Childhood Onset Schizophrenia

Childhood Onset Schizophrenia (COS) is known to result in a more severe and debilitating form of schizophrenia. It is rare, but often studied, as researchers try to look at the factors that lead to the adult disease, focusing on the neurodevelopmental theory. They have looked at overall development of children born to parents who have schizophrenia. They have looked at the frequency of obstetrical complications in individuals with schizophrenia. They have looked at the brain development of those with COS as compared to adolescents and adults. In each area they find clues to the reasons behind this illness. It is fascinating to see how many early events have a part in the development of this disease.

Even before childhood, at birth these individuals seem to have factors that are part of their eventual development of schizophrenia. Cannon has postulated that obstetrical complications combined with genetic factors lead to schizophrenia. He has found that early onset schizophrenia (EOS) is 7.30 times more likely to have had hypoxic obstetrical complications than those with adult onset. This can contribute to the early brain lesion that researchers feel is ultimately behind the development of schizophrenia. Cannon also proposes that this earlier onset in COS allows for an earlier and more robust pruning of synapses during adolescence – “variations in the rate of synaptic pruning would vary the age of clinical onset of schizophrenia” (Cannon 2000).

In terms of development, there have been studies that look back at the early lives of people with schizophrenia to see if there are any early signs that might give a clue as to who will develop the disease. In interviewing parents, it has been found that those who go on to develop schizophrenia have delayed speech milestones, difficulty in reading and writing, and greater overall developmental deviance. They show poor premorbid adjustment in childhood. Particularly boys show even more as they move through adolescence. There are cognitive deficiencies and some motor difficulties. Finally, they show more Schizophrenia Spectrum trait (Hollis 1995). What’s particularly interesting is that they have found more impairment in COS than in even EOS. One study by Vourdes has shown a 19.4% delay in language and speech in COS as compared with EOS. They also found that schizophrenia spectrum traits were more pronounced in COS. They exhibited more deviance in bizarre ideas and perceptions, more of a restricted affect and odd speech (Vourdes 2003). Nicholson has found that there is a much higher incidence of PDD in children that go on to develop COS. 25% of those with COS had a premorbid PDD, showing a social impairment most predominantly, he reports that PDD in COS is more likely to be a marker of severe early abnormal neurodevelopment (Nicholson 2003). So, there are significant early markers for this illness. These could in fact lead to earlier diagnosis, before the devastating symptoms emerge and then maybe earlier treatment that might prevent some of the brain destruction.

Moving into the more specific changes that are found in the brains of adolescent and COS. Thompson took a cohort of COS and took 3 MRI’s at 2 year intervals to see the progression of brain changes between childhood through adolescence “Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search, and frontal executive impairments in the disease” (Thompson 2001). Researchers are trying to connect symptoms to brain areas and finding some correlations. This has been attempted over the years, but it seems they are finally finding some real connections. It was also found that in some areas of the brain the tissue loss was faster the younger the client was and that the faster there was tissue loss, the more severe the symptoms.
Coming at this from another angle – looking at the loss of grey matter in COS Gogtay compared COS with children with atypical psychosis. Gogstay suggests that there is a diagnostically specific GM volume loss in COS that was not seen in children with atypical psychosis. “An ongoing neurodevelopmental process and/or brain response specific to the illness could account for these changes.” (Gogtay 2004)
There are a number of factors that all seem to play into the development of schizophrenia from a very early age. Comparing the neurodevelopment of those with the more severe COS with those without yields much interesting data. (Rapoport 2004) It seems to point to an element – genetic – that is then compounded by environmental effects. The maturing brain then adapts to this maladaptation and develops in specific patterns the symptoms. The more we can learn about the early indicators of this illness, the closer we can get to the root causes. Interesting work is being done on looking at all these factors as they relate to the interconnectivity of the disorder. It is clearly not one gene or birth insult or developmental pattern. It is rather the interplay of all these factors that will lead into understanding more fully the causes and development of this devastating disease.

Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J & Nicolson R
et al.. Mapping adolescent brain change reveals dynamic wave of
accelerated gray matter loss in very early-onset schizophrenia.
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Cannon TD, Rosso IM, Hollister JM, Bearden CE, Sanchez LE & Hadley T.
A prospective cohort study of genetic and perinatal influences in
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Hollis C. Child and adolescent (juvenile onset) schizophrenia. A case
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Psychiatry 1995; 166: 489−495.

Gogtay N, Sporn A, Clasen LS, Nugent TF, III, Greenstein D & Nicolson R
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childhood-onset schizophrenia with that in childhood-onset
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Vourdas A, Pipe R, Corrigall R & Frangou S. Increased developmental
deviance and premorbid dysfunction in early onset schizophrenia.
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Sex Differences in Depression

Across many nations, cultures, and ethnicities, women are about twice as likely as men to develop depression (Nolen-Hoeksema, 1995).  By late adolescence, girls are twice as likely as boys to be depressed, and this gender ratio remains more or less the same throughout adulthood. The absolute rates of depression in women and men vary substantially across the life span, however.  Because women have less power and status than men in most societies, they tend to experience certain traumas, particularly sexual abuse, more often than men. They also experience more chronic strains, such as poverty, harassment, lack of respect, and constrained choices. Moreover, even when women and men experience the same stressors, women may be more likely than men to develop depression because of gender differences in biological responses to stressors, self-concepts, or coping styles (Nolen-Hoeksema, 2001).

It is these differences in biological responses to stress between females and males that capture my imagination as they might relate to our class discussions.  In a brief section in the depression chapter, Higgins and George (2013) refer to the notion of gene expression in which genes for depression, in this case, are expressed when some individuals encounter stressful events.  This theory seeks to explain why some individuals are more likely to lapse into depression when faced with difficult life situations while others who face the same or similar life situations do not.  The authors refer to two versions of the gene that produces the serotonin transporter – a short allele and a long allele.  According to one study the authors cite, individuals with copies of the short allele who encountered a stressful event were predisposed to develop major depression while individuals with copies of the long allele were not.  Unfortunately, a meta-analysis combining 14 studies did not yield evidence that the gene that produces the serotonin transporter was alone responsible for elevated risk of depression.  Higgins and George (2013) sagely point out that the disappointing results are likely due to the narrow focus on one gene when depression is likely the result of several genes.  Fair enough, but I was still intrigued that at least one gene has been identified that is surely implicated in depression and that that gene might account for some of the gender differences one finds in major depression.  I looked further.

I found a team of Swedish researchers who in a 2006 article explored sex differences in the prediction of depression when there was interaction of the serotonin transporter gene and adverse social conditions (Sjöberg et al.).  From a randomized sample of 81 boys and 119 girls ages 16 to 19 years old, 61% of the males and 74% of the females had the short allele.  The study yielded two very intriguing results.  First, males and females with the short allele respond to different environmental factors.  Based on a psychosocial interview protocol, the male students were negatively affected, on a significant level, by living in public housing rather than in a home their family owned, and they were negatively affected by living with separated parents.  The female students, on the other hand, were negatively affected by traumatic events within the family unit.  Although we cannot draw any definitive conclusions from one study with a small sample size, these findings can help point us in the right direction as we try to understand differences in triggers for depression in males and females.  This first finding suggests that triggers for male depression might be variables that are closely associated with social status.  In this example, living in public housing may stigmatize the males in a way that makes it difficult for them to save face with their peers.  While males with the long allele may be able to recover from such a stigma, males with the short allele are vulnerable to depressive episodes.  The female triggers for depression appear to be closely associated with variables for interpersonal relationships.  Females with the short allele may have difficulty recovering from disruptions in their primary relationships, which can then lead to depressive episodes.

The second important finding is that females and males carrying the short allele had responses to environmental stress that went in opposite directions.  Females tended to develop depressive symptoms in response to environmental stress, whereas their male counterparts appeared to be “protected” from depressive symptoms, according to the depression scale used in the study.  One possibility is that adolescent males develop other pathological behaviors, which might be a variant of male depression but that produces inverted scores on the depression scale.  This finding has important implications for the diagnosis of depression in males.

Gene expression as the result of interactions with environmental stressors is an exciting new field that promises to expand our understanding of the etiology of mental illness.  With a better understanding of the etiology of mental illness will come better ways to not only treat the symptoms of mental illness, which we are already fairly good at, but also in pre-empting mental illness from occurring at all.


Higgins, E. S., George, M. S. The Neuroscience of Clinical Psychiatry:  The Pathophysiology of Behavior and Mental Illness, 2nd edition.  Philadelphia, PA:  Lippincott Williams & Wilkins; 2013.

Nolen-Hoeksema, S. Gender differences in coping with depression across the lifespan. Depression. 1995; 3: 81.

Nolen-Hoeksema, S. Gender differences in depression.  Current Directions in Psychological Science. 2001; 10: 173.

Sjöberg, R. L., Nilsson, K. W., Nordquist, N., Öhrvik, J., Leppert, J., Lindstrom, L., and Oreland, L.  Development of depression:  Sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene.  International Journal of Neuropsychopharmacology 2006; 9: 443.

Using Biology to Treat Depression

Imagine Mike. For the past year Mike has become increasingly less interested in playing soccer (his favorite sport) and finds it difficult to get out of bed every morning. He feels tired all day since he has trouble sleeping and has difficulty concentrating at work. When his job becomes very stressful, he feels that life may be better if he was not around. According to the DSM-5, Mike is diagnosed with Major Depressive Disorder (MDD). This disorder has a lifetime prevalence of 17-21% worldwide, but only 30-40% of patients respond to the standard first line treatment of antidepressants (Rocha et. al., 2016). This means that a majority of clients diagnosed with MDD will not have a successful and stabilized response to the first choice of treatment. In order to improve the success of first line therapy and decrease side effects, researchers are currently on the hunt for the biological basis of depression. One protein found in the brain that proves some promise is the relationship between brain derived neutrophic factor (BDNF) and depression. This growth factor is the first of its kind to link the effectiveness of a variety of treatments such as antidepressants, stimulation, and exercise to the normalizing levels of BDNF. If there was a direct way to target BDNF with minimal side effects, an effective treatment for depression may be discovered (Higgins & George, 2013).

BDNF is a growth factor plays a role neurogenesis, or the creation and differentiation of neurons. More specifically, BNDF creates a link between a given treatment and the depressive symptoms. Biologically, depression has shown to prevent the expression of BDNF, which inhibits the proliferation and differentiation of neurons in the brain (Higgins & George, 2013). A reduction in BDNF also shows links to immobility, which may explain the psychomotor delay found in some patients diagnosed with major depressive disorder (Galvez-Contreras et. al., 2016). Current research is focusing on the role and regulation of BDNF levels in the brain to treat depression. For example, studies have shown that a single infusion of BDNF into the ventricles of the brain, or directly into the hippocampus, is enough to induce a rapid and sustained anti-depressant-like effect (Bjorkholm and Monteggia, 2016). This study suggests that normalizing BDNF levels in the brain plays a direct role in treating depression. While researchers know that BDNF plays some role in treating depression, the current focus is to determine the exact mechanism BDNF plays in depression, and how new treatments can focus on re-establishing these levels with minimal side effects.

One treatment that has shown significant improvements in treatment refractory depression is the use of electroconvulsive therapy (ECT), or the induction of seizure activity through a controlled passage of electrical current in the brain. ECT is typically reserved for severe depression, and is most effective for patients who do not respond to antidepressants or other front line options (Rocha et. al., 2016). In a meta-analysis (2016), it was concluded that ECT treatment increases BDNF and is one of the most potent and rapid enhancers of the hippocampus. This is significant since the hippocampus is one part of the brain that has been found to decrease in volume with major depressive disorder. In order to predict the level of response in ECT, further studies were conducted to determine the link between BDNF and the rate of cognitive improvement. While baseline cognitive performance did not play a role in successful ECT treatment response, the rate at which cognitive performance increased predicted a successful response (Mikoteit et. al., 2015). Currently, the success of ECT relies on the rate at which cognitive improvement occurs and the severity of the depression. While this is a step in the right direction, much more research needs to be conducted to prove the effectiveness of ECT with accuracy.

Non-pharmacological treatment that targets the regulation of BDNF provides an alternative to the standard anti-depressant medications. With side effects such as increased falls and weight gain, anti-depressant medications are not specifically targeting the origin of one’s depression. Exercise, a non-pharmacological alternative, has been proven to normalize BDNF levels in the brain and has even shown a greater protection against relapse compared to medications (Dotson et. al., 2016). More specifically, prescribed exercise (with a specific goal in mind) has shown to increase BDNF (Meyer et. al., 2016). The study suggests that being directed to exercise at a given intensity was more effective than having a participant exercise at his/her preferred intensity. Providing clear and measureable expectations for exercise may lead to better depressive symptom management since the individual has an opportunity to feel successful. Therefore, preferred and self-directed exercise intensity limits the participant’s perception of success compared to the success from an exercise regimen set by a health care provider.

The initial connection between BDNF and depression can lead to a host of different treatments that can be more effective than the current treatments. Not only does more research need to be conducted to determine the biological basis of depression, subsequent research needs to be conduced to determine specific treatments for depression that target BDNF levels. As new research occurs, BDNF will continue to play a critical role in new treatments for depression with fewer side effects. Therefore, Mike may have a treatment in the near future that targets his specific depression with minimal side effects.



American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

Björkholm, C., & Monteggia, L. M. (2016). BDNF – a key transducer of antidepressant effects. Neuropharmacology, 102, 72-79. doi:10.1016/j.neuropharm.2015.10.034

Dotson, V. M., Hsu, F., Langaee, T. Y., McDonough, C. W., King, A. C., Cohen, R. A., . . . Pahor, M. (2016). Genetic Moderators of the Impact of Physical Activity on Depressive Symptoms. J Frailty Aging, 5(1), 6-14. doi:10.14283/jfa.2016.76

Galvez-Contreras, A. Y., Campos-Ordonez, T., Lopez-Virgen, V., Gomez-Plascencia, J., Ramos-Zuniga, R., & Gonzalez-Perez, O. (2016). Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders. Cytokine & Growth Factor Reviews. doi:10.1016/j.cytogfr.2016.08.004

Higgins, E. & George, M. (2013). The neuroscience of clinical psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins.

Meyer, J. D., Ellingson, L. D., Koltyn, K. F., Stegner, A. J., Kim, J., & Cook, D. B. (2016). Psychobiological Responses to Preferred and Prescribed Intensity Exercise in Major Depressive Disorder. Medicine & Science in Sports & Exercise, 48(11), 2207-2215. doi:10.1249/mss.0000000000001022

Mikoteit, T., Hemmeter, U., Eckert, A., Brand, S., Bischof, R., Delini-Stula, A., . . . Beck, J. (2015). Improved Alertness Is Associated with Early Increase in Serum Brain-Derived Neurotrophic Factor and Antidepressant Treatment Outcome in Major Depression. Neuropsychobiology, 72(1), 16-28. doi:10.1159/000437439

Rocha, R. B., Dondossola, E. R., Grande, A. J., Colonetti, T., Ceretta, L. B., Passos, I. C., . . . Rosa, M. I. (2016). Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: A meta-analysis study. Journal of Psychiatric Research, 83, 47-53. doi:10.1016/j.jpsychires.2016.08.004

DBS for Treatment Refractory OCD

At the time our course book was published, the DSM-IV categorized anxiety disorders together, including obsessive-compulsive and related disorders (OCRD) (American Psychiatric Association [APA], 1994). With updates to the DSM-5, OCRDs have been placed in their own category that includes: obsessive-compulsive disorder (OCD), body dysmorphic disorder, hoarding disorder, trichotillomania, and excoriation disorder (APA, 2013). The APA separated OCRDs from anxiety disorders because, although anxiety symptoms are a key feature in OCRDs, there are unique differences in symptom presentation among OCRDs that do not overlap with anxiety disorders, such as repetitive thoughts, distressing emotions, and compulsive behaviors (APA, 2013).

OCD is a chronic and disabling disorder characterized by repetitive unwanted thoughts (obsessions) or repetitive actions (compulsions) (de Koning, Figee, van den Munckhof, Schuurman, and Denys, 2011; Zarei et al., 2011). OCD affects approximately 1% of youth and 2% of adults (Heyman, Fombonne, Simmons, Ford, Meltzer, and Goodman, 2001). Functional and structural neuroimaging in adults with OCD has suggested that components of the cortico-striato-thalamic loops are likely the cause of OCD symptoms in both children and adults (Del Casale et al., 2011), however there is less imaging evidence available in youth. One recent study explored the differences in grey matter and white matter in adolescents with OCD and matched controls using fMRI (Zarei et al., 2011). In this study, adolescents with OCD had increased grey matter volume in the caudate bilaterally and right putamen, as well as hypertrophy of the dorsal caudate. In addition, symptom severity was correlated with increased grey matter volume in the right insula, posterior orbitofrontal cortex, brainstem, and cerebellum. Thus, there are notable differences in neuroanatomy in adolescents with OCD compared to healthy controls.

The gold standard, first-line treatment for OCD is cognitive behavioral therapy (CBT) (Denys, 2006). Pharmacotherapy with SSRIs is also an effective treatment for OCD (de Koning et al., 2011), however patients with early onset OCD tend to respond less well to pharmacotherapy (Zarei et al., 2011). Despite these treatment options, approximately 10% of individuals suffer from treatment refractory OCD (Denys, 2006). For these patients, deep-brain stimulation (DBS) is a last resort option. DBS requires the implantation of electrodes in the brain that send electrical impulses to specific locations in the brain based (de Koning et al., 2011). Interestingly, DBS of the balsal ganglia is a treatment utilized for movement disorders, such as Parkinson’s disease, essential tremor and dystonia, suggesting that there is a similarity in the anatomical structures involved in OCD and movement disorders (Haq et al., 2010).

Approximately 100 individuals with treatment-refractory OCD have undergone DBS and 5 different anatomical locations have been used (de Koning et al., 2011). For example, in one of the first trials, DBS in the anterior limb of the internal capsule led to a 40% reduction in symptoms in 4 patients (Nuttin, Gabriels, Cosyns, 2002). In 11 patients who underwent ventral capsule stimulation, a 35% reduction in symptoms was found over 3 years (Greenberg, Malone, Friehs, 2006). Because OCD has been associated with the reward system, the nucleus accumbens (NAc), a neurological structure associated with reward processing, has been considered a viable target for DBS (Figee, Vink, de Geus, 2011). As such, a clinical trial of DBS on the NAc in 10 individuals with OCD showed a 10% reduction in symptoms (Huff, Lenarz, Schormann, 2010).

Our text indicates that the orbitofrontal cortex, anterior cingulate gyrus, and basal ganglia are involved in the psychopathology of OCD (p. 271). Two areas of the brain that are a part of these structures have been tested in studies of DBS. The subthalamic nucleus (STN), a part of the basal ganglia, is considered an effective target for Parkinson’s disease. In a study of 2 participants with comorbid Parkinson’s disease and OCD who underwent DBS of the STN, and 82% reduction in symptoms was found after 6 months. The last area of the brain that has been tested is the inferior thalamic peduncle (ITP), a part of the orbitofrontal cortex. One study on DBS in the ITP has been conducted. In this study, the average response rate in 5 participants over 12 months was 49% (Jiminez-Ponce, Velasco-Campos, Castro-Farfan, 2009).

Although the evidence is too limited to be generalizable, DBS in all five of these areas of the brain appears to have approximately a 30 to 40% remission rate in treatment refractory OCD. There are several risks and potential adverse effects that may occur as a result of DBS. One way these risks are managed is through setting the parameters of voltage, pulse, and frequency of the electrical impulses (Haq et al., 2010). This process is often guided by trial and error. Haq et al. (2010) completed a multi-year trial of DBS in the anterior limb of the internal capsule and nucleus accumbens regions in 6-patients with treatment refractory OCD. They presented one case in which a participant manifested a manic episode as a result of the treatment. Thus, they discuss that while research clinicians are improving their skills around the use of DBS based on the limited work that has been done in this field, that there are still several questions about which areas of the brain are responsible for OCD symptom manifestation and what the best parameters are to target those areas.


American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association.

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

de Koning, P. P., Figee, M., van den Munckhof, P., Schuurman, P. R., & Denys, D. (2011). Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Current psychiatry reports, 13(4), 274-282.

Del Casale, A., Kotzalidis, G. D., Rapinesi, C., Serata, D., Ambrosi, E., Simonetti, A., … & Girardi, P. (2011). Functional neuroimaging in obsessive-compulsive disorder. Neuropsychobiology, 64(2), 61-85.

Denys D. (2006) Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders. Psychiatr Clin North Am. 29(2):553–84.

Figee, M., Vink, M., de Geus, F., Vulink, N., Veltman, D. J., Westenberg, H., & Denys, D. (2011). Dysfunctional reward circuitry in obsessive-compulsive disorder. Biological psychiatry, 69(9), 867-874.

Greenberg, B. D., Gabriels, L. A., Malone, D. A., Rezai, A. R., Friehs, G. M., Okun, M. S., … & Malloy, P. F. (2010). Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Molecular psychiatry, 15(1), 64-79.

Haq, I. U., Foote, K. D., Goodman, W. K., Ricciuti, N., Ward, H., Sudhyadhom, A., … & Okun, M. S. (2010). A case of mania following deep brain stimulation for obsessive compulsive disorder. Stereotactic and functional neurosurgery, 88(5), 322-328.

Heyman, I., Fombonne, E., Simmons, H., Ford, T., Meltzer, H., and Goodman, R. (2001). Prevalence of obsessive-compulsive disorder in the British nationwide survey of child mental health. Br J Psychiatry. 179: 324–329.

Huff, W., Lenartz, D., Schormann, M., Lee, S. H., Kuhn, J., Koulousakis, A., … & Sturm, V. (2010). Unilateral deep brain stimulation of the nucleus accumbens in patients with treatment-resistant obsessive-compulsive disorder: Outcomes after one year. Clinical neurology and neurosurgery, 112(2), 137-143.

Jiménez, F., Nicolini, H., Lozano, A. M., Piedimonte, F., Salín, R., & Velasco, F. (2013). Electrical stimulation of the inferior thalamic peduncle in the treatment of major depression and obsessive compulsive disorders. World neurosurgery, 80(3), S30-e17.

Nuttin BJ, Gabriels LA, Cosyns PR. (2002). Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder. Neurosurgery. 52(6):1263–72.

Zarei, M., Mataix-Cols, D., Heyman, I., Hough, M., Doherty, J., Burge, L., … & James, A. (2011). Changes in gray matter volume and white matter microstructure in adolescents with obsessive-compulsive disorder. Biological psychiatry, 70(11), 1083-1090.

Who Gets Anxious?

One of the things I find most interesting about anxiety is where it comes from. Many of the psychiatric disorders we discuss are assessed on a continuum; where even the “normal” person may feel some level of the symptoms we describe. Anxiety is perhaps the pinnacle of this, because it develops as an evolutionary survival response (Higgins & George, 2013). None of us can live our lives without feeling, at some time, a hint of anxiety.

So where does it all go wrong? How do we go from functioning individuals who are able to tell when something is really threatening, to avoidant ones who are paralyzed by fear? As with many disorders, we talk a lot about the intersection between genetics and the environment. Nature versus nurture. There are a lot of ways we can look at this, and nowadays general opinion tends to be that anxiety, along with other psychiatric disorders, develops as a combination of both. We can easily identify environmental stressors that might cause us to experience anxiety. They can be anything from major stressors such as growing up in a violent neighborhood or being the victim of abuse, to more minor things like getting stuck in an elevator or being the last one picked up from school every day. Biological determinants can be a little more difficult to understand.

The amygdala has long been thought of as the part of the brain associated with fear responses (Higgins & George, 2013). For this reason, I’ve chosen to steer away from the amygdala and talk a little bit about another part of the brain that is not as well understood in terms of it’s relation to anxiety disorders. The hippocampus.

In a 2002 study of monozygotic twins who were “discordant for trauma exposure,” a group of researchers from Boston found that smaller hippocampal volumes were associated with the development of PTSD (Gilbertson et al., 2002). They also identified positive correlations between the non-trauma exposed twin’s hippocampal volume and the development of PTSD in his trauma exposed twin, suggesting that having a small hippocampus may be a predisposing factor for developing PTSD (Gilbertson et al., 2002). This research fascinated me, so I looked into other studies that examined the link between hippocampal volume and anxiety.

One question I had was why some people have smaller hippocampal volume than others. A recent study I found examined maternal cortisol levels as it relates to the volume of both the amygdala and the hippocampus (Buss et al., 2012). This study did not find any associations between maternal cortisol levels and hippocampal volume, although it did find that higher maternal cortisol levels were associated with increased amygdala volume and greater affective problems in female offspring (Buss et al., 2012). Although this is only one study, it does suggest that maternal anxiety isn’t what’s having the impact on her offspring’s hippocampal volume. So what is? A study conducted by Swedish researchers using transgenic mice implanted with the CYP2C19 gene suggests that this gene, when expressed prenatally, may be responsible for the decrease in size of the hippocampus (Persson et al., 2014). Their results suggest that this “polymorphism” may be a precursor for some psychiatric disorders, including anxiety.

As we start to understand more about the brain determinants of anxiety, we can begin to target different areas of the brain with treatment. But perhaps we can also focus on earlier identification of individuals who might be vulnerable to developing anxiety, as we do with many other medical illnesses, and work to prevent them from having experiences that might, in combination with their biology, perpetuate a pathologic illness. This will likely be difficult to do, as anxiety-provoking experiences are a part of all of our lives, but it’s certainly a possible new direction.

This led me to wonder about other possible predictors of anxiety disorders. Were there other things, besides brain differences, which might suggest that an individual would develop an anxiety disorder later in life? Research on temperament has suggested that children who are “highly emotionally reactive” as youngsters are more likely to develop anxiety disorders as an adult (Kagan & Snidman, 1999). “Highly reactive” in this case means that the children were fearful or avoidant of unfamiliar events and people (Kagan & Snidman, 1999). Furthermore, they found other associations that suggested a biological correlate to this behavioral analysis. Children in the highly reactive group also had narrower facial skeletons, higher sitting diastolic blood pressures and “a greater magnitude of cooling of the temperature of the fingertips while listening to a series of digits they were asked to remember” (Kagan & Snidman, 1999). The researchers were not surprised by what, to me, seemed to be a rather odd and likely coincidental correlation between reactive temperament and narrow facial structure. They argued that the genes that control the growth of the maxilla were likely correlated with the genetic factors that inhibit behavior (Kagan & Snidman, 1999). In other words, the genes that code for having a narrower face may also be the ones that determine reactive temperament. This was particularly fascinating to me. It led me to imagine a world where we could identify psychopathology based on physical appearance. While I think this is unlikely to become the norm, it may become the case that we identify genes that code for both physical and emotional traits more and more in the future.


Buss, C., Poggi Davis, E., Shahbaba, B., Pruessner, J., Head, K., & Sandman, C. Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(20): 1312-1319.

Gilbertson, M., Shenton, M., Ciszewski, A., Kasai, K., Lasko, N., Orr, S., & Pitman, R. Smaller hippocampal volume predicts pathologic vulnerability to psychologic trauma. Nature Neuroscience. 2002; 5: 1242-1247.

Higgins, E. & George, M. (2013). The neuroscience of clinical psychiatry. Philadelphia, PA: Lippincott Williams & Wilkins.

Kagan, J & Snidman, N. Early childhood predictors of adult anxiety disorders. Biological Psychiatry. 1999; 46(11): 1536-1541.

Persson, A., Sim, S.C., Virding, S., Onischenko, N., Schulte, G., & Ingelman-Sundberg, M. Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Molecular Psychiatry. 2014; 19: 733-741.

Attachment & Children with Autism

In class we were able to study attachment and its different theorist and their ideas. One of those, Bowlby, emphasized the essentialness of security and insecurity when it comes to attachment and came up with the Strange Situation procedure, which is used to measure attachment in infants (Capps, Sigman, & Mundy, 1994; Ainsworth, Blehar, Waters, & Wall, 1978). During the time of the article, there were not many studies that measured attachment in children who suffer from autism. There were two that we will discuss shortly.

Just for reference, the Strange Situation is a scenario where a mother and her child were placed into a room where the child is able to play with toys and explore the room at will. After a while, a stranger comes into the room and begins to talk with the mother and eventually focuses attention on the child. The mother walks out of the room without the child knowing and the child is left alone with the stranger. The mother eventually comes back into the room where we see how the child reacts. The mom then briefly spends more time with the child and then leaves with the stranger only to have the stranger come back in alone a little while later. Again, the mom will enter the room again to greet the child one last time to end the situation. We are looking for how the child did with exploration and how the child responded to the mom coming back into the room after sneaking out of the room.

In one of those studies listed above, Shapiro et al (1987), found that almost half of the participants who suffered from autism were found as being securely attached to their mother. Something I found interesting in this study was that 65 percent of the children involved showed an emotional change when separated from mom, and 44 percent had a mood that was measured as being negative. With that, 64 percent of the children in the study did show some sort of effect due to the separation they experienced.

The second of those studies, Rogers et al (1991) found that the majority of the children with autism in their study appeared to be attached securely. In fact, these children were noted to be just as securely attached as the comparison children in the study. The interesting portion of this study, in my mind, is that the researchers found that no relation was had when comparing the secure attachment and the severity of autism.

This last statement is an interesting one because a meta-analysis completed by Rutgers, Bakermans-Kranenburg, van IJzendoorn, & Berckelaer-Onnes (2004), found that children who suffer from autism were much less secure when it comes to attachment than those who did not have autism. The authors referred to the definition of autism having an impact on the previous studies performed. The authors found that in their meta-analysis that when autism was defined more stringently, the effects on attachment were larger when compared to children who do not have autism; they were less responsive to the separation between them and their mothers. This helps to confirm that some of the children with autism do have secure attachments and show signs of seeking their mother after being separated, but that the effect may be less than the studies listed above stated.

The original article I read reinforced the idea that children who suffer from autism are able to form relationships with attachments (Capps, Sigman, & Mundy, 1994). The difference with this study is that the authors added a “D” classification that dealt with disorganized and disoriented attachment. This was added to the three attachment categories that the strange situation already had in place: secure (b), avoidant (a), and insecure-resistant (c) (Ainsworth, Blehar, Waters, & Wall, 1978). The authors felt the study confirmed the use of Ainsworth’s system when studying children with autism and felt the chance of causality entering the conversation cannot be ignored.

While I am not completely sure if these studies showing evidence that children with autism can form secure attachments as their counterparts without autism are correct, it is an interesting concept to look into. Attachment, as we learned in class, is something that is evolutionarily protective for all of us. We run to those we are attached to in times of fear and danger for comfort and support. The children with autism seem to have the chance to form secure attachments, but not sure if they are able to form much more than the superficial aspects of a relationship. I do agree that we need to define “autism” the same in each study in terms of having a stricter definition. Seeing as how some of these were done a while ago, it is hard because the criteria are different and having a stricter definition will help us to have more consistency in studies. These are very fascinating to me because I love working with those who suffer from autism.



Ainsworth, M. D. S., Blehar, M. D., Waters, E., & Wall, S. (1978). Patterns of attachment. Hillsdale, NJ: Erlbaum.

Capps, L., Sigman, M., & Mundy, P. (1994). Attachment security in children with autism. Development and Psychopathology6(2), 249–261. doi:10.1017/S0954579400004569

Rogers, S. J., Ozonoff, S., & Maslin-Cole, C. (1991). A comparative study of attachment behavior in young children with autism or other psychiatric disorders. Journal of the American Academy  of  Child Adolescent Psychiatry,  30, 483-488.

Rutgers, A. H., Bakermans-Kranenburg, M. J., van IJzendoorn, M. H., & Berckelaer-Onnes, I. A. (2004). Autism and attachment: a meta-analytic review. Journal of Child Psychology and Psychiatry, 45:6, 1123-1134.

Shapiro, R., Sherman, M., Calamari, G., & Koch , D. (1987). Attachment in autism and other develop mental disorders. Journal of the American Academy of Child Adolescent Psychiatry,  26, 485-490.

ADHD and exercise

Attention-deficit/hyperactive disorder, commonly referred to as ADHD is a neurobiological disorder that affects around 10% of children and 5% of adults throughout the world. ADHD is the most commonly diagnosed neurobehavioral disorder in childhood with boys being more than twice as likely to be diagnosed (13.2%) than girls (5.6%) (Kessler 2006). Possible causes for this disorder is still a topic of controversy as there is no single risk factor that leads to ADHD. Rather, there are multitude of factors including genes, psychosocial factors, and environmental toxins that may contribute. Nonetheless, it can seriously debilitate someone’s life by affecting the academic, interpersonal, and occupational areas of someone’s life (Biederman 2005). Research suggests that an underlying manifestation of ADHD may be due to the failures of neural processes that regulate inhibitory control (Barkley 1997). Pharmacological treatments have proven to be effective in managing the symptoms of ADHD, however, some barriers to effective treatment include high costs, adverse side effects, and incomplete responses (Solanto 2001). An alternative treatment may be exercise; specifically moderate intensity aerobic exercise.

There are many benefits to regular physical activity and exercise including a decrease in the risk of developing type II diabetes, cardiovascular disease, colon and breast cancer, and mental disorders (Voss et al. 2011).  Despite the availability of this knowledge, the amount of dedicated time of physical activity and exercise has decreased during the school day (Andersen et al. 1998).  Only 50% of children 6-11 and 8 percent of adolescents 12-19 in the United States are active for the national recommendation of 60 minutes a day for 4 or more days a week (Booth 2010).

Research has shown that children’s cognitive and neural development may be positively affected from physical activity (Diamond 2000). Exercise has been associated with better grades and academic achievement (Coe, Pivarnik, Womack, Reeves, & Malina, 2006; Taras, 2005). Executive function including goal directed behaviors, response selection and inhibition, goal setting, and self-control have been shown to be particularly sensitive to aerobic exercise. People diagnosed with ADHD are deficient in many areas controlled by executive function (Lezak, Howieson, & Loring, 2004).  Another study has shown that exercise can have a profound impact on brain plasticity. Specifically, exercise stimulates the action of brain-derived neurotropic factor (BDNF) which is a molecule that is involved with neuronal excitability, learning, and memory (Vaynman et al. 2004). BDNF polymorphisms are implicated in the cause and development of ADHD (Muller et al. 2010). In other studies, exercise has been shown to increase the availability of dopamine in the substantia nigra and the striatum. Dopamine helps regulate neuronal motor control, cognition, and emotion. When dopamine signaling is compromised, it can lead to behavioral symptoms of ADHD (Bowton et al. 2010). Exercise also has the added benefit of increased attentional allocation and greater response execution in people with ADHD compared to people without the disorder (Hillman 2009). Finally, exercise has been shown to have a profound positive impact on the brain which helps reduce stress, anxiety, depression, self-destructive behaviors, poor impulse control, inattentiveness, and negative behaviors such as bad conduct. Since many of these behaviors and symptoms overlap with the profile of ADHD, exercise intervention can be used as an effective intervention tool in people diagnosed with ADHD (Post 2010).

Although medication has proven to be effective in alleviating symptoms of ADHD, many researchers questions whether or not the side effects of ADHD medication warrant the use of the medication long term, especially in children.  The two main classes of medications that are used to treat ADHD are stimulants, which are first line drugs, and non-stimulants. Stimulants aim to block the reuptake of norepinephrine and dopamine into to presynaptic neurons. Some examples include methylphenidate, and amphetamine mixed salts. These medications have a high potential for abuse and are classified as controlled substances. Non-stimulants, such as atomoxetine, are selective norepinephrine reuptake inhibitors. However, the onset of the therapeutic effect is 2-4 weeks increasing the likelihood of non-adherence (Dopheide 2008). However, researchers have shown the exercise is at least as effective as methylphenidate, a stimulant, in ADHD rats (Cho 2014). Both exercise and medication management are effective at regulating dopamine and norepinephrine levels in the brain. However, there are many side effects of stimulants that include loss of appetite, disturbed sleep patterns, increased heart rate, irritability, and in extreme cases, psychosis and hallucinations. Some researchers suggest that a combination of medication management and exercise could be the most effective method of alleviating ADHD symptoms. However, due to the highly complex neurological components of ADHD which is not yet fully understood, each patient may respond to treatment differently. Even the type of exercise that is beneficial for people with ADHD is under debate as some theories involve combining both and aerobic activity and concentration such as martial arts or rock climbing. In conclusion, exercise and medication have both produced positive results in people with ADHD and treatment for the disease should be individualized according to what treatment is most effective for a particular person (Dopheide 2008).



Andersen, R.E., Crespo, C.J., Bartlett, S.J., Cheskin, L.J., Pratt, M., 1998. Relationship of physical activity and television watching with body weight and level of fatness among children: results from the Third National Health and Nutrition Examination Survey. J. Am. Med. Assoc. 279, 938–942.

Barkley RA. Behavioral inhibition, sustained attention, and executive functions. Psychol Bull 1997;121:65-94.

Biederman J. Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry. 2005;57(11):1215–1220.

Booth FW, Laye MJ. The future: genes, physical activity and health. Acta Physiol (Oxf) 199: 549 –556, 2010.

Bowton E, Saunders C, Erreger K, Sakrikar D, Matthies HJ, Sen N, Jessen T, Colbran RJ, Caron MG, Javitch JA, Blakely RD, Galli A. Dysregulation of dopamine transporters via dopamine D2 autoreceptors triggers anomalous dopamine efflux associated with attention-deficit hyperactivity disorder. J Neurosci. 2010;30(17):6048-57

Cho, H. S., Baek, D. J., & Baek, S. S. (2014). Effect of exercise on hyperactivity, impulsivity and dopamine D2 receptor expression in the substantia nigra and striatum of spontaneous hypertensive rats. Journal of exercise nutrition & biochemistry, 18(4), 379-384.

Coe, D. P., Pivarnik, J. M., Womack, C. J., Reeves, M. J., & Malina, R. M. (2006). Effect of physical education and activity levels on academic achievement in children. Medicine and Science in Sports and Exercise, 38, 1515–1519.

Diamond, A. (2000). Close interrelation of motor development and cognitive development and of the cerebellum and prefrontal cortex. Child Development, 71, 44 –56.

Dopheide JA, Tesoro JT, Malkin M. Childhood disorders. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008:1029-1040.

Hillman CH, Pontifex MB, Raine LB, Castelli DM, Hall EE, Kramer AF. The effect of acute treadmill walking on cognitive control and academic achievement in preadolescent children. Neurosci 2009;159:1044-54.

Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. Am J Psychiatry. 2006;163(4):716–723.

Lezak, M. D., Howieson, D. B., & Loring, D. W. (2004). Neuropsychological assessment (4th ed.). New York: Oxford University Press.

Muller DJ, Chiesa A, Mandelli L, De Luca V, De Ronchi D, Jain U, Serretti A, Kennedy JL (2010) Correlation of a set of gene variants, life events and personality features on adult ADHD severity. J Psychiatr Res 44:598–604

Post RM (2010) Mechanisms of illness progression in the recurrent affective disorders. Neurotox Res 18:256–271

Solanto MV, Arnsten AT, Castellanos FX. Stimulant drugs and ADHD: basic and clinical neuroscience. New York: Oxford University Press; 2001.

Vaynman, S., Ying, Z. & Gomez-Pinilla, F. (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur. Neurosci., 20, 2580–2590.

Voss, M. W., Nagamatsu, L. S., Liu-Ambrose, T., & Kramer, A. F. (2011). Exercise, brain, and cognition across the life span. Journal of applied physiology111(5), 1505-1513.


Social Attachment & Autism

The works of many researchers across time and domains have explored many interacting forces, biological and environmental, which inform our understanding of attachment. Historically speaking, when we hear “attachment theory,” researchers John Bowlby and Mary Ainsworth come to mind. Bowlby put forth the foundational ideas of attachment theory, emphasizing the importance of the “attachment figure” to the infant – that which promotes a sense of safety idea, allows the infant to develop an internal schema of the self with attachment figure, and soothes distress if the infant becomes upset. Further, Bowlby had thoughts regarding the negative implications of separation, deprivation, and bereavement, and Mary Ainsworth expressed the idea of the caregiver as providing a “secure base from which an infant can explore the world” (Bretherton, 1992).

What is happening on a neural, cellular level contributing to all of these parental behaviors and their subsequent effects on infants? What is the pathophysiology of attachment and what brain changes may occur given different types of attachment styles?

Following Bowlby and Ainsworth, a large body of research discovered neurobiological variables that influence parental behaviors and subsequent infant attachment. Hormones including oxytocin, estrogen, progesterone, prolactin, and neurotransmitters such as dopamine are among a few of the cellular influences that play huge role in gestation and subsequent maternal behavior (Higgins & George, 2007). Neurobiological factors influence parent behaviors, providing the biological underpinnings that facilitate parental actions that of which help nurture the child, reduce stress, and form attachment bonds. Adding an additional influential element into the mix, parental nurturing behaviors or lack thereof can result in epigenetic changes in a child (Higgins & George, 2007). For example, Meaney et al. found that when rats received more attention from their mothers, there was a subsequent reduction in methylation of the promoter region of the glucocorticoid gene, which resulted in more glucose receptors. As we learned in the context of stress, an increase in glucose receptors should reduce the HPA response. Subsequently, they found decreased corticosterone levels, and produced more resilient rats compared to controls with less attention from their mothers (Higgins & George, 2007). Of note, parental sensitivity is one of the most recurrently recognized causal factors contributing to infant attachment security (Ijzendoorn et al., 2007).

Given the biological changes contributing to the formation of attachment bonds and neurochemically influencing adaptive nurturing behaviors of parents, these findings beg the question – how important is parenting during the first years of life? What variance in interpersonal sociability can be explained by attachment formation when controlling for genetics? Bokhorst et al. (2003) sought to tease out the genetic and environmental influences on infant attachment in a sample of 157 monozygotic and dizygotic twins. They found that the influence of genetics on infant attachment behavior patterns was negligible; moreover, in their sample, both shared and non-shared environmental factors were significantly related to patterns of infant attachment behaviors. Specifically, in comparing securely versus non-securely attached infants, 52% of the variance in attachment security was related to shared environment and 48% was explained by unique environmental factors and measurement error. This study suggests that above genetics, environmental influences (more specifically – parental sensitivity, as relating to attachment theory) may primarily account for individual differences in attachment behaviors.

With the previous study in mind – how does early attachment ultimately affect brain development? Longitudinal studies have discovered unique presentations of development from infants with discrete types of attachment styles (Siegel, 2001). For example, attachment studies found that children with avoidant attachment styles have scant recollections from their childhood, when compared with children with securely attached caregiver relationships (Siegel, 1999). These differences could be related to the effects of stress and chronic activation of the HPA axis on the hippocampus, long-term potentiation, and subsequently, memory. Moreover, in studies of prairie voles, which demonstrate pair ponding as a species, research has shown that oxytocin influenced the activation of the HPA axis by increasing positive social behaviors and thus reducing HPA reactivity (Carter, 1998). Importantly, from a neuro-developmental perspective, we know that from fetal week 30 through age 2, there is a huge increase in the production of neurons and axons, as well as the creation of synaptic connections according to experience. Accompanying this development is the pruning of “unused” synpases; the “selective elimination of the genetically produced excess” (Siegel, 2001). Synaptic pruning continues until the child reaches puberty. Thus, during early years, positive or negative interpersonal interactions with ones environment can strongly influence the production and destruction of synapses.

On the other side, neurobiological research on autism complicates the basic idea that parental sensitivity and positive social interactions results in secure attachment behaviors. Autism spectrum disorder is characterized by “severe social dysfunctions, early communication failure, and the presence of repetitive, rigid, and stereotypic behaviors” (Higgins & George, 2007). Importantly, there have been a number of research findings related to neurological alterations in the study of autism, including but not limited to increased brain volume that dramatically grows during the first year of life (initially reduced) and returns to normal during adult life, reduced or absent stimulation of the mirror neuron network, insula, and amygdala (Higgins & George, 2007), and brain structural abnormalities in the lateral occipital lobe, the pericentral region, the medial temporal lobe, the basal ganglia, and proximate to the right parietal operculum (Nickl-Jockschat et al., 2011).

Knowledge of some of the structural and neural anomalies related to autism gives rise to the question of the interaction between autism and parental sensitivity/positive social relationships as it relates to attachment style in individuals with autism spectrum disorders. IJzendoorn et al. conducted a study in 2007 examining sensitivity and attachment in toddlers with autism spectrum disorder, mental retardation, language delay, and typical development. Interestingly, they found that parental sensitivity only related to more securely attached children in the groups of individuals without autism spectrum disorders, suggesting that parental sensitivity may not influence attachment style patterns in individuals with autism spectrum disorder in the same ways that it influences individuals with typical development. However, individual differences in attachment style in persons with autism have been examined – Capps, Sigman and Mundy (1994) found that though each autistic child in their sample displayed “disorganized attachment patterns,” 40% of them were sub-classified as securely attached, and when assessed with their mothers, these children initiated more social interactions with their mothers compared to the group sub-classified as insecurely attached. Moreover, the group sub-classified as securely attached showed additional receptiveness to efforts for joint attention, asked for things more frequently, and showed greater receptive language skills than children sub-classified as insecurely attached. This study did not examine parental sensitivity, however in discordance with the study by Ijzendoorn et al., this study sheds light on the potential significance of positive social interactions and parental sensitivity on children with autism in terms of social receptiveness as well as language skills.

As illustrated in earlier paragraphs, though research has revealed robust findings suggesting the importance of parental sensitivity in infant attachment formation, there is still much to be learned regarding the major players in the development of attachment styles in regards to biology and environment. Moreover, the findings related to attachment style development are obscured and challenged by the interaction with autism spectrum disorder.

Works Cited

Bokhorst, C. L., Bakermans-Kranenburg, M. J., Fearon, R. M., Ijzendoorn, M. H., Fonagy, P., & Schuengel, C. (2003). The Importance of Shared Environment in Mother-Infant Attachment Security: A Behavioral Genetic Study. Child Development, 74(6), 1769-1782. doi:10.1046/j.1467-8624.2003.00637.x

Bretherton, I. (1992). The origins of attachment theory: John Bowlby and Mary Ainsworth. Developmental Psychology, 28(5), 759-775. doi:10.1037//0012-1649.28.5.759

Capps, L., Sigman, M., & Mundy, P. (1994). Attachment security in children with autism. Development and Psychopathology, 6(02), 249. doi:10.1017/s0954579400004569

Carter, C. S. (1998). Neuroendocrine Perspectives On Social Attachment And Love. Psychoneuroendocrinology, 23(8), 779-818. doi:10.1016/s0306-4530(98)00055-9

Higgins, E. S., & George, M. S. (2007). The neuroscience of clinical psychiatry: The pathophysiology of behavior and mental illness. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.

Ijzendoorn, M. H., Rutgers, A. H., Bakermans-Kranenburg, M. J., Swinkels, S. H., Daalen, E. V., Dietz, C., . . . Engeland, H. V. (2007). Parental Sensitivity and Attachment in Children With Autism Spectrum Disorder: Comparison With Children With Mental Retardation, With Language Delays, and With Typical Development. Child Development, 78(2), 597-608. doi:10.1111/j.1467-8624.2007.01016.x

Nickl-Jockschat, T., Habel, U., Michel, T. M., Manning, J., Laird, A. R., Fox, P. T., . . . Eickhoff, S. B. (2011). Brain structure anomalies in autism spectrum disorder-a meta-analysis of VBM studies using anatomic likelihood estimation. Human Brain Mapping, 33(6), 1470-1489. doi:10.1002/hbm.21299

Siegel, D. J. (2001). Toward an interpersonal neurobiology of the developing mind: Attachment relationships, ?mindsight,? and neural integration. Infant Mental Health Journal, 22(1-2), 67-94. doi:10.1002/1097-0355(200101/04);2-g






Childhood trauma, the HPA axis and Depression

In the United States more than one million children are exposed to sexual or physical abuse or severe neglect (Sedlack 1996). The repercussion of these traumatic events early in life has long lasting effects on brain development. Particularly, the neural and endocrine systems that mediate the response to stress reveal long lasting adaptations. Studies have shown that adults with depression and a history of early life trauma respond differently than other patients to normal treatment modalities.

The brain is the main player when it comes to activating the stress response and is an important regulatory organ controlling the hypothalamic- pituitary-adrenal (HPA) axis. The HPA axis is a neuroendocrine system that is involved in the production of the stress hormone cortisol by the adrenal glands. Cortisol is a glucocorticoid and alters the function of tissues in order to mobilize or store energy to meet the demands of stressors. Corticotropin releasing hormone is the main peptide involved in activating the HPA axis. It signals to the anterior pituitary to release ACTH which leads to the secretion of glucocorticoids (Higgins & George, 2013).

Physical stimuli such as hunger and inflammation consistently cause activation of the HPA axis (Straub et al., 2011). On the other hand, psychological stressors such as social or mental stress are inconsistent and have large inter-individual variation (Trestman et al, 1991). The glucocorticoid hypothesis states that stress exposure of the brain, mediated by the neurotoxic effects of cortisol and neuroinflammation causes damage to brain structure and function. This occurs due to excessive exposure to glucocorticoids that causes a reduction in the feedback inhibition of the HPA axis and leads to excess cortisol excretion.

The hippocampus is central to learning and memory function and mediating the cortisol- induced feedback inhibition of the HPA axis (Goosens and Sapolsky, 2007). Studies have shown that when cortisol levels are artificially acutely elevated or reduced below or above average rates, impairments in learning and memory occur (Lupien et al., 2002). These functional changes of the HPA axis and alterations in brain structures are associated with major depression (Frodl & O’Keane 2013).

So what happens when children are exposed to traumatic and stressful events during development, a crucial time of learning and memory? One of the most commonly known consequences of childhood trauma is a higher risk in adulthood of developing depression. While most of us experience stress on a day to day basis- stressful events such as the death of a parent, or physical or sexual abuse early in life cause adaptations that lead to physical and behavioral changes. These early life stressors alter neurobiological systems that are involved with the pathophysiology of depression and have long term damaging effects on the entire body.

It has been long known that hyperactivity of the HPA axis is a consistent biological finding in major depression. Recently, it has been shown that increased activity of the HPA axis may expose a susceptibility to depression that is programmed through early life events. This could mean that HPA hyperactivity seen in depression may not be a consequence, but more of a manifestation of persistent neurobiological abnormalities predisposing patients to depression (Carmine et al, 2008).

Saridjan et al (2010) found that infants experiencing social disadvantage and family adversity have higher cortisol response to awakening (CAR) than infants not exposed to social or familial adversity. Carpenter et al (2007) established similar results that emotional neglect and sexual abuse strongly predicted maximal cortisol release. High levels of cortisol lead to hippocampal damage as seen in patients with major depressive disorder and a history of emotional neglect during childhood. These patients had reduced left hippocampal white matter compared to those without a history of emotional neglect (Frodl et al 2010). This evidence indicates that childhood trauma changes hippocampal structures during brain development leading to higher vulnerability for stress related psychiatric disease later in life such as depression.

Childhood trauma is associated with decreased responsiveness to pharmacological treatment (Hayden and Klein, 2001) and a higher likelihood of relapse (Lara et al, 2000). Among chronically depressed patients with no history of early trauma, combination pharmacological (nafazodone) and psychotherapy treatment was most effective in attaining remission. In contrast, in chronically depressed patients with early-life trauma, remission rates were significantly higher for psychotherapy alone versus nefazodone. For these patients with early life trauma, combination treatment did not have any further advantage over psychotherapy alone. This suggests that psychotherapy is an essential element of treatment for depressed patients with childhood trauma.

How can we apply this to clinical practice? I think that first it is important to recognize that not everybody with childhood trauma develops depression, and vice versa. Gaining a thorough background and history during the diagnostic interview and assessment becomes important in order to understand the role of trauma and/or neglect in our patients. Part of this process should also reflect the fact that our interpretation and understanding of trauma may differ greatly from our patients. Children often try to protect and defend their parents- they may minimize abuse or may not view certain actions as abuse. An adult that has experienced childhood trauma may not want to revisit these events.

It is clear from the above data that psychotherapy should be the core component of treatment for depressed patients with a history of early childhood stress. It is also important to consider the role of different types of traumas at different developmental stages in order to elucidate whether there are precise developmental time periods for prevention of the adverse outcomes of childhood trauma. While the aforementioned studies and data give us useful knowledge on the neurophysiological basis of the effects of childhood trauma on depression, it is only one piece of the complicated puzzle in building a therapeutic relationship and treatment plan with our patients.


Works Cited


Carpenter, L.L., Carvalho, J.P., Tyrka, A.R., Wier, L.M., Mello, A.F., Mello, M.F., et al., 2007. Decreased adrenocorticotropic hormone and cortisol responses to stress in healthy adults reporting significant childhood maltreatment. Biol. Psychiatry 62, 1080–1087.


Carmine M. Pariante, Stafford L. Lightman, The HPA axis in major depression: classical theories and new developments, Trends in Neurosciences, Volume 31, Issue 9, September 2008, Pages 464-468, ISSN 0166-2236,


Frodl, T., Reinhold, E., Koutsouleris, N., Reiser, M., Meisenzahl, E.M., 2010. Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J. Psychiatr. Res. 44, 799–807


Goosens, K.A., Sapolsky, R.M., 2007. Stress and Glucocorticoid Contributions to Normal and Pathological Aging


Hayden, E.P., Klein, D.N., 2001. Outcome of dysthymic disorder at 5-year follow-up: the effect of familial psychopathology, early adversity, personality, comorbidity, and chronic stress. Am. J. Psychiatry 158, 1864–1870.



Higgins, E. S., & George, M. S. (2013). Neuroscience of Clinical Psychiatry: the pathophysiology of behavior and mental illness. Lippincott Williams & Wilkins.


Lara, M.E., Klein, D.N., Kasch, K.L., 2000. Psychosocial predictors of the short-term course and outcome of major depression: a longitudinal study of a nonclinical sample with recent-onset episodes. J. Abnorm. Psychol. 109, 644–650.


Lupien, S.J., Wilkinson, C.W., Briere, S., Menard, C., Ng Ying Kin, N.M., Nair, N.P., 2002. The modulatory effects of corticosteroids on cognition: studies in young human populations. Psychoneuroendocrinology 27, 401–416.


Saridjan, N.S., Huizink, A.C., Koetsier, J.A., Jaddoe, V.W., Mackenbach, J.P., Hofman, A., et al., 2010. Do social disadvantage and early family adversity affect the diurnal cortisol rhythm in infants? The Generation R Study. Horm. Behav. 57, 247–254


Sedlack AJ, Broadhurst DD. Third National Incidence Study of Child Abuse and Neglect. Washington, DC: US Department of Health and Human Services; 1996.


Straub, R.H., Buttgereit, F., Cutolo, M., 2011. Alterations of the hypothalamic–pituitary– adrenal axis in systemic immune diseases — a role for misguided energy regulation. Clin. Exp. Rheumatol. 29, S23–S31.


Trestman, R.L., Coccaro, E.F., Bernstein, D., Lawrence, T., Gabriel, S.M., Horvath, T.B., et al., 1991. Cortisol responses to mental arithmetic in acute and remitted depression. Biol. Psychiatry 29, 1051–1054.


Vreeburg, S.A., Hoogendijk, W.J., van Pelt, J., Derijk, R.H., Verhagen, J.C., van Dyck, R., et al., 2009. Major depressive disorder and hypothalamic–pituitary–adrenal axis activity: results from a large cohort study. Arch. Gen. Psychiatry 66, 617–626.




Stress and the HPA Axis

When living during hunter and gatherer times, humans needed to be able to respond in a split second should a threat occur. The capacity to harness immediate energy to react is highly adaptive when living in the wild, when an aggressive animal could enter the home at any moment, or when catching game was the primary means to obtain sustenance. But how does this stress response fare during modern times? What happens when the threat to survival is an abusive relationship or neglectful caregiver?

The sympathetic response in the autonomic nervous system (ANS) is designed to respond to danger- it is the natural hard wiring that alerts our body and focuses the brain. This response is highly adaptive—if faced at gunpoint, our brains snap into a state of hyper vigilance, with a razor focus towards the gunpoint, rather than wondering whether the laundry was put in the dryer. The stress response that responds to threats to homeostasis is modulated by the hypothalamus-pituitary-adrenal (HPA) axis and utilizes input from the endocrine, nervous, and immune systems (Smith & Vale, 2006).

The hypothalamus serves as the control center of the HPA axis, and receives input from higher areas the brain and monitors for homeostasis through chemoreceptors and hormonal feedback systems (Higgins & George, 2013). When the hypothalamus detects a threat to homeostasis, it responds by secreting corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH further signals the adrenal cortex to release cortisol into the bloodstream; a glucocorticoid that causes systemic changes allowing the body to harness energy (Lee & Gorzalka, 2015).

The primary glucocorticoid of interest in the stress response is cortisol. Cortisol promotes glucose metabolism, increases cardiac work, and also suppresses growth reproduction and immunity in order to sustain a state of catabolism and energy usage (Lee & Gorzalka, 2015). While this adaptive for periodic episodes of stress, exposure to chronic stress leads to pathologic changes. Elevated glucocorticoids can present with symptoms similar to Cushing’s disease, and leads to higher rates of infection due to immunosuppression by the HPA axis. As healthcare providers, it is necessary to understand how trauma impacts the brain and body in order to most effectively treat the cause of a presenting symptom.

In addition the physiologic consequences of maintaining a chronic state of arousal such as diabetes and cardiovascular disease, sustained HPA activation is related to depression and anxiety (Lee & Gorzalka, 2015). The amygdala, which is active during states of anxiety and anger, and the hippocampus, which helps to develop and store memories, are intertwined with the stress response (Higgins & George, 2013). Both the hippocampus and amygdala are rich in glucocorticoid receptors, and are impacted by increased levels of cortisol (Higgins & George, 2013).

The amygdala is activated in anxiety and further amplifies the HPA response, perpetuating the release of cortisol (Higgins & George, 2013). Normally, the hippocampus is involved in a negative feedback system and inhibits the HPA response (Lee & Gorzalka, 2015). However, if continuously exposed to stress, the amygdala is constantly activated and the HPA response remains turned on. Exposure to chronic stress disrupts the hippocampus’s ability to store memories and decreases neurogenesis (Higgins & George, 2013).

What happens to a child’s brain when there is a chronic threat to safety and a constant underlay of anxiety? The developing brain of a child is particularly vulnerable to functional changes because of its high state of plasticity. As it develops, the child’s brain forges synaptic connections from experience and prunes away connections that are not utilized. Children are particularly vulnerable to pathologic stimulation of the HPA response due to their reliance on caretakers and inability to control their environment. If a child is exposed to chronic stress, the synaptic connections that form the foundation of their schema of themselves and the world will be skewed towards the traumatic event, at the expensive of a healthier synaptic network balanced on different experiences and healthy relationships.

The hypervigilant state activated by the HPA response disrupts the ability to focus and learn, and will have consequences for the child’s success in school. A child living in a neglectful home who feels constant duress has an impaired ability to focus on schoolwork; this state of hyper vigilance is not conducive to learning or social functioning. The disrupted ability to learn due to maladaptive levels of anxiety is compounded by the physiologic changes to the hippocampus and impaired ability to store memories and recall information (Lee & Gorzalka, 2015).

In addition to impaired memory formation and focus on school, an overactive HPA axis due to trauma is associated with emotional and behavioral dysregulation. Although research indicates that childhood trauma impairs HPA development, the research offers differing data regarding the nature of the dysregulation. Pfefferbaum, Tucker, and Nitiema (2015) note that studies have found that children who have experienced trauma may have higher, lower, or the same levels of cortisol as non-traumatized children. Children with higher levels of cortisol were associated with increased rates of anxiety and depression (Pfefferbaum et al., 2015). Children who have adapted to chronic stress by producing lower levels of cortisol may have developed a high threshold for what is perceived as stress, and may have an impaired ability to react to daily stressors in the environment. This tolerance for stress may put them at risk for unhealthy relationships or situations.

In addition to early childhood, the adolescent brain is particularly sensitive to developmental changes due to trauma. The HPA axis is believed to surge in development when gonadal hormones begin circulating in puberty (Lee & Gorzalka, 2015). Exposure to chronic stress during adolescence is more likely to create long-term HPA axis impairment that leads to difficulties regulating emotions as an adult (Lee & Gorzalka, 2015).

This information is vital for providers, educators, and childcare providers, and can be used to justify the implementation of trauma-based services in healthcare systems and schools. As providers, it is important to be aware of the pathophysiology behind how our bodies and brains adapt to chronic stress and trauma. The impact of trauma on the brain presents with symptoms that can mask as multiple diagnoses- emotional lability, impulsivity, inattention, hyperactivity, forgetfulness, depression, anxiety, to name a few. Having a trauma informed perspective that integrates psychopathology and neural changes due to chronic stress is essential in treating the correct cause of a symptom, and can aid in more accurate diagnoses and treatment.




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Lee, T. T., & Gorzalka, B. B. (2015). Evidence for a role of adolescent endocannabinoid signaling in regulating HPA axis stress responsivity and emotional behavior development. International Review of Neurobiology, 125, 49-84. doi:10.1016/bs.irn.2015.09.002 [doi]

Pfefferbaum, B. (2015). Adolescent survivors of hurricane katrina: A pilot study of hypothalamic-pituitary-adrenal axis functioning. Child & Youth Care Forum, 44, 527; 527-547; 547. Retrieved from CINAHL Complete database.

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