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Funding Science in a Time of Austerity

12 Mar

Funding Science in a Time of Austerity is a blog post by Tom Insel, director of the National Institute of Mental Health (NIMH) in the US.

I’ve discussed many news stories of late which discuss special education in these tight fiscal times. Naturally research will be impacted as well. While the article by Tom Insel does not discuss autism specifically, it is worth a read. NIMH has not had a final appropriation from the government for this fiscal year (which started in Oct. 2010). And they are expecting cuts for fiscal year 2012.

Following is a post by Tom Insel, director of the NIMH:

C. S. Lewis once said that the “task of a modern educator is not to cut down jungles but to irrigate deserts.” The same might be said of an NIH institute today. But our ability to irrigate deserts may be compromised as we appear to be facing an austere funding future. As the Nation struggles to regain its economic footing, the final budgets for NIH in 2011 and 2012 remain uncertain. But there is little doubt that these will be tough years for NIMH funding.

Here is a quick synopsis. Following the doubling of the NIH budget from 1998-2003, NIMH has received budgets with sub-inflationary increases each year. By 2009, we had lost about 18 percent of our purchasing power relative to 2003, but through strategic cuts in awards, reductions in the out-years of multi-year grants, and elimination of programs, NIMH was able to maintain relatively stable funding throughout this period. By stable funding, I mean that we continued to support roughly 550 new research grants (R01 and R21-type grants) each year, representing at least 15 percent of proposals.

In 2009 and 2010, the American Recovery and Reinvestment Act (ARRA) brought a surge in funding to create jobs. With over $370M, NIMH was able to support several innovative projects, create or retain jobs, and fund some additional R01-type grants (for 2 years) on top of our regular appropriated budget. But this one-time surge from ARRA obscured the longer-term pattern of flat budgets that continued in 2009 and 2010 beneath the ARRA bubble. In 2010, the NIMH budget was 2.6 percent higher than 2009, still losing ground to inflation.

What about 2011? Although our budget year began October 1, 2010, we are still awaiting a final appropriation. Last week, Congress passed a continuing resolution until March 18, which means we will continue to operate under our 2010 budget rather than the President’s 2011 budget proposed last February. Prior to March 18th, Congress must vote either to extend the continuing resolution or to appropriate a budget for the remainder of the year. Both houses of Congress are concerned about the growing deficit and are committed to reining in spending, especially within the 12 percent of the budget labeled as “discretionary.” This will almost certainly mean a reduction in the NIH and NIMH budgets, but we do not know the extent of this reduction. The House voted for a $1.6B reduction below the 2010 NIH budget for 2011, including a 4.1 percent reduction (-$60M from 2010) for NIMH, but this budget still needs to be considered by the Senate.

In the absence of a final budget for this year and with expectations that we will likely see reductions in 2012, NIMH has been cautious about funding grants. We have a few principles that have guided us: prioritize research relevant to our strategic plan, support innovation, maximize the number of R01 grants, and protect early stage scientists. In support of these principles, we have reduced our intramural program, funded fewer centers, and reduced support of some large programs.

But even with these changes, the 2010 budget leaves us short in 2011. Partly because of the number of continuing grants and partly because of the increasing average cost of new awards, if we receive the full 2010 budget for 2011, we are projecting 481 new grants, representing roughly 10 percent of proposals. This would be the first time since 1999 that we would fund fewer than 500 new grants and would mark the lowest success rate in over 15 years. If the 2011 appropriation is 4.1 percent less than the 2010 budget, the actual number of new grants funded will likely be below 400.

Not surprisingly, this situation is creating anxiety in the scientific community. Basic scientists believe that the money has been shifted to translation. Clinical researchers say that funds are only going to basic science. But in fact, the Division of Neuroscience and Basic Behavioral Science, which was 27 percent of the total NIMH budget in 2005, was 29 percent in 2010 and will likely be close to this portion again in 2011.

Some have suggested that the funds are going to Centers or the intramural program instead of investigator-initiated R01 grants. But the percentage of R01s has only increased over the past decade.

A few scientists have suggested that the problem is a recent change in the review policy, allowing only a single re-submission. While this policy must seem catastrophic for someone who just missed the payline with a re-submitted grant, re-instating the “A2” would only delay funding for those within the payline. It may not increase the number of grants funded or the success rate.

For scientists, this may feel like a funding desert. During this relative drought, there may be many reasons for complaints. But the bottom line is that funds for new grants are the lowest we have seen in several years and the average costs of new grants is higher than ever ($419K in 2010 vs $313K in 2005). NIMH is committed to funding the highest impact science with the available funds. But as much as we would like to “irrigate the desert,” some outstanding science will, unfortunately, not get funded. And those projects selected for funding may receive less than optimal support.

What makes this desert especially difficult is that the scientific opportunities have never been better. We have unprecedented traction in the science necessary to make progress for helping people with mental illness. However, in this period of austerity, we will not at this time be able to fund some of the science that will make a difference for those in greatest need.

Release of the 2011 IACC Strategic Plan for Autism Spectrum Disorder Research

28 Feb

The IACC has released the 2011 Strategic Plan. I have quoted the announcement below, which includes the links:

The Interagency Autism Coordinating Committee (IACC) and the Office of Autism Research Coordination (OARC) are pleased to announce the release of the 2011 IACC Strategic Plan for Autism Spectrum Disorder Research. The updated Strategic Plan contains 16 new research objectives covering a variety of issues, including use and accessibility of interventions for non-verbal people with ASD, health promotion for people with ASD, and issues related to safety for people on the spectrum. The HTML version of this year’s Strategic Plan is fully hyperlinked throughout to websites with information about funders, programs and over 180 ASD-related publications, which should make the Plan an especially useful resource for people with ASD, families, providers, research funders, researchers, policymakers, and the public. A formatted, downloadable PDF version of the Plan is also available. Links to the new Strategic Plan and related information, including a news update about the Plan, can be accessed from the IACC Home Page.

Increase in NIH autism projects over the past decade

18 Jan

We hear repeatedly how research interest in autism has climbed in the past decade. I was looking through the NIH database of autism research projects and I decided to check on the number of projects that the NIH has funded by year.

Here are those data: research projects by fiscal year. In the past 10 years, the number of projects funded per year has increased by about 3x or 4x.

Quantity isn’t the same thing as quality by a long shot. But I do find this very encouraging.

Stakeholder meeting October 29: Study of Health Outcomes in Children with ASD and Their Families

26 Oct

The United States National Institute of Mental Health has called a meeting to discuss a study on health outcomes on children with ASD and their families. The meeting will also be a chance for community input.

I don’t see an easy way to provide input in advance of the meeting.

There are many topics I can think of for input, but a big piece of information would be to question why this is limited to children with ASD?

Meeting Announcement

Study of Health Outcomes in Children with ASD and Their Families – Stakeholders’ Meeting

October 29, 2010
NIH Neuroscience Center
6001 Executive Blvd.
Conference Room C
Rockville, MD 20852

Sponsored by:

National Institute of Mental Health (NIMH)

NIMH recently awarded a two-year contract to The Lewin Group to conduct a study of health outcomes in children with autism spectrum disorders (ASD) and their families. The objective of this study is to advance our understanding of ASD, including variables related to diagnosis, health conditions, and health care outcomes, using existing administrative data.

NIMH will host an informational stakeholders’ meeting, inviting participation from individuals with ASD, parents of children with ASD, community care providers, ASD researchers, and patient advocates. The Health Outcomes research team will provide an overview of the goals, objectives, and methods of the study. The meeting is also a venue for input from the community about the particular health issues that are of the greatest concern, as well as ASD-specific challenges or complications related to health care service provision and utilization

The meeting will be open to the public, and will be held on October 29, 2010, 2:00pm to 4:00pm EDT at the NIH Neuroscience Center. Participation by webinar is also possible. To register for in-person attendance at the meeting, or for webinar participation, please go to: .

It seems likely that this study will address questions such as whether there is a higher incidence of gastrointestinal problems in autistics, and how GI issues evolve with time in those kids who have it. I would expect attention on questions such as whether autistic kids are more prone to infections and/or get more antibiotics, how medicated these kids are, the incidence of epilepsy, the incidence of apraxia, and how these conditions progress with time.

I hope a good method is made for input for this meeting, other than attendance.

GFCF of no benefit

19 May

This post is from Eureka Alert

A popular belief that specific dietary changes can improve the symptoms of children with autism was not supported by a tightly controlled University of Rochester study, which found that eliminating gluten and casein from the diets of children with autism had no impact on their behavior, sleep or bowel patterns.

The study is the most controlled diet research in autism to date. The researchers took on the difficult yet crucial task of ensuring participants received needed nutrients, as children on gluten-free, casein-free diets may eat inadequate amounts of vitamin D, calcium, iron and high quality protein. Unlike previous studies, they also controlled for other interventions, such as what type of behavioral treatments children received, to ensure all observed changes were due to dietary alterations. Past studies did not control for such factors. And although no improvements were demonstrated, the researchers acknowledged that some subgroups of children, particularly those with significant gastrointestinal (GI) symptoms, might receive some benefit from dietary changes.

“It would have been wonderful for children with autism and their families if we found that the GFCF diet could really help, but this small study didn’t show significant benefits,” said Susan Hyman, M.D., associate professor of Pediatrics at Golisano Children’s Hospital at the University of Rochester Medical Center (URMC) and principal investigator of the study which will be presented Saturday (May 22) at the International Meeting for Autism Research in Philadelphia. “However, the study didn’t include children with significant gastrointestinal disease. It’s possible those children and other specific groups might see a benefit.”

In response to widespread parent-reported benefits, URMC initiated the trial in 2003 to scientifically evaluate the effects of the gluten-free and casein-free diet, which eliminates wheat, rye, barley and milk proteins. Parent observation has played an important role in earlier treatment discoveries in children with autism, such as melatonin’s benefits for sleep.

Hyman’s study enrolled 22 children between 2 ½- and 5 ½-years-old. Fourteen children completed the intervention, which was planned for 18 weeks for each family. The families had to strictly adhere to a gluten-free and casein-free diet and participate in early intensive behavioral intervention throughout the study. Children were screened for iron and vitamin D deficiency, milk and wheat allergies and celiac disease. One child was excluded because of a positive test for celiac disease and one was excluded for iron deficiency. Other volunteers who were excluded were unable to adhere to the study requirements. The children’s diets were carefully monitored throughout the study to make sure they were getting enough vitamin D, iron, calcium, protein and other nutrients.

After at least four weeks on the strict diet, the children were challenged with either gluten, casein, both or placebo in randomized order. They were given a snack once weekly with either 20 grams of wheat flour, 23 grams of non fat dried milk, both, or neither until every child received each snack three times. The type of snack was given in randomized order and presented so that no one observing – including the family, child, research staff and therapy team – knew what it contained. The snacks were carefully engineered to look, taste and feel the same, which was an exercise in innovative cooking. In addition, the nutrition staff worked closely with the families to make a snack that met their child’s preferences. Casein was disguised in pudding, yogurt or smoothies and gluten in banana bread, brownies, or cookies depending on the child’s food preferences.

Parents, teachers and a research assistant filled out standardized surveys about the child’s behavior the day before they received the snack, at two and 24 hours after the snack. (If the child’s behavior wasn’t usual at the scheduled snack time, the snack would be postponed until the child was back to baseline.) In addition, the parents kept a standard diary of food intake, sleep and bowel habits. Social interaction and language were evaluated through videotaped scoring of a standardized play session with a research assistant.

Following the gluten and casein snacks, study participants had no change in attention, activity, sleep or frequency or quality of bowel habits. Children demonstrated a small increase in social language and interest in interaction after the challenges with gluten or casein on the Ritvo Freeman Real Life Rating Scale; however, it did not reach statistical significance. That means because of the small difference and the small number of participants in the study, the finding may be due to chance alone.

The investigators note that this study was not designed to look at more restrictive diets or the effect of nutritional supplements on behavior. This study was designed to look at the effects of the removal of gluten and casein from the diet of children with autism (without celiac disease) and subsequent effect of challenges with these substances in a group of children getting early intensive behavioral intervention.

Hyman said, “This is really just the tip of the iceberg. There are many possible effects of diet including over- and under-nutrition, on behavior in children with ASD that need to be scientifically investigated so families can make informed decisions about the therapies they choose for their children.”

Dr. Tom Insel on Demystifying Autism

12 May

Dr. Tom Insel wears many hats, as they say. He is the director of the National Institute of Mental Health (NIMH), one of the National Institutes of Health run by the US Government. As part of his function there, he chairs the Interagency Autism Coordinating Committee (IACC). The IACC prepares the “Strategic Plan” for the government’s activities in autism research.

Dr. Insel has obviously taken autism research very seriously. He doesn’t just chair the IACC, he obviously spends a lot of time reviewing autism research. I doubt many people at the Director level at NIH would spend the amount of time Dr. Insel obviously spends on autism.

He has recently given a few talks on autism, the current state of knowledge and the directions for research. One such talk was at NIH and was titled Demystifying Autism . Another talk was given at MIT and was hosted by the Simons Foundation. (sorry, I can’t find embed code for those talks)

Dr. Insel talks about how there is a large diversity in the autism population. The “spectrum” is broad, as likely most readers to this blog will already know. In both talks, Dr. Insel uses video from Dov Shestak (son of Portia Iverson and Jon Shestak, founders of Cure Autism Now, which is now part of Autism Speaks). This is used to give an example of regression in autistics.

Of course one large section is devoted to the increasing autism prevalence. Dr. Insel mentions the epidemiological work of Peter Bearman, which shows that much of the increase in the California Department of Developmental Services autism caseload can be accounted for by diagnostic changes and social factors. But, not all of the increase has been accounted for. Dr. Insel uses the term that the burden of proof is on those who would say that the increase is not “real”. I would put it differently–that given the lack of definitive information on the causes of the rise, we should continue to look for possible environmental causes. Many use the term “environmental cause” to mean “vaccines”. That’s not what I, or it appears, Dr. Insel mean though.

Dr. Insel discusses one yet-unpublished study: the California Twin Study.

Here is his power point slide (which you can click to enlarge if you wish):

Slide showing results of yet unpublished twin study

Dr. Insel's slide on Twin Study


Narrow criteria:
monozygotic (“identical”)–80% concordance
dizygotic (“fraternal”)– 26% concordance
broad criteria
monozygotic–87% concordance
dizygotic– 39% concordance

This is consistent with a recent study from the Kennedy Kreiger Institute at Johns Hopkins. While this wasn’t discussed by Dr. Insel, I include the abstract for that study below:

OBJECTIVES: To examine patterns of autism spectrum disorder (ASD) inheritance and other features in twin pairs by zygosity, sex, and specific ASD diagnosis. DESIGN: Cross-sectional study. SETTING: Internet-based autism registry for US residents. PARTICIPANTS: Survey results from 277 twin pairs (210 dizygotic [DZ] and 67 monozygotic [MZ]) aged 18 years or younger with at least 1 affected twin. MAIN EXPOSURES: Zygosity and sex. OUTCOME MEASURES: Concordance within twin pairs of diagnosis, natural history, and results from standardized autism screening. RESULTS: Pairwise ASD concordance was 31% for DZ and 88% for MZ twins. Female and male MZ twins were 100% and 86% concordant, respectively, and DZ twin pairs with at least 1 female were less likely to be concordant (20%) than were male-male DZ twin pairs (40%). The hazard ratio for ASD diagnosis of the second twin after a first-twin diagnosis was 7.48 for MZ vs DZ twins (95% confidence interval, 3.8-14.7). Affected DZ individual twins had an earlier age at first parental concern and more frequent diagnoses of intellectual disability than did MZ twins; MZ twins had a higher prevalence of bipolar disorder and Asperger syndrome and higher concordance of the latter. Results of autism screening correlated with parent-reported ASD status in more than 90% of cases. CONCLUSIONS: Our data support greater ASD concordance in MZ vs DZ twins. Overall higher functioning, psychiatric comorbidity, and Asperger syndrome concordance among affected MZ vs DZ twins may also suggest differential heritability for different ASDs. For families in which one MZ twin is diagnosed with ASD, the second twin is unlikely to receive an ASD diagnosis after 12 months. In addition, Internet parent report of ASD status is valid.

Concordance is when one child has an ASD, does the other one? 100% concordance would mean that if one twin has an ASD, the other twin does as well. That would indicate that autism is purely genetic.

Most people will concentrate on the monozygotic concordance. Even with the broad criteria, there is 87% concordance. That would indicate that at least some fraction of the cause of autism is not genetic. This is a very complicated question, as Joseph at the Autism Natural Variation blog has discussed.

What is astounding to me is the dyzogotic concordance. Take the 39% for the broad criteria. My recollection is that the concordance for siblings is about 4% if one sibling is male, and about 10% if one sibling is female. I’m trying to find the study on this. But, is there a higher concordance for dizygotic twins than for siblings in general?

Dr. Insel spends a fair amount of time on the genetic studies involved in autism. He attributes about 15% of the current autistic population as being linked to known genetic conditions. This is a pretty common estimate in the community.

One interesting fact: the known genes associated with autism are neurodevelopmental and involved with synapses. He even titles the slide as “Autism as a synaptic disease” and proposes that synaptic function might be the unifying feature of autism.

Dr. Insel notes that there are many chemicals whose neurotoxicity have not been determined. He also notes that there are some known chemicals which increase the risk of autism–valproic acid, Thalidomide and misoprostal. For all of these there is a critical window of time–in the first or early second trimester of pregnancy–where the autism risk is increased. Thalidomide, for example, is considered to be causal in a short period of time–from 20 to 24 days gestation.

If you want to see the direction Dr. Insel may take autism research in the future, these talks are worth listening to. I think it safe to say that autism research will continue to look for causes, genetic and environmental. Environmental cause research will likely focus on prenatal exposures. Study will continue on the physical structure of the brain, the “circuitry” to help define what autism is and what the phenotypes may be. Study will continue on interventions, with a look towards earlier interventions (before age 1, possibly before symptoms are visible). Intervention research will look to be tailored to the individual, which will require some way to phenotype autism.

As I noted above, I think Dr. Insel is taking a close interest in autism. He doesn’t dictate the goals for autism research, but I think listening to what he has to say gives in interesting insight into the directions it may be going.

Kathleen Sebelius and Francis Collins to speak at next IACC meeting

21 Apr

The Interagency Autism Coordinating Committee (IACC) will hold its next meeting on Friday, April 30. I checked the agenda for this meeting and found that Kathleen Sebelius, Secretary of Health and Human Services, and Francis Collins, Director of the NIH will be speaking.

The meeting will be videocast and available via telephone.

Here is the agenda for the next IACC meeting:

IACC Full Committee Meeting Agenda

Friday, April 30, 2010
9:00 a.m. – 5:00 p.m. Eastern

The Ronald Reagan Building and International Trade Center
Rotunda Room
1300 Pennsylvania Avenue, N.W.
Washington, DC 20004

Time Event
9:00 a.m. Registration

10:00 Call to Order and Opening Remarks

Thomas Insel, M.D.
Director, National Institute of Mental Health and Chair, IACC
10:05 Kathleen Sebelius
Secretary, Department of Health and Human Services

10:20 Welcome and Introductions of IACC Members

10:55 Francis Collins, M.D., Ph.D.
Director, National Institutes of Health

11:10 Break

11:25 Research Update: Autism Treatment Network
Geraldine Dawson, M.D.
Chief Science Officer, Autism Speaks

11:50 Research Update: Autism in the DSM-V
Susan E. Swedo, M.D.
Senior Investigator, Behavioral Pediatrics Section
Pediatrics and Developmental Neurospsychiatry Branch, NIMH

12:15 Lunch

1:30 Public Comments

2:00 Research Update: Stem Cell Talk

James Battey, M.D.
Director, National Institute on Deafness and Other Communication Disorders

2:25 Research Update: NIH Nonverbal ASD Workshop
Helen Tager-Flusberg, Ph.D.
Director, Laboratory of Developmental Cognitive Neuroscience, Boston University

Ann Wagner, Ph.D.
Chief, Neurobehavioral Mechanisms and Mental Disorders Branch, NIMH

2:50 Research Update: Building the Infrastructure for Comparative Effectiveness Research on Disability Issues
Rosaly Correa-de-Araujo, M.D., MSc, Ph.D.
Deputy Director, Office on Disability, Office of the Secretary

3:15 Approval of January 19, 2010 IACC Committee Minutes

3:20 Update: Planning Subcommittee
Thomas Insel, M.D.
Director, National Institute of Mental Health and Chair, IACC

3:50 Break

4:00 OARC Update

* 2009 Summary of Advances
* IMFAR Update

4:20 Public Comments Discussion Period
4:50 Closing Comments
5:00 Adjournment

IACC conference call on the Strategic Plan

8 Apr

I just received this announcement from the IACC:

A Conference Call and Webinar of the Interagency Autism Coordinating Committee (IACC) Subcommittee for Planning the Annual Strategic Plan Updating Process

Please join us for a conference call and webinar of the IACC Subcommittee for Planning the Annual Strategic Plan Updating Process that will take place on Monday, April 19, 2009 from 10:00 a.m. to 12:00 p.m. ET.

No registration is required

Conference Call Access
USA/Canada Phone Number: 888-577-8995
Access code: 1991506

Webinar Access

The agenda for this conference call is to discuss plans for updating the 2010 IACC Strategic Plan for Autism Spectrum Disorder Research.

Please visit the IACC Events page for the latest information about the conference call, including access information, as well as all other IACC events.

For more information about the IACC, please visit

Now follow the IACC on Twitter (

The Contact Person for this conference call is:
Ms. Lina Perez
Office of Autism Research Coordination
National Institute of Mental Health, NIH
6001 Executive Boulevard, NSC
Room 8185a
Rockville, MD 20852
Phone: 301-443-6040
Please Note: This conference call may end before 12:00 PM if the discussion is completed ahead of schedule.

Clinical trial on Clinical and Immunological Investigations of Subtypes of Autism

24 Mar

The National Institutes of Health (NIH) have recently updated their webpage of featured clinical trials for autism. Many of the clinical trial recently discussed here at LeftBrainRightBrain are on that list. One that is on the featured list that I caught my eye is Clinical and Immunological Investigations of Subtypes of Autism. It is an old trial (started in 2006), but I thought it worth bringing up again.

The description is quoted below:

The purpose of this study is to learn more about autism and its subtypes. Autism is a developmental disorder in which children have problems with communication and social skills and display restricted interests and repetitive behaviors.

This study has several goals. One aim is to look at types of autism that are known, such as the regressive subtype, (where skills are lost). We will explore whether there is a unique change in immune functioning related to this subtype. Another aim is to serve as one of the sites that will pilot a larger natural history study, entitled Autism Phenome Project. The goal is to further understand autism by identifying other subtypes.

We will look at several types of medical issues that may be related to autism, including immunologic problems. Children will be followed over the course of several years. We aim to capture medical problems that may be related to autism as they develop, and study outcomes in areas such as behavior and language, in order to explore known and new subtypes of autism.

Normally developing children (aged 1) with autism (age 1, and developmental delays other than autism (age 1), may be eligible for this study.

Depending on each child’s study group and age, participants may undergo the following tests and procedures:

Baseline Visit

* Medical and developmental history, physical examination, psychological, cognitive and medical tests to assess symptoms of autism or other developmental disorders, photographs of the child’s face, collection of hair, urine and baby teeth samples. If available, hair samples from the baby’s first haircut and from the biological mother’s hair are also collected.
* Overnight electroencephalogram (EEG): A special cap with electrodes is placed on the child’s head to measure brain waves (brain electrical activity) while the child sleeps in the hospital overnight. Healthy volunteers do not undergo this procedure.
* Magnetic resonance imaging (MRI) scan: The child stays in the scanner, lying still for 10 to 15 minutes at a time. Since it may be difficult for the child to lie still, the test may be scheduled for a time when the child is likely to be sleepy, or the child may be sedated.
* Lumbar puncture (for children in the autism). This test and the MRI may be done under sedation.

Follow-Up Visits

Follow-up visits are scheduled at different intervals, depending on study group, age and aspect of the study the child is enrolled in. The visits include a short interview session with the child’s caregiver and assessment of the child’s development and behavior. Some of the assessment measures used during the baseline examination are repeated, including symptoms ratings, behavioral tests and a blood test. For some children, the final visit will include repeats of the medical procedures.

The section that jumps out to my eye: We will explore whether there is a unique change in immune functioning related to this subtype. Another aim is to serve as one of the sites that will pilot a larger natural history study, entitled Autism Phenome Project. The goal is to further understand autism by identifying other subtypes.

Yes, the NIH is looking at whether regression and immune functioning might be linked. As noted above, this study has been ongoing for some time: the trial was first listed in 2006. But, hey, I figure if I forgot about this one and found it interesting, others might be interested in this as well.

Clinical trial of Donepezil for improving REM sleep in autistic children

23 Mar

A recent lecture I heard discussed how as many as 25% of autistic children get little or no REM (rapid eye movement) sleep. REM sleep is an important sleep phase and it is thought this could contribute to cognition and behavior problems in these children.

Anecdotally (and probably confirmed by studies is my guess) many autistic children have sleep problems. Children are reported to sleep fewer hours, have problems getting to sleep and wake up in the middle of the night. This new result, to me at least, is the first I’ve heard of reduction or lack in REM sleep.

In response to this finding, a clinical trial is underway to study the use of Donepezil (Aricept) with autistic children.

The clinical trial description is:

Detailed Description:

Autism spectrum disorders are defined by aberrant development of communication and socialization in the presence of restrictive and/or repetitive behaviors. Recent epidemiologic studies have documented an increase in the number of children identified with autism spectrum disorder over the past decade and according to some, the current numbers indicate a prevalence of 1 per 150 (CDC, MMWR 2007, Feb 9th release). Despite the pressing need to identify causal factors, etiology remains elusive. Furthermore, the heterogeneity of presentation complicates attempts to locate autism’s home in the brain.

Polysomnography is a reliable non-invasive tool that can be used to study the basic pathophysiological mechanisms of autism and other developmental and neuropsychiatric disabilities. Our preliminary data in young children with autism supports a growing body of literature demonstrating that sleep architecture is abnormal in this disorder. Previous studies in children with autism have identified various abnormalities in REM sleep including the following: immature organization, decreased quantity, abnormal twitches, undifferentiated sleep and REM sleep behavior disorder characterized by the absence of the muscle atonia that is normal in REM sleep and resulting in an acting out of dreams phenomenon (Tanguay et al ,.1976, Elia et al., 2000, Diomedi et al. 1999, and Thirumalai et al., 2002).

Our cohort spent an abnormally short time in the REM sleep stage of sleep compared to total sleep time (hereafter referred to as SPT REM% for REM sleep as a percent of sleep period time), and had a prolonged latency to REM sleep. The function of REM sleep and its relationship to cognition and overall neurological health is unknown and a subject of ongoing research. We know from animal studies that REM sleep increases after intensive learning sessions. These laboratory findings formed the basis for the hypothesis that this sleep stage is important for cognitive processes and that REM sleep may be useful as an indicator of brain plasticity. Current studies continue to add support for this idea. REM sleep has most recently been implicated in the process of human memory consolidation and several studies suggest that it is crucial to normal cognitive function and in the processing of emotion in memory systems. Acetylcholine (Ach) is one of the major neurotransmitters necessary for normal sleep transitions and abnormalities in Ach have been implicated in REM deficient sleep in other populations, most notably Alzheimer’s disease.

This proposal is for a 6 to 20 week, single arm, open-label study to evaluate the ability of donepezil hydrochloride to enhance REM sleep in children with autism spectrum disorder found to have a low SPT REM% (defined as below 2 standard deviations of observed normative data for age). All patients will come through the screening protocol 06-M-0065. Those who meet a research diagnosis of autism spectrum disorder and are ages 2 to 11 (through the tenth year) will be evaluated for inclusion/exclusion criteria for the study.

The primary outcome measure of this protocol is to increase the SPT REM% in children with autism such that their REM/non-REM ratios begin to approach normative values. Donepezil enhanced REM sleep has been achieved in young healthy adults, in elderly, healthy adults and in elderly, demented adults with Alzeheimer’s disease. Furthermore, the studies in Alzheimer disease by Mizuno et al showed a positive correlation between improved cognition and increased SPT REM %. If REM sleep is necessary for normal cognition, and its deficiency or absence can be remedied by pharmacologic intervention, then it may follow that improvement of REM sleep correlates with improved short and long term cognition in children with autism. Donepezil enhanced REM sleep has not been documented in children. Polysomnography provides a non-invasive tool to assess the effects of enhancing cholinergic tone on the abnormal sleep architecture we have documented in our pediatric, autistic population.

My guess is that some are thinking, “why look at this drug when many already use melatonin to help autistic children sleep”. After all, Aricept is an Alzheimer’s drug, with little study in children.

OK, I admit I did. So I did a quick search and found that melatonin has not been found to increase REM sleep.

Aside from my reservations about giving an Alzheimer’s drug to 2 year olds, this is the type of clinical trial I like to see. A clear question is presented that is supported by data. A clear outcome (increased REM sleep) is measurable. Secondary outcomes, improved cognition and behavior, are also measurable and defined.


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