Brain activity and connectivity in response to negative affective stimuli: Impact of dysphoric mood and sex across diagnoses

Abstract

Negative affective stimuli elicit behavioral and neural responses which vary on a continuum from adaptive to maladaptive, yet are typically investigated in a dichotomous manner (healthy controls vs. psychiatric diagnoses). This practice may limit our ability to fully capture variance from acute responses to negative affective stimuli to psychopathology at the extreme end. To address this, we conducted a functional magnetic resonance imaging (fMRI) study to examine the neural responses to negative valence/high arousal and neutral valence/low arousal images as a function of dysphoric mood and sex across individuals (n=99) who represented traditional categories of healthy controls, major depressive disorder, bipolar psychosis, and schizophrenia. Observation of negative (vs. neutral) stimuli elicited BOLD responses in the following circuitry: periaqueductal gray [PAG], hypothalamus [HYPO], amygdala [AMYG], hippocampus [HIPP], orbitofrontal cortex [OFC], medial prefrontal cortex [mPFC], and greater connectivity between AMYG and mPFC. Across all subjects, severity of dysphoric mood was associated with hyperactivity of HYPO, and, among females, right (R) AMYG. Females also demonstrated inverse relationships between severity of dysphoric mood and connectivity between HYPO - R OFC, R AMYG - R OFC, and R AMYG - R HIPP. Overall, our findings demonstrated sex-dependent deficits in response to negative affective stimuli increasing as a function of dysphoric mood state. Females demonstrated greater inability to regulate arousal as mood became more dysphoric. These findings contribute to elucidating biosignatures associated with response to negative stimuli across disorders and suggest the importance of a sex-dependent lens in determining these biosignatures.

Neural - hormonal responses to negative affective stimuli: Impact of dysphoric mood and sex

“…The ability of this task to evoke BOLD responses in the neural circuitry associated with arousal and negative affect has been demonstrated in multiple studies of ours over the last 11 years in healthy populations and distinct psychiatric disorders (i.e., Goldstein et al, 2005; and 2010; Holsen et al, 2011; 2012; 2013; Jacobs et al, 2014), and recently, we demonstrated shared brain activity responses in the regions listed above across healthy and ill populations in the same sample as reported here (Mareckova et al, 2016). The ability of this task to elicit HPA response has been demonstrated by Admon et al (2015) and Holsen et al (2013).…”

“…Further exclusion criteria included MRI exclusion criteria, the use of caffeine in the morning prior to the fasting blood sample, alcohol consumption 24 hours prior to the blood draw, and any current substance use disorders, as assessed by the Structured Clinical Interview for the DSM (SCID). For details of the demographics and clinical characteristics of the sample, see Mareckova et al 2016. In brief, there were no significant differences between men and women in ethnicity, handedness, age, body mass index, parental SES, educational level, WAIS-R vocabulary scores, rate of DSM diagnoses, or the proportion taking psychotropic medication.…”

“…This is not surprising given that brain regions that regulate responses to negative affective stimuli, subsequently referred to as “stress response”, are highly sexually dimorphic (Tobet et al, 1993; Filipek et al, 1994; Giedd et al, 1996; Goldstein et al, 2001; Tobet et al, 2009), regulate the hypothalamic pituitary adrenal and gonadal (HPA and HPG) axes (Keverne, 1988; Tobet & Hanna, 1997; Ostlund et al, 2003; Swaab, 2004; Bao et al, 2005), arousal (Keverne, 1988; McEwen & Magarinos, 1997; Price, 1999) and mood (Mareckova et al, 2016). Brain regions include: periaqueductal gray (PAG), hypothalamus (HYPO), amygdala (AMYG), hippocampus (HIPP), and medial and orbital prefrontal cortices (mPFC, OFC) (see Mareckova et al, 2016), areas of the brain that have been found to be abnormal structurally and functionally across a number of psychiatric disorders.…”

“…This study builds on the fMRI findigns of Mareckova et al (2016) and extends them by studying the coupled hormonal responses acquired in real time during the functional imaging. Based on the substantial body of functional imaging work relating endocrine function with mood regulation (e.g.…”

“…We predicted that women would demonstrate stronger coupling between neural and cortisol responses to negative affective stimuli than men and that these sex differences would be further modulated by the levels of androgens in men and estradiol in women.We also predicted that the coupling of neural and cortisol responses would increase as a function of worsening mood. These hypotheses were explored initially in the context of BOLD response and additionaly in the context of connectivity between hypothalamus, the key relay station for HPA axis function, and the other ROIs defined in Mareckova et al (2016). Findings will contribute to elucidating the neural and physiologic mechanisms regulating stress and mood responses and the impact of sex.…”