo (Pereira et al, 2007). Linking neurogenesis to improvement in depression symptomatology would justify seeking new treatments that increase not only neurogenesis but also plasticity, cell survival, and integration into functional networks.

Duration of posttraumatic stress disorder predicts hippocampal grey matter loss

To examine the impact of environmental stress on grey matter volume in posttraumatic stress disorder (PTSD), we investigated the relationship between duration of PTSD and grey matter volume of hippocampus and anterior cingulate cortex. Twenty-one participants with PTSD and 17 trauma-exposed controls, matched for age and sex and with no history of substance dependence, underwent a T1-weighted structural MRI scan and voxel-based morphometry was employed. After controlling for age, depression and whole-brain volume, analysis of covariance revealed significant reductions in hippocampus and rostral anterior cingulate cortex in PTSD, and there was a significant negative correlation between right hippocampal volume and PTSD duration. This pattern suggests that prolonged PTSD may have cumulative adverse effects on hippocampal volume, highlighting the potential role of genetic-environmental interactions.

Increased Left Subgenual Prefrontal Cortex and Right Infralimbic Cortex Volumes in Post-Traumatic Stress Disorder

Increased Left Subgenual Prefrontal Cortex and Right Infralimbic Cortex Volumes in Post-Traumatic Stress Disorder

Amygdala Volume in Adults with Posttraumatic Stress Disorder: A Meta-Analysis

Posttraumatic stress disorder (PTSD) may be associated with structural abnormalities in the amygdala. To better characterize amygdala volume in PTSD, the authors conducted a meta-analysis comparing amygdala volumes in PTSD patients and comparison subjects. Using electronic databases, the authors found nine studies comparing amygdala volumes in adult subjects with PTSD with amygdala volumes in comparison subjects (participants unexposed to trauma and participants exposed to trauma but without PTSD). Results showed no significant differences in amygdala volumes between the groups. Within each group, the right amygdala was significantly larger than the left, indicating an asymmetrically lateralized amygdala volume that is preserved in trauma exposure and in PTSD.

Hippocampal and Amygdalar Volumes in Breast Cancer Survivors with Posttraumatic Stress Disorder

Hippocampal and Amygdalar Volumes in Breast Cancer Survivors with Posttraumatic Stress Disorder