GxExAge

23 05 2014

Here are fascinating findings regarding the Genes – Enviroment interaction and mental illness onset:

http://www.nimh.nih.gov/news/science-news/2014/genes-impact-suspect-cortex-areas-more-as-youth-mature.shtml





What we know, and mostly don’t know about ASD in 2014

28 03 2014

Autism Awareness: April 2014

By 

Autism Awareness Month arrives this year with a package of new, important research findings. Below I describe a few of these. The field is moving so rapidly that, by the end of April, there will likely be yet a new crop of findings—so this is, at best, a progress report for the beginning of Autism Awareness Month.

Today the Centers for Disease Control and Prevention (CDC) released new numbers on the prevalence of autism, based on the most recent results from their long running Autism and Developmental Disabilities Monitoring  (ADDM) network.  Looking at administrative data on 8-year-olds from 11 sites across the country, ADDM reported a prevalence of autism of 1 in 68 children in 2010 (based on children born in 2002), up from 1 in 88 in 2008 (based on children born in 2000).  There was considerable variation across the 11 sites: from 1 in 45 in New Jersey to 1 in 175 in Alabama. As in previous surveys, boys were almost 5 times more likely to have an autism label. The prevalence in boys was 1 in 42; in girls, 1 in 189.

One of the best things about the ADDM network is that it has provided surveillance using similar methods for over a decade. The prevalence of autism as estimated from administrative records has increased:  by 125 percent since 2002 and by 29 percent just between 2008 and 2010.  How much of this increase is “more detected” versus “more affected”? Is this increase a mark of better care, with more cases identified and treated, or is this a reflection of a continually growing public health care emergency due to more children affected? ADDM cannot answer these questions, but it does point to the need for a population-wide study, as currently planned by CDC and Autism Speaks in South Carolina. A previous total population study of all 7- to12-year-olds in a town in South Korea (more than 55,000 children) used standardized diagnostic instruments for children who screened positive and reported a prevalence of 1 in 38 children. Could that figure, which is in the range of the ADDM estimate of 1 In 45 for New Jersey, serve as a reasonable estimate for the actual prevalence once everyone with autism is detected? Perhaps the ADDM numbers will continue to rise, indicating better detection as awareness of the signs and symptoms increase.

Whatever the meaning of the new ADDM report, there is little doubt that more children and more adults on the autism spectrum will require more services. Ganz estimated the lifetime economic cost of autism to be $3.2 million per individual, back in 2006 when the prevalence was thought to be closer to 1 in 150.1 A new economic analysis looks at the cost, including education and indirect costs, based on three national data sets.2 The additional cost of having a child with autism was $17,081 per year in 2011. Only 18 percent of these costs were related to health care; half were attributed to school costs. Assuming 673,000 children ages 3 to 17 with a diagnosis of autism spectrum disorder, the total societal cost would be roughly $11.5 billion per year. Of course, with new estimates from the CDC about the increase in prevalence, these costs may need to be adjusted upward.

On the brain research front, a new report in the New England Journal of Medicine describes changes seen in the architecture of post-mortem brains in 10 of 11 children who had an autism diagnosis.3 Similar changes were found in  only 1 of 11 unaffected children. Dr. Eric Courchesne and his colleagues at the University of California, San Diego and Dr. Ed Lein and colleagues at the Allen Institute of Brain Science found patches of abnormal anatomy in parts of the brain associated with social and communication functions. Given that the pattern of cell layers in the cortex is laid down prenatally, these findings, if replicated, suggest that brain changes in autism are likely to have originated before birth, although the disorder is usually diagnosed behaviorally after age 4 years.

In 2014, the mystery of autism remains largely unsolved. We describe autism as a neurodevelopmental disorder, but even with the new report mentioned above, we do not know precisely how to define what the brain disorder is or when it occurs. We realize that as many as 30 percent of children with autism have spontaneous genetic mutations, but these large genetic changes have not yet been shown to cause the disorder, since other children with some of the same changes don’t have autism. We have treatments for autistic symptoms, helping many children to enter regular classrooms and ultimately function fully in society. But these behavioral treatments are expensive and intensive and often not available to children in need. Medical treatments have lagged behind.

All of this reminds us that for both children and adults with autism we need more science as well as more services. Indeed, the best way to better services will be through better science. As we understand what happens in the developing brain that renders a child unable to communicate or unable to engage the social world, we will be better able to provide earlier detection and better interventions. As we identify the many forms of autism, some more genetic, some more environmental, we can expect better tools for prevention and treatment. And as we understand better the evolution of autism in adults, we should be able to provide better care and offer better outcomes. Autism awareness reminds us of the vital importance of committing to both science and service for an increasing number of our fellow citizens.

References

1 Ganz ML. The lifetime distribution of the incremental societal costs of autism.  Arch Pediatr Adolesc Med. 2007 Apr;161(4):343-9.

2 Lavelle TA et al. Economic burden of childhood autism spectrum disorders.  Pediatrics. 2014 Mar;133(3):e520-9. doi: 10.1542/peds.2013-0763. Epub 2014 Feb 10.

3 Stoner R et al. Patches of disorganization in the neocortex of children with autism. N Engl J Med. 2014;370:1209-19. DOI:10.1056/NEJMoa1307491.





NIMH & DSM5 take 2…

16 05 2013

Thomas R. Insel, M.D., Director, NIMH
Jeffrey A. Lieberman, M.D., President-elect, APA

NIMH and APA have a shared interest in ensuring that patients and health providers have the best available tools and information today to identify and treat mental health issues, while we continue to invest in improving and advancing mental disorder diagnostics for the future.

Today, the American Psychiatric Association’s (APA) Diagnostic and Statistical Manual of Mental Disorders (DSM), along with the International Classification of Diseases (ICD) represents the best information currently available for clinical diagnosis of mental disorders. Patients, families, and insurers can be confident that effective treatments are available and that the DSM is the key resource for delivering the best available care. The National Institute of Mental Health (NIMH) has not changed its position on DSM-5. As NIMH’s Research Domain Criteria (RDoC) project website states, “The diagnostic categories represented in the DSM-IV and the International Classification of Diseases-10 (ICD-10, containing virtually identical disorder codes) remain the contemporary consensus standard for how mental disorders are diagnosed and treated.”

Yet, what may be realistically feasible today for practitioners is no longer sufficient for researchers. Looking forward, laying the groundwork for a future diagnostic system that more directly reflects modern brain science will require openness to rethinking traditional categories. It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. This is the focus of the NIMH’s Research Domain Criteria (RDoC) project. RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness.

The evolution of diagnosis does not mean that mental disorders are any less real and serious than other illnesses. Indeed, the science of diagnosis has been evolving throughout medicine. For example, subtypes of cancers once defined by where they occurred in the body are now classified on the basis of their underlying genetic and molecular causes.

All medical disciplines advance through research progress in characterizing diseases and disorders. DSM-5 and RDoC represent complementary, not competing, frameworks for this goal. DSM-5, which will be released May 18, reflects the scientific progress seen since the manual’s last edition was published in 1994. RDoC is a new, comprehensive effort to redefine the research agenda for mental illness. As research findings begin to emerge from the RDoC effort, these findings may be incorporated into future DSM revisions and clinical practice guidelines. But this is a long-term undertaking. It will take years to fulfill the promise that this research effort represents for transforming the diagnosis and treatment of mental disorders.

By continuing to work together, our two organizations are committed to improving outcomes for people with some of the most disabling disorders in all of medicine.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.





Respond to Criticism of DSM-5 by NIMH Director

7 05 2013

Statement by David Kupfer, MD
Chair of DSM-5 Task Force Discusses Future of Mental Health Research

The promise of the science of mental disorders is great. In the future, we hope to be able to identify disorders using biological and genetic markers that provide precise diagnoses that can be delivered with complete reliability and validity. Yet this promise, which we have anticipated since the 1970s, remains disappointingly distant. We’ve been telling patients for several decades that we are waiting for biomarkers. We’re still waiting. In the absence of such major discoveries, it is clinical experience and evidence, as well as growing empirical research, that have advanced our understanding of disorders such as autism spectrum disorder, bipolar disorder, and schizophrenia.
This progress will soon be recognized in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The new manual, due for release later this month, represents the strongest system currently available for classifying disorders. It reflects the progress that we have made in several important areas.
 A revised chapter organization signals how disorders may relate to each other based on underlying vulnerabilities or symptom characteristics.
 Disorders are framed in the context of age, gender, and cultural expectations, in addition to being organized along a valuable developmental lifespan within each chapter.
 Key disorders were combined or reorganized because the relationships among categories clearly placed them along a single continuum, such as substance use disorder and autism spectrum disorder.
 A new section introduces emerging measures, models and cultural guidance to assist clinicians in their evaluation of patients. For the first time, self-assessment tools are included to directly engage patients in their diagnosis and care.
DSM, at its core, is a guidebook to help clinicians describe and diagnose the behaviors and symptoms of their patients. It provides clinicians with a common language to deliver the best patient care possible. And through content such as the new Section III, the next manual also aims to encourage future directions in research.
Efforts like the National Institute of Mental Health’s Research Domain Criteria (RDoC) are vital to the continued progress of our collective understanding of mental disorders. But they cannot serve us in the here and now, and they cannot supplant DSM-5. RDoC is a complementary endeavor to move us forward, and its results may someday culminate in the genetic and neuroscience breakthroughs that will revolutionize our field. In the meantime, should we merely hand patients another promissory note that something may happen sometime? Every day, we are dealing with impairment or tangible suffering, and we must respond. Our patients deserve no less.
The American Psychiatric Association is a national medical specialty society whose physician members specialize in the diagnosis, treatment, prevention and research of mental illnesses, including substance use disorders. Visit the APA at http://www.psychiatry.org.
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National Institute of Mental Health VS. DSM-5

5 05 2013

The [American] National Institute of Mental Health – the world’s biggest mental health research funder, has recently announced that    it will be “re-orienting its research away from DSM categories” because the “DSM-5 lacks validity” and that “patients with mental disorders deserve better”. NIMH approach is driven by the latest neuroscience research that claims that psychiatric disorders should be diagnosed based on evidence based biological markers and not only on a consensus about clusters of clinical symptoms. Dr. Insel, head of the NIMH describes the DSM method by stating that “in the rest of medicine this [DSM diagnostic system, AT] would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. This clash between NIMH and the American Psychiatric Association that publishes the DSM, is another evidence for the revolution in the way psychiatric disorders will be conceptualize, diagnosed and treated in the future. Stay tuned for more updates.

For the full article by NIMH director entitled: Transforming Diagnosis click HERE





Brain Awareness Month by NIMH Director

12 03 2013

This is the time of March Madness, Daylight Savings Time, and what Emily Dickinson famously called the “month of expectation.” March is also Brain Awareness Month, an annual celebration with school visits, community lectures, and lab tours to introduce the public to the mind-blowing world of neuroscience. A list of Brain Awareness events can be found at http://www.dana.org/brainweek where you will also find that March 10 -16 is the peak for related public events around the world.

Since NIMH began focusing on mental disorders as brain disorders nearly two decades ago, educating people about the brain has been a priority for us.1 We often say that with the powerful tools of neuroscience, we can now use the brain to understand the mind, fulfilling the original vision that Freud had for a scientific psychology. But we have to remain humble about our understanding of the brain, because even our most powerful tools remain pretty blunt instruments for decoding the brain. In fact, we still do not know how to decipher the basic language of how the brain works.

A few numbers can help to define the challenge. The human brain is thought to have close to 86 billion neurons, each making on average about 10,000 connections. In contrast to most animals, our brains are largely made up of a heavily folded cortex, accounting for 80 percent of brain mass and about 100,000 miles of axons that provide the highways between neurons.2

How many different kinds of neurons are there in the brain? We really don’t know. Unlike the heart or kidney, which have a small, defined set of cell types, we still do not have a taxonomy of neurons and neuroscientists still argue about whether specific types of neurons are unique to humans. But there is no argument that neurons are only about 10 percent of the cells in the human brain. Most of our brain cells are glial cells, once thought to be mere support cells but now understood as having a critical role in brain function. Glial cells in the human brain are markedly different from glial cells in other brains, suggesting that they may be important in the evolution of brain function. As one hint to their function, an NIMH-supported study reported last week that human glial cells (but not mouse glial cells) transplanted into the mouse brain improve memory.3

How does the brain work? Again, we really don’t know. We have a very detailed understanding of how the heart pumps and the kidney filters, but how the brain encodes, stores, and retrieves information is still largely a mystery. We have known for over a century that most of the cortex is organized horizontally into six precise layers and much of the cortex has vertical mini-columns, but how this matrix of horizontal and vertical structures computes information is not really clear.

Neuroscientists talk a lot about brain circuits. In fact, the word “circuit” is probably misleading. We do not know where most circuits begin and end. And unlike an electrical circuit, brain connections are heavily reciprocal and recursive, so that a direction of information flow can be inferred but sometimes not proven. We believe there are “emergent properties” of the brain that convert electrical signals into memories or dreams, but how this happens is still a mystery. Recent studies have shown that diffuse waves of synchronization across the brain may be critical for attention or learning, but we are just learning about these slow waves of activity, and whether they occur at the “speed of thought” is still debated.4

Of course, the spectacular images from MRI and PET scans have already given us maps for perception and fear and language and many other functions. As scanners have improved their resolution from 1.5T (tesla) to 3T to recent 7T magnets and the protocols and analytic approaches have evolved, we now can map the cortical real estate associated with complex tasks like decision-making and face recognition. But these approaches even with the best current technology are still a 30,000 foot view of the action. Jay Giedd here at NIMH estimates that each gray matter voxel – the individual 3D pixels of 1 cubic mm that make up the scan – contains about 90,000 neurons, 400 meters of dendrites, and 4.5 million synapses. Each scan has over 650,000 voxels. And the actual measure is not neural activity per se but local blood flow, which changes slowly relative to the speed of thought.

In a sense, functional MRI is providing an image of something like the power grid of a city. fMRI slowly maps where and when different parts of the brain wake up, based on blood oxygen metabolism. By contrast, the street map of the brain is being mapped by the Human Connectome Project. Supported by the NIH Blueprint for Neuroscience Research, scientists working across the country are building something like a Google map for the human brain. In the first two years of the Human Connectome Project, scientists at Massachusetts General Hospital have created new MRI scanners with greatly enhanced resolution for looking at the geometric structure of the human brain.5 One remarkable claim from that work (still controversial) is that the fiber connections which heretofore looked like a bowl of spaghetti might actually have a relatively simple grid structure, allowing comparisons of connectomes between people. This kind of comparison is already underway at Washington University where the connectome group is obtaining the wiring diagrams of 1200 healthy adults, including 300 twin pairs. Last week, data from the first 68 volunteers were released on the Connectome website.

Whether March for you means basketball, changing clocks, or expectations, I hope you will check out some of the Brain Awareness events. Brain science has become one of the most exciting frontiers of science. When I was a kid, the scientific frontier was “outer space.” Today it seems to be “inner space” that fascinates the boldest and brightest young minds (or should we say young brains). We are still at the beginning of what could be an era of brain exploration, with great promise for understanding more about how each of us thinks and dreams and loves, but perhaps even greater promise for helping people with mental disorders.

References

 1 Insel T. Mental disorders as brain disorders. TEDxCaltech talk 18 January 2013. California Institute of Technology, Pasadena, CA.

 2 Lent R, Azevedo FA, Andrade-Moraes CH, Pinto AV. How many neurons do you have? Some dogmas of quantitative neuroscience under revision. Eur J Neurosci. 2012 Jan; 35(1):1-9. doi: 10.1111/ j.1460-9568. 2011. 07923.x.

 3 Han X et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell. 2013 Mar 7; 12: 342-353. doi: 10.1016/ j.stem. 2012. 12.015.

 4 Salazar RF, Dotson NM, Bressler SL, Gray CM. Content-specific fronto-parietal synchronization during visual working memory. Science. 2012 Nov 23; 338(6110): 109-100. doi: 10.1126/ science.1224000.

 5 Wedeen VJ et al. The geometric structure of the brain fiber pathways. Science. 2012 Mar 30; 335(6076): 1628-34. doi: 10.1126/ science. 1215280.





The Earliest the Better

16 01 2013

So many times we heard about the great importance of  early diagnosis and intervention in preventing or reducing the effect of health conditions. Well, that is true, in life, the earliest you identify a problem and address the better.  This time, I want to share with you the recent post of Dr. Insel, NIMH director about this issue in the context of mental health.  Enjoy!

 

The Case for Preemption

By Thomas Insel on January 16, 2013

Let’s start with some good news. Over the past few decades in the United States, we have seen dramatic reductions in mortality due to coronary artery disease (an over 60 percent reduction, with 1.1 millions deaths averted each year), AIDS (a 40 percent reduction, with over 30,000 deaths averted each year), and stroke (a 30 percent reduction, with over 20,000 deaths averted each year). Indeed, last month AIDS was declared a chronic disease, recognizing that a young person who becomes infected with HIV will likely survive for decades and die of other causes. These are extraordinary achievements, largely due to biomedical research. More specifically, research has taught us to detect each of these diseases early and intervene quickly to preempt later stages. The simple concept of “treatment as prevention,” whether to reduce heart attacks and strokes or to prevent the spread and advance of AIDS, has yielded better outcomes than treating the late stages of these disorders.

Unfortunately, when we look at the big picture and consider overall longevity, compared to the rest of the world, our news is not so good. A report out last week from the Institute of Medicine and the National Research Council describes high rates of mortality for Americans under 50, relative to rates of mortality in 18 other developed countries.1 It’s a sobering report. American men ranked last and American women ranked next to last in life expectancy within this age range. The authors cite car accidents, gun violence, and drug overdoses as factors contributing to higher mortality rates in this country. For people with mental disorders, the news from the United States is especially concerning. Suicide rates are trending higher not lower, especially in select demographic groups. Longevity, which has increased in the U.S. general population, remains shortened by years, possibly decades, in people with serious mental illness.

Is there a lesson to be learned from the successes of biomedical research? One observation that is driving the science of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease is that changes in the brain precede changes in behavior, sometimes by more than a decade. The brain appears wired to preserve behavior even in the face of massive cell death or cortical atrophy. Much of our research effort today in Alzheimer’s disease focuses on identifying these earlier stages and developing interventions that will preempt or forestall dementia. In Parkinson’s disease, where the symptoms only emerge after 80 percent of dopamine cells have been lost, if we could halt the disorder when only 40 percent of cells have died, the symptoms might be prevented.

What about mental disorders or, as we often call them, “behavioral disorders”? We now understand these as brain circuit disorders, but we define them based on changes in behavior. If the symptoms of psychosis are a late stage of schizophrenia, are we missing the most important time to intervene? A recent review looks at the evidence for a prodrome or high-risk syndrome before the psychosis of schizophrenia, analogous to the stages of heart disease before a heart attack.2 Most of the studies of this high-risk state have relied on behavioral symptoms, suggesting that we are already late in the process. Nevertheless, as this review concludes, this approach has already revealed an interlude before psychosis when intervention could prevent psychosis.

Of course, we face two big questions going forward in this research. First, can changes in brain function or some biomarker yield better prediction and longer lead-times for intervening to preempt psychosis? We now have the neuroimaging and cerebrospinal fluid measures in Alzheimer’s disease and the cardiac imaging and lipid measures in heart disease to define risk with more precision. Imagine the cognitive, imaging, and plasma measures that might redefine what we now call the risk state for schizophrenia so that early prediction becomes precise for any given individual.

The second question is how to intervene. The first studies with medications have been disappointing.2 We do not have a “statin” for preempting psychosis. But medication might not be the best way to build prefrontal circuits or strengthen executive function. Imagine a toolkit of interventions with cognitive training, family supports, and social engagement to prevent psychosis in even 20 percent of the 100,000 young people who will have a first episode this year.

The NIMH-supported North American Prodrome Longitudinal Study (NAPLS) has been on this path for the past decade. This dedicated consortium of scientists is not there yet, but already they are working on a combination of neurocognitive testing, neuroimaging, and plasma biomarkers that can redefine how we think about schizophrenia, revealing that psychosis is indeed a late event in a process that starts many years earlier. This year we will avert 1.1 million deaths from heart disease because we have not waited for a heart attack to diagnose and treat coronary artery disease. The 100,000 young Americans who will have a first episode of psychosis this year will join over 2 million with schizophrenia. Nearly 5 percent of people with schizophrenia will die by suicide. Our best hope of reducing mortality from this and other brain disorders will come from realizing that just like other medical disorders, we need to diagnose and intervene before the symptoms become manifest.

effect of early prevention on schizophrenia

References

1 National Research Council and Institute of Medicine. (2013). U.S. Health in International Perspective: Shorter Lives, Poorer Health. Panel on Understanding Cross-National Health Differences Among High-Income Countries, Steven H. Woolf and Laudan Aron, Eds. Committee on Population, Division of Behavioral and Social Sciences and Education, and Board on Population Health and Public Health Practice, Institute of Medicine. Washington, DC: The National Academies Press.

 2 Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rössler A, Schultze-Lutter F, Keshavan M, Wood S, Ruhrmann S, Seidman LJ, Valmaggia L, Cannon T, Velthorst E, De Hann L, Cornblatt B, Bonoldi I, Birchwood M, McGlashan T, Carpenter W, McGorry P, Klosterkötter J, McGuire P, Yung A. The Psychosis High-Risk State.JAMA Psychiatry. 2013;70(1):107-120. doi:10.1001/jamapsychiatry.2013.269.