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Measuring the activity of a panel of genes may provide enough information to diagnose bipolar disorder from a blood sample, according to a study published August 4th in the journalTranslational Psychiatry. Currently, bipolar disorder is diagnosed by experienced clincians based on a subjective evaluation of a patient’s symptoms; there is no blood test or brain scan that can diagnose the disorder.

In the study, which included 37 patients with rapid-cycling bipolar disorder and 40 healthy controls, researchers found that a composite measure of activity within a set of 19 genes offered diagnostic sensitivity and specificity corresponding to a “moderately accurate” test. Their analysis also identified specific genes whose activity is lower in people with bipolar disorder than in healthy individuals, as well as an additional gene whose activity spikes when patients with bipolar disorder are in a depressed state. Those findings call attention to biological pathways likely to be involved in the disorder.

To carry out the study, a team of scientists including first author Klaus Munkholm, M.D., at the University of Copenhagen, identified 19 genes that previous studies had indicated might behave differently in people with bipolar disorder, and for which relevant variations were likely to be detectable in blood cells. They took blood samples from the patients over a period of six to 12 months, keeping track of whether patients were in manic, depressed, or euthymic (neither manic nor depressed) states at the time each sample was collected.

The team, which included Lars Vedel Kessing, M.D., a 2012 NARSAD Distinguished Investigator and 2010 Foundation Colvin Prizewinner, then measured the activity of the 19 genes they had selected. Each sample received a gene expression score that considered the activity of all 19 genes together. These scores were sufficiently different between healthy participants and those with bipolar disorder to distinguish between the two, most of the time. For a portion of their blood samples, the scientists used the gene expression score to correctly identify 78 percent of samples from patients with bipolar disorder. Sixty percent of the samples from healthy individuals were correctly identified.

Further studies will be necessary to evaluate the gene panel as a potential biomarker of bipolar disorder. Including additional information in the score, such as levels of specific proteins, might improve its diagnostic sensitivity and specificity, the scientists say.

The study also generated some insight into the biology of bipolar disorder.  Two of the genes that were tracked in the study—POLG and OGG1—were significantly less active in people with bipolar disorder than they were in healthy controls. Another, NDUFV2, showed increased activity during depressed states among people with bipolar disorder, when gene activity was compared during individual patients’ different mood states. Together, these findings point toward problems with mitochondrial function and DNA damage repair, the team says.

Researchers have found new clues as to how brain plasticity can overcome a genetic predisposition to bipolar disorder. Tweet This >

Reporting their findings online January 5 in Translational Psychiatry, a research team compared connections between different brain regions among people with bipolar disorder, their relatives who shared features predicting bipolar disorder but showed no symptoms, and unrelated people without bipolar disorder.

The team focused on brain regions that contribute to working memory — the ability to hold on to new information temporarily.  They also tested how those in the study interpreted faces displaying different emotions. Both of these faculties are often impaired in bipolar disorder. Participants underwent imaging to measure brain activity during one working memory task where they tracked letters presented on cards, and another task where they distinguished between human faces showing different emotions or  neutral expressions.

The paper’s first author was 2014 NARSAD Young Investigator grantee Danai Dima, Ph.D., of King’s College London and the Icahn School of Medicine at Mount Sinai. The team was led by 2002 Young Investigator and 2008 Independent Investigator grantee Sophia Frangou, M.D., Ph.D., also of the Icahn School of Medicine at Mount Sinai. The team also included Ed Roberts, Ph.D., of Imperial College London.

The study’s key findings concerned communication patterns within the brain. Both the participants with bipolar disorder and their relatives showed increased connections between the amygdala, crucial for emotional responses, and the ventromedial prefrontal cortex, part of the brain’s executive center that helps inhibit emotions and make decisions. These increased connections seem to reflect a propensity toward bipolar disorder.

This raises the question of why the unaffected relatives had never shown signs of the illness, despite having this same pattern of greater connectivity. A possible answer comes from the finding that these relatives additionally showed increased connections between brain regions involved in visual processing, particularly face recognition. These connections may compensate for any processing dysfunction caused by the unusual amygdala-ventromedial prefrontal cortex connectivity.

Thus, the brain appears to have the capacity to “defeat” a predisposition to bipolar disorder, or at least delay onset of the disease, since none of the relatives in this study showed any history of symptoms and were all past the age range in which bipolar typically appears. This insight could help identify strategies to prevent bipolar disorder among people genetically predisposed to it, the researchers say.

The study participants with bipolar disorder uniquely showed reduced connections between the brain regions responsible for working memory. Those connections grew less robust the longer people had been living with the illness, and they predicted the level of working memory deficits. However, the researchers note, other studies suggest that working memory is sensitive to irregularities in other brain connection, and thus is not specific to bipolar disorder.

Researchers have discovered new clues as to how exercise beneficially impacts brain activity in young people with bipolar disorder.

Cognitive dysfunction is common among adolescents with bipolar disorder during and between mood episodes – depression-like lows and “manic” highs — contributing to social and functional impairment. The ability to pay attention and make decisions (executive function) tends to be most affected.

Some prior studies have shown that exercise can relieve symptoms among teenagers and young adults with the disorder. In a new study published May 17 in Translational Psychiatry, a research team identified underlying mechanisms in the brain that may drive these improvements.

How does exercise change brain activity to treat bipolar disorder? @Sunnybrook researchers uncovered part of the storyTweet →

Exercise restored normal activity levels in the brain during a task involving attention, reported the team, led by 2007 NARSAD Young Investigator grantee and 2014 Independent Investigator grantee Benjamin I. Goldstein, M.D., Ph.D., of the Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, Toronto, Canada.

The attention task required young adults aged 13 to 20 both with and without bipolar disorder to monitor numbers on screen, responding to some and ignoring others.

Before exercise, functional magnetic resonance imaging (fMRI) showed that participants with bipolar disorder had unusual activity patterns in certain brain regions during the task—patterns that reflect the brain shifting resources to monitor numbers. But after spending 20 minutes on a stationary bike, the youth with bipolar disorder showed more normal activation patterns. This change suggests that exercise lessens cognitive symptoms of bipolar disorder by targeting these neural mechanisms.

The findings were strongest in two brain areas: part of the striatum, a major player in the brain’s reward system, and part of the anterior cingulate cortex, involved in processing errors. Exercise reversed below-normal activity in the striatum that correlated with more severe bipolar systems, possibly because endorphins—opiates naturally produced in the brain—that were released during exercise acted on the reward system, the researchers reported. In an opposite pattern, exercise reversed above-normal activity in the anterior cingulate cortex, which the researchers suggest may reflect general deficits in bipolar disorder involving the brain’s executive control system.

The researchers also found that exercise’s restorative effects were stronger among people not taking antipsychotic medication, who overall had experienced less severe bipolar symptoms throughout their lives. Future studies, the researchers say, should consider the impact of medication.

Takeaway: Exercise may relieve some cognitive symptoms of bipolar disorder by restoring normal activity patterns in the brain’s error processing and reward systems.

In animal research reported in the November 12 issue of the journal Nature, scientists have identified a specific region of the brain that helps regulate behaviors and physiological changes associated with anxiety. Cells in this area, known as the basomedial amygdala, differentiate between safe and potentially threatening environments, and work together to suppress anxiety when conditions seem safe.

Better understanding of how the brain regulates fear and anxiety is likely to help researchers develop more effective treatments for anxiety disorders.

The new work was conducted in the lab of BBRF Scientific Council member and 2005, 2007 NARSAD Young Investigator Karl Deisseroth, M.D., Ph.D., a Howard Hughes Medical Instituteinvestigator at Stanford University. Avishek Adhikari, Ph.D., a NARSAD 2014 Young Investigator, led the work together with Talia Lerner, Ph.D., and Joel Finkelstein.

In their study, the scientists examined connections between the brain’s medial prefrontal cortex and the amygdala, regions known to be involved in regulating fear and anxiety. Connections between these regions have been found to be disrupted in people with anxiety disorders.

Using powerful technologies, the team traced connections in the mouse brain from the medial prefrontal cortex to a specific part of the amygdala, its basomedial region, and showed that artificially activating these connections reduced anxiety-related behaviors in the mice. When the connections were switched on by the experimenters – using a method Dr. Deisseroth and colleagues invented called optogenetics — the animals were more likely to explore open spaces. What’s more, the increase in breathing rate usually associated with anxiety was not seen, even when the animals were in an exposed environment, which mice usually perceive as threatening.

The opposite effects were seen when the researchers experimentally inhibited the same connections: mice exhibited signs of anxiety even in a safe and familiar environment.

Many of the cells in the basomedial amygdala fire more actively when a mouse is in a safe environment, suggesting that these cells differentiate between safety and potential threats.

The scientists further showed that connections between the medial prefrontal cortex and the basomedial amygdala are important for extinguishing learned fears – that is, learning through experience to dissociate a feared stimulus from expectation of a negative outcome. Mice that had been trained to fear an auditory tone overcame these fears more quickly when the researchers artificially stimulated medial prefrontal cortex-basomedial amygdala connections.

From The Quarterly, January 2016

Dr. Huda Akil is one of the world’s leading experts on what scientists call the neurobiology of emotions. She and her colleagues are now two decades into an investigation of what goes on in the brain when we experience emotions, with the objective of discovering new ways to target imbalances and biological abnormalities that contribute to depression, anxiety and substance abuse.

A member of the Foundation’s Scientific Council, Dr. Akil co-directs the Molecular & Behavioral Neuroscience Institute at the University of Michigan, where she is a Distinguished University Professor. Born in Syria, she is the daughter of a father who introduced modern concepts of psychology to Arab culture; the sister of a psychiatrist; and mother of a son, Dr. Brendon Omar Watson of Weill Cornell Medical College who received a 2014 Young Investigator Grant to conduct brain research.

The constructive role that emotions play in our lives highlights what Dr. Akil and other scientists call their “adaptive” value. Scientists believe that emotions arose in higher organisms because they helped them survive. Problems with biological systems that regulate the emotions often have precisely the opposite effect: having major depression or chronic, acute anxiety makes daily survival that much more difficult.

“We simply can’t live without emotions,” Dr. Akil emphasizes. “If you experience something positive, you want to remember it in a certain way, perhaps so you can experience it again. The same with things that are negative— you want to remember them so as to avoid them in the future. It’s when you get stuck or disconnected from reality that emotions become a problem.”

Early in her career, Dr. Akil and colleagues discovered that endorphins, naturally occurring opioids in the human system, including the brain, are activated by stress and can relieve pain. Following this discovery, Dr. Akil gravitated to an even larger research question: whether, or how, individual temperament affects mood disorders.

“We all know from looking at people and how they react and suffer, that people are really different,” she says. “We were especially interested [in this subject] because many genetic studies in psychiatric disorders hinted that temperament is really important, especially in determining who is prone to develop depression or anxiety disorders, or to become a substance abuser.”

“I felt we didn’t have a good way of studying differences in temperament in the lab,” she says. That led Dr. Akil’s team to develop rodent models of two fundamental behavioral types that she suspected—correctly—had much to do with individual susceptibility to depression, anxiety and substance abuse. Genetically distinct rat lines were bred by Dr. Akil and her colleagues to be either “high reactivity” (HR) or “low reactivity” (LR). HR lab rats tend to be explorers of their space and are interested in social interactions with cage-mates. LR rats tend to find a corner and remain there, eschewing interaction with others. The team continued the breeding until they emerged with animals that reliably displayed one tendency or the other, in an extreme form. One thing this showed was that “this trait is very genetic—it breeds true,” Dr. Akil says. “One set is very adventuresome and the other is very inhibited.”

This became a solid platform for probing how animals with these two exaggerated temperaments differed from normal animals and from one another. Dr. Akil looked for differences in the way their genes were expressed, and in how the proteins they encode vary and influence emotional behavior in a range of tests. High-reactivity animals tended to be resilient to stress, resistant to depression, but at the same time were notable risk-takers and explorers. HR rats were inclined to experiment with cocaine when the drug was made available to them. It was the reverse with the “low-reactivity” animals. The LR rates tended to be prone to depression and anxiety; did not react well to stress; tended to isolate themselves; and were not especially interested in experimenting with drugs or very much else in their environment.

The accompanying story (Message of Hope: There Are Many Places To Attack Depression) discusses some of the key molecules Dr. Akil discovered to be correlated with these models of temperament and emotion. Those findings were based partly on research with the rodent models. But they also derive in part from another major thrust of her research: postmortem investigations of the brains of people who suffered major depression and bipolar illness. Dr. Akil leads one of six groups in the international Pritzker Neuropsychiatric Research Consortium, which has assembled a collection of these very valuable brains, donated by families of deceased patients.

This work, “for which we owe so much to the families, has taught us a great deal,” Dr. Akil says. “It has reframed my entire thinking about depression.” The postmortem brains “enabled us to see a summary of everything that happened in that entire life” in terms of the brain—how the person’s unique genetic inheritance played out, how the brain developed, the effects of aging and gender, and of course the effect of the illness on the brain.

The striking revelation: “When you look at the brains of chronically, severely depressed people, you realize it’s a whole-brain change. Almost every part of the brain is altered and touched by the illness. There is evidence of pervasive changes, in the number of genes that are affected, the number of brain regions affected,” Dr. Akil says.

Among the lessons Dr. Akil has learned from this is the importance of treating depression as early in life as possible, ideally when it first appears. Looking at the postmortem brains of people who were depressed for many years “makes you appreciate why depression can become ‘treatment-resistant,’” she says.

It’s as if the long-depressed brain is in a deep slumber, a kind of perpetual winter. “We need to get people rapidly out of their negative mood and deep depression early—and use every means available, whether fast-acting antidepressants, psychotherapy, physical activity, better eating, social support— to actively re-engage all the affected brain circuits,” she says. “Because by the time you have had multiple episodes and the person has become isolated, living in a socially stressful or impoverished state, is inactive, not sleeping or eating right…the brain does not look any longer like a normal brain. It will take so much more work to reverse that.”

Message of Hope: There Are Many Places To Attack Depression

About 10 years ago, Dr. Huda Akil and her colleagues in the Pritzker Consortium began scrutinizing the brains of deceased people who had suffered depression, using increasingly sensitive and powerful tools to measure gene activity in multiple brain regions. To their surprise, one set of molecules, called the FGF family, kept topping the lists they made of most-altered factors in these brains. FGF stands for fibroblast growth factor—one of various kinds of molecules that serve to stimulate and sometimes regulate the growth and activity of nerve cells in the brain.

FGFs were at first thought to play their main role early in the brain’s development. Dr. Akil’s team discovered that FGFs also played a role over the lifespan, helping to regulate emotions, specifically, on a moment-to-moment basis and over the long haul. “In rats, we can manipulate the FGF system and within minutes see a change in anxiety behavior,” she says. This makes certain members of the family—notably FGF2, levels of which decline in depression—targets for next-generation drugs.

The discovery that FGFs play two roles—helping to wire the brain and then, later, to help regulate and “bias” the emotions (for instance, to incline an individual to be more or less resilient to the impact of stress)—makes them even more attractive targets. Dr. Akil’s team has recently noted that FGFs are “interaction partners” with the “neurotransmitter systems we all know,” like serotonin, which is the target of SSRI antidepressants such as Prozac or Lexapro.

Dr. Akil noted, “We’ve shown that FGFs are important, but there are multiple players in multiple parts of the brain, acting in different registers at different times. We like FGFs because they have a wide playing field—lots of interacting molecular partners, at different times in life and throughout life. This makes them very attractive in our efforts to address some of those key changes that affect the whole brain in a disease like depression. Ours is a message of hope: there are a lot of places to attack depression and other emotional disorders, we have lots of options, lots of strategies we want to deploy. These will take time to test, but we will deploy them.”