Cutting, or non-suicidal self injury, is a serious problem among adolescents, and few treatments are available. Researcher Kathryn Cullen and colleagues have found that N-acetylcysteine (NAC), an antioxidant nutritional supplement that has been effective in the treatment of depression and many addictions and habit-related behaviors, can reduce cutting.
The study included 25 participants with a history of non-suicidal self injury, aged 13–21, and 12 controls. They participated in brain scans before and after treatment. Compared to the controls, the self-injurers showed greater overall psychopathology, greater activation in a few brain regions (precuneus, posterior cingulate, insula, and temporal lobes), and reduced lower left frontal activation. Patients who received NAC up to 900mg twice daily in weeks 5–8 of the study reduced their cutting and also showed reduced psychopathology. An increase in frontal activation in response to negative emotion was linked to the reduction in cutting.
Editor’s Note: NAC improves mood in depression, many addictions, and many habits including trichotillomania (excessive hair-pulling), nail biting, and cutting. It may do this by increasing glial glutamate transporters in the nucleus accumbens, the brain’s reward center, which lessens the magnitude of the glutamate signal, mediating the compulsion to engage in the habitual behavior.
Researchers hope to map out the neurocircuitry by which stress leads to compulsive drug taking. A recent study by Klaus Miczek and colleagues examined different rodents’ responses to the stress of being repeatedly placed in the cage of a larger, more aggressive rodent, developing what is known as defeat stress, a set of behaviors that mimic human depression. Mice and rats showed increases in the stress hormone corticosterone that did not diminish over repeated run-ins with a larger animal. Rodents who were exposed to this stress became sensitized to cocaine or amphetamine, showing hyperactivity that increased each time they accessed the drug (the opposite of a tolerance response). Some also “binged” on cocaine, which they were able to self-administrate by pushing a lever to receive infusions. The mice and rats that went through the social defeat showed elevated levels of dopamine in the nucleus accumbens, the brain’s reward center. Levels were related to the severity of their stressful experience.
Later the rodents had a choice between water and a 20% alcohol solution. The researchers determined what type of stress led the rodents to consume the alcohol solution instead of the water. The maximal effect was seen in two types of mice that suffered an attack of less than five minutes that resulted in a moderate number of attack bites (30); this resulted in the mice consuming large amounts (15–30 g/kg/day) of the alcohol solution. Earlier sensitization to cocaine or amphetamine did not predict later alcohol or cocaine self-administration.
When the researchers injected the rodents with antagonists of the receptors for corticotropin-releasing factor, a hormone and neurotransmitter important in stress response, prior to each episode of social defeat, the rodents did not escalate their cocaine or alcohol self-administration, indicating that CRF plays an essential role in the process by which stress makes animals prone to using substances.
In related research by Camilla Karlsson and colleagues, IL-1R1 and TNF-1R, the receptors for two inflammatory cytokines, mediated the effects of social stress on escalated alcohol use in mice.
Life experiences such as adversity in childhood have been linked to epigenetic changes to DNA. These changes do not affect the sequence of DNA, but can change how tightly DNA is wound, and thus how easily it is transcribed. One epigenetic change that can occur following adversity in childhood is methylation of the gene for the glucocorticoid receptor (NR3C1). A recent study by Kathryn Ridout and colleagues examined links between early adversity, methylation of this gene, and behavioral problems in childhood. Adversity was linked to methylation of the gene at exons 1D and 1F in the promoter of NR3C1. Methylation of the gene was associated with internalizing behaviors (e.g. depression, anxiety) but not externalizing behaviors (e.g. attention deficit hyperactivity disorder (ADHD) or oppositional defiant disorder) in children of preschool age. The NR3C1 methylation was a significant mediator of the internalizing behaviors in children who had experienced adversity.
Editor’s Note: Similar associations of methylation of the glucocorticoid receptor with childhood adversity have been reported in other clinical and animal studies and provide a mechanism for the long-lasting adverse effects of stressors in childhood.
People and animals can rapidly learn to associate environmental stimuli with positive or negative outcomes, learning what to approach or avoid as they go through daily life. The amygdala plays a role in this type of emotional learning, which can be disrupted by mood disorders. In new research, Praneeth Namburi and colleagues determined that activity at the synapses in the basolateral amygdala reveals differences in the creation of fear memories and reward memories.
In animals trained with reward and fear conditioning tasks, photostimulation of neurons that then travel from the basolateral amygdala complex to the nucleus accumbens (the brain’s reward center) is positively reinforcing, while photostimulation of neurons that will travel from the basolateral amygdala complex to the centromedial nucleus of the amygdala causes aversion. There are genetic differences between the two types of neurons, including a difference in the gene for the neurotensin-1 receptor. The researchers found that neurotensin, a neuropeptide, modulates glutamate’s effect on neurons, causing some to project to the nucleus accumbens and some to project to the centromedial nucleus of the amygdala.
The researchers wrote that the results “provide a mechanistic explanation, on both a synaptic and circuit level, for how positive and negative associations can be rapidly formed, represented, and expressed within the amygdala.”
Editor’s Note: The amygdala’s creation of opposing outputs may provide clues to the mechanisms behind mania (involving the nucleus accumbens) and depression (involving the centromedial nucleus of the amygdala).
Events like surgery or heart attacks that cause inflammation can lead to cognitive deficits or depression for months or years afterward, even though the direct effects of inflammation wear off within weeks. In a recent study, Natalie Tronson and colleagues subjected mice to surgical heart attack, sham surgery, or no operation, and observed how well they absorbed new learning eight weeks later.
Both male and female mice had impairments in fear learning following surgical heart attacks. Female mice that received sham surgery also showed deficits in fear learning. When the researchers dissected the mice, analyzing their blood and hippocampi after the eight-week period, inflammatory cytokine measures had normalized as expected, but the researchers found other abnormalities.
Intracellular signaling was dysregulated, and there had been epigenetic changes in cells of the hippocampus. (Epigenetic changes refer to those that change the structure of DNA, such as how tightly it is wound, rather than its sequence. For example, the addition of acetyl groups to DNA or the histones around which it is wound.) The researchers observed increased histone acetylation and phospho-acetylation following the heart attacks.
The researchers concluded that a systemic inflammatory event, such as heart attack or surgery, can cause long-term memory impairment and changes in mood through epigenetic mechanisms. They compared the findings to those of other studies in which normal aging and memory-impairing treatments such as chemotherapy had also been associated with increases in histone acetylation or decreases in histone deacetylase activity.
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.
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.
Regulation of the amygdala (the brain’s emotional center), particularly through its interaction with the ventral anterior cingulate cortex, has been implicated in the experience of fear in animals, and anxiety and depression in humans. Connectivity between the two structures is critical for emotion modulation. Repeated transcranial magnetic stimulation (rTMS) is a method of stimulating outer regions of the brain with magnets. Researchers Desmond Oathes and Amit Etkin are investigating whether rTMS can also be used to influence these deeper brain areas, or their interaction with each other.
The researchers’ study used single-pulse probe TMS delivered at a rate of 0.4 Hz at 120% of each participant’s motor threshold, targeted at the anterior or posterior medial frontal gyrus on either side of the brain. The researchers also used functional magnetic resonance imaging (fMRI) of the whole brain to observe connectivity between different sections.
RTMS to the right side of the medial frontal gyrus increased connectivity between the amygdala and the ventral anterior cingulate cortex more than stimulation to the left side. Stimulation of the posterior portion of the medial frontal gyrus increased connectivity more than stimulation of the anterior portion.
Editor’s Note: These data indicate that rTMS can alter brain activity in these deeper regions and can influence inter-regional connectivity. This is important because abnormalities in the connectivity of brain regions have increasingly been found in patients with mood disorders. Oathes and Etkin hope that these findings can be applied to others and that rTMS can be used to correct patterns of regional connectivity in the brain in order to improve emotion regulation.
Electroconvulsive therapy is often considered a primary treatment option for patients with severe bipolar disorder that has resisted pharmacological treatment. Researcher Helle K. Schoeyen and colleagues recently published the first randomized controlled trial comparing ECT (in this case right unilateral brief pulse ECT) with algorithm-based pharmacological treatment in 76 patients with treatment-resistant bipolar depression.
The response rate was significantly higher in the ECT group than in the patients who received drug treatment (73.9% versus 35.0%). However, the two treatment groups had similarly low remission rates (34.8% for ECT and 30.0% for pharmacological treatment).
The algorithm-based pharmacological treatment used in the study was based on a sequence of treatments endorsed by researchers Frederick K. Goodwin and Kay Redfield Jamison in their 2007 book Manic-Depressive Illness. A selected treatment was chosen for each participant based on his or her medical history. If the first treatment was ineffective or intolerable, the patient would be switched to the next treatment option. Antipsychotics, antidepressants, anxiety-reducing drugs, and hypnotics were some of the other treatments included in the algorithms.
Patients in the study had previously showed a lack of response to at least two different antidepressants and/or mood stabilizers with documented efficacy in bipolar disorder (lithium, lamotrigine, quetiapine, or olanzapine) in adequate doses for a period of 6 weeks (or until they quit because of side effects).
Editor’s Note: Even when ECT is effective, there is the issue of how to maintain that good response. We previously reported that in a 2013 study by Axel Nordenskjöld et al. in the Journal of ECT, intensive followup treatment with right unilateral brief pulse ECT combined with pharmacotherapy was more effective than pharmacology alone at preventing relapses. Patients who improved after an acute series of ECT (three times/week) then received weekly ECT for six weeks and every two weeks thereafter, totaling 29 ECT treatments in one year.
Other studies of more intermittent continuation ECT have not proved more effective than medication. Thus high intensity right unilateral brief pulse ECT is one option for extending the effects of successful ECT.
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.