Negar Fani

Emotion dysregulation and negative affect: association with psychiatric symptoms.

OBJECTIVE A growing body of research focuses on the development and correlates of emotion dysregulation, or deficits in the ability to regulate intense and shifting emotional states. Current models of psychopathology have incorporated the construct of emotion dysregulation, suggesting its unique and interactive contributions, along with childhood disruptive experiences and negative affect, in producing symptomatic distress. Some researchers have suggested that emotion dysregulation is simply a variant of high negative affect. The aim of this study was to assess the construct and incremental validity of self-reported emotion dysregulation over and above childhood trauma and negative affect in predicting a range of psychopathology. METHOD Five hundred thirty individuals aged 18 to 77 years (62% female) were recruited from the waiting areas of the general medical and obstetric/gynecologic clinics in an urban public hospital in Atlanta, Georgia. Participants completed a battery of self-report measures obtained by interview, including the Childhood Trauma Questionnaire, the Positive and Negative Affect Schedule, and the Emotion Dysregulation Scale. Regression analyses examined the unique and incremental associations of these self-report measurements of childhood traumatic experiences, negative affect, and emotion dysregulation with concurrent structured interview-based measurements of psychiatric distress and history of self-destructive behaviors. These measures included the Clinician-Administered PTSD Scale, the Alcohol Use Disorders Identification Test, the Short Drug Abuse Screening Test, the Beck Depression Inventory, and the Global Adaptive Functioning Scale from the Longitudinal Interval Follow-Up Evaluation. The presented data were collected between 2005 and 2009. RESULTS Regression models including age, gender, childhood trauma, negative affect, and emotion dysregulation were significantly (P ≤ .001) associated with each of the studys criterion variables, accounting for large portions of the variance in posttraumatic stress symptoms (R² = 0.21), alcohol and drug abuse (R² = 0.28 and 0.21, respectively), depression (R² = 0.55), adaptive functioning (R² = 0.14), and suicide history (omnibus χ² = 74.80, P < .001). Emotion dysregulation added statistically significant (P < .01) incremental validity to each regression model (β = 0.25, 0.34, 0.35, 0.34, and -0.18, and Wald = 24.43, respectively). CONCLUSIONS Results support the conceptualization of emotion dysregulation as a distinct and clinically meaningful construct associated with psychiatric distress that is not reducible to negative affect. Emotion dysregulation is a key component in a range of psychiatric symptoms and disorders and a core target for psychopharmacologic and psychosocial treatment interventions.

Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder.

Many features of posttraumatic stress disorder (PTSD) can be linked to exaggerated and dysregulated emotional responses. Central to the neurocircuitry regulating emotion are functional interactions between the amygdala and the ventromedial prefrontal cortex (vmPFC). Findings from human and animal studies suggest that disruption of this circuit predicts individual differences in emotion regulation. However, only a few studies have examined amygdala-vmPFC connectivity in the context of emotional processing in PTSD. The aim of the present research was to investigate the hypothesis that PTSD is associated with disrupted functional connectivity of the amygdala and vmPFC in response to emotional stimuli, extending previous findings by demonstrating such links in an understudied, highly traumatized, civilian population. 40 African-American women with civilian trauma (20 with PTSD and 20 non-PTSD controls) were recruited from a large urban hospital. Participants viewed fearful and neutral face stimuli during functional magnetic resonance imaging (fMRI). Relative to controls, participants with PTSD showed an increased right amygdala response to fearful stimuli (p(corr) < .05). Right amygdala activation correlated positively with the severity of hyperarousal symptoms in the PTSD group. Participants with PTSD showed decreased functional connectivity between the right amygdala and left vmPFC (p(corr) < .05). The findings are consistent with previous findings showing PTSD is associated with an exaggerated response of amygdala-mediated emotional arousal systems. This is the first study to show that the amygdala response may be accompanied by disruption of an amygdala-vmPFC functional circuit that is hypothesized to be involved in prefrontal cortical regulation of amygdala responsivity.

FKBP5 and Attention Bias for Threat: Associations With Hippocampal Function and Shape

IMPORTANCE The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamic-pituitary-adrenal axis functioning and has been associated with many stress-related psychiatric disorders. The study of intermediate phenotypes, such as emotion-processing biases and their neural substrates, provides a way to clarify the mechanisms by which FKBP5 dysregulation mediates risk for psychiatric disorders. OBJECTIVE To examine whether allelic variations for a putatively functional single-nucleotide polymorphism associated with FKBP5 gene regulation (rs1360780) would relate differentially to attention bias for threat. this was measured through behavioral response on a dot probe task and hippocampal activation during task performance. Morphologic substrates of differential hippocampal response were also measured. DESIGN Cross-sectional study conducted from 2010 to 2012 examining associations between genotype, behavioral response, and neural response (using functional magnetic resonance imaging [fMRI]) on the dot probe; voxel-based morphometry and global and local shape analyses were used to measure structural differences in hippocampi between genotype groups. SETTING Participants were recruited from primary care clinics of a publicly funded hospital in Atlanta, Georgia. PARTICIPANTS An African American cohort of adults (N = 103) was separated into 2 groups by genotype: one genotype group included carriers of the rs1360780 T allele, which has been associated with increased risk for posttraumatic stress disorder and affective disorders; the other group did not carry this allele. Behavioral data included both sexes (N = 103); the MRI cohort (n = 36) included only women. MAIN OUTCOME MEASURES Behavioral and fMRI (blood oxygen level-dependent) response, voxel-based morphometry, and shape analyses. RESULTS Carriers of the rs1360780 T allele showed an attention bias toward threat compared with individuals without this allele (F1,90 = 5.19, P = .02). Carriers of this allele demonstrated corresponding increases in hippocampal activation and differences in morphology; global and local shape analyses revealed alterations in hippocampal shape for TT/TC compared with CC genotype groups. CONCLUSION Genetic variants of FKBP5 may be associated with risk for stress-related psychiatric disorders via differential effects on hippocampal structure and function, resulting in altered attention response to perceived threat.

Neural Correlates of Attention Bias to Threat in Post-traumatic Stress Disorder

Attentional biases have been proposed to contribute to symptom maintenance in posttraumatic stress disorder (PTSD), although the neural correlates of these processes have not been well defined; this was the goal of the present study. We administered an attention bias task, the dot probe, to a sample of 37 (19 control, 18 PTSD+) traumatized African-American adults during fMRI. Compared to controls, PTSD+ participants demonstrated increased activation in the dorsolateral prefrontal cortex (dlPFC) in response to threat cue trials. In addition, attentional avoidance of threat corresponded with increased ventrolateral prefrontal cortex (vlPFC) and dorsal anterior cingulate cortex (dACC) activation in the PTSD group, a pattern that was not observed in controls. These data provide evidence to suggest that relative increases in dlPFC, dACC and vlPFC activation represent neural markers of attentional bias for threat in individuals with PTSD, reflecting selective disruptions in attentional control and emotion processing networks in this disorder.

PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus

Significance Higher circulating pituitary adenylate cyclase-activating polypeptide (PACAP) and a polymorphism in its receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, have recently been linked with posttraumatic stress disorder (PTSD) in women and not men. The current study examined the influence of ADCYAP1R1 genotype on brain function among traumatized women. In individuals with the risk genotype, the amygdala showed greater reactivity to threat stimuli and decreased functional connectivity with the hippocampus. ADCYAP1R1 genotype had larger effects than PTSD diagnosis, suggesting that amygdala reactivity is an intermediate phenotype for anxiety-related psychopathology. Amygdala reactivity has been identified as a possible predisposing risk factor for PTSD, and the current findings indicate a possible genetic mechanism. Findings also point to a neurobiological explanation for increased PTSD prevalence in women. We have recently found higher circulating levels of pituitary adenylate cyclase-activating polypeptide (PACAP) associated with posttraumatic stress disorder (PTSD) symptoms in a highly traumatized cohort of women but not men. Furthermore, a single nucleotide polymorphism in the PACAP receptor gene ADCYAP1R1, adenylate cyclase activating polypeptide 1 receptor type 1, was associated with individual differences in PTSD symptoms and psychophysiological markers of fear and anxiety. The current study outlines an investigation of individual differences in brain function associated with ADCYAP1R1 genotype. Forty-nine women who had experienced moderate to high levels of lifetime trauma participated in a functional MRI task involving passive viewing of threatening and neutral face stimuli. Analyses focused on the amygdala and hippocampus, regions that play central roles in the pathophysiology of PTSD and are known to have high densities of PACAP receptors. The risk genotype was associated with increased reactivity of the amygdala and hippocampus to threat stimuli and decreased functional connectivity between the amygdala and hippocampus. The findings indicate that the PACAP system modulates medial temporal lobe function in humans. Individual differences in ADCYAP1R1 genotype may contribute to dysregulated fear circuitry known to play a central role in PTSD and other anxiety disorders.

Genetic approaches to understanding post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is increasingly recognized as both a disorder of enormous mental health and societal burden, but also as an anxiety disorder that may be particularly understandable from a scientific perspective. Specifically, PTSD can be conceptualized as a disorder of fear and stress dysregulation, and the neural circuitry underlying these pathways in both animals and humans are becoming increasingly well understood. Furthermore, PTSD is the only disorder in psychiatry in which the initiating factor, the trauma exposure, can be identified. Thus, the pathophysiology of the fear and stress response underlying PTSD can be examined and potentially interrupted. Twin studies have shown that the development of PTSD following a trauma is heritable, and that genetic risk factors may account for up to 30-40% of this heritability. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review will examine gene pathways that have recently been analysed, primarily through candidate gene studies (including neuroimaging studies of candidate genes), in addition to genome-wide associations and the epigenetic regulation of PTSD. Future and on-going studies are utilizing larger and collaborative cohorts to identify novel gene candidates through genome-wide association and other powerful genomic approaches. Identification of PTSD biological pathways strengthens the hope of progress in the mechanistic understanding of a model psychiatric disorder and allows for the development of targeted treatments and interventions.

White Matter Integrity in Highly Traumatized Adults With and Without Post-Traumatic Stress Disorder

Prior structural imaging studies of post-traumatic stress disorder (PTSD) have observed smaller volumes of the hippocampus and cingulate cortex, yet little is known about the integrity of white matter connections between these structures in PTSD samples. The few published studies using diffusion tensor imaging (DTI) to measure white matter integrity in PTSD have described individuals with focal trauma rather than chronically stressed individuals, which limits generalization of findings to this population; in addition, these studies have lacked traumatized comparison groups without PTSD. The present DTI study examined microstructural integrity of white matter tracts in a sample of highly traumatized African-American women with (n=25) and without (n=26) PTSD using a tract-based spatial statistical approach, with threshold-free cluster enhancement. Our findings indicated that, relative to comparably traumatized controls, decreased integrity (measured by fractional anisotropy) of the posterior cingulum was observed in participants with PTSD (p<0.05). These findings indicate that reduced microarchitectural integrity of the cingulum, a white matter fiber that connects the entorhinal and cingulate cortices, appears to be associated with PTSD symptomatology. The role of this pathway in problems that characterize PTSD, such as inadequate extinction of learned fear, as well as attention and explicit memory functions, are discussed.

Fear load: The psychophysiological over-expression of fear as an intermediate phenotype associated with trauma reactions.

Psychophysiological measures of fear expression provide observable intermediate phenotypes of fear-related symptoms. Research Domain Criteria (RDoC) advocate using neurobiological intermediate phenotypes that provide dimensional correlates of psychopathology. Negative Valence Systems in the RDoC matrix include the construct of acute threat, which can be measured on a physiological level using potentiation of the acoustic startle reflex assessed via electromyography recordings of the orbicularis oculi muscle. Impairments in extinction of fear-potentiated startle due to high levels of fear (termed fear load) during the early phases of extinction have been observed in posttraumatic stress disorder (PTSD). The goals of the current work were to examine dimensional associations between fear-related symptoms of PTSD and fear load variables to test their validity as an intermediate phenotype. We examined extinction of fear-potentiated startle in a cohort (n=269) of individuals with a broad range of civilian trauma exposure (range 0-13 traumatic events per person, mean=3.5). Based on previously reported findings, we hypothesized that fear load would be significantly associated with intrusion and fear memories of an index traumatic event. The results indicated that early extinction was correlated with intrusive thoughts (p=0.0007) and intense physiological reactions to trauma reminders (p=0.036). Degree of adult or childhood trauma exposure, and depression severity were not associated with fear load. After controlling for age, sex, race, income, level of prior trauma, and level of fear conditioning, fear load during extinction was still significantly predictive of intrusive thoughts (p=0.004). The significance of these findings is that they support dimensional associations with symptom severity rather than diagnostic category and, as such, fear load may emerge as a transdiagnostic intermediate phenotype expressed across fear-related disorders (e.g., specific phobia, social phobia).

Attention Bias in Adult Survivors of Childhood Maltreatment with and without Posttraumatic Stress Disorder

Childhood maltreatment increases risk for Posttraumatic Stress Disorder (PTSD). Maladaptive patterns of attention to emotionally salient stimuli warrant examination as possible mediators of the relationship between childhood maltreatment and PTSD. It remains unclear whether persistent attentional biases are differentially apparent in adults who were maltreated as children and either did or did not develop later PTSD symptomatology. The present study examined associations among attention bias, childhood maltreatment, and PTSD in adults. We tested the hypothesis that attentional bias for emotional cues (angry faces, happy faces), measured using the Dot Probe Task, would significantly mediate associations between childhood maltreatment and adult PTSD symptoms in a sample of 161 adults with and without childhood maltreatment histories and/or current PTSD symptoms. We found that attention bias toward happy faces partially mediated the relationship between childhood maltreatment and PTSD avoidance and numbing symptoms.

FKBP5 Genotype and Structural Integrity of the Posterior Cingulum

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.