Mild Traumatic Brain Injury and Deployment Associated with Inflammatory Abnormalities in Veterans of the Iraq and Afghanistan Wars
Mild traumatic brain injury from improvised explosive devices is an injury particular to veterans of the wars in Iraq and Afghanistan. As has been seen in some athletes who sustain repeated mild traumatic brain injuries, such as boxers and football players, neurodegenerative dementias such as chronic traumatic encephalopathy can follow these repeated brain injuries. Researchers are hoping to identify biomarkers that would help in the diagnosis and monitoring of repeated blast-induced mild traumatic brain injury. Researcher Elaine Peskind and colleagues have determined that both deployment to these wars and mild traumatic brain injuries received there are associated with increased inflammatory cytokines in cerebrospinal fluid.
In the study, veterans who had been deployed to Iraq or Afghanistan and had received mild traumatic brain injuries were compared to veterans who were deployed but who were not similarly injured and community participants who had neither been deployed nor experienced a brain injury. The average number of concussion-inducing blasts veterans in the first group had experienced was 14, with the latest occurring an average of four years prior to the study.
Inflammatory cytokine IL-7 was elevated in the spinal fluid of those veterans who had sustained brain injuries. IL-6 was higher both in those deployed and in those who sustained blasts. Eotaxin and granulocyte colony stimulating factor were higher in all of the veterans who had been deployed.
These cytokine abnormalities could account for behavior and cognitive difficulties associated with traumatic brain injury. The researchers concluded that both deployment and mild traumatic brain injury were associated with neural damage and neuroimmune responses.
Editor’s Note: Michael E. Hoffer et al. reported in the journal PLosOne in 2013 that veterans with blast-induced mild traumatic brain injury had a better acute outcome when they were given the antioxidant N-acetylcysteine (NAC) within the first 24 hours after the trauma. It is interesting to speculate whether this could be explained by NAC’s anti-inflammatory effects, its enhancement of another antioxidant (glutathione), or its ability to increase glial glutamate transporters.
Researcher Dewleen Baker reported in a personal communication to this editor (Robert Post) that in her patients, traumatic brain injury was also associated with white matter abnormalities, and that these injuries conveyed an increased risk of developing PTSD as well.
Telomeres 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, while some healthy behaviors including exercising, eating healthy, avoiding smoking, and even being married can help maintain telomere length. New data from researcher Elizabeth Hoge and colleagues suggests that a particular type of meditation can lengthen telomeres.
Previous research has found that three months of full-time meditation increased telomerase, an enzyme that repairs telomeres. Loving-Kindness meditation, which comes from the Vipassana Buddhist tradition and focuses on positive intentions, unselfish kindess, and warmth towards all people, has been found to produce positive effects in individuals who practice it, including increasing positive emotions and sense of purpose, and bringing about improvement in physical symptoms including headaches, nasal congestion, and weakness. Hoge and colleagues hypothesized that people who practice Loving-Kindness meditation would have longer telomeres than control participants of the same age, gender, education level, and experience of depression.
Participants who practiced Loving-Kindness meditation had been doing so near-daily for at least four years, and averaged 512 lifetime hours of this particular type of meditation, and 4,927 lifetime hours of any type of meditation.
The researchers found a trend toward longer relative telomere length in the Loving-Kindess meditation group compared to the control group, and significantly longer telomeres in women who meditated than in women who did not. The researchers conclude that meditation may have a positive effect on mortality.
Other habits that are focused on others, such as caring for a spouse, volunteering in the community, and practicing compassion, forgiveness, and altruism have been found to have health benefits. In a 2012 longitudinal study of elderly participants by Loren Toussaint et al. in the Journal of Behavioral Medicine, forgiveness was associated with longevity. Thaddeus W.W. Pace et al. reported in a 2009 article in Psychoneuroendocrinology that compassion meditation reduced levels of certain inflammatory markers.
Editor’s Note: People with affective disorders or at risk for them should consider making some of these positive lifestyle practices part of their daily routine.
Telomeres 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.
Sensory gating is a process by which the brain filters out unimportant information, to avoid flooding higher cortical centers with irrelevant stimuli. New research from Randal Ross and colleagues shows that infants of mothers with anxiety have deficits in the way their brains inhibit response to this type of irrelevant information.
Mothers who were rated higher on the trait of anxiety had paradoxically lower levels of the inflammatory cytokine interleukin 6 at week 16 of their pregnancy, and their one-month-old infants showed more deficits in sensory gating. The reasons for these relationships requires further investigation.
Choline is a nutrient found in liver, muscle meats, fish, nuts, and eggs, and it may help. In a 2013 article in the American Journal of Psychiatry, Ross and colleagues showed that the supplement phosphatidylcholine (which converts to choline), taken during the second and third trimesters of pregnancy (at doses of 6300 mg/day, the equivalent of about three eggs) and followed up with 700 mg/day in the infant, led to improvements in sensory gating in the infants. These infants went on to have fewer behavioral problems as toddlers.
Ross and colleagues suggest that pre- and post-natal choline supplementation may be able to reverse the effects of maternal anxiety on infants. The researchers believe it could be helpful in the prevention of schizophrenia, as insufficient cerebral inhibition (decreased sensory gating) is a characteristic of that illness as well.
Depression is common following heart attacks, and it can complicate recovery. A recent study by Jae-Min Kim and colleagues investigated the safety of treating depression with escitalopram in people recovering from acute coronary syndrome. In a 2015 article in the Journal of Clinical Psychiatry, they reported that 217 people with depression and acute coronary syndrome were randomized to receive either escitalopram (in flexible doses ranging from 5–20 mg/day) or placebo for 24 weeks. Patients who received escitalopram saw more improvement in their depression on a variety of scales, and also showed improvements in social and occupational functioning. There were no adverse cardiac effects from escitalopram, though some people taking it did experience dizziness.
Researcher Ben Goldstein reported at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry that children with bipolar disorder have levels of inflammatory markers in the same range as people with inflammatory illnesses, such as rheumatoid arthritis. In his research, increases in the inflammatory marker c-reactive protein (CRP) occurred in proportion to the severity of manic symptoms in the children.
Goldstein also discussed cognitive dysfunction, which is often seen early in the course of childhood onset bipolar disorder. Goldstein described studies showing that this type of cognitive dysfunction consists of a decrease in reversal learning, a measure of cognitive flexibility. Elevated CRP was significantly associated with deficits in a child’s composite score for reversal learning.
Together these data suggest that inflammation could play a role in disease disability and cognitive dysfunction in childhood bipolar disorder.
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.
The incidence of irritable bowel disease has been increasing in recent years as obesity has increased. At a symposium at the 2014 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Eva Szigethy discussed depression in inflammatory bowel disease, which most often involves Crohn’s disease or ulcerative colitis. These conditions are associated with increased levels of inflammatory markers such as interleukin 1 (IL-1), interleukin 6 (IL-6), and TNF alpha, and these in turn induce the acute phase reactive protein called c-reactive protein (CRP). The interleukins peak in the first 12 hours after an inflammatory challenge and CRP peaks at 48 hours and returns to normal at 120 hours. Il-6 is most closely associated with the somatic symptoms of inflammation, including depression, fatigue, loss of appetite, and decreased sleep, while TNF alpha is associated with non-somatic symptoms, such as irritability.
Szigethy found that in a randomized trial of cognitive behavior therapy versus supportive therapy in children with inflammatory bowel disease, inflammatory activity decreased significantly with cognitive behavioral therapy, and the therapy particularly helped the somatic symptoms of fatigue, sleep disorder, anhedonia (loss of interest in activities once enjoyed), appetite suppression, and mood dysregulation. In contrast, when antidepressants are given to those with inflammatory bowel disease, the drugs are not particularly helpful for these somatic symptoms. Inflammatory bowel diseases are treated with steroids in 21% of patients and with a genetically engineered drug called infliximab in 30%. Adding cognitive behavioral therapy to the regimen decreases CRP and red cell sedimentation rate, an associated measure of inflammation.
The discussant of the symposium on inflammation, Frank Lotrich, described how inflammation alters sleep, and this appeared to interact with genetic risk of illness. For example, those with certain genetic variations (the short SS allele of the serotonin transporter and the val-66-met allele of proBDNF) were most likely to experience sleep disturbance following treatment with interferon gamma, a treatment that fights the virus that causes Hepatitis C, creating inflammation in the process. Interferon gamma causes depression in about one-third of the patients who take it.
Lotrich pointed out that low levels of omega-3 fatty acids are associated with increased irritability and anger, and this is related to the presence of the A allele of TNF alpha. TNF alpha is also closely linked with irritability and anger, suggesting the possible benefits of omega-3 fatty acid supplementation to target irritability and anger more selectively. This would be consistent with the data of researcher Mary A. Fristad.
Il-6 is closely associated with the somatic symptoms of depression, particularly poor sleep, which is itself associated with increases in depression. This is consistent with inflammation being a marker of poor response to antidepressants; Lotrich noted that the selective serotonin reuptake inhibitors (SSRIs), which help depression, are far more effective against the non-somatic aspects of depression and less effective against low energy, decreased interest, and fatigue. However, extrapolating from the data on inflammatory bowel disease, cognitive behavioral therapy may be most helpful on these somatic symptoms.
Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striatum.
People with major mental disorders such as schizophrenia and bipolar disorder are at increased risk for medical symptoms including overweight, obesity, high cholesterol or triglycerides, diabetes, and the metabolic syndrome, all of which increase risk of cardiovascular disease (heart attack), cerebrovascular disease (or strokes), and other medical difficulties. In a 2013 review article in the journal Bipolar Disorders, researcher Chittaranjan Andrade discussed the use of statins to prevent cardiovascular events in people with major mental disorders.
Statins decrease lipids, and have significant benefits in decreasing cardiac events, but their use is low among psychiatric populations. Psychiatric patients often receive less cardiac care. It may be up to their psychiatrists to push for aggressive prevention of cardiac illnesses.
The most significant side effect of statins is the possibility that they can increase risk of diabetes. In a meta-analysis by Preiss et al., intensive dosing with statins increased the risk of diabetes but also lowered the risk of cardiovascular events. In a year, 1,000 patients would get two extra cases of diabetes but 6.5 fewer cases of cardiovascular events. For patients at high risk for heart attack or stroke, a cardiovascular event is more dangerous than diabetes, so it makes sense to treat these patients with statins. In patients at lower risk, there is some evidence that diabetes risk was a problem mostly in patients with other risk factors for diabetes, including metabolic syndrome, impaired fasting glucose levels, a body mass index of 30 kg/m2 or higher, or glycated haemoglobin A (1c) above 6%.
Most studies of statins are conducted on patients in middle age, but there is a rationale for treating even younger patients with statins. Patients with bipolar disorder develop cardiovascular disease more than a decade earlier than controls. There is some evidence that cholesterol deposits in arteries begin even before age 20, and are cumulative. The risk-benefit ratio for statin use improves with years of use, so starting it earlier may lead to better prevention. Long-term use may reduce the risk of Alzheimer’s disease and Parkinson’s disease and some cancers in addition to reducing heart attacks and strokes.
Despite the risk of diabetes, it is important to consider statin use in psychiatric patients, especially those who receive antipsychotic medications. Read more