- Imperial College London, United Kingdom;
- University College London, United Kingdom;
- Kings College London, United Kingdom;
- NIHR University College London Hospitals Biomedical Research Centre, United Kingdom;
- St Pancras Hospital, Camden and Islington NHS Foundation Trust, United Kingdom;
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, United Kingdom;
- University of Bath, United Kingdom
Research Article Nov 12, 2019
Cite this articleas: eLife 2019;8:e46797 DOI: 10.7554/eLife.46797
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Chronic psychosocial adversity induces vulnerability to mental illnesses. Animal studies demonstrate that this may be mediated by dopaminergic dysfunction. We therefore investigated whether long-term exposure to psychosocial adversity was associated with dopamine dysfunction and its relationship to psychological and physiological responses to acute stress. Using 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F]-DOPA) positron emission tomography (PET), we compared dopamine synthesis capacity in n = 17 human participants with high cumulative exposure to psychosocial adversity with n = 17 age- and sex-matched participants with low cumulative exposure. The PET scan took place 2 hr after the induction of acute psychosocial stress using the Montréal Imaging Stress Task to induce acute psychosocial stress. We found that dopamine synthesis correlated with subjective threat and physiological response to acute psychosocial stress in the low exposure group. Long-term exposure to psychosocial adversity was associated with dampened striatal dopaminergic function (p=0.03, d = 0.80) and that psychosocial adversity blunted physiological yet potentiated subjective responses to acute psychosocial stress. Future studies should investigate the roles of these changes in vulnerability to mental illnesses
Chronic psychosocial adversity increases the risk of mental illnesses including schizophrenia and depression (van Os et al., 2010; Howes and Murray, 2014; Parker, 1983). These adverse factors include developmental psychological trauma (Bendall et al., 2008) and adult life events (situations or occurrences that bring about a negative change in personal circumstances and involve threat) (Beards et al., 2013; Brown and Birley, 1968). Several lines of evidence indicate a potential causative component to these relationships as these risk exposures demonstrate dose-response relationships (Janssen et al., 2004; Morgan and Fisher, 2007; Pedersen and Mortensen, 2001). Reverse causality in the form of recall bias does not appear to be driving these associations (Cutajar et al., 2010), and the cessation of stressor reduces the risk of illness (Kelleher et al., 2013). However, we lack a precise mechanistic understanding of how exposure to these risk factors induces vulnerability to mental illness, and why these exposures all increase risk. Understanding this is important to identify targets for prevention and novel treatment. One common component underlying these factors is exposure to psychosocial stress (Howes and Murray, 2014) via activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system as part of the normal biological stress response (Taylor, 2010).
The striatum is functionally connected to the threat detection system (Haber, 2014). Animal research has demonstrated that acute stressors including aversive stimuli induce a pronounced activation of the dopamine system in terms of dopamine neuron population activity (i.e. the numbers of neurons firing) and with regard to amphetamine-induced behaviours (Valenti et al., 2011). Long-lasting changes in dopamine function occur after single stress exposures, including altered responsivity to future stimulation (Holly and Miczek, 2016) in a manner similar to that induced by drugs of abuse (Saal et al., 2003) and such that stress plays a powerful role in the initiation, escalation, and relapse to drug abuse via dopaminergic mechanisms (Koob and Volkow, 2016).
In humans, childhood sexual abuse is associated with elevated urinary dopamine metabolites in childhood (De Bellis et al., 1994) and acute psychosocial stressors induce greater dopamine release in people with low self-reported maternal care (Pruessner et al., 2004). Stress-induced elevations in cortisol levels have been directly correlated with amphetamine-induced dopamine release (Wand et al., 2007) on the one hand, while corticotrophin-releasing hormone administration results in dopamine release on the other (Payer et al., 2017). In terms of long-term exposure, using fMRI in humans, there is evidence that institutional neglect is associated with reduced striatal reward function, which is mediated by the dopamine system (Mehta et al., 2010), and similar findings have been observed in prospective cohorts following childhood adversity (Dillon et al., 2009) suggestive of a possible causal relationship between childhood adversity and alterations of the dopamine system. Furthermore, maltreatment-associated reduced striatal function is associated with adverse outcomes including disrupted attachment (Takiguchi et al., 2015) and depression (Hanson et al., 2015). One study (Oswald et al., 2014) found positive associations between childhood trauma and amphetamine-induced dopamine release, which may be due to the phenomenon of cross-sensitization. Furthermore, within people who are at ultra-high clinical risk of psychosis raised dopamine synthesis capacity has been reported in those patients with high levels of childhood adversity (Egerton et al., 2016). In light of these findings, we wanted to examine the relationships between the autonomic, endocrine and subjective threat responses to an acute psychosocial stressor and dopaminergic function.
The relationships between neurobiological pathways and stress-induced physiological and subjective responses have yet to be fully elucidated in humans. Studies of psychosocial stressors and dopamine function have typically investigated risk factors in isolation, despite the fact that the risk factors cluster together and may share common underlying mechanisms (Hjern et al., 2004; Morgan and Fisher, 2007; Wicks et al., 2005). Since associations between one exposure and outcomes remain after controlling for the other exposures (Schäfer and Fisher, 2011), it is likely that additive effects and/or synergistic effects operate between risk factors (Morgan et al., 2014; Guloksuz et al., 2015; Lataster et al., 2012; Morgan et al., 2008; Schäfer and Fisher, 2011). Furthermore, there is evidence that childhood trauma increases risk of psychopathology in response to adult stressors (McLaughlin et al., 2010). It is also likely that ethnic minority status can increase the risk of psychopathology through social isolation, experiences of discrimination, victimisation and social defeat, which are all considered stressors (Morgan et al., 2010; Bécares et al., 2009; Cooper et al., 2008; Cooper et al., 2017; Selten and Cantor-Graae, 2005; Selten et al., 2012; Sharpley et al., 2001; Tidey and Miczek, 1996). Cognitive models propose that minority status is associated with greater levels of social threat (Combs et al., 2002; Morgan and Fisher, 2007). Indeed we have found evidence that black minority ethnic status is associated with greater amygdalar activation to out-group (i.e. white faces) than vice versa, neurobiological correlates of these theories/findings (McCutcheon et al., 2018) (McCutcheon et al., 2018). Taken with findings that experiences of racism are correlated with amygdala activation to white faces in black individuals (Greer et al., 2012), this suggests that ethnic minority status is associated with functional alterations in the brain circuits involved in threat processing. As minority ethnicity status has been found to be a chronic stressor and increase the risk of mental illness via chronic stress rather than a genetic component (Akdeniz et al., 2014), we included minority ethnic status as a stressor. The combined effect of the risk factors on dopamine function in humans is unknown. Furthermore, previous studies (Egerton et al., 2016; Oswald et al., 2014; Pruessner et al., 2004) in humans have investigated childhood factors alone. Given animal evidence that exposure to mild stressors potentiate dopaminergic activity whilst severe chronic stressors is associated with dopaminergic blunting (Holly and Miczek, 2016), a key outstanding question remains – what is the effect of chronic adversity, across both child and adult stages of life, on dopaminergic function? We therefore aimed to investigate the effects of exposures to multiple psychosocial risk factors for psychosis on dopaminergic function and the acute stress response. Given the findings of dopaminergic dysfunction associated with childhood maltreatment presented above, we hypothesised that healthy humans with a high cumulative exposure to psychosocial stressors would have altered striatal dopamine synthesis, compared to humans with a low exposure. We also sought examine the relationship between dopaminergic function and the subjective threat and physiological responses to acute psychosocial stress using the Montréal Imaging Stress Task (MIST), a validated stress task involving mental arithmetic under negative social appraisal (Dedovic et al., 2005; Lederbogen et al., 2011). We sought to measure salivary α-amylase, secreted from the parotid gland in response to adrenergic activity and a marker of stress-induced adrenergic activity (van Stegeren et al., 2006) which is associated with a faster increase during psychosocial stress than salivary cortisol (Maruyama et al., 2012), and mean arterial pressure (MAP), the product of cardiac output and total peripheral resistance, reflecting organ perfusion and providing a physiological measure of sympathetic activation.