STRUCTURAL AND FUNCTIONAL CONNECTIVITY IN POSTTRAUMATIC STRESS DISORDER: ASSOCIATIONS WITH FKBP5.
ABSTRACT: BACKGROUND:The integrity of connections between the hippocampus and the anterior cingulate cortex (ACC) is critical for adaptive cognitive and emotional processing; these connections may be compromised in posttraumatic stress disorder (PTSD). However, there is a lack of PTSD research that combines structural and functional connectivity data, and no studies have examined whether abnormal ACC-hippocampal connectivity is associated with genetic variability, particularly for polymorphisms of a gene that has been previously associated with PTSD, FKBP5. This was the goal of the present study. METHODS:Fifty-four women with and without PTSD underwent diffusion tensor imaging and resting-state MRI. Probabilistic tractography was used to examine ACC-hippocampal structural connectivity; mean fractional anisotropy (FA) values were extracted from connectivity streamlines, which represent the cingulum bundle. Genotype data were collected for a single nucleotide polymorphism (SNP) of FKBP5, rs1360780. RESULTS:Participants with PTSD demonstrated poorer structural connectivity (lower cingulum FA) compared to traumatized controls (F1, 50 = 6.77, P < .05). An interaction of FKBP5 genotype and diagnostic group was also observed (F1, 37 = 4.52, P = .04), indicating lower cingulum FA in carriers of two risk alleles for this SNP, compared to other diagnostic and genotype groups. Carriers of two FKBP5 risk alleles also demonstrated poorer hippocampus-ACC connectivity at rest (P < .05). When cingulum FA was used a regressor in a brain-wide, seed-based regression analysis, significant associations were found between the hippocampus and dorsal regions of the ACC (P < .05). CONCLUSIONS:Individuals with PTSD demonstrated compromised structural connectivity of the hippocampus-ACC pathway. Altered hippocampus-ACC connectivity may represent a highly salient intermediate neural phenotype for PTSD.
Project description:Alterations in the microarchitecture of the posterior cingulum (PC), a white matter tract proximal to the hippocampus that facilitates communication between the entorhinal and cingulate cortices, have been observed in individuals with psychiatric disorders, such as depression and post-traumatic stress disorder (PTSD). PC decrements may be a heritable source of vulnerability for the development of affective disorders; however, genetic substrates for these white matter abnormalities have not been identified. The FKBP5 gene product modulates glucocorticoid receptor function and has been previously associated with differential hippocampal structure, function, and affect disorder risk. Thus, FKBP5 is an attractive genetic target for investigations of PC integrity. We examined associations between PC integrity, measured through diffusion tensor imaging (DTI) and fractional anisotropy (FA; an index of white matter integrity), and polymorphisms in the FKBP5 SNP rs1360780 in a sample of 82 traumatized female civilians. Findings indicated that, compared with individuals without this allele, individuals who carried two 'risk' alleles for this FKBP5 SNP (T allele; previously associated with mood and anxiety disorder risk) demonstrated significantly lower FA in the left PC, even after statistically controlling for variance associated with age, trauma exposure, and PTSD symptoms. These data suggest that specific allelic variants for an FKBP5 polymorphism are associated with decrements in the left PC microarchitecture. These white matter abnormalities may be a heritable biological marker that indicates increased vulnerability for the development of psychiatric disorders, such as PTSD.
Project description:Post-traumatic stress disorder (PTSD) is a debilitating condition which can develop after exposure to traumatic stressors. Seventy-five adults were recruited from the community, 25 diagnosed with PTSD along with 25 healthy and 25 trauma-exposed age- and gender-matched controls. Participants underwent clinical assessment and magnetic resonance imaging. A previous voxel based morphometry (VBM) study using the same subject cohort identified decreased grey matter (GM) volumes within frontal/subcortical brain regions including the hippocampus, amygdala, and anterior cingulate cortex (ACC). This study examines the microstructural integrity of white matter (WM) tracts connecting the aforementioned regions/structures. Using diffusion tensor imaging, we investigated the integrity of frontal/subcortical WM tracts between all three subject groups. Trauma exposed subjects with and without PTSD diagnosis were identified to have significant disruption in WM integrity as indexed by decreased fractional anisotropy (FA) in the uncinate fasciculus (UF), cingulum cingulate gyrus (CCG), and corpus callosum (CC), when compared with healthy non-trauma-exposed controls. Significant negative correlations were found between total Clinician Administered PTSD scale (CAPS) lifetime clinical subscores and FA values of PTSD subjects in the right UF, CCG, CC body, and right superior longitudinal fasciculus (SLF). An analysis between UF and SLF FA values and VBM determined rostral ACC GM values found a negative correlation in PTSD subjects. Findings suggest that compromised WM integrity in important tracts connecting limbic structures such as the amygdala to frontal regions including the ACC (i.e., the UF and CCG) may contribute to impairments in threat/fear processing associated with PTSD.
Project description:OBJECTIVE:Serotonin-1A receptors (5-HTR1A) is suggested to be involved in the etiology of several psychiatric disorders including panic disorder (PD). A few imaging studies have suggested the alterations of the cingulum bundle in PD. The objective of this study is to examine the structural changes of cingulum related to the 5-HTR1A polymorphism rs6295 in the patients with PD. METHODS:Thirty-two right-handed patients with PD [11 men, 21 women; 40.34±13.17 (mean±SD) age] who met the diagnostic criteria in Structured Clinical Interview for DSM-IV were examined by means of MRI at 3 Tesla. We divided the patients with PD into CC genotype group and non CC genotype group (GG/CG genotype group) of the 5-HTR1A rs6295 polymorphism to compare the cingulum white matter connectivity. RESULTS:Tract-based spatial statistics showed significantly increased fractional anisotropy (FA) values in cingulate gyrus process of left cingulum in 5-HTR1A CC genotype compared to GG/CG genotype in PD. Significant positive correlations were shown between the Albany Panic and Phobia Questionnaire (APPQ) interoceptive fear subscale scores, the Anxiety Sensitivity Inventory-Revised fear of publicly observable anxiety reaction subscale scores and FA values of cingulate gyrus process of left cingulum in 5-HTR1A rs6295 GG/CG genotype group. In CC genotype group, APPQ total, APPQ agoraphobia subscale and APPQ social phobia subscale scores also showed significant positive correlations with FA values of hippocampal process of right cingulum. CONCLUSION:This preliminary study suggests that 5-HTR1A polymorphism may be associated with the cingulum white matter connectivity in PD.
Project description:Posttraumatic stress disorder (PTSD) is an anxiety disorder that is often diagnosed with comorbid depressive disorder. Therefore, neuroimaging studies investigating PTSD typically include both patients with and without comorbid depression. Differences in activity of the anterior cingulate cortex (ACC) and insula have been shown to differentiate PTSD patients with and without major depressive disorder (MDD). Whether or not comorbid MDD affects resting state functional connectivity of PTSD patients has not been investigated to our knowledge. Here, resting state functional connectivity of PTSD patients with (PTSD+MDD; n=27) and without (PTSD-MDD; n=23) comorbid MDD was investigated. The subgenual ACC and insula were investigated as seed regions. Connectivity between the subgenual ACC and perigenual parts of the ACC was increased in PTSD+MDD versus PTSD-MDD, which may reflect the presence of depressive specific symptoms such as rumination. Functional connectivity of the subgenual ACC with the thalamus was reduced, potentially related to more severe deficits in executive functioning in the PTSD+MDD group versus the PTSD-MDD group. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus compared to the PTSD-MDD group. However, this cluster was no longer significantly different when PTSD patients that were using medication were excluded from analyses. Thus, resting state functional connectivity of the subgenual ACC can distinguish PTSD+MDD from PTSD-MDD, and this may therefore be used as a neurobiological marker for comorbid MDD in the presence of PTSD. As PTSD+MDD are more treatment resistant, these findings can also guide treatment development, for example by targeting the subgenual ACC network with treatment.
Project description:Posttraumatic stress disorder (PTSD) is a debilitating disorder that has been associated with brain abnormalities, including white matter alterations. However, little is known about the effect of treatment on these brain alterations. To investigate the course of white matter alterations in PTSD, we used a longitudinal design investigating treatment effects on white matter integrity using diffusion tensor imaging (DTI). Diffusion tensor and magnetization transfer images were obtained pre- and posttreatment from veterans with (n=39) and without PTSD (n=22). After treatment, 16 PTSD patients were remitted, and 23 had persistent PTSD based on PTSD diagnosis. The dorsal and hippocampal cingulum bundle, stria terminalis, and fornix were investigated as regions of interest. Exploratory whole-brain analyses were also performed. Groups were compared with repeated-measures ANOVA for fractional anisotropy (FA), and magnetization transfer ratio. Persistently symptomatic PTSD patients had increasing FA of the dorsal cingulum over time, and at reassessment these FA values were higher than both combat controls and the remitted PTSD group. Group-by-time interactions for FA were found in the hippocampal cingulum, fornix, and stria terminalis, posterior corona radiata, and superior longitudinal fasciculus. Our results indicate that higher FA of the dorsal cingulum bundle may be an acquired feature of persistent PTSD that develops over time. Furthermore, treatment might have differential effects on the hippocampal cingulum, fornix, stria terminalis, posterior corona radiata, and superior longitudinal fasciculus in remitted vs persistent PTSD patients. This study contributes to a better understanding of the neural underpinnings of PTSD treatment outcome.
Project description:The stress-related gene FKBP5 has been related to dysregulated glucocorticoid receptor (GR) signaling, showing increased GR sensitivity in trauma-exposed subjects with post-traumatic stress disorder (PTSD) but not in those without PTSD. However, the neural mechanism underlying the effects of FKBP5 remains poorly understood. Two hundred and thirty-seven Han Chinese adults who had lost their only child were included. Four FKBP5 single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080) were genotyped. All 179 participants were successfully divided into three FKBP5 diplotype subgroups according to two major FKBP5 H1 and H2 yin yang haplotypes. Brain average spectral power was compared using a two-way (PTSD diagnosis and FKBP5 diplotypes) analysis of covariance within four separate frequency bands (slow-5, slow-4, slow-3, and slow-2). Adults with PTSD showed lower spectral power in bilateral parietal lobules in slow-4 and in left inferior frontal gyrus (IFG) in slow-5. There was significant FKBP5 diplotype main effect in anterior cingulate cortex (ACC) in slow-4 (H1/H1 higher than other two subgroups), and in precentral/postcentral gyri and middle cingulate cortex (MCC) in slow-3 (H2/H2 higher than other two subgroups). Also, there was a significant diagnosis × FKBP5 diplotype interaction effect in right parietal lobule in slow-3. These findings suggest that adults with PTSD have lower low-frequency power in executive control network regions. Lower power in ACC and greater power in the motor/sensory areas in FKBP5 high-risk diplotype group suggest a disturbance of emotional processing and hypervigilance/sensitization to threatening stimuli. The interaction effect of diagnosis × FKBP5 in parietal lobule may contribute to PTSD development.
Project description:Purpose of the Study:Prior studies showed posttraumatic stress disorder (PTSD)-related alterations in white matter integrity, but most of these studies have used region-based approaches. We address this limitation by investigating the relationship between PTSD severity and fractional anisotropy (FA) using a tract-based approach. Procedures:Structural and diffusion magnetic resonance imaging were acquired from 67 combat-exposed US Veterans and processed using FSL/FreeSurfer TRActs Constrained by UnderLying Anatomy. Partial correlations were conducted between PTSD severity and FA of the cingulum and uncinate fasciculi covarying for age, sex, and head motion. Results:Only FA of the left cingulum angular bundle (CAB) was positively correlated with PTSD symptom severity (r = 0.433, p = 0.001, df = 57) and remained significant after Bonferroni correction. Conclusions:This finding may imply greater organization of the CAB with increasing PTSD severity. The CAB connects directly to the cingulate cortex and the hippocampal subiculum, critical nodes of the default mode network, as well as being implicated in neurodegeneration pathology, decision-making, and executive functions, which may help explain previously shown alterations in this network in PTSD. Message of the Paper:Further study of white matter tract integrity in PTSD is warranted, particularly to investigate whether the CAB connections with both higher-order cognitive functioning and emotion processing regions contribute to the pathophysiology and comorbidity of PTSD.
Project description:INTRODUCTION: Current pathophysiological theories of schizophrenia highlight the role of altered brain functional and anatomical connectivity. The cognitive division of anterior cingulate cortex (ACC-cd) is a commonly reported abnormal brain region in schizophrenia for its importance in cognitive control process. The aim of this study was to investigate the functional and anatomical connectivity of ACC-cd and its cognitive and clinical manifestation significance in schizophrenia by using the resting-state functional magnetic resonance imaging (fMRI) and the diffusion tensor imaging (DTI). METHODS: Thirty-three medicated schizophrenics and 30 well-matched health controls were recruited. Region-of-interest (ROI)-based resting-state functional connectivity analysis and Tract-Based Spatial Statistics (TBSS) were performed on 30 patients and 30 controls, and 24 patients and 29 controls, respectively. The Pearson correlation was performed between the imaging measures and the Stroop performance and scores of the Positive and Negative Syndrome Scale (PANSS), respectively. RESULTS: Patients with schizophrenia showed significantly abnormal in the functional connectivity and its hemispheric asymmetry of the ACC-cd with multiple brain areas, e.g., decreased positive connectivity with the bilateral putamen and caudate, increased negative connectivity with the left posterior cingulated cortex (PCC), increased asymmetry of connectivity strength with the contralateral inferior frontal gyrus (IFG). The FA of the right anterior cingulum was significantly decreased in patients group (p=0.014). The abnormal functional and structural connectivity of ACC-cd were correlated with Stroop performance and the severity of the symptoms in patients. CONCLUSIONS: Our results suggested that the abnormal connectivity of the ACC-cd might play a role in the cognitive impairment and clinical symptoms in schizophrenia.
Project description:Posttraumatic stress disorder (PTSD) is a heterogeneous disorder with disturbances in hyper-arousal or avoidance behaviors, and intrusive or re-experiencing thoughts. The uncinate fasciculus (UF) and cingulum bundle are white matter pathways implicated in stress and trauma pathophysiology, yet their structural integrity related to PTSD symptom domains is yet to be understood. Forty-four trauma-exposed young adults underwent structural and diffusion-weighted MRI. Stress and trauma exposure indices and severity of PTSD symptoms were collected and used to predict current integrity of the UF and cingulum bundle. Severity of re-experiencing PTSD symptoms was significantly related to increased fractional anisotropy (r=.469 p<.001) and decreased mean diffusivity (r=-.373, p=.013) of the right posterior cingulum bundle. No other findings emerged with respect to stress exposure or of hyper-arousal (p's>0.05) or avoidance (p's>0.2) PTSD symptoms. The posterior cingulum connects medial temporal lobe structures with visual areas in the occipital lobe and has been implicated in visual memory and self-referential thought. Increased structural connectivity along this pathway may therefore explain the emergence of re-experiencing PTSD symptoms. This along with the lack of results with respect to stress exposure suggests structural aberrations in white matter pathways are more strongly linked with the actual experience of stress-related psychological symptoms than just exposure to stress.
Project description:Post-traumatic stress disorder (PTSD) is an anxiety disorder that is associated with structural and functional alterations in several brain areas, including the anterior cingulate cortex (ACC). Here, we examine resting state functional connectivity of ACC subdivisions in PTSD, using a seed-based approach. Resting state magnetic resonance images were obtained from male veterans with (n?=?31) and without (n?=?25) PTSD, and healthy male civilian controls (n?=?25). Veterans with and without PTSD (combat controls) had reduced functional connectivity compared to healthy controls between the caudal ACC and the precentral gyrus, and between the perigenual ACC and the superior medial gyrus and middle temporal gyrus. Combat controls had increased connectivity between the rostral ACC and precentral/middle frontal gyrus compared to PTSD patients and healthy civilian controls. The resting state functional connectivity differences in the perigenual ACC network reported here indicate that veterans differ from healthy controls, potentially due to military training, deployment, and/or trauma exposure. In addition, specific alterations in the combat controls may potentially be related to resilience. These results underline the importance of distinguishing trauma-exposed (combat) controls from healthy civilian controls when studying PTSD.