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

Brain Posts Cracks Technorati Top Ten: Thanks!

I try to minimize self-promotion on this blog but today I'm going to do a little of that.  I started this blog nearly two years ago for personal motivation to stay current with research in the clinical neurosciences.  Blogging about recent research in clinical neuroscience kept me scanning PubMed abstracts directed to my Google Reader and kept me focused on succinctly summarizing work I felt was important.  Additionally, as I approach the end of my career, I felt a non-commercial blog might be a way give something back to my profession that has given so much to me.

Like many bloggers I follow my page views to see topics that might track more than typical interest.  I follow some of the blog ranking sites to gain perspective on Brain Posts.  This last week I was pleased to see that the Technorati algorithm ranked Brain Posts as the tenth ranked blog in the Family category and 40th in the Health category.  Technorati follows over 14,000 blogs in the Family category and over 15,000 blogs in the Health category.  I am very humbled and flattered by this recognition.

I don't understand the ranking algorithms (or their validity).  The numbers seem to jump around quickly and frequently.  But I do know that followers accessing the site and referencing the site play a key role in the rankings.  So this is really a post to thank those of you who have been visitors, commenters and post links to the site.

I plan to continue posting on clinical neuroscience research topics over the next year.  Additionally, I will be putting together some of the posts into electronic book formats.  This will involve selecting posts that might be of interest to specific reader groups.  Look for compilations of Brain Posts into eBooks formats under some of the following titles:

• Brain Science for Physicians
• Brain Science for Parents
• Brain Science for Teachers

Thanks again to all!

Vilazodone: A Novel Antidepressant

Vilazodone was approved by the Food and Drug Administration in the U.S. earlier this year, but is just now becoming available in pharmacies for prescription use.  The drug is marketed in the U.S. under the trade name Viibyd.  It is novel in that it the only antidepressant that combines two mechanisms that can increase serotonin in the brain cortex: selective serotonin reuptake inhibition and partial agonism of the 5HT1A receptor.  There are multiple selective serotonin reuptake inhibitors, i.e. fluoxetine (Prozac), sertraline (Zoloft), and escitalopram (Lexapro).  

There are also compounds that have an agonistic effect on the 5HT1A receptor.  These include:
Antidepressants: trazodone, nefazodone
Antianxiety drugs: buspirone
Atypical antipsyhotics: aripiprazole, ziprasidone, clozapine, asenapine
Illicit drugs/compounds: MDMA (ecstasy), LSD, psylocybin, cannabidiol (cannabis)
Antimigraine compounds: ergotamine
Other compounds: yohimbine

The combination of SSRI and 5HT1A agonist effect may synergistically increase serotonergic transmission.  

Two published clinical trials on vilazodone are available on PubMed.  The table below summarizes some of the key findings from the two published trials.

The dose of vilazodone studied was 40 mg in both studies.  Because of the common occurrence of gastrointestinal side effects, doses are typically initiated at a smaller level and increased to 40 mg over the first week or so.  The pattern and prevalence of gastrointestinal side effects with vilazodone appears similar to levels seen in previous SSRI trials.  Although headache was commonly reported with vilazodone, the rate did not differ from the rate endorsed by placebo.  Dizziness, dry mouth, insomnia and abnormal dreaming were endorsed at a higher level with vilazodone but by less than 10% of the subjects.

Although vilazodone was statistically superior to placebo on almost all depression measures, it was not statistically superior in remission rates in the Kahn study.  This finding along with the relatively low absolute response rate of 27.3% in the vilazodone group is a little disappointing.

The response and remission rates found in these two studies were similar to SSRIs.  Head to head comparison with an SSRI would be informative to see if vilazdone has any effectiveness or adverse event superiority.  Sexual side effects are common with the SSRIs and the two randomized vilazodone studies reported no difference in sexual side effects between vilazodone and placebo.  Additionally, the Rickels study showed some evidence for anxiety symptom reduction.  Clinical trials examining the effectiveness of vilazodone for anxiety disorders will likely be soon completed.

Disclosure:  The author has no stock in the parent company of vilazodone (Forest Labs).  Additionally no honoraria or research grant support has been received related to this drug.  The author received no reimbursement for writing this post and the comments are entirely those of the author.

Information on the agonists for the 5HT1A receptor obtained from Wikipedia.

Chemical molecular structure of vilazodone from Creative Commons file at Wikepedia by author Meodipt.

Rickels K, Athanasiou M, Robinson DS, Gibertini M, Whalen H, & Reed CR (2009). Evidence for efficacy and tolerability of vilazodone in the treatment of major depressive disorder: a randomized, double-blind, placebo-controlled trial. The Journal of clinical psychiatry, 70 (3), 326-33 PMID: 19284933


Khan A, Cutler AJ, Kajdasz DK, Gallipoli S, Athanasiou M, Robinson DS, Whalen H, & Reed CR (2011). A randomized, double-blind, placebo-controlled, 8-week study of vilazodone, a serotonergic agent for the treatment of major depressive disorder. The Journal of clinical psychiatry, 72 (4), 441-7 PMID: 21527122

Persistent Insomnia in Depression Responding to Antidepressants

Sleep problems commonly occur as part of a problem with mood disorders including depression.  Changes in sleep duration (insomnia or hypersomnia) are one of the criteria for the diagnosis of depression in the Diagnostic and Statistical Manual of Mental Disorders.  Although not absolutely required for the diagnosis, insomnia is a complaint in the the majority of subjects presenting for clinical trials in the treatment of depression.

The selective serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac) have become one recommended strategy in the treatment of depression.  However, unlike other antidepressants, the SSRIs commonly do not have a sedative effect.  It is possible that when someone gets an antidepressant response to an SSRI, sleep disturbance also resolves.  However, in clinical practice, SSRIs commonly produce a partial remission of depression but fail to improve problems with insomnia.  So what does this type of response mean and what can be done for those with improvement in depression but residual sleep complaints.

Gulec and his research team from Turkey have some recent research on this topic posted online at the Journal of Affective Disorders.  They followed a group of adults with major depression treated naturalistically--i.e. treating psychiatrists could select the antidepressant drug although algorithms for dose and sequencing were followed.  Subjects were followed with research rating scales for a period of 52 weeks.  Some subjects responded and remained well.  Some subjects responded but had a recurrence of depression in the one year follow up period.  The key findings from the study:

• Persistent insomnia rates were high in those who had a recurrence of depression
• The recurrent groups showed the following rates of insomnia prior to recurrence: onset insomnia (difficult falling asleep) 58%, terminal insomnia (early morning awakening) 33% and middle of the night insomnia 8%.
• Only 26% of those subjects whose depression remained remitted throughout the 52 week follow up period endorsed any persistent insomnia complaint.

The authors note their study is consistent with other studies supporting insomnia as a marker for poor prognosis is depression.  Reynolds and colleagues found that subjects who remitted with an antidepressant drug (including improvement in subjective sleep) had had high rate of continued remission of depression with psychotherapy alone.  Those whose insomnia persisted were less likely to benefit from psychotherapy alone as a long term maintenance strategy.


So an important question is what to do when insomnia persists despite a general antidepressant response.  It appears this is a problem that is too important to ignore and hope it goes away.  Options appear to include adding a sedative antidepressant, switching to another antidepressant, adding a sedative hypnotic treatment for insomnia or adding cognitive behavioral treatment for insomnia.  Here there is little data to support one of these choices over the others.  A research study examining these types of options is needed to aid patients and their clinicians in the management of this common clinical situation.

Photo of Moth Hovering Over Flower Courtesy of Tim Yates

Gulec M, Selvi Y, Boysan M, Aydin A, Besiroglu L, & Agargun MY (2011). Ongoing or re-emerging subjective insomnia symptoms after full/partial remission or recovery of major depressive disorder mainly with the selective serotonin reuptake inhibitors and risk of relapse or recurrence: A 52-week follow-up study. Journal of affective disorders PMID: 21684011

Reynolds CF 3rd, Frank E, Houck PR, Mazumdar S, Dew MA, Cornes C, Buysse DJ, Begley A, & Kupfer DJ (1997). Which elderly patients with remitted depression remain well with continued interpersonal psychotherapy after discontinuation of antidepressant medication? The American journal of psychiatry, 154 (7), 958-62 PMID: 9210746

Brain Basis for Emotion Recognition Deficits in Depression

There is a emerging understanding of the role of social perception problems in depression and anxiety disorders.  Depression appears to effect the cognitive ability to judge the facial expression of others.  This impairment poses a challenge for interpersonal function and social relationships.  Research is now pinning down the neural basis for this deficit and to determine it’s persistence and the effect of depression remission on this social cognition function.

van Wingen and colleagues from the Netherlands recently published an fMRI study on this topic in Psychological Medicine.  The study had the following elements in research design:

• Subjects: Twenty case subjects with first episode of major depression (medication naive), Twenty one case subjects recovered from a first episode of depression and 30 healthy individuals without a history of depression
• f MRI Task: Visual recognition of anger or fearful face by semantic labelling or visual matching compared to a control task of matching facial orientation without attention to emotion
• Additional Neuropsychological Testing: Depression symptom level, anxiety (state and trait) symptom level, IQ, memory, visual learning, attention, psychomotor speed and executive function.

The depression case subjects were not different from recovered depressed subjects and controls on most of the tests of neuropsychological function.  As expected, they did have higher depression symptom severity scores (Hamilton Depression Scale average for the depressed group was 21.8) and higher anxiety symptom severity scores.

The depressed group performed as well as the remitted group on the control task and the visual emotion matching task.  However, they performed worse than both groups on the semantic matching task, i.e. selecting the correct word label for the emotion displayed visually.  

The brain regions that correlated (increased activation) with impaired semantic emotion labeling included three distinct regions:

• right amygdala
• left inferior frontal gyrus
• anterior cingulate cortex

The authors propose that one explanation for this finding in three distinct brain regions.

“The left inferior frontal gyrus is thought to integrate language with other information (Hagoort, 2005;Willems et al. 2007). Therefore, we suggest that the inferior frontal gyrus may integrate the semantic knowledge about the concepts of anger and fear with the emotional information conveyed by the faces by interacting with the amygdala. The concurrent activation of these systems may subsequently trigger automatic negative thoughts and stimulate task unrelated processes such as rumination (Siegle et al. 2002; Ray et al. 2005), and thereby hinder task appropriate behaviour.”

This explanation fits with the cognitive behavioral theory of depression.  The core concept being that depression is characterized by increased automatic negative thoughts about the self, the future and the environment.  The thoughts are generated by a maladaptive negative cognitive schema.  Activation of these automatic thoughts (i.e. by being shown negative facial emotions) produces distraction from tasks (i.e. correctly labelling these facial emotions). This process appears limited to when depression is present as the recovered depression group showed no deficit.

The authors also conclude the findings could be due to a compensatory mechanism for inadequate behavior or an altered coping mechanism for dealing with demanding situations. 

This study provides additional support that fMRI research may lead to advances in the treatment of depression by both psychotherapy and psychopharmacologic interventions.

Screen shot of 3D Brain showing the limbic system structures amygdala and cingulate cortex (along with the inferior frontal cortex) thought to be involved in impaired facial recogniton in depression.

van Wingen, G., van Eijndhoven, P., Tendolkar, I., Buitelaar, J., Verkes, R., & Fernández, G. (2010). Neural basis of emotion recognition deficits in first-episode major depression Psychological Medicine, 41 (07), 1397-1405 DOI: 10.1017/S0033291710002084

Limiting Debt May Be Good For Your Mental Health

Article first published as Limiting Debt May Be Good For Your Mental Health on Technorati.

The relationship between financial status and risk for medical and mental disorders is complex. Premorbid functioning (level of function prior to the onset of a condition) may influence cognitive performance, motivation and the social interaction skills necessary for gaining employment and career success. Failure to obtain (or maintain) a rewarding job can contribute to increased stress and possible reduced access to treatment for medical or mental health conditions. Two recent studies examined the relationship between financial factors and risk for mental disorders. These studies provide potential strategies for the prevention of some common clinical neuroscience conditions.

Jenkins and colleagues in the United Kingdom studied the relationship between a variety of economic indicators and risk for presence of a mental disorder in over 8000 individuals in England, Scotland and Wales. The previous well-documented association between lower socioeconomic status and increased risk for mental disorders was found in this research study. Risk for any mental disorder (neurotic disorder, psychotic disorder, alcohol or drug use disorder) ranged from 24% of the highest earners to over 40% for lowest income group in men. For women the difference was 18% for the highest income group compared to 33% for the lowest income group.

Examining the relationship between income and risk for mental disorder in more detail in this sample produced an interesting finding. Income was strongly associated with the number of debts and the number of debts strongly correlated with rates of mental disorders. When the presence of personal debt (and other socioeconomic factors) was controlled, the association of income and mental illness vanished or was greater reduced. A small effect for income on rates of neurosis persisted after controlling for number of debts.

The authors of this study note that it was a cross-sectional study and there was no ability to examine the sequence of events. Perhaps the primary association is that those with a mental disorder are more likely to take on debt (whether out of necessity or perhaps because of impaired financial decision making associated with cognitive limitations). But the authors do note an important implication of their research. The role of personal debt and risk of mental disorder is rarely studied. Personal debt levels are increasing in many countries around the world. The role of debt in risk of (and management) of mental disorders is an emerging public health issue.

A second abstract that caught my attention in this topic area is a study by Lang and colleagues in the UK and the U.S. They noted that the prevalence of common mental disorders tends to rise up through midlife when a peak rate is reached. Their study found this effect occurred only in the lowest income group. Those in higher income groups appeared to be protected from this midlife prevalence rate increase. There was no mention of the potential role of debt in this common epidemiological finding.

These findings have influenced how I assess and manage patients. I tend to be more likely to ask about personal debt levels and the influence of debt (and intrusive debt collectors) in mood, anxiety levels and personal distress. Using debt counseling resources and encouraging the limitation of personal debt may become more common important components of clinical neuroscience.

Photo of credit card from Creative Commons file at Wikipedia.

Jenkins R, Bhugra D, Bebbington P, Brugha T, Farrell M, Coid J, Fryers T, Weich S, Singleton N, & Meltzer H (2008). Debt, income and mental disorder in the general population. Psychological medicine, 38 (10), 1485-93 PMID: 18184442

Lang, I., Llewellyn, D., Hubbard, R., Langa, K., & Melzer, D. (2010). Income and the midlife peak in common mental disorder prevalence Psychological Medicine, 41 (07), 1365-1372 DOI: 10.1017/S0033291710002060

ADHD and the Athlete

Athletes are not spared from the risk of developmental disorders like learning disabilities and attention deficit hyperactivity disorder (ADHD).  Once an athlete is diagnosed with ADHD, the effect of this disorder and it's treatment on athletic performance becomes important.  

Dr. J. W. Parr recently published a comprehensive review of recent research and understanding of ADHD in the athlete.   The review includes a look at diagnostic issues as well as a summary of the neurobiology of ADHD.  After this general introduction, the review focuses on some key issues in athletes with ADHD.


Although some children with ADHD have motor performance problems the majority do not.  The effect of ADHD on athletic performance is somewhat related to individual sporting activity.  ADHD may be more of a sport performance problem in sports requiring prolonged attention, i.e. fencing and less of a problem in large muscle performance sports such as swimming and track and field.  Indeed, some of the world's most successful athletes have been diagnosed with ADHD.  Parr notes that multiple Olympic gold medal winner Michael Phelps has made it publicly known he has ADHD.


Additionally, Parr notes that ADHD appears to be as common in athletes as in the general population.  Using his unpublished observations of athletes at Texas A & M University, he estimates that 7 to 9% of all athletes are receiving stimulant and nonstimulant medications for ADHD.  Given the estimated community prevalence of ADHD at 4 to 7%, the prevalence of ADHD medication use in the Texas A & M athlete population suggests a prevalence at least as high as the general population.

Parr reviews the risk of substance abuse with stimulant medication.  He notes that the oral stimulant drugs in ADHD typically lack significant euphoric effects found with intravenous stimulant illicit drug use (i.e. cocaine or methamphetamine). 


There is increasing research examining the effect of ADHD stimulant drug use and performance.  Acute administration of methylphenidate or placebo to a group of cyclists (without ADHD) resulted in prolonged peak performance.   Whether chronic administration of stimulants in those with ADHD improves performance in unclear.  However, there is some data that supports a drop in motor performance in athletes with ADHD on days they skip or miss their ADHD medication.

Athletes commonly develop a pattern of dosing their medication in a manner that accommodates their sporting activity and perceived effects of medication on performance.  Parr notes this is somewhat of an individual decision.  He notes some baseball pitchers that always use their ADHD medications on days they are charting pitches but many do not take it before days they actually pitch.


Dr. Parr does not recommend routine EKG testing of athletes taking medication for ADHD.  He feels that there is no data to support an increased risk of cardiac death in athletes with ADHD on stimulant treatment.  However, he does note one area of medical concern with athletes using ADHD medications.  Some stimulants may impair thermoregulation and increase the risk of heat exhaustion or heat stroke.  He notes physicians and trainers should make sure to provide athletes with ADHD adequate hydration and increased surveillance for heat-related illness.

Many college athletes with ADHD are diagnosed at an early age.  Dr. Parr recommends all college level athletes receiving ADHD drugs submit a copy of the prescribing physicians assessment and treatment recommendations.  The NCAA recommends student athlete documentation in ADHD include:

• Comprehensive clinical evaluation
• Observations and results from ADHD rating scales
• Specific diagnosis
• Recommended treatment

Such prior documentation is necessary should an athlete test positive for a stimulant on urine drug testing.  Disclosure of stimulant use for medical reasons at the time of submitting a urine sample and prior documentation will be needed to address any positive urine drug test results.

This review of ADHD in the athlete is well-written and information for physicians, trainers and other medical staff working in a sports medicine setting.

Photo of 2011 Spring Training game between St. Louis Cardinals and Minnesota Twins in Jupiter, Florida courtesy of Yates photography. 

Parr JW (2011). Attention-deficit hyperactivity disorder and the athlete: new advances and understanding. Clinics in sports medicine, 30 (3), 591-610 PMID: 21658550

Mild Cognitive Impairment in the Elderly

 The presence of mild cognitive impairment (MCI) in elderly individuals is often a clinical challenge of uncertain prognostic value.  Defined as cognitive function below the normal range but insufficient for a diagnosis of dementia, MCI is receiving increased research attention.  This week in the New England Journal of Medicine, Dr. Ronald Petersen, a neurologist from the Mayo Clinic in Rochester, Minnesota highlighted what is known about MCI.  His review summarizes some of the recent research related to MCI as well as some issues in clinical assessment and management.

Dr. Petersen noted that MCI is typically separated into two categories.  The first is amnestic MCI where memory impairment is predominant.  The second is nonamnestic MCI where deficits in other domains such as language, attention or visuospatial function.

Prevalence (70-89 year old non-dementia sample)

• 11.1% amnestic MCI
• 4.9% nonamnestic MCI

Amnestic MCI may be harbinger of Alzheimer's disease

Nonamnestic MCI may be harbinger of frontotemperal lobe degeneration or dementia with Lewy bodies

Risk of dementia in elderly about 1% to 2% per year

Risk for those with MCI raised to 5% to 10% per year

Assessment

•     Brief Minimental Status Exam (MMSE) often insensitive to early impairment
•     Better tools include the Short Test of Mental Status and Montreal Cognitive Assessment
•     Comprehensive neuropsychological testing necessary for definitive diagnosis and severity rating

Mild cases may be due to depression or the cognitive effects of medication

Differentiating from dementia primarily by level of functional impairment

This may be assessed using the Functional Activities Questionnaire

Predictors of progression of amnestic MCI to dementia (primarily research tools at this point)

•     More severe MCI
•     Presence of the Apolipoprotein epsilon 4 gene
•     Hippocampal volume less than the 25%tile for age by magnetic resonance imaging
•     PET imaging shows temporal and parietal brain hypometabolism
•     Cerebrospinal fluid assay shows low beta amyloid 42 to tau protein ratio
•     Brain amyloid plaques on PET imaging using Pittsburgh compound B

Treatment--No medication approved by FDA for treatment of MCI

• Alzheimer's drugs donepezil, galantamine and rivastigmine have negative placebo-controled clinial trial results in MCI.  Donepezil but not Vitamin E reduced progression to Alzheimers disease in MCI in one trial for first two years but not at three years of treatment
• Some evidence that cognitive rehabilitation may be helpful in short term improvement of memory in MCI
• Treat reversible cardiovascular risk factors if they are present
• Encourage brisk walking exercise 150 minutes per week

Given that 15% of elderly individuals demonstrate a form of MCI, it is likely this condition will generate significant ongoing research interest.  An intervention that would reduce the risk of progression of dementia after the onset of MCI would be a major advance in the prevention of Alzheimer's Disease.

Dr. Petersen provides copies of the Short Test of Mental Status, the Montreal Cognitive Assessment and the Functional Activities Questionnaire in an online appendix to the review.  Readers who do not have access to the online New England Journal of Medicine can contact me for alternate options to receive copies of the instruments. 

Photo of PET scan of patient with Alzheimer's Disease showing reduced glucose metabolism in the temporal lobes courtesy of Wikipedia Commons file from the National Institute on Aging,  Alzheimer's Disease Education and Referral Center.   
 

Petersen, RC (2011). Mild Cognitive Impairment New Engl J Med, 364, 2227-2234