Researchers create a roadmap of bipolar disorder and how it affects the brain

A new study has found brain abnormalities in people with bipolar disorder.

In the largest MRI study to date on patients with bipolar disorder, a global consortium published new research showing that people with the condition have differences in the brain regions that control inhibition and emotion.

By revealing clear and consistent alterations in key brain regions, the findings published in Molecular Psychiatry on May 2 offer insight to the underlying mechanisms of bipolar disorder.

"We created the first global map of bipolar disorder and how it affects the brain, resolving years of uncertainty on how people's brains differ when they have this severe illness," said Ole A. Andreassen, senior author of the study and a professor at the Norwegian Centre for Mental Disorders Research at the University of Oslo.

Bipolar disorder affects about 60 million people worldwide, according to the World Health Organization. It is a debilitating psychiatric disorder with serious implications for those affected and their families. However, scientists have struggled to pinpoint neurobiological mechanisms of the disorder, partly due to the lack of sufficient brain scans.

The study was part of an international consortium led by the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine of USC: ENIGMA (Enhancing Neuro Imaging Genetics Through Meta Analysis) spans 76 centers and includes 26 different research groups around the world.

Thousands of MRI scans
The researchers measured the MRI scans of 6,503 individuals, including 2,447 adults with bipolar disorder and 4,056 healthy controls. They also examined the effects of commonly used prescription medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions.

The study showed thinning of gray matter in the brains of patients with bipolar disorder when compared with healthy controls. The greatest deficits were found in parts of the brain that control inhibition and motivation -- the frontal and temporal regions.

Some of the bipolar disorder patients with a history of psychosis showed greater deficits in the brain's gray matter. The findings also showed different brain signatures in patients who took lithium, anti-psychotics and anti-epileptic treatments. Lithium treatment was associated with less thinning of gray matter, which suggests a protective effect of this medication on the brain.

"These are important clues as to where to look in the brain for therapeutic effects of these drugs," said Derrek Hibar, first author of the paper and a professor at the USC Stevens Neuroimaging and Informatics Institute when the study was conducted. He was a former visiting researcher at the University of Oslo and is now a senior scientist at Janssen Research and Development, LLC.

Early detection
Future research will test how well different medications and treatments can shift or modify these brain measures as well as improve symptoms and clinical outcomes for patients.

Mapping the affected brain regions is also important for early detection and prevention, said Paul Thompson, director of the ENIGMA consortium and co-author of the study.

"This new map of the bipolar brain gives us a roadmap of where to look for treatment effects," said Thompson, an associate director of the USC Stevens Neuroimaging and Informatics Institute at the Keck School of Medicine. "By bringing together psychiatrists worldwide, we now have a new source of power to discover treatments that improve patients' lives."

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University of Southern California.

AI that can shoot down fighter planes helps treat bipolar disorder

The artificial intelligence that can blow human pilots out of the sky in air-to-air combat accurately predicted treatment outcomes for bipolar disorder, according to a new medical study by the University of Cincinnati.

The findings open a world of possibility for using AI, or machine learning, to treat disease, researchers said.

David Fleck, an associate professor at the UC College of Medicine, and his co-authors used artificial intelligence called "genetic fuzzy trees" to predict how bipolar patients would respond to lithium.

Bipolar disorder, depicted in the TV show "Homeland" and the Oscar-winning "Silver Linings Playbook," affects as many as six million adults in the United States or 4 percent of the adult population in a given year.

"In psychiatry, treatment of bipolar disorder is as much an art as a science," Fleck said. "Patients are fluctuating between periods of mania and depression. Treatments will change during those periods. It's really difficult to treat them appropriately during stages of the illness."

The study authors found that even the best of eight common models used in treating bipolar disorder predicted who would respond to lithium treatment with 75 percent accuracy. By comparison, the model UC researchers developed using AI predicted how patients would respond to lithium 100 percent of the time. Even more impressively, the UC model predicted the actual reduction in manic symptoms after lithium treatment with 92 percent accuracy.

The study authors found that even the best of the eight most common treatments was only effective half the time. But the model UC researchers developed using AI predicted how patients would respond to lithium treatment with 88 percent accuracy and 80 percent accuracy in validation.

It turns out that the same kind of artificial intelligence that outmaneuvered Air Force pilots last year in simulation after simulation at Wright-Patterson Air Force Base is equally adept at making beneficial decisions that can help doctors treat disease. The findings were published this month in the journal Bipolar Disorders.

"What this shows is that an effort funded for aerospace is a game-changer for the field of medicine. And that is awesome," said Kelly Cohen, a professor in UC's College of Engineering and Applied Science.

Cohen's doctoral graduate Nicholas Ernest is founder of the company Psibernetix, Inc., an artificial intelligence development and consultation company. Psibernetix is working on applications such as air-to-air combat, cybersecurity and predictive analytics. Ernest's fuzzy logic algorithm is able to sort vast possibilities to arrive at the best choices in literally the blink of an eye.

"Normally the problems our AIs solve have many, many googolplexes of possible solutions -- effectively infinite," study co-author Ernest said.

His team developed a genetic fuzzy logic called Alpha capable of shooting down human pilots in simulations, even when the computer's aircraft intentionally was handicapped with a slower top speed and less nimble flight characteristics. The system's autonomous real-time decision-making shot down retired U.S. Air Force Col. Gene Lee in every engagement.

"It seemed to be aware of my intentions and reacting instantly to my changes in flight and my missile deployment," Lee said last year. "It knew how to defeat the shot I was taking. It moved instantly between defensive and offensive actions as needed."

The American Institute of Aeronautics and Astronautics honored Cohen and Ernest this year for their "advancement and application of artificial intelligence to large scale, meaningful and challenging aerospace-related problems."

Cohen spent much of his career working with fuzzy-logic based AI in drones. He used a sabbatical from the engineering college to approach the UC College of Medicine with an idea: What if they could apply the amazing predictive power of fuzzy logic to a particularly nettlesome medical problem?

Medicine and avionics have little in common. But each entails an ordered process -- a vast decision tree -- to arrive at the best choices. Fuzzy logic is a system that relies not on specific definitions but generalizations to compensate for uncertainty or statistical noise. This artificial intelligence is called "genetic fuzzy" because it constantly refines its answer, tossing out the lesser choices in a way analogous to the genetic processes of Darwinian natural selection.

Cohen compares it to teaching a child how to recognize a chair. After seeing just a few examples, any child can identify the object people sit in as a chair, regardless of its shape, size or color.

"We do not require a large statistical database to learn. We figure things out. We do something similar to emulate that with fuzzy logic," Cohen said.

Cohen found a receptive audience in Fleck, who was working with UC's former Center for Imaging Research. After all, who better to tackle one of medical science's hardest problems than a rocket scientist? Cohen, an aerospace engineer, felt up to the task.

Ernest said people should not conflate the technology with its applications. The algorithm he developed is not a sentient being like the villains in the "Terminator" movie franchise but merely a tool, he said, albeit a powerful one with seemingly endless applications.

"I get emails and comments every week from would-be John Connors out there who think this will lead to the end of the world," Ernest said.

Ernest's company created EVE, a genetic fuzzy AI that specializes in the creation of other genetic fuzzy AIs. EVE came up with a predictive model for patient data called the LITHium Intelligent Agent or LITHIA for the bipolar study.

"This predictive model taps into the power of fuzzy logic to allow you to make a more informed decision," Ernest said.

And unlike other types of AI, fuzzy logic can describe in simple language why it made its choices, he said.

The researchers teamed up with Dr. Caleb Adler, the UC Department of Psychiatry and Behavioral Neuroscience vice chairman of clinical research, to examine bipolar disorder, a common, recurrent and often lifelong illness. Despite the prevalence of mood disorders, their causes are poorly understood, Adler said.

"Really, it's a black box," Adler said. "We diagnose someone with bipolar disorder. That's a description of their symptoms. But that doesn't mean everyone has the same underlying causes."

Selecting the appropriate treatment can be equally tricky.

"Over the past 15 years there has been an explosion of treatments for mania. We have more options. But we don't know who is going to respond to what," Adler said. "If we could predict who would respond better to treatment, you would save time and consequences."

With appropriate care, bipolar disorder is a manageable chronic illness for patients whose lives can return to normal, he said.

UC's new study, funded in part by a grant from the National Institute of Mental Health, identified 20 patients who were prescribed lithium for eight weeks to treat a manic episode. Fifteen of the 20 patients responded well to the treatment.

The algorithm used an analysis of two types of patient brain scans, among other data, to predict with 100 percent accuracy which patients responded well and which didn't. And the algorithm also predicted the reductions in symptoms at eight weeks, an achievement made even more impressive by the fact that only objective biological data were used for prediction rather than subjective opinions from experienced physicians.

"This is a huge first step and ultimately something that will be very important to psychiatry and across medicine," Adler said.

How much potential does this have to revolutionize medicine?

"I think it's unlimited," Fleck said. "It's a good result. The best way to validate it is to get a new cohort of individuals and apply their data to the system."

Cohen is less reserved in his enthusiasm. He said the model could help personalize medicine to individual patients like never before, making health care both safer and more affordable. Fewer side-effects means fewer hospital visits, less secondary medication and better treatments.

Now the UC researchers and Psibernetix are working on a new study applying fuzzy logic to diagnosing and treating concussions, another condition that has bedeviled doctors.

"The impact on society could be profound," Cohen said.

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News Source:
University of Cincinnati.

Area of brain linked to bipolar disorder pinpointed

A volume decrease in specific parts of the brain's hippocampus -- long identified as a hub of mood and memory processing -- was linked to bipolar disorder in a study led by researchers at The University of Texas Health Science Center at Houston (UTHealth). The research was published today in Molecular Psychiatry, part of the Nature Publishing Group.

"Our study is one of the first to locate possible damage of bipolar disorder in specific subfields within the hippocampus," said Bo Cao, Ph.D., first and corresponding author and a postdoctoral fellow in the Department of Psychiatry and Behavioral Sciences at McGovern Medical School at UTHealth. "This is something that researchers have been trying to answer. The theory was that different subfields of the hippocampus may have different functions and may be affected differently in different mood disorders, such as bipolar disorder and major depression disorder."

Cao hopes the study, which was funded in part by the National Institute of Mental Health (NIMH), will pioneer future research on details within the hippocampus as a marker for precise diagnosis and positive treatment response of bipolar disorder.

Approximately 6 million Americans suffer from bipolar disorder. Bipolar I disorder is characterized by mood changes that can swing from a high-energy, manic state to a low-energy, depressive state. The disorder can affect sleep, energy level and the ability to think clearly, according to the National Institutes of Health. It can interfere with a person's ability to work and perform daily living activities, and could lead to suicide attempts. Patients with bipolar II disorder do not experience the full-blown manic episodes, but may have a less severe high-energy state.

The research team used a combination of magnetic resonance imaging (MRI) and a state-of-the-art segmentation approach to discover differences in the volumes of subfields of the hippocampus, a seahorse-shaped region in the brain. Subjects with bipolar disorder were compared to healthy subjects and subjects with major depressive disorder.

Researchers found that subjects with bipolar disorder had reduced volumes in subfield 4 of the cornu ammonis (CA), two cellular layers and the tail portion of hippocampus. The reduction was more severe in patients with bipolar I disorder than other mood disorders investigated.

Further, in patients with bipolar I disorder, the volumes of certain areas such as the right CA 1 decreased as the illness duration increased. Volumes of other CA areas and hippocampal tail were more reduced in subjects who had more manic episodes.

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News Source:
University of Texas Health Science Center at Houston

Parents with bipolar benefit from self-help tool

Online self-management support for parents with Bipolar Disorder leads to improvements in parenting and child behaviour.

That is the finding of researchers from the Spectrum Centre for Mental Health Research at Lancaster University, who recruited 97 parents with Bipolar Disorder who have children aged between 3 and ten years old.

They were split into two groups, with one being offered an Integrated Bipolar Parenting Intervention (IBPI) online.

This includes sixteen modules lasting half an hour each looking at different aspects of parenting, supported by video and audio material.

The site aims to support parents in two ways:

• To learn more both their bipolar disorder and how best to self manage it building on their own personal strengths
• To enhance their current parenting skills to encourage desirable behaviour in their children Child behaviour, parenting sense of competence and parenting stress improved significantly in the group using online support for the whole of the 48 weeks study, which is published in the Journal of Child Psychology and Psychiatry.

Lead author Professor Steven Jones said: "People with bipolar disorder may find that their changes in mood make the delivery of consistent parenting more difficult than for parents without bipolar disorder.

"This online parenting support programme combines self-management strategies for bipolar disorder. It looks at the impact of extremes of mood on parenting and how to maintain consistency in parenting."

As this intervention requires very little professional support, it could be offered as a supplement to current services without significant additional investment.

Further research will be needed to explore in the longer term whether the beneficial impacts of the intervention translate into reduced risks of longer-term mental health problems in addition to shorter term improvements in current child behaviour.

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Lancaster University

Underlying molecular mechanism of bipolar disorder

An international collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP), with major participation from Yokohama School of Medicine, Harvard Medical School, and UC San Diego, has identified the molecular mechanism behind lithium's effectiveness in treating bipolar disorder patients.

The study, published in Proceedings of the National Academy of Sciences (PNAS), utilized human induced pluripotent stem cells (hiPS cells) to map lithium's response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. It may also provide the basis to discover new drugs that are safer and more effective than lithium.

Bipolar disorder is a mental health condition causing extreme mood swings that include emotional highs (mania or hypomania) and lows (depression) and affects approximately 5.7 million adults in the U.S. Lithium is the first treatment explored after bipolar symptoms, but it has significant limitations. Only approximately one-third of patients respond to lithium treatment, and its effect is only found through a trial-and-error process that takes months -- and sometimes years -- of prescribing the drug and monitoring for response. Side effects of lithium treatment can be significant, including nausea, muscle tremors, emotional numbing, irregular heartbeat, weight gain, and birth defects, and many patients choose to stop taking the medicine as a result.

"Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks," said Evan Snyder, M.D., Ph.D., professor and director of the Center for Stem Cells and Regenerative Medicine at SBP, and senior author of the study. "Importantly, our findings open a clear path to finding safe and effective new drugs. Equally as important, it helped give us insight into what type of mechanisms cause psychiatric problems such as these."
"We realized that studying the lithium response could be used as a 'molecular can-opener' to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene -- in this case, CRMP2, an intracellular protein that regulates neural networks," added Snyder.

In hiPS cells created from lithium-responsive and non-responsive patients, researchers observed a physiological difference in the regulation of CRMP2, which rendered the protein to be in a much more inactive state in responsive patients. However, the research showed that when lithium was administered to these cells, their regulatory mechanisms were corrected, restoring normal activity of CRMP2 and correcting the underlying cause of their disorder. Thus, the study demonstrated that bipolar disorder can be rooted in physiological -- not necessarily genetic -- mechanisms. The insights derived from the hiPS cells were validated in actual brain specimens from patients with bipolar disorder (on and off lithium), in animal models, and in the actions of living neurons.

"This 'molecular can-opener' approach -- using a drug known to have a useful action without exactly knowing why -- allowed us to examine and understand an underlying pathogenesis of bipolar disorder," said Snyder. "The approach may be extended to additional complex disorders and diseases for which we don't understand the underlying biology but do have drugs that may have some beneficial actions, such as depression, anxiety, schizophrenia and others in need of more effective therapies. One cannot improve a therapy until one knows what molecularly really needs to be fixed."

This study was performed in collaboration with Veterans Administration Medical Center in La Jolla, University of California San Diego, Yokohama City University, Massachusetts General Hospital, Harvard Medical School, Mailman Research Center at McLean Hospital, University of Connecticut School of Medicine, University of Pittsburgh Medical Center, National Institute of Mental Health, Vala Sciences, Inc., Broad Institute of MIT and Harvard University, Dalhousie University, Beth-Israel Deaconess Medical Center, Örebro University, Janssen Research & Development Labs, Waseda University, and RIKEN .

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Sanford Burnham Prebys Medical Discovery Institute.

Scientists Discover Gene Variations Associated to Bigger Chance of Bipolar Disorder

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified small variations in a number of genes that are closely linked to an increased risk of bipolar disorder, a mental illness that affects nearly six million Americans, according to the National Institute of Mental Health.

"Using samples from some 3,400 individuals, we identified several new variants in genes closely associated with bipolar disorder," said Scripps Florida Professor Ron Davis, who led the new study, which was published recently by the journal Translational Psychiatry.

A strong tendency towards bipolar disorder runs in families; children with a parent or sibling who has bipolar disorder are four to six times more likely to develop the illness, according to the National Institute of Mental Health.

While the genetic basis for bipolar disorder is complex and involves multiple genes, it appears to be associated with a biochemical pathway known as cyclic adenosine monophosphate (cAMP) signaling system. The Davis laboratory and others have previously shown that the cAMP signaling plays a critical role in learning and memory processes. The new study focused on this signaling pathway.

"As far as I know, this has not been done before -- to query a single signaling pathway," said Davis. "This is a new approach. The idea is if there are variants in one gene in the pathway that are associated with bipolar disorder, it makes sense there would be variants in other genes of the same signaling pathway also associated with the disorder."

The new study examined variations in 29 genes found in the two common types of bipolar disorder -- bipolar disorder I (the most common form and the most severe) and bipolar disorder II. Genes from a total of 1,172 individuals with bipolar disorder I; 516 individuals with bipolar disorder II; and 1,728 controls were analyzed.

Several statistically significant associations were noted between bipolar disorder I and variants in the PDE10A gene. Associations were also found between bipolar disorder II and variants in the DISC1 and GNAS genes.

Davis noted that the location of PDE10A gene expression in the striatum, the part of the brain associated with learning and memory, decision making and motivation, makes it especially interesting as a therapeutic target.

Giving Lithium to Those Who Need It

Lithium is a 'gold standard' drug for treating bipolar disorder, however not everyone responds in the same way. New research published in BioMed Central's open access journal Biology of Mood & Anxiety Disorders finds that this is true at the levels of gene activation, especially in the activation or repression of genes which alter the level the apoptosis (programmed cell death). Most notably BCL2, known to be important for the therapeutic effects of lithium, did not increase in non-responders. This can be tested in the blood of patients within four weeks of treatment.

A research team from Yale University School of Medicine measured the changing levels of gene activity in the blood of twenty depressed adult subjects with bipolar disorder before treatment, and then fortnightly once treatment with lithium carbonate had begun.

Over the eight weeks of treatment there were definite differences in the levels of gene expression between those who responded to lithium (measured using the Hamilton Depression Rating Scale) and those who failed to respond. Dr Robert Beech who led this study explained, "We found 127 genes that had different patterns of activity (turned up or down) and the most affected cellular signalling pathway was that controlled programmed cell death (apoptosis)."

For people who responded to lithium the genes which protect against apoptosis, including Bcl2 and IRS2, were up regulated, while those which promote apoptosis were down regulated, including BAD and BAK1.

The protein coded by BAK1 can open an anion channel in mitochondrial walls which leads to leakage of mitochondrial contents and activation of cell death pathways. Damage similar to this has been seen within the prefrontal cortex of the brain of patients with bipolar disorder. BAD protein is thought to promote BAK1 activity, while Bcl2 binds to BAK1 and prevents its ability to bind to the channel.

Dr Beech continued, "This positive swing in regulation of apoptosis for lithium responders was measurable as early as four weeks after the start of treatment, while in non-responders there was a measureable shift in the opposite direction. It seems then, that increased expression of BCL2 and related genes is necessary for the therapeutic effects of lithium. Understanding these differences in genes expression may lead towards personalized treatment for bipolar disorder in the future."