• NIBIB News Room, 2016 | Worldwide study seeks to unlock the brain’s genetic code

• Fierce Biotech Research, 2015 | Researchers identify brain abnormalities in people with schizophrenia 

• MLU – Machines Like Us, 2015 | New study identifies schizophrenic brain abnormalities 

• Mental Health Recovery, 2015 | Structural brain abnormalities linked to schizophrenia

• Brookhaven Hospital, 2015 | Schizophrenia linked to decreased volume in regions of the brain 

• The Lancet, 2015 | ENIGMA: crowdsourcing meets neuroscience

• International Innovation, 2015 | Cracking the Brain’s Genetic Code (high res) (low res)

• Biomedical Computation Review, June 2015 | Integrating the Fragmented Mind: Bringing the Whole Elephant into View

• Nature Neuroscience, 2014 | Consorting with big science

• Brain Imaging and Behavior, 2014 | The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Chronic depression shrinks brain’s memories and emotions

The hippocampus, an area of the brain responsible for memory and emotion, shrinks in people with recurrent and poorly treated depression, a global study has found.

The findings highlighted the importance of treating depression early, particularly in teenagers and young adults, the study concluded.

Fifteen research institutes around the world, including from the US, Europe and Australia, collaborated to combine the results of their existing, smaller studies comparing the hippocampuses of depressed and healthy people.

This allowed them to examine the brain magnetic resonance imaging data of 8,927 people, 1,728 of whom had major depression and the rest of whom were healthy.

The researchers found 65% of the depressed study participants had recurrent depression and it was these people who had a smaller hippocampus, which is near the centre of the brain and is involved with long-term memory, forming new memories, and connecting emotions to those memories.

The findings of the largest international study to compare brain volumes in people with and without major depression were published in the medical journal Molecular Psychiatry.

The University of Sydney’s brain and mind research institute led the Australian arm of the study. Its co-director, Professor Ian Hickie, said those people in the study experiencing their first depressive episode had a normal hippocampus size.

“But the more episodes of depression a person had, the greater the reduction in hippocampus size,” he said.

“So recurrent or persistent depression does more harm to the hippocampus the more you leave it untreated. This largely settles the question of what comes first: the smaller hippocampus or the depression? The damage to the brain comes from recurrent illness.”

Hickie, who is also a national mental health commissioner, said it meant identifying and treating depression effectively when it first occurred was vital to prevent this damage, particularly among teenagers and young adults.

But there was good evidence that with treatment, the damage was reversible, he said.

“Other studies have demonstrated reversibility, and the hippocampus is one of the unique areas of the brain that rapidly generates new connections between cells, and what are lost here are connections between cells rather than the cells themselves,” Hickie said.

“Treating depression effectively does not just mean medicines. If you are unemployed, for example, and then sit in a room doing nothing as a result, this can shrink the hippocampus. So social interventions are just as important, and treatments such as fish oils are also thought to be neuro-protective.”

There was some evidence that the hippocampus was larger in those patients taking antidepressants, Hickie said, indicating these medications could have a protective effect.

“There is a lot of nonsense said about antidepressants that constantly perpetuates the evils of them, but there is a good bit of evidence that they have a protective effect,” he said.

“But that doesn’t mean they are the only treatment. There are, in fact, a broad range of treatments that should be explored, and in young people psychotherapy would often be explored as the first line of treatment, not medicines.”

A co-author of the study, Associate Professor Jim Lagopoulos, said the findings provided new insight on brain structures and possible mechanisms responsible for depression.

It also indicated the findings that were possible through collaboration.

“Despite intensive research aimed at identifying brain structures linked to depression in recent decades, our understanding of what causes depression is still rudimentary,” he said.

“One reason for this has been the lack of sufficiently large studies, variability in the disease and treatments provided, and the complex interactions between clinical characteristics and brain structure.”

BBRF (formerly NARSAD) June 26, 2015

Innovative Analysis Finds Unique Brain Structure Patterns in People with Schizophrenia

In the first study of its kind, researchers have found unique brain structure patterns among people with schizophrenia, providing insight into how the condition may develop and respond to treatment.

Differences in brain structure have been noted in people with schizophrenia for decades. Ideally, such information should help us understand causes, progression and even treatment effects. Yet brain differences are influenced by many factors, some with opposing effects. Moreover, studies performed by different teams with different methods and standards have made it hard to distill results.

Reporting June 2nd in Molecular Psychiatry, an international team called the ENIGMA Schizophrenia Working Group––19 of whose members are current and past NARSAD grantees*––presented a profile of brain abnormalities based on 15 schizophrenia cohorts worldwide. It was a first test of a way to analyze imaging data across traditional diagnostic boundaries. The aim: to generate “robust and consistent anatomical fingerprints associated with brain disorders to help formulate improved diagnostic classifications based on both brain and behavioral evaluations,” the team said.

The ENIGMA group confirmed that people with schizophrenia had some smaller brain regions compared with healthy controls: the hippocampi, twin structures on either side of the brain that are associated with memory; the amygdalae, another paired structure found in both brain hemispheres that are important for emotional processing; and the thalami, twin structures associated with the relay of sensory and motor information. They also noted that intracranial volume, a general measure of brain size, was smaller than average in people with the illness.

The team found two structures larger than normal in people with schizophrenia: the pallidum, involved in motivation and emotion; and the lateral ventricles, important cavities in the brain. These findings add to the evidence that schizophrenia is characterized by specific abnormalities of deep brain structures.

The structural differences linked with schizophrenia in this study varied depending on factors such as age and sex, highlighting the variability of the illness. The biggest difference among people with schizophrenia was their smaller hippocampi, most pronounced among people who had never received medicine (typically, antipsychotic medicine) for their schizophrenia symptoms. This finding supports previous evidence that untreated schizophrenia may involve abnormal development of the hippocampus and that this can be reduced or reversed by treatment with antipsychotic medication.

Future work will examine how these structural differences unfold across the lifespan in affected individuals who take antipsychotic medications and those who do not. The team calls for attention in future studies to environmental and lifestyle factors that can affect brain structure, including nutrition levels, water intake, exercise, drug use, social isolation, and stress. Future research by ENIGMA will include the study of brain characteristics among family members of people with schizophrenia, as well as different measures of brain structure, and possible relationships between the structural differences found in this study and individual patients’ experience of schizophrenia symptoms.

Biomedical Computation June 1, 2015 Schizophrenia and the Thinking Brain: A Matter of Gray Matter

Schizophrenia patients often experience disorganized thinking, hallucinations, and problems with attention, memory and language. And that in turn suggests a problem with the brain’s gray matter. “The gray matter is where the good stuff happens,” says Jessica Turner, PhD, associate professor of psychology and neuroscience at Georgia State University. “It’s where the synapses are—where the cells fire. Without gray matter you can’t think.”

In imaging studies, researchers have long observed gray matter abnormalities in the brain structures of schizophrenic patients. Some such studies look at gray matter volume—the amount of gray matter inside the borders of particular brain structures—and some look at gray matter concentration—the density of gray matter judged by characteristics of the voxels. Most look for clusters of voxels that differ from healthy controls (univariate approaches) while a few have begun looking for patterns of variation among those clusters (using multivariate approaches). Schizophrenia researchers also struggle with sample sizes that may be insufficient to reach statistical significance.

Seeking to generate reliable, replicable results, Turner and her colleagues set out to conduct an international mega-analysis of gray matter concentration using a multivariate approach and a large dataset. They gathered together MRI images from eight prior studies, including scans of 936 healthy controls and 784 people diagnosed with schizophrenia. The method they used—called parallel independent components analysis (ICA)—lets the data speak for itself, revealing spatial patterns that co-occur in patients compared to healthy controls. And the data did speak, revealing nine “components” or spatial patterns of interest. One pattern in particular caught the researchers’ attention: reduced gray matter concentration in three areas (superior temporal gyrus, inferior frontal gyrus and insula) of the brains of schizophrenic patients. And the pattern was highly replicable. “You can find this over and over again in chronic schizophrenia,” Turner says. “You can put it in the bank.” The work was published in the Schizophrenia Bulletin in 2014.

Is there potential for similar mega-analyses to reveal patterns in other mental illnesses? “Oh my goodness, yes!” says Turner. But she also points to the ENIGMA consortium as a model for future work. Rather than a mega-analysis, which brings all the data to one lab, ENIGMA leaves the data where it is and sends software scripts to participating investigators whose results are then combined. “ENIGMA gets more power out of collaboration and cooperation than we could out of doing our own little studies,” Turner says.

For example, in 2008, the dynamic wave of gray matter loss that occurs as schizophrenia develops was revealed in a collaborative effort by 40 labs around the world led by Paul Thompson, PhD, professor in the Keck School of Medicine at the University of Southern California and director of the ENIGMA Consortium. In work published in 2008, Thompson and his colleagues also used time-lapse imaging to study the effects of various schizophrenia medications on the brain over the course of a year. Remarkably, they found one medication, olanzapine, that seemed to reduce gray matter loss compared with others.

Turner and her colleagues are now combining imaging and genetics approaches to schizophrenia to see if there’s a relationship between the pattern of gray matter loss they observed in their mega-analysis and genetics. “Let’s see if there’s a relationship between this imaging pattern and cases/controls in GWAS,” she says. An earlier project with a smaller number of subjects suggested the pattern of loss in schizophrenic patients is heritable. The results of Turner’s team’s genetics work are due out soon.

ENIGMA, which stands for Enhancing NeuroImaging Genetics through Meta-Analysis, is also driving forward with the emerging field of neuroimaging genomics. The idea is to use brain images to screen the genome for common variants that might affect the brain. To date, such approaches have identified genes linked to such things as brain or hippocampal size as well as a few genes linked to Alzheimer’s Disease.

These early studies suggest, however, that neuroimaging sample sizes will need to be quite large if they are to avoid the problem of false positives—genes that seem linked to imaging features in a particular sample but cannot be replicated in other samples. This concern has led to the ENIGMA Consortium’s efforts to combine images from many labs.

To date, the ENIGMA Consortium’s Schizophrenia and Bipolar Working Groups have been focused on extracting meaningful information from neuroimages. But with support from the NIH’s Big Data to Knowledge (BD2K) program, they hope to soon publish work that ties these results to genetics.

In a Nature paper published in January 2015, the ENIGMA network showed the potential promise of such work. That study found eight common variants (SNPs) that consistently predict the size of structures on brain MRI scans from over 30,000 people from 33 countries worldwide. Although non-genetic factors are clearly important, a tantalizing question is whether these genetic variants that correlate with brain structure also correlate with risk for brain diseases. For example, those eight genetic hotspots seem to affect the size of several brain regions implicated in schizophrenia, and some of them appear to affect risk for Alzheimer’s disease, Parkinson’s disease, and obsessive-compulsive disorder (OCD). An ongoing partnership between the Psychiatric Genomics Consortium and ENIGMA is comparing the two groups’ findings to see if risk genes for schizophrenia might exert their affect by influencing the composition and integrity of the brain.

May 4th, 2015 | Issue 179: ‘The Enigma’ Professor Paul Thompson, and Drs Derrek Hibar and Neda Jahanshad discuss the significant progress being made by taking a global-scale ‘big data’ approach to understanding brain function and the underlying causes of neuropathogenesis. ENIGMA in Science Magazine October 9, 2014 Hoping to tame the torrent of data churning out of biology labs, the National Institutes of Health (NIH) today announced [awards] in 2014 to help researchers develop ways to analyze and use large biological data sets. Professor Dan Stein in Cape Town South Africa talks about ENIGMA October 14, 2014 The combined data is so vast that no one scientist could ever analyse it on their own. Together, we can screen each other’s data to discover genes or medications that influence a range of neuropsychiatric disorders. 2012 ENIGMA Newsletter December 20, 2012 2012 has been a productive year for ENIGMA! Read about all our successful efforts this year and working groups set up for projects in 2013. If you are interested in joining any project, individual contact information is provided. GWAS and Anatomy April 20, 2012 Alzheimer’s Research Forum – Pooled Data Fingers Genes Driving Brain Size, IQ Giant imaging study identifies genes that govern brain size April 19, 2012 SFARI – The largest brain imaging study ever performed has identified candidate genes that influence brain size and general intelligence… ENIGMA-KCBS Thompson Interview April 16, 2012 Listen to an interview with principle investigator, Paul Thompson, about ENIGMA’s work. Tiny gene change affects brain size, IQ: scientists April 16, 2012 Agence France Presse, Tehran Times – An international team of scientists said Sunday the largest brain study of its kind had found a gene linked to intelligence, a small piece in the puzzle as to why some people are smarter than others. also World News Australia Crowd-Sourcing Expands Power of Brain Research April 15, 2012 New York Times – In the largest collaborative study of the brain to date, scientists using imaging technology at more than 100 centers worldwide have for the first time zeroed in on genes that they agree play a role in intelligence and memory. Scientists at UCLA, worldwide collaborate to map brain size genes April 15, 2012 LA Times – Scientists have published a new map of gene variations that influence the risk for various brain diseases and conditions, including Alzheimer’s.