Effect of childhood physical abuse on social anxiety is mediated via reduced frontal lobe and amygdala-hippocampus complex volume in adult clinical high-risk subjects

Abstract

Background

Childhood adverse experiences (CAE) are associated with clinical psychiatric disorders and symptoms, and with volumetric abnormalities in the amygdala-hippocampus complex (AmHiC) and frontal lobe (FroL) in adulthood.

Aim

To study whether CAE are associated with reduced AmHiC and FroL and whether these structures mediate the effect of CAE on social anxiety and depression.

Method

In seven European centres, 374 patients with recent onset of psychosis (n = 127), clinical high-risk to psychosis (n = 119) or recent onset of depression (n = 128) were scanned with MRI and their FroL and AmHiC volumes were measured. They all completed self-report scales for assessment of CAE, social anxiety and depression.

Results

Of the CAE domains, physical abuse was associated specifically with reduced grey and white matter volumes of FroL and AmHiC in psychotic and high-risk patients. After controlling intracranial volume, PhyAb associated significantly with FroL and its grey matter volume in high-risk patients only. In mediation analyses, the effect of physical abuse on social anxiety was mediated via reduced FroL grey mater volume in high-risk patients. In them, when the effects of AmHiC and depression were controlled, the effect of physical abuse on social anxiety was mediated via FroL grey matter volume reduction.

Conclusions

Childhood physical abuse is associated with reduced frontal lobe and amygdala-hippocampus complex volume in adult subjects with psychotic symptoms. Reduced frontal lobe and amygdala-hippocampus complex volume mediate the effect of physical abuse on social anxiety in high-risk patients. The effect of physical abuse on depression-independent social anxiety is mediated via reduced frontal lobe.

Introduction

Childhood Adverse Experiences (CAE) are common in the general population, as well as among those who experience mental disorder (Read et al., 2007; Iffland et al., 2013; Schüssler-Fiorenza et al., 2014; Hughes et al., 2016; Salokangas et al., 2016). Recent reviews and meta-analyses have demonstrated that each core domain of CAE, i.e., emotional neglect and abuse, physical neglect and abuse, and sexual abuse (Burgermeister, 2007; Thabrew et al., 2012), is significantly individually associated with adult mental disorders, in particular with psychotic, affective, anxiety and substance use disorders (Enoch, 2011; Brady and Back, 2012; Varese et al., 2012; Bonoldi et al., 2013; Lindert et al., 2014; Fernandes and Osório, 2015; Mandelli et al., 2015; Aas et al., 2016; Nelson et al., 2017).

The CAE domains correlate strongly with each other and this potentially obscures the possible specific effects on clinical disorders. However, there is some evidence that certain CAE domains have specific effects on mental health outcomes: for example, Trauelsen et al. (2015) found that emotional abuse, emotional neglect, and physical abuse associated specifically with psychosis. Bentall et al. (2012) found a specific association between sexual abuse and psychosis, and Upthegrove et al. (2015) between sexual abuse and hallucinations. Salokangas et al. (2019) recently found that when interrelations are controlled, emotional neglect predicts affective disorders.

CAE have also been associated with neuroanatomical changes, especially with reduced grey matter volume in the amygdala and hippocampus, and cerebral cortex (Teicher and Samson, 2016), and abnormalities in these structures have been reported in psychosis, schizophrenia, bipolar disorder and depression (Armio et al., 2019; Geuze et al., 2005; Shin and Liberzon, 2010; Suslow et al., 2013; Grotegerd et al., 2014; Goodman et al., 2014).

Much of the existing literature is in established disorder, with chronic illness and medication effects, or in population based samples, and does not take into account the potential multiple clinical presentations' outcomes of childhood trauma within early psychosis groups or those at clinical high risk.

Amygdala and hippocampus, as well as pyramid cells in cortex are densely populated with glucocorticoid receptors (Sarrieau et al., 1986; Morimoto et al., 1996; Sinclair et al., 2011) and therefore highly vulnerable for chronic childhood stress with excessive glucocorticoid levels (Sapolsky et al., 1985), such as cortisol (Teicher and Samson, 2016). In amygdala and hippocampus, mechanisms of emotions, memory and cognition are intertwined from early perception to reasoning. The amygdala-hippocampus complex (AmHiC) is linked to two independent memory systems, which in emotional situations interact with each other. Specifically, the amygdala can modulate hippocampal-dependent memories, episodic memory for emotional stimuli, while the hippocampus can influence amygdala response when emotional stimuli are encountered (Dolcos et al., 2004; Phelps, 2004, Phelps, 2006). Basolateral amygdala inputs to ventral hippocampus bi-directionally modulate social behavior (Felix-Ortiz and Tye, 2014) indicating a tight connection between these two structures. Thus, the amygdala and hippocampus can be considered as a joint functional structure, amygdala-hippocampus complex (AmHiC).

Both psychosis and depression can be preceded by, and are comorbid with, generalised anxiety, PTSD and social anxiety (Gilbert, 2000; Brunet et al., 2012). Recent human and non-human studies indicate that manifestation of social anxiety is related to neural circuits including the amygdala, hippocampus and frontal cortex (Fox and Kalin, 2014). Subjects with posttraumatic stress disorder (PTSD) have exhibited exaggerated amygdala responses and diminished medial prefrontal cortex responses to fearful versus happy facial expressions suggesting that exaggerated amygdala responsivity is related to diminished medial prefrontal cortex responsivity in PTSD (Shin et al., 2005). Thus, it is possible that the affective disorders, social anxiety in particular, related to functional disturbances in AmHiC may be contributed by impaired function of frontal lobe (FroL). CAE may be a specific etiological pathway to this impaired function, with impact across affective and psychotic disorders.

We hypothesized first that CAE associate inversely with AmHiC and FroL and that reduced AmHiC and FroL mediate the effects of CAEs on social anxiety. We expected that the mediation process via AmHiC is more emphasized than that via FroL and that these processes would be more pronounced in early psychosis groups, defined as recent onset of psychosis and clinical high risk of psychosis, compared to recent onset depression and would vary by gender.