Neurobiological indicators of disinhibition in posttraumatic stress disorder

PTSD is increasingly recognized as involving deficits in impulse control and self-regulation, as evidenced by inclusion of the new “reckless and self-destructive behavior” symptom in DSM-5 (American Psychiatric Association, 2013). It is associated with elevated rates of substance abuse, violent outbursts, impulsive self-injury, and other behaviors marked by impulse control problems (Elbogen et al., 2010; Jacobsen et al., 2001; Miller et al., 2006; Nock and Prinstein, 2005; Wolf et al., 2012). However, research on the neurobiology of impulse control failures and disinhibition in the context of PTSD is relatively sparse, which presents a significant barrier to understanding the mechanisms that initiate and maintain impulsive behavior in this disorder. Inhibition is a multifaceted higher-order cognitive function that is essential for self-control, and it can be parsed into overlapping, yet distinct, inhibitory control processes (Nigg, 2000). Proposals on the taxonomy of inhibition-related processes typically distinguish between response inhibition, which involves control of an automatic or dominant motor response, and interference control or resistance to distractor interference, which involve the ability to resolve conflicting information (e.g., Nigg, 2000; Friedman and Miyake, 2004). In regards to PTSD, impaired inhibitory processes have been identified as both a potential vulnerability for the development of the disorder and implicated in the maintenance of posttraumatic stress reactions over time (Aupperle et al., 2012; Jovanovic and Ressler, 2010; Verwoerd et al., 2009). For example, diminished control of cognitive, emotional, and behavioral reactions to trauma-related stimuli have been linked to reexperiencing symptoms (e.g., failure to suppress intrusive trauma-related memories; Verwoerd et al., 2009) and hyperarousal symptoms (e.g., failure to suppress fear responses in the presence of safety cues; Jovanovic and Ressler, 2010). Thus, inhibitory dysfunction appears to play a central role in the etiology and progression of PTSD. The purpose of this study was to examine the neurobiology of response inhibition in PTSD, because this component of inhibition has been closely tied to problems with impulsivity (Keilp et al., 2005), but has not been as thoroughly characterized in neurobiological studies of PTSD as other types of inhibition (e.g., interference control with the Stroop). A sizeable body of research has focused on identifying areas of the brain that mediate response inhibition and impulsivity. The Go/No-Go (GNG) task is one of the most widely studied measures of response inhibition, as it measures effortful control of a motor response without imposing demands on other high-level cognitive control systems (e.g., distractor suppression, interference control) (Rubia et al., 2001; Schulz et al., 2007). Functional magnetic resonance imaging (fMRI) studies using this task have consistently found task-based activation differences in prefrontal cortex (PFC), particularly right inferior frontal gyrus (IFG) (Aron et al., 2004). According to a recent meta-analysis of 30 neuroimaging studies, activation in response to No-Go stimuli is most consistently seen in a predominately right-lateralized network of brain regions in healthy adults, including bilateral IFG, right dorsolateral PFC, superior temporal gyrus, supplementary motor cortex, anterior cingulate cortex (ACC), and left insula (Criaud and Boulinguez, 2013). Inhibitory control has also been related to IFG activation during emotional processing, with inhibition and emotional processing showing additive activation effects in this region (Brown et al., 2012). These findings converge with prior work implicating IFG in inhibitory control and emotional regulation (Fortier et al., 2014; Ochsner et al., 2004). To our knowledge, only three prior neuroimaging studies have examined response inhibition using GNG tasks in PTSD, and none have examined these processes in relation to structural brain morphology. In a sample of adolescents, PTSD symptoms during a Go/No-Go task were associated with decreased No-Go activation in left middle frontal cortex as well as greater activation in left cuneus, left inferior occipital/temporal gyri, and bilateral medial frontal gyrus/ACC (Carrion et al., 2008). Consistent with these findings, research suggests that adults with PTSD demonstrate relatively reduced No-Go task activation in right ventral and medial PFC, dorsolateral PFC, and temporoparietal junction, and relatively greater activation in postcentral gyrus and cuneus compared to those without PTSD (Jovanovic et al., 2013; Falconer et al., 2008). Thus, studies published to date suggests that PTSD is associated with less activation in frontal brain regions that are typically recruited during response inhibition in healthy controls and greater activation in motor areas. Structural differences associated with response inhibition in PTSD have yet to be examined but are an important next step for several reasons. First, structural variation may partially or completely explain differences in functional activation. For instance, individuals with PTSD may activate the cortex to the same degree as healthy controls but show weaker activation, because loss of cortical thickness dilutes the strength of the activation signal. Second, it is crucial to differentiate between functional and structural differences, as structural differences may be less amenable to treatment and thus may require a different strength, duration, and/or type of intervention. Finally, not all structural differences are reflected in functional activation. Thus, it is necessary to directly examine brain structure in order to form a more comprehensive model of the disinhibition-related neural disturbances that occur in the context of PTSD symptoms. The primary aims of this study were to investigate the cortical substrates of response disinhibition in PTSD and the impact of PTSD symptom severity on disinhibition-related variation in morphology. To better understand the functional significance of variations in morphology, we conducted exploratory resting-state functional connectivity analyses to examine whether regions with altered cortical thickness, in turn, displayed disruptions in interregional communication. This allowed us to gain insight into the impact of morphological variation within the larger context of neural circuitry. Resting-state fMRI was examined (as opposed to task fMRI), because resting-state coupling is thought to represent stable individual differences, similar to the structural morphology that was also examined. To rule-out potential confounds, we examined whether conditions that influence brain structure and frequently co-occur with PTSD symptoms, specifically depression symptoms, alcohol consumption, and mild traumatic brain injury (mTBI), could account for our findings. We recruited a large sample of trauma-exposed Operation Enduring Freedom or Operation Iraqi Freedom (OEF/OIF) service members, presenting with a range of current PTSD symptom severity. Participants completed a GNG task with emotional stimuli and then underwent magnetic resonance imaging. Unlike the task-based fMRI studies reviewed above, this study examined whether disinhibition (measured by GNG commission errors on a task performed outside the scanner) and PTSD symptom severity interacted to predict individual variation in brain structure and connectivity in the resting state (as opposed to functional activation to Go vs. No-Go stimuli). We selected commission errors as our measure of disinhibition, because previous studies have shown that commission errors are elevated in syndromes associated with impulse control problems (e.g., borderline personality disorder, attention deficit hyperactivity disorder (Swann et al., 2002; Moeller et al., 2001) and correlate with trait measures of disinhibition (e.g., impulsive personality traits; Keilp et al., 2005). We used a GNG task with arousing stimuli (emotional words) given that impulse control failures during emotional processing may be particularly relevant to PTSD. We hypothesized that the degree of disinhibition on the emotional GNG task would relate to cortical thickness in brain regions consistently linked to inhibitory control, most notably IFG. Specifically, we predicted that higher levels of disinhibition would be associated with reduced cortical thickness. We also expected that greater PTSD symptoms would predict reduced structural integrity and abnormal functional connectivity in regions associated with disinhibition based on prior functional neuroimaging work examining GNG task activation and PTSD.