Suicide and depression have both been linked to elevated levels of inflammatory cytokines in the blood and cerebrospinal fluid. A recent study finds that these inflammatory markers are also elevated in the brains of teens and depressed adults who died from suicide.
In autopsy studies, researcher Ghanshyam N. Pandey measured levels of the inflammatory cytokines interleukin-1beta, interleukin 6, and TNF-alpha in the brains of teen suicide victims, and compared these to the brains of teens who died from other causes. Pandey also measured levels of interleukin-1beta, interleukin 6, interleukin 8, interleukin 10, interleukin 13, and TNF-alpha in the prefrontal cortex of depressed adult suicide victims and compared them to levels in adults who died of other causes.
There were abnormalities in the inflammatory markers in the brains of those who died from suicide compared to their matched controls. The suicide victims had higher levels of interleukin-1beta, interleukin 6, and TNF-alpha than the controls. Among the adults, levels of the anti-inflammatory cytokine interleukin 10 were low in the suicide victims while levels of Toll-like receptors (TLR3 and TLR4), which are involved in immune mechanisms, were high.
Brain inflammation has also been observed in positron emission tomography (PET) scans of depressed patients, where signs of microglial activation can be observed. Elevated inflammatory cytokines are also found in the blood of some people with bipolar disorder, depression, and schizophrenia.
Pandey presented this research at the 2016 meeting of the Society of Biological Psychiatry.
A recent study clarified how cognitive behavioral therapy improves symptoms of depression and post-traumatic stress disorder (PTSD). The participants were 62 adult women. One group had depression, one had PTSD, and the third was made up of healthy volunteers. None were taking medication at the time of the study. The researchers, led by Yvette Shelive, used functional magnetic resonance imaging (fMRI) to analyze participants’ amygdala connectivity.
At the start of the study, participants with depression or PTSD showed diminished connectivity between the amygdala and brain areas related to cognitive control, the process by which the brain can vary behavior and how it processes information in the moment based on current goals. The lack of connectivity reflected the severity of the participants’ depression. Twelve weeks of cognitive behavioral therapy improved mood and connectivity between the amygdala and these control regions, including the dorsolateral prefrontal cortex and the inferior frontal cortex. These regions also allow for executive functioning, which includes planning, implementation, and focus.
Many studies have found links between levels of inflammatory molecules in the blood and depression or depressive symptoms. There has been less research about inflammation in the brain and its possible role in depressive illness. Improvements in positron emission topography (PET) scan technology now allow for better brain imaging that can reveal when microglia are activated. (Microglia serve as the main immune responders in the central nervous system.)
A study by researcher Jeffrey Meyer found evidence of microglial activation in several brain regions (including the prefrontal cortex, the anterior cingulate cortex, and the insula) in people in an episode of depression who were not receiving any treatments. Participants with more microglial activation in the anterior cingulate cortex and insula had more severe depression and lower body mass indexes.
Meyer, who presented this research at a scientific meeting in December, called it strong evidence for brain inflammation in depressive episodes, and suggested that treatments that target microglial activation would be promising for depression.
However, at the same meeting, researcher Erica Richards reported that she had not been able to replicate Meyer’s results. Her research, which included depressed participants both on and off medication and non-depressed participants, found that depressed participants did show more inflammation in the two brain regions she targeted, the anterior cingulate and the subgenual cortices, but this difference did not reach statistical significance, particularly when patients taking antidepressants were included in the calculations. Richards hopes that with a greater sample size, the data may show a significant difference in brain inflammation between depressed and non-depressed participants.
One-fifth of children in America grow up in poor families. Poverty can affect development, health, and achievement, and new evidence shows it even affects brain structure.
New unpublished research suggests that early poverty can affect the brain’s structure into adulthood. At a 2015 scientific meeting, researcher James Swain reported that socio-economic status at age 9 was associated with the integrity of white matter in several regions of the brain, including the hippocampus, parahippocampal gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, corpus collosum, and thalamus at age 23–25, regardless of income at that time.
The brain regions affected by childhood poverty support executive function (planning and implementation skills), social cognition, memory, and language processing. White matter provides the physical connections between parts of the brain, so damage to white matter may lead to problems with functional connectivity of the brain.
A 2016 study by Peter S. Bloomfield and colleagues in the American Journal of Psychiatry used PET scans to compare the activity of microglia, immune cells in the central nervous system, in healthy controls, people with schizophrenia, and those at high risk for the illness. It found that both people with schizophrenia and those at high risk had greater brain inflammation than the healthy controls.
The study was the first to show that microglial activity was elevated in people at high risk (who showed some preliminary symptoms of schizophrenia). The finding had a large effect size.
Microglial activity was also correlated with symptom severity in the high-risk participants. Increased microglial activity was not linked to depression, suggesting that it is specific to the development of psychosis.
These findings resemble those of other recent studies showing increased inflammation in people at high risk for psychosis.
The study suggests that increased microglial activity occurs before a first episode of psychosis. That means it could help identify people who may develop schizophrenia. The findings also suggest that anti-inflammatory treatment could theoretically be used to prevent psychosis.
Repeated transcranial magnetic stimulation (rTMS) is a treatment for depression in which magnets placed near the skull stimulate electrical impulses in the brain. In a poster presented at the 2015 meeting of the Society of Biological Psychiatry, Martin Lan and colleagues presented results of the first study of structural changes in the brain following rTMS.
In the study, 27 patients in an episode of major depression underwent magnetic resonance brain scans before and after receiving rTMS treatment over their left prefrontal cortices. Lan and colleagues reported that several cortical regions related to cognitive appraisal, the subjective experience of emotion, and self-referential processing increased in volume following rTMS treatment: the anterior cingulate, the cingulate body, the precuneous, right insula, and gray matter in the medial frontal gyrus. The increases ranged from 5.3% to 15.7%, and no regions decreased in volume. More than 92% of the participants showed increased gray matter in all of these regions.
The brain changes were not correlated with antidepressant response to rTMS, but suggest a possible mechanism by which rTMS is effective in some people. Lan and colleagues concluded that rTMS likely had neuroplastic effects in areas of the brain that are important for emotion regulation.
There is growing evidence of a link between inflammation of depression. At the 2015 meeting of the Society of Biological Psychiatry, researcher Jeff Meyer summarized past studies on inflammatory markers. These are measurements, for example of certain proteins in the blood, that indicate the presence of inflammation in the body.
Common inflammatory markers that have been linked to depression include IL-6, TNF-alpha, and c-reactive protein. At the meeting, Meyer reviewed the findings on each of these. Twelve studies showed that IL-6 levels are elevated in the blood of patients with depression. Four studies had non-significant results of link between IL-6 and depression, and Meyer found no studies indicating that IL-6 levels were lower in those with depression. Similarly, for TNF-alpha, Meyer found 11 studies linking elevated TNF-alpha with depression, four with non-significant results, and none showing a negative relationship between TNF-alpha and depression. For c-reactive protein, six studies showed that c-reactive protein was elevated in people with depression, six had non-significant results, and none indicated that c-reactive protein was lower in depressed patients.
Most studies that have linked inflammation to depression have done so by measuring inflammatory markers in the blood. It is more difficult to measure inflammation in the brain of living people, but Meyer has taken advantage of new developments in positron emission tomography (PET) scans to measure translocator protein binding, which illustrates when microglia are activated. Microglial activation is a sign of inflammation. Translocator protein binding was elevated by about 30% in the prefrontal cortex, anterior cingulate cortex, and insula in study participants who showed symptoms of a major depressive episode compared to healthy control participants. The implication is that the depressed people with elevated translocator protein binding have more brain inflammation, probably via microglial activation.
The antibiotic minocycline reduces microglial activation. It would be interesting to see if minocycline might have antidepressant effects in people with depression symptoms and elevated translocator protein binding.
Many people suffer problems with mental functioning after an apparent concussion (otherwise known as mild traumatic brain injury, or mTBI) that does not show abnormalities on traditional brain imaging measures such as the MRI. New technology called diffusion tensor imaging (DTI) shows that the integrity of white matter tracts may be disturbed by concussions. White matter comprises parts of the brain where myelin wraps around axons, as opposed to grey matter, which reflects the presence of neuronal cell bodies.
In a longitudinal study published in the Journal of Neurotrauma, Vigneswaran Veeramuthu and colleagues compared 61 people with an mTBI to 19 healthy controls. The mTBI participants had their neuropsychological faculties assessed an average of 4.35 hours after their trauma, and participated in DTI scans an average of 10 hours after the trauma. Both the neuropsychological assessment and the DTI scan were repeated six months later. When the acute and follow-up assessments were compared to the same assessments in control participants, the two groups showed differences in numerous white matter tracts at the six-month mark. There was also an association between the degree of abnormality observed on the DTI scans and decrements in performance on the tests of neuropsychological functioning both immediately after the trauma and six months later.
The researchers concluded that their results “provide new evidence for the use of DTI as an imaging biomarker and indicator of [white matter] damage occurring in the context of mTBI, and [the results] underscore the dynamic nature of brain injury and possible biological basis of chronic neurocognitive alterations.”
Editor’s Note: People should be aware of these findings, which confirm earlier studies, and begin rehabilitative treatment as soon as possible after a concussion. New research should target white matter tract changes, with the goal of secondary prevention, i.e. limiting damage to the brain after a traumatic injury has occurred. There are several promising drugs that can prevent damage if administered immediately after an mTBI, including the antioxidant supplement N-acetylcysteine (NAC), which has shown promise in preliminary clinical and laboratory studies, and many others, including lithium and valproate, as reported by De-Maw Chuang and this editor Robert M. Post in a 2015 article in the Journal of Neurology and Stroke titled “Preventing the Sequelae of Concussions and Traumatic Brain Injury.”
Both bipolar disorder and unipolar depression often begin in childhood or adolescence, but it can be difficult to distinguish the two using symptoms only. People with bipolar illness may go a decade without receiving a correct diagnosis. Researcher Jorge Almeida and colleagues recently performed a meta-analysis of previous studies to determine what neural activity is typical of children with bipolar disorder versus children with unipolar depression while processing images of facial emotion. They found that youth with bipolar disorder were more likely to show limbic hyperactivity and cortical hypoactivity during emotional face processing than youth with unipolar depression. Almeida and colleagues hope that this type of data may eventually be used to diagnose these disorders or to measure whether treatment has been successful.
A new technology is making it possible to view the mammalian brain’s structure and connectivity for the first time. Karl Deisseroth discussed the technology, called CLARITY, at a plenary lecture at the 2014 meeting of the International College of Neuropsychopharmacology.
The way CLARITY works is by replacing lipids in the brain with a hydrogel substance. This preserves the structure of the brain’s neural networks, leaves proteins and nucleic acids intact, but allows for observation by rendering the brain transparent. This can be done in a system as large as the entire adult mouse brain. Early attempts took a whole day, but Deisseroth eventually found a way to render a mouse’s brain transparent in a matter of minutes.
The pictures are truly amazing, allowing for the visualization of previously microscropic neurons, dendrites, axons and connections in life-sized images. Pictures and details are available at www.clarityresourcecenter.org.
Deisseroth and colleagues have used CLARITY imaging to determine where neurons fire during different social activities. By placing photosensitive fibers in selected neurons using a virally based gene insertion technique, Deisseroth and colleagues were able to selectively fire dopamine neurons in the ventral tegmental area, part of the brain’s reward system, and thus increase or decrease the social interaction of mice by increasing or decreasing firing. The effects were selective to social interaction; the firing did not affect locomotor activity or exploration of an inanimate object.
The ventral tegmental area contains neurons that project to several locations in the brain, and Deisseroth and colleagues hoped to observe which were important to social interaction. Stimulating the ventral tegmental area to drive the medial prefrontal cortex caused anxiety in the mice and made them averse to social interaction. However, when the ventral tegmental area was used to selectively drive the nucleus accumbens, another part of the brain’s reward system, social interaction increased.
Deisseroth wanted to know if the nucleus accumbens was also involved in normal spontaneous social interactions. The researchers used a virus to insert an opsin-sensitive calcium gene that could give an ongoing readout of neural activity. (Opsin is a light-sensitive receptor found in cells in the retina.) The team found that the nucleus accumbens was implicated in social interaction with another mouse, but not in exploration of a novel object. Based on CLARITY imaging of the structure of ion channels (which are so small they cannot even be seen with an electron microscope), Deisseroth was able to selectively alter ion fluxes and turn neuronal firing on or off at will.
In the last 50 years, the brain and its billions of neurons and hundreds of trillions of synapses have gone from complete inaccessibility toward increasing clarity.