Influence of Childhood Maltreatment on Morphometry and Brain Network Architecture in Bipolar Disorder
Martin Teicher of McLean Hospital, Harvard Medical School, reported on the influence of childhood maltreatment on morphometry and brain network architecture in Bipolar Disorder.
“Childhood maltreatment (MAL) is common in individuals with bipolar disorder (BP) and is associated with earlier onset, more severe course, and more comorbidities.” They found that reduced hippocampal volume and white matter alterations were present in those with a history of childhood maltreatment. They concluded that “MAL may act as a sensitizer promoting the emergence of bipolar symptoms in individuals with less severe network abnormalities” than in BP patients with no MAL.
Potential of Environmental Enrichment to Prevent Transgenerational Effects of Paternal Trauma
Gapp, K. et al. wrote about the “Potential of Environmental Enrichment to Prevent Transgenerational Effects of Paternal Trauma” in Neuropsychopharmacol 41, 2749–2758 (2016).
They “used a mouse model of unpredictable maternal separation combined with unpredictable maternal stress (MSUS) to examine the consequences of traumatic stress on coping behaviors in adulthood and across generations, and the potential contribution of (glucocorticoid receptors) GR. We show that MSUS affects avoidance behaviors and learning in aversive environments in exposed fathers and their male offspring. This is associated with an increase in GR expression in the hippocampus, and with decreased DNA methylation of GR promoter in the hippocampus and in germ cells. We show that transmission of the effects of paternal trauma can be prevented by paternal (environmental enrichment) EE, suggesting a reversibility of these effects.”
Editors Note: Dad’s early environmental adversity alter his response to traumatic stress as an adult, and this can be passed to the next generation via epigenetic changes in DNA methylation, histone and microRNA chemical changes persisting in sperm. If the dad with early life adversity is housed in an enriched environment, he does not have the altered response to stress or the changes in GR, and his offspring do not have the transgenerational alterations in stress responsively. This could probably happen in people if we could only figure out to super good environmental enrichment in those having early life adversity. Having lots of stress as a neonate and then being adopted out to wonderful foster family could be the basis for a naturalistic study of this sort of result.
Low Levels of Acetyl-L-Carnitine Associated with Insulin Resistance in Traumatized Children
Researcher Carla Nasca and colleagues from the Rockefeller University reported at a late-2018 scientific meeting that depressed patients with a history of childhood adversity had low levels of the amino acid acetyl-L-carnitine and also exhibited insulin resistance. This is noteworthy because in a series of small studies, acetyl-L-carnitine supplements have had antidepressant effects. In laboratory animals, acetyl-L-carnitine also sensitizes insulin receptors. This suggests the possibility that the supplements could provide a two-for-one benefit in depressed patients with a history of adversity in childhood.
Inflammatory Marker IL-6 is Elevated in People with Depression and Those with a History of Childhood Trauma
In a 2018 article in the journal Psychiatry Research, researcher Ana Munjiza and colleagues reported that the inflammatory marker IL-6 was higher in 64 depressed people than in 53 non-depressed people, and that levels of IL-6 among people in the depressed group were significantly correlated with scores on a questionnaire in which participants reported traumas experienced in childhood. They reported more physical abuse, physical neglect, and emotional abuse.
Munjiza and colleagues indicate that trauma in childhood is a risk factor for depression in adulthood, as other researchers have suggested, and that inflammation could mediate the relationship between childhood adversity and depression.
Editor’s Note: IL-6 has been associated with antidepressant treatment resistance. IL-6 is secreted from white cells in the blood and from monocytes from the bone marrow in response to stress. It enters the brain and starts an inflammatory cascade that induces depressive behaviors. Animal studies have shown that if IL-6 secretion is blocked, depressive-like behaviors do not occur.
Another indicator of inflammation is CRP, and elevations in CRP have been associated with poor response to selective serotonin reuptake inhibitor (SSRI) antidepressants, and better response to the noradrenergic tricyclic antidepressant nortriptyline and the dopamine active antidepressant bupropion.
Treatments for depressed people with histories of childhood trauma may include psychotherapy, somatic therapies such as repeated transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), and medication. More research is needed to determine the optimal treatment regimens for this subgroup of depression sufferers, including whether anti-inflammatory drugs could play a helpful role in preventing or treating depression. People with elevated inflammatory markers (such as IL-6, CRP, IL-1, or TNF-alpha) are likely to be better candidates for adjunctive anti-inflammatory treatments than those with normal or low baseline levels of inflammation.
A Calculator of Risk for Bipolar Disorder in Youth
Daniella Hafeman of the University of Pittsburgh described a risk calculator for predicting an individual’s risk for bipolar disorder, which is available at www.pediatricbipolar.pitt.edu. Possible factors included in the risk calculation include a parent’s early age of onset of bipolar disorder, mood shifts early in life, a child’s anxiety or depression symptoms, later affective mood shifts, and new onset of subthreshold mania.
Editor’s Note: A “poor man’s” assessment of risk can also be of help to a family or clinician. There are four components. The first is genetic. Having one parent with bipolar disorder is a potent risk factor, and can be further magnified if the other parent also has a mood disorder. If three or more first degree relatives or three or more generations of first degree relatives have a mood disorder, this further increases risk four- to six-fold.
Perinatal vulnerability is another factor. Beyond these genetic vulnerabilities, a history of maternal toxoplasmosis or a viral infection during pregnancy, or the infant being noticeably underweight at birth can contribute to bipolar risk.
Childhood adversity also contributes to vulnerability to early onset of bipolar illness. A history of psychosocial stress in the child’s early years, such as abuse or abandonment, can be an added risk factor.
Prodromal or preliminary symptoms are also a risk factor. The development of an anxiety or depressive disorder, a disruptive behavioral disorder, or a bipolar not-otherwise-specified diagnosis (BP-NOS, used to describe manic symptoms of short duration) further increases risk. In studies by David Axelson and Boris Birmaher, 50% of children with an initial diagnosis of BP-NOS developed full-blown bipolar I or II illness upon several years of followup if there was a family history of bipolar disorder. About one-third converted to full bipolar disorder if there was no family history of bipolar disorder.
Thus, if a child has three or all four types of risk factors, their risk would be substantial. In this case, one might consider attempts at prevention. This could include a good diet rich in omega-3 fatty acids, regular exercise, joining a school sports team, developing good sleep habits, playing a musical instrument, and engaging in something akin to family focused therapy. Family focused therapy emphasizes psychoeducation, good communication skills, and problem solving. Attending to and treating parents’ symptoms and building a support system for both parents and the child can also help.
While these endeavors are not a guarantee to prevent the onset of more severe illness, they are all health-promoting in general and have few downsides.
Traumatic Events in Childhood Linked to Shorter Telomeres
Telomeres are bits of DNA at the end of chromosomes that protect the DNA as it replicates. Shorter telomeres have been linked to aging and increases in multiple types of medical and psychiatric disorders. A 2016 article in PNAS, the Proceedings of the National Academy of Sciences of the United States of America, reported that cumulative life adversity and particularly stressful or traumatic events in childhood, predict shorter telomere length.
The study by Eli Puterman and colleagues included 4,590 individuals from the US Health and Retirement Study who reported stressful events that had experienced. A single experience of adversity was not linked to short telomeres, but lifetime cumulative adversity predicted 6% greater odds of having shorter telomeres. This result was mainly explained by adversity that occurred in childhood. Each stressful or traumatic event in childhood increased the odds of short telomeres by 11%. These were mostly social or traumatic experiences rather than financial stresses.
Brain Volumes Affected by Type and Timing of Childhood Abuse
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
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
Dysregulation 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
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.
