PTB and hyperarousal predict unique variance in vmPFC activation.!

Distinct medial prefrontal mechanisms associated with perceived threat bias!and hyperarousal symptoms in OEF/OIF veterans!Dan Grupe, Joe Wielgosz, Jack Nitschke, and Richie Davidson University of Wisconsin-Madison, Departments of Psychology and Psychiatry and the Center for Investigating Healthy Minds at the Waisman Center

References!Hayes JP et al. (2012). Biology of Mood and Anxiety Disorders, 2, 9. King DW et al. (1995). Journal of Abnormal Psychology, 104, 184–195. Keane TM et al. (1989). Psychological Assessment, 1, 53-55. Vogt D et al. (2011). Journal of Abnormal Psychology, 120, 819-831.

Funding support provided by an NSF graduate research fellowship, NIMH Training Grant in Emotion Research, The Dana Foundation, and the UW Institute for Clinical and Translational Research contact: grupe@wisc.edu

uThreat - uSafe Anticipatory Activation N = 50, p < 0.05 (corrected)

Threat anticipation Safe anticipation

Increased PTB is associated with decreased vmPFC-amygdala functional connectivity

What are the neural mechanisms underlying heterogeneity in PTSD symptomatology?

Perceived Threat Bias (PTB) A new construct for PTSD research

x = -6y = -6R

There is a push to move beyond approaches to psychopathology that transcend categorical and symptom-based definitions of disorders. In a study of veterans with a broad range of PTSD symptoms, we investigated the neural correlates of two constructs of high-relevance for combat PTSD: perceived threat while deployed and hyperarousal symptoms. Using an anticipation of unpredictable threat task, we sought to elicit individual differences in brain activation that would map onto these constructs. We examined functional activation and connectivity of the medial prefrontal cortex and amygdala, regions of high relevance for this task that have been implicated in previous research on PTSD (Hayes et al., 2012).

Participants were 50 male Operation Enduring Freedom Operation Iraqi Freedom (OEF/OIF) veterans with a broad spectrum of PTSD symptomatology. On the basis of total Clinician-Administered PTSD Scale (CAPS) scores, veterans were divided into a PTSD-symptoms (PTSS) group (CAPS scores ≥ 20) and a combat-exposed control (CEC) group (CAPS scores < 10). Primary analyses, however, were conducted across all veterans irrespective of group. Previous research has demonstrated that the impact of combat exposure on PTSD symptoms is mediated by individual differences in perceived threat (Vogt et al., 2011). We quantified the relationship between these measures by creating a measure of Perceived Threat Bias (PTB). After z-transforming scores on the Combat Exposure Scale (Keane et al., 1989) and Perceived Threat from the DRRI (King et al., 1995), we subtracted the former from the latter. The resulting PTB reflects, in standard deviation units, over- or under-estimates of perceived threat relative to the amount of combat experienced.

AA The PTSS group had significantly greater perceived threat during deployment relative to the CEC group (t(48) = 3.24, p = 0.002), whereas the groups had comparable self-reported combat exposure (t(48) = 1.22, p = 0.23). Each of these measures was approximately normally distributed across the entire sample. B A plot of combat exposure vs. perceived threat, with the dashed line indicating zero PTB. Individuals

During fMRI scanning, participants viewed blue and yellow squares that were explicitly paired with threat of shock and safety from shock (counter-balanced). We measured anticipatory BOLD activation during the subsequent 4-10 s while a clock with a rotating hand appeared. On predictable threat trials, a red mark on the clock indicated to participants when they could receive a shock. Here, we focus on unpredictable trials, for which no red mark appeared and the shock could occur at any time.

During unpredictable threat anticipation, there was increased activation in the anterior mid-cingulate cortex (aMCC), and deactivation (relative to unpredictable safety) in the ventromedial PFC (vmPFC) and bilateral amygdala.

PTB and hyperarousal are independent predictors of vmPFC activation during unpredictable threat anticipation

B

Cabove this line reported elevated perceived threat relative to the amount of combat experienced and thus have a positive PTB, whereas individuals below the line have a negative PTB. C The CEC group had marginally lower PTB than the PTSS group (t(48) = 1.53, p = 0.13). In the 17 PTSS participants with positive PTB (“PTSS.High”), there was no relationship between CE and PT (r = -0.08, p = 0.75). However, there was a strong relationship between CE and PT in the 16 PTSS participants with negative PTB (“PTSS.Low”; r = 0.87, p < 0.001) and in the CEC group (r = 0.70, p = 0.002).

Positive

PTB

Negati

ve PTB

Amygdala vmPFC

aMCC

PTB and hyperarousal predict anatomically unique variance in vmPFC activation.

Increased PTB was associated with elevated pregenual anterior cingulate (pACC) activation for unpredictable threat anticipation. Increased hyperarousal was associated with elevated medial orbitofrontal cortex (mOFC) activation for unpredictable threat anticipation. The same clusters also appeared for regressions of vmPFC activation on each measure separately (data not shown).

PTB and hyperarousal are not correlated

Multiple regression of functionally defined vmPFC activation on PTB and CAPS hyperarousal symptoms. Together, these variables explained 22.8% of the variance in vmPFC activation. No relationships were seen for the amygdala or aMCC.

Term b SE ß t p

Constant -0.162 0.016 -9.844 <0.001

PTB 0.041 0.014 0.370 2.942 0.005

Hyperarousal 0.004 0.002 0.328 2.608 0.012

MODEL SUMMARY: F(2,47) = 8.24, P < 0.001, Adjusted R2 = 0.228

Overall connectivity between the pACC and R amygdala was significant and positive (p = 0.001).

Increased PTB was correlated with less positive pACC-amygdala connectivity during unpredictable threat anticipation (r = -0.38, p = 0.007)

Using PPI, we assessed task-modulated functional connectivity (uThreat - uSafe) between the pACC and anatomically defined amygdala bilaterally (no effects were identified for the mOFC seed).

Full sample: r(48) = 0.07, p = 0.64 PTSS only: r(31) = -0.23, p = 0.21

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Simultaneous regression:!uThreat - uSafe on!PTB and Hyperarousal!p < 0.05, corrected We present here a new construct for research on combat trauma,

Perceived Threat Bias (PTB), that quantifies biased subjective perceptions of threat relative to the amount of combat experienced. PTB and hyperarousal symptoms predicted unpredictable threat activation in anatomically distinct vmPFC regions. These data suggest that vmPFC abnormalities in PTSD may actually reflect multiple independent mechanisms, and that further exploring the relationship between these constructs and vmPFC activation may shed light on heterogeneity in PTSD.

Amygdala and medial prefrontal involvement in the instructed anticipation of threat and safety