Neurocognitive markers of childhood abuse in individuals with PTSD: Findings from the INTRuST Clinical Consortium
Introduction
Posttraumatic stress disorder (PTSD) consists of four symptom clusters (re-experiencing, avoidance, negative cognitions and mood, and dysregulation in arousal (APA, 2013)). PTSD is associated with abnormal functioning and connectivity of limbic and prefrontal brain regions during affective processing (Akiki et al., 2017; Garfinkel and Liberzon, 2009; Lanius et al., 2015; Liberzon and Sripada, 2008). Moreover, reductions in volume and cortical thickness are observed in brain regions including the ventromedial prefrontal cortex (vmPFC), dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC), amygdala, and hippocampus (e.g., Akiki et al., 2017; Karl et al., 2006). Functional and structural integrity differences in these regions may underlie the cognitive and emotional dysregulation observed in PTSD (Garfinkel and Liberzon, 2009).
Presence of early maltreatment is thought to produce heterogeneity among individuals with psychiatric disorders (Teicher and Samson, 2013; Teicher et al., 2016). Childhood maltreatment refers to physical, emotional, or sexual abuse, and may also include neglect – failing to provide for physical, social, or emotional needs (Teicher and Samson, 2013). Childhood maltreatment is widespread, associated with significant socioeconomic costs, and linked to worse physical and affective outcomes (Anda et al., 2006; Chartrand and Bargh, 1999; Dube et al., 2009; Gould et al., 2012; Green et al., 2010; Hart and Rubia, 2012; Pechtel and Pizzagalli, 2011). Within psychiatric diagnoses there are clinically-relevant differences in individuals who have experienced childhood maltreatment, including earlier disorder onset and greater treatment resistance, relative to those who have not (Alvarez et al., 2011; Hovens et al., 2015; Nanni et al., 2012).
Maltreatment experiences are associated with a host of stress-related physiological sequelae, the long-term consequences of which could be reflected in neurobiological characteristics in adulthood (e.g., brain structure or function, Teicher and Samson, 2013). Exposure to early adverse events may alter neurodevelopmental trajectories by catalyzing hormonal and neurotransmitter changes (e.g., glucocorticoids, Heim and Nemeroff, 2001) that likely impact neurogenesis, pruning, and myelination processes involved in gray and white matter organization during development (de Graaf-Peters and Hadders-Algra, 2006; McEwen et al., 2012; Nemeroff, 2016; Teicher et al., 2002). As a result, individuals who experience childhood maltreatment may demonstrate abnormalities in stress-vulnerable brain structures and cognitive functions. Such abnormalities may be partially independent of diagnostic classification, representing a discernible subtype within a given patient population with distinct neurobiological, cognitive, and/or affective characteristics (Teicher et al., 2016).
Data from MRI and neuropsychological studies provide evidence for the lasting effects of childhood maltreatment exposure. Abnormalities in the PFC (e.g., Chaney et al., 2014; Fonzo et al., 2013; Tomoda et al., 2009b; van Harmelen et al., 2010), insula and ACC (Dannlowski et al., 2012), occipital cortex (Tomoda et al., 2009a, 2012), and the amygdala and hippocampus (Dannlowski et al., 2012; Gurvits et al., 1996), as well as network architecture across these brain regions (Ohashi et al., 2017), are documented in individuals with a history of childhood maltreatment. Two recent meta-analyses synthesized voxel-based morphology (VBM) studies on this topic and concluded that childhood maltreatment impacts brain regions including orbitofrontal and temporal regions, inferior frontal cortex, ACC, vmPFC, dlPFC, and postcentral gyrus (Lim et al., 2014; Paquola et al., 2016). Cognitive dysfunction has also been observed following childhood maltreatment - and in some cases linked to neural changes (Pechtel and Pizzagalli, 2011). The majority of evidence for deficits across cognitive domains come from data collected during childhood, temporally close to the onset of trauma (Beers and De Bellis, 2002; Bucker et al., 2012; De Bellis et al., 2009; Nolin and Ethier, 2007). However, impairments in memory, executive functioning, attention and working memory, and global cognitive functioning performance are also observed distally in adults with history of childhood maltreatment (Majer et al., 2010; Navalta et al., 2006; Nikulina and Widom, 2013).
Despite growing evidence for the neural impact of childhood maltreatment, the relative contribution of these experiences to neuroimaging and neuropsychological findings in PTSD remains unclear. Structural brain regions identified as sensitive to childhood maltreatment tend to overlap with brain regions identified in PTSD (e.g., ACC, vmPFC), which may be a consequence of methodological features of existing studies. For example, some prior studies included patients with PTSD secondary to childhood maltreatment but did not include PTSD without maltreatment or maltreatment-only patient control groups (Landre et al., 2010; Thomaes et al., 2010). Also, studies have not routinely examined the possibility that within PTSD, maltreatment is associated with distinct neurocognitive features. One exception to this is a study by Fonzo and colleagues (Fonzo et al., 2013), who reported that severity of childhood maltreatment was correlated with functional and structural abnormalities in brain regions that included the insula, ACC, and precentral gyrus in a sample of women with PTSD secondary to intimate partner violence. To date, studies of cognitive sequelae of PTSD point to deficits in memory, executive functioning, and attention (Aupperle et al., 2012; Golier and Yehuda, 2002; Qureshi et al., 2011; Vasterling et al., 2002) and a recent meta-analysis in children suggested that maltreatment with PTSD was associated with worse performance than maltreatment alone across many cognitive domains, (Malarbi et al., 2017). Taken together, there remains a need to determine if neurobiological and cognitive features observed in extant studies are due to childhood maltreatment, psychiatric symptoms, or to their interaction (Hart and Rubia, 2012; Teicher et al., 2016).
The current study evaluated neurocognitive features in a sample of individuals with PTSD, with and without a history of childhood maltreatment (including abuse or neglect), compared to a non-exposed healthy comparison group. As part of the broader aims of the INjury and TRaUmatic STress Clinical Consortium (INTRuST; W81XWH-08-2-0159), individuals with PTSD with and without a history of mild traumatic brain injury (mTBI) were included, allowing us to also explore if mTBI history impacted the pattern of findings. Groups were compared on whole-brain structural metrics and brain regions of interests (ROIs) identified by prior reviews (Lim et al., 2014; Paquola et al., 2016; Teicher et al., 2016). Volume and cortical thickness were examined separately based on evidence that combining these measures provide distinct information (e.g., developmental trajectories, genetic correlates; Panizzon et al., 2009; Raznahan et al., 2011; Winkler et al., 2010) and greater sensitivity (Hutton et al., 2009). Group differences in neuropsychological functioning, which may be impacted by neurobiological or affective correlates of childhood maltreatment and PTSD (Dickerson et al., 2008), were also examined. It was hypothesized that groups would differ on brain volume, cortical thickness, and neuropsychological test performance such that individuals in the PTSD with childhood maltreatment group would demonstrate the worst neuropsychological and neuroimaging outcomes, followed by individuals with PTSD without childhood maltreatment, followed by healthy comparison participants.
Section snippets
Participants
Participants were 223 individuals from the INTRuST imaging data repository. Individuals completed a written informed consent, questionnaires, neuropsychological assessments, and a magnetic resonance imaging (MRI) scan. Participants were individuals who enrolled in one of the INTRuST consortium parent trials and who agreed to participate in the repository or individuals who were recruited specifically for the repository (see Supplemental Materials, section 1 for details on inclusion and
Demographic and clinical variables
Table 1 presents a summary of demographic and clinical variables. Groups were significantly different on age, such that individuals in the HC group were younger than individuals in the PTSD + M group (Mdiff = −6.86, SE = 2.44, p = .005), and gender, such that the HC group contained a higher proportion of women than either PTSD group (HC-PTSD χ2 = 17.87, p < .001; HC-PTSD + M χ2 = 13.56, p < .001). The HC group endorsed lower PTSD symptoms relative to the two PTSD groups (HC-PTSD Mdiff = −39.59,
Discussion
The current study evaluated whether individuals with PTSD and a history of childhood maltreatment demonstrate brain structure and cognitive performance differences compared to individuals with PTSD without childhood maltreatment and/or healthy comparison participants without childhood maltreatment. The HC, PTSD, and PTSD + M groups did not statistically differ on global brain structural metrics (e.g., total gray matter volume), or brain volume in predetermined ROIs. However, the PTSD + M group
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgements
The authors thank the INTRuST consortium contributors for contributions to the study design and execution. This work was supported by the CDMRP award W81XWH-08-2-0159 (Stein et al.), the VA Office of Academic Affairs (J. Bomyea) and a Career Development Award from the US Department of Veteran Affairs (CSR&D CX001600-01A1; J. Bomyea). Thank you to Charles Kim for his assistance with the preparation of this manuscript.
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