Neuroscience

New findings led by Dr. Michael Lombardo, Prof. Simon Baron-Cohen and colleagues at the University of Cambridge indicate that testosterone levels early in fetal development influence later sensitivity of brain regions related to reward processing and affect an individual’s susceptibility to engage in behavior, that in extremes, are related to several neuropsychiatric conditions that asymmetrically affect one sex more than the other.

Although present at low levels in females, testosterone is one of the primary sex hormones that exerts substantial influence over the emergence of differences between males and females. In adults and adolescents, heightened testosterone has been shown to reduce fear, lower sensitivity to punishment, increase risk-tasking, and enhance attention to threat. These effects interact substantially with context to affect social behavior.

This knowledge about the effects of testosterone in adolescence and adulthood suggests that it is related to influencing the balance between approach and avoidance behavior. These same behaviors are heightened in the teenage years and also emerge in extremes in many neuropsychiatric conditions, including conduct disorder, depression, substance abuse, autism, and psychopathy.

Scientists have long known that sex differences influence many aspects of psychiatric disorders, including age of disease onset, prevalence, and susceptibility. For example, according to the World Health Organization, depression is twice as common in women than men, whereas alcohol dependence shows the reverse pattern. In addition to many other factors, sex hormone levels are likely to be important factors contributing to sex differences in psychopathology.

However, research to date has mainly focused on sex hormone levels during adolescence and adulthood, when hormone levels are heightened and built upon substantial prior developmental experience. Sex hormone levels are also heightened during critical periods of fetal brain development, but the impact of such prenatal surges in sex hormone levels on subsequent adult brain and behavioral development has received relatively little attention.

"This study is the first to directly examine whether testosterone in fetal development predicts tendencies later in life to engage in approach-related behavior (e.g., fun-seeking, impulsivity, reward responsivity) and also how it may influence later brain development that is relevant to such behaviors," said first author Lombardo.

In this study, they tested a unique cohort of boys, 8-11 years of age, whose fetal testosterone had been previously measured from amniotic fluid at 13-20 weeks gestation. The boys were scanned with functional magnetic resonance imaging technology to assess changes in brain activity while viewing pictures of negative (fear), positive (happy), neutral, or scrambled faces.

They found that increased fetal testosterone predicted more sensitivity in the brain’s reward system to positively, compared to negatively, valenced facial cues. This means that reward-related brain regions of boys with higher fetal testosterone levels respond more to positive facial emotion compared to negative facial emotion than boys who with smaller levels of fetal testosterone.

In addition, increased fetal testosterone levels predicted increased behavioral approach tendencies later in life via its influence on the brain’s reward system. Lombardo explained, “This work highlights how testosterone in fetal development acts as a programming mechanism for shaping sensitivity of the brain’s reward system later in life and for predicting later tendency to engage in approach-related behaviors. These insights may be especially relevant to a number of neuropsychiatric conditions with skewed sex ratios and which affect approach-related behavior and the brain’s reward system.”

Dr. John Krystal, Editor of Biological Psychiatry, commented, “These remarkable data provide new evidence that hormonal exposures early in life can have lasting impact on brain function and behavior.”

Low levels of vitamin D may be associated with longevity, according to a study involving middle-aged children of people in their 90s published in CMAJ (Canadian Medical Association Journal).

"We found that familial longevity was associated with lower levels of vitamin D and a lower frequency of allelic variation in the CYP2R1 gene, which was associated with higher levels of vitamin D," writes Dr. Diana van Heemst, Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands, with coauthors.

Previous studies have shown that low levels of vitamin D are associated with increased rates of death, heart disease, diabetes, cancer, allergies, mental illness and other afflictions. However, it is not known whether low levels are the cause of these diseases or if they are a consequence.

To determine whether there was an association between vitamin D levels and longevity, Dutch researchers looked at data from 380 white families with at least 2 siblings over age 90 (89 years or older for men and 91 year or older for women) in the Leiden Longevity Study. The study involved the siblings, their offspring and their offsprings’ partners for a total of 1038 offspring and 461 controls. The children of the nonagenarians were included because it is difficult to include controls for the older age group. The partners were included because they were of a similar age and shared similar environmental factors that might influence vitamin D levels.

The researchers measured levels of 25(OH) vitamin D and categorized levels by month as they varied according to season. Tanning bed use, which can affect vitamin D levels, was categorized as never, 1 times per year and 6 times per year. The researchers controlled for age, sex, BMI (body mass index), time of year, vitamin supplementation and kidney function, all factors that can influence vitamin D levels. They also looked at the influence of genetic variation in 3 genes associated with vitamin D levels.

"We found that the offspring of nonagenarians who had at least 1 nonagenarian sibling had lower levels of vitamin D than controls, independent of possible confounding factors and SNPs [single nucleotide polymorphisms] associated with vitamin D levels," write the authors. "We also found that the offspring had a lower frequency of common genetic variants in the CYP2R1 gene; a common genetic variant of this gene predisposes people to high vitamin D levels.

These findings support an association between low vitamin D levels and familial longevity.” They postulate that offspring of nonagenarians might have more of a protein that is hypothesized to be an “aging suppressor” protein. More research is needed to understand the link between lower vitamin D levels, genetic variants and familial longevity.

Over the last 15 years, researchers have found a significant association between vascular diseases such as hypertension, atherosclerosis, diabetes type 2, hyperlipidemia, and heart disease and an increased risk of Alzheimer’s disease. In a special issue of the Journal of Alzheimer’s Disease, leading experts provide a comprehensive overview of the pathological, biochemical, and physiological processes that contribute to Alzheimer’s disease risk and ways that may delay or reverse these age-related abnormalities.

“Vascular risk factors to Alzheimer’s disease offer the possibility of markedly reducing incident dementia by early identification and appropriate medical management of these likely precursors of cognitive deterioration and dementia,” says Guest Editor Jack C. de la Torre, MD, PhD, of the University of Texas, Austin. “Improved understanding coupled with preventive strategies could be a monumental step forward in reducing worldwide prevalence of Alzheimer’s disease, which is doubling every 20 years.”

The issue explores how vascular disease can affect cerebral blood flow and impair signaling, contributing to Alzheimer’s disease (AD). The diagnostics of cardiovascular risk factors in AD are addressed, as are potential therapeutic approaches.

Paradoxically, the presence of vascular risk factors in middle age is associated with the development of AD more strongly than late-life vascular disease. In fact, some research suggests that vascular symptoms later in life may have a protective effect against the development of the disease. The physiopathological mechanisms that may underlie this phenomenon are discussed.

To date, trials that target major cardiovascular risk factors in the prevention of AD remain inconclusive but have become an important focus of international research as described by contributors of this special volume in their overviews. The multifactorial nature of AD and the need to identify the proper time window for intervention when designing possible interventions, and methodological issues that will have to be addressed to achieve an optimal design of new randomized controlled trials, are discussed. Promising avenues for treatment, such as the potential of low-level light therapy to increase the rate of oxygen consumption in the brain and enhance cortical metabolic capacity, and the possibility that some antihypertensive drug classes reduce the risk and progression of AD more than others, are discussed.

Dr. de la Torre notes that the presence of vascular risk factors is not an absolute pathway to dementia, and it may be as important to study how or why individuals who are cognitively normal but have vascular risk are able to avoid dementia. “Reducing Alzheimer’s disease prevalence by focusing right now on vascular risk factors to Alzheimer’s disease, even with our limited technology, is not a simple or easy task. But the task must begin somewhere and without delay because time is running out for millions of people whose destiny with dementia may start sooner rather than later,” he concludes.

Dr. James Russell and a research team at the University of Cambridge recently published work on young children’s conception of personal visibility, which furthers the understanding of cognitive development and of our emerging sense of self.

The research involved children three to four years of age. Researchers placed an eye mask on each of the children and asked them if they could be seen when wearing it. They then asked each child if an adult who was wearing a similar mask could be seen. The majority of the children involved in the study believed they were not visible when wearing the mask. Most also believed that the adult wearing the eye mask was also hidden.

Additional tests revealed a unique layer of complexity, demonstrating that although the children thought they were invisible when there eyes were covered, they still believed that their head and body were able to be seen.

The research team concluded by process of elimination that the factor that makes children believe they are visible is eye contact with another person.

“… it would seem that children apply the principle of joint attention to the self and assume that for somebody to be perceived, experience must be shared and mutually known to be shared, as it is when two pairs of eyes meet,” the researchers reported. “Young children’s natural tendency to acquire knowledge intersubjectively, by joint attention, leads them to undergo a developmental period in which they believe the self is something that must be mutually experienced for it to be perceived.”

Evidently, children only believe they exist when making eye contact with another person. The implications point to a simple but necessary way to make children feel present and involved. Cultures worldwide seem to have some version of “peek-a-boo,” as a quick Google image search reveals. Lack of eye contact in children has been linked as an early sign of autism, while the presence of eye contact is associated with empathy. Dr. Russell’s team seems to have discovered a key facet of cognitive development.

The results of Dr. Russell’s study were published in the Journal of Cognition and Development.

A daily multivitamin supplement may improve brain efficiency in older women, according to new research from Swinburne University of Technology.

Centre for Human Psychopharmacology researcher at Swinburne, Dr Helen Macpherson’s four month study of the commercial product Swisse Women’s Ultivite 50+ found some evidence that multivitamin supplements may influence cognitive function by altering electrical activity in the brain.

"The main finding of the study was that 16 weeks supplementation with the Swisse Women’s 50+ multivitamin modulated brain activity," Dr Macpherson said.

"This is an important result as it shows there are direct effects of multivitamins on the brain.

"Previous research has used measures of behaviour to determine whether multivitamins can affect brain function, but this is the first trial to directly measure brain activity."

The study was conducted over 16 weeks with 56 women aged between 64 and 79 who were concerned about their memory or experiencing memory difficulties. They were randomly assigned to take the multivitamin supplement or a placebo daily.

Volunteers underwent a recording of their brain electrical activity whilst performing a spatial working memory task.

The research was published in Physiology and Behavior.

A previous paper published in Psychopharmacology reported that multivitamin supplementation improved behavioural performance on a similar task, in the same group of participants.

The study concluded that 16 weeks of supplementation with a combined multivitamin, mineral and herbal formula may benefit memory, by enabling the brain to work in a more efficient way.

"When considered with our other findings of benefits to memory performance, there is increasing evidence that multivitamins may be useful to combat cognitive decline in the elderly," Dr Macpherson said.

In a column appearing in the current issue of the journal Nature, McLean Hospital biostatistician Nicholas Lange, ScD, cautions against heralding the use of brain imaging scans to diagnose autism and urges greater focus on conducting large, long-term multicenter studies to identify the biological basis of the disorder.

"Several studies in the past two years have claimed that brain scans can diagnose autism, but this assertion is deeply flawed," said Lange, an associate professor of Psychiatry and Biostatistics at Harvard Medical School. "To diagnose autism reliably, we need to better understand what goes awry in people with the disorder. Until its solid biological basis is found, any attempt to use brain imaging to diagnose autism will be futile."

While cautioning against current use of brain imaging as a diagnostic tool, he is a strong proponent of using this technology to help scientists better understand autism. Through the use of various brain imaging techniques, including functional magnetic resonance imaging (MRI), positron emission tomography (PET), and volumetric MRI, Lange points out that researchers have made important discoveries related to early brain enlargement in the disorder, how those with autism focus during social interaction and the role of serotonin in someone with autism.

"Brain scans have led to these extremely valuable advances, and, with each discovery, we are getting closer to solving the autism pathology puzzle," said Lange. "What individuals with autism and their parents urgently need is for us to carry out large-scale studies that lead us to find reliable, sensitive and specific biological markers of autism with high predictive value that allow clinicians to identify interventions that will improve the lives of people with the disorder."

Autism and autism spectrum disorder (ASD) are terms regularly used to describe a group of complex disorders of brain development. This spectrum characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors, whose criteria have been revised in the newly proposed Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The prevalence of ASD in the United States has increased 78 percent in the last decade, with the Centers for Disease Control estimating that one in 88 children has ASD.

UC Santa Barbara has reported an important discovery in the interdisciplinary study of split-brain research. The findings uncover dynamic changes in brain coordination patterns between left and right hemispheres.

Split-brain research has been conducted for decades, and scientists have long ago shown that language processing is largely located in the left side of the brain. When words appear only in the left visual field –– an area processed by the right side of the brain –– the right brain must transfer that information to the left brain, in order to interpret it. The new study at UCSB shows that healthy test subjects respond less accurately when information is shown only to the right brain.

While hemispheric specialization is considered accurate, the new study sheds light on the highly complex interplay –– with neurons firing back and forth between distinct areas in each half of the brain. The findings rely on extremely sensitive neuroscience equipment and analysis techniques from network science, a fast-growing field that draws on insights from sociology, mathematics, and physics to understand complex systems composed of many interacting parts. These tools can be applied to systems as diverse as earthquakes and brains.

Fifty years ago, UC Santa Barbara neuroscientist Michael S. Gazzaniga moved the field forward when he was a graduate student at the California Institute of Technology and first author of a groundbreaking report on split-brain patients. The study, which became world-renowned, was published in the Proceedings of the National Academy of Sciences (PNAS) in August 1962. This week, in the very same journal, Gazzaniga and his team announced major new findings in split-brain research. The report is an example of the interdisciplinary science for which UCSB is well known.

"The occasion of this paper is on the 50th anniversary of the first report on human split-brain research reported in PNAS," said Gazzaniga. "That study showed how surgically dividing the two hemispheres of the human brain –– in an attempt to control epilepsy –– allowed for studying how each isolated half-brain was specialized for cognitive function.

"In the present study, new techniques –– not present 50 years ago –– begin to allow for an understanding of how the normal, undivided brain integrates the special functions of each half brain. It is a new beginning and very exciting," said Gazzaniga, professor of psychology in UCSB’s Department of Psychological and Brain Sciences, and director of UCSB’s SAGE Center for the Study of Mind.

There are a growing number of clues that immune and inflammatory mechanisms are important for the biology of schizophrenia. In a new study in Biological Psychiatry, Dr. Mar Fatjó-Vilas and colleagues explored the impact of the interleukin-1β gene (IL1β) on brain function alterations associated with schizophrenia.

Fatjó-Vilas said that “this study is a contribution to the relatively new field of ‘functional imaging genetics’ which appears to be potentially powerful for the study of schizophrenia, where genetic factors are of established importance and cognitive impairment – affecting particularly executive function and long-term memory – is increasingly recognized as a core feature of the disorder.”

To conduct this study, they recruited patients with schizophrenia and healthy volunteers, all of whom completed a working memory task while undergoing a functional magnetic resonance imaging scan in the laboratory. This allowed the researchers to determine which areas of the brain became activated during the task. Each participant was also genotyped to determine which allelic combination of the -511C/T polymorphism at the promoter region of the IL1β gene they carry: CC, TT, or CT.

Patients who were homozygous for the C allele (CC) showed reduced prefrontal cortex activation associated with working memory than patients who had at least one copy of the T allele. Among the healthy volunteers, frontal brain activation did not differ according to genotype.

“The analyzed genetic variant exerts an influence on prefrontal cortex function and this influence is different in healthy subjects and patients with schizophrenia,” summarized Fatjó-Vilas.

An important issue is that the -511C/T seems to have a role in regulating the levels of IL1B expression, in which case it would influence neuronal activity dependent on the protein availability. This means that the T allele has been reported to be more active than the C allele, suggesting that a tendency for greater expression of IL1β is associated with greater compromise of frontal cortical functions underlying cognition.

Interleukin-1β is released in the blood under stressful conditions and its release is one of the ways that stress promotes inflammation. IL-1β levels in the blood are altered, for example, in patients with depression and other neuropsychiatric disorders.

Apart from having a role in the immune system, interleukins are also involved in a variety of developmental and functioning processes of the central nervous system. Thus, this study provides further clues for identifying specific biological mechanisms of the disorder associated with both neurodevelopmental processes and immunological and stress response functions.

Dr. John Krystal, Editor of Biological Psychiatry, commented, “We are just beginning to explore the functional impact of inflammatory mechanisms in schizophrenia and the current findings increase our curiosity about these novel mechanisms.”

Research led by Chu Chen, PhD, Associate Professor of Neuroscience at LSU Health Sciences Center New Orleans, has identified an enzyme called Monoacylglycerol lipase (MAGL) as a new therapeutic target to treat or prevent Alzheimer’s disease. The study was published online November 1, 2012 in the Online Now section of the journal Cell Reports.

The research team found that inactivation of MAGL, best known for its role in degrading a cannabinoid produced in the brain, reduced the production and accumulation of beta amyloid plaques, a pathological hallmark of Alzheimer’s disease. Inhibition of this enzyme also decreased neuroinflammation and neurodegeneration, and improved plasticity of the brain, learning and memory.

"Our results suggest that MAGL contributes to the cause and development of Alzheimer’s disease and that blocking MAGL represents a promising therapeutic target," notes Dr. Chu Chen, who is also a member of the Department of Otolaryngology at LSU Health Sciences Center New Orleans.

The researchers blocked MAGL with a highly selective and potent inhibitor in mice using different dosing regimens and found that inactivation of MAGL for eight weeks was sufficient to decrease production and deposition of beta amyloid plaques and the function of a gene involved in making beta amyloid toxic to brain cells. They also measured indicators of neuroinflammation and neurodegeneration and found them suppressed when MAGL was inhibited. The team discovered that not only did the integrity of the structure and function of synapses associated with cognition remain intact in treated mice, but MAGL inactivation appeared to promote spatial learning and memory, measured with behavioral testing.

Alzheimer’s disease is a neurodegenerative disorder characterized by accumulation and deposition of amyloid plaques and neurofibrillary tangles, neuroinflammation, synaptic dysfunction, progressive deterioration of cognitive function and loss of memory in association with widespread nerve cell death. The most common cause of dementia among older people, more than 5.4 million people in the United States and 36 million people worldwide suffer with Alzheimer’s disease in its various stages. Unfortunately, the few drugs that are currently approved by the Food and Drug Administration have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods, and none has shown a clear effect on disease progression or prevention.

"There is a great public health need to discover new therapies to prevent and treat this devastating disorder," Dr. Chen concludes. The research was supported by grants from the National Institutes of Health. In addition to scientists from LSU Health Sciences Center New Orleans, the research team also included investigators from the Massachusetts Institute of Technology.

In a new study appearing this month in the Journal of Neuroscience, researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases. 

“One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells,” said University of Rochester Medical Center (URMC) neurologist Steve Goldman, M.D., Ph.D., lead author of the study. “This study demonstrates that – in the case of certain populations of brain cells – we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells.”

The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons.

Read more

New research in The FASEB Journal suggests that dysfunction in the SRGAP3 protein may lead to schizophrenia, hydrocephalus, mental retardation and some forms of autism in childhood

A new research discovery has the potential to revolutionize the biological understanding of some childhood psychiatric disorders. Specifically, scientists have found that when a single protein involved in brain development, called “SRGAP3,” is malformed, it causes problems in the brain functioning of mice that cause symptoms that are similar to some mental health and neurological disorders in children. Because this protein has similar functions in humans, it may represent a “missing link” for several disorders that are part of an illness spectrum. In addition, it offers researchers a new target for the development of treatments that can correct the biological cause rather than treat the symptoms. This discovery was published in November 2012 print issue of The FASEB Journal.

"Developmental brain disorders such as schizophrenia, hydrocephalus, mental retardation and autism are among the most devastating diseases in children and young adults," said Dusan Bartsch, Ph.D., a researcher involved in the work from the Department of Molecular Biology at the Central Institute of Mental Health at the University of Heidelberg in Mannheim, Germany. "We hope that our findings will contribute to a better understanding, and in the end, to better treatments for these disorders."

Bartsch and colleagues made this discovery using mice with the SRGAP3 protein inactivated. Then they conducted several experiments comparing these mice to normal mice. The mice with inactive SRGAP3 showed clear changes in their brains’ anatomy, which resulted in altered behavior similar to certain symptoms in human neurological and psychiatric diseases. An involvement of SRGAP3 in different brain disorders could indicate that these disorders are possibly connected, as SRGAP3 is a key player in brain development. These different disorders could be connected via the SRGAP3 protein because they all emerge from disturbed development of the nervous system.

"Since Freud put biological psychiatry on the map, we’ve slowly increased our understanding of how mental health is dictated by chemistry," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Eventually we’ll understand the complex biology underlying most psychiatric illnesses, from genes to proteins to cell signaling to overt behaviors. Along the way, as in this report, we’re likely to find single targets close to the roots of apparently different mental illnesses."