White Matter Abnormalities Linked to Irritability in Both Bipolar Disorder and DMDD
At a 2018 scientific meeting, researcher Julia Linke of the National Institute of Mental Health reported that there were white matter tract abnormalities in young people who had irritability associated with either bipolar disorder or disruptive mood dysregulation disorder (DMDD). Thus, while these two disorders differ in terms of diagnosis, presentation, and family history, they seem to have this neurobiological abnormality in common.
Scientific Mechanisms of Rapid-Acting Antidepressants
A pyramidal cell (Photo by Bob Jacobs, Laboratory of Quantitative Neuromorphology Department of Psychology Colorado College)
At a recent symposium, researcher Francis McMahon provided electrophysiological evidence that several different types of rapid-acting antidepressants—low-dose ketamine, scopolamine, and rapastinel (a partial agonist of the neurotransmitter NMDA)—act by decreasing the inhibitory effects of GABAergic interneurons on excitatory neurons called pyramidal cells, thus increasing synaptic firing.
Researcher Ronald Duman further dissected these effects, showing that ketamine and its active metabolite norketamine reduce the steady firing rate of GABA interneurons by blocking NMDA receptors, while the partial agonist rapastinel acts on the glutamate neurons directly, and both increase the effects of a type of glutamate receptors known as AMPA. These effects were demonstrated using a virus to selectively knock out GluN2B glutamate receptor subunits in either GABA interneurons or glutamate neurons.
Increasing AMPA activity increases synapse number and function and also increases network connectivity, which can reverse the effects of stress. Duman and colleagues further showed that when light is used to modulate pyramidal cells (a process called optogenetic stimulation) in the medial prefrontal cortex, different effects could be produced. Stimulating medial prefrontal cortex cells that contained dopamine D1 receptors, but not D2 receptors, produced rapid and sustained antidepressant effects. Conversely, inhibiting these neurons blocked the antidepressant effects of ketamine. Stimulating the terminals of these D1-containing neurons in the basolateral nucleus of the amygdala was sufficient to reproduce the antidepressant effects. These data suggest that stimulation of glutamate D1 pyramidal neurons from the medial prefrontal cortex to the basolateral nucleus of the amygdala is both necessary and sufficient to produce the antidepressant effects seen with ketamine treatment.
Researcher Hailan Hu reported that NMDA glutamate receptors drive the burst firing of lateral habenula (LHb) neurons, which make up the depressogenic or “anti-reward center” of the brain and appear to mediate anhedonic behavior (loss of interest or enjoyment) in animal models of depression. Ketamine blocks the burst firing of the LHb neurons, which disinhibits monoamine reward centers, enabling ketamine’s rapid-onset antidepressant effects. This may occur because inhibitory metabotropic glutamate receptors (mGluR-2) are activated, decreasing the release of glutamate.
MGluR-2 may also help explain the antidepressant effects of acetyl-L-carnitine supplements. L-carnitine is an amino acid that is low in the blood of depressed patients. The supplement acetyl-L-carnitine (ACL) activates the DNA promoter for mGluR-2, increasing its production and thus decreasing excess glutamate release. The acetyl group of the ACL binds to the DNA promoter for mGluR-2, thus this process seems to be epigenetic. Epigenetic mechanisms affect the structure of DNA and can be passed on to offspring even though they are not encoded in the DNA’s genetic sequence.
Inflammation and Depression: Treatment Implications
Vladimir Maletic of the University of South Carolina School of Medicine Greenville gave a plenary talk at the 2018 meeting of the North Carolina Psychiatric Association that described a variety of ways that inflammation can drive depression.
Maletic explained that stress can increase neurotransmitters that activate brain macrophages, increase NFkB (a protein that controls DNA transcription and cell survival), and increase brain inflammation, evidenced by elevated levels of the inflammatory markers IL-1b, IL-6, TNF-alpha, and C-reactive protein (CRP). These signs of inflammation are associated with changes in brain function and connectivity that are consistent with depression, fatigue, and cognitive slowing.
Inflammation measured outside of the brain and spinal cord is associated with increased activity of the insula (a key brain sensor and modulator of emotions), disconnection between the prefrontal cortex and the reward circuits in the nucleus accumbens, and decreased function and structural changes to the hippocampus (critical for memory).
Maletic also explained that inflammation changes the way the amino acid tryptophan is metabolized. Normally tryptophan is converted into kyneurenic acid, which prevents excitotoxicity and has anticonvulsant effects. Stress can lead to tryptophan being metabolized instead into quinolinic acid, which is neurotoxic and has been linked to certain psychiatric disorders and neurodegenerative processes. This in turn impairs synaptic functioning, including increasing glutamate and decreasing brain-derived neurotrophic factor (BDNF), impairing a type of glia called oligodendroglia (which produce myelin), and the formation of new neural connections.
These findings have several important implications for treatment. Increases in inflammation have been linked to the atypical type of depression characterized by increased appetite, weight gain, and increased sleep rather than the more classic presentation of depression that includes loss of appetite, weight loss and insomnia. Thus, weight gain, waist circumference, and body mass index (BMI) are correlated with inflammation and can signal a poor response to medications (including the rapid-acting antidepressant ketamine and some other antidepressants). If someone with unipolar depression has high levels of CRP, they tend to have a poorer response to selective serotonin reuptake inhibitor (SSRI) antidepressants, and may respond better to the noradrenergic tricyclic antidepressant nortryptyline, the serotonin and norepinephrine reuptake inhibitors (SNRIs), and the dopamine active antidepressant bupropion.
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Depression and Suicidal Thoughts Linked to Brain Inflammation
A 2017 article by Sophie E. Holmes and colleagues in the journal Biological Psychiatry reports that people with major unipolar depression, especially those with suicidal thoughts, have higher levels of the inflammatory marker translocator protein than do healthy individuals.
The participants with depression and suicidal thinking had high levels of translocator protein in the anterior cingulate cortex, which suggests that inflammation is affecting microglia.
Many studies have found links between different indicators of inflammation and mood disorders, leading researchers to speculate whether targeting the immune system could be an effective way to treat mood disorders. Patients with high levels of inflammation often fail to respond to typical treatments for depression.
Some previous research has found evidence of microglial activation in the brains of people who died from suicide.
The small study by Holmes and colleagues used positron-emission tomography, or PET scans, to observe evidence of translocator protein levels in the brain in 14 medication-free participants in a major depressive episode and 13 healthy volunteers. Those with depression, and particularly those with suicidal thoughts, showed more evidence of neuroinflammation.
Link Clarified Between Gut Microbes and Emotions
A 2017 article in the journal Microbiome suggests that gene-regulating molecules called microRNAs in the brain may be the link between microbes in the gut and emotions.
The research by Alan E. Hoban and colleagues looked at mice raised in a sterile, microbe-free environment. These mice had fewer anxiety-like behaviors than mice raised among the usual bacteria, viruses, and fungi. This finding implies that the microbiome—the trillions of microbes that live in and around our bodies—affects brain functions. In this case, the affected regions were the prefrontal cortex and the amygdala, which both play a role in the detection and response to fearful stimuli. These regions showed alterations in the level of microRNAs present.
When Hoban and colleagues introduced microbes into the animal’s systems, some microRNAs did not bounce back, suggesting that there may be a crucial window early in life when the presence of microbes is needed for the brain to develop normally.
In general, this research shows that microRNAs are key to understanding the link between the microbiome and the brain.
Type of Trauma Affects Gene Transcription Effects in PTSD
In a 2017 article in the journal Neuropsychopharmacology, researcher Michael S. Breen and colleagues analyzed five separate studies of post-traumatic stress disorder (PTSD) and found that sex and type of trauma affected the immunological pathways that changed with PTSD. People with PTSD showed disruptions in gene expression in specific immunological pathways depending on what type of trauma they had experienced.
Men exposed to combat traumas showed downregulation in a pathway related to wound healing, while men who were exposed to interpersonal traumas had upregulation in a signaling pathway mediated by the inflammatory marker IL-12. Women exposed to interpersonal traumas showed upregulation of two pathways—one related to lipid metabolism and the other related to MAPK (or mitogen-activated protein kinase) activity.
The participants with PTSD also showed a lot of the same disruptions across all types of trauma, including disruptions that affected cytokine, innate immune, and type 1 interferon pathways.
These data show that immune dysregulation and inflammatory pathways play a role in the pathophysiology of PTSD.
Different Types of Trauma Affect Brain Volume Differently
Post-traumatic stress disorder (PTSD) has been associated with decreased volume of gray matter in the cortex. Research by Linghui Meng and colleagues has revealed that the specific types of trauma that precede PTSD affect gray matter volume differently.
At the 2016 meeting of the Society for Neuroscience, Meng reported that PTSD from accidents, natural disasters, and combat led to different patterns of gray matter loss. PTSD from accidents was associated with gray matter reductions in the bilateral anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC). PTSD from natural disasters was linked to gray matter reductions in the mPFC and ACC, plus the amygdala and left hippocampus. PTSD from combat reduced gray matter volume in the left striatum, the left insula, and the left middle temporal gyrus.
Meng and colleagues also found that severity of PTSD was linked to the severity of gray matter reductions in the bilateral ACC and the mPFC.
In a 2016 article in the journal Scientific Reports, Meng and colleagues reported that single-incident traumas were associated with gray matter loss in the bilateral mPFC, the ACC, insula, striatum, left hippocampus, and the amygdala, while prolonged or recurrent traumas were linked to gray matter loss in the left insula, striatum, amygdala, and middle temporal gyrus.
Brain Scans Differentiate Suicidal from Non-Suicidal Patients with Bipolar Disorder
People with bipolar disorder are at high risk for suicidal behavior beginning in adolescence and young adulthood. A 2017 study by Jennifer A. Y. Johnston and colleagues in the American Journal of Psychiatry uses several brain-scanning techniques to identify neurobiological features associated with suicidal behavior in people with bipolar disorder compared to people with bipolar disorder who have never attempted suicide. Clarifying which neural systems are involved in suicidal behavior may allow for better prevention efforts.
The study included 26 participants who had attempted suicide and 42 who had not. Johnston and colleagues used structural, diffusion tensor, and functional magnetic resonance imaging (MRI) techniques to identify differences in the brains of attempters and non-attempters.
Compared to those who had never attempted suicide, those who had exhibited reductions in gray matter volume in the orbitofrontal cortex, hippocampus, and cerebellum. They also had reduced white matter integrity in the uncinate fasciculus, ventral frontal, and right cerebellum regions. In addition, attempters had reduced functional connectivity between the amygdala and the left ventral and right rostral prefrontal cortex. Better right rostral prefrontal connectivity was associated with less suicidal ideation, while better connectivity of the left ventral prefrontal area was linked to less lethal suicide attempts.
Breathing in Through the Nose Enhances Judgment and Memory
A 2016 study published in the Journal of Neuroscience reported that the rhythm of breathing changes electrical activity in the brain and can improve emotional judgments and recall. Breathing in through the nose seemed to produce benefits compared to breathing out or to breathing in through the mouth.
Participants more easily identified a fearful face if they viewed it while breathing in. They also had an easier time remembering objects they observed while breathing in. The effects were not seen if the participants breathed through their mouth.
The researchers, led by Christina Zelano, reported that there was a major difference in brain activity in the amygdala and hippocampus during inhalation versus exhalation. Breathing in, in addition to stimulating the olfactory cortex responsible for smell perception, seems to activate the entire limbic system, the emotional center of the brain.
Levels of Amino Acid Proline Interact with COMT Genotype to Affect Negative Symptoms
In a 2016 article, researcher Catherine L. Clelland and colleagues reported that a patient’s levels of the amino acid proline interact with their genetic profile to influence the seriousness of their negative symptoms. Negative symptoms of schizophrenia and bipolar disorder include flat affect and lack of volition and can be some of the hardest symptoms to treat.
High levels of proline in the central nervous system have been linked to schizophrenia. Proline is a precursor to the neurotransmitter glutamate, and high proline levels have been found to alter glutamate and dopamine signaling in mice. This is one of the factors affecting negative symptoms.
The other factor affecting negative symptoms is the COMT gene. The enzyme catechol-o-methlyl transferase (COMT) metabolizes dopamine in the prefrontal cortex. There are several common versions of the gene for COMT. The most efficient is known as val-158-val, identifying that the gene has two valine amino acids at position 158. People with high proline levels and the val-158-val version of the COMT gene had fewer negative symptoms than people with high proline levels and another version of the gene, val-158-met (indicating one valine and one methionine amino acid at position 158).
Clelland and colleagues hypothesized that high proline levels may actually counteract the dopamine shortages common in the prefrontal cortex in people with the val-158-val genotype of COMT, which is more efficient at breaking down dopamine in this region.
The mood stabilizer valproate increases proline levels. In the study, which was published in Translational Psychiatry, people with schizophrenia and the val-val genotype had fewer negative symptoms when treated with valproate than those with the val-met genotype who received the same treatment.
