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1.  Habenula Volume in Bipolar Disorder and Major Depressive Disorder: A High Resolution MRI Study 
Biological psychiatry  2010;69(4):336-343.
Background
Increased activity of the habenula has been implicated in the etiology of major depressive disorder (MDD), in which reductions in habenula volume are present at postmortem. We conducted the first MRI analysis of habenula volume in MDD and bipolar disorder (BD).
Methods
High-resolution images (resolution≈0.4mm3) 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. Seventy-four healthy controls (HC) were compared to both medicated (lithium/divalproex, n=15) and unmedicated, depressed BD (n=22) patients, unmedicated, depressed MDD patients (n=28), and unmedicated MDD patients in remission (RD, n=32).
Results
The unmedicated BD patients displayed significantly smaller absolute (p<0.01) and normalized (p<0.05) habenula volumes than the HC subjects. In post hoc assessments analyzing males and females separately, the currently-depressed females with MDD had smaller absolute (p<0.05) habenula volumes than the healthy control females. None of the other psychiatric groups differed significantly from the HC group.
Conclusions
We provide further evidence for the involvement of the habenula in affective illness, but suggest that a reduction in volume may be more pronounced in unmedicated, depressed BD subjects and female, currently depressed MDD subjects. The habenula plays major roles in the long-term modification of monoamine transmission and behavioral responses to stress, and in the suppression of dopamine cell activity following the absence of an expected reward. A reduction in habenula volume may thus have functional consequences which contribute to the risk for developing affective disease.
doi:10.1016/j.biopsych.2010.09.027
PMCID: PMC3030670  PMID: 21094939
major depressive disorder; bipolar disorder; habenula; magnetic resonance imaging; high resolution; lithium
2.  Different Regional Gray Matter Loss in Recent Onset PTSD and Non PTSD after a Single Prolonged Trauma Exposure 
PLoS ONE  2012;7(11):e48298.
Objective
Gray matter loss in the limbic structures was found in recent onset post traumatic stress disorder (PTSD) patients. In the present study, we measured regional gray matter volume in trauma survivors to verify the hypothesis that stress may cause different regional gray matter loss in trauma survivors with and without recent onset PTSD.
Method
High resolution T1-weighted magnetic resonance imaging (MRI) were obtained from coal mine flood disaster survivors with (n = 10) and without (n = 10) recent onset PTSD and 20 no trauma exposed normal controls. The voxel-based morphometry (VBM) method was used to measure the regional gray matter volume in three groups, the correlations of PTSD symptom severities with the gray matter volume in trauma survivors were also analyzed by multiple regression.
Results
Compared with normal controls, recent onset PTSD patients had smaller gray matter volume in left dorsal anterior cingulate cortex (ACC), and non PTSD subjects had smaller gray matter volume in the right pulvinar and left pallidum. The gray matter volume of the trauma survivors correlated negatively with CAPS scores in the right frontal lobe, left anterior and middle cingulate cortex, bilateral cuneus cortex, right middle occipital lobe, while in the recent onset PTSD, the gray matter volume correlated negatively with CAPS scores in bilateral superior medial frontal lobe and right ACC.
Conclusion
The present study identified gray matter loss in different regions in recent onset PTSD and non PTSD after a single prolonged trauma exposure. The gray matter volume of left dorsal ACC associated with the development of PTSD, while the gray matter volume of right pulvinar and left pallidum associated with the response to the severe stress. The atrophy of the frontal and limbic cortices predicts the symptom severities of the PTSD.
doi:10.1371/journal.pone.0048298
PMCID: PMC3498281  PMID: 23155380
3.  Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans 
Psychiatry research  2012;203(2-3):139-145.
Prior studies have examined differences in brain volume between 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 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 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.
doi:10.1016/j.pscychresns.2012.02.005
PMCID: PMC3466380  PMID: 23021615
neuroimaging; anxiety; circuitry; trauma; PTSD
4.  Mapping of the internal structure of human habenula with ex vivo MRI at 7T 
The habenula is a small but important nucleus located next to the third ventricle in front of the pineal body. It helps to control the human reward system and is considered to play a key role in emotion, showing increased activation in major depressive disorders. Its dysfunction may underlie several neurological and psychiatric disorders. It is now possible to visualize the habenula and its anatomical subdivisions—medial habenula (MHB) and lateral habenula (LHB)—using MR techniques. The aim of this study was to further differentiate substructures within human lateral habenula (LHB) using ex vivo ultra-high field MR structural imaging, distinguishing between a medial part (m-LHB) and a lateral part (l-LHB). High resolution T1w images with 0.3-mm isotropic resolution and T2*w images with 60-micrometer isotropic resolution were acquired on a 7T MR scanner and quantitative maps of T1 and T2* were calculated. Cluster analysis of image intensity was performed using the Fuzzy and Noise Tolerant Adaptive Segmentation Method (FANTASM) tool. Ultra-high resolution structural MRI of ex vivo brain tissue at 7T provided sufficient SNR and contrast to discriminate the medial and lateral habenular nuclei. Heterogeneity was observed in the lateral habenula (LHB) nuclei, with clear distinctions between lateral and medial parts (m-LHB, l-LHB) and with the neighboring medial habenula (MHB). Clustering analysis based on the T1 and T2* maps strongly showed 4–6 clusters as subcomponents of lateral and medial habenula.
doi:10.3389/fnhum.2013.00878
PMCID: PMC3870283  PMID: 24391571
human habenula; habenular nuclei; lateral habenula; medial habenula; ex vivo; MRI; 7T
5.  Evidence for Acquired Pregenual Anterior Cingulate Gray Matter Loss from A Twin Study of Combat-Related Post-Traumatic Stress Disorder 
Biological psychiatry  2007;63(6):550-556.
Background
Controversy exists over the nature and origin of reduced regional brain volumes in post-traumatic stress disorder (PTSD). At issue is whether these reductions represent pre-existing vulnerability factors for developing PTSD upon traumatic exposure or acquired PTSD signs due to the traumatic stress that caused the PTSD and/or the chronic stress of having PTSD. We employed a case-control design in monozygotic twin pairs discordant for combat exposure to address the pre-existing vs. acquired origin of brain morphometric abnormalities in this disorder.
Method
We used voxel-based morphometry to search for gray matter density reductions in magnetic resonance imaging (MRI) data obtained in a previous study of combat-exposed Vietnam veteran twins with (n=18) vs. without (n=23) PTSD and their “high-risk” vs. “low-risk” (respectively), identical, combat-unexposed co-twins.
Results
Compared to the combat-exposed twins without PTSD, the combat-exposed twins with PTSD showed significant gray matter density reductions in four predicted brain regions: right hippocampus, pregenual anterior cingulate cortex (ACC), and left and right insulae. There was a significant PTSD Diagnosis × combat Exposure interaction in pregenual ACC, in which combat-exposed PTSD twins had lower gray matter density than their own combat-unexposed co-twins as well as than the combat-exposed twins without PTSD and their co-twins.
Conclusion
The results point to gray matter volume diminutions in limbic and paralimbic structures in PTSD. The pattern of results obtained for pregenual ACC suggests that gray matter reduction in this region represents an acquired sign of PTSD that is consistent with stress-induced loss.
doi:10.1016/j.biopsych.2007.06.022
PMCID: PMC2752671  PMID: 17825801
6.  Defining the habenula in human neuroimaging studies 
Neuroimage  2013;64(100):722-727.
Recently there has been renewed interest in the habenula; a pair of small, highly evolutionarily conserved epithalamic nuclei adjacent to the medial dorsal (MD) nucleus of the thalamus. The habenula has been implicated in a range of behaviours including sleep, stress and pain, and studies in non-human primates have suggested a potentially important role in reinforcement processing, putatively via its effects on monoaminergic neurotransmission. Over the last decade, an increasing number of neuroimaging studies have reported functional responses in the human habenula using functional magnetic resonance imaging (fMRI). However, standard fMRI analysis approaches face several challenges in isolating signal from this structure because of its relatively small size, around 30 mm3 in volume. In this paper we offer a set of guidelines for locating and manually tracing the habenula in humans using high-resolution T1-weighted structural images. We also offer recommendations for appropriate pre-processing and analysis of high-resolution functional magnetic resonance imaging (fMRI) data such that signal from the habenula can be accurately resolved from that in surrounding structures.
doi:10.1016/j.neuroimage.2012.08.076
PMCID: PMC3650642  PMID: 22986224
Habenula; High-resolution MRI; Segmentation; T2-weighted; Pre-processing; Analysis
7.  Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion 
Brain research  2006;1073-1074:229-239.
The habenula complex modulates the a ctivity of dopamine and serotonin systems in the brain. An important question remains whether there is a link between habenula dysfunction and monoamine-related disorders, such as schizophrenia. In this study, we describe an interaction between habenula lesions and stress that produces long-lasting effects on behavior. Mice received control lesions or bilateral electrolytic lesions of the habenula and were tested for fear-potentiated startle and freezing measures of conditioned fear. They w ere also tested for prepulse inhibition (PPI) and locomotor activity in the presence or absence of a dopaminergic agonist (apomorphine) or an atypical antipsychotic with mixed dopamine/serotonin antagonist properties (clozapine). There were no detectable effects of habenula lesions on fear conditioning and no effects on PPI in the absence o f stress. However, following conditioned fear stress, habenula-lesioned animals showed decreased PPI which normalized with clozapine. Lesioned animals also showed diminished activity at baseline, with hyperlocomotion following apomorphine. These data support the hypothesis that the habenula may be normally involved in stress-dependent regulation of monoamine systems.
doi:10.1016/j.brainres.2005.12.053
PMCID: PMC2561201  PMID: 16442084
PPI; Serotonin; Dopamine; Startle; Clozapine; Schizophrenia
8.  Cortical Thinning in Patients with Recent Onset Post-Traumatic Stress Disorder after a Single Prolonged Trauma Exposure 
PLoS ONE  2012;7(6):e39025.
Most of magnetic resonance imaging (MRI) studies about post-traumatic stress disorder (PTSD) focused primarily on measuring of small brain structure volume or regional brain volume changes. There were rare reports investigating cortical thickness alterations in recent onset PTSD. Recent advances in computational analysis made it possible to measure cortical thickness in a fully automatic way, along with voxel-based morphometry (VBM) that enables an exploration of global structural changes throughout the brain by applying statistical parametric mapping (SPM) to high-resolution MRI. In this paper, Laplacian method was utilized to estimate cortical thickness after automatic segmentation of gray matter from MR images under SPM. Then thickness maps were analyzed by SPM8. Comparison between 10 survivors from a mining disaster with recent onset PTSD and 10 survivors without PTSD from the same trauma indicates cortical thinning in the left parietal lobe, right inferior frontal gyrus, and right parahippocampal gyrus. The regional cortical thickness of the right inferior frontal gyrus showed a significant negative correlation with the CAPS score in the patients with PTSD. Our study suggests that shape-related cortical thickness analysis may be more sensitive than volumetric analysis to subtle alteration at early stage of PTSD.
doi:10.1371/journal.pone.0039025
PMCID: PMC3374792  PMID: 22720021
9.  Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans 
Human brain mapping  2012;34(11):10.1002/hbm.22117.
Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n=30) with comorbid PTSD and depression and non-TBI participants from primary (n=42) and confirmatory (n=28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (p < .05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with “feeling dazed or confused,” but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events.
doi:10.1002/hbm.22117
PMCID: PMC3740035  PMID: 22706988
mild traumatic brain injury; high angular resolution diffusion imaging; white matter; crossing fibers; posttraumatic stress disorder
10.  Insular cortex involvement in declarative memory deficits in patients with post-traumatic stress disorder 
BMC Psychiatry  2009;9:39.
Background
Neuroimaging studies have proved that hippocampus relate to the deficient of memory in patients with post-traumatic stress disorder (PTSD). Many studies in healthy subjects also shown that insular cortex (IC) be involved in the declarative memory. This study was designed to investigate whether insular cortex is involved in declarative memory deficits in patients with PTSD.
Methods
Twelve subjects with PTSD and 12 subjects without PTSD victims underwent functional magnetic resonance imaging and magnetic resonance imaging. All subjects performed encoding and retrieval memory tasks during the fMRI session. Voxel-based morphometry method was used to analyze gray-matter volume, and the Statistical Parametric Mapping (SPM2) was used to analyze activated brain areas when performing tasks.
Results
Grey matter volume was significantly reduced bilaterally in the insular cortex of PTSD subjects than non-PTSD. PTSD group also had lower level of activation in insular cortex when performing word encoding and retrieval tasks than non-PTSD group.
Conclusion
The study provides evidence on structural and function abnormalities of the insular cortex in patients with PTSD. Reduced grey-matter volume in insular cortex may be associated with declarative memory deficits in patients with PTSD.
doi:10.1186/1471-244X-9-39
PMCID: PMC2704184  PMID: 19538748
11.  Reduced Posterior Hippocampal Volume in Posttraumatic Stress Disorder 
The Journal of clinical psychiatry  2008;69(7):1087-1091.
Objective
Hippocampal volume is reduced in posttraumatic stress disorder (PTSD). In the present study, we sought to determine whether volume loss is homogenously distributed or confined to certain part of the structure.
Method
Twenty-two adult outpatients with PTSD (11 after prolonged prepubertal trauma and 11 after single adult trauma) and 22 matched healthy subjects were scanned at the National Institute of Mental Health using high-resolution 3T magnetic resonance imaging between September 2003 and August 2004. PTSD diagnosis was conferred using the Structured Clinical Interview for DSM-IV. Volumes of whole, anterior, and posterior hippocampus and subiculum were compared between groups.
Results
Total hippocampal volume was lower in patients with PTSD (p = .2), with a significant diagnosis by hippocampal-subregion interaction (p = .2). Post hoc analysis revealed significantly smaller posterior hippocampi in PTSD (p = .006), with no difference in the volumes of anterior hippocampus or subiculum. No volume differences were found between PTSD participants with prolonged childhood abuse compared to single adult trauma exposure.
Conclusions
The posterior hippocampus has been associated with storage, processing, and retrieval of spatiotemporal memories, central to the protective function of fear conditioning. Volume deficit in the posterior hippocampus may indicate malfunction in this faculty, leading to the exaggerated conditioned fear response observed in PTSD.
PMCID: PMC2684983  PMID: 18572983
12.  Exposure to Parental Verbal Abuse is Associated with Increased Gray Matter Volume in Superior Temporal Gyrus 
NeuroImage  2010;54S1:S280-S286.
Objective
Exposure to parental verbal aggression (PVA) during childhood increases risk for the development of psychopathology, particularly mood and anxiety disorders. Other forms of childhood abuse have been found to be associated with alterations in brain structure. The aim of this study was to ascertain whether exposure to PVA was associated with discernible effects on brain morphology.
Methods
Optimized voxel based morphometry was performed on 21 unmedicated, right-handed subjects (18–25 years) with histories of PVA and 19 psychiatrically healthy controls of comparable age and gender. Group differences in gray matter volume (GMV) – covaried by age, gender, parental education, financial stress, and total GMV – were assessed using high-resolution, T1-weighted, volumetric MRI data sets (Siemens 3T trio scanner).
Results
GMV was increased by 14.1% in the left superior temporal gyrus (STG, BA 22) (P = 0.004, corrected cluster level). GMV in this cluster was associated most strongly with levels of maternal (β = 0.544, P < 0.0001) and paternal (β = 0.300, P < 0.02) verbal aggression and inversely associated with parental education (β = −0.577, P < 0.0001).
Conclusion
Previous studies have demonstrated an increase in STG GMV in children with abuse histories, and found a reduction in fractional anisotropy in the arcuate fasciculus connecting Wernicke’s and frontal areas in young adults exposed to PVA. These findings and the present results suggest that the development of auditory association cortex involved in language processing may be affected by exposure to early stress and/or emotionally-abusive language.
doi:10.1016/j.neuroimage.2010.05.027
PMCID: PMC2950228  PMID: 20483374
13.  Hippocampus and amygdala volumes in patients with borderline personality disorder with or without posttraumatic stress disorder 
Background
Several studies have investigated volumetric brain changes in patients with posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD). Both groups exhibit volume reductions of the hippocampus and amygdala. Our aim was to investigate the influence of comorbid PTSD on hippocampus and amygdala volumes in patients with BPD.
Methods
We compared 2 groups of unmedicated female patients with BPD (10 with and 15 without comorbid PTSD) and 25 healthy female controls. We used T1- and T2-weighted magnetic resonance images for manual tracing and 3-dimensional reconstruction of the hippocampus and amygdala.
Results
Hippocampus volumes of patients with BPD and PTSD were smaller than those of healthy controls. However, there was no significant difference between patients with BPD but without PTSD and controls. Impulsiveness was positively correlated with hippocampus volumes in patients with BPD.
Limitations
Our study did not allow for disentangling the effects of PTSD and traumatization. Another limitation was the relatively small sample size.
Conclusion
Our findings highlight the importance of classifying subgroups of patients with BPD. Comorbid PTSD may be related to volumetric alterations in brain regions that are of central importance to our understanding of borderline psychopathology.
PMCID: PMC2702446  PMID: 19568480
14.  The role of major depression in neurocognitive functioning in patients with posttraumatic stress disorder 
European Journal of Psychotraumatology  2013;4:10.3402/ejpt.v4i0.19979.
Background
Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) frequently co-occur after traumatic experiences and share neurocognitive disturbances in verbal memory and executive functioning. However, few attempts have been made to systematically assess the role of a comorbid MDD diagnosis in neuropsychological studies in PTSD.
Objective
The purpose of the current study is to investigate neurocognitive deficits in PTSD patients with and without MDD. We hypothesized that PTSD patients with comorbid MDD (PTSD+MDD) would have significantly lower performance on measures of verbal memory and executive functioning than PTSD patients without MDD (PTSD–MDD).
Method
Participants included in this study were 140 treatment-seeking outpatients who had a diagnosis of PTSD after various single traumatic events and participated in a randomized controlled trial comparing different treatment types. Baseline neuropsychological data were compared between patients with PTSD+MDD (n=84) and patients with PTSD–MDD (n=56).
Results
The PTSD+MDD patients had more severe verbal memory deficits in learning and retrieving words than patients with PTSD alone. There were no differences between the groups in recall of a coherent paragraph, recognition, shifting of attention, and cognitive interference.
Conclusions
The results of this study suggest that a more impaired neurocognitive profile may be associated with the presence of comorbid MDD, with medium-sized group differences for verbal memory but not for executive functioning. From a clinical standpoint, being aware that certain verbal memory functions are more restricted in patients with comorbid PTSD and MDD may be relevant for treatment outcome of trauma-focused psychotherapy.
doi:10.3402/ejpt.v4i0.19979
PMCID: PMC3644057  PMID: 23671761
neuropsychology; cognitive functioning; PTSD; major depressive disorder; comorbidity
15.  White Matter Microstructure Alterations: A Study of Alcoholics with and without Post-Traumatic Stress Disorder 
PLoS ONE  2013;8(11):e80952.
Many brain imaging studies have demonstrated reductions in gray and white matter volumes in alcoholism, with fewer investigators using diffusion tensor imaging (DTI) to examine the integrity of white matter pathways. Among various medical conditions, alcoholism and post-traumatic stress disorder (PTSD) are two comorbid diseases that have similar degenerative effects on the white matter integrity. Therefore, understanding and differentiating these effects would be very important in characterizing alcoholism and PTSD. Alcoholics are known to have neurocognitive deficits in decision-making, particularly in decisions related to emotionally-motivated behavior, while individuals with PTSD have deficits in emotional regulation and enhanced fear response. It is widely believed that these types of abnormalities in both alcoholism and PTSD are related to fronto-limbic dysfunction. In addition, previous studies have shown cortico-limbic fiber degradation through fiber tracking in alcoholism. DTI was used to measure white matter fractional anisotropy (FA), which provides information about tissue microstructure, possibly indicating white matter integrity. We quantitatively investigated the microstructure of white matter through whole brain DTI analysis in healthy volunteers (HV) and alcohol dependent subjects without PTSD (ALC) and with PTSD (ALC+PTSD). These data show significant differences in FA between alcoholics and non-alcoholic HVs, with no significant differences in FA between ALC and ALC+PTSD in any white matter structure. We performed a post-hoc region of interest analysis that allowed us to incorporate multiple covariates into the analysis and found similar results. HV had higher FA in several areas implicated in the reward circuit, emotion, and executive functioning, suggesting that there may be microstructural abnormalities in white matter pathways that contribute to neurocognitive and executive functioning deficits observed in alcoholics. Furthermore, our data do not reveal any differences between ALC and ALC+PTSD, suggesting that the effect of alcohol on white matter microstructure may be more significant than any effect caused by PTSD.
doi:10.1371/journal.pone.0080952
PMCID: PMC3832443  PMID: 24260518
16.  AMYGDALA VOLUME IN DEPRESSED PATIENTS WITH BIPOLAR DISORDER ASSESSED USING HIGH RESOLUTION 3T MRI: THE IMPACT OF MEDICATION 
NeuroImage  2009;49(4):2966.
MRI-based reports of both abnormally increased and decreased amygdala volume in bipolar disorder (BD) have surfaced in the literature. Two major methodological weaknesses characterizing extant studies are treatment with medication and inaccurate segmentation of the amygdala due to limitations in spatial and tissue contrast resolution. Here, we acquired high-resolution images (voxel size=0.55×0.55×0.60mm) using a GE 3T MRI scanner, and a pulse sequence optimized for tissue contrast resolution. The amygdala was manually segmented by one rater blind to diagnosis, using coronal images. Eighteen unmedicated (mean medication-free period 11±10 months) BD subjects were age and gender matched with 18 healthy controls, and 17 medicated (lithium or divalproex) subjects were matched to 17 different controls. The unmedicated BD patients displayed smaller left and right amygdala volumes than their matched control group (p<0.01). Conversely, the BD subjects undergoing medication treatment showed a trend towards greater amygdala volumes than their matched HC sample (p=0.051). Right and left amygdala volumes were larger (p<0.05) or trended larger, respectively, in the medicated BD sample compared with the unmedicated BD sample. The two control groups did not differ from each other in either left or right amygdala volume. BD patients treated with lithium have displayed increased gray matter volume of the cortex and hippocampus relative to untreated BD subjects in previous studies. Here we extend these results to the amygdala. We raise the possibility that neuroplastic changes in the amygdala associated with BD are moderated by some mood stabilizing medications.
doi:10.1016/j.neuroimage.2009.11.025
PMCID: PMC2818548  PMID: 19931399
17.  Volume of cerebellar vermis in monozygotic twins discordant for combat exposure: Lack of relationship to post-traumatic stress disorder 
Psychiatry research  2006;148(2-3):143-149.
Several functional neuroimaging studies have implicated the cerebellar vermis in post-traumatic stress disorder (PTSD), but there have been no structural neuroimaging studies of this brain structure in PTSD. We utilized magnetic resonance imaging (MRI) with manual tracing to quantify the volumes of three divisions of the mid-sagittal vermis, and their total, within an identical, cotwin control design that employed Vietnam veterans discordant for combat exposure in Vietnam. Each structure’s volume was significantly correlated between twins, indicating a partial familial determination: for anterior superior vermis, r=0.73; for posterior superior vermis, r=0.47; for inferior posterior vermis, r=0.51; and for total vermis, r=0.57. There were no significant differences between the PTSD and non-PTSD veterans for any vermis volume, and no significant main effects or interactions when their non-combat-exposed co-twins were added to the analyses. Thus, the results do not support the structural abnormality of cerebellar vermis in combat-related PTSD.
doi:10.1016/j.pscychresns.2006.01.013
PMCID: PMC2768053  PMID: 17097862
Cerebellum; Vermis; Stress disorders, post-traumatic; Magnetic resonance imaging; Twins; Monozygotic
18.  Alterations in White Matter Microstructure as Vulnerability Factors and Acquired Signs of Traffic Accident-Induced PTSD 
PLoS ONE  2013;8(12):e83473.
It remains unclear whether white matter (WM) changes found in post-traumatic stress disorder (PTSD) patients are stress-induced or precursors for vulnerability. The current study aimed to identify susceptibility factors relating to the development of PTSD and to examine the ability of these factors to predict the course of longitudinal PTSD. Sixty two victims who had experienced traffic accidents underwent diffusion tensor imaging using a 3.0T MRI system within 2 days after their accidents. Of these, 21 were diagnosed with PTSD at 1 or 6 months using the Clinician-Administered Ptsd Scale (CAPS). Then, 11 trauma-exposed victims with PTSD underwent the second MRI scan. Compared with the victims without PTSD, the victims with PTSD showed decreased fractional anisotropy (FA) in WM of the anterior cingulate cortex, ventromedial prefrontal cortex (vmPFC), temporal lobes and midbrain, and increased mean diffusivity (MD) in the vmPFC within 2 days after the traumatic event. Importantly, decreased FA of the vmPFC in the acute phase predicted greater future CAPS scores. In addition, we found decreased FA in the insula in the follow-up scan in the victims with PTSD, which correlated with the decreased FA of the vmPFC in their baseline scan. These results suggested that the WM might have changed within 2 days after the traumatic event in the individuals who would later develop PTSD. Furthermore, decreased FA of the vmPFC could be a possible vulnerability marker predicting future development of PTSD and may provide an outcome prediction of the acquired signs.
doi:10.1371/journal.pone.0083473
PMCID: PMC3862719  PMID: 24349515
19.  Cognitive behavioral therapy for the treatment of post-traumatic stress disorder: a review 
Background:
Post-traumatic stress disorder (PTSD) is a psychiatric sequel to a stressful event or situation of an exceptionally threatening or catastrophic nature. Cognitive behavioral therapy (CBT) has been used in the management of PTSD for many years. This paper reviews the effectiveness of CBT for the treatment of PTSD following various types of trauma, its potential to prevent PTSD, methods used in CBT, and reflects on the mechanisms of action of CBT in PTSD.
Methods:
Electronic databases, including PubMed, were searched for articles on CBT and PTSD. Manual searches were conducted for cross-references in the relevant journal sites.
Results:
The current literature reveals robust evidence that CBT is a safe and effective intervention for both acute and chronic PTSD following a range of traumatic experiences in adults, children, and adolescents. However, nonresponse to CBT by PTSD can be as high as 50%, contributed to by various factors, including comorbidity and the nature of the study population. CBT has been validated and used across many cultures, and has been used successfully by community therapists following brief training in individual and group settings. There has been effective use of Internet-based CBT in PTSD. CBT has been found to have a preventive role in some studies, but evidence for definitive recommendations is inadequate. The effect of CBT has been mediated mostly by the change in maladaptive cognitive distortions associated with PTSD. Many studies also report physiological, functional neuroimaging, and electroencephalographic changes correlating with response to CBT.
Conclusion:
There is scope for further research on implementation of CBT following major disasters, its preventive potential following various traumas, and the neuropsychological mechanisms of action.
doi:10.2147/NDT.S10389
PMCID: PMC3083990  PMID: 21552319
post-traumatic stress disorder; cognitive behavioral therapy; prevention; treatment; mechanisms of action; trauma
20.  Relations among Posttraumatic Stress Disorder, Comorbid Major Depression, and HPA Function: A Systematic Review and Meta-Analysis 
Clinical Psychology Review  2012;32(4):301-315.
Exposure to traumatic stress is associated with increased risk for posttraumatic stress disorder (PTSD) and alterations of hypothalamic-pituitary-adrenocortical (HPA) function. Research linking traumatic stress with HPA function in PTSD has been inconsistent, however, in part due to (a) the inclusion of trauma-exposed individuals without PTSD (TE) in control groups and (b) a failure to consider comorbid major depressive disorder (MDD) and moderating variables. This meta-analysis of 47 studies (123 effect sizes, N=6,008 individuals) revealed that daily cortisol output was lower for PTSD (d=−.36, SE=.15, p=.008) and PTSD+MDD (d=−.65, SE=.25, p=.008) groups relative to no trauma controls (NTC); TE and NTC groups did not differ significantly from each other. Afternoon/evening cortisol was lower in TE (d=−.25, SE=.09, p=.007) and PTSD (d=−.27, SE=.12, p=.021) groups and higher in PTSD+MDD groups (d=.49, SE=.24, p=.041) relative to NTC. Post-DST cortisol levels were lower in PTSD (d=−.40, SE=.12, p<.001), PTSD+MDD (d=−.65, SE=.14, p<.001), and TE groups (d=−.53, SE=.14, p<.001) relative to NTC. HPA effect sizes were moderated by age, sex, time since index event, and developmental timing of trauma exposure. These findings suggest that enhanced HPA feedback function may be a marker of trauma-exposure rather than a specific mechanism of vulnerability for PTSD, whereas lower daily cortisol output may be associated with PTSD in particular.
doi:10.1016/j.cpr.2012.02.002
PMCID: PMC3340453  PMID: 22459791
PTSD; Trauma; Comorbidity; Depression; Cortisol
21.  Single-prolonged stress induces apoptosis in dorsal raphe nucleus in the rat model of posttraumatic stress disorder 
BMC Psychiatry  2012;12:211.
Introduction
Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Meta-analyses of the brainstem showed that midsagittal area of the pons was significantly reduced in patients with PTSD, suggesting a potential apoptosis in dorsal raphe nucleus after single-prolonged stress (SPS). The aim of this study is to investigate whether SPS induces apoptosis in dorsal raphe nucleus in PTSD rats, which may be a possible mechanism of reduced volume of pons and density of gray matter.
Methods
In this study, rats were randomly divided into 1d, 7d and 14d groups after SPS along with the control group. The apoptosis rate was determined using annexin V-FITC/PI double-labeled flow cytometry (FCM). Levels of Cytochrome c (Cyt-C) was examined by Western blotting. Expression of Cyt-C on mitochondria in the dorsal raphe nucleus neuron was determined by enzymohistochemistry under transmission electron microscopy (TEM). The change of thiamine monophosphatase (TMP) levels was assessed by enzymohistochemistry under light microscope and TEM. Morphological changes of the ultrastructure of the dorsal raphe nucleus neuron were determined by TEM.
Results
Apoptotic morphological alterations were observed in dorsal raphe nucleus neuron for all SPS-stimulate groups of rats. The apoptosis rates were significantly increased in dorsal raphe nucleus neuron of SPS rats, along with increased release of cytochrome c from the mitochondria into the cytoplasm, increased expression of Cyt-C and TMP levels in the cytoplasm, which reached to the peak of increase 7 days of SPS.
Conclusions
The results indicate that SPS induced Cyt-C released from mitochondria into cytosol and apoptosis in dorsal raphe nucleus neuron of rats. Increased TMP in cytoplasm facilitated the clearance of apoptotic cells. We propose that this presents one of the mechanisms that lead to reduced volume of pons and gray matter associated with PTSD.
doi:10.1186/1471-244X-12-211
PMCID: PMC3549289  PMID: 23181934
Posttraumatic stress disorder; Dorsal raphe nucleus; Neuron; Apoptosis; Thiamine monophosphatase; Cytochrome c
22.  Distinguishing between Unipolar Depression and Bipolar Depression: Current and Future Clinical and Neuroimaging Perspectives 
Biological psychiatry  2012;73(2):111-118.
Differentiating bipolar disorder (BD) from recurrent unipolar depression (UD) is a major clinical challenge. Main reasons for this include the higher prevalence of depressive relative to hypo/manic symptoms during the course of BD illness and the high prevalence of subthreshold manic symptoms in both BD and UD depression. Identifying objective markers of BD might help improve accuracy in differentiating between BD and UD depression, to ultimately optimize clinical and functional outcome for all depressed individuals. Yet, only eight neuroimaging studies to date directly compared UD and BD depressed individuals. Findings from these studies suggest more widespread abnormalities in white matter connectivity and white matter hyperintensities in BD than UD depression, habenula volume reductions in BD but not UD depression, and differential patterns of functional abnormalities in emotion regulation and attentional control neural circuitry in the two depression types. These findings suggest different pathophysiologic processes, especially in emotion regulation, reward and attentional control neural circuitry in BD versus UD depression. This review thereby serves as a “call to action” to highlight the pressing need for more neuroimaging studies, using larger samples sizes, comparing BD and UD depressed individuals. These future studies should also include dimensional approaches, studies of at risk individuals, and more novel neuroimaging approaches, such as, connectivity analysis and machine learning. Ultimately, these approaches might provide biomarkers to identify individuals at future risk for BD versus UD, and biological targets for more personalized treatment and new treatment developments for BD and UD depression.
doi:10.1016/j.biopsych.2012.06.010
PMCID: PMC3494754  PMID: 22784485
Bipolar Disorder; Major Depressive Disorder; Major Depressive Episode; Magnetic Resonance Imaging; Neuroimaging; Mood Disorder; Functional Imaging; Structural Imaging
23.  White Matter Integrity in Highly Traumatized Adults With and Without Post-Traumatic Stress Disorder 
Neuropsychopharmacology  2012;37(12):2740-2746.
Prior structural imaging studies of post-traumatic stress disorder (PTSD) have observed smaller volumes of the hippocampus and cingulate cortex, yet little is known about the integrity of white matter connections between these structures in PTSD samples. The few published studies using diffusion tensor imaging (DTI) to measure white matter integrity in PTSD have described individuals with focal trauma rather than chronically stressed individuals, which limits generalization of findings to this population; in addition, these studies have lacked traumatized comparison groups without PTSD. The present DTI study examined microstructural integrity of white matter tracts in a sample of highly traumatized African-American women with (n=25) and without (n=26) PTSD using a tract-based spatial statistical approach, with threshold-free cluster enhancement. Our findings indicated that, relative to comparably traumatized controls, decreased integrity (measured by fractional anisotropy) of the posterior cingulum was observed in participants with PTSD (p<0.05). These findings indicate that reduced microarchitectural integrity of the cingulum, a white matter fiber that connects the entorhinal and cingulate cortices, appears to be associated with PTSD symptomatology. The role of this pathway in problems that characterize PTSD, such as inadequate extinction of learned fear, as well as attention and explicit memory functions, are discussed.
doi:10.1038/npp.2012.146
PMCID: PMC3473340  PMID: 22871912
post-traumatic stress disorder; MRI; DTI; TBSS; cingulum; hippocampus; cingulum; DTI; hippocampus; imaging; clinical or preclinical; mood/anxiety/stress disorders; neurophysiology; post-traumatic stress disorder; psychiatry and behavioral sciences; TBSS
24.  High-dose prazosin for the treatment of post-traumatic stress disorder 
Patients with post-traumatic stress disorder (PTSD) are frequently symptomatic despite being on medications currently approved by the US Food and Drug Administration for PTSD. There is evidence to support the notion that prazosin is effective for PTSD nightmares. However, PTSD-related nightmares often do not resolve completely on a low dose of prazosin. The capacity of prazosin to treat daytime symptoms of PTSD which are distressing to patients has not been well studied. Clinicians are reluctant to increase the dose of prazosin due to side effect concerns. To date, the highest reported dose of prazosin used for PTSD is 16 mg daily. We illustrate two case reports using high-dose (up to 30 and 45 mg) prazosin for PTSD with comorbid treatment-resistant mood disorders. We report that high-dose prazosin was safe, tolerable and effective for PTSD in adults. To our knowledge, this is the first case series to highlight the importance of using high-dose prazosin for the treatment of PTSD. In patients with partial response to currently available medications for PTSD, greater utilization of high-dose prazosin for the management of PTSD may lead to better outcomes.
doi:10.1177/2045125313500982
PMCID: PMC3896131  PMID: 24490030
High dose prazosin; post-traumatic stress disorder; comorbid depression
25.  Prevalence of post-traumatic stress disorder among patients with substance use disorder: it is higher than clinicians think it is 
European Journal of Psychotraumatology  2012;3:10.3402/ejpt.v3i0.17734.
Objectives
This study had three objectives. Firstly, the prevalence of post-traumatic stress disorder (PTSD) and trauma exposure was compared between individuals with and without substance use disorder (SUD). Secondly, we compared self-rating of PTSD and clinical judgement. Thirdly, an analysis of the characteristics of SUD/PTSD patients was performed.
Methods
The sample consisted of 423 patients with SUD and 206 healthy controls. All individuals were screened on PTSD using the self-rating inventory for PTSD.
Results
Significantly higher numbers of PTSD and trauma exposure were found in the SUD group (resp. 36.6 and 97.4%). PTSD went frequently unnoticed when relying on clinical judgement alone. Patients with SUD/PTSD were significantly more often unemployed and had a lower educational level. Axis I comorbidity and especially depressive disorders were more common in the SUD/PTSD group.
Conclusion
It is concluded that patients with SUD/PTSD are a substantial and vulnerable subgroup in addiction treatment facilities and that a systematic screening for PTSD is required.
doi:10.3402/ejpt.v3i0.17734
PMCID: PMC3415609  PMID: 22893849
prevalence; trauma exposure; post-traumatic stress disorder; substance use disorder; clinical judgment

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