Refugee Mental Health Through the Lens of Neuroscience and Genetics

This is part of our special feature on Forced Migration, Cultural Identity, and Trauma.

 

As Europe copes with the presence of nearly a million refugees, national medical care systems have become strained. The primary focus of medical care is acute (somatic) illness, rather than mental health. Even if mental health needs are addressed, doctors focus on acute symptoms instead of the long-term sequelae of trauma, and they do not include the patient’s psycho-social context. The neglect of a long-term, integrated bio-psycho-social perspective of both somatic and mental illness will ultimately be costly, as it ignores important interrelations between these variables that may predict individual differences in vulnerability and resilience. The emergent research literature examining the interrelations is largely based on studies conducted in non-traumatized or non-refugee cohorts, with small sample sizes and cross-sectional (as opposed to longitudinal) study designs. I argue in favor of large-scale longitudinal bio-psycho-social studies conducted in collaboration with refugee participants. The goal of this research agenda is to understand what drives individual differences in disease vulnerability and resilience. Such discoveries can ultimately benefit patients to be matched to tailored treatment protocols, and guide policy-makers to design an integrated approach to migration that minimizes future healthcare burdens and maximizes well-being in, and productive contributions by, the newly arrived migrant populations in Europe.

 

Mind the Gap – Surprising connections between physical and mental health

In Germany, the medical treatment of asylum seekers is guided by the Asylbewerberleistungsgesetz (AsylbLG), which only considers acute illness and pain-related illness as grounds for a medical visit. A request by an asylum seeker for treatment of other medical needs is subject to review by the Sozialbehoerde and can be turned down or delayed. Indeed, 15 percent of requests by asylum seekers for psychotherapy are turned down, compared to 1-3 percent in the general population (Bundesweite Arbeitsgemeinschaft der Psychosozialen Zentren für Flüchtlinge und Folteropfer (2015) Versorgungsbericht. Zur psychosozialen Versorgung von Flüchtlingen und Folteropfern in Deutschland.BAfF e. V.,Berlin, cited in (Bottche, Heeke, & Knaevelsrud, 2016)). Such denials or delays can dramatically increase the incidence of mental illness. For example, a U.S. study of migrated torture survivors reported levels of post-traumatic stress disorder (PTSD) and depression that were 3.3 and 4.5 times higher (as measured by “Odd Ratio”), respectively, in individuals who had only received clinical care after more than a year post-migration, compared to those who received clinical care within one year post-migration (Song, Kaplan, Tol, Subica, & de Jong, 2015). Yet, the need for mental health among refugees and asylum seekers is profound: recent studies of Syrian refugees documented a prevalence rate of 34 percent for PTSD (Alpak et al., 2015) and 30 percent for depression (Gammouh, Al-Smadi, Tawalbeh, & Khoury, 2015).

Policy-makers and even many medical professionals may not appreciate the significant interplay between body and mind, somatic and psychiatric illness. In fact, there is a rapidly growing literature linking psychiatric conditions such as PTSD and depression to somatic conditions, particularly gastrointestinal disorders, inflammation, and infection.

A common gastrointestinal disorder is irritable bowel syndrome (IBS), which is characterized by abdominal pain and altered bowel movements. IBS compromises the function of the hypothalamic–pituitary–adrenal (HPA) axis, which acts as a major stress regulatory system. In healthy individuals, the HPA axis acutely releases stress hormones (such as cortisol) as an adaptive short-term stress response to a threat. However, in chronically stressed individuals the levels of stress hormones stay elevated, damaging organs and even neurons in the brain (McEwen, 2007). Indeed, brain imaging studies reveal IBS-related changes in a number of regions including those that process emotion (Fadgyas-Stanculete, Buga, Popa-Wagner, & Dumitrascu, 2014).  Furthermore, IBS is associated with a number of psychiatric disorders such as generalized anxiety disorder, panic disorder, major depressive disorder, bipolar disorder, schizophrenia, and PTSD (Fadgyas-Stanculete et al., 2014; Fond et al., 2014; Irwin et al., 1996; Sibelli et al., 2016). The pathogenesis of IBS is multi-faceted, involving the interaction of environmental, psychological, inflammatory, neural, and genetic variables. These genes exist in multiple forms (so-called “polymorphisms”), so that genetic variation may render some individuals more vulnerable to IBS (and/or to its co-morbid psychiatric disorders) than others. There is evidence from one large-scale study of almost 4,700 patients and 18,800 matched controls that IBS can precede later psychiatric diagnosis: IBS was associated with increased risk for newly-diagnosed depression, anxiety disorders, and sleep disorders one, five, and more than five years after IBS diagnosis (Lee et al., 2015).

A recent study catalogued health care needs among Middle Eastern asylum seekers in Central Europe (Pfortmueller, Schwetlick, Mueller, Lehmann, & Exadaktylos, 2016): of the 880 patients, the most common (n= 132, 15 percent) complaint among unspecified somatic symptoms was gastrointestinal disorders. A study of refugees and asylum seekers in Munich (Alberer, Wendeborn, Loscher, & Seilmaier, 2016) found that 56/548 (10 percent) of patient visits were due to gastrointestinal illnesses, which was the third-leading cause, after unspecific viral infections (152 visits, 28 percent) and neuropsychiatric illness (68 visits, 12 percent). Thus, clinicians should pay attention to somatic symptoms among refugees and asylum-seekers, as they may be indicators of existing co-morbid psychiatric conditions or harbingers of psychiatric conditions yet to come.

Inflammation is associated with a range of psychiatric conditions, including PTSD (Pace & Heim, 2011) and depression (Dantzer, O’Connor, Freund, Johnson, & Kelley, 2008). One mechanism by which trauma exposure precipitates inflammation involves activation of the HPA axis that ultimately leads to activation of specific (beta-2 adrenergic) receptors on immune cells, and the subsequent increase of pro-inflammatory cytokines (Neigh & Ali, 2016). In fact, levels of the pro-inflammatory cytokine IL-6 were found to correlate with PTSD symptom severity (Passos et al., 2015). These cytokines can be detected in blood, which suggests that blood-based biomarkers for PTSD may be developed (Daskalakis et al., 2016). Furthermore, there is now accumulating evidence that anti-inflammatory drugs may reduce depressive symptoms (Kappelmann, Lewis, Dantzer, Jones, & Khandaker, 2016), opening the door for novel therapies built around the molecular biology of immune system regulation in the brain (Miller, Haroon, & Felger, 2016).

One variable that may distinguish vulnerable individuals from resilient ones is the degree to which genes are activated that play a role in the immune system. For example, a study of Bosnian refugees reported abnormal levels of pro-inflammatory gene expression after exposure to an acute stressor (Nowotny et al., 2010). The underlying mechanism for such differential inflammation-related gene expression may be epigenetic, i.e., the modification of molecules that regulate gene expression without altering the DNA sequence itself. One epigenetic mechanism is DNA methylation, by which a methyl molecule is attached to regions of DNA in which a Cytosine is followed by a Guanine (so-called “CpG islands”); by doing so, DNA methylation can impede expression of genes containing these CpG islands. Studies of U.S. military service members and veterans with PTSD and controls found differential DNA methylation in inflammation-related genes (Bam et al., 2016; Rusiecki et al., 2013). Two studies of mothers and their newborns in the Democratic Republic of Congo discovered that maternal war stress was associated with differential methylation at the glucocorticoid receptor gene in newborns and with genome-wide elevated levels of DNA methylation in mothers (Kertes et al., 2016; Rodney & Mulligan, 2014). These studies illustrate that war-related trauma experience can alter gene expression related to stress- and inflammation-related biological systems, which can adversely impact mental health.

I have argued in academic writings (Canli, 2014b, 2015) and in a TEDxStony Brook public lecture (Canli, 2014a) that depression, at least in some patients, may be caused by a virus, bacterium, or parasite that can affect neural circuits underlying cognitive and emotional/motivational processes. As an illustration that such pathogens have already been discovered (which suggests there may be many more yet-to-be-discovered pathogens using similar mechanisms) I spoke about toxoplasma gondii (T. gondii), which is a parasite that lives in the intestines of cats. When its eggs are released into the environment by the cat’s excretions, they can infect rodents. In the rodent’s brain, T. gondii then reprograms fear and sexual arousal centers, such that a rat that would usually avoid cats is now attracted to the scent of a cat’s urine. Ultimately, the infected rat will fall prey to another cat and T. gondii has completed its life cycle.

Humans are exposed in massive numbers to T. gondii: it is estimated that one-third of the world’s population (Montoya & Liesenfeld, 2004) and one-fifth of the U.S. population (CDC, 2014) is infected with T. gondii. Although the exact mechanisms by which T. gondii may affect the human brain remain to be investigated in detail, there is epidemiological evidence that infection is associated with psychopathology. Across twenty European countries, one study found a significant correlation between T. gondii prevalence rates and national suicide rates (Lester, 2010). Depressed or bipolar patients with a history of suicide attempt were found to have higher T. gondii antibody titers (Arling et al., 2009). In addition to its link to suicidality, T. gondii infection is also linked to schizophrenia (Hsu, Groer, & Beckie, 2014; Torrey, Bartko, Lun, & Yolken, 2007; Torrey, Bartko, & Yolken, 2012).

Syrian refugees and asylum seekers may be at increased risk for T. gondii exposure. A recent study conducted in a Turkish hospital compared Toxoplasma seroprevalence between pregnant Syrian refugees and the local population (Bakacak et al., 2015). Toxoplasma Immunoglobulin M (IgM) seropositivity, an indicator of acute infection, was around 2 percent in the local population but close to 5 percent among Syrian refugees. Toxoplasma Immunoglobulin G (IgG) seropositivity, an indicator of a later response, was around 48 percent in the local population but close to 70 percent among Syrian refugees. Both IgM and IgG measures were significantly different between these two cohorts. Thus, tests for T. gondii exposure may be useful in screening this refugee population for potential infection that carries the risk of subsequent psychopathology.

All the lonely people – the long-term cost of social isolation

Another element by which psycho-social factors can influence biological systems related to health is the subjective experience of social isolation, commonly called “loneliness.” Loneliness may be quite common among refugee populations: a Dutch study of refugees from twenty-one different countries of origin reported that 78 percent expressed an unmet need for company (Strijk, van Meijel, & Gamel, 2011).

Subjective social isolation is associated with poor mental and physical health. Its association with depression (Cacioppo, Hawkley, & Thisted, 2010; Cacioppo, Hughes, Waite, Hawkley, & Thisted, 2006; Green et al., 1992; Holvast et al., 2015; Houtjes et al., 2014; Jaremka et al., 2014) may not be a surprise, but loneliness is also associated with impaired cognitive processes such as accelerated cognitive decline and incident Alzheimer’s disease (Wilson et al., 2007). Loneliness is even associated with physical illnesses that appear to have little to do with it, such as heart disease, hypertension, stroke, and lung disease (Petitte et al., 2015), as well as cancer, infectious and inflammatory diseases (Antoni et al., 2006; Cohen, Doyle, Skoner, Rabin, & Gwaltney, 1997; Cole, Kemeny, Fahey, Zack, & Naliboff, 2003; Luanaigh & Lawlor, 2008; Nausheen, Gidron, Peveler, & Moss-Morris, 2009).

Social neuroscientists try to understand how these associations can be explained at the level of molecular-genetic mechanisms. Contrary to a common understanding of genetics, genes are not “destiny”–they neither predict what happens to a person (except for very few genetic diseases), nor are they in a permanent “on” or “off” position to encode a protein or not. Instead, they can be regulated by hundreds of molecules to turn them “on,” off,” or leave them activated somewhere in-between (thereby producing intermediate amounts of protein). One influential theory builds on the discovery that prolonged periods of loneliness increase a person’s stress hormone levels, and hypothesizes that these stress hormones act as molecular signals that turn on disease-related genes (Cacioppo, Cacioppo, Capitanio, & Cole, 2015). Indeed, this hypothesis is supported by studies of gene expression in blood samples from lonely individuals versus controls (Cole, Hawkley, Arevalo, & Cacioppo, 2011; Cole et al., 2007).

Given that loneliness is a subjective experience, what role does the brain play, and is there evidence for differential gene expression in the human brain as a function of loneliness? This question is difficult to answer because it requires the removal of brain tissue for analysis. We (Canli et al., 2016) recently did exactly that, based on postmortem brain tissue available from deceased donors who were participants in a longitudinal study on aging and who had reported on their subjective experience of social isolation. We discovered close to 1,600 genes that were differentially expressed as a function of loneliness. Analysis of the function of these genes yielded a surprising discovery: many of them played a role in fundamental processes of cellular function (metabolism, cellular aging, cell death etc.) that are commonly impacted across many different types of diseases. Thus, we found evidence for a “genetic architecture” that could explain why loneliness is associated with so many, seemingly unconnected, disease outcomes. The implications of this finding, if replicated, may lead to new therapeutic molecular targets for the treatment of a range of diseases that are exacerbated by loneliness.

Given the significant health burden associated with loneliness, in combination with evidence for widespread feelings of social isolation among refugees (Strijk et al., 2011) and the large number of newly arrived migrant in Europe, social isolation may turn into a concern of epidemic proportions for the health care system of host nations, which need to be addressed with proper interventions and policy-actions. One prescription for interventions to increase social cohesion is to develop community and family-focused programs centered around creative expression such as art, theater, or singing (Jefee-Bahloul, Barkil-Oteo, Pless-Mulloli, & Fouad, 2015). Such programs would be particularly powerful in countering the long-term sequelae of trauma, which can exacerbate preexisting mental health conditions and may even be transmitted trans-generationally (Jefee-Bahloul et al., 2015).

Conclusions

In this article, I surveyed some of the current research literature linking psycho-social and biological variables related to somatic conditions and mental health. This work illustrates that a simple separation of physical and mental health conditions is outdated and likely costly in terms of long-term health burdens for individual patients and national health care systems. Yet, most studies cited here are limited by small sample sizes, cross-sectional, and largely based on non-refugee populations. The research literature that focuses on refugee populations tends to be epidemiological or clinical, rather than bio-psycho-social, in orientation and it also has significant limitations. For example, a recent systematic review (Bozorgmehr et al., 2016) surveyed the research health literature on refugees and asylum seekers in Germany and found that 63 percent of studies only used a single time point, highlighting a need for longitudinal study designs. Furthermore, of the fifty-two studies included in the review, only six addressed childhood illness and no study addressed the health needs of refugee or asylum-seeking women during pregnancy and child birth. These gaps in the literature should motivate a concerted effort to develop a comprehensive research agenda on the bio-psycho-social factors that affect European refugee and asylum seeking populations. The findings would be critical in developing individualized treatment interventions for patients and guide policy-makers to maximize stretched resources.

 

Turhan Canli, Ph.D., is Professor of Psychology and Psychiatry at Stony Brook University, NY, where he is also Director of the SCAN (Social, Cognitive, and Affective Neuroscience) Center and Director of the Mind/Brain Center on War and Humanity.

Photo: Sanliurfa Turkey, Tolga Sezgin | Shutterstock

 

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Published on February 1, 2017.

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