In the past, I have posted quite a few time about how adverse childhood experiences (ACE) can have a profound impact on physical and mental health (see here, here, here, here, here, and here, for example). This new study looks at how maternal separation in a mouse model impacts brain development.

It' easy to dismiss research like this because it involves mice, not humans. First of all, we could never do this research with humans - it's not ethical. More importantly, however, nearly all mammals hve similar parent/offspring bonding drives and needs, so for the first few months of life, we can model these behaviors in rodents with relative assurance that they will at least partially translate to humans.

In this particular mini-review, the researchers are seeking a molecular explanation of how early life stress impacts brain development and dysfunction (hint: stress hormones).

Full Citation: 
Nishi, M., Horii-Hayashi, N. and Sasagawa, T. (2014, Jun 17). Effects of early life adverse experiences on the brain: implications from maternal separation models in rodents. Frontiers in Neuroscience: Neuroendocrine Science; 8:166. doi: 10.3389/fnins.2014.00166

Effects of early life adverse experiences on the brain: implications from maternal separation models in rodents

Mayumi Nishi, Noriko Horii-Hayashi and Takayo Sasagawa

• Department of Anatomy and Cell Biology, Nara Medical University, Kashihara, Japan

During postnatal development, adverse early life experiences affect the formation of neuronal networks and exert long-lasting effects on neural function. Many studies have shown that daily repeated maternal separation (MS), an animal model of early life stress, can regulate the hypothalamic-pituitary-adrenal axis (HPA axis) and affect subsequent brain function and behavior during adulthood. However, the molecular basis of the long-lasting effects of early life stress on brain function has not been fully elucidated. In this mini review, we present various cases of MS in rodents and illustrate the alterations in HPA axis activity by focusing on corticosterone (CORT). We then show a characterization of the brain regions affected by various patterns of MS, including repeated MS and single time MS at various stages before weaning, by investigating c-Fos expression. These CORT and c-Fos studies suggest that repeated early life stress may affect neuronal function in region- and temporal-specific manners, indicating a critical period for habituation to early life stress. Next, we introduce how early life stress can impact behavior, namely by inducing depression, anxiety or eating disorders, and alterations in gene expression in adult mice subjected to MS.

Introduction

As our contemporary society changes rapidly, changes in family structure can have a large influence on the mother–child relationship, as well as on other social environmental factors. In adult patients with various neuropsychiatric disorders, childhood abuse including sexual and/or physical abuse and neglect, is one of the most serious causes (Bremne and Vermetten, 2001; Heim and Nemeroff, 2001; Teicher et al., 2006). Adverse experiences occurring during critical periods of development, such as perinatal life, harmfully influence behavior, and physiological functions, including growth, metabolism, reproduction, and immune responses. Stressful environments in early life may induce permanent rather than transient consequences in animals. Previous studies have indicated that early unfavorable events augment the risk of behavioral disorders in adulthood, including neuropsychiatric disorders, such as depression (Kendler et al., 2002) and psychosis (Morgan et al., 2007). In rodent and primate models, adverse environments during the neonatal periods seem to play a critical role in developing the brain systems important to regulate behavior and stress responsiveness. In particular, the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis can be deteriorated by interrupting usual mother-pup interactions, which may induce persistent changes in the neurobiology, physiology, and emotional behavior in adult animals (Ellenbroek et al., 1998; Lyons et al., 1998; Pryce et al., 2005; Enthoven et al., 2008; Nishi et al., 2013).

In this mini review, we will focus on the response of corticosterone (CORT), an end product of the HPA axis in rodents, and c-Fos expression for examining the activated brain regions induced by maternal separation (MS), a model of rodent early life stress. Furthermore, we will also present alterations of behavioral aspects and alterations in gene expression.

Early MS

The inventive studies of Levine and colleagues, and consequently of Meaney, Plotsky, and their collaborators have demonstrated that changes in rodents' early postnatal experiences can induce profound long-lasting effects on emotionality and stress response (Levine, 1967; Meaney, 2001; Plotsky et al., 2005), which have spurred the employment of the rodent MS for investigating early life stress. This early life stress model is based on the evidence that unfavorable events in early life cause the vulnerability for developing various kinds of diseases in later life. In this type of study, MS should be carefully discussed in comparison to the appropriate control group, which may or may not be undisturbed from mother.

The procedure of MS showed a variety of the duration (e.g., 60 min–24 h) and the number of days (e.g., 1–14 days, 15–21 days) for the separation experiences among laboratories (Biagini et al., 1998; Caldji et al., 2000; Barreau et al., 2004; Arborelius and Eklund, 2007; Carrera et al., 2009; Tjong et al., 2010). In MS paradigm, many experiments, but certainly not all, have demonstrated that separation of pups from their mothers during the early postnatal period permanently increased anxiety-like behaviors in adulthood (Francis et al., 1999; Huot et al., 2001, 2004; Menard et al., 2004). As to the HPA axis activity, the response to stress is relatively low during early postnatal life (Walker et al., 1991; Levine, 2005), while MS could lead to life-long hyperactivity of the HPA axis (Holmes et al., 2005; Lippmann et al., 2007; Aisa et al., 2008; Marais et al., 2008). In contrast, short-term disturbance (e.g., 15 min), which has been called “handling,” appeared to reduce anxiety-like behaviors, decrease HPA axis tone and reduce the response to stress in adulthood (Levine, 2005; Plotsky et al., 2005). The process of handling may imitate natural mice rearing, whereby the mother leaves her pups for short periods of time to collect foods. Thus, the short-term MS, handling, might be considered a more natural event.

The effect of MS also varies depending upon whether pups are separated in a group of littermates during MS or isolated singly. Miyazaki and colleagues recently reported that rat pups isolated singly from the mother during PND7 to PND11 presented disturbance of cortical function, whereas pups separated but gathered from PND7 to PND11 showed no cortical disruption (Miyazaki et al., 2012).

Characterization of Maternally Separated Animals

Serum Level of CORT

In rodents, there is an unique period during which the HPA axis shows a rapid regression known as the stress hyporesponsive period (SHRP) (Levine, 2001). This period extends from PND4 to PND14 in rats and from PND2 to PND12 in mice. During the course of SHRP, ACTH in increased and baseline plasma glucocorticoid levels are lower than normal (Rosenfeld et al., 1991). Because, during ontogeny, the maintenance of low and stable levels of CORT is necessary for normal growth and development of the central nervous system (CNS), the SHRP is hypothesized to be neuroprotective against stress-induced excessive stimulation of glucocorticoid receptors (GRs) (Sapolsky and Meaney, 1986; Sapolsky, 1996). In rodents, the presence of the mother appears to suppress HPA axis activity, which primarily preserves the SHRP. Indeed, even during the SHRP, MS is a compelling inducer of a stress response. Meaney and his colleagues suggest that the quality of the mother-pup interactions, such as increased maternal licking, grooming, and arched-back nursing, is an important aspect for the preservation of this dampened HPA axis activity (Francis et al., 1999). The disturbance of SHRP induced by MS could cause an excessive exposure of the brain to high concentrations of glucocorticoids and activation of GRs, which may subsequently regulate brain and behavior in later life. Enhanced secretion of stress-induced CORT was observed in pups separated from their mothers for 1 h on PND2 to PND9 (McCormick et al., 1998). Nevertheless, a recent study indicated that repeated MS for 8 h daily from PND3 to PND5 rapidly desensitized the HPA axis activity of neonatal mice (Enthoven et al., 2008). We also reported that repeated MS for 3 h daily from PND1 to PND14 did not elevate a baseline level of CORT on PND14, whereas a single-time MS for 3 h at PND14 raised a baseline CORT level (Figure 1) (Horii-Hayashi et al., 2013). In contrast to the effects of MS on neonatal animals, repeated MS for 3 h daily from PND1 to PND14 significantly raises a CORT level in adulthood, as reported by many studies (Ryu et al., 2008; Jahng et al., 2010; Horii-Hayashi et al., 2013).

FIGURE 1  

Figure 1. Plasma CORT levels of repeated maternal separation (RMS) and single-time maternal separation (SMS) mice on PND14 and PND21 (Horii-Hayashi et al., 2013). The graphs show plasma CORT concentrations of PND14 (A) and PND21 (B) (n = 5–9 for each group). Blood samples were collected before (pre-RMS) and after (post-RMS) the final separation from RMS mice and after the separation from SMS mice. *P < 0.05 vs. control, #P < 0.05 vs. Pre-MS.

Activated Brain Regions Analyzed by c-Fos Expression

The expression of the immediate early gene product c-Fos is a reliable molecular marker to investigate neuronal activation. The examination of c-Fos expression has revealed that many brain regions are activated by MS, which differs depending on age and the type of stress. We recently analyzed the c-Fos expression induced by repeated MS and single-time MS during different developmental stages and time periods. Mice were exposed to 3 h repeated MS daily from PND1 to PND14 or from PND14 to PND21, or to single-time MS at PND14 or PND21 (Horii-Hayashi et al., 2013). We clarified that MS activated many brain regions and that c-Fos expression patterns changed developmentally (Figure 2). Single-time MS at both ages activated many regions of the hypothalamus and limbic forebrain, while the pattern of c-Fos expression in the repeated MS groups were significantly different on PND14 and PND21. In repeated MS of PND14 mice, the c-Fos expression levels in many regions were markedly increased compared with age-matched controls, excepting the VMH, Arc, BST, DG, Ce, MePV, and MePD. By contrast, in repeated MS on PND21 mice, c-Fos expression was reduced to control levels in all observed brain regions except for the LS and CA3. These findings suggest that repetition of a homotypic stimulus suppresses c-Fos expression by PND21, but that such suppression is barely observed on PND14. Moreover, in animals exposed to repeated homotypic stress during the postnatal period, increase in adrenal CORT secretion does not always associate with increased c-Fos expression in the PVN. Such developmental differences in c-Fos expression detected in the repeated MS groups may be associated with a developmental critical period for stress responses involving the HPA axis, during which animals are more susceptible to MS and other environments. In rodents, the critical period is the first two postnatal weeks. Thus, in early life, a repeated stress will be unlikely to suppress c-Fos expression. In turn, inappropriately activated c-Fos target genes may drastically alter how neurons function in critical neural circuits. Indeed, the suppression of increased c-Fos expression in repeated MS of PND14 mice was observed in specific regions (BST, Ce, MePD, and MePV) that form anatomical neural connections. These regions are referred to as an extended amygdala, which are closely associated with anxiety, fear, and psychiatric disorders (Davis et al., 2010). Therefore, even at PND14, repeated homotypic stress may reduce neural activity in the circuit of the extended amygdala. Moreover, in the SFO, where neurons are influenced by osmolality, calcium, and sodium concentrations in the systemic circulation (Smith and Ferguson, 2010), c-Fos expression was increased in both repeated and single-time MS mice, as compared to controls, on PND14. However, there were no changes in any of the groups on PND21. This difference may reflect the increased resistance of physical growth to the hyperosmolality induced by deprivation of lactation.

FIGURE 2  

Figure 2. c-Fos expression in the hypothalamus and limbic forebrain after MS (Horii-Hayashi et al., 2013). The graphs show the numbers of c-Fos-positive cells on PND14 (A) and PND21 (B) in non-separated control (white bar), RMS (gray bar), and SMS (black bar) mice (n = 4–5 for each group). In both RMS and SMS, the sampling point is just after MS procedure. *P < 0.05 vs. control; #P < 0.05 vs. RMS. MPO, medial preoptic area; PVN, paraventricular nucleus; SFO, subfornical organ; DM, dorsomedial hypothalamic nucleus; VMH, ventromedial hypothalamic nucleus; PrL, prelimbic cortex; MO, medial orbital cortex; LS, lateral septum; Cg, cingulate cortex; BST, bed nucleus of stria terminalis; CA1, hippocampal area CA1; CA3, hippocampal area CA3; DG, dentate gyrus; RSG, retrosplenial granular cortex; La, lateral amygdaloid nucleus; BLA, anterior part of the basolateral amygdaloid nucleus; Ce, central amygdaloid nucleus; MePD, posterodorsal part of the medial amygdaloid nucleus; MePV, posteroventral part of the medial amygdaloid nucleus; Pir, piriform cortex.

Behavioral Changes Induced by MS in Rodents

Early life adverse experiences including MS is one of the greatest contributing factors for mental health problems across life stages (Levine, 2005), relating not only to risk for mental health disorders but also to transdiagnostic features common in many psychological disorders (Glaser et al., 2006). I will introduce some of the behavioral aspects observed in animal model of MS.

Depression- and anxiety-like behaviors

Numerous studies have demonstrated a strong relationship between traumatic events during early life and development of behavioral abnormalities later in life. Early life adversity, such as that induced by MS, child physical, sexual, and emotional abuse, and general neglect has been linked to serious psychiatric impairment in adulthood (MacMillan et al., 2001). Particularly, a stressful life event such as early parental loss is associated with unipolar and bipolar depression, as well as anxiety disorders, beyond familial or genetic factors (Kendler et al., 1992; Agid et al., 1999; Furukawa et al., 1999; Heim and Nemeroff, 2001). Many human studies have reported that major depression and anxiety disorders are frequent in adults with a history of childhood abuse (Stein et al., 1996; Felitti et al., 1998). There have been numerous reports of the behavioral changes induced by MS in animal studies. Neonatal MS induces permanent alterations in the characteristics of the HPA response to stress in the offspring later in life (Ladd et al., 1996; Vazquez et al., 2000). Many studies of repeated MS during the first 2 weeks of neonatal life showed depression- and anxiety-like behaviors in adulthood (Newport et al., 2002; Daniels et al., 2004; Lee et al., 2007; Ryu et al., 2009). In these studies, ambulation and rearing decreased, immobility during a forced swim test increased, and time spent in the closed arms of an elevated plus maze increased.

Fear response

Until recently, no one had investigated how early experiences affected fear retention and extinction development, although these forms of emotional learning could be critically involved in the pathogenesis and treatment of mental health problems. Recent several studies showed that the timing of the maturation of fear learning is not set in static, but can be dynamically regulated by early experiences. Although the exact mechanisms are still unknown, when rats are reared under stressful conditions then they exhibit adult-like fear retention and extinction behaviors at an earlier stage of development (Callaghan et al., 2013). Chocyk et al. reported that MS decreased freezing time in both contextual and auditory fear conditioning in adolescent and adult rats (Chocyk et al., 2014). These results suggest that early life stress may permanently affect fear learning and memory.

Food intake and response to food deprivation

Previous studies showed that repeated MS during the first 2 weeks after birth may not permanently affect food intake and body weight gain of the offspring as long as the pups are reared in a group (Iwasaki et al., 2000; Kalinichev et al., 2002; Ryu et al., 2008). In contrast, post-weaning social isolation promotes food intake and weight gain of adolescent MS pups, with impacts on anxiety-like behaviors (Ryu et al., 2008). Anhedonia to palatable food, one of the major symptoms of depression, was reported in adolescent MS pups with disruption of the mesolimbic dopaminergic activity in response to stress (Noh et al., 2008). Another study showed that sustained hyperphagia observed in the MS pups subjected to a fasting/re-feeding cycle repeated during adolescent period of MS pups induced a binge-like eating disorder, in which increased activity of the HPA axis responding to such metabolic challenges appeared to play a role, at least partly, in mediation with the hypothalamic neuro peptide Y (NPY) (Jahng, 2011).

Gene Expression

Many animal studies, including MS, have improved our knowledge of gene-environment interactions and elucidated the pathways that program an animal in response to its early life experiences (Meaney and Szyf, 2005). Epigenetic mechanisms involving DNA methylation, post-translational modification of histone proteins and non-coding RNAs (most notably micro-RNA) are major candidates for regulating gene expression and integrating intrinsic and environmental signals in the genome (Jaenisch and Bird, 2003). Murgatroyd and colleagues showed that in the parvocellular subdivision of the paraventricular nucleus of the hypothalamus, MS in mice persistently upregulates Avp gene expression associated with reduced DNA methylation of a region in the Avp enhancer. This early life stress-responsive region serves as a binding site for the methyl-CpG binding protein 2, which in turn is regulated through neuronal activity. They also found that the ability of methyl-CpG binding protein 2 to control transcription of the Avp gene and induce DNA methylation occurred by recruiting components of the epigenetic machinery (Murgatroyd et al., 2009; Murgatroyd and Nephew, 2013). Other groups investigated DNA methylation levels at a specific sequence motif upstream of the GR gene (Nr3c1) in the hippocampus of offspring, and found that subjecting pups to a single 24 h MS increases methylation levels (Kember et al., 2012). The epigenetic alterations of these genes suggest that the HPA axis could be dysregulated by MS. Importantly, however, the DNA methylation differences were also often strain specific (Kember et al., 2012). Taken together, these findings demonstrate the importance of investigating environmental effects on a range of genetic backgrounds, emphasizing the need for the further examination of environmental, genetic, and epigenetic interactions.

Conclusions

Adverse environments and experiences during the neonatal period can dramatically affect the development of the HPA axis that underlies adaptive behavioral responses. MS experiments, as a model of early life stress, demonstrate that CORT levels and c-Fos expression change depending upon the different experimental conditions of MS, e.g., age at testing and frequency of repetition. Furthermore, separation conditions (isolation with or without a littermate) could also influence the results of the MS experiments. MS can induce various behavioral changes manifested in later life, which could be caused, at least in part, by alterations in gene expression, particularly through epigenetic mechanisms.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This work was supported by Grants-in-Aid for Scientific Research (23390040 to Mayumi Nishi and AstraZeneca Research Grant 2009). We thank Dr. Julian G. Mercer, a chief editor of J Neuroendocrinology, for permitting the reuse of our own figures published in J Neuroendocrinology.

References available at the Frontiers site.

Adverse Childhood Experiences and Our Conceptions of Mental Illness (by me) - Part 1

I have mentioned several times in recent weeks that I have been working on a paper dealing with adverse childhood experiences and adult mental illness - more specifically a rejection of the bio-bio-bio model of psychology that currently is dominating the landscape and offering support for more integrated biopsychosocial model (which used to be "the thing" a decade ago).

This is roughly the first 13 page of the text (with references at the end). It is a VERY rough draft and has not been edited more than a cursory once over to ensure it makes at least a little sense. When I do revise, I'm sure it will grow with more references and more explanation.

Feedback is welcome.

Adverse Childhood Experiences and Our Conceptions of Mental Illness

William Harryman, MSC, NCC, MS

The world of counseling and psychotherapy is rapidly approaching a potential future in which it no longer exists in its current form due to the rise of the biomedical model of mental illness and of psychopharmacology as the primary research and treatment avenue. Even the Federal government is backing the biomedical model. On 2 April 2013, President Barack Obama announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, with a requested $100 million dollars in funding for the 2014 fiscal year (Insel, Landis & Collins, 2013). In March of 2014, President Obama requested an increase in funding to $200 million for fiscal year 2015 (NIH, 2014). There is nothing remotely comparable in funding available for research into psychosocial intervention models. How we (counselors, social workers, psychotherapists) navigate the next decade or so could determine if there is a future for counseling and psychotherapy. In fact, we must do much more than navigate this difficult situation—we must advocate for our profession, for psychosocial causes and treatments for mental illness, and for a greater understanding of how adverse childhood experiences contribute to nearly all mental illness, from depression to anxiety disorders, from personality disorders to the various psychoses.

* * *

In 2005, Dr. Steven Sharfstein, then president of the American Psychiatric Association, wrote an article called, "Big Pharma and American Psychiatry: The Good, the Bad, and the Ugly." He was worried, and rightfully so, that psychiatry had been reduced to a pill-pushing profession. He warned that if psychiatrists were perceived to be "mere pill pushers and employees of the pharmaceutical industry, our credibility as a profession is compromised.” Sharfstein went so far as to urge his colleagues to "examine the fact that as a profession, we have allowed the bio-psychosocial model to become the bio-bio-bio model."

The end result of this unfortunate disregard for the incredibly well-documented impact of a dysfunctional early environment on mental health issues in adults (Edwards, et al, 2003; Anda, et al, 2006; Bemporad & Romano, 1993; Famularo et al., 1992; Silverman et al., 1996) is that the National Institutes for Mental Health (NIMH) earlier this year declared that only research oriented toward identifying organic, biological causes for mental illness would receive funding. NIMH director Thomas Insel has set out a very limited agenda for future funding, as outlined in his February 27, 2014 NIMH Director’s Blog.

Insel is mandating three serious changes to how the NIMH funds future research, but it is the first proposed change that is most relevant to those who favor a more integrated model for the etiology of mental illness:

First, future trials will follow an experimental medicine approach in which interventions serve not only as potential treatments, but as probes to generate information about the mechanisms underlying a disorder. Trial proposals will need to identify a target or mediator; a positive result will require not only that an intervention ameliorated a symptom, but that it had a demonstrable effect on a target, such as a neural pathway implicated in the disorder or a key cognitive operation. (Insel, 2014)

This approach seems short-sighted in that many new drugs are discovered to be effective in reducing some type of symptom, but the mechanism of action remains unclear for years or even decades. In the well-known Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (Trivedi, Rush, Wisniewski, 2006), a range of medications that impact serotonin, norepinephrine, and dopamine showed no statistical differences in effect, suggesting that the commonly accepted notion of depression as a serotonin-based illness is not supported by the evidence. Considering this outcome, would Insel’s NIMH fund such a study under these new guidelines?

In the blog post referenced above, Insel goes on to say that there will be funding set aside for other approaches:

Moreover, a subset of the funding announcements will support clinical trials that evaluate the effectiveness or increase the clinical impact of pharmacological, somatic, psychosocial, rehabilitative, and combination interventions. (Insel, 2014)

It remains unclear how these projects might be funded if they are made to conform to the criteria presented above, although there is some acceptance of manualized treatment protocols such as cognitive behavioral therapy (CBT) and interpersonal therapy (IP). A psychosocial intervention is likely not going to offer a single target gene, neural circuit, or brain region as the mediator in a given mental illness. Despite this, in the STAR*D trial mentioned above, CBT outperformed all of the medications but took slightly longer to do so (Rush, Trivedi, Wisniewski, et al., 2006).

Relationship of Early Adverse Experience on Adult Mental Health

We now have incredible piles of research, and decades of clinical evidence, that adverse childhood events are associated with mental health issues, including depression, anxiety, PTSD, personality disorders, and substance use disorders (Kessler et al., 2010; Read & Bentell, 2012). Even serious mental illnesses often thought to be genetic, such as schizophrenia and psychosis, have been profoundly linked to childhood trauma (Bebbington, 2009; Larkin & Read, 2008; Varese, et al., 2012). In fact, the genetic evidence for causation in schizophrenia is somewhat mixed, while there is substantial support for environmental causes. The National Institutes of Health (NIH) states that there are roughly 2.4 million Americans with schizophrenia, but then admits a few sentences later that genetic mutations can only explain a few thousand of these cases. Here are the comments by Dr. Francis Crick (2014):

Over the last five years, multiple research projects known as genome-wide association studies (GWAS) have identified dozens of common variations in the human genome associated with increased risk of schizophrenia [2]. However, the individual effects of these variants are weak, and it’s often not been clear which genes were actually affected by the variations. Now, advances in DNA sequencing technology have made it possible to move beyond these association studies to study the actual DNA sequence of the protein-coding region of the entire genome for thousands of individuals with schizophrenia. Reports just published have revealed a complex constellation of rare mutations that point to specific genes—at least in certain cases.

These are not convincing comments on the state of genetic research. A very recent article on environmental causes for schizophrenia cites new GWAS research that offers a much lower causative factor for genes as opposed to environment:

In a new GWAS study, Ripkeetal (2013) estimated that in schizophrenia about 8.300 [single nucleotide polymorphisms] SNPs contribute to a common risk of 32%, suggesting that environmental factors interacting with the genetic background contribute to the pathophysiology (Manolioetal, 2009). In schizophrenia, environmental factors are proposed to play a role up to 60% (Benrosetal, 2011). (Schmitt, Malchow, Hasan, and Falkai, 2014)

Based on this research, environmental factors are twice as likely to cause schizophrenia as are genetic factors and yet the research community seems to buy into the genetic causation model.

According to the DSM-IV-TR, there are five “characteristic symptoms” of schizophrenia: hallucinations, delusions, thought disorder (disorganized thinking), grossly disorganized or catatonic behavior, and negative symptoms (APA 2000). One inpatient study (Read and Argyle 1999) found one or more of these symptoms in 75% of those subjects who had suffered childhood physical abuse (CPA), in 76% of those who had suffered childhood sexual abuse (CSA), and in 100% of those subjected to incest. In a study of outpatient schizophrenics, 35% had experienced emotional abuse, 42% had experienced physical neglect, and 73% had experienced emotional neglect (Holowka et al, 2003). The same study found that among adult outpatients diagnosed with schizophrenia, 85% had experienced some form of childhood abuse or neglect, 73% emotional neglect, and 50% sexual abuse.

A review of 40 studies in which 50% of the subjects had been diagnosed psychotic, both inpatient and outpatient, found that half of the women had experienced childhood sexual abuse, and a majority of women (69%) and men (60%) experienced either childhood sexual or physical abuse (Read et al, 2004). Read, van Os, Morrison, and Ross (2005) report that patients subjected to CSA or CPA have “earlier first admissions, longer and more frequent hospitalizations, spend longer in seclusion, receive more medication, are more likely to self-mutilate and to try to kill themselves, and have higher global symptom severity” (Beck & van der Kolk, 1987; Briere et al, 1997; Garno et al, 2005; Goff et al, 1991; Lange et al, 1995; Lipschitz et al, 1996; Mullen et al, 1993; Read, 1998; Read et al, 2001; Rose, Peabody, & Stratigeas, 1991; Sansonnet-Hayden et al, 1987). In another study, childhood abuse was a better predictor of suicidality in adult out-patients than was a current depression diagnosis (Read et al, 2001).

Childhood abuse and neglect are possibly more related to psychoses such as schizophrenia than they are to anxiety or mood disorders.

Many studies, however, provide further evidence that child abuse and neglect may be even more strongly related to diagnoses of schizophrenia than to diagnoses indicating less severe disturbance. (Read, Rudegeair & Farrelly, 2006)

This is an important statement. If this is true, there must be an effort to prevent abuse and neglect at the same level in which there is an effort to cure HIV or to cure cancer. A society should be judged by how well it takes care of its weak and vulnerable, and there are no members of this society as vulnerable as are children. We are failing them—and in the most extreme outcomes, they respond to a world that is unfathomable and intolerable with psychosis.

* * *

In the 1950s, schizophrenia was often conceptualized as a disease resulting from poor parenting skills on the part of the mother and in her use of the “double bind” in verbal and non-verbal interactions with the child. Gregory Bateson (1956) was the primary architect of this theory, and it still echoes in the folk psychology of schizophrenia. Here is a definition of the “double bind” as given in Bateson’s seminal paper on the subject:

We hypothesize that there will be a breakdown in any individual's ability to discriminate between Logical Types whenever a double bind situation occurs. The general characteristics of this situation are the following:

1. When the individual is involved in an intense relationship; that is, a relationship in which he feels it is vitally important that he discriminate accurately what sort of message is being communicated so that he may respond appropriately.

2. And, the individual is caught in a situation in which the other person in the relationship is expressing two orders of message and one of these denies the other.

3. And, the individual is unable to comment on the messages being expressed to correct his discrimination of what order of message to respond to, i.e., he cannot make a meta-communicative statement. (Bateson et al., 1956)

In point two Bateson presents the fundamental conflict of the double bind: the caretaker (rather than always the mother) feels hostility or anxiety with the child, but instead of processing those feelings they get pushed down and she tries to pretend she feels nothing but love for the child. For the child, this creates a situation of having to choose between the words or the actions (the somatic experience) of the caretaker, forcing them into having to deny or disregard one or more aspects of their own experience. Furthermore, the child is forbidden either implicitly or explicitly from objecting to the bind in which she is place.

This act of denial can stem from something as simple as the mother saying, “Mommy loves you,” while simultaneously being physically rigid or emotionally distant. To that end, Bateson and his team make the following assertion:

[W]e hypothesize that the mother of a schizophrenic will be simultaneously expressing at least two orders of message. These orders of message can be roughly characterized as (a) hostile or withdrawing behavior which is aroused whenever the child approaches her, and (b) simulated loving or approaching behavior which is aroused when the child responds to her hostile and withdrawing behavior, as a way of denying that she is withdrawing. (Bateson et al., 1956)

For the child in this situation, there is no good option. He must reject his own inner sense of the mother’s emotional state and accept her false loving behaviors. Thus he is in a double bind.

The only way the child can really escape from the situation is to comment on the contradictory position his mother has put him in. However, if he did so, the mother would take this as an accusation that she is unloving and both punish him and insist that his perception of the situation is distorted. (Bateson et al, 1956)

The obvious fallacy in this model is that parents who place their children in a double bind will have children who become schizophrenic. Clearly, there is a lot of double bind communication in families that never results in psychosis or schizophrenia. It is more likely, however, that double bind communication patterns are one of the environmental factors leading to schizophrenia and, it seems logical to assume, other forms of mental illness (as already outlined above).

Bugenthal et al. (1971) found that in families with “disturbed members” (children who were referred by schools because of disruptive behavior and chronic emotional problems), a greater number of mothers engaged in conflicting verbal-nonverbal communication than did mothers in families without “disturbed members” during a five-minute period families were observed discussing family related issues (cited in Koopmans, 1997). This finding seems to add some more foundation to the power of double bind and conflicting communications to have negative impacts on some children, likely those with genetic vulnerability and/or those who have experienced other forms of abuse or neglect.

* * *

While one might be tempted to assume that harsh or highly demonstrative parental communication (yelling, screaming, and so on) would be at the root of mental illness in their offspring, the opposite seems to be the case. Considerable research (Gross & Levenson, 1997; Jenkins, Karno, de la Selva, & Santana, 1986; Left & Vaughn, 1985) has shown that it is low emotional expression that is most common in families with schizophrenic children. This defies the folk understanding of the etiology of mental illness, yet it also explains the observed “confusion of message and meta-message” in the communication of schizophrenics (Bateson, et al., 1962). In a family with low emotional expression, the double bind might be, “We love you” (the first order message), “But we don’t show emotions in this family” (the second order message). On top of that contradiction, the child is also forbidden to be aware of or to mention the contradiction.

In more obviously abusive families, especially sexual abuse, there is profound connection between double binds and dissociation. David Spiegel (1986) suggests that the double bind is a primary factor is dissociative experience in individuals who are disposed to such experience (which is equivalent to being easily hypnotized).

There is a triggering traumatic event—the first episode of sexual abuse—that is repeated over time in a family environment that all too often fails to restoratively provision the victim. Rather, the family double binds the child by insisting that she simultaneously become a demure “good girl” and a sultry sexual partner to the perpetrator and further enjoins her not to know about or point out the contradictory demands. (Davies & Frawley, 1994)

In order to cope with both the abuse and the double bind, the child dissociates. Over time the child will resort to dissociation, because it works, whenever reality becomes too averse. To extend this out into the adult life of this child, if the abuse continues and the double binds continue, there is a much higher risk of psychosis, as the statistics presented about illustrate.

The renowned psychoanalyst, and co-founder (with Robert Stolorow and Donna Orange) of the intersubjective systems theory of relational psychoanalytic therapy (Atwood & Stolorow, 1984; Stolorow et al., 1987; Stolorow & Atwood, 1992; Orange, 1995; Orange et al., 1997), George Atwood, posits that for some who fall into psychosis, the cause is a profound enmeshment with the caregiver in childhood (Atwood, 2011). In line with Atwood’s thinking, but using different terminology, Munich and Munich (2009) outline what they term “overparenting”:

In psychological terms, overparenting includes an excessive involvement with and concern about the child’s mental state and adaptive capacity that leads to a relative absence of space for the development of structuralized self and object relations. This also involves difficulty with separation, especially evident as the child leaves home.

According to these authors, we are seeing the results of this “helicopter parenting” in college-age young adults.

The sequelae of this level of parental involvement can be seen in a dramatic increase in demand for college counseling services for students with severe adjustment disorders, presentations of low self-esteem, and ongoing difficulties in feeling autonomous, as well as disorders of the self, represented not as much by cognitive or instrumental deficits, but more with feelings of emptiness and confusion about direction. (Munich and Munich, 2009)

According to Atwood, this type of overparenting or enmeshment can lead to a sense of annihilation for the child, and annihilation in this context is the “abyss of madness.”

An accommodation has taken place at a very young age in which the agenda of the caregiver–it can be the mother, the father, or both–becomes the supreme principle defining the child’s developing sense of personal identity. The experience of the child as an independent person in his or her own right is nullified, so that they child the parents wish for can be brought into being. Very often there are no outward signs of anything amiss, as family life unfolds in a seeming harmony. Somewhere along the way, however, the false self begins to crumble, and a sense of the degree to which the child has been absent from life arises. (Atwood, 2011, p. 60)

For the child, there is the sense of emptiness mentioned above by Munich and Munich, of never having been a unique self. There is the very real sense of having been controlled and manipulated by outside forces. This sense of emptiness and external control may take on concrete reality for the child, who is now at least a teen or young adult, as a delusion that begins to replace reality, for example in the image of an influencing machine (Tausk, 1933; Orange et al., 1997). “What looks like a breakdown into psychosis and delusion thus may represent an attempted breakthrough, but the inchoate ‘I’ does require an understanding and responsive ‘Thou’ in order to have a chance to consolidate itself” (Atwood, 2011, p. 61).

* * *

Returning to the topic of seeking biological explanations and treatments for psychosis and schizophrenia, the synthesis of the first antipsychotic medication, Thorazine (chlorpromazine hydrochloride), in 1951 and its subsequent use as the primary treatment for schizophrenia in the late 1950s and early 1960s, resulting in a shift for the whole model of treating mental illness from psychosocial to biological. At the time, there was a power struggle between the old guard of psychoanalysis on one side, and the rise of biological psychiatry on the other (Rissmiller & Rissmiller, 2006). “Chlorpromazine was instrumental in the development of neuropsychopharmacology, a new discipline dedicated to the study of mental pathology with the employment of centrally acting drugs” (Ban, 2007). Thorazine led to tricyclic antidepressants in the 1960s and, eventually, to the creation of selective-serotonin-reuptake-inhibitors (SSRI) antidepressants, the first one being fluoxetine (Prozac), discovered in 1974 (Wong, et al.) and approved by the Food and Drug Administration in 1987.

With the rise of psychopharmacology to manage mental illness, the “mental asylum” became a thing of the past. In 1955, the mentally ill population in public psychiatric hospitals peaked at 560,000 (Pan, 2013). By 2004, the number of seriously mentally ill people in jails and prisons outnumbers those in hospitals by three-to-one—320,000 people in prison (16% of all inmates) and about 100,000 in public and private hospitals (Pan, 2013). According to the Bureau of Justice Statistics (2006), the numbers are much higher—by midyear of 2005 more than half of all prison and jail inmates had a mental health problem,

including 705,600 inmates in State prisons, 78,800 in Federal prisons, and 479,900 in local jails. These estimates represented 56% of State prisoners, 45% of Federal prisoners, and 64% of jail inmates. (BJS, 2006)

We have literally recreated the “bedlam” approach to housing the mentally ill. More alarming, perhaps, is that only 1 in 3 State prisoners and 1 in 6 jail inmates with mental health issues are getting any form of treatment after admission (BJS, 2006).

As the number of people in psychiatric hospitals declined over the past four decades, so did the number of psychiatrists treating those people with anything other than medications. According to a 2011 New York Times article (Harris):

A 2005 government survey found that just 11 percent of psychiatrists provided talk therapy to all patients, a share that had been falling for years and has most likely fallen more since. Psychiatric hospitals that once offered patients months of talk therapy now discharge them within days with only pills.

We are left, then, with the NIMH only offering funding for research that adheres to a biological model of mental illness, with more mentally ill adults in prisons than in psychiatric hospitals (where few of them are receiving treatment), and with only 11% of psychiatrists still offering therapy to all of their clients. Clearly, the biological model has won the battle.

So, then, what are we to do with all of the clinical and research evidence of how intensely early adverse relational experiences impact adult mental health status?

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