Autism and MRI Physical Biomarkers

Minor physical anomalies (MPAs) commonly occur in those with autism.  I have previously published a post on a study outlining the type and prevalence of these anomalies in a series of case of autism and austim spectrum disorder.

One of the MPAs noted in the 1970s in autism spectrum disorder is an increased intraorbital distance (distance between the eyes).   This abnormality also noted as hypertelorism has been noted in a variety of brain developmental abnormalities as well as in some normal individuals.

The brain developmental correlates of hypertelorism have not been studied extensively.  It is possible that developmental hypertelorism may reflect brain developmental variations linked to clinical disorders.

Cheung et al and colleagues from the University of Hong Kong and Harvard School of Dental Medicine recently published a brain MRI study of intraorbital distance in autism spectrum disorder in PloS One.  This study examined the correlation of intraorbital distance with a variety of brain structural measurements.

Thirty six children between the ages of 7 and 16 years with autism spectrum disorder were compared to a group of 55 developmentally normal children matched by age and gender.  The two groups were in the normal intelligence range with the verbal IQ of the autism spectrum group 112 compared to a verbal IQ of 117 in the control group.

Magnetic resonance imaging scans were used to accurately measure the intraorbital distance.  This measurement was then compared with brain structure volumes.

Intraorbital distance correlated with several brain regions volumes in the autism spectrum group but not in the control group.  The areas with increased volume correlating with intraorbital distance in the autism spectrum group included:

• Bilateral amygdala
• Bilateral medial temporal lobe regions
• Left inferior frontal cortex lobes

Amygdala developmental abnormalities have previously been noted in studies of autism.  The medial lobe appears to be important in social and language skills developments.

The authors note the possible relationship between intraorbital distance and brain development in this statement from the manuscript discussion section: 

     "The inference is that in this group, the growth of midline bony and brain regions are tightly linked; that is, regions involved in the regulation of socialization, emotion and memory appear to enlarge with the visual system".

These finding suggest that MRI intraorbital distance may be a potential biomarker for autism spectrum disorders.   Additional longitudinal studies of intraorbital distance and brain development in children may provide additional support for the findings in this cross-sectional studies.

Image of intraorbital distance measurement in autism from Cheung et al distributed under the terms of Creative Commons Attributions License which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 

Cheung C, McAlonan GM, Fung YY, Fung G, Yu KK, Tai KS, Sham PC, & Chua SE (2011). MRI study of minor physical anomaly in childhood autism implicates aberrant neurodevelopment in infancy. PloS one, 6 (6) PMID: 21687660

Why Antidepressants Can Cause Gut Pain

Selective serotonin reuptake inhibitors frequently produce significant gastrointestinal side effects.  Nausea was reported by up to 26% of subjects and diarrhea in up to 30% of subjects in a recent review of the new antidepressant vilazodone.  Gastrointestinal side effects tend to be seen with the initiation of antidepressant drugs commonly followed by a period of improved tolerability.

The mechanism for this gastrointestinal effect is poorly understood.   The gut is known to have serotonin receptors.  Some gastrointestinal therapeutic agents target the serotonin receptor as their mechanism of action.  For example, the antinausea drug ondansetron appears to act through it's antagonism of the 5HT (serotonin) 3 receptor.  This results in inhibition of gastric activity while components of activity of the small intestine remain functional.

To better understand the effects of serotonin on GI motility, Janssen and colleagues from the University of Leuven conducted a novel experiment.  Twenty healthy subjects were studied in a GI motility study following administration of placebo and the selective serotonin reuptake inhibitor citalopram.

The authors found that administration of citalopram significant reduced the gastrointestinal transit time compared to that found at baseline and placebo (see chart).

Upper gastrointestinal transit time is composed of three separate phases known as the migrating motor complex of MMC.  Citalopram appeared to reduce the duration of phase 1 and phase 2 while the time spent in phase 3 was unchanged.

The authors attribute the change in transit time to a direct effect of citalopram on GI serotonin receptors although a central CNS effect could not be ruled out.  The speculate this effect may be potentially therapeutic in individuals with constipation predominant irritable bowel syndrome.

This study did not directly address the issue of GI side effects associated with the SSRI antidepressants.  Nevertheless, it suggests acute increased GI transit times with SSRIs may be a mechanism that contributes to GI side effects of nausea, diarrhea, cramping and pain.

Further studies of this effect are needed looking at a longer time frame.  Since most GI side effects improve with prolonged administration, it is possible a receptor compensation mechanism may be involved in changes in side effects over time.

Graph of gastrointestinal transit times is an original graph produced by the author from data in the manuscript.

Janssen P, Vos R, & Tack J (2010). The influence of citalopram on interdigestive gastrointestinal motility in man. Alimentary pharmacology & therapeutics, 32 (2), 289-95 PMID: 20456311

New Exercise Guidelines Add Neuromotor Domain

Article first published as New Exercise Guidelines Are Here on Technorati.

The American College of Sports Medicine (ACSM) recently published an update on their recommendations for exercise.  These guidelines follow an extensive review of the research literature and update guidelines that were previously published in 1998.

The guidelines note four specific areas of exercise: cardiorespiratory fitness and reduction in risk of cardiovascular and metabolic disease, maintenance of muscular fitness, flexibility and neuromotor fitness.

The guidelines provide a very extensive review of exercise research.  I will summarize the key recommendations by area of exercise:

Cardiovascular fitness and reduction in risk of cardiovascular and metabolic risk factors:

• Moderate intensity aerobic exercise for 30 minutes per day on five or more days per week or
• Vigorous intensity aerobic exercise for 20 minutes per on three or more days per week or
• A combination of moderate and vigorous aerobic exercise resulting in a total energy expenditure of 500 to 1000 MET minutes per week

The MET (metabolic equivalent of task) minutes per week is a method of quantifying exercise.   By definition, the amount of energy needed at rest is one MET.  Moderate intensity is assigned activities such as walking that can be rated in the 3 to 6 MET range.  Vigorous exercise (such as jogging or running) is rated at MET levels about 6.  A person walking at a 4 MET level for 200 minutes per week would expend 1000 MET minutes in a week meeting the exercise guidelines

Muscular fitness
Resistance training for each of the major muscle groups two or three times per week

Flexibility
Complete a series of flexibility exercises two or more days per week (60 seconds per each of the major muscle and tendon groups

Neuromotor Exercise
Exercise focusing on balance, agility and coordination for 20 minutes on two or more days per week

The benefits and recommendations have been expanded in this version of the ACSM guidelines.  The authors note the growing literature supporting the benefits of exercise such as tai chi and yoga in promoting balance and flexibility.  Balance and flexibility become increasingly important to counteract the effects of aging.  There is more research support for these types of exercise programs to reduce risk of falls and fall-related medical complications in older individuals.

The ACSM notes the limited compliance with exercise guideline compliance in the general population.  Although walking is ranked as the more frequency physical activity in adults, less than 10% of walkers meet the weekly guideline threshold for duration and intensity.

The ACSM makes some recommendations to increase compliance with the guidelines:

• Patients and their physicians should work together to develop and monitor customized programs
• Use behavioral strategies of "goal setting, social support, reinforcement, problem solving and relapse prevention
• Further research targeting factors promoting maintenance of exercise compliance over extended periods

The ACSM has provided a valuable to put together a comprehensive exercise program with benefits in many areas.  Now it's time for more individuals to adopt a healthy lifestyle that includes meeting these recommended guidelines.

Photo of women getting exercise by walking from the author's private collection.

Garber, C., Blissmer, B., Deschenes, M., Franklin, B., Lamonte, M., Lee, I., Nieman, D., & Swain, D. (2011). Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory, Musculoskeletal, and Neuromotor Fitness in Apparently Healthy Adults Medicine & Science in Sports & Exercise, 43 (7), 1334-1359 DOI: 10.1249/MSS.0b013e318213fefb

Cannabis Use Declines with Aerobic Exercise

Improvement in addiction treatment interventions in needed.  Many substance dependence individuals end up with with a chronic illness with frequent relapse following periods of abstinence.

Aerobic exercise appears to be a candidate for a treatment component in a variety of addictive disorders.  Aerobic exercise may produce a variety of changes in the brain that may influence craving and drug use.

Mechanisms induced by aerobic exercise that might influence drug craving and drug use include:

• Alteration in the brain reward circuit
• Increased release of brain dopamine and changes in dopamine receptor sensitivity
• Decrease in anxiety and depressive symptoms 

Maciej Bukowski and colleagues at Vanderbilt University recently published a trial of cannabis craving and use in a series of subjects.  Regular cannabis user were enrolled in a ten session intervention that included ten 30 minute supervised treadmill periods.  Subjects exercised at 60% of their calculated maximum heart rate. 

All subjects met DSM-IV criteria for cannabis dependence.  Subjects were not involved in any formal substance abuse treatment program and did not express a desire to reduce or discontinue their cannabis use.  Subjects were using an average of 33.5 standard joint equivalents of cannabis at the beginning of the study.  The average daily cannabis use of the subjects is displayed in the plot below taken from the manuscript:

The plot demonstrates a significant reduction in daily cannabis use during the active aerobic exercise period. Daily joint use dropped from approximately six joints per day to an average of about two to three joints per day during the exercise period.  Following completion of the exercise phase, daily joint use climbed up again approaching the run-period levels.

This study was not done in a treatment-seeking sample.  It is unclear whether a similar effect would be seen in treatment seeking samples.  The study did not include a control sample.  Nevertheless, this study should stimulate research in treatment samples.  It suggests that regular aerobic exercise may be a valuable component of treatment for cannabis dependence.  Extended aerobic exercise may be valuable in the longer term reduction of cannabis use in those with cannabis dependence.

Chemical model of tetrahydrocannabinol (the psychoactive substance in cannabis) from the Creative Commons file at Wikipedia authored by Ben Mills.

Cannabis use Creative Commons Attribution License plot from Plos One manuscript authored by Maciej Bukowski and colleagues referenced below.

Buchowski MS, Meade NN, Charboneau E, Park S, Dietrich MS, Cowan RL, & Martin PR (2011). Aerobic exercise training reduces cannabis craving and use in non-treatment seeking cannabis-dependent adults. PloS one, 6 (3) PMID: 21408154

More Time In Bed Boosts Basketball Performance

Looking for that extra edge on the basketball court?  Want to increase your free throw percentage and gain an extra step in quickness?  Is it a new performance enhancing drug or training technique?  No, a new study suggests it may be as easy as spending a few extra hours in bed.

Cheri Mah and colleagues from Stanford University and the University of California, San Francisco recently published their research on sleep and athletic performance in the journal Sleep.  They introduce the study by noting that extensive research documents the adverse effect of limited sleep.  However, little research examines the effect of increased sleep on performance.  Their study objective was to do just that.

Members of the Stanford University mens basketball team were recruited for the study.  The study took place over two seasons and included a baseline period of usual sleep patterns.  Then the intervention group extended their sleep pattern with a goal of a minimum of 10 hours in bed daily.

Compliance with this intervention was measured through sleep journals and actigraphy.  Actigraphy is accomplished by a wrist device that is worn and measures movement.  From this data the total sleep time can be estimated.  Sleep journal data and activity data estimated the increase in total daily sleep time to be between 100 and 150 minutes of additional sleep during the intervention period.

Athletes in the intervention groups were tested on a variety of psychometric and basketball performance skills during the baseline and intervention period.  The results of the intervention were pretty impressive.  Here is a summary of the improvement noted in the study:

• Free throw percentage increased by 11%
• Three point percentage increased by 14%
• Sprint test time decreased by 4%

Other psychometric variables were improved including a reduction in time on the Psychomotor Vigilance Task, a reduction in the Epworth Sleepiness Scale score and improvement on multiple components of the Profile of Mood States including ratings of fatigue, depression and tension.

The authors note the study has some significant limitations in research design.  Only eleven athletes received the intervention.  Subjects were not blinded as to the intervention and it is possible a some of the improvement came from an expectancy effect.  Travel schedules made it difficult to assure compliance with the 10 hours in bed intervention for every day of the study.

However, this study does suggest that many athletes may be performing in the context of ongoing sleep deprivation.  Forcing compliance with an extended sleep duration holds promise of improving performance on the basketball court.  This effect appears to occur in the context of subjective improvement in psychological function.

If I were an NCAA basketball athlete, I would send a copy of this study to my coach and training staff.  Athletes now have some research to support the importance of getting plenty of sleep to achieve peak performance.

Photo of Los Angeles Clipper Player Blake Griffin Shooting Free Throw Courtesy of Tim Yates

Mah CD, Mah KE, Kezirian EJ, & Dement WC (2011). The Effects of Sleep Extension on the Athletic Performance of Collegiate Basketball Players. Sleep, 34 (7), 943-950 PMID: 21731144

Autism Spectrum: Why Boys Are At Higher Risk

It is no secret gender plays a key role in the risk for a variety of childhood developmental disorders. Discussion of this issue is often difficult as biases in how boys and girls are raised and evaluated can contribute to confusion. Nevertheless, research progresses in explaining why boys are more likely to develop autism spectrum condition (ASC) and other neurodevelopmental abnormalities.

Baron-Cohen and colleagues from the UK and US recently summarized some of the potential mechanisms for male predominance in autism spectrum. They note a significant male predominance in a group of childhood neurodevelopmental disorders in addition to ASC:

• ADHD
• Conduct disorder
• Developmental reading disorders (dyslexia)
• Specific language impairment
• Tourette Syndrome

They note rates for ASC in boys is 4:1 compared to girls and for full autism is estimated as high as 11:1.

The authors note that predominance of ASC and other neurodevelopmental disorders in boys may be an “extreme expression of the male brain”. This concept states that boys and girls brains begin to differ early in the uterus. These differences result in different strengths and weaknesses. ASC may be an example of the male brain development gone too far.

Females appear to have a stronger drive to empathize (identify and respond to the feelings of others) while the male brain appears to have a stronger drive to systemize (analyze and construct rule based systems). The ASC as extreme male brain theory would propose the ASC brain is just the prototypical male brain gone to far in masculinization.

Males typically have three surges of the male hormone or androgen testosterone. The first surge occurs between 2 and 6 months in the uterus. This surge if felt to be responsible for brain masculization. The second surge occurs in the first six months of life and the third and final surge occurs in adolescence around puberty. If ASC is an example of the extreme male brain, then the fetal testosterone surge might be expected to be higher in those with ASC.

Progress in this front has evolved by comparing fetal testosterone levels with a variety of cognitive, behavioral and and emotional traits. Among normal children the following relationships have be discovered:

Positive associations with fetal testosterone levels (high levels with higher evidence of trait)

• Autistic traits
• Restricted or reduced interests
• Tendency to systemize
• Rightward asymmetry of brain corpus callosum (isthmus)

Negative associations with fetal testosterone (high levels with lower evidence of trait)

• Amount of eye contact
• Quality of social relationships
• Vocabulary size
• Empathy

Studies in those with ASC also appear to support the extreme brain hypothesis. Ten genes related to sex steroid synthesis, transport or metabolism have been linked to ASC or empathy traits. Testosterone levels tend to be higher in males with ASC than those without. Research in progress is likely to provide additional information on the merit of the extreme male brain hypothesis

The authors note there are other theories that might be supported in future research on the gender ratio in ASC. Two of these theories stem from differences in the X and Y chromosome.

A better understanding of why boys are at higher risk of ASC and autism is important. Such understanding might provide insight into avenues for early diagnosis and treatment.

Molecular model of the chemical structure of testosterone from Wikipedia Creative Commons file by Ben Mills. 


Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, & Knickmeyer R (2011). Why are autism spectrum conditions more prevalent in males? PLoS biology, 9 (6) PMID: 21695109