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.

Keywords: FKBP5; PTSD; anterior cingulate; connectivity; diffusion tensor imaging; genetics; hippocampus; neuroimaging.

Figure 1

Example probabilistic tracts of the cingulum.

Figure 2

Participants with two copies of the (T) risk allele for an FKBP5 polymorphism (rs1360780) and a diagnosis of PTSD demonstrate poorer cingulum connectivity compared to the other genotype and diagnostic groups.

Figure 3

When cingulum FA was used as a regressor in a whole-brain, seed-based analysis, the hippocampus demonstrated significant functional connectivity to dorsal regions of the anterior cingulate, exclusively (p<.05, FWE corrected across the whole brain). Left panel depicts atlas-based ACC mask; right panel depicts regions of ACC activation corresponding with hippocampal activation (unmasked image).