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June 17, 2013
12:03 PM
76 views

Brain Insula Signals Response to Depression Treatment

by William Yates, M.D. in Brain Posts

In a previous post, I reviewed a research summary of the potential for brain imaging to be a clinical tool in the diagnosis of brain disorders in the mood disorders domain.One of the key points in that review is the value of finding brain biomarkers for response to specific treatments.To follow up on this point, a recent research study has been published that proposes the brain insular cortex region may be key to determining specific treatment response in major depressive disorder.Helen Mayberg from Emory University and colleagues examined a series of subjects with major depressive disorder using positron emission tomography (PET) prior to treatment.The key elements of the design of this study included:Study subjects: Adults between the ages of 18 and 60 with a primary diagnosis of DMS-IV-TR major depressive disorder using the SCID interview followed by psychiatrist interview confirmation. Subjects were required to meet criteria for moderate to severe depression based on a score of 15 or more on the Hamilton Depression Rating Scale. Subjects were also required to be off antidepressants at least 7 days to not be receiving psychotherapyTreatment: Subjects randomized to either escitalopram (Lexapro) 10 to 20 mg or cognitive behavioral psychotherapy (CBT) twice weekly for 4 weeks and then weekly for 8 weeks (16 sessions)Outcome: Following treatment, subjects were grouped into remission versus non-responders based on achieving a lowering of the Hamilton Depression rating scale to 7 or less at both 10 and 12 weeks of treatmentImaging/Analysis: PET brain images were obtained following injection of the tracer drug fludeoxyglucose F18 (FDG). PET images were correlated with MRI anatomical images and analyzed using 2-way analysis of variance (ANOVA) using treatment (CBT/escitalopram) and outcome (remission/nonresponse)The primary finding this research study was that higher glucose metabolism in the right anterior insula region was linked to nonresponse to CBT, while higher glucose metabolism was linked to response to response to drug (escitalopram treatment).From data presented in the study, the rates of meeting a cutpoint for high glucose metabolism in the right anterior insula are noted in the figure to the left.All of the subjects in the CBT nonresponse group had high right anterior insula metabolism. However approximately 90% of drug treatment responders had high right anterior insulsa hypermetabolism demonstrating a treatment by response rate interaction.Another interesting finding from the study was a statistical link between the level of anxiety and response to treatment. CBT nonremitters had higher baseline Hamilton Anxiety Scale scores. High baseline anxiety scores did not influence rate of response in the escitalopram group. The authors did not compare the accuracy of response prediction for the insula PET imaging status to the anxiety level status. Obviously, adminstration of an anxiety rating scale would be much easier and less expensive for clinical utility.The authors note in the discussion that an appropriate next-step study would be a randomized prospective trial of CBT and drug treatment where assignment is informed by right insula metabolism status. Comparing the remission rates with this approach with a simple random assignment would give an estimate of the potential yield of this biomarker in the clinical setting.This study is a very important study that builds on the growing evidence that brain imaging hold promise in improving diagnosis and treatment selection in depression and other brain disorders.Readers with more interest in this research can access the free full-text article by clinical on the link in the citation below.Figure of brain insular cortex is from an iPad screen shot of the app Brain Tutor.Chart of remission rates by group is an original chart produced from the research manuscript.McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, & Mayberg HS (2013). Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder. JAMA psychiatry (Chicago, Ill.), 1-9 PMID: 23760393... Read more »

McGrath CL, Kelley ME, Holtzheimer PE, Dunlop BW, Craighead WE, Franco AR, Craddock RC, & Mayberg HS. (2013) Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder. JAMA psychiatry (Chicago, Ill.), 1-9. PMID: 23760393

June 12, 2013
11:25 AM
84 views

Brain Imaging for Diagnosis of Mood Disorders

by William Yates, M.D. in Brain Posts

Brain imaging holds promise for improving the accuracy of diagnosis in brain disorders falling under the psychiatric domain.No reliable and valid brain imaging techniques currently exist for the diagnosis of depression or bipolar disorder. However, research progress has been rapid.Jonathan Savitz from the Laureate Institute for Brain Research and colleagues at Harvard University and Johnson and Johnson Research and Development recently summarized the current state of knowledge in brain imaging for the diagnosis of mood disorders.Savitz participated in an American Psychiatric Association Consensus group that worked on a consensus document on this topic. The current paper addresses some of the elements of this effort.Following an introduction the topic, the manuscript reviews the importance of biomarker definition, validation and qualification of this topic. Key points in this area include:NIH definition of a biomarker: "A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic response to a therapeutic intervention".US FDA and European Medicines Agency definition of types of biomarkers that can be applied to drug development: prognostic biomarkers, predictive biomarkers, pharmacodynamic biomarkers and surrogate end point biomarkersIt is important to distinguish between the validation and qualification in determining the utility of a biomarkerValidation refers to the reliability, sensitivity and specificity of a measurement in the targeted biological constructQualification refers to the approval of a biomarker that "refers to the establishment of a credibility of a biomarker in its application to questions specifically relevant to drug development".Savitz summarizes some of what is known about brain imaging research in mood disorders that may be promising targets for biomarkers, diagnostic assessment and response to treatment:Brain gray matter volume reductions: major depression and risk for major depression appear to be linked to gray matter reductions in multiple brain regions including the hippocampus, anterior cingulate cortex, prefrontal cortex, hypothalamus, pallidum and habenulaBrain white matter abnormalities: late onset depression appears linked to white matter hyperintensities suggesting a vascular pathology, both major depression and bipolar disorder subjects show white matter diffusion tensor imaging changes suggestive of structure integrity pathologyIn vivo neuroreceptor abnormalities: Positron imaging technology (PET) imaging studies show reduction in postsynaptic serotonin 1A receptor function in the temporal cortex of both major depression and bipolar depression subjectsFunctional MRI response to tasks: A study of fMRI hemodynamic response to sad faces produced a test with 82% sensitivity and 89% specificity to classify subjects as depressed or non-depressedResponse to pharmacological treatment: A study using machine learning techniques and voxel-based morphology was able to predict response to fluoxetine in depression with a sensitivity of 89% and a specificity of 89%In the conclusion section of the manuscript, the authors note using brain imaging in the diagnosis of mood disorders may be hampered by the limitations of the current classification approach. They note, research advances in this area may be quickened through use of the NIMH Research Domain. This effort seeks to improve the future of neuroscience nosology (classification) using constructs (such as response to reward attainment) known to be linked to underlying neurobiology.Despite significant challenges, I see significant progress in biomarker research in the mood disorders. I think the current approach will ultimately lead to useful clinical tools in diagnosis, treatment selection and treatment research. Dr. Savitz and colleagues have done an excellent job in summarizing the current state of knowledge on this topic and interested readers are directed to the free full-text manuscript that can be accessed by clicking on the link below.Disclosure: I have been employed as a research psychiatrist at the Laureate Institute for Brain Research.Photo of naso tang is from the author's files and was taken at the Oklahoma Aquarium.Savitz JB, Rauch SL, & Drevets WC (2013). Clinical application of brain imaging for the diagnosis of mood disorders: the current state of play. Molecular psychiatry, 18 (5), 528-39 PMID: 23546169... Read more »

Savitz JB, Rauch SL, & Drevets WC. (2013) Clinical application of brain imaging for the diagnosis of mood disorders: the current state of play. Molecular psychiatry, 18(5), 528-39. PMID: 23546169

June 11, 2013
10:54 AM
33 views

Sleep Effects of Orexin Receptor Drugs in Insomnia

by William Yates, M.D. in Brain Posts

In a previous post, I reviewed a recently clinical trial studying the effect of an orexin receptor blocking agent in the treatment of insomnia.Orexin appears to be a neurochemical involved in arousability and motor activity. Preliminary studies suggest the orexin receptor may provide a novel target for hypnotics in the treatment of insomnia.An important question in the effects of orexin is whether the hypnotic effect of orexin simulates the same sleep effects as seen by the more studied benzodiazepine and GABA hypnotics?Bettica and colleagues provide some insight into this question in a study recently published in the journal Neuropsychopharmacology.In their study, human subjects completed a crossover trial of the orexin antagonist SB-649868 with a commonly used hypnotic drug zolpidem. The key elements of the design of their study included:Study subjects: 51 adult males, predominantly of Causcasian raceSleep paradigm: two back to back nightly sleep studies with the first night a baseline polysomnography study followed by a second night with active drug agents. On the second night, subjects were exposed to a recording of ambient traffic noise to simulate sleep disturbanceStudy drugs: SB-649868 10 mg, 30 mg, zolpidem 10 mg and placeboOutcome measures: standard sleep architecture measures as well as analysis of brain EEG spectra analysisStatistical analysis: outcome measures were analyzed using exploratory ANCOVA with cognitive performance after baseline night as a covariate, period and treatment were fixed effects and the subject the random effect in the modelSignificant differences were noted between sleep parameters under the SB-649868 and zolpidem:Total sleep time increased with both doses of SB-649868 and with zolpidem--but the 30 mg dose of SB-649868 produced a statistically significant increase in total sleep time of 19 minutes over zolpidemSlow wave sleep percent increased with zolpidem but not with either dose of SB-649868Sleep latency (time to persistent sleep) was decreased to 19 min in SB-649868 10, 9 min in SB-649868 22 minutes with zolpidem 10 mg compared to 27 minutes with placeboREM sleep latency diminished with both doses of SB-649868 but not with zolpidem EEG power spectra did not change during SWS for both SB-649868 doses. However, zolpidem. However, zolpidem increased EEG spectra low delta activity and decreased 2.25-11.0 Hertz activitySubjective assessment of sleep tended to be consistent with polysomnography results. Subjects rated sleep onset improved the most with 30 mg of SB-649868.Morning cognitive testing results were similar in the three active drug groups compared to placebo. Adverse events were relatively mild, although 29% of the 30 mg SB649868 group endorsed somnolence, a rate higher than the placebo, 10 mg SB649868 and zolpidem 10 mg groups. The authors note that one theoretical concern about orexin receptor drugs is the potential to induce narcolepsy and cataplexy. Some data suggests deficiency in orexin may contribute to risk for narcolepsy.I agree with the authors that orexin antagonist drugs are hold promise in the treatment of insomnia. This study suggest a potential novel mechanism of improving sleep and that these types of drugs are not just "me too" compounds.Photo of clown fish from the Oklahoma Aquarium is from the author's files.Readers with more interest in this research can access the free full-text manuscript by clicking on the link below. Bettica, P., Squassante, L., Groeger, J., Gennery, B., Winsky-Sommerer, R., & Dijk, D. (2012). Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia Neuropsychopharmacology, 37 (5), 1224-1233 DOI: 10.1038/npp.2011.310... Read more »

Bettica, P., Squassante, L., Groeger, J., Gennery, B., Winsky-Sommerer, R., & Dijk, D. (2012) Differential Effects of a Dual Orexin Receptor Antagonist (SB-649868) and Zolpidem on Sleep Initiation and Consolidation, SWS, REM Sleep, and EEG Power Spectra in a Model of Situational Insomnia. Neuropsychopharmacology, 37(5), 1224-1233. DOI: 10.1038/npp.2011.310

June 6, 2013
10:06 AM
42 views

Orexin Antagonist Drugs for Insomnia Treatment

by William Yates, M.D. in Brain Posts

Current drug treatment approaches for insomnia have significant limitations. Benzodiazepine receptor drugs have clinical effectiveness but may contribute to morning sedation and cognitive impairment.One promising drug development target is the orexin receptor. The effect of orexin-A on arousal and sleep has been extensively studied in rat models. Injection of orexin-A into the brain in rats results in increased firing of the locus coeruleus, increased physical activity, reduced sleep time, reduced REM sleep and reduced slow wave or deep sleep.These effects have led to studies of orexin receptor antagonist drugs in both animals and human trials. Paolo Bettica and colleagues in Italy and Germany recently published a study of an orexin antagonist drug in a series of men with primary insomnia.The key elements of the design of this study included:Subjects: 52 males with a diagnosis of primary insomnia confirmed by two baseline nights of polysomnography (sleep lab study) that demonstrated less the 7 hours sleep per night, sleep latency 30 minutes or more and an average time awake after sleep onset of 30 minutes or moreStudy drug: orexin receptor antagonist SB-649868 administered at 10, 30 or 60 mg 90 minutes before bedtime compared to placeboStudy design: multicenter, randomized, double-blind, placebo-controlled crossover designPrimary outcome measures: polysomnography measures of sleep latency, wake after sleep onset and total sleep timeAdverse effects measures: morning cognitive function testing including the Digit Symbol Substitution Test (DSST) and Verbal Learning Memory TestStatistics: Mixed effect modeling with period and treatment assignment as fixed effects and subjects as random effect. The main findings from the study were:Sleep latency: significant dose-dependent reduction in sleep latency times-55 minutes placebo, 29 minutes 10 mg dose, 22 minutes 30 mg dose and 11 minutes 60 mg dosePercentage of time in REM sleep: significant effects at 30 and 60 mg dose (23%, 25% versus 21% for placebo)Wake time after sleep onset: significant reductions in time awake after onset of sleep was noted for the 30 and 60 mg dose (45 minutes and 35 minutes versus 64 minutes for placebo)Total sleep time: significant dose-dependent increase in total sleep time-368 minutes placebo, 390 minutes 10 mg dose, 418 minutes 30 mg dose, 438 minutes 60 mg doseCognitive testing: 10 mg dose was associated with improved DSST scores, study drug administration was associated with a slight reduction in verbal memory performanceAdverse effects: increased study drug dose was associated with increased ratings of dry mouthStudy drug serum levels were analyzed with a consistent relationship between serum drug levels and improved sleep parameters.The authors noted a primary limitation of their study was restriction to a male sample only. This was done as the authors noted at the time of the study no data on reproductive toxicology in women had been completed. The study only focused on acute effects and does not provide any information on long-term effects of the drug on sleep.This study is an important study and will likely lead to additional clinical trials of orexin receptor antagonist drugs in insomnia. In the U.S., a Food and Drug Administration Advisory Committee recently recommended approval of the orexin receptor antagonist suvorexant for the treatment of insomnia. This signals that this class of agent may soon be available for clinical use.Photo of yellow crowned night heron from the authors files. Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, & Ratti E (2012). The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep, 35 (8), 1097-104 PMID: 22851805... Read more »

Bettica P, Squassante L, Zamuner S, Nucci G, Danker-Hopfe H, & Ratti E. (2012) The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep, 35(8), 1097-104. PMID: 22851805

June 4, 2013
11:01 AM
208 views

Melatonin for Insomnia: Research Summary

by William Yates, M.D. in Brain Posts

Molecular Model of MelatoninInsomnia is a common problem in the general population and is linked to greater health care utilization and increased mortality risk.Primary sleep disorder including primary insomnia are conditions that are not explained by a medical, substance use or mental disorder. Treatment options for primary sleep disorders include psychological interventions and medications. Melatonin is a commonly used drug that is available over the counter in the United States.The effectiveness of melatonin in the treatment of sleep disorders has received significant attention in multiple clinical trials in adults and children. Eduardo Ferracioli-Oda from the University of Sao Paulo in Brazil along with U.S. colleagues recently published a meta-analysis of melatonin clinical trials in the journal PLOS One.In the literature review the authors identified 19 studies that met criteria for inclusion of:Diagnosis: primary sleep disorder by DSM-IV criteriaDesign: randomized placebo controlled trials with at least 10 subjects (5 subjects if design was crossover)Study drug: primary study drug was melatoninResults published in EnglishUsing this approach, the authors were able to examine the effect of melatonin in a total of 1683 subjects with a primary sleep disorder. The summary of their analysis included the following key points:Dosage: melatonin dosage ranged from 0.5 mg to 5 mg in the studiesEffect on sleep latency (time to fall asleep): using all available data the effect of melatonin on sleep latency was a 7.1 minute reduction in time to fall asleep (95% confidence interval of 4.4 to 9.8 min)Effect on total sleep time: melatonin increased total sleep time by and estimated 8.3 minutes (95% confidence interval of 1.8 to 14.8 minutes)Effect on sleep efficacy (percent of time asleep while in bed): standardized mean difference of .22 (95% confidence interval of .13 to .32)The authors note in the discussion, that their analysis generally supports the effectiveness of melatonin in the treatment of primary sleep disorders including insomnia. They note the reduction in sleep latency seen with melatonin is somewhat less that with prescription hypnotic drugs in the benzodiazepine class. Studies of prescription hypnotics typically find a 10 to 20 minute reduction in sleep latency.Nevertheless, I agree with the author's conclusions that melatonin has a role to play in insomnia treatment due to it's relatively safe side effect profile, low cost and lack of long-term risk for tolerance and dependence.Although available without a prescription, individuals with significant sleep complaints should have a medical assessment to rule out a primary medical or mental disorder. Then an informed discussion of the options for treatment of primary sleep problems can be reviewed with a clinician.Molecular model of the chemical melatonin is from a Wikipedia Commons file authored by sbrools.Individuals with more interest in this meta-analysis of melatonin can access the full free-text article by clicking on the link below.Ferracioli-Oda E, Qawasmi A, & Bloch MH (2013). Meta-analysis: melatonin for the treatment of primary sleep disorders. PloS one, 8 (5) PMID: 23691095... Read more »

Ferracioli-Oda E, Qawasmi A, & Bloch MH. (2013) Meta-analysis: melatonin for the treatment of primary sleep disorders. PloS one, 8(5). PMID: 23691095

June 3, 2013
11:09 AM
42 views

Can Brain Imaging Aid in the Diagnosis of ADHD?

by William Yates, M.D. in Brain Posts

Brain Cerebellum Highlighted in PurpleBrain imaging advances to date are predominantly within the domain of research with limited clinical utility.However, brain imaging techniques such as sensitive structural imaging methods, functional connectivity imaging, combined EEG and structural brain imaging and diffusion tensor imaging hold promise for clinical applications.An obvious application would be the use of brain imaging in confirmation of the diagnosis of brain disorders. Such methods would be particularly helpful in disorders with atypical presentations or diagnostic uncertainty.Lim and colleagues from the United Kingdom and Singapore recently published a study examining brain MRI with voxel-based morphometry in the classification of adolescents with ADHD.This study had the following key components in design:Study subjects: 29 male adolescents (primarily ADHD medication-naive) between the ages of 10 and 18 with ADHD combined typeControl subjects: 29 age-matched males without a diagnosis of ADHD and with low ADHD symptom scoresPsychiatric control subjects: 19 age-matched adolescents with a diagnosis of autism spectrum disorder (ASD)Imaging technique: whole brain MRI imaging with a GE 3T scanner using voxel-based morphometry (VBM) with application of the DARTEL algorithmStatistical analysis: multivariate pattern recognition comparing ADHD, controls and ASD groupsThe study identified significant patterns in ADHD, ASD and control groups:ADHD adolescents showed early development of ventral brain regions of the frontal, premotor, temporal, limbic and brain stem regionsControl adolescents showed later brain development in regions of the dorsolateral prefrontal cortex, anterior cingulate, dorsal striatum, thalamus and inferior parietal regionsASD adolescents could be discriminated from ADHD adolescents by difference in the cerebellum, anterior cingulate cortex, caudate/thalamus, temporal and parietal regionsIn the more traditional VBM analysis, the most statistically different findings between ADHD and controls was a reduction in grey matter involving the right and left cerebellumThe authors noted in the discussion that regions identified with the most discrimination power for ADHD included key brain regions known in "mediating the higher level cognitive control, attention and timing functions that are impaired in ADHD". Accuracy of diagnosis is a key statistical measure of the power of a diagnostic tool. In this study, the algorithm achieved an overall accuracy of 79.3% in classifying cases and controls.This study will need to be replicated in independent samples by independent laboratories to confirm specific brain region findings and to confirm the accuracy estimate. Additionally, because imaging is an expensive tool, it's utility will need to be contrasted with other less expensive diagnostic tools such as rating scales and neuropsychological testing.Nevertheless, this study points to the approaching utility of brain imaging as a diagnostic tool in the diagnosis of ADHD and other brain disorders. Early accurate identification can provide clinicians with the opportunity to provide early interventions that may modify the course and severity of the disorder.So what is the answer to the question "Can Brain Imaging Aid in the Diagnosis of ADHD?" I would propose the answer is yes, but not yet. However, I believe further research including advances in cost-effectiveness will soon make structural brain imaging an important diagnostic tool in ADHD.Image of brain cerebellum is from an iPad screen shot using the app 3D Brain.Readers with more interest in this research can access the full free text article in the citation link below.Lim L, Marquand A, Cubillo AA, Smith AB, Chantiluke K, Simmons A, Mehta M, & Rubia K (2013). Disorder-specific predictive classification of adolescents with attention deficit hyperactivity disorder (ADHD) relative to autism using structural magnetic resonance imaging. PloS one, 8 (5) PMID: 23696841... Read more »

Lim L, Marquand A, Cubillo AA, Smith AB, Chantiluke K, Simmons A, Mehta M, & Rubia K. (2013) Disorder-specific predictive classification of adolescents with attention deficit hyperactivity disorder (ADHD) relative to autism using structural magnetic resonance imaging. PloS one, 8(5). PMID: 23696841

May 30, 2013
11:30 AM
199 views

Serotonin 2 Receptor May Be A Key Cocaine Addiction Target

by William Yates, M.D. in Brain Posts

3-Dimensional Model of Cocaine MoleculeCocaine dependence remains a significant public health problem in the U.S. and throughout the world. Relapse rates in cocaine dependence are high despite aggressive psychological interventions. No evidence-based pharmacological treatments are currently available as adjunctive measures in cocaine dependence.However, drug development in the treatment of cocaine dependence is an active area of research. Although cocaine and other stimulants appear to target dopamine and the dopamine receptor, serotonin receptors also appear to be key in the biological mechanisms of initiation, maintenance and relapse.Cunningham and colleagues recently published a paper in the journal ACS Chemical Neuroscience looking at serotonin receptor subtype synergism as a promising target for cocaine addiction.The authors begin by noting that behavioral impulsivity and cue reactivity are key components to relapse. These relapse behaviors appear to be regulated by serotonergic receptors and brain circuits affected by serotonin neurons.In their experiment, they set out to conduct a proof-of-concept analysis to determine the effect of a combination of a serotonin 2A receptor antagonist (M100907) and a serotonin 2C receptor agonist (WAY 163909) on a rat model of markers for behavioral impulsivity and cue reactivity.The key elements of the design of their study included a series of controlled experiments on male Sprague-Dawley rats. Some of these experiments took place in rats that self-administered cocaine.The primary findings from the study were that a combination of M100907 and WAY163909 synergistically produced in the rat model:a reduction in cocaine-induced hyperactivitya reduction in impulsive behaviors (inherent and cocaine-evoked)a reduction in cocaine-seeking behavior in a a cue and cocaine-primed reinstatement task Of note, neither of the experimental compounds alone produced similar behaviors underscoring the need for a synergistic serotinin 2A antagonist and 2C agonist combination for the desired effect.The authors note that the mechanism for the synergism in these two serotonin receptors is unknown but that "the synergy between M100907 and WAY163909 suggests the potential for bifunctional ligands with therapeutic efficacy and limited side effects in cocaine dependence".The potential for these types of compounds in other types of stimulant dependence, such as methamphetamine dependence is also promising. Readers with more interest in this topic can access the full text article for a limited type courtesy of the American Chemical Society by clicking HERE.Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE, Watson CS, Gilbertson SR, Rice KC, Rosenzweig-Lipson S, & Moeller FG (2013). Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS chemical neuroscience, 4 (1), 110-21 PMID: 23336050Molecular model of cocaine is from the Wikipedia Commons file authored by Fuse809.Readers with more interest can also view a 3 minute interview of Dr. Cunningham and a colleague discussing their research.... Read more »

Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE, Watson CS, Gilbertson SR, Rice KC, Rosenzweig-Lipson S.... (2013) Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS chemical neuroscience, 4(1), 110-21. PMID: 23336050

May 29, 2013
09:49 AM
38 views

Epidemiology of Childhood Brain Disorders: Conduct Disorder

by William Yates, M.D. in Brain Posts

The U.S. Centers for Disease Control recently published an excellent review of the epidemiology of childhood brain disorders.In a previous post, I reviewed the findings in ADHD and in autism/autism spectrum disorder. In this post, I will summarize some of the key findings of the review for conduct disorder and oppositional defiant disorder.Conduct disorder and oppositional defiant disorder share some characteristics and can be conceptualized as two disorders along a line of severity. Oppositional defiant disorder is typically somewhat less severe and the diagnosis requires at least four of the following frequent behaviors/attitudes for at least six months:losing temperarguing with adultsfailure to comply with rules/adult requestsdeliberate annoyance of otherstendency to blame otherseasily annoyed by othersangry attitudevindictive toward othersChildren with conduct disorder often display features of oppositional defiant disorder but their behavior extends to more serious activities such as aggression towards persons, animals and property. They may also show evidence of serious rule breaking leading to juvenile offenses. Conduct disorder is important to identify because it is an indicator of high risk for future adult antisocial personality disorder and substance abuse. In epidemiological studies of children/adolescents, oppositional defiant disorder and conduct disorder are often estimated by asking parents if their child has been diagnosed/treated for a behavior or conduct disorder. Using this approach the following key findings are noted in the CDC summary:4.6% of children between 3 and 17 years of age have a history of a diagnosed behavioral or conduct disorder3.5% of children in this age range are displaying current symptoms of a behavioral or conduct disorderBehavioral disorder diagnoses are relatively rare before age 5 but increase in rates through out childhood and adolescenceBoys are twice as likely as girls to have a behavioral or conduct disorder with up to 6.2% of boys with a lifetime historyBehavioral disorders appear higher in households with lower educational attainment, lower household incomeHighest rates of behavioral problems in black non-Hispanic children2.1% of children between 8 and 15 years have met criteria for the more severe conduct disorder in the past 12 monthsThis summary highlights the frequency of behavioral disorders. In a typical classroom of 20 to 25 students, one would expect one child to have a diagnosed behavior or conduct disorder.Recent treatment students suggest early identification and behavioral treatment interventions are effective in reducing target problem behaviors and attitudes. Aggressive early identification and treatment of childhood behavioral disorders holds promise to reduce adult antisocial behavior.Individuals with more interest in the CDC summary can access the free full-text article by clicking on the link in the citation below.Photo of clown fish from the Oklahoma Aquarium are from the author's files.Perou R, Bitsko RH, Blumberg SJ, Pastor P, Ghandour RM, Gfroerer JC, Hedden SL, Crosby AE, Visser SN, Schieve LA, Parks SE, Hall JE, Brody D, Simile CM, Thompson WW, Baio J, Avenevoli S, Kogan MD, Huang LN, & Division of Human Development and Disability, National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia (2013). Mental health surveillance among children - United States, 2005-2011. Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 62 (2), 1-35 PMID: 23677130... Read more »

Perou R, Bitsko RH, Blumberg SJ, Pastor P, Ghandour RM, Gfroerer JC, Hedden SL, Crosby AE, Visser SN, Schieve LA.... (2013) Mental health surveillance among children - United States, 2005-2011. Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 62(2), 1-35. PMID: 23677130

May 20, 2013
11:55 AM
82 views

Epidemiology of Childhood Brain Disorders: ADHD and Autism

by William Yates, M.D. in Brain Posts

The U.S. Centers for Disease Control has published a comprehensive summary of the epidemiology of childhood brain disorders in the most recent Morbidity and Mortality Weekly Report.This report produced some sensationalized headlines that up to 20% of children suffer from a mental disorder. However, I was more interested in looking at the prevalence estimates for some of the individual disorders from the report.The report collates data collected from a variety of surveys and data sets including the NHANES, NHIS and the National Survey of Children's Health (NSCH). These surveys typically use parental report to estimate prevalence ratesFor the purposes of this post, I will focus on two childhood brain disorders: attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).The key findings from the report in ADHD include:7.6% of parents reported their child between 3-17 years had received a diagnosis of ADHD in the NHIS8.9% of parents reported their child received a diagnosis of ADHD in the NSCH study9.6% to 12.3% of boys had received a diagnosis of ADHD3.8% to 5.4% of girls had received a diagnosis of ADHDA diagnosis of ADHD was more with older age, in children with health insurance and higher income groupsA diagnosis of ADHD was not related to parental education level The key findings from the report for autism and autism spectrum disorder include:.8% to 1.1% of parents reported their child between 3-17 years had received a diagnosis of autism1.8% of parents reported their child had received a diagnosis of ASDSurveys consisted noted a male predominance with boys having an estimated 3.5 to 4.5 times higher rate of autism and ASD diagnosisAgain having health insurance increased the rate of autism or ASD diagnosis by around two foldAutism and ASD prevalence rates were somewhat higher in the Northeast region of the U.S. and in white, non-Hispanic childrenIn contrast to ADHD, ASD rates were similar across parental income categoriesThe report notes in the discussion section: "Substantial but not insurmountable challenges to surveillance of mental disorders in children exists." They note current methods focus on parental reports and are biased by variability in access to health and mental health providers. The also note the imperfect diagnostic approach to childhood mental disorders and the need for more consistent diagnostic approaches.This report is a good comprehensive summary of what we know about these childhood brain disorders in the United States. Readers with more interest in this topic can access the free full text report in the citation below. In the next two posts, I will summarize key findings in the conduct disorder and affective disorder categories.Photo of clown fish from the Oklahoma Aquarium is from the author's files.Perou R, Bitsko RH, Blumberg SJ, Pastor P, Ghandour RM, Gfroerer JC, Hedden SL, Crosby AE, Visser SN, Schieve LA, Parks SE, Hall JE, Brody D, Simile CM, Thompson WW, Baio J, Avenevoli S, Kogan MD, Huang LN, & Division of Human Development and Disability, National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia (2013). Mental health surveillance among children - United States, 2005-2011. Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 62 (2), 1-35 PMID: 23677130... Read more »

Perou R, Bitsko RH, Blumberg SJ, Pastor P, Ghandour RM, Gfroerer JC, Hedden SL, Crosby AE, Visser SN, Schieve LA.... (2013) Mental health surveillance among children - United States, 2005-2011. Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 62(2), 1-35. PMID: 23677130

May 10, 2013
10:33 AM
102 views

Insula Activation as a Biomarker for Depression Risk

by William Yates, M.D. in Brain Posts

Right and Left Insula Cortex Highlighted in TealBiomarker research in brain disorders including schizophrenia and mood disorders is an important pathway to early identification and prevention.In a previous post, I reviewed a summary of current biomarker research in schizophrenia. This summary suggested that accelerated brain gray matter volume decline during childhood and adolescence is a candidate biomarker in schizophrenia.In this post, I will look at a similar imaging biomarker study in bipolar and unipolar mood disorder. Heather Whalley and colleagues from the Division of Psychiatry at the University of Edinburgh recently published a fMRI activation study in a group of asymptomatic high-risk mood disorder subjects.The key elements of the design of their study included the following:Study subjects: 98 case subjects were identified between the ages of 16-25 with a first degree relative identified as having a diagnosis of bipolar I. Control subjects were identified as a matched age group with no first degree relative with bipolar disorder.Clinical assessment: Cases and control were interviewed at baseline and two years later for presence of a mood disorder using a structured interview of DSM-IV diagnoses (SCID)Imaging protocol: fMRI imaging was completed for cases and controls using the Hayling sentence completion test. This test provides a sentence with the last word missing and subjects are expected to think of a word to complete the sentence while being scanned.Statistical analysis: 18 case subjects developed major depression disorder (MDD) during the follow-up period and were compared to a group of cases who did not develop MDD and controls who did not develop MDD. Groups were also compared on baseline psychometric scores on cyclothymia, neuroticism and extraversion. Potential confounding variables (alcohol and drug use frequency) were also examined.The key results from this study included:fMRI results: High-risk mood disorder subjects who developed MDD in the follow-up period demonstrated increased bilateral insula activation with the sentence completion task compared to high-risk subjects not developing MDD and healthy controls. Receiver operating characteristic analysis showed the area under the curve for identifying those developing MDD was 0.77 and 0.73 for the right and left insulaPsychometric tests: High-risk individuals who developed MDD in follow-up showed higher baseline scores on cyclothymia and depression on the Temperament and Personality Measures (TEMPS-A) score and higher scores on the neuroticism and extraversion subscale of the NEO-Five Factor Inventory. The authors note the insula is known to be a "part of a network of regions that plays a key role in the regulation of emotion, including emotional processing, response inhibition, and in the experience of emotion".Psychometric measures of cyclothymia, neuroticism and extraversion correlated with increased insula hyperactivity supporting the validity of these measures as additional biomarkers for depression risk. Since these measures are relatively inexpensive to obtain, they may hold clinical utility in identifying high-risk adolescents for close monitoring.Due to cost, fMRI is not yet practical for use in clinical populations. However, this study supports the promise of fMRI in future studies that might identify mechanisms and potential treatments to prevent depression in those at highest risk.Readers with more interest in this subject can access the free full-text manuscript by clicking on the PMID link in the citation below.The image of the bilateral insula cortex is an iPad screen shot from the Brain Tutor app.Whalley HC, Sussmann JE, Romaniuk L, Stewart T, Papmeyer M, Sprooten E, Hackett S, Hall J, Lawrie SM, & McIntosh AM (2013). Prediction of depression in individuals at high familial risk of mood disorders using functional magnetic resonance imaging. PloS one, 8 (3) PMID: 23483904... Read more »

Whalley HC, Sussmann JE, Romaniuk L, Stewart T, Papmeyer M, Sprooten E, Hackett S, Hall J, Lawrie SM, & McIntosh AM. (2013) Prediction of depression in individuals at high familial risk of mood disorders using functional magnetic resonance imaging. PloS one, 8(3). PMID: 23483904

May 9, 2013
11:24 AM
76 views

Biomarkers for Psychosis and Schizophrenia Risk

by William Yates, M.D. in Brain Posts

Prefrontal Cortex Highlighted in RedIdentifying valid biomarkers for psychosis and schizophrenia is an active focus in brain research.Tyronne Cannon, Ph.D. from Yale University recently presented a summary of research on this topic at the William K. Warren Neuroscience Symposium in Tulsa, Oklahoma. Here are my notes from his presentation along with related free full-text research references.Biomarker research in psychosis is important because current treatment for psychosis with the antipsychotic drugs is limited by:discovery by serendipity without a specific molecular mechanismabsence of effect on psychosis negative symptoms (anergia, anhedonia and amotivation)poor tolerability of antipsychotic drugs with significant compliance issuesno evidence that antipsychotic drugs modify the progression of the diseaseBiomarker research in psychosis is promising because an extended prodrome period is present in childhood and adolescence. Biomarker research can be divided into markers with a progressively deviant pattern and those with a stable deviant pattern.Two studies are available to summarize current findings: The North American Prodrome Longitudinal Study, parts I and II (NAPLS I and NAPLS II). These studies have identified three biomarker candidate categories:Hormonal disruption involving the hypothalamic-pituitary-adrenal (HPA) axisEvent related potential abnormalities including the p300 marker and an NMDA synapse-related marker identified in a negativity mismatch taskBrain magnetic resonance imaging (MRI) showing a greater cortical gray matter volume decline (primarily in bilateral frontal cortex regions) in high-risk individuals who later convert to psychosisThe first two biomarkers appear to be of the stable deviant type while the gray matter deficit biomarker appears to be a progressive deviant markerAn important potential confounding issue in gray matter deficits is the role of antipsychotic drug exposure in producing gray matter changes. Research to date supports an independent contribution of psychosis progression risk with frontal gray matter reductionProgress in understanding the MRI biomarker changes in psychosis/schizophrenia require a better understanding of the mechanism of this change. At least three avenues of research for a mechanism are promising:Disruption of neuroplasticity: fetal hypoxia environments produce impairment in brain neuroplasticity possibly through disruption of the BDNF systemDisruption of brain inflammation: risk for progression to psychosis is linked to increase blood inflammation using a multiplex composite variable. This variable is associated with 35% of the variance in brain gray matter volumesHPA-Glutamate pathways: The glutamate pathway is known to be involved in psychosis with the psychotic effect produce by PCP and ketamine. It is possible glutamate disruption effects gray matter reduction through effects on the microgliaAlthough not discussed in this lecture, other promising targets for understanding psychosis mechanism and risk include: neuropsychologic deficits, brain white matter abnormalities and fMRI activation abnormalities and resting connectivity deficits.Further identification of biomarkers in psychosis will be key in designing prevention strategies and in smart drug development through understanding the mechanism of risk and progression of the disease.Readers with more interest in this topic are directed to the free full-text citations below.Image of the frontal cortex noted to be a biomarker of psychosis risk above is from a iPad screen shot from the Sun D, van Erp TG, Thompson PM, Bearden CE, Daley M, Kushan L, Hardt ME, Nuechterlein KH, Toga AW, & Cannon TD (2009). Elucidating a magnetic resonance imaging-based neuroanatomic biomarker for psychosis: classification analysis using probabilistic brain atlas and machine learning algorithms. Biological psychiatry, 66 (11), 1055-60 PMID: 19729150... Read more »

Sun D, van Erp TG, Thompson PM, Bearden CE, Daley M, Kushan L, Hardt ME, Nuechterlein KH, Toga AW, & Cannon TD. (2009) Elucidating a magnetic resonance imaging-based neuroanatomic biomarker for psychosis: classification analysis using probabilistic brain atlas and machine learning algorithms. Biological psychiatry, 66(11), 1055-60. PMID: 19729150

Seidman LJ, Giuliano AJ, Meyer EC, Addington J, Cadenhead KS, Cannon TD, McGlashan TH, Perkins DO, Tsuang MT, Walker EF.... (2010) Neuropsychology of the prodrome to psychosis in the NAPLS consortium: relationship to family history and conversion to psychosis. Archives of general psychiatry, 67(6), 578-88. PMID: 20530007

Gee DG, Karlsgodt KH, van Erp TG, Bearden CE, Lieberman MD, Belger A, Perkins DO, Olvet DM, Cornblatt BA, Constable T.... (2012) Altered age-related trajectories of amygdala-prefrontal circuitry in adolescents at clinical high risk for psychosis: a preliminary study. Schizophrenia research, 134(1), 1-9. PMID: 22056201

May 2, 2013
10:38 AM
146 views

Redefining Mental Disorders as Brain Disorders: TED Talk of Thomas Insel

by William Yates, M.D. in Brain Posts

Components of Brain Limbic SystemAdvances in the diagnosis and treatment of brain disorders like bipolar disorder, schizophrenia and autism are a public health priority.Dr. Thomas Insel, director at NIMH recently presented a TED talk that emphasized the need to rethink how we conceptualize and study these types of disorders. He argues for a need to redefine mental disorders as brain disorders. Advances in brain research tools are likely to provide improvements in early diagnosis and early treatment to reduce the morbidity and mortality of these brain disorders.I am posting my notes on Dr. Insel's presentation, as well as the fifteen minute YouTube video of the presentation.Additionally, I have provided links to two free full-text manuscripts on this topic for readers with more interest.MY NOTES on TED presentation Mental Disorders as Brain Disorders: Dr. Thomas InselScience can save lives-evidenced by many startling advances in medicine over the last 20 to 30 yearsChildhood cute lymphoblastic leukemia mortality decreased dramatically (90% to 10%)63% reduction in mortality due to heart diseaseAIDS mortality decliningStroke mortality decreasing due to early intervention programsEarly detection and early intervention are keyHowever, some areas are not improvingOne example of this is suicide--38,000 suicides per year in U.S., one every 15 minutesSuicide rates have not declined over the last 20 to 30 years90% of suicides linked to diagnosable mental disorders, depression, bipolar disorder, schizophreniaDisability is also common in mental disorders30% of all disability can be traced to disorders of the brain or neuropsychiatric disordersDisability in mental disorders due to fact many have early age of onsetMany are chronic disorder beginning in adolescents and young adultsNew terminology needed to change our thinking and research focusThese diseases are not mental disorders or behavioral disorders but brain disordersHuman brain complex 100 billion neurons, 100 trillion synapsesEvidence these are disorders of the human connectome (wiring circuites of the brain)Depression, OCD, PTSD show evidence of connectivity deficitsSchizophrenia: early deficits in brain gray matter volume of brain cortexGray matter pruning excess in schizophrenia crosses the threshold for psychosisBehavior often the last thing to to change in brain disordersNew tools are emerging in brain disordersThese tools promise early detection and early intervention in brain disordersHow soon with this occur? We don't know but the following quote is relevant:"We always overestimate the change that will occur in the next two years and underestimate the change that will occur in the next ten." quote by Bill Gates, Jr.MY COMMENTS: I agree with the need to redefine many disorders previously defined as mental disorders as brain disorders. The motto of this blog with continue to be "Translating neuroscience research into better care for brain disorders". I believe new brain research tools can lead the way to early diagnosis and treatment. Brain image is an iPad screen shot from the Brain Tutor app.Collins, P., Insel, T., Chockalingam, A., Daar, A., & Maddox, Y. (2013). Grand Challenges in Global Mental Health: Integration in Research, Policy, and Practice PLoS Medicine, 10 (4) DOI: 10.1371/journal.pmed.1001434 Insel, T. (2011). A bridge to somewhere Translational Psychiatry, 1 (4) DOI: 10.1038/tp.2011.4... Read more »

Collins, P., Insel, T., Chockalingam, A., Daar, A., & Maddox, Y. (2013) Grand Challenges in Global Mental Health: Integration in Research, Policy, and Practice. PLoS Medicine, 10(4). DOI: 10.1371/journal.pmed.1001434

Insel, T. (2011) A bridge to somewhere. Translational Psychiatry, 1(4). DOI: 10.1038/tp.2011.4

May 1, 2013
11:54 AM
91 views

Advances In Parkinson's Disease Treatment: Part II

by William Yates, M.D. in Brain Posts

Globus Pallidus Region of Brain Targeted in DBS in YellowIn a previous post, I summarized some of the highlights of a recent review of Parkinson's disease management by the German neurologists Pedrosa and Timmerman.The first post can be located here and was limited to the drug treatment of the motor symptoms of Parkinson's disease.In part II, I want to focus on deep brain stimulation and the treatment of non-motor symptoms.The authors of the review note the following key points regarding deep brain stimulation:Deep brain stimulation (DBS) therapy for Parkinson's disease is considered most effective when the anatomical target is a small area known as the subthalamic nucleus (STN)STN deep brain stimulation improves all the cardinal symptoms of Parkinson's diseaseHowever, compared to previous DBS targets, STN brings with it new short-term adverse effects including "postoperative dysphoria, hypomania and a higher risk of suicide"Adverse effects of STN-DBS appear greater in older patients making this intervention most effective when used in younger patients with severe motor symptomsAn alternative to STN-DBS is surgery targeting the inferior globus pallidus--this target had been felt by some to be less effective than STN-DBS in treating motor symptomsHowever, globus pallidus DBS is regaining some advocates because it is easier to target and appears to cause less psychiatric and cognitive side effects than STN-DBSGlobus pallidus DBS might be best used in older patients with non-motor symptom predominanceAlthough DBS in Parkinson's disease is generally accepted due to clinical experience with thousands of subjects, there is still some debate on whether to use unilateral or bilateral approaches-the authors favor bilateral treatmentDBS is typically reserved for patients with inadequate response to drug treatment Earlier use of DBS holds promise as a potential boost to quality of lifeA randomized trial of earlier use of DBS, the EARLYSTIM study will soon be published and will be important in providing guidance on the timing of DBSThe decision to use DBS should be made by patients and their families after a comprehensive assessment from an interdisciplinary team of neurologists, neurosurgeons, psychiatrists, physical, occupational and speech therapistsReaders with more interest in DBS for Parkinson's disease may find a recent consensus manuscript on the topic that I have previously reviewed here.The current review also includes a detailed discussion of the treatment of non-motor symptoms including sleep disorders (insomnia, REM sleep behavior disorder and restless leg syndrome), excessive daytime sleepiness, autonomic dysfunction (orthostatic hypotension, gastrointestional motility dysfucntion, and urinary dysfunction), erectile dysfunction, impulse control disorders, medication-induced psychosis, dementia and depression.It outside the scope of this post to review the author's recommendations for management of all of the non-motor symptoms of Parkinson's disease. I did find interesting the author's recommendation for use of low-dose clozapine 12.5 mg to 50 mg or quetiapine 25 to 75 mg at bedtime for the management of psychosis. They also noted donepezil at 5 to 10 mg per day may improve psychosis in patients with Lewy body dementia.Additionally, the review highlighted the use of pramipexole 0.35 to 0.7 mg three times daily for the treatment of depression in Parkinson's disease with lower evidence of the effectiveness for standard tricyclic antidepressants or selective serotonin reuptake inhibitors.Readers with more interest in specific non-motor symptom treatment in Parkinson's disease are directed to the free full text manuscript that can be access by clicking on the reference below.Image of globus pallidus is an iPad screen shot from the app Brain Tutor.Pedrosa, D., & Timmermann, . (2013). Review: management of Parkinson's disease Neuropsychiatric Disease and Treatment DOI: 10.2147/NDT.S32302... Read more »

Pedrosa, D., & Timmermann, . (2013) Review: management of Parkinson's disease. Neuropsychiatric Disease and Treatment, 321. DOI: 10.2147/NDT.S32302

April 30, 2013
11:31 AM
173 views

Treatment Advances in Parkinson's Disease: Part I

by William Yates, M.D. in Brain Posts

3D Molecular Model of L-DopaDrug treatment of Parkinson's disease is a complex clinical problem. This complexity relates to several factors including incomplete response, multiple symptom domains and adverse effects of commonly used drugs.David Pedrosa and Lars Timmerman from the Department of Neurology at University Hospital Cologne in Germany have recently published an excellent review of Parkinson's disease management.The review is packed with comprehensive tables with specific drug information. I will summarize some of the review recommendations based on specific symptom category. This summary will be divided into three posts given the volume of clinical management information in the review. Part I will cover the area of motor symptoms in Parkinson's disease, Part II will cover the area of non-motor symptom management. Part III will summarize the author's review of deep brain stimulation.Disease modification: Disease modification is an approach targeting prevention of symptoms or modification of disease progression through early drug treatment. The authors note some progress has been made in Parkinson disease animal models of disease modification. Randomized controlled trials in humans are lacking but the monoamine b inhibitor rasagiline 1 mg daily for 18 months is a possible candidate for Parkinson's disease modification.Management of motor symptoms: Dopaminergic medications including levodopa remain a key category of drugs for motor symptoms. Levodopa is recommend in "older patients as monotherapy or in combination with other drugs even as the first-line option, as it shows high efficacy and good safety".Other dopaminergic agents a key treatment components for younger patients with Parkinson's disease and include: pramipexole, ropinirole, rotigotine and pribedil. The authors note these agents are more likely than levodopa to induce psychiatric and nonmotor side effects and require careful monitoring. COMT-inhibitors such as entacapone, are often combined with levodopa and the combination appears to "improve activities of daily living". MAO B inhibitors such as selegiline and rasagiline appear also to boost the effect of levodopa.Management of specific motor symptoms in Parkison's disease.Dyskinesias and fluctuations: pramipexole, ropinirole, amantadine and clozapine (5-HT and dopamine agonist) are recommended optionsTremor: propanolol (beta blocker of adrenoreceptor), biperiden (muscarinic receptor antagonist) and clozapineFreezing of gait: This phenomen in Parkinson's describes an intermittent behavior seen in advanced disease with sudden freezing behavior of gait, speech or upper limbs. When freezing behavior occurs during "on" medication cycles the authors recommend reducing the dose of dopaminergic medication. A variety of drug approaches for dealing with freezing gait during "off" cycles including amantidine, antidepressant drugs including selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors the stimulant methylphenidate. The authors also note botulism toxin leg injections and deep brain stimulation therapy can be considered here. The lack of randomized controlled trials in freezing gait make this area controversial.Camptocormia: Camptocormia is the phenomenon of severe trunk flexion that can occur both in sitting and standing/walking. The authors note that in this symptom options include dopamine dose adjustment and combining levodopa with entacopone and botulinum toxin injection. Additionally, physical therapy and using a walker with high handle bar position should be considered.One promising innovative area in drug management is the use of pump therapy in Parkinson's disease. These innovations include the implantation of a levodopa/carbidopa intestinal gel (LCIG) pump and a subcutaneous pump using the potent dopamine drug apomorphine. LCIG involves infusion of drug through a percutaneous gastrostomy tube while the apomorphine pump is subcutaneous (under the skin). Both of these pump approaches are relatively early in development but the authors note the promise of LCIG in older patients with levodopa sequelae and patients at high risk for hallucinations. Interested readers can access the free full-text of the review by clicking on the link below.Molecular model of levodopa is from the Wikipedia Commons file authored by Sean Ohlinger.Pedrosa, D., & Timmermann, . (2013). Review: management of Parkinson's disease Neuropsychiatric Disease and Treatment DOI: 10.2147/NDT.S32302... Read more »

Pedrosa, D., & Timmermann, . (2013) Review: management of Parkinson's disease. Neuropsychiatric Disease and Treatment, 321. DOI: 10.2147/NDT.S32302

April 29, 2013
10:37 AM
99 views

Essential Tremor as a Risk Factor for Parkinson's Disease

by William Yates, M.D. in Brain Posts

The number people suffereing from Parkison's disease in the United States is estimated to be between 500,000 and 1,000,000.The key symptoms of Parkinson's disease include tremor and slowed movement or bradykinesia.Known risk factors for Parkinson's disease include advanced age, male gender, family history of Parkinson's disease and exposure to pesticides.Of note, smokers appear to have a reduced risk of Parkinson's disease although the mechanism for this protective effect is unknown.Romero and colleagues from Spain have recently published an important study of the of the epidemiology of essential tremor. This manuscript outlines findings from a large geriatric population based study known as Neurological Disorders of Central Spain (NEDICES).Essential tremor has previously been thought to be a benign condition where cases demonstrate a tremor at rest most notable in the hands and upper extremities. The research team identified 256 cases of essential tremor in a study of over 5000 individuals age 65 and older.The key findings in this study for essential tremor included:Prevalence: 4.8% of individuals over 65 have essential tremor with a slight but not statistically significant higher rate in women (5.0% vs 4.6%)Mortality: Essential tremor was associated with a higher risk of death during follow-up (relative risk estimate of 1.59, 95% confidence interval (CI) of relative risk 1.11 to 2.27)Depression comorbidity: Essential tremor cases were twice as likely to report depressive symptoms and three times more likely to be taking antidepressant medicationCognitive impairment: Essential tremor cases had higher rates of mild cognitive impairment (relative risk 1.57, 95% CI 1.03-2.38) and higher rates of dementia (relative risk 1.70, 95% CI 1.04-2.76)Hearing impairment: Essential tremor suffers had a 30% increased risk of hearing impairmentAlcohol use and smoking: Heavier alcohol use was linked to higher risk of essential tremor and smoking was linked to lower risk of essential tremorA key finding in the study was a link of essential tremor with risk for Parkinson's disease. Although this association had previously been suggested the current study provides one of the first estimates of relative risk for Parkinson's disease in essential tremor.The relative risk for Parkinson's disease (after adjusting for confounding variables) in essential tremor was estimated at over four times that of those without essential tremor. Risk of developing Parkinson's disease in the follow-up period was estimated at a relative risk 3.47, 95% CI 1.82-6.59.For clinicians, this study provides some guidance in the care and surveillance among elderly suffering from an essential tremor. Essential tremor subjects should be monitored closely for the early identification and treatment of Parkinson's disease.Embedded below is a short Youtube video discussing essential tremor along with medical treatment and deep brain stimulation.Readers with more interest in the reviewed manuscript, can access the free full text article by clicking on the citation link below.Photo of osprey is from the author's files.Romero JP, Benito-León J, & Bermejo-Pareja F (2012). The NEDICES Study: Recent Advances in the Understanding of the Epidemiology of Essential Tremor. Tremor and other hyperkinetic movements (New York, N.Y.), 2 PMID: 23439396... Read more »

Romero JP, Benito-León J, & Bermejo-Pareja F. (2012) The NEDICES Study: Recent Advances in the Understanding of the Epidemiology of Essential Tremor. Tremor and other hyperkinetic movements (New York, N.Y.). PMID: 23439396

April 26, 2013
10:51 AM
253 views

MRI Biomarker for Parkinson's Disease Progression

by William Yates, M.D. in Brain Posts

Brain Putamen Highlighted in OrangeThe search for biomarkers for Alzheimer's disease is very active. I have summarized some of the relevant Alzheimer's biomarker research here and here.Biomarker research in Parkinson's disease has been less active.However, a recent research study published in Plos One demonstrated the potential for brain magnetic resonance imaging in Parkinson's disease.Miguel Ulla and colleagues in France conducted a prospective MRI study of 27 subjects with Parkinson's disease and 26 control subjects. The key elements of the design of their study included:Subjects: Case subjects met criteria for idiopathic Parkinson's disease using the criteria from the "Parkinson's Disease Society Brain Bank". Mini Mental Status Examination (MMSE) scores were 26 or greater in the case group indicating the absence of any significant dementia.Parkinson's Disease Severity Measures: Hoehn and Yahr stages, right and left motor scores from the Unified Parkinson's Disease Rating ScaleMRI: 1.5 Telsa MRI focusing on brain ganglia regions mapping the proton transverse relaxation rate R2*.Statistical Analysis: Cases were compared to controls on R2* and cases with two longitudinal MRI scans had R2* compared at each time point and changes were compared with changes in Parkinson's Disease Severity scoresThe results of the study showed promise for the R2* as a biomarker for Parkinson's disease. R2* measures in the basal ganglia regions of the substantia nigra and the caudate putamen were increased in cases compared to controls. Cases rescanned an average of 3 years later showed increases in R2* measures that correlated with the measures of the worsening of motor symptoms.The authors note the R2* relaxation rate in the basal ganglia is likely influenced by the level of iron deposition. Iron deposition is a known pathology in the basal ganglia of Parkinson's disease and correlated with the level of dopamine reduction.The authors note their study is limited by the relatively small sample size and the use of a relatively less powerful 1.5T magnet used in MRI. The note their findings need to be replicated by other sites in larger samples of subjects.Valid Parkinson biomarkers holp promise for several clinical applications. Sensitive biomarkers may allow for early diagnosis and early intervention before the development of clinical symptoms. Clinical symptoms develop relatively late in the course of basal ganglia pathology making earlier identification important.Additionally, the authors note that this type of biomarker may be valuable in assessing the "efficiency of specific iron chelators and disease-modifying treatments".Readers with additional interest in this research can access the full-text article at the link in the reference below.Image of the putamen, a brain region affected in Parkinson's disease is from a screenshot of the iPad app 3D Brain.Ulla M, Bonny JM, Ouchchane L, Rieu I, Claise B, & Durif F (2013). Is R2* a new MRI biomarker for the progression of Parkinson's disease? A longitudinal follow-up. PloS one, 8 (3) PMID: 23469252... Read more »

Ulla M, Bonny JM, Ouchchane L, Rieu I, Claise B, & Durif F. (2013) Is R2* a new MRI biomarker for the progression of Parkinson's disease? A longitudinal follow-up. PloS one, 8(3). PMID: 23469252

April 25, 2013
11:15 AM
121 views

White Matter Changes in Schizophrenia

by William Yates, M.D. in Brain Posts

Schizophrenia is a disabling brain disorder characterized by psychotic symptoms such as hallucinations and delusions.Schizophrenia has a prevalence rate of about 1% of the population with relatively stable rates across nations and cultures.Early brain imaging studies focused on regional evidence of brain atrophy primarily in brain gray matter. However, with the development of diffusion tensor imaging, there is a growing body of research examining white matter changes in schizophrenia. White matter typically functions as connection pathways between brain regions allowing for functional circuitry.Alba-Ferrara and de Erausquin recently summarized what is known about white matter changes in schizophrenia in the journal Frontiers in Integrative Neuroscience. Here are some of the key highlights from their review:The diffusion tensor imaging (DTI) measure of white matter integrity known as fractional anisotropy (FA) is an indirect measure that has limitationsFA is felt to reflect abnormalities in white matter myelinization that may produce functional brain impairmentBrain oligodendrocytes are key neuron components in myelin and abnormalities of oligodendrocytes have been identified in schizophreniaGenetic abnormalities identified in schizophrenia include genes related to oligodendrocyte development and regulationFA abnormalities in schizophrenia include evidence for both increased and decreased FA in multiple brain white matter bundles and brain regionsFA has been found to be increased in schizophrenia in the superior longitudinal fasciculus, arcuate fasciculus, corpus callosum, substantia nigra and ventral tegmental areasFA has been found to be decreased in schizophrenia in the inferior fronto-occipital fasciculus, right anterior corona radiata, left uncinate fasciculus, posterior corona radiata and in whole brainThe distribution of increases in FA are consistent with playing a role in the positive symptoms of schizophrenia, i.e. hallucinations and delusionsThe distribution of decreases in FA are consistent with playing a role in the negative symptoms of schizophrenia, i.e. lack of motivation, apathy, social withdrawalThe authors examined first-degree relatives of individuals with schizophrenia and found evidence of similar (but to a lesser degree) FA abnormalities that have been found in schizophrenic subjectsThese early findings suggest white matter pathology may play a key role in schizophrenia possibly by "aberrant axonal pruning through neurodevelopment leading to maintenance of inefficient/redundant neural networks as in the case of dopaminergic projections".The limitations of FA methodology makes it necessary to cautiously interpret these early studies, new improved white matter analytical techniques are neededI think the authors of this review have provided a good summary of what is known about white matter abnormalities in schizophrenia. Early findings are intriguing but need to be cautiously interpreted. Improved imaging techniques of brain white matter structure and function are needed.Readers with more interest in this topic can access the free full-text review by clicking on the reference below.Photo of sunset in Florida Keys is from the author's files.Alba-Ferrara, L., & de Erausquin, G. (2013). What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia Frontiers in Integrative Neuroscience, 7 DOI: 10.3389/fnint.2013.00009... Read more »

Alba-Ferrara, L., & de Erausquin, G. (2013) What does anisotropy measure? Insights from increased and decreased anisotropy in selective fiber tracts in schizophrenia. Frontiers in Integrative Neuroscience. DOI: 10.3389/fnint.2013.00009

April 24, 2013
11:12 AM
124 views

DTI Identifies Brain Aging Changes

by William Yates, M.D. in Brain Posts

Brain white matter plays a key role in connecting functional brain areas. These connections are required for complex brain processing required for memory and executive functions, i.e planning and problem solving.Diffusion tensor imaging (DTI) is a relatively recent brain imaging tool that provides a method of analyzing regional human white matter function. Additionally, when DTI is paired with cognitive testing it allows for study of the brain regions and circuits responsible for specfic cognitive domains.Efrat Sasson and colleagues from Tel Aviv University in Israel and the United States recently published a study of DTI paired with neuropsychological testing in 52 subjects ranging in age from 25 to 82 years of age. They focused on the effects of aging on changes in neuropsychological performance and white matter imaging.The key elements of the design of their study included:Subjects: 52 right-handed adults (20 males and 32 females) without a history of any neurological or psychological disorderNeuropsychological testing: Each subject completed a computerized cognitive test battery known as Mindstreams testing "memory, executive function, visual spatial processing, verbal function, attention, information processing speed and motor skills".Cognitive domain identification: 20 cognitive function areas were analyzed using factor analysis to identify relevant common factors. Three cogntive domains were identified in the factor analysis including: executive function, memory and information processing speedImaging: 3T MRI brain images were obtained white matter bundle regions of interest were identified including the cingulum, the fornix, the inferior longitudinal fasciculus, the superior longitudinal fasciculus and the uncinate fasciculusStatistical analysis: Regression analysis of regional DTI indices, age and neuropsychological test performance. The findings of this study are really quite impressive and highlight the specific white matter bundles associated with cognition and the effects of age on white matter changes. The findings demonstrate the key role white matter temporal lobe projections play:Cingulum bundle: memoryFornix bundle: memorySuperior longitudinal fasciculus bundle: executive function and information processing speedInferior longitudinal fasciculus bundle: memory and information processing speedUncinate fasciculus: memoryThe image on the right shows areas of the right and left temporal lobes identified in green. White matter bundle projections to the temporal lobe have been shown in this study to play a key role in cognitive function.Measures of white matter integrity (fractional anisotropy) from DTI show deterioration with age in these key regional bundles. This implies white matter deterioration may contribute the decline in executive function, memory and information processing found with aging.Understanding this effect may point the way to interventions that might slow the rate of white matter aging in the brain. These types of interventions may reduce the level of age-related cognitive decline in humans.Readers with more interest in this important study can access the free full-text manuscript by clicking on the reference below.Photo of great blue heron from the authors file.Image of temporal lobes is an iPad screen shot from the app Brain Tutor.Sasson E, Doniger GM, Pasternak O, Tarrasch R, & Assaf Y (2013). White matter correlates of cognitive domains in normal aging with diffusion tensor imaging. Frontiers in neuroscience, 7 PMID: 23493587... Read more »

Sasson E, Doniger GM, Pasternak O, Tarrasch R, & Assaf Y. (2013) White matter correlates of cognitive domains in normal aging with diffusion tensor imaging. Frontiers in neuroscience, 32. PMID: 23493587

April 23, 2013
11:15 AM
137 views

Hypothalaumus Connectivity Changes in Cluster Headaches

by William Yates, M.D. in Brain Posts

Cluster headaches are a relatively rare but serious pain disorder. Unlike the female-predominant migraine headache, cluster headaches occur predominantly in men. These headaches tend to be acute in onset and affect only one side of the head.The term cluster describes the typical chronological pattern of these headaches. The tend to occur regularly for days or weeks and are then separated by periods of remission lasting months or years.Attacks typically last between 15 minutes and 3 hours. This type of pattern makes cluster headache a good candidate for imaging studies conducted during and between attacks.Qui and colleagues from the People's Republic of China conducted a brain conductivity study in a series of male subjects. The key elements of the design of the study included:Subjects: 12 male right-handed men between the ages of 19 and 46 off medication with a control group of 12 right-handed men without a history of cluster headachesImaging sequence: Case subjects completed two fMRI scans. One was done during an acute attack and a second scan was completed at least four hours after an attack but during the cluster period. Imaging protocol: Resting-state functional connectivity with focus on the hypothalamus, a brain region linked to cluster headache in previous studies.The key findings from this study were:Statistically significant increased right hypothalamus connectivity occurred during the cluster attack phase compared to between attacks in the cluster subjectsThis increased hypothalamic connectivity could be linked to three regions/circuitsFirst region: Anterior cingulate cortex (ACC), several frontal cortex regions, the parahippocampal region and the amygdalaSecond region: precuneus, supramarginal gyrus and the supratemporal gyrusThird region: precuneus, parietal lobe, posterior cingulate cortex (PCC)Case subjects between cluster attacks continued to show connectivity patterns distinct from controls in the right hypothalamus and circuits connected to regions of the temporal lobe, the insular cortex, the occipital lobe and the uncusThe authors note their findings confirm that the ipsilateral hypothalamus (hemi-hypothalamus on the same side as the headache) appears to be a key area of involvement in cluster headache. The brain image on the left highlights the right hypothalamus in the green color.The authors also note (acronym clarifications in parentheses added by me): "Our findings in the acute spontaneous CH (cluster headache) attack showed that the altered rs-FC (resting state functional connectivity) of the hypothalamus is involved in the processing and modulation of pain referred to as the pain matrix, and/or is involved in cognitive and emotional modulation of pain". The findings of a connection between the hypothalamus and the occipital (or vision lobe) is interesting as this occipital lobe is typically not involved in brain pain circuitry. However, the authors note that many cluster headache sufferers have light sensitivity (photophobia) and symptom may reflect some changes in the occipital lobe connectivity.The typical pattern of cluster headaches makes it a promising model to study not only headaches but pain processing in general. This is an informative and important study and interested readers can access the free full-text article by clicking on the reference below. Photo of sandhill crane taken at Venice, Florida rookery is from the author's files. Brain hypothalamus figure is an iPad screenshot from the 3D Brain app.Qiu E, Wang Y, Ma L, Tian L, Liu R, Dong Z, Xu X, Zou Z, & Yu S (2013). Abnormal brain functional connectivity of the hypothalamus in cluster headaches. PloS one, 8 (2) PMID: 23460913... Read more »

Qiu E, Wang Y, Ma L, Tian L, Liu R, Dong Z, Xu X, Zou Z, & Yu S. (2013) Abnormal brain functional connectivity of the hypothalamus in cluster headaches. PloS one, 8(2). PMID: 23460913

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William Yates, M.D.

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