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October 31, 2012
10:56 AM
272 views

Driving Simulation and Parkinson's Disease

by William Yates, M.D. in Brain Posts

In two previous posts, I reviewed research relevant to driving performance in patients Alzheimer's disease and in patients with sleep apnea.These posts noted that driving impairment appears present in very early Alzheimer's disease, at a stage when family and medical personnel may not be aware of the disorders.Additionally, in sleep apnea, driving impairment is commonly present with some improvement, but not normalization with continuous positive airway pressure. The stimulant drug modafinil appears to be effective in improving alertness and driving performance during periods when CPAP is not being used. In a final post of driving simulation in neuroscience medicine, will review two studies in patients with Parkinson's disease. In the first study, Matt Rizzo and his colleauges at the University of Iowa studied six subjects with Alzheimer's disease along with nine subjects with Parkinson's disease. Parkinson's disease is a neurogenerative disorder typically affecting older individuals. Motor symptoms include psychomotor slowing, muscular rigidity, and tremor. Additional common symptoms include cogntive impairment, depression and behavioral disturbances.Subjects in this study completed a driving simulation task using a desktop computer while sitting in front of a computer screen. Subjects were presented scenarios involving visual objects that drivings were given 3 or 1 second to respond. Parkinson's disease subjects in the study performed more poorly than controls on the collision detection task. Poor performance on the driving simulator correlated with lower scores on cognitive skills as well as lower visual acuity skills. This suggests that driving crash risk in Parkinson's disease tracts with general cognitive decline and impairment in visual acuity.A second study from the Iowa neurology group examined driving performance in Parkinson's disease under low light conditions using a more advanced driving simulator known as the Simulator for Interdisciplinary Research in Ergonomics and Neuroscience (SIREN). In this study, 67 subjects with mild to moderate Parkinson's disease with a mean age of about 66 years were compared to a neurologically normal age-controlled group of drivers. Driving performance in this study was compared during simulation of clear sky compared to low-contrast scenarios that simulated driving during foggy condition. Parkinson's disease subjects showed significant impairment in the foggy condition scenario with increased crash rates and slower reaction time.In the Parkinson's disease group, poor driving performance correlated with a variety of neuropsychological task parameters including:visual processing speed and attentionmotion perceptioncontrast sensitivityvisuospatial constructionmotor speed activities of daily living scoreThe authors noted in their discussion that their findings "suggest that a large proportion of drivings with PD maybe at further risk of unsafe driving during fog or twilight because of visual, cognitive, and motor impairments".These two studies combined support personal and family monitoring of driving performance in patients with Parksinson's diseasee. During early stages of the disease, reduced driving frequency and avoidance of low-light driving may reduce risk of crash. During more advanced stages, discussion of disease management should include a plan for making an informed decision on cessation of driving.Photo of snowy egret near Fort Myers, FL from the author's files.Vaux LM, Ni R, Rizzo M, Uc EY, & Andersen GJ (2010). Detection of imminent collisions by drivers with Alzheimer's disease and Parkinson's disease: a preliminary study. Accident; analysis and prevention, 42 (3), 852-8 PMID: 20380912 Uc EY, Rizzo M, Anderson SW, Dastrup E, Sparks JD, & Dawson JD (2009). Driving under low-contrast visibility conditions in Parkinson disease. Neurology, 73 (14), 1103-10 PMID: 1980572620380912... Read more »

Vaux LM, Ni R, Rizzo M, Uc EY, & Andersen GJ. (2010) Detection of imminent collisions by drivers with Alzheimer's disease and Parkinson's disease: a preliminary study. Accident; analysis and prevention, 42(3), 852-8. PMID: 20380912

Uc EY, Rizzo M, Anderson SW, Dastrup E, Sparks JD, & Dawson JD. (2009) Driving under low-contrast visibility conditions in Parkinson disease. Neurology, 73(14), 1103-10. PMID: 19805726

October 30, 2012
11:39 AM
282 views

Driving Simulation and Sleep Apnea

by William Yates, M.D. in Brain Posts

In a previous post, I examined a research study simulator of the effect of mild to moderateAlzheimer's disease on driving performance. This study found that even mild probable Alzheimer'sdisease subjects demonstrated significant impairment in a variety of driving performance domains.In this post, I will summarize three research studies related to driving performance in the sleepdisorder sleep apnea. The first study focused on changes in driving performance following theinitiation of continuous positive airway pressure (CPAP). The second examined the effect ofa drug commonly used in sleep apnea, modafinil and it's effect on driving performance. The finalstudy examines a potential specific driving deficit that may contribute to driving problems in patients with sleep apnea.Vakulin and colleagues in Australian recently published a study of eleven subjects with severeobstructive sleep apnea compared to a control group without the sleep disorder. The key elements of their study design included:Sleep apnea subjects underwent simulator testing at baseline and 3 months (without CPAP)Control subjects without sleep apnea were tested identically at baseline and 3 monthsDriving simulator testing parameters: lateral steering, reaction time and crash frequencyStatistical analysis included paired and unpaired t-tests and linear mixed model analysisThe key findings from the study included:Sleep apnea subjectes showed high lateral driving deviation at baseline. This parameter improved following CPAP but did not normalized to control functionThe two groups did not differ breaking reaction timeFour simulated crashes in the sleep apnea groups (2 baseline and 2 at 3 months).Crash number differences between groups did not reach statistical signficanceThe study highlights the potential of treatment of sleep apea with CPAP to improve driving performance in sleep apnea. However, the effect is not of sufficient size to normalize driving performance.A second informative research study looked at the potential of the drug modafinil to improvedriving performance. In this study, the primary focus was to see whether modafinil could improveperformance in sleep apnea during brief periods of CPAP withdrawal. Patients with sleepapnea commonly have short periods off their machines, i.e. when traveling for a few days. Thissecond study looked a driving performance on and off modafinil with off CPAP therapy.... Read more »

Vakulin A, Baulk SD, Catcheside PG, Antic NA, van den Heuvel CJ, Dorrian J, & McEvoy RD. (2011) Driving simulator performance remains impaired in patients with severe OSA after CPAP treatment. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 7(3), 246-53. PMID: 21677893

Williams SC, Marshall NS, Kennerson M, Rogers NL, Liu PY, & Grunstein RR. (2010) Modafinil effects during acute continuous positive airway pressure withdrawal: a randomized crossover double-blind placebo-controlled trial. American journal of respiratory and critical care medicine, 181(8), 825-31. PMID: 20056901

Tippin J, Sparks J, & Rizzo M. (2009) Visual vigilance in drivers with obstructive sleep apnea. Journal of psychosomatic research, 67(2), 143-51. PMID: 19616141

October 25, 2012
11:47 AM
261 views

Driving Simulation and Alzheimer's Disease

by William Yates, M.D. in Brain Posts

In previous posts I have summarized research studies of the role of cannabis in risk for motor vehicle accidents (MVA). This research suggests that risk of MVA with cannabis use is comparable to that of driving with a blood alcohol concentration of 0.8 g/L. A research study review found that cannabis use carries an overall risk of doubling the chances for serious MVA.Driving simulation research provides a laboratory tool to better understand the key elements in driving skill. Additionally, driving simulation research can aid in understanding the role of alcohol and drug use on driving performance. Driving simulation research can also provide insight into the effect of specific medical conditions on the type and magnitude of driving performance impairment.An example of this type of research is recent study of driving simulator performance in a series of patients with Alzheimer's disease. Stein and Dubinsky from the Department of Neurology at the University of Kansas designed and completed a study of driving performance in seventeen patients with Alzheimer's disease (AD) compared to a group of similar aged individuals without evidence of cognitive impairment. This study was designed to look at the timing of driving impairment across the spectrum of AD severity.There are a variety of ways to simulate driving ranging in complexity, cost and fidelity to a true driving test. The Kansas team used a mid-sized sedan along with a computer monitor system that has been validated to accurately assess a variety of driving skills. In their simulation study they presented drivers with a variety of driving scenarios including:Traffic signal scenario: drivers respond to green, yellow and red light presentationsUncontrolled intersections: intersections without traffic lights or stop signs where drivers are presented with scenarios of pedestrian traffic and motor vehicle cross trafficCurve negotiation scenario: road curve scenario with speed limit of 40 mphSpeed control scenarios: variation of posted speed limits were drivers are "ticketed" for driving 5 mph or more above the posted speed limit Alzheimer disease subjects included a group of 8 subjects with mild cognitive impairment and a clinical diagnosis of probable AD. This group has impairment levels that might not be noticed by family members or clinicians and had a Minimental Status (MMSE) score of 26.5/30. Nine subjects met full criteria for AD with a MMSE score of 22.6/30. All subjects had a valid drivers license and were driving an average of about 14,000 miles per year.Both the probable AD and AD demonstrated impaired driving performance compared to control subjects on the following driving performance variables:Running off the road accidentsCollisions with other vehiclesTime to completion of the road course (slower performance)Number of traffic light errors The probable AD and AD drivers were not different from the control drivers on:Traffic light reaction timesIntersection errorsNumber of times speedingThe authors concluded that significant driving impairment occurs relatively early in the course of AD. Significant impairment may be present even before the disease progresses to a degree that is recognizable by family and even primary care clinicians. The authors note their study is limited by a small sample size of subjects and will need replication in larger samples. Additionally, their is a need to validate driver simulation research findings with actual driving and accident records. However, the study underscores the need for screening to detect early AD and other forms of dementia. Patients with early AD need assessment of the effect of their illness on a variety of functional parameters including driving performance.Photo of Florida scrub jay from the Oscar Scherer State Park from the author's files.Stein AC, & Dubinsky RM (2011). Driving simulator performance in patients with possible and probable Alzheimer's disease. Annals of advances in automotive medicine / Annual Scientific Conference ... Association for the Advancement of Automotive Medicine. Association for the Advancement of Automotive Medicine. Scientific Conference, 55, 325-34 PMID: 22105407... Read more »

Stein AC, & Dubinsky RM. (2011) Driving simulator performance in patients with possible and probable Alzheimer's disease. Annals of advances in automotive medicine / Annual Scientific Conference .. Association for the Advancement of Automotive Medicine. Association for the Advancement of Automotive Medicine. Scientific Conference, 325-34. PMID: 22105407

October 24, 2012
11:05 AM
291 views

Cannabis Use and Car Accident Risk

by William Yates, M.D. in Brain Posts

In a previous post, I summarized a recent study of the relative contribution of cannabis and alcohol to motor vehicle accident (MVA) risk. This Belgium study estimated that risk of motor vehicle accident with cannabis use was comparable to that of alcohol at a blood alcohol concentration of about 0.8 to 1.0 g/L.The Belgium study estimated the odds ratio for motor vehicle risk with cannabis at about 5.8. Asbridge and colleagues recently published a review of acute cannabis consumption and MVA risk. This review published in the British Medical Journal preceded the Belgium study. It included analysis of nine independent studies using a variety of methodologies.Examining the effect of cannabis use on MVA risk by specific study methodology found the following odds ratio estimates:Case-control studies: 2.79High quality studies: 2.21Fatal collision studies: 2.10Medium quality studies: 1.78Non-fatal collision studies: 1.74Culpability studies: 1.65In the perspective of previous studies, the Belgium study produced a higher estimate of the role of cannabis in accident risk.There are individual studies that have failed to find an association of MVA risk with cannabis use. However, the Asbridge et al meta-analysis suggests the preponderance of evidence finds an elevated risk of MVA with cannabis use. Using a best estimate of the odds ratio from combining studies produces a summary odds ratio of 1.92.The authors note experimental studies of cannabis use on cognitive function have been done "suggesting that cannabis impairs performance of the cognitive and motor tasks necessary for safe driving, increasing the risk of collision".A key methodological issue in estimating the role of cannabis use in MVA risk is the potential role of alcohol and other drug effects. Many drivers using cannabis have additional drugs and alcohol in blood toxicology tests. This makes estimating the specific effects of cannabis difficult.Additionally, there is very little research looking at the effect of acute cannabis use versus chronic cannabis use on cognitive performance and MVA accident risk. This is an topic that deserves additional research attention. The evolving use of driving simulator technology provides an opportunity to better understand the role of alcohol, cannabis, other illicit drugs and prescription drugs on motor vehicle driving performance. In upcoming posts, I will examine how driving simulators are providing important insight in the effect of a variety of cognitive factors in driving performance.Halloween photo from Busch Gardens in Tampa, Florida from the authors files.Asbridge M, Hayden JA, & Cartwright JL (2012). Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ (Clinical research ed.), 344 PMID: 22323502... Read more »

Asbridge M, Hayden JA, & Cartwright JL. (2012) Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ (Clinical research ed.). PMID: 22323502

October 23, 2012
11:41 AM
270 views

Alcohol, Cannabis and Accident Risk

by William Yates, M.D. in Brain Posts

TThe magnitude of risk for motor vehicle accident (MVA) with alcohol consumption is well known. However, the risk for MVA with other drugs is less clear. Additionally, the risk for the combination of alcohol with other drugs has received limited study. This is despite the fact that alcohol-impaired drivers commonly have additional psychotropic and illicit drugs in their system. Kuypers and colleagues from the Netherlands and Belgium have recently published an informative study on this topic in the journal PLOS One. Their study estimated the risk of serious motor vehicle accident with a variety of levels of alcohol and non-alcohol drug use. The key elements of the study design included:Cases: Drivers involved in a MVA leading to hospitalization in Belgium between 2008 and 2010Controls: Random Belgium drivers not involved in an MVA who agreed to participate in a study that included breathalyzer tests and blood and saliva samplesBlood analysis: Alcohol and twenty five other prescription and illicit drugs were analyzed with quantitative levels Statistical analysis: Case/control MVA accident risk estimation adjusted for age, gender and time of week for sample collection.The relative contribution of cannabis to MVA risk is shown in the original figure here using data presented in the study.When any cannabis is present, the estimate for the risk (or odds ratio) for MVA is 5.79. This means that any cannabis is present, there is about a six fold increased risk for serious MVA. From the chart you can see that this risk is somewhere between the risk for MVA at blood level categories of 0.5 to 0.8 g/L and 0.8 and 1.2 g/L.However, when cannabis is present with higher levels higher levels of blood THC, the MVA risk was estimated to be even higher at approximately twenty fold compared to drivers without high blood levels of THC. Blood levels of alcohol over 1.2 g/L had MVA risk elevation to an estimate odds ratio of 76.4. The estimated risk for MVA reached highest levels when alcohol was found in combination with other drugs and when other drugs were combined without alcohol. Here are the MVA odds ratio estimates from other drugs and combinations:Prescription opiates: 2.9Multiple sedative drugs: 13.7Alcohol plus a stimulant drug: 20.3Alcohol plus a sedative: 67.2Stimulant drug plus sedative drug: 211.0 The odds ratio estimations in this study have broad confidence intervals due to the relatively small number of cases for some drug classes and some drug combinations. Nevertheless, the implications of this study are clear. Use of cannabis appears to represent a significant risk for MVA and the combination of alcohol with other drugs is a significant contributor to the potentiation of MVA risk.Photo of Halloween pumpkin scene from Busch Gardens from the author's files.Kuypers KP, Legrand SA, Ramaekers JG, & Verstraete AG (2012). A case-control study estimating accident risk for alcohol, medicines and illegal drugs. PloS one, 7 (8) PMID: 22952694... Read more »

Kuypers KP, Legrand SA, Ramaekers JG, & Verstraete AG. (2012) A case-control study estimating accident risk for alcohol, medicines and illegal drugs. PloS one, 7(8). PMID: 22952694

October 22, 2012
10:29 AM
270 views

Dyslexia Intervention Changes the Brain

by William Yates, M.D. in Brain Posts

In previous posts, I reviewed recent research findings in reading disorder (dyslexia). These studies estimated the prevalence of dyslexia at approximately 10% of children with rates in boys nearly twice that of girls. Twin studies show a significant genetic contribution to the risk for dyslexia. Brain imaging studies show deficits in the structure and function of inferior parietal and supramarginal gray matter regions in those with dyslexia.Brain imaging is beginning to be used as a tool to direct and monitor the effect of psychological treatment. Real-time fMRI appears to be a promising approach to individualizing psychotherapy in PTSD and other brain disorders. Krafnick and colleagues at Georgetown University Medical Center and Wake Forest University recently published results of a study of brain structure following a reading intervention in children with dyslexia.Eleven children between 7 and 12 years of age with dyslexia completed an 8-week intensive reading skills intervention following a program called Seeing Stars. This program includes the following key elements:Imaging and visualization starting with single letters increasing in complexity to one, two and three syllable wordsA motor and tactile component where students trace letters with their fingersA language component where students say the letter or word orally while they traceMagnetic resonance imaging scans were completed before the intervention, immediately after the 8-week intensive intervention and 8 weeks after the completion of the intervention. Brain gray matter volume measurements were estimated for a variety of brain regions using a technique known as voxel-based morphometry.The important findings from this study included:Students demonstrated a statistically significant improvement in reading skills such as phonemic awareness, real and pseudo word reading and passage comprehensionBrain gray matter volumes increased between 2 and 4 percent in the left fusiform/hippocampus, left precuneus, right hippocampus and right cerebellum regions after the interventionImprovement in reading skills and the increase in brain gray matter volumes persisted 8 weeks after the completion of the interventionThe left fusiform brain region has been noted to show deficits in dyslexia in other cross-sectional brain imaging studies. The authors note this region is "commonly engaged in tasks involving object processing and object naming and may suggest that the dyslexic students are relying on this region to improve their processing of words".The authors also note that this research may be important in providing a tool for "refining interventions and improve the learning experience".Intensive dyslexia treatment improves reading skills and appears to stimulate brain growth in regions known to be involved in reading. Children with dyslexia need to be identified early and to be provided the specific interventions that are effective in reducing reading deficits.Halloween photo is from Busch Gardens in Tampa, Florida and is from the author's photo files.Krafnick AJ, Flowers DL, Napoliello EM, & Eden GF (2011). Gray matter volume changes following reading intervention in dyslexic children. NeuroImage, 57 (3), 733-41 PMID: 21029785... Read more »

Krafnick AJ, Flowers DL, Napoliello EM, & Eden GF. (2011) Gray matter volume changes following reading intervention in dyslexic children. NeuroImage, 57(3), 733-41. PMID: 21029785

October 17, 2012
11:19 AM
413 views

Brain Imaging in Reading Disorder (Dyslexia)

by William Yates, M.D. in Brain Posts

In two previous posts I summarized research in to the epidemiology and twin studies related to reading disorder--also known as dylsexia. These posts noted reading disorder occurs in approximately 10% of children with boys showing higher rates than girls. Twin studies show a strong genetic contribution to the risk for dyslexia. Additionally, dyslexia may have common genetic links to ADHD through common deficits in processing speed.Advances in brain imaging research provide a better understanding of the specific brain regions and brain circuits affected in dyslexia. It has been known for quite some time that the left ventral occipital temporal (LvOT) regions contribute to reading ability. Stroke patients who suffer a stroke involving the LvOT often lose their ability to read. Reading therapy following stroke in this region can result in return of some reading abilities including ability to read simple short words.Linkersdorfer and colleagues recently published a brain imaging study that combined results from a series of structural and functional studies in dyslexia. Structural studies of brain gray matter volumes commonly find thinning or reduction in several gray matter regions in dyslexia. Using a techique of meta-analysis, this research study summarized the brain regions where a technique known as voxel-based morphology has demonstrated deficits in gray matter volume in dyslexia including:left supramarginal gyrusright supramarginal gyrusright superior temporal gyrusleft fusiform gyrusleft inferior temporal gyrusThe German, Swiss and Netherlands research group led by Linkersdorfer, then went an additional step and examined published studies of brain functional activation in dyslexia. After identifying specific brain regional functional deficits (hypoactivation) in dyslexia, they then overlayed the structural findings with the functional findings. This technique known as conjunction analysis provides a powerful tool for honing in on the most likely key regions related to dyslexia. The conjunction analysis identified three key regions in the left hemisphere found to demonstrate structural as well as functional deficits in dylexia including:left fusiform gyrus/inferior temporal gyrusleft supramarginal gyrusleft cerebellumThe left fusiform gyrus/inferior temporal gyrus region of the brain is highlighted in the screen shot from the iPad app 3D Brain on the left. The fusiform gyrus region of the inferior temporal gyrus occupies a region more interior to the marker on this image.Additionally, below that image you will find a screen shot of the left and right supramarginal gyrus from the iPad app Brain Tutor. The supramarginal gyrus is highlighted in burnt orange colorThe authors note their findings correspond to some of the key regions that have previously been described in developmental dyslexia. The authors note that their analysis cannot determine whether the brain deficits in these regions predate the onset of dyslexia. They note the findings could be "secondary, experience-dependent development changes."This is a key question: Which comes first? Is there a structural and functional brain abnormality that leads to reading problems? Or, alternately, do the brain changes found in dyslexia occur after educational exposure? It might be possible that once a child begins to struggle with reading, the brain response leads to changes in areas related to reading.A second study, supports the first hypothesis: Brain abnormalities predate the development of dyslexia.Nora Maria Raschle and colleagues from Harvard University studied a series of children at high-risk for dyslexia before they began reading training. This fMRI activation study found deficits in bilateral occipitotemporal and temperoparietal regions in the high-risk pre-reading children group. There study "suggests that functional and structural brain alterations are fundamental to DD (developmental dyslexia) and cannot be a result of reading failure itself".But we do know brain cognitive training can change brain structure and function. In the last post in this series, I will review a study of brain changes in children with dyslexia following an intensive reading skills training intervention.Photo of a Florida scrub jay from the author's files. Brain images are iPad screen shots from the author's files.Linkersdörfer J, Lonnemann J, Lindberg S, Hasselhorn M, & Fiebach CJ (2012). Grey Matter Alterations Co-Localize with Functional Abnormalities in Developmental Dyslexia: An ALE Meta-Analysis. PloS one, 7 (8) PMID: 22916214 ... Read more »

Linkersdörfer J, Lonnemann J, Lindberg S, Hasselhorn M, & Fiebach CJ. (2012) Grey Matter Alterations Co-Localize with Functional Abnormalities in Developmental Dyslexia: An ALE Meta-Analysis. PloS one, 7(8). PMID: 22916214

Raschle NM, Zuk J, & Gaab N. (2012) Functional characteristics of developmental dyslexia in left-hemispheric posterior brain regions predate reading onset. Proceedings of the National Academy of Sciences of the United States of America, 109(6), 2156-61. PMID: 22308323

October 16, 2012
10:57 AM
342 views

Twin Studies of Reading Disorder (Dyslexia)

by William Yates, M.D. in Brain Posts

In a previous post, I reviewed recent research into the prevalence of reading disorder, commonly called dyslexia in children and adolescents. The estimated prevalence for dyslexia in girls is estimated at about 7%, while in boys it is estimated as high as 14%. Research confirms high rates of dyslexia in both boys and girls with a diagnosis of ADHD.Twin studies can provide valuable insight into the contribution of genetic and environmental differences in a variety of developmental disorders. The role of genetic influences can be determined by analyzing concordance rates between monozygotic twin pairs compared to dyzygotic twin pairs.Support for a genetic contribution is found when the rates of concordance for a disorder is higher in monozygotic twins than in dizygotic twins.There are several excellent twin cohorts that have been studied for reading ability and reading disorders. I will summarize some of the recent research on this topic from two recently published free access manuscripts.Hensler and colleagues from Florida State University conducted a study of 1024 first grade twin pairs from the Florida Twin Project on Reading. In this study, all subjects in the study completed the Stanford Achievement Test-Reading subtest (SAT-10) a validated measure of reading ability.Analyses of reading performance were compared for overall reading ability and presence of reading disorder defined by performance at the 15%tile or lower on the SAT-10. These analyses found the following contributions:For general reading ability, 53% of the performance was due to genetic factors, 25% was due to shared environmental factors while 21% was due to unshared environmental factorsThe concordance rates for reading disorder in the monozygotic twins was .58 while for the dizygotic twins it was .32 indicating a significant genetic contribution to dyslexiaAs noted in the post on the epidemiology of reading disorder, understanding the overlap between reading disorder and ADHD is important. A twin study from the Colorado Learning Disabilities Research Center is informative for understanding the overlap in these two developmental disorders.Erik Willcutt along with colleagues from the University of Colorado, Regis University and Massachusetts General Hospital conducted a analysis of 457 twin pairs. They conducted a study starting from six cognitive domains:phoneme awareness (ability to hear, identify and manipulate the smallest units of sound)verbal reasoningworking memoryinhibitory controlprocessing speednaming speedThey found in their analysis confirmation of previous findings that "measures of single-word reading, inattention, and hyperactivity-impulsivity are highly heritable."Additionally, their twin analysis found that reading disorder was linked to independent deficits in phoneme awareness, verbal reasoning and working memory. ADHD was linked independently to deficits inhibitory control, while reading disorder and ADHD shared a common deficit in processing speed.The note in the discussion, that this finding might inform study design using molecular genetic approaches to reading disorder and ADHD. Molecular genetic analyses might benefit from the collection of measures of cognitive function. Specifically, processing speed measures may aid identification of genes that increase risk of both reading disorder and ADHD.In the next post, I will review some of the brain imaging findings linked to reading disorder to better understand the anatomical and brain functional correlates of this developmental disorder.Photo of the Florida scrub jay at Oscar Scherer State Park from the author's files.Hensler BS, Schatschneider C, Taylor J, & Wagner RK (2010). Behavioral genetic approach to the study of dyslexia. Journal of developmental and behavioral pediatrics : JDBP, 31 (7), 525-32 PMID: 20814252Willcutt EG, Betjemann RS, McGrath LM, Chhabildas NA, Olson RK, DeFries JC, & Pennington BF (2010). Etiology and neuropsychology of comorbidity between RD and ADHD: the case for multiple-deficit models. Cortex; a journal devoted to the study of the nervous system and behavior, 46 (10), 1345-61 PMID: 20828676... Read more »

Hensler BS, Schatschneider C, Taylor J, & Wagner RK. (2010) Behavioral genetic approach to the study of dyslexia. Journal of developmental and behavioral pediatrics : JDBP, 31(7), 525-32. PMID: 20814252

Willcutt EG, Betjemann RS, McGrath LM, Chhabildas NA, Olson RK, DeFries JC, & Pennington BF. (2010) Etiology and neuropsychology of comorbidity between RD and ADHD: the case for multiple-deficit models. Cortex; a journal devoted to the study of the nervous system and behavior, 46(10), 1345-61. PMID: 20828676

October 15, 2012
11:07 AM
289 views

Epidemiology of Reading Disorder (Dyslexia)

by William Yates, M.D. in Brain Posts

In the next few posts, I will review recent research related to reading disorder (RD), commonly known as dyslexia. The ability to read and comprehend written communication is a key cognitive skill that is linked to academic and occupational success. Better understanding of the scope and biological mechanisms for reading disorder is needed to design prevention and intervention strategies.One of the key issues in reading disorder is the co-occurrence or comorbidity of reading disorder with attention deficit hyperactivity disorder (ADHD). Rates of RD are elevated in ADHD emphasizing the need for comprehensive neuropsychological assessment of children and adults with ADHD.Yoshimasu and colleagues published a free access study of the prevalence rates for RD in a population-based cohort of children and adolescents in Rochester, Minnesota.The researchers in this study used analysis of multiple school and academic records to estimate the prevalence of reading disorder in a cohort of 5718 children. Reading disability was assessed by comparing measures of IQ and reading achievement. Using several validated formulas, reading disability can be assigned with reading achievement falls significant below what would be expected based on individual intelligence. Additionally, ADHD was estimated in the cohort using assessment of DSM-IV criteria, ADHD questionnaire results and evidence by records of a clinical diagnosis of ADHD.The key findings from this epidemiologic study included:508 cases of reading disability were indentified in the cohort379 cases of ADHD were identified and as expected 75% of ADHD cases occurred in boysFor those without ADHD, the estimated rates for reading disorder were 14.5% for boys and 7.7% for girlsRates for reading disorder were markedly elevated for children with ADHD with estimates of the prevalence of RD in boys with ADHD at 51.0% and for girls with ADHD 46.7%A key finding from the study is the effect of a diagnosis of ADHD in girls on rates of RD. Female gender is a relative protective factor for RD, but once the diagnosis of ADHD is present, this protective effect is lost.I was surprised at the rates of reading disorders identified in this cohort. The findings support aggressive screening for reading disorder in all children with early interventions to address and limit the effect of this disorder.Up future posts, I will review genetics studies of the risk overlap for ADHD and RD that helps to explain the high rates of co-occurrence of these two important developmental disorders. Photo of Florida Scrub Jay from Oscar Scherer State Park is from the author's files.Yoshimasu K, Barbaresi WJ, Colligan RC, Killian JM, Voigt RG, Weaver AL, & Katusic SK (2010). Gender, attention-deficit/hyperactivity disorder, and reading disability in a population-based birth cohort. Pediatrics, 126 (4) PMID: 20876182... Read more »

Yoshimasu K, Barbaresi WJ, Colligan RC, Killian JM, Voigt RG, Weaver AL, & Katusic SK. (2010) Gender, attention-deficit/hyperactivity disorder, and reading disability in a population-based birth cohort. Pediatrics, 126(4). PMID: 20876182

October 3, 2012
10:58 AM
309 views

Nicotine, Neuropeptide Y and Weight

by William Yates, M.D. in Brain Posts

In a previous post, I summarized a review of the weight gain associated with smoking cessation. The mechanism for nicotine to influence appetite and energy metabolism is the topic of significant research.In this post I will take a look two studies. The first is a free access article summarizing the effects of cigarette smoking and brain regulation of energy metabolism. The second study examined the effect of smoking cessation on plasma neuropeptide Y and leptin levels.Chen and colleagues published a good review of metabolic effects of cigarette smoking in the journal Frontiers in Pharmacology. Here are some of the key points they emphasize that relate to nicotine and energy metabolism:The brain hypothalamus is known to be a key region of appetite regulationThe hypothalamus contains a significant number of nicotine receptorsNeuropeptide Y is a key peptide that contributes to appetite regulation and it is found throughout the brainIn animal models, administration of neuropeptide Y in several brain regions results in hyperphagia, increased fat deposition, weight gain and obesityIn the mouse model, exposure to cigarette smoke results in significantly reduced neuropeptide Y levels in the hypothalamusOther hypothalamic neuropeptides are important in weight regulation including agouti-related protein (AgRP) and melatonin related compounds including proopiomelanocortin (POMC)The hypothalamus contains and number of appetite stimulating neurons (orexigenic) and appetite suppressive neurons (anorexigenic) that are in balance but can be susceptible to the effects of nicotineSmoking during pregnancy increases fetal brain serotonin, fetal brain dopamine but reduces fetal hypothalamic levels of neuropeptide Y, POMC and fetal blood leptinThese effects of nicotine on the fetal brain can promote fetal growth retardation but a post-natal preference for junk food, catch up growth and later increased risk of obestiyChen and colleagues note that smoking can actually contribute to abdominal obesity and lower weight in smokers may be due to lean body mass loss. They do note that research into nicotine analogs without addiction potential may provide new drugs for the treatment of obesity.Husain and colleagues from Saudi Arabia published an informative study of neuropeptide Y and leptin in a series of smokers during smoking cessation and controls. They examined the plasma levels of these to appetite regulating hormones and found:Smokers had lower baseline weights and lower plasma neuropeptide Y and leptin levelsWith smoking cessation, weight and waist circumference increased in former smokers as did the plasma levels of neuropeptide Y and leptinThe increase in leptin levels appeared secondary to an increase in fat mass, while the increase in neuropeptide Y appeared to have a more primary effect on weightThe study of plasma levels of leptin and nueropeptide Y are limited because peripheral hormonal effects may be quite different than brain hypothalamic effects. However, taken together these two research publications support a role for neuropeptide Y in weight regulation and in weight gain with smoking cessation. Further understanding of this relationship may provide insight into methods to reduce risk of weight gain with smoking cessation and to understand potential pharmacologic strategies to reduce rates of obesity.Photo of a red panda from the author's files.Chen H, Saad S, Sandow SL, & Bertrand PP (2012). Cigarette smoking and brain regulation of energy homeostasis. Frontiers in pharmacology, 3 PMID: 22848202Hussain T, Al-Daghri NM, Al-Attas OS, Draz HM, Abd Al-Rahman SH, & Yakout SM (2012). Plasma neuropeptide Y levels relate cigarette smoking and smoking cessation to body weight regulation. Regulatory peptides, 176 (1-3), 22-7 PMID: 22387704... Read more »

Chen H, Saad S, Sandow SL, & Bertrand PP. (2012) Cigarette smoking and brain regulation of energy homeostasis. Frontiers in pharmacology, 147. PMID: 22848202

Hussain T, Al-Daghri NM, Al-Attas OS, Draz HM, Abd Al-Rahman SH, & Yakout SM. (2012) Plasma neuropeptide Y levels relate cigarette smoking and smoking cessation to body weight regulation. Regulatory peptides, 176(1-3), 22-7. PMID: 22387704

October 2, 2012
11:09 AM
329 views

Weight Gain After Smoking Cessation

by William Yates, M.D. in Brain Posts

One barrier to smoking cessation is the risk of weight gain. It is important to understand the amount and pattern of weight gain commonly associated with smoking cessation. Understanding this effect provides clinicians with information to assist patients with smoking cessation interventions.A recent meta-analysis of weight gain following smoking cessation has been published by Aubin and colleagues in the British Medical Journal.This study reviewed 62 research trials of smoking cessation using a variety of interventions including nicotine replacement, bupropion, varenicline and exercise. Combining data across a variety of studies produces a good estimate of the amount and pattern of weight gain.This study also examined the potential effect of weight gain concern on weight outcome. It is possible that those most concerned about weight gain might make adjustments in dietary intake or exercise level to moderate the effect of smoking cessation.Additionally, the research team examined the effect of specific type of intervention on weight gain. Bupropion is one of the drugs being investigated as a potential weight loss drug and is a common drug used for smoking cessation. It is reasonable to think that bupropion might be a good smoking cessation intervention in those most concerned about weight gain.The graph presented here summarizes the amount and pattern of weight gain in those successfully stopping smoking. The meta-analysis estimated the average weight gain in the year after smoking cessation was a little more than ten pounds. Most of the weight gain occurs within six months of smoking cessation with approximately half occuring in the first two months.Weight gain is not inevitable with smoking cessation. In the meta-analysis approximately 20% of the quitters lost weight after 12 months. On the flip side, approximately 15% of the quitters gained over 20 pounds by the end of one year.Pre-smoking cessation weight gain concern did not appear to reduce the amount of weight gain. Those most concerned about weight gain, had less weight gain at one and two months but still gained about the same amount of weight by one year.Unfortunately, the review did not find any support for pharmacotherapy to reduce the amount or pattern of weight gain. Bupropion, nicotine replacement and varenicline treatment groups all gained about the same amount of weight as those not treated with pharmacotherapy.The authors of the study note the clinical implications of this study would "suggest that doctors might usefully give patients a range of expected weight gain, although further research should identify the subgroups most at risk of gaining weight and clarify the optimum content and timing of interventions to prevent weight gain after cessation".The economic, health and quality of life benefits of smoking cessation are clear. This study supports the need for additional research to moderate the weight gain that occurs in some individuals successfully quitting cigarettes. Photo of orangutan at the San Diego zoo is from the author's files. The graph in this post is an original graph using data presented in the manuscript.Aubin HJ, Farley A, Lycett D, Lahmek P, & Aveyard P (2012). Weight gain in smokers after quitting cigarettes: meta-analysis. BMJ (Clinical research ed.), 345 PMID: 22782848... Read more »

Aubin HJ, Farley A, Lycett D, Lahmek P, & Aveyard P. (2012) Weight gain in smokers after quitting cigarettes: meta-analysis. BMJ (Clinical research ed.). PMID: 22782848

October 1, 2012
11:42 AM
285 views

The Genetics of Smoking Cessation

by William Yates, M.D. in Brain Posts

Molecular Model of NicotineResearch studies support a significant genetic contribution to alcohol, drug and nicotine dependence. There may be some genetic factors that contribute to a general substance dependence vulnerability. Additionally, some genetic factors may increase risk to specific substances of abuse.A recent review of studies of European descent subjects found a link between cigarette consumption level (number of cigarettes smoked per day) and a region on chromosome 15. This link has biological plausibility because it contains genes related to the cholingergic nicotinic receptor (CHRN).Genetic factors related to nicotine dependence may act in several ways. They may contribute to smoking risk through increasing risk for initiation, increasing risk for heavy smoking and increasing risk for persistence of smoking. Persistent smoking risk may present with failure to respond to smoking cessation interventions.Chen and colleagues from Washington University School of Medicine and the University of Wisconsin recently published an informative study on genetic risk factors and smoking cessation success in the American Journal of Psychiatry.The key elements of the design for this studied included two major components:Smoking Phenotype and Genotype: Over 16,000 U.S. subjects between the ages of 45 and 64 participated in a prospective study of the epidemiology of atherosclerosis. This study included assessment of smoking behavior and genotypingRandomized Clinical Smoking Cessation Trial: Over 1,000 U.S. subjects participated in a clinical trial where they were randomized to one of six interventions: placebo, nicotine patch, nicotine lozenge, sustained release bupropion, nicotine patch plus nicotine lozenge, sustained release bupropion plus nicotine lozenge. All subjects received brief indvidual counseling sessions The research findings from this study were:Smoking Phenotype and Genotype: Specific cholinergic nicotinic receptor haplotypes involving the A5, A3 and B4 receptors were linked to number of daily cigarettes smoked and to the age of smoking cessation. Smoking more cigarettes on a daily basis was associated with a later age at smoking cessation.Randomized Clinical Smoking Cessation Trial: 47.3% of subjects were abstinent from smoking at 8 weeks and receiving any active intervention increased abstinence rates by 87% compared to the placebo group. Pharmacological treatment increased abstinence in the heavy smoking risk genotype but did not increase abstinence in subjects without the heavy risk genotype. The heavy risk genotype subject group had the lowest abstinence rates in those receiving placebo indicating a "resistance" to a placebo effectThe authors note clinical implications of their findings "suggest that the biological effects of these haplotypes affect both smoking heaviness and a decreased ability to quit and that the interaction suggests that pharmacologic treatments are more effective for individuals who are biologically predisposed to have difficulty quitting". The randomized controlled trial in this study did not include the newest U.S. FDA approved smoking cessation drug varenicline. Varenicline is a nicotine receptor partial agonist suggesting it's effectiveness may interact with nicotinic receptor genotype.This study supports the evolution of a more personalized approach to smoking cessation and other drug dependence treatment. Genotyping individual patients holds promise as a way to determine each individual's best treatment approach.Molecular model of the drug nicotine is in the public domain from Wikipedia Commons authored by Esquilo.Tobacco and Genetics Consortium (2010). Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature genetics, 42 (5), 441-7 PMID: 20418890Chen LS, Baker TB, Piper ME, Breslau N, Cannon DS, Doheny KF, Gogarten SM, Johnson EO, Saccone NL, Wang JC, Weiss RB, Goate AM, & Bierut LJ (2012). Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. The American journal of psychiatry, 169 (7), 735-42 PMID: 22648373... Read more »

Tobacco and Genetics Consortium. (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature genetics, 42(5), 441-7. PMID: 20418890

Chen LS, Baker TB, Piper ME, Breslau N, Cannon DS, Doheny KF, Gogarten SM, Johnson EO, Saccone NL, Wang JC.... (2012) Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. The American journal of psychiatry, 169(7), 735-42. PMID: 22648373

September 27, 2012
10:03 AM
331 views

Prazosin for Nightmares in PTSD

by William Yates, M.D. in Brain Posts

Nightmares are a common distressing feature in post-traumatic stress disorder (PTSD). Nightmares pose a difficult clinical challenge as they often do not respond to medications that may reduce other symptoms of PTSD One drug that has received a significant amount of research attention for nightmares is PTSD is the drug prazosin.Prazosin is classified as a sympatholytic drug that is a member of the drug class known as alpha-adrenergic blockers. Prazosin specifically blocks the alpha-1 adrenergic receptor that typically respond to endogenous norepinephrine. Alpha-1 adrenergic receptors on found on smooth muscle and throughout the central nervous system.Prazosin is primarily used for the treatment of hypertension due to it's blockage of norepinephrine-induced vasconstriction. However, through serendipitous clinical experience, prazosin was found to reduce the frequency and severity of nightmares in some individuals.This clinical experience has led to some clinical research on this topic. Hudson and colleagues from Auburn University and the University of South Alabama recently summarized the published research on prazosin for the treatment of nightmares in PTSD. Here are the key findings from their literature review of prazosin for nightmares:Eleven studies have been published (4 open-label trials, 4 chart reviews and 3 placebo-controlled clinical trials)Doses studied typically ranged from 1 mg per day up to 20 mg per day--often beginning at 1 mg and titrated up based on response and adverse effectsA large study of over 200 subjects compared prazosin to quetiapine (an atypical antipsychotic drug) and found prazosin to have equal efficacy in short-term treatment and superior efficacy in long-term treatmentThree placebo-controlled studies enrolled a total of 57 subjects from veteran and civilian populationsAll three placebo-controlled trials found prazosin superior to placeboSome studies found that in addition to improvement in nightmares, prazosin also reduced other PTSD symptomsThe most common adverse effects (dizziness and orthostatic hypotension) tended to be mild and tolerable in most subjectsOne additional important study of prazosin for nightmares has recently been published (the Hudson et al review covered published research through March 2011). Germaine and colleagues from the University of Pittsburgh conducted a randomized, controlled clinical trial comparing prazosin to a behavioral sleep intervention. In this study both prazosin and the behavioral sleep intervention proved superior to placebo. Significant sleep improvements were noted in about 62% of the prazosin and behavioral sleep intervention compared to 25% improvement in the placebo group.Prazosin is not FDA approved for the treatment of nightmares or PTSD and therefore any use in this area is considered "off-label". Individual treatment decisions about prazosin or other drug treatment of nightmares in PTSD should be done with a personal physician who reviews the risk/benefit ratio for treatment options. Behavioral interventions should also be considered as a viable option for the treatment of nightmares.Photo of a pair of eclectus parrots from the San Diego Zoo are from the author's files.Hudson SM, Whiteside TE, Lorenz RA, & Wargo KA (2012). Prazosin for the treatment of nightmares related to posttraumatic stress disorder: a review of the literature. The primary care companion to CNS disorders, 14 (2) PMID: 22943034 Germain A, Richardson R, Moul DE, Mammen O, Haas G, Forman SD, Rode N, Begley A, & Nofzinger EA (2012). Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans. Journal of psychosomatic research, 72 (2), 89-96 PMID: 22281448... Read more »

Germain A, Richardson R, Moul DE, Mammen O, Haas G, Forman SD, Rode N, Begley A, & Nofzinger EA. (2012) Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans. Journal of psychosomatic research, 72(2), 89-96. PMID: 22281448

September 26, 2012
10:49 AM
361 views

Brain Hippocampus Volume in Insomnia/Narcolepsy

by William Yates, M.D. in Brain Posts

Neurogenesis, or the formation or growth of new neurons occurs in relatively few brain regions. One region where neurogenesis occurs is the brain hippocampus--specifically in the region of the hippocampus known as the CA3/dentate gyrus.Neurogenesis in the hippocampus is important because of the key role this region plays in memory. Since memory is an ongoing process, the ability of this region to grow neurons is needed throughout life.However, the hippocampus appears to be vulnerable to environmental and genetic insults. In Alzheimer's disease, early and persistent memory impairment is related to degenerative changes in the hippocampus. In a previous post, I reviewed a brain imaging study that found reduction in brain hippocampal regions for individuals with bipolar affective disorder.In this post, I will review two studies that examined the association of chronic insomnia and the sleep.Neylan and colleagues from the San Francisco VA Medical Center, UCSF and Shanghai Medical Center imaged the brains of 14 male veterans with PTSD and compared them with a control group of veterans without PTSD. Subjects in this study had assessment for the presence and severity of insomnia as well as the quality of sleep.The key results from their study included:PTSD subjects had smaller CA3/dentate gyrus hippocampal volumesSeverity of insomnia ratings correlated negatively with hippocampal volumes in the CA3/dentate subfields (those with more severe insomnia showed greater atrophy of this brain region)Severity of insomnia was strongly correlated with PTSD severitySeverity of insomnia independently contributed about to about 13% of the variance in the CA3/dentate gyrusThe authors note in the discussion section, that their study highlights the important role of insomnia in PTSD and that effective treatment of insomnia may provide a strategy for reducing the brain impact of the disorder.A second study Joo and colleagues from South Korea examined brain hippocampal volumes in a series of subjects with the sleep disorder known as narcolepsy. Narcolepsy is estimated to affect up to 200,000 in the U.S. with only a minority of those affected being diagnosed and treated. Narcolepsy symptoms include excessive daytime sleepiness and a phenomenon known as cataplexy. Cataplexy is a sudden and transient loss of muscle tone often precipitated by intense emotions. Individuals with cataplexy may unexpectedly fall to the ground with temporary paralysis.In the South Korean study, individuals with narcolepsy accompanied by cataplexy demonstrated about a 5 to 6% reduction in the size of the hippocampus compared to the control subjects. Additionally, this study found that hippocampal atrophy (volume reduction) correlated with sleep architecture abnormalities including sleep latency and REM sleep latency measures. The authors conclude their study "provides supportive evidence of the functional and anatomical deficits in medial temporal areas that are related to the severity of narcolepsy".One potential mechanism for insomnia and other sleep disorders to be linked to brain hippocampal atrophy is through a link to autonomic hyerarousal with elevated blood hormonal stress markers such as cortisol. Chronic high cortisol levels appear to contribute to hippocampal damage and atrophy.These two studies emphasize the clinical importance of insomnia and sleep disruption. Long-term sleep disruption may impact have adverse effects on brain structure and function. Some of this brain impairment may relate to insults to the brain hippocampusIn the next post, I will examine a review of the treatment of nightmares with the drug prazosin.Figure highlighting the brain hippocampus is from a screen shot from the iPad app 3D Brain from the author's files.Neylan TC, Mueller SG, Wang Z, Metzler TJ, Lenoci M, Truran D, Marmar CR, Weiner MW, & Schuff N (2010). Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. Biological psychiatry, 68 (5), 494-6 PMID: 20598672... Read more »

Neylan TC, Mueller SG, Wang Z, Metzler TJ, Lenoci M, Truran D, Marmar CR, Weiner MW, & Schuff N. (2010) Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. Biological psychiatry, 68(5), 494-6. PMID: 20598672

Joo EY, Kim SH, Kim ST, & Hong SB. (2012) Hippocampal volume and memory in narcoleptics with cataplexy. Sleep medicine, 13(4), 396-401. PMID: 22361297

September 25, 2012
11:11 AM
299 views

Twin Studies of the Genetics of Insomnia

by William Yates, M.D. in Brain Posts

Genetic and environmental factors contribute to the risk for insomnia. Understanding these contributions may provide insight into the biological mechanisms and treatment strategies. Twin studies allow for estimation of the relative role of genetic and environmental factors. Two recent research studies using a twin design focused on insomnia in children, adolescents and adults. Gehrman and colleagues from the University of Pennsylvania and Virginia Commonwealth University conducted a study of insomnia symptoms in a series of 1412 twin pairs ages 8 to 16 years. Approximately half of these twin pairs were monozygotic and half dizygotic pairs.This study also focused on the potential overlap of genetic contributions to anxiety and depression and the effect these disorders might have on the specific heritability of insomnia symptoms. Insomnia symptoms are common in anxiety disorders and mood disorders. A genetic risk for either of these disorders may also pass along a elevated risk for insomnia symptoms.The prevalence of insomnia symptoms in the twin samples was estimated using ratings obtained from the child and parents. Child ratings of clinically significant insomnia were positive in 19.5% of the sample. Parental ratings of their child's sleep patterns showed only 6.6% with clinically insomnia ratings. Overanxious disorder was relatively common in the twin sample (18.0%) while depression was relatively rate at 1.3% of the sample.Genetic contributions to insomnia symptoms in this twin sample ranged from 31% to 51% depending on whether child, parent or combined reports were analyzed. Unique environmental effects (rather than shared environmental effects) appeared to contribute to the remaining insomnia risk. However, this study did not find a specific heritability risk for insomnia once genetic risks for overanxious disorder and depression were controlled. A single genetic factor appeared to explain the risk for depression, overanxious disorder and insomnia symptoms. One unique environmental factor was found to contribute to insomnia risk.A second twin study conducted by Drake and colleagues at Wayne State College of Medicine and the University of Colorado focused on insomnia symptoms in twins with a mean age of 22.5 years. This study also looked a phenomenon known as sleep reactivity. I had not been familiar with this concept but it relates to a subjective rating of sleep difficulty in nine situations:before an important meeting the next dayafter a stressful experience during the dayafter a stressful experience during the eveningafter receiving bad news during the dayafter watching a scary movie or television showafter a bad day at workafter an argumentbefore a public speaking engagementbefore going on a scheduled vacationA sleep reactivity total score was obtained using a validated questionnaire known as the FIRST in the twin adult sample. The prevalence of insomnia in this sample was 21%. The heritability for sleep reactivity was estimated at 29% for women and 43% for men. The heritability for insomnia was estimated at 43% for women and 55% for men. The remainder of the risk for sleep reactivity and insomnia was explained by unique environmental contributions. Sleep reactivity ratings and insomnia symptoms shared a common genetic factor in this adult twin sample. The authors note in the conclusion section of the manuscript that their findings may indicate "that sleep reactivity is, at least in part, a genetic predisposing factor for insomnia" and "sleep reactivity may be a necessary but nonsufficient trait that conveys a vulnerability to insomnia that is manifested following exposure to stressful triggers over time". The potential role for anxiety and depression in the contribution to insomnia risk was also examined in the adult twin sample. FIRST scores were elevated in twins with anxiety or depression. But the analysis indicated sleep reactivity is in part "a dimension independent of these mood disorders". Combined these two studies support a genetic contribution to insomnia explained in part by the genetic contribution to anxiety and depression. However, sleep reactivity appears to be a valid trait worthy of further study in the genetics and pathophysiology of insomnia.Photo of Eurasian owl from the San Diego Zoo from the author's files. Gehrman PR, Meltzer LJ, Moore M, Pack AI, Perlis ML, Eaves LJ, & Silberg JL (2011). Heritability of insomnia symptoms in youth and their relationship to depression and anxiety. Sleep, 34 (12), 1641-6 PMID: 22131600 Drake CL, Friedman NP, Wright KP Jr, & Roth T (2011). Sleep reactivity and insomnia: genetic and environmental influences. ... Read more »

Gehrman PR, Meltzer LJ, Moore M, Pack AI, Perlis ML, Eaves LJ, & Silberg JL. (2011) Heritability of insomnia symptoms in youth and their relationship to depression and anxiety. Sleep, 34(12), 1641-6. PMID: 22131600

Drake CL, Friedman NP, Wright KP Jr, & Roth T. (2011) Sleep reactivity and insomnia: genetic and environmental influences. Sleep, 34(9), 1179-88. PMID: 21886355

September 24, 2012
11:10 AM
264 views

Epidemiology of Insomnia

by William Yates, M.D. in Brain Posts

Insomnia is a common clinical symptom found in a variety neuroscience disorders. In the next series of posts, I will look at some of the recent research in the epidemiology, genetics, neuroimaging and treatment of insomnia.Defining the trends in prevalence and treatment for insomnia is an important part of clinical knowledge. Calem and colleagues recently published the results of their research for the trends in prevalence and treatment of insomnia in England over the period of 1993 to 2007.This study contrasted the rates for insomnia in the general British population using the British National Surveys of Psychiatric Morbidity. In this study they limited their population to participating subjects between the ages of 16 and 64. Data on older subjects is available in later surveys but not for the earlier surveys.For the purposes of the study, the research team looked at four definitions of insomnia. The key element for each of these definitions included:1. Symptoms of insomnia: any complaint of onset or sleep maintenance insomnia in the preceding month2. Moderate severity insomnia: spending more than one hour falling asleep or getting back to sleep at least four times in the past week3. Insomnia with daytime fatigue: Any onset or sleep maintenance insomnia in the past month accompanied by endorsement of significant daytime fatigue in the last month4. Diagnosis of insomnia: symptoms consistent with a DSM-IV diagnosis of insomnia: moderate severity insomnia (as in 2 above), daytime fatigue and duration of at least six monthsThe prevalence of each type of insomnia definition increased in prevalence over time. Rates for any symptoms of insomnia increased from 35.0% of the population in 1993 to 38.6% of the population in 2007. Rates for moderate severity insomnia increased from 9.3% to 13.2%, rates of insomnia with daytime fatigue increased from 12.6% to 13.9% and rates of an insomnia diagnosis increased from 3.1% to 5.8% of the population.Risk factors for reaching a clinical diagnostic threshold for insomnia included:Female genderOlder ageLower educationUnemployed, retired, in full-time education or homemakerWidowed, divorced or separated marital statusMost of the risk factors reached modest odds ratios, i.e. 1.0 to 2.3. However, presence of depression had a high odds ratio for clinical insomnia diagnosis at 10.9.The survey also examined rates of psychotropic hypnotic use in the population. The rate for sleeping pill use increased from 0.4% of the population to 0.8% of the population between 1993 and 2000, but did not increase between the 2000 and 2007 surveys.The authors conclude that the increasing rates of insomnia in the population mean that "service delivery needs to be considered at multiple levels" in the British National Health System. Additionally, they note that future studies of insomnia need to examine the economic and quality of life effects for this common condition. Photo of a red panda at the San Diego Zoo from the author's files.Calem M, Bisla J, Begum A, Dewey M, Bebbington PE, Brugha T, Cooper C, Jenkins R, Lindesay J, McManus S, Meltzer H, Spiers N, Weich S, & Stewart R (2012). Increased prevalence of insomnia and changes in hypnotics use in England over 15 years: analysis of the 1993, 2000, and 2007 National Psychiatric Morbidity Surveys. Sleep, 35 (3), 377-84 PMID: 22379244... Read more »

Calem M, Bisla J, Begum A, Dewey M, Bebbington PE, Brugha T, Cooper C, Jenkins R, Lindesay J, McManus S.... (2012) Increased prevalence of insomnia and changes in hypnotics use in England over 15 years: analysis of the 1993, 2000, and 2007 National Psychiatric Morbidity Surveys. Sleep, 35(3), 377-84. PMID: 22379244

September 21, 2012
11:56 AM
308 views

The Adolescent Brain: TED Talk By Blakemore

by William Yates, M.D. in Brain Posts

Brain imaging technology advances provide an opportunity to better understand brain development through childhood and adolescents.Historically, brain developmental research during childhood predominated. However, we are now are beginning to understand the role of adolescence in the final stages of brain development.Sarah-Jayne Blakemore studies social neuroscience from her lab in England. She recently presented a summary of her research in adolescent brain development at the 2012 TED. Here are my notes from her TED presentation that is about 12 minutes long. The video is embedded below for those interested in viewing the presentation:fMRI technology allows better understanding of structural and functional brain developmentOur understanding of human brain development is expandingAdolescence=beginning of puberty to time of independence as an adultPrefrontal cortex is key to a variety of cognitive functionsDecision makingPlanningInhibiting inappropriate behaviorSocial interactionSelf awarenessGray matter volume:Peaks in early adolescence (later for boys than girls)During adolescence gray matter declines in volumeDecline in gray matter volume related to synaptic pruningWeaker branches (connections) pruned so other circuits can thriveFunctional MRI:Our lab focuses on the social brainPhoto of soccer game shows social brain and the instinctiveness of emotional responseHumans are excellent at judging emotional response of othersIn our lab, adolescents mPFC brain regions are more active during emotional responseAdolescents and adults use different approaches to decision makingError improvement in social decision making stalls during early adolescenceHistorical evidence exists of the behavioral problems of adolescents (Shakespeare)Risk taking is increased during adolescents, particularly when with peersBrain limbic system modulates risk taking and rewards for behaviorThe prefrontal cortex is the brake on the limbic system but lags development of risk/reward brain regionsThe adolescent brain presents "fantastic opportunity" to for education and brain trainingA more comprehensive scientific review of the work of Dr. Blakemore has been recently published in Nature Neuroscience. In this manuscript she reviews a series of brain imaging experiments in adolescent subjects. Her review is structured into the following sections:Impulsivity and inhibitory control: The delayed development of the prefrontal cortex (PFC) appears to result in a relative lack of inhibitory control thereby increasing impulsive behaviors. Adolescents may tap into PFC when judging risk but this appears to require quite a bit of regional brain activation compared to adults.Intertemporal choice: Studies of cases where individuals have damage to the ventromedial PFC provide insight into the adolescent brain. Without a well-functioning PFC, individuals tend to lose the ability to learn from mistakes as they lack ability to retrieve emotional memories related to poor choices. Similar deficits in adolescents may contribute to poor decision making particularly when in the context of emotional arousal with peers. Learning and prediction errors: Heightened brain reward system development (i.e. the ventral striatum) occurs in adolescents. Adolescents may be more vulnerable to engaging in elevated reward seeking behaviors even in the face of high risk.Impact of emotion on decisions: Adolescents commonly appear to have a deficit in being able to use emotional cues to evaluate risk in decision making. Both children and adults reduce risk taking behaviors when in an emotionally charged setting, while adolescents do not show this control.... Read more »

Blakemore SJ, & Robbins TW. (2012) Decision-making in the adolescent brain. Nature neuroscience, 15(9), 1184-91. PMID: 22929913

September 20, 2012
11:22 AM
234 views

Treatments Options For Pathological Gambling

by William Yates, M.D. in Brain Posts

The quantity and quality of research related to treatment in pathological gambling is disappointing. A good first step in planning treatment interventions in this population is a comprehensive assessment for common co-occurring conditions. A study from Hong Kong in a series of gamblers seeking treatment for their gambling behaviors found a high rate of mood disorders and substance use disorders. Nearly 64% of the sample had one or more major mental disorders.I was unable to find a good recent free-access research review for this post. So, I will highlight several studies of options in treatment.Many individual states in the United States have established online gambling resources. These are typically free resources that can provide assessment and local treatment referrals. Two examples of these types of state site include Iowa's 1-800-BetsOff and California's Office of Problem Gambling.Cognitive behavior therapy (CBT) appears to have the most research support for effectiveness in the treatment of pathological gambling. Motivational interviewing (MI) may also be an effective intervention although the research support for MI lags that of CBT. Psychological Interventions: One study conducted in Sweden compared the effectiveness of CBT and MI in a series of problem and pathological gamblers seeking treatment. CBT consisted of 8 weekly group sessions lasting 3 hours each. MI consisted of one-on-one sessions typically lasting about an hour and including 4 sessions over an eight week period. Both CBT and MI in this randomized trial proved effective in reducing gambling behavior in a one-year follow up of the participants. Psychopharmacological Interventions: There are no FDA approved pharmacological treatments for the indication of pathological gambling. All research studies have examined a variety of potential "off label" drugs. The two categories of drugs that appear potentially promising for the treatment of pathological gambling are opiate receptor antagonists, i.e. naltrexone and drugs in classes that target the glutamate receptor, i.e. topiramate. One randomized controlled trial of the opiate receptor antagonist nalmefene (20 mg or 40 mg vs placebo) found reduction in the primary outcome measure for the 40 mg dose but not the 20 mg dose.One small study of the glutamatergic drug topiramate found reduction in measures of impulsivity in pathological gamblers. However, this study did not report specific outcomes for gambling behavior.A variety of drug classes have not shown promise for the treatment of pathologic gamblings. Drug classes with some research failing to find effectiveness include: selective serotonin reuptake inhibitors, atypical antipsychotics and mood stabilizers.Conclusion: My review of treatment options in pathological gambling points to a need for larger, well-designed randomized trials of psychological as well as pharmacological interventions. Given the large amount of money involved in the gambling industry, there should be an avenue to finance these types of studies.Gamblers seeking treatment for out of control gambling behavior may want to use local internet or telephone resources for initial education and referral. Cognitive behavior treatment resources (CBT) may be the best route for psychological treatment. Psychiatric assessment for co-occurring mental disorders may also prove helpful. Opiate receptor antagonists or drugs targeting the glutamate receptor may be considered in the context of individual assessment and risk/benefit review with a personal physician.Photo of juvenile male cardinal is from the author's files. Shek DT, Chan EM, & Wong RH (2012). Associations between pathological gambling and psychiatric comorbidity among help-seeking populations in Hong Kong. TheScientificWorldJournal, 2012 PMID: 22778700Carlbring P, Jonsson J, Josephson H, & Forsberg L (2010). Motivational interviewing versus cognitive behavioral group therapy in the treatment of problem and pathological gambling: a randomized controlled trial. Cognitive behaviour therapy, 39 (2), 92-103 PMID: 19967577Grant JE, Odlaug BL, & Schreiber LR (2012). Pharmacological Treatments in Pathological Gambling. British journal of clinical pharmacology PMID: 22979951... Read more »

Shek DT, Chan EM, & Wong RH. (2012) Associations between pathological gambling and psychiatric comorbidity among help-seeking populations in Hong Kong. TheScientificWorldJournal, 571434. PMID: 22778700

Grant JE, Odlaug BL, & Schreiber LR. (2012) Pharmacological Treatments in Pathological Gambling. British journal of clinical pharmacology. PMID: 22979951

Grant JE, Odlaug BL, Potenza MN, Hollander E, & Kim SW. (2010) Nalmefene in the treatment of pathological gambling: multicentre, double-blind, placebo-controlled study. The British journal of psychiatry : the journal of mental science, 197(4), 330-1. PMID: 20884959

Berlin HA, Braun A, Simeon D, Koran LM, Potenza MN, McElroy SL, Fong T, Pallanti S, & Hollander E. (2011) A double-blind, placebo-controlled trial of topiramate for pathological gambling. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. PMID: 21486110

September 19, 2012
11:00 AM
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The Gambler's Brain: Striatum Responsivity

by William Yates, M.D. in Brain Posts

In two previous posts, I have highlighted what is known about the genetic contribution to pathological gambling behavior and the cognitive bias known as illusion of control that may contribute to gambling risk.In this post, I will review a recent fMRI study of brain response to cues in pathological gamblers compared to controls.van Holst and colleagues from the Netherlands recently published the results of a fMRI study of 16 problem gamblers in the journal Plos One.The authors of this study note in their introduction the developing model of substance dependence that highlights the key role of response inhibition and salience attribution. Brain responsivity patterns in pathological gamblers appear to have similarities to patterns of substance dependence populations. The brain response to visual gambling cues in gamblers mimics some of the brain response to visual drug cues in substance dependence populations.In the van Holst et al study, behavioral response and salience attribution were studied using a Go/Nogo task and visual cues showing gamble, positive or negative affect and neutral themes.The key findings from the study were:Pathological gamblers made fewer errors in gamble and positive affect trial decisions, but took a longer time to make decisions compared to controlsPathological gamblers showed heightened response to gambling cues in the striatum, dorsolateral prefrontal cortex (DLPFC) and cingulate cortexPathological gamblers appeared to used a brain compensatory mechanism to facilitate their response inhibition in gambling scenariosThese findings support a heightened reward response to gambling stimuli in pathological gamblers. The brain striatum appears to be a key structure in reward response across a wide variety of reward stimuli. Over time, the striatum adapts to an individuals experience and preference for different types of rewards. For the Renior art aficionado, the brain reward response in the striatum, DLPFC and cingulate cortex is activated when viewing the paintings of Renoir. For the pathological gambler, the same reward response system is activated in their favorite gambling settings.The striatum in the human is divided into to regions known as the caudate and the putamen. The figure above demonstrates the locations of these striatum substructures found in the sub-cortical region of the brain.A key new finding from the current study is the apparent adaptive compensatory changes found in brain responsivity in pathological gamblers. Although pathological gamblers have deficits in response inhibition, during gambling tasks they have enhanced activation of brain decision- making circuits. This allows them to be as accurate as controls in decision-making in this environment, albeit with a higher cognitive load and a slower response time.The clinical take home from this study is that changing the enhanced salience response in the gambling setting may be a key component of treatment interventions. Rather than just trying to extinguish the "buzz" gamblers experience in the gambling setting, it may be valuable to establish new healthier reward response cues.Photo of the brain basal ganglia structures including components of the striatum are the author's iPad screen shot from the app 3D Brain.van Holst RJ, van Holstein M, van den Brink W, Veltman DJ, & Goudriaan AE (2012). Response inhibition during cue reactivity in problem gamblers: an fMRI study. PloS one, 7 (3) PMID: 22479305... Read more »

van Holst RJ, van Holstein M, van den Brink W, Veltman DJ, & Goudriaan AE. (2012) Response inhibition during cue reactivity in problem gamblers: an fMRI study. PloS one, 7(3). PMID: 22479305

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William Yates, M.D.

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