HPA axis & Brain changes: cortisol, amygdala, hippocampus, cytokines, & epigenetics (Part 3 of ACE series) — Psychiatry & Psychotherapy Podcast
David Puder
Liam Browning, David Puder MD   Peer reviewed by Erica Vega,&nbsp; Joanie Burns      None of the authors or presenters have any conflicts of interest to report.    In this week’s episode, we continue our series on Adverse Childhood Experiences by delving deeper into the lasting effect of ACEs on
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It should be noted that many of these studies do not account for confounders related to sleep, smoking, diet, exercise, or socioeconomic status. Inflammation has also not yet been linked to disrupted neural development in humans.

BDNF has also been studied, and most studies have shown no differences plasma/blood levels in those with high maltreatment history vs low/no maltreatment history (Vyas et al., 2023), while some authors argue for a mediating role of decreased BDNF in the relationship between maltreatment and psychopathology in adulthood (Watt et al., 2020; Maes et al., 2023).

ACEs Inconsistently Impact FMRI Resting-State Connectivity Of Large-Scale Brain Networks

As far as our understanding goes for large-scale network connectivity (default mode network [mPFC, PCC, temporoparietal junction], salience network [insular cortex, ACC, amygdala], central executive/frontoparietal network [dlPFC, posterior parietal cortex]) there is very limited understanding for how these networks normally develop in children, let alone in response to trauma (Holz et al., 2023).

Conventionally, depression is associated with increased intrinsic connectivity of the DMN, which may be related to rumination (Hamilton et al., 2015) and decreased intrinsic connectivity of the CEN/FPN (Liston et al., 2009; Kaiser et al., 2015), which may account for cognitive dysfunction.

Meanwhile, PTSD and BPD are thought to be characterized by decreased resting state connectivity within anterior and posterior parts of the DMN, which may indicate altered self-referential processing or recall of autobiographical memories, and increased salience network activity that may be related to hyperarousal (Koch et al., 2016; Shafie et al., 2022). There is inconsistent evidence detailing the functional changes in these networks in response to maltreatment specifically (for review see: Ross et al., 2021), but changes in connectivity between anterior and posterior DMN have also been observed in healthy adults with ACEs (Phillip et al., 2012) and in women with PTSD resulting from sexual abuse in childhood (Bluhm et al., 2008).

More consistent evidence exists for task-induced changes in corticolimbic connectivity (i.e. PFC with hippocampus and amygdala) that may be mediated by increased inflammation (Kraynak et al., 2019), but the directionality of these changes varies with age (Holz et al., 2023).

ACEs Increase Amygdala Reactivity To Negative Emotional Stimuli

Four meta-analytic studies have compared those with ACE history and those without on brain activation during task-based fMRI (Mothersill and Donohoe, 2016; Heany et al., 2018; Hein and Monk, 2017; Kraaijenvanger et al., 2020). All studies included were cross-sectional and retrospectively measured ACEs. These studies were primarily analyses of passive emotional tasks, most commonly viewing emotional faces, although there was a high degree of heterogeneity in the methods used.

Results have primarily converged on the amygdala, with all meta-analytic studies supporting increased activation in participants with a history of ACEs, especially during negative stimuli. Effect sizes were not calculated due to heterogeneity.

2/4 meta-analyses distinguished healthy volunteers from patients. Both meta-analyses showed persistent amygdala hyperactivation. However, it was not clear how “healthy” participant was defined.

One meta-analysis (Heany et al., 2018) specifically looked at studies using CTQ and socioaffective cues (faces, voices, pain)

Results revealed those with high CTQ compared to low CTQ showed:

Increased activation in the left superior frontal gyrus and left middle temporal gyrus

Decreased activation in the left hippocampus and left superior parietal lobule

Right amygdala and left ventral ACC activation was positively related to CTQ scores in response to negative faces

Heightened right amygdala reactivity in response to negative/neutral psychosocial cues have also been observed in patients with BPD and PTSD (Schulze et al., 2018)

Some authors theorize that because heightened amygdala activity is a risk factor for later depression, it represents a tendency towards a more negative perceptual bias (Mattson et al., 2017). Indeed, children exposed to violence tend to have a greater sensitivity to identifying anger and classify more faces displaying negative emotions as angry and attribute more hostile intentions, and this may be mediated by heightened amygdala reactivity (Dodge et al., 1990; Dodge et al., 1995).

ACEs Decrease Reward Anticipation

There have been seven studies assessing reward system activity via fMRI and the monetary incentive task. The standard version of the monetary incentive task involves prompting the participant to hit a button after seeing a flash of light. If the participant is fast enough they will receive a reward. Before the light flash is presented, the participant is cued about the degree of value for the reward. This allows researchers to study the anticipatory aspects of attaining a reward and the effects of receiving the reward.

Six of the seven studies on adults and adolescents with early childhood family adversity (Boeker et al., 2014; Holz et al., 2017; Hanson et al., 2015), emotional neglect (Hanson et al., 2015), or institutionalization (Goff et al., 2013; Mehta et al., 2010) have shown reduced activity of the ventral striatum during the anticipation of a reward while one study showed increased activity (Dennison et al. 2017). Only one study reported a beta of −0.26 for level of adversity and ventral striatum activation, and most studies reported r values around -.2 to -.3 (Hanson et al., 2015). This study also suggested that life stress experienced in early childhood (ages 5-8) was most highly correlated with blunted ventral striatum activity (β−0.327, P = 0.009), while stress experienced in late childhood (β = 0.015, P = 0.9) and adolescence (β = 0.08, P = 0.57) were not statistically correlated.

These results are interesting given decreased striatal activation during reward anticipation is seen in people with substance use disorder (Luijten et al., 2017), anhedonia (Pizzagalli, 2022), and with inflammatory stressors (Eisenberger et al., 2010). Also, considering the striatum receives a high amount of unidirectional input from the amygdala and PFC and that these brain regions all undergo protracted development into adolescence, it seems plausible that ACEs disrupt the development of these circuits.

One potential contributing mechanism to this perturbation could be through modulation of endogenous opioid receptors.

Evidence primarily from animal models suggests that maternal separation modulates the expression and sensitivity of endogenous opioid receptors, leading to increased pain sensitivity and addictive behaviors (Nakamoto and Tokuyama, 2023). In humans, postmortem biopsies of depressed patients who committed suicide and had a history of childhood abuse showed decreased expression of kappa opioid receptors in the anterior insula compared to those without a history of abuse (Lutz et al., 2018), and one study comparing the subjective effects of morphine suggested that healthy participants with a high CTQ score reported liking the drug more than those with low CTQ scores (Carlyle et al., 2021).

These biological changes in those with ACEs may explain some of their propensity for developing a substance use disorder later in life (see episode 204) and should increase our compassion for those with substance use disorders. Decreasing the shame felt by patients who struggle with addiction is vital for promoting connection, as it is a chronic relapsing disorder. Cultivating a stable, longitudinal connection with these patients and increasing their mentalizing capabilities can help them to overcome addiction through enhancing their protective relationships outside of therapy.

Conclusion

ACEs undeniably leave a lasting impact on a person's biology. However, the effects on the HPA-axis or the hippocampus may not be the most crucial aspects of ACEs' impact on the brain. ACEs likely alter cortical development in ways that make abilities like mentalizing and self-regulation more challenging. These capabilities are difficult to measure through neuroimaging but are vital for fostering deep, intimate connections. As a result, patients who have experienced early life traumas often struggle with forming and maintaining meaningful relationships, impacting their ability to connect with others throughout their lives. It is these abilities that we should strive to improve in our patients as mental health professionals. Improving our patients' capacity to reflect on the mental states and intentions of attachment figures and others, can have profound impacts on their relationships outside of therapy. This progress is crucial for reversing the impacts of childhood trauma.

As mental health professionals, we have a responsibility to facilitate these improvements. Our ability to do so depends not only on our clinical skills but also on our capacity to manage our own emotional responses and be patient and fully present with our patients, especially in the face of difficult interpersonal situations that inevitably arise in therapy. By managing our countertransference, addressing vicarious trauma, and improving our reflective functioning through engaging in our own therapy, we can create a therapeutic environment that promotes the healing and growth of our patients.

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