Brain Volumes Affected by Type and Timing of Childhood Abuse

December 13, 2016 · Posted in Risk Factors · Comment 

age when abused affects brain volume

Maltreatment during childhood has been linked to brain changes and mental illness. In a study by researcher Carl M. Anderson and colleagues that was presented at the 2016 meeting of the Society of Biological Psychiatry, maltreatment at particular ages was statistically linked to deficits in the size of certain brain areas in young adulthood.

The brain areas under examination are critical for the regulation of emotion and behavior, and this research suggests that early experiences can stunt their development, perhaps through  altered production of synapses or via the synaptic pruning process that occurs during preadolescence. The details, summarized below, are perhaps less important than the overall finding that maltreatment in childhood affects brain volume, and this effect varies based on the timing and type of maltreatment. Abuse and neglect earlier in life affected the left side of the brain, while later maltreatment affected the right side.

Severity of physical abuse at age 3 affected the volume of the ventromedial prefrontal cortex in women. Physical abuse at ages 3 and 8 in men affected left ventromedial prefrontal cortical volume, while later abuse at ages 7 and 12 predicted volume of the right side.

In women, dorsal anterior cingulate area on the left was predicted by physical abuse at age 5 and by emotional neglect at ages 7 and 11. Later emotional neglect at ages 15 and 16 and physical abuse by a peer at age 10 was associated with smaller right dorsal anterior cingulate. In men, smaller left dorsal anterior cingulate area was predicted by physical neglect at age 2 and emotional abuse by a peer and witnessing abuse of a sibling at ages 5 and 10, and right area by physical neglect at age 12.

Link Between Childhood Trauma and Difficult Course of Bipolar Disorder Clarified

November 9, 2015 · Posted in Genetics, Risk Factors · Comment 

Trauma in childhood linked to course of bipolar disorder

A collaboration between Norwegian and French researchers led by Bruno Etain has clarified the pathway by which childhood trauma is linked to worse outcomes among people with bipolar disorder. The researchers, who presented their work in a poster at the 2015 meeting of the Society of Biological Psychiatry, replicated earlier findings by this editor (Robert Post) that patients who experienced trauma as a child had a more adverse course of bipolar disorder. Etain and colleagues found a link between childhood trauma and an earlier age of onset of bipolar disorder, rapid cycling, suicide attempts, and cannabis misuse.

The researchers identified more than 550 patients with bipolar disorder, who answered questionnaires about their history of bipolar disorder and childhood trauma. Their DNA was also analyzed, and the researchers found that the effect of childhood trauma on age of onset was mediated by the presence of common genetic variants in proteins related to stress (the serotonin transporter) and immune function (Toll-like receptors). They also found that the traits of mood lability (or moodiness) and impulsivity mediated the effects of trauma on clinical outcomes.

The lasting epigenetic effects of child maltreatment and adversity noted in the above abstract are consistent with a large literature showing more epigenetic effects in these individuals than in controls. While genetics are important, the impact of the environment is also substantial.

Molecular Biology of Depression

October 1, 2015 · Posted in Neurobiology, Risk Factors · Comment 

molecular biology of depressionDysregulation of the brain in early life can have lasting effects, and the effects of stress and depression can also accumulate. At the 2015 meeting of the Society of Biological Psychiatry, researcher Huda Akil explained that behavioral pathology can “take on a life of its own, leading to deteriorating course of illness and treatment resistance.” She illustrated how preclinical work in animals can help clarify the molecular biology of depression and develop new targets for therapeutics.

Early Life Experiences are Key

Akil discuss studies of rodents in which she used new molecular genetic techniques to increase the number of glucocorticoid receptors in the hippocampus early in life (prior to weaning). Glucocorticoid receptors mediate the effects of the stress hormone cortisol in people and corticosterone in rodents. More receptors help shut off cortisol secretion after a stressful event. People with post-traumatic stress disorder (PTSD) have high levels of glucocorticoid receptors while people with depression have low levels, leading to over-secretion of cortisol in depression.

The increased glucocorticoid receptors led to a long-term increase in anxiety behaviors and response to stimulants. When Akil carried out the same manipulation on rats that had already been weaned, it had no long-lasting effects, showing that there is a vulnerability window for some long-lasting effects on behavior.

CLOCK Genes and Circadian Rhythms

Akil also studied CLOCK genes in rodents. These genes, including BMAL-1, Per 1, Per 2, and Per3, play a role in circadian rhythms, and their transcription induces these 24-hour cycles. In rodents who were induced into a depression-like state, the CLOCK genes were dysregulated and did not correspond to normal circadian rhythms. These data show that depressive states can induce changes in CLOCK genes and circadian rhythms. Others have shown the converse, that abnormal CLOCK genes can induce behavioral abnormalities including mania-like behaviors.

Fibroblast Growth Factor

Levels of fibroblast growth factor 2 (FGF2) in the hippocampus are low in people with depression. In rodents, FGF2 inhibits anxiety. Decreases in FGF2 are seen in the hippocampus of animals in a depression-like state following repeated defeat by a larger animal. It appears that FGF2 is an endogenous antidepressant (i.e. one that is produced by the brain). When the rodent brain is manipulated to eliminate FGF2, the animals become anxious.

In addition, animals bred to have high stress, low social responsivity, and resistance to new learning also have low FGF2. Treatment with FGF2 reversed these behavioral abnormalities and also increased the production of new neurons. For the stressed rats, receiving FGF2 on their second day of life increased new neuron production, decreased anxiety, decreased proneness to social defeat stress and increased the bonding hormone oxytocin in the amygdala into adulthood.

FGF2 had no effect on rats bred for low stress and high social responsivity, indicating that it only worked for the rats that needed it. Akil compared FGF2 to “personalized medicine for rats.”

Defeat stress affects the way genes are transcribed, and FGF2 was able to reverse one of these specific transcriptional effects, suggesting it could potentially ameliorate some of the long-lasting effects of stress and depression.

The Human Brain

Akil also studied the brains of people who had died of depression, bipolar disorder, or schizophrenia. In bipolar disorder, the nucleus accumbens, the reward center of the brain, was enlarged.

In contrast, Akil described the brains of those people who had died with depression as being “low on fertilizer.” That is, they showed less cell growth, less production of new neurons, more abnormalities in cell shape, and more cell death. Akil said that by the time someone is severely ill, the pathology is all over the brain. The changes Akil saw in the brains of people who were depressed are also consistent with data indicating that several neuroprotective factors, including BDNF and VEG-F, are low in the frontal cortex and the hippocampus of depressed people (while BDNF is high in the nucleus accumbens).

Low Oxytocin Linked to Depression in Moms

September 21, 2015 · Posted in Risk Factors · Comment 

postpartum depression

At a panel at the 2015 meeting of the Society of Biological Psychiatry, researcher Andrea Gonzales described her team’s study of mechanisms related to postpartum depression and the bonding hormone oxytocin. In the study of 26 women at eight months postpartum, the team examined whether there were connections between a mother’s levels of oxytocin at baseline and after interacting with her child, her mood symptoms, and whether she was mistreated in childhood.

Those women who scored low on a history of maltreatment in childhood had bigger increases in oxytocin in their blood and saliva after interacting with their children. Those with high trauma scores but low levels of depression also saw big boosts in oxytocin after seeing their children. Those women who had both a history of trauma in childhood and current depressive symptoms did not get as big a boost of oxytocin after interacting with their children.

Gonzales and colleagues concluded that postpartum depression is linked to dysregulation of oxytocin levels, and that a history of trauma in the mother’s childhood can make this worse.

The researchers hope that these findings may make it easier to identify which women are at risk for postpartum depression, and that they may point to possible treatments in the future.

Postpartum depression is a problem for about 13% of mothers in the year after they give birth, and mother-child bonding may be disturbed if a mother is depressed. One way to foster better bonding between a depressed mother and her newborn is to use video feedback. A mother views video of herself interacting with her child while a trained professional helps her identify opportunities for greater physical contact.

Early Life Stressors Lead to Lifetime Increase in Inflammation in Mice

March 9, 2015 · Posted in Risk Factors · Comment 

mother mouse and pups

Stressors in early life can contribute to the risk of developing mood disorders. Given that many treatments for mood disorders work by blocking the serotonin 5-HT transporter, Nicole Baganz and colleagues designed a study to see whether an early life stressor, in this case maternal separation, would affect immune processes that in turn affect serotonin signaling.

In this study as in many before it, mice that were removed from their mothers exhibited behaviors that resembled human anxiety and depression. They were also found to have elevated messenger RNA for several inflammatory cytokines (including IL-1beta and IL-6) in their brain and blood. Mice that had a gene for the interleukin-1 receptor (IL-1R) removed exhibited neither the depressive behavioral effects nor the changes in cytokine levels following maternal separation, showing that the IL-1R gene plays a necessary role in the signaling process that leads to this type of depression. Levels of the stress hormone corticosterone in the blood did not differ in the mice with and without the IL-1R gene.

The researchers concluded that early life stressors can cause lifelong changes in inflammatory cytokine levels in mice.

Young Rats That Witness Maternal Abuse Show Depression-Like Behavior in Adulthood

March 5, 2015 · Posted in Risk Factors · Comment 

rat mother and baby

Rodents that are subjected to social defeat (being overpowered by a bigger, more aggressive animal) develop a syndrome that resembles human depression—they avoid social interaction, lose interest in sucrose, and do less exploring of new places or other animals. A recent finding showed that even witnessing the social defeat of a peer was enough to bring about the depressive behaviors. The same researchers, led by Samina Salim, recently found that young rats (aged 21–27 days) that witnessed their mother go through the trauma of social defeat showed depression-like behavior themselves as adults (at age 60 days).

The rats saw their mothers defeated by the larger rat every day for seven days. As adults, those who witnessed this abuse exhibited depression-like behavior compared to rats of the same age and gender that had not witnessed abuse. The depressive rats gave up more quickly on a test of forced swimming. Male rats showed great depression-like behavior than female rats.

It has been estimated by the American Psychological Association that 15.5 million children in the US witness physical or emotional abuse of a parent (usually their mother). Children who witness domestic violence often show symptoms of post-traumatic stress disorder (PTSD). This rodent research may lead to a better understanding of the consequences of witnessing trauma in childhood, and potential treatments that could help.

Editor’s Note: These data show that rats have something like empathy, and that the psychological aspects of stress (including verbal abuse in humans and witnessing another’s abuse in rodents) may have profound and lasting consequences on behavior.

Maternal Childhood Adversity Associated with Low Infant Birth Weight

February 17, 2015 · Posted in Genetics · Comment 

mother and infant

In a study of the effect on infant health of a mother’s experience of adversity in childhood by researcher Deborah Kim and colleagues, both adversity in childhood (such as physical abuse or the loss of a parent) and stress during pregnancy were associated with low infant birth weight and lower gestational age at birth.

Among 146 women enrolled in the study, 58.2% percent scored a 0 on the Adverse Childhood Experience Questionnaire (ACE), 24% scored a 1, and 17.8% scored a 2. Those who scored higher on the ACE also scored higher on a scale measuring perceived stress. A score of 2 or higher on the ACE was associated with lower gestational age at birth, indicating infants born prematurely. Greater stress during pregnancy was associated with lower gestational age at birth and lower infant birth weight. When potential confounding demographic factors were removed from the analyses, ACE scores of 2 or higher were still associated with lower infant birth weight, while perceived stress was no longer associated with either low birth weight or gestational age.

Childhood adversity is associated with increases in inflammation and multiple adverse medical consequences in adults. The researchers called childhood adversity a “significant predictor of poor delivery outcomes” for women.

Editor’s Note: This research shows that a mother’s health and earlier life stressors could have an adverse effect on her child.

Childhood adversity leaves behind a residue of neuroendocrine and neuroclinical alterations that can persist into adulthood. Many are mediated by epigenetic changes, consisting of small chemical marks that attach to DNA and the histones around which it is wrapped.

In addition to these neurobiological alterations mediated by epigenetic effects, there is new evidence that some epigenetic marks can be passed on to the next generation via a mother’s egg or a father’s sperm. Thus, either directly or indirectly, parents’ adverse life experiences can influence the health of their offspring.

Childhood Adversity Associated with Shorter Telomeres

February 13, 2015 · Posted in Risk Factors · Comment 

Gold stylized chromosome pairTelomeres sit at the end of DNA strands and shorten with each cell replication. Shorter telomeres are associated with aging and an increase in multiple medical and psychiatric disorders. New research draws connections between the production of mitochondrial DNA, telomere length, the experience of childhood adversity, and mental illness.

Researcher Audrey Tyrka and colleagues divided 290 healthy adults into four categories based on whether or not they had experienced adversity in childhood and whether they had been diagnosed with a mental illness in their lifetime, including depression, anxiety, and substance abuse. The researchers also analyzed the participants’ telomere lengths and the copy number of their mitochondrial DNA. Both stressful events in childhood (such as maltreatment or the loss of a parent) and a history of mental illnesses (depression and anxiety) were associated with shorter telomeres and higher mitochondrial DNA copy numbers, a measure of cellular aging. Substance abuse was associated with higher mitochondrial DNA copy numbers.

Editor’s Note: This research replicates earlier findings that adversity is associated with shortening telomeres. The finding that mitochondrial DNA could play a role in the long-term effects of early life adversity and mental illnesses is new.

Childhood Maltreatment Leads to Inflammation and Depression in Adulthood

January 9, 2015 · Posted in Risk Factors · Comment 

sad little girl

Researcher Andrea Danese discussed the influence of childhood maltreatment on inflammation in a symposium at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry. Danese indicated that inflammation is part of the normal immune system, which includes the blood brain barrier, recognition of self- versus non-self proteins, activation of cytokines and endothelial cells, and response by phagocytes and acute phase proteins. In an acute phase inflammatory response, the liver secretes proteins including c-reactive protein (CRP) and fibrinogen into the blood, where their levels can be measured.

Normal amounts of inflammation can be protective, while excessive or persistent inflammation can be damaging and pathological. The inflammatory cytokines interferon gamma and tumor necrosis factor (TNF alpha) induce an enzyme called indoleamine oxidase (IDO) that shunts the amino acid tryptophan away from its normal path, which yields serotonin, so that it instead yields kynurenine and then kynurenic acid, which inhibits the action of glutamate at NMDA receptors. Kynurenine can also be hydroxylated and turned into quinolinic acid, which activates glutamate NMDA receptors and causes toxicity.

In addition, inflammatory cytokines such as interleukin six (Il-6) can cross the blood brain barrier and directly influence neurotransmission. Meta-analyses have shown that inflammatory markers CRP, IL-6, IL-1, and IL-1 Ra all increase significantly in depression. A direct demonstration of the relationship between inflammation and depression is the finding that when hepatitis C is treated using the inflammatory treatment interferon gamma, there is about a 30% incidence of depression, which responds to the antidepressant paroxetine.

Stress can also increase the activity of the sympathetic nervous system, driving inflammation, and decrease parasympathetic activity, resulting in further inflammation. In addition, glucocorticoid receptor resistance can develop, enhancing depression, and increasing inflammation.  Thus there are multiple ways inflammation can develop.

Danese described a study from New Zealand in which 1000 participants were observed over several decades—from childhood through age 38. The small percentage of participants who experienced maltreatment as children (aged three to eleven) showed a linear increase in CRP in adulthood as a function of their histories of previous child maltreatment. The maltreatment included parental rejection in 14%, sexual abuse in 12%, harsh discipline in 10%, changing caretakers in 6%, and physical abuse in 4%. Childhood maltreatment was also associated with some unfortunate outcomes in adulthood, including lower socioeconomic status, more major depression, more persistent depression, more cardiovascular risk, and more smoking. In other studies, Danese found that compared with controls, patients with depression alone, and patients with maltreatment alone, a greater number of patients with both depression and maltreatment (about 30%) had elevated CRP.

Danese noted that in a study by Ford et al. (2004), recurrent depressions, but not single depressions, were also significantly associated with increased CRP. In a meta-analysis by Nanni et al. in the American Journal of Psychiatry in 2012, Danese and colleagues found that across multiple studies, childhood maltreatment was associated with a twofold increase in the incidence of depression and a twofold increase in the persistence of depression (chronic depression or treatment resistance). The traditional optimal treatment for depression, combined psychotherapy and pharmacotherapy, was also significantly less effective in those with histories of childhood maltreatment. However, psychotherapy alone was equally effective in those with and without childhood maltreatment.

Together these data suggest that childhood maltreatment, partly through an inflammatory pathway, results in multiple difficulties in adulthood, including depression and treatment resistance. These data speak to the importance of attempting to prevent maltreatment in the first place, and ameliorating its consequences should it occur.

Editor’s Note: In a 2014 article in the Journal of Nervous and Mental Disorders, this editor Robert Post and colleagues reported that childhood adversity (verbal, physical, or sexual abuse) is associated with increases in medical comorbidities in adult patients with bipolar illness, and it is likely that inflammation could play a role in some of these medical conditions.

Childhood adversity, epigenetics, and hippocampal volume

September 26, 2014 · Posted in Genetics, Risk Factors · Comment 

upset boy

At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Booij reported that in humans, there is an interaction between adversity experienced during childhood, and an epigenetic variation in the short form of the serotonin transporter (5HT-T ss, or SLC6A4), which can influence hippocampal volume during depression.

Epigenetics refers to environmental influences on the way genes are transcribed. The impact of life experiences such as stress is not registered in DNA sequences, but can influence the structure of DNA or tightness of its packaging. Early life experiences, particularly psychosocial stress, can lead to the accumulation of methyl groups on DNA (a process called methylation), which generally constricts DNA’s ability to start transcription (turning on) of genes and the synthesis of the proteins the genes encode. DNA is tightly wound around proteins called histones, which can also be methylated or acetylated based on events in the environment.  When histones are acetylated, meaning that acetyl groups are attached to them, DNA is wound around them more loosely, facilitating gene transcription (i.e. the reading out of the DNA code into messenger RNA, which then arranges amino acids in order to construct proteins). Conversely, histone methylation usually tightens the winding of DNA and represses transcription.

Booij followed 33 children who had experienced some form of adversity at a young age until they were 15 or 16, examining methylation of the serotonin transporter in their T cells and monocytes compared to 36 children who had not experienced adversity during childhood. He found that in children who had experienced abuse in childhood, the degree of that abuse was correlated with methylation of the serotonin transporter and was inversely related to the volume of the hippocampus, as measured using magnetic resonance imaging (MRI). Thus, child abuse yields lasting epigenetic effects (methylation of the serotonin transporter) and has anatomical consequences in teenagers, as seen in smaller hippocampi. These data parallel converse findings by Joan Luby et al. published in the journal PNAS in 2012, in which increased maternal warmth directed toward a child aged 4-7 was associated with increased volume of the hippocampus several years later.

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