Brain Posts

Epidemiology of Brain Cancer

2012-01-26T11:39:00.000-06:00

A recent summary of the trends in cancer highlighted the epidemiology of brain and other nervous system tumors. In the United States, 213,500 brain and other nervous system tumors were diagnosed during the four year period from 2004 through 2007.

Brain and other nervous systems (ONS) tumors rank fourteenth in the top 15 cancers for men and fifteenth in the top 15 cancers for women in the United States.

Overall rates for brain and ONS tumors during this period were 22.37 per 100,000 for men and slightly higher at 26.55 per 100,000 for women.

In adults, the majority (66.3%) of brain and ONS tumors were benign. Although brain and ONS tumors are less common in children, when they occur they are less likely (34.8%) to be benign.

The most common histological types of brain and ONS tumors in the most recent analysis were (rate per 100,000):

Meningioma (9.2)
Glioblastoma (4.4)
Tumors of the sella turcica region (3.6)
Acoustic neuroma (1.5)
Astrocytomas (1.2)

Glioblastomas and astrocytomas are malignant brain cancers while the other three types of tumors are overwhelmingly benign with less than 3% classified as malignant.

Five year survival rates for the malignant brain cancers have improved over the last approximately twenty year periods. Here are the most recent five year survival rates group by age:

19 and younger (75.3%)
20-39 (65.1%)
40-64 years (26.6%)
65 and older (<5%)

The five year survival rates demonstrate a significant trend for a poorer prognosis with older age groups. This represents a trend for brain cancer in older populations to be of a more aggressive type with poorer response to surgery, radiation and chemotherapy interventions.

The rates of brain cancer are relatively similar throughout the geographic regions of the United States and throughout the world. This supports a predominant genetic role for brain cancer risk. Known risk factors for brain cancer are:

Family history of brain cancer
Caucasian race
Advanced age
Exposure to ionizing radiation
Exposure to toxic chemicals

Several studies have demonstrated that individuals with atopic diseases such as eczema, seasonal allergies and asthma have a reduced risk of malignant gliomas. The mechanism for this protective effect is unclear.

In the next two posts, I will summarize some of the recent research related to cell phone use and brain cancer rates. Additionally, I will review an interesting study suggesting the antiseizure drug valproic acid may contribute to increased survival duration in brain cancer.

Photo of bird known as the plain chachalaca from the author's files.

Kohler, B., Ward, E., McCarthy, B., Schymura, M., Ries, L., Eheman, C., Jemal, A., Anderson, R., Ajani, U., & Edwards, B. (2011). Annual Report to the Nation on the Status of Cancer, 1975-2007, Featuring Tumors of the Brain and Other Nervous System JNCI Journal of the National Cancer Institute, 103 (9), 714-736 DOI: 10.1093/jnci/djr077

Parent Training and Conduct Disorder Outcome

2012-01-21T11:46:00.000-06:00

Three previous posts examined the clinical neuroscience disorder antisocial personality disorder (ASPD). This condition results in high societal costs for crime and incarceration for individuals with ASPD.

ASPD appears to have significant genetic contributions and brain imaging studies show abnormal brain maturational patterns in the premotor cortex area as well as impaired processing of facial emotional expression.

Antisocial personality is an early age of onset disorder with conduct disorder symptoms emerging during childhood and adolescence. Their is no evidence-based consensus on pharmacological treatment options in conduct disorder and ASPD.

This leaves psychological and behavioral interventions as the current primary treatment option. But do these types of interventions work and do they produce lasting changes in the longitudinal trajectory of ASPD.

Drugli and colleagues from Norway published an outcome study of conduct disorder following a randomized controlled trial of a parental training intervention known as "The Incredible Years".

The Incredible Years parent training program emphasized developing parental skills to improve the child's social and behavioral development. Key features include instruction on how to play with other children, social and emotional skills training, establishment of routines and rules to promote responsibility, strategies to manage misbehavior and teaching problem solving. More information about The Incredible Years program can be found here.

Drugli and colleagues followed a subgroup of children in their initial randomized trial. This follow up lasted five to six years. Control children in the original study were on a wait list for six months and then received The Incredible Years intervention so no controlled group outcome can be made. However, in the follow up analysis the research team found only one third of children enrolled with an initial diagnosis of oppositional defiant disorder or conduct continued to meet diagnostic criteria for the disorder.

Predictors for persistence of a clinical diagnosis at outcome included:

female gender
living with mother only
a baseline diagnosis of conduct disorder rather than oppositional defiant disorder
higher levels of conduct disorder symptoms
higher baseline levels of internalizing symptoms such as anxiety or depression
maternal depressive symptoms after treatment intervention
maternal stress rating of parenting

The predictor findings suggest that parental factors play a key role in the effectiveness of the parental training intervention. Single mothers and those with higher stress and depression symptoms may have more trouble in continuing to use the skills learned with the intervention.

Additionally, this intervention may not be as effective for children with more severe conduct disorders.

Parental training in childhood behavioral disorders provides a reasonable first step for early treatment of those at risk of antisocial personality. However, such an intervention strategy is limited by frequent parental emotional and behavioral problems found in the families of high-risk children.

Increased research targeting the secondary prevention of aggressive behaviors and ASPD in children with conduct disorder should be a priority.

Photo of a flicker searching for food from the author's file.

Drugli MB, Larsson B, Fossum S, & Mørch WT (2010). Five- to six-year outcome and its prediction for children with ODD/CD treated with parent training. Journal of child psychology and psychiatry, and allied disciplines, 51 (5), 559-66 PMID: 20015193

Brain Imaging in Antisocial Personality: II

2012-01-19T11:07:00.000-06:00

This is the second in a series of posts looking at recent imaging findings in antisocial personality. In the first post, I reviewed an fMRI study that found deficits in connectivity maturation involving the premotor cortex in a sample of incarcerated juveniles.

In this post, I will review a study looking a emotional face processing. Accurately assessing the emotions of others and adjusting ones own behavior is a key component to social development and appropriate social behavior.

Individuals with antisocial personality disorder commonly display childhood and adolescent forms of the disorder. These child and adolescent behaviors often meet the criteria for conduct disorder. About 75% of children with conduct disorder will go on to develop adult antisocial personality disorder.

Passamonti and colleagues from the University of Cambridge in England recently completed and published a study of emotional face processing in a series of male adolescents with conduct disorder and control adolescents without conduct disorder.

Conduct disorder adolescents were divided into those with an earlier age of onset (at least one significant conduct disorder symptoms prior to age 10) and those whose first significant symptom developed at 10 or later. This classification is considered valid as adolescents with later emerging conduct disorder problems are felt to be more influenced by peer group behaviors.

Subjects completed a series of face emotion tasks while being imaged using functional magnetic resonance imaging. Emotional images presented fell into one of three emotions--angry faces, sad faces or a neutral facial expression.

The key findings from the study related to amygdala responses were:

Both groups of adolescents with conduct disorder demonstrated a reduced responses in brain regions felt to be linked to antisocial behavior
Early onset conduct disorder adolescents showed reduced amygdala activation for sad versus neutral faces
Early onset conduct disorder adolescents showed reduced amygdala activation for sad faces relative to the control fixation task

The conduct disorder groups also demonstrated abnormal responses to facial emotions in ventromedial prefrontal cortex, orbitofrontal cortex and the insula.

The authors note their study provides some support for the distinction between early and late onset conduct disorder. Although these groups share some features in emotional processing, early onset conduct disorder appears to be associated with more severe deficits in accurately processing sad faces.

This study suggests emotional processing deficits may contribute to some of the behaviors of antisocial personality. Such individuals are typically seen to lack empathy and to behave without regard for the effect of their behavior on others. Part of this pattern may be a reduced ability to recognize emotional expression in others. A part of their behavior may represent a partial "blindness" to sad emotional states of those around them including family members and peers.

The authors note their study my provide a impetus to describing a phenotype with a poor prognosis and likely continuation of antisocial behavior into adulthood. Functional MRI studies of neural markers may aid in defining high-risk groups for more intensive secondary prevention intervention.

Photo of great blue heron at sunrise in South Padre Island, Texas from the author's files.

Passamonti L, Fairchild G, Goodyer IM, Hurford G, Hagan CC, Rowe JB, & Calder AJ (2010). Neural abnormalities in early-onset and adolescence-onset conduct disorder. Archives of general psychiatry, 67 (7), 729-38 PMID: 20603454

Brain Imaging in Antisocial Personality: I

2012-01-18T11:23:00.004-06:00

Antisocial personality disorder (ASPD) is linked to a variety of emotional and behavioral abnormalities with significant public health implications.

Key components of antisocial personality disorder include irritability with anger dysregulation. Individuals with ASPD are quick tempered with anger outbursts commonly leading to physical or emotional aggressiveness towards others.

The emotional and behavioral abnormalities in ASPD may provide a model for studying specific brain regions controlling these functions. In the next few posts, I will review some of the brain imaging abnormalities that have been linked to ASPD. I will first begin by looking at a study of functional connectivity in juvenile offenders.

Shannon from Washington University in Saint Louis and colleagues from the Oregon Health and Science University and the University of New Mexico have published a study of the default network in a group of juvenile offenders.

The authors of this study note functional connectivity is a developmental process. Children's brain show different functional connectivity patterns than that of adults--children have strong short-distant connections while adults have stronger long-distant connections. They note that abnormal maturation patterns in functional connectivity have been linked to several clinical neuroscience disorders including ADHD, autism, schizophrenia, Alzheimer's disease and Parkinson's disease. These finding support the potential for abnormal maturation patterns in conduct disorder and antisocial personality disorder.

The key elements in the design of their study were:
Subjects: 122 juveniles incarcerated for a variety of crimes including physical and sexual assault contrasted with 95 control individuals
Scanning method: Mobile fMRI 1.5T scanner (cases) and 3.0T scanner (controls)
Scanning analysis: Resting state connectivity among brain systems
Psychometric assessment: Hare Psychopathy Checklist (PCL-YV) consisting of a empathy subfactor and an impulsivity/need for stimulation factor

No resting connectivity abnormalities were linked to the empathy factor from the PCL-YV. However, some interesting findings were noted in the impulsivity domain. The found differences linked to impulsivity in the motor planning region of the cortex (premotor cortex).

High impulsivity scores common in the juvenile offender group was associated with connections between the motor planning region and regions linked to spontaneous behavior and self-referential cogniton.

In contrast, low impulsivity offenders and controls showed associations between this motor planning region with spatial attention and executive function and control.

Interestingly, the high impulsivity pattern of connectivity appeared common in the youngest controls. Older controls showed the typical motor planning-executive functioning connectivity.

The authors propose that "impulsivity in the offender population is a consequence of delay in typical development rather than a distinct abnormality".

The authors note that their finding raises the possibility that specific intervention strategies to modify functional maturation connectivity may promising. The relatively focal nature of deficits in this study support the potential for specific therapeutic remediation.

This finding in juvenile populations needs to be replicated in adult offender populations. Impulsivity and aggressiveness abnormalities in ASPD have an early age of onset and is persistent into adulthood for many individuals.

Nevertheless, designing specific impulsivity remediation treatments with serial functional connectivity maturation analysis holds promise for new secondary prevention strategies in ASPD.

Filtered image of a pair of laughing gulls from the author's file. Original photo can be found here.

Shannon BJ, Raichle ME, Snyder AZ, Fair DA, Mills KL, Zhang D, Bache K, Calhoun VD, Nigg JT, Nagel BJ, Stevens AA, & Kiehl KA (2011). Premotor functional connectivity predicts impulsivity in juvenile offenders. Proceedings of the National Academy of Sciences of the United States of America, 108 (27), 11241-5 PMID: 2170923621709236

Twin Study of Antisocial Personality Disorder

2012-01-17T11:59:00.000-06:00

Twin studies provide a valuable method to explore the genetic and environmental contributions to a variety of clinical neuroscience disorders.

Twin studies use a method where identical twins (monozygotic) sharing 100% of their genes are compared to non-identical twins (dizygotic) who share 50% of their genes.

Disorders that are entirely environmental would be found at the same rates in non-identical twins and indentical twins. Disorders with a strong genetic contribution would be more likely to be found in monozygotic twin (where one twin is affected) than in a dizygotic twin (where one twin is affected).

Antisocial personality disorder (ASPD) is an early-onset disorder characterized by aggressive behavior, frequent rule breaking and failure to consider the effect of one's behavior on other individuals. It represents one of the most valid of the personality disorder diagnoses as many defining characteristics are behavioral in nature. More common in men than in women, this condition contributes significantly to the burden of violent and non-violent crime, substance abuse and prison crowding.

Kendler and colleagues recently published a twin study of the DSM-IV criteria for ASPD in a cohort of twins from the Virginia Adult Psychiatric and Substance Use Disorders. Data from 4291 twins were used in the analysis and included a factor analysis of the ASPD phenotype followed by twin analysis.

The research group found two distinct ASPD phenotypes in the factor analysis with specific ASPD criteria loading on each factor:
Factor 1: nonconformance, irritability/aggression and reckless disregard for others
Factor 2: deceitfulness, impulsivity/failure to plan, irresponsibility and lack of remorse for behavior

The subsequent twin analysis confirmed two genetic factors in adult ASPD with a confirmation of the factor analysis criteria loading. Heritability (an estimate of genetic contribution) for individual ASPD criteria varied from .12 to .57.

Additional support for these two factors came from a study of discriminant validity--the ability of the genetic factors to describe a unique clinical presentation. The clinical features found in each of the two factors were:
Factor 1: presence of childhood conduct disorder, early age at first alcoholic drink, high number of maximum drinks consumed in 24 hours, treatment seeking for alcohol dependence and lower educational level
Factor 2: novelty seeking personality and history of major depression

The authors note their study supports a view of two types of adult antisocial phenotypes. Factor one matches the general description of the psychopath with many traits persistent throughout adult life. Factor two matches primarily a deficit of disinhibition the may "reflect disturbances in anterior brain systems mediating affective and behavioral control".

This is an important study the supports more vigorous phenotypic description of adults with antisocial personality. These subtype descriptions may play a key role in understanding cognitive, structural and functional imaging studies in adult ASPD.

In the next few posts, I will review some of the emerging imaging research related to ASPD.

Photo of olive sparrow from the author's file.

Kendler KS, Aggen SH, & Patrick CJ (2012). A Multivariate Twin Study of the DSM-IV Criteria for Antisocial Personality Disorder. Biological psychiatry, 71 (3), 247-53 PMID: 21762879

The Economic Costs of Brain Disorders

2012-01-16T11:16:00.000-06:00

Clinical disorders involving the brain are common and produce a variety of economic costs to society.

Cost analyses provide an overview of the types of disorders and their relative contribution to the overall costs to society. Such types of analyses can aid public health officials in targeting strategies to reduce the burden of brain disorders.

Andlin-Sobocki and colleagues recently published an analysis of the costs of brain disorder in Europe. This study included both neurological and mental disorders.

This analysis included a comprehensive outline of the components of the costs related to brain disorders. The rank list of cost components (% of total costs) in the analysis were:

Sick leave (33%)
Hospitalization (20%)
Social services (13%)
Outpatient care (12%)
Premature death (7%)
Early retirement (7%)
Pharmaceutical costs (3%)
Informal care (3%)
Other direct costs (2%)

The authors estimated that the total costs related to brain disorders at 386 billion euro per year. The ranking for brain disorder total costs by disease area (and yearly costs in euro billions)

Mood disorders (106 B €)
Addictions (57 B €)
Dementia (55 B €)
Anxiety disorders (41 B €)
Psychotic disorders (35 B €)
Migraine/Headache (27 B €)
Stroke (22 B €)
Epilepsy (16 B €)
Parkinson's disease (11 B €)
Multiple sclerosis (9 B €)
Brain tumor (8 B €)
Brain trauma (3 B €)

Total costs represent estimations of the prevalence for individual disorders multiplied by the yearly cost for each disorder. The authors estimate that brain tumors represent the highest cost component an nearly 40,000 € per year. Multiple sclerosis was estimated as the second most costly component at 25,000 € per year followed by stroke at about 16,000 € per year.

The mental disorders (mood, addictions, dementia and anxiety disorders) have relatively lower cost per case estimates but their total cost contribution is high due to the higher prevalence rates for these disorders.

The study reaffirms brain disorders as a key element in total direct and indirect health care costs. Indirect costs related to work function (sick leave and reduced productivity) are important areas for further study in the mental disorders.

Economic costs represent only one aspect to the burden of disease. Individual pain and suffering and the effects on family members were not addressed in this analysis.

This study supports the need for adequate research financing for the diagnosis, treatment and prevention of brain disorders.

Photo of a pair of laughing gulls at sunrise from South Padre Island, Texas from the authors files.

Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B, on behalf of the CDBE2010 study group, & the European Brain Council (2012). The economic cost of brain disorders in Europe. European journal of neurology : the official journal of the European Federation of Neurological Societies, 19 (1), 155-162 PMID: 22175760

The Neuropsychology of Opioid Abuse

2012-01-16T09:09:00.000-06:00

This is the last post in a series on prescription opioid abuse and dependence. Prescription opioid overdose fatalities is a growing public health problem in the United States. This problem varies by state of residence. There are effective pharmacological strategies for the treatment of opioid dependence, but relapse rates are high.

With this growing problem, an important clinical question is "What are the cognitive effects of chronic opioid use/abuse/dependence?". One of the problems in studying the effects of chronic illicit drug use is finding the problems linked to specific drugs of abuse and separating the effects due to the drug itself from potential premorbid deficits typical in substance abuse populations.

Individuals developing alcohol and drug dependence differ from the general population. Premorbid ADHD and learning disabilities occur in substance abusers more commonly in those without substance abuse. Premorbid anxiety disorders, mood disorders and psychotic disorders also are common in substance abuse populations.

Fernando-Serrano and colleagues from the University of Granada in Spain recently published a summary of the effects of specific drugs of abuse on neuropsychological performance in the journal Neuroscience and Biobehavioral Reviews.

The conducted a comprehensive review of neuropsychological performance from studies of primarily single drug class abuse "pure users" along with studies controlling for multiple drug use and found the following findings by drug class:

Opioids: Impaired decision making, delayed time in making decisions
Methamphetamines: Increased impulsivity and impaired cognitive flexibility
MDMA: Impaired spatial processing, reduced perceptual speed and attention
Cannabis: Impaired immediate and delayed episodic memory and reduced visual processing speed

The authors note the need for better designed research to study the effect of specific drugs on chronological cognitive functioning, i.e. subacute (24 to 48 hours), short-term (48 hours to 1 month), mid-term (1-6 months) and long term (6 months or more).

Unfortunately, this research review found no studies in prescription opioid abusers as the only studies in opioid abuse/dependence were done in heroin or methadone users.

There is a important need to conduct studies of neuropsychological effects in prescription opioid drug abuse populations. This population (and the effects of prescription opioid abuse/dependence) may differ significantly from results found in heroin and methadone clinical groups.

Additionally, neuropsychological research is needed on the effect of substitution therapy, i.e. buprenorphine/naloxone (Suboxone) on neuropsychological performance. Does substitution therapy reduce cognitive effects of prescription opioid abuse? How do prescription opioid abusers placed on substitution therapy differ from controls without a history of prescription opioid abuse.

Neuropsychological effects of prescription opioid abuse may contribute to social and occupational impairment, response to treatment and risk for opioid overdose fatality. The time is now to put more money and research into this emerging problem.

Photo of great blue heron on South Padre Island, Texas from the author's files.

Fernández-Serrano MJ, Pérez-García M, & Verdejo-García A (2011). What are the specific vs. generalized effects of drugs of abuse on neuropsychological performance? Neuroscience and biobehavioral reviews, 35 (3), 377-406 PMID: 20451551

Suboxone Treatment for Prescription Opioid Abuse

2012-01-06T11:22:00.001-06:00

Chemical Structures for Buprenorphine and Naloxone

In three previous posts I have reviewed several aspects of prescription opioid abuse including posts on epidemiology, toxicology and clinical pathways to abuse.

Given the growing numbers of individuals with prescription opioid abuse, safe and effective treatment options become increasingly important.

Opioid withdrawal can be quite painful and often leads to resumption of opioid use. Treatment of opioid withdrawal can include non-opioid drugs or opiod drugs that target withdrawal symptoms.

Symptomatic withdrawal treatment alone results in high relapse rates. This outcome has produced efforts to find more effective long-term treatments for prescription opioid abusers.

Short or long-term opioid substitution treatment appears to produce an incremental improvement in outcomes. Methodone substitution or substitution with the combined drug buprenorphine and naloxone (Suboxone) provide two options for clinicians and patients.

Buprenorphine is classified as a partial opioid agonist stimulating the opioid receptor with limited euphoric effect. Naloxone is felt to reduce the misuse of the combined drug compound by blocking/reducing euphoria with intravenous administration.

A recent study examined the effectiveness of Suboxone in a group of 653 outpatients seeking treatment for prescription opioid dependence. The key elements of the design of this study included:
Phase one: 2-week stablization on buprenorphine-naloxone, 2-week taper and 8-week follow-up
Phase two: Individuals who relapsed after phase one entered a longer 12-week stabilization on buprenorphine-naloxone followed by a 4-week taper and 8-week follow-up
Adjunctive counseling: Half the subjects received adjunctive counseling using a manual-based program emphasizing education, skills training and life-style modification.
Outcome Assessment: During the follow-up period abstinence was measured by urine-test verified self report

Only 7% of subjects achieved a successful outcome by the end of phase one. At the end of the treatment phase of phase 2, 49% of subjects were rated as having a successful outcome. However, after phase 2 tapering successful outcome rates dropped to 9%. Adjunctive counseling did not appear to improve outcomes in either phase.

The authors note the study supports use of Suboxone with a primary medical management approach (without a formal substance abuse counseling component) in the clinician's office. Approximately 50% of users will experience a successful outcome during treatment with Suboxone.

However, with the high relapse rates after the taper in phase 2 of the study, the study authors note: "What length of buprenorphine-naloxone treatment, if any, would lead to substantially better outcomes during a taper?" This study supports a longer term treatment trial using six months or a year of Suboxone treatment.

Only a minority of clinicians are certified to give Suboxone in the U.S. It requires a specific 8 hour training course before certification. Suboxone costs about $10 per day and this may limit it's use. Nevertheless, it provided opioid prescription abusers and their clinicians an important treatment option.

A resource to identify physicians certified to use Suboxone in the U.S. can be found here.

Molecular structure of buprenorphine and naloxone from the PubChem Compound site.

Weiss RD, Potter JS, Fiellin DA, Byrne M, Connery HS, Dickinson W, Gardin J, Griffin ML, Gourevitch MN, Haller DL, Hasson AL, Huang Z, Jacobs P, Kosinski AS, Lindblad R, McCance-Katz EF, Provost SE, Selzer J, Somoza EC, Sonne SC, & Ling W (2011). Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Archives of general psychiatry, 68 (12), 1238-46 PMID: 22065255

Pathways to Prescription Opioid Overdose

2012-01-05T12:26:00.000-06:00

The majority of initial prescriptions for opioid analgesics in acute pain management occur without development of a pattern of misuse or abuse.

However, in some individuals, opioid prescriptions produce a pathway for misuse, abuse and risk of opioid overdose death. In two previous posts, I have outlined the epidemiology of opioid overdose death and the toxicology of these compounds.

Risk factors for the development of prescription opioid drugs have not been extensively studied. However, it is reasonable to think that risks for prescription opioid abuse might be similar to the known risk factors for alcohol abuse and non-prescription drug abuse. These general risk factors for substance abuse include:

Male gender
Family history of alcoholism or drug abuse
Nicotine dependence
Antisocial personality disorder
Pre-existing mood or anxiety disorder
Early age onset of of alcohol or other drug use
Peer group substance use and approval of drinking/drug use
Accessibility and affordability of alcohol/drug substance

Although studies examining risk factors for prescription drug abuse are limited, one recent study published in journal Pain Medicine examined characteristics of a series of cases of overdose deaths in individuals prescribed controlled substances.

Individuals who died of an unintentional drug overdose in the state of New Mexico over an 18 month period were identified. A control group of individuals were identified based on recently receiving prescriptions utilizing a state prescription monitoring database.

This case control study found some interesting risk factors associated with unintentional drug overdose deaths including:

Male gender
Older age
Sedative/hypnotic prescriptions
Multiple prescriptions for controlled substances
Prescriptions from multiple providers and multiple pharmacies
Specific prescriptions for buprenorphine, fentanyl, hydromorphone (Dilaudid), methadone, or oxycodone (Oxycontin)
Daily opioid prescription dose greater than the equivalent of 40 mg of morphine

This study found prescriptions for at least one controlled substance was found in 44% of all individuals 10 years and older during the study period.

The authors conclude their study supports the potential for centralized state pharmacy controlled substance databases to reduce the numbers of unintentional overdose deaths. Such databases could alert providers and pharmacies to high-risk individuals who may be abusing the medical system. Such programs would not address other potential access routes such as purchase of controlled prescription drugs off the street or via internet orders.

In the next post, I will review some of the recent research related to pharmacological approaches to the treatment of opioid abuse and dependence.

Photo of sea gull flying over Arkansas River near Tulsa, Oklahoma from the author's files.

Paulozzi, L., Kilbourne, E., Shah, N., Nolte, K., Desai, H., Landen, M., Harvey, W., & Loring, L. (2011). A History of Being Prescribed Controlled Substances and Risk of Drug Overdose Death Pain Medicine DOI: 10.1111/j.1526-4637.2011.01260.x

Prescription Opioid Overdose Toxicology

2012-01-04T12:30:00.002-06:00

My previous post examined the epidemiology of rise in opioid abuse and opioid overdose deaths in the U.S. The number of these deaths has increased fourfold in the last decade and appears to be higher in states with higher rates of prescriptions for the opioid drug class.

Members of the prescribed opioid compounds includes the following generic (Trade name) drugs in the U.S.:

Methadone
Oxycodone (Oxycontin/Percodan)
Hydromorphone (Vicodin/Lortab)
Meperidine (Demerol)
Hydromorphone (Dilaudid)
Codeine

Drug overdoses of the opioid drug classes produce somnolence, CNS depression and in severe cases the central drive to breath is suppressed to the point of respiratory failure, hypoxia and death. Cardiac arrhythmias due to direct drug toxicity or to the effects of hypoxia.

One feature of the toxicity of the opioid compounds is the relatively narrow therapeutic window. This means the dose for therapeutic indication is close to the lowest potential fatal dose or blood level. For example, the adult drug therapeutic dose for oxycodone is listed as 10 mg every 12 hours. However, a single dose of only 40 mg in a drug intolerant individual is potentially lethal. Individuals with chronic pain often develop tolerance to opioids and may be prescribed 60 mg (or more) per day of oxycodone.

So the daily dose that opioid-tolerant grandma requires for cancer pain may be sufficient to kill her grandchild who decides to "try one".

The toxicity of opioids appears to increase in the context of other drug use. Most forensic studies of opioid-related deaths find the presence of other drugs that can reduce respiratory drive. In fact, death due to a overdose of a single opioid prescription drug appears to make up a small minority of opioid-related deaths. In one study of 172 deaths with a positive blood oxycodone level in Palm Beach County, Florida found only 18 where oxycodone toxicity was the sole cause of death. One hundred seventeen were judged to be due to combined toxicity with another drug.

In a recent study of deaths due to oxycodone overdose in Australia, multiple drug classes were identified. The most frequent drug classes (and specific drug in that class) in this study were:

Sedatives (diazepam) 69%
Other opioids (codeine) 54%
Antidepressants (tricyclics) 41%
Alcohol 33%
Antipsychotics (olanzapine) 19%

So the key clinical facts to consider in prescription opioid toxicity and risk for overdose death are the narrow therapeutic window and the risk of toxicity with other CNS depressants. Prescription opioids drugs are effective short-term analgesic agents but are dangerous when used outside the therapeutic range and in combination with other drugs and alcohol.

In upcoming posts, I will examine some of the factors that make some individuals more vulnerable to development of prescription opioid abuse.

Molecular model of the opioid drug oxycodone from the Wikipedia Commons file authored by subdural12.

Wolf BC, Lavezzi WA, Sullivan LM, & Flannagan LM (2005). One hundred seventy two deaths involving the use of oxycodone in Palm Beach County. Journal of forensic sciences, 50 (1), 192-5 PMID: 15831018

Darke S, Duflou J, & Torok M (2011). Toxicology and characteristics of fatal oxycodone toxicity cases in New South Wales, Australia 1999-2008. Journal of forensic sciences, 56 (3), 690-3 PMID: 21361931

Epidemiology of Prescription Opioid Abuse in U.S.

2012-01-03T11:21:00.002-06:00

Prescription opiate abuse and accidental deaths are on the rise in the U.S. The Center for Disease Controls (CDC) estimates that opiate pain reliever drugs were responsible for approximately 74% of all prescription drug overdose deaths in the U.S. in 2008.

The CDC recently published a study of the epidemiology of opiate pain reliever deaths in the U.S. between 1999 and 2008 the last year full statistics are available. The trends in this area are a public health concern driving efforts to reduce drug deaths due to this drug class.

The rates of death in the prescription opiate reliever class has nearly quadrupled over this ten year period from about 1.3 deaths/100,000 population to nearly 5.0 deaths per 100,000 population.

Opiate pain reliever deaths in the U.S. now exceed the number of deaths due to heroin and cocaine combined.

The pathways to opiate pain reliever death are complex. Some occur unintentionally in individuals prescribed opiates for valid medical reasons. Unintentional deaths in populations with valid prescriptions may result from relatively modest dose excess particularly if used in combination with other sedatives, alcohol or prescription drugs that can increase opiate drug blood levels.

However, it appears the majority of unintentional deaths with the opiate pain relievers occur in individuals meeting the criteria for opiate drug abuse or dependence. Individuals abusing opiates may obtain drugs from multiple physician prescriptions, street drug sources or even internet-based international sources.

The CDC study documents a wide range of prescriptions for opiate pain relievers between states in the United States. Figure 1. from the CDC shows a pattern of correlation between the states with highest prescription rates for these drugs and overdose opiate death rates. Darker shading indicates higher rates with the top map the rates of opiate drug overdose deaths and the bottom figure representing rates of opiate pain reliever prescribing.

Even as the rate of opiate pain reliever prescriptions varies widely by state, between physician prescribing rate also vary greater. One study reports that 3% of physicians write 62% of all opiate pain reliever prescriptions. Many of these prescriptions may be valid but in view of the abuse/dependence risk and unintentional overdose risk physician prescribing patterns will come under more scrutiny.

The CDC report notes "Public health interventions to reduce prescription drug overdose must strike a balance between reducing misuse and abuse and safeguarding legitimate access to treatment".

This is an emerging public health issues and in the next few posts I will review some of the characteristics of opiate pain reliever abuse including treatment options.

Figure from the CDC public domain in the attached manuscript.

Centers for Disease Control and Prevention (CDC) (2011). Vital signs: overdoses of prescription opioid pain relievers---United States, 1999--2008. MMWR. Morbidity and mortality weekly report, 60, 1487-92 PMID: 22048730

Slow Wave Sleep Deprivation in Depression

2011-12-21T11:50:00.000-06:00

Sleep abnormalities commonly occur in depression and are included in the diagnostic criteria for the disorder. Acute sleep deprivation temporarily improves the symptoms of major depression in approximately 50 to 60 percent of patients. The mechanism for this effect is not well understood.

Sleep architecture abnormalities in depression include reduced REM latency (period of time from falling asleep to first REM period). A significant amount of research has focused on REM sleep issues in depression. However, other sleep architecture parameters including slow wave sleep may be involved in the pathophysiology of depression.

Eric Landsness and colleagues at the University of Wisconsin recently published a study of selective slow wave sleep deprivation in a group of subjects with major depression. They noted previous evidence that an antidepressant effect of sleep deprivation in depression was associated with a high delta sleep ratio (percent of time spent in slow wave activity during first non-REM sleep cycle). From this association, they developed a hypothesis that selective slow wave sleep deprivation may produce an antidepressant response.

To selectively interrupt slow wave sleep, the sleep architecture was dynamically monitored throughout the night using a technique called high-density EEG. Slow wave sleep was interrupted by linking an audible tone during periods of slow wave sleep. The sound was sufficient to disrupt slow wave sleep but not loud enough to produce awakening. Subjects completed three overnight sleep sessions--a baseline session, a slow wave sleep deprivation session and a rebound session after sleep deprivation.

Slow wave sleep deprivation produced a statistically significant reduction in self-reported depression and researcher-administered depression ratings. However, the magnitude of improvement in depression found in this cohort was small (self-report IDS decreased from 16.5 to 15.0 and Hamilton Depression Rating Scale-13 item reduced from 10.7 to 7.8. Previous studies of overnight total sleep deprivation have produced greater improvement in measures of depression severity.

The reduction in depression symptoms correlated with measures of slow wave activity during the baseline and rebound sessions.

This study provides evidence for the feasibility of producing sleep deprivation specific to slow wave sleep phases. Additionally, the study demonstrates the utility of high-density EEG to examine the effect of localized sleep EEG patterns in depression.

The antidepressant effects of sleep deprivation in depression unfortunately lasts for only a day or so. This limits the clinical utility of this intervention for patient populations. Nevertheless, understanding the sleep markers of depression and understanding the mechanism for the antidepressant effect of sleep deprivation may lead to improved treatment strategies.

Photo of sea gull from the author's files.

Landsness EC, Goldstein MR, Peterson MJ, Tononi G, & Benca RM (2011). Antidepressant effects of selective slow wave sleep deprivation in major depression: a high-density EEG investigation. Journal of psychiatric research, 45 (8), 1019-26 PMID: 21397252

Antidepressant Effects in Healthy Brains

2011-12-20T11:41:00.000-06:00

In a previous post I summarized some of what is known about the effect of antidepressants in healthy brains. This issue is important because antidepressant drugs have indications outside of mood and anxiety disorders including peripheral neuropathy and migraine prophylaxis. Additionally, understanding the effects of antidepressants in healthy brains may also provide insight into the brain mechanisms related to depression.

A recent fMRI imaging study provides some additional insight into antidepressant effects in healthy brains. McCabe and Mishor conducted a study of functional connectivity in a group of healthy research volunteers who received seven days of citalopram (a selective serotonin re-uptake inhibitor), or reboxetine (a selective norepinephrine re-uptake inhibitor) or placebo.

Functional connectivity is a research imaging technique that examines connection signal strengths between a "seed" region and other brain regions. In the present study, seed regions felt related to mood and reward regulation were selected including the amygdala, nucleus accumbens, dorsolateral prefrontal cortex, and the subgenual region.

In a resting brain state, connectivity signals exist in what has been defined as the default mode network. During scanning for assessment of the default mode network, subjects are asked to lie in a darkened room, to think of no specific thing and not remain awake. Connectivity signals between seed regions and other brain regions are felt to give an estimate of the strength of specific brain circuits.

The study identified several changes related to citalopram and reboxetine including:

Citalopram

Reduced functional connectivity between the amygdala and the ventral medial prefrontal cortex
Reduced functional connectivity between the dorsomedial prefrontal cortex and the hippocampus

Reboxetine

Reduced connectivity between the amygdala and the orbitofrontal cortex
Reduced connectivity between the nucleus accumbens and the mid orbitofrontal cortex

There were no effects of either antidepressant drug in functional connectivity related to the subgenual region seed.

The authors note the results of their study parallel some of what is known about brain region and circuit abnormalities in depression. Amygdala activity and amygdala-frontal cortex circuit activity appear increased in patients with depression. Depressed patients also have been shown to have enhanced activation of circuits connecting the striatum (nucleus accumbens), amygdala and hippocampus during the processing of negative emotions.

The study suggests that the effects of antidepressants on brain activity are not limited to individuals with depression. Healthy subjects in the study did not experience any changes in mood, anxiety, anhedonia or alertness. The authors did not comment on the issue of potential adverse issues related to healthy individuals taking antidepressants.

Although antidepressants appear to modulate brain circuitry in healthy individuals, this effect does not appear to reach clinical significance. Studies of the safety of antidepressants in non-depressed populations with disorders such as peripheral neuropathy or fibromyalga have not demonstrated significant adverse central nervous effects.

Photo of sea gulls along Arkansas River near Tulsa, Oklahoma from the author's personal files.

McCabe C, & Mishor Z (2011). Antidepressant medications reduce subcortical-cortical resting-state functional connectivity in healthy volunteers. NeuroImage, 57 (4), 1317-23 PMID: 21640839

Glutamate Receptors and Genetics of ADHD

2011-12-19T12:08:00.001-06:00

Genetic association studies in attention-deficit hyperactivity disorder (ADHD) have been inconsistent despite a heritability estimated as high as 90% for the disorder.

Recently, novel approaches examining gene copy number variations (CNV) have shown promise in neurodevelopmental disorders such as autism.

CNV represent genetics changes where a portion of DNA is present in an abnormal quantity. The DNA in CNV cases may be normal (not carrying specific gene defects) but by being present in an abnormal quantity they can produce cellular dysfunction.

CNV can occur with with either too few copies (deletions) or too many copies (duplications).

Now a large multicenter CNV study in ADHD has been published online at Nature Genetics. This large study examined the prevalence and type of CNV in nearly 2500 individuals with ADHD compared with over 9000 controls.

The research team in this study used a two-stage approach. In the first stage a subset of ADHD cases were compared to a group of controls using 550,000 SNPs (genetic regions of interest). Twelve SNPs with CNVs were identified in the first stage cohort. Four of these SNPs were confirmed in the second cohort or replication sample.

CNVs identified in this study all affected the glutamate receptor gene network. The number and type of CNVs found in ADHD in the study included:

Ten cases showed glutamate receptor metabotropic five (GRM5) deletions
Six cases showed GRM7 deletions
Eight cases showed GRM8 deletions
Eight cases showed GRM1 duplications

These CNVs findings were found in only a small percentage (about one percent) of individuals with ADHD. This means specific CNVs are rare in ADHD but even more rare in individuals without ADHD.

Although these specific CNVs were rare in ADHD, the investigators examined genes related to the glutamate receptor gene network and found that approximately 10% of ADHD had CNVs in the extended glutamate receptor network.

Glutamate and the glutamate receptor network appear involved in a neurodevelopmental processes including neurogenesis, synaptic transmission and neuronal migration. This suggests the finding in this study is feasible and deserves further exploration.

One potential benefit of this study is the clue for searching for novel drug treatments in ADHD. The authors concluded "Further work will determine whether clinical studies using selective GRM (glutamate receptor metabotropic) agonists as a potential treatment for ADHD are warranted in individuals with ADHD and variants in GRM genes."

Current ADHD stimulant drugs primarily work through the dopamine and norepinephrine neurotransmitter network. Exploration of glutamate network targeted drugs would provide a potential new class of therapeutic compounds for ADHD.

Photo of Canadian goose in the Arkansas River near Tulsa, Oklahoma from the author's private collection.

Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, Sleiman PM, Zhang H, Kim CE, Robison R, Lyon GJ, Flory JH, Bradfield JP, Imielinski M, Hou C, Frackelton EC, Chiavacci RM, Sakurai T, Rabin C, Middleton FA, Thomas KA, Garris M, Mentch F, Freitag CM, Steinhausen HC, Todorov AA, Reif A, Rothenberger A, Franke B, Mick EO, Roeyers H, Buitelaar J, Lesch KP, Banaschewski T, Ebstein RP, Mulas F, Oades RD, Sergeant J, Sonuga-Barke E, Renner TJ, Romanos M, Romanos J, Warnke A, Walitza S, Meyer J, Pálmason H, Seitz C, Loo SK, Smalley SL, Biederman J, Kent L, Asherson P, Anney RJ, Gaynor JW, Shaw P, Devoto M, White PS, Grant SF, Buxbaum JD, Rapoport JL, Williams NM, Nelson SF, Faraone SV, & Hakonarson H (2011). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nature genetics PMID: 22138692

Brain and Gut in Processing Emotion

2011-12-14T10:17:00.000-06:00

Ventrolateral Prefrontal Cortex in Blue

Intense emotional experiences frequently occur with bodily sensations such as a rapid heart rate or gastrointestinal distress.

It appears that bodily sensation (interoception) can be an important source of information when judging one's emotional. How the brain processes interoception is becoming better understood.

However, how the brain integrates interoceptive signals with other brain emotional processing circuits is less well understood.

Terasawa and colleagues from Japan recently presented results of their research on this interaction of interoception and emotion.

Eighteen graduate and undergraduate students were scanned using a 3T fMRI scanner.

Stimulus cues were separated into those in the interoceptive domain using the Body Perception Questionnaire and the emotional domain using the Positive and Negative Affect scale.

Interoceptive cues included cues such as "I have a fast pulse" while a typical emotional cue was "I am happy". Each cue was compared to a control possession cue such as "I have money".

The authors then contrasted brain regions activated by interoceptive, emotional or both interoceptive and emotional cues.

Brain regions identified as being activated during interoceptive cues included:
Interoception only: supplementary motor area (Brodmann area 6), inferior parietal gyrus
Interoception and emotional cues: right insular cortex (Brodmann area 13), ventromedial prefrontal cortex (Brodmann area 11) and the bilateral lingual cortex (Brodmann area 17).

The authors propose these finding support the role of the insula and ventromedial prefrontal cortex in the integration of interoception and central brain emotional signaling. They conclude "Our findings indicate that activation in these areas (ventromedial prefrontal cortex and right insula) and precuneus are functionally associated for subjective awareness of the emotional state".

Some may argue that in making important decisions you should "Go with your gut feeling".

The findings from this study suggest a more informed approach might be "Use your gut and other bodily signals (interoception) integrated with central brain signals in accurately judging your emotional state for making decisions"

This study suggests the brain has allocated specific regions to aid in the integration of body and brain signals to accurately judge and assess one's own emotional state.

Figure of ventrolateral prefrontal cortex from a screen shot of the iPad app Brain Tutor HD.

Terasawa, Y., Fukushima, H., & Umeda, S. (2011). How does interoceptive awareness interact with the subjective experience of emotion? An fMRI Study Human Brain Mapping DOI: 10.1002/hbm.21458

Weight Suppression and Bulimia Recovery

2011-12-13T12:01:00.002-06:00

Weight suppression is a variable that is defined as highest ever historical weight minus current weight. It represents a measure of the level of weight lost since being at the highest weight over a lifetime.

Although many individuals with bulimia nervosa are within normal weight ranges, these individuals tend to have higher levels of weight suppression than those without an eating disorder.

Weight loss in bulimia may increase drive for binge eating. Weight suppression may similarly be a marker for drive for binge eating among those with a diagnosis of bulimia.

Lowe and colleagues recently published a study of the correlation between weight suppression and the time to remission in a group of women. If weight suppression is a valid prognostic variable, higher levels of weight suppression should predict a poorer prognosis and a longer time to remission.

Here are the key elements of design of the study:
Sample: 110 women with DSM-IV bulimia nervosa recruited from treatment centers
Weight suppression groups: lowest third group less than 9 pounds, medium third group 9 to 25 pounds and high weight suppression group over 25 pounds
Follow-up: In person or telephone interviews every 6 to twelve months for approximately 9 years
Definition of recovery: Full remission of bulimia nervosa: absence of bulimia symptoms or only residual symptoms for a period of 8 consecutive weeks
Statistical analysis: Cox proportional hazard modeling of the effect of baseline weight suppression on time to first recovery

Weight suppression was statistically related to time to recovery. The highest tertile (1/3) group in weight suppression took nearly three times as long to recovery (see chart above). The highest tertile group took over three years for 50% of the group to meet recovery. This was significantly longer that the low weight suppression group that took only about 12 months for 50% of the group to recover.

This study supports collecting weight suppression data on women in treatment for bulimia nervosa. Those weighing 25 pounds less than their maximum weight appear to represent a poor prognosis group.

Individuals with bulimia and high weight suppression may require more intense psychological therapy than those with lower weight suppression scores. Additionally, they may need combination therapy with behavior therapy paired with a pharmacological intervention. Fluoxetine is an FDA approved drug for the treatment of bulimia nervosa. Topiramate appears to be a promising drug for the reduction of binge eating.

Figure is original chart by author from data presented in manuscript.

Lowe, M., Berner, L., Swanson, S., Clark, V., Eddy, K., Franko, D., Shaw, J., Ross, S., & Herzog, D. (2011). Weight suppression predicts time to remission from bulimia nervosa. Journal of Consulting and Clinical Psychology, 79 (6), 772-776 DOI: 10.1037/a0025714

Best Test for Diagnosing Alzheimer's Dementia

2011-12-12T10:12:00.001-06:00

PET Image Normal

Definitive diagnosis of Alzheimer's disease (AD) from other forms of dementia is a complex clinical challenge. Positron imaging tomography (PET) scans are widely available in the United States. A more recent approach has used the estimation of brain amyloid levels using an amyloid ligand Pittsburgh Compound B (PiB). PiB imaging is primarily a research tool at the present.

I have previously summarized some of the research related to PiB imaging from a lecture presented by Dr. Chet Mathis here. Now a study comparing the sensitivity and specificity of the PiB imaging method with PET imaging using fluorodeoxyglucose has been published.

Rabinovici and colleagues from the University of California, San Francisco, the University of California, Berkeley and the University of Pennsylvania used both scans in a group of 62 subjects with AD and a group of 45 subjects with frontotemporal dementia (FTD). An additional group of 25 age-matched normal controls participated in the study.

The two dementia groups had similar levels of cognitive impairment scoring around 22 on the 30 item Mini-mental status exam. This indicates a relatively mild level of dementia.

PET Image in Alzheimers-Temporal Deficits

The assignment of a diagnosis of AD or FTD was done by clinical diagnosis that included MRI information but was blind to PET imaging results. Additionally, genetic testing for the APOE genotype, progranulin mutations, tau protein and mutations in presenilin-1 and presenilin 2 were obtained. A subset of 11 subjects died after completion of scanning and ten underwent brain autopsy providing histopathology information for group assignment.

Two raters blinded to clinical diagnosis reviewed the scans and assigned a qualitative diagnosis of AD, FTD or normal. Additionally, quantitative scoring of the scans was completed using an quantitative thresholds for assignment of AD or FTD.

Key sensitivity and specificity for the correct diagnosis in the study were (mean rater scores followed by quantitative scoring)

PET-FDG: sensitivity 78%, 73%, specificity 84%, 98%
PiB: sensitivity 90%, 89%, specificity 83%, 83%

Tests with the highest sensitivity and specificity provide the best diagnostic tool. This study comparison supports the current clinical use of PET-FDG for testing for AD. The PiB imaging in this study showed better sensitivity for diagnosis compared to the PET-FDG. The authors note their study supports the use of PiB for a biomarker for differentiating AD from FTD.

Quantitative scoring in PET-FDG proved superior to visual ratings by experts in specificity. This suggest the value of incorporating quantitative score in clinical settings where PET is used to test for AD.

The results of the study suggest that rather than one test being superior, they appear to be complementary.

The authors note PiB is unlikely to become widely used due to the short half-life of the amyloid tracer (20 minutes). However, newer amyloid tracers are in development that would make use of this imaging method more clinically feasible.

In summary, amyloid tracer imaging appears to be a promising method for improving accurate diagnosis of Alzheimer's and other dementias. Until this method becomes available, PET-FDG is a sensitive and accurate tool, particularly when quantitative methods are used to assist in assignment of the diagnosis.

PET images from Wikipedia Creative Commons files authored by Jens Langner (normal) and U.S. National Institute of Aging, Alzheimer's Disease Education and Referral Center (AD).

Rabinovici GD, Rosen HJ, Alkalay A, Kornak J, Furst AJ, Agarwal N, Mormino EC, O'Neil JP, Janabi M, Karydas A, Growdon ME, Jang JY, Huang EJ, Dearmond SJ, Trojanowski JQ, Grinberg LT, Gorno-Tempini ML, Seeley WW, Miller BL, & Jagust WJ (2011). Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD. Neurology, 77 (23), 2034-42 PMID: 22131541

Risk Factors for ADHD Symptoms in Childhood

2011-12-07T11:25:00.001-06:00

U.S. Survey Rates of Ever Being Diagnosed with ADHD (ages 4-17)

ADHD symptoms emerge early in childhood and vary over time. In some children, symptoms will resolve without treatment. For others, ADHD symptoms persist and in some children the symptoms may worsen.

Identifying risk factors for poor prognosis of early childhood ADHD symptoms would assist in targeting secondary prevention interventions.

Galera and colleagues recently outlined a study of early risk factors for ADHD symptoms in a cohort of Canadian children. The study followed over 2,000 children from the ages of 5 months until 8 years.

Following ADHD symptoms over time, the researchers found three group patterns. Approximately 16% of the children followed a high hyper-activity-impulsivity pattern (high symptoms at 17 months of age through 8 years of age) and 13% demonstrated a high inattention pattern. Hyperactivity-impulsivity symptom scores tended to diminish slight with time, while inattention symptoms scores increased most notably in the high inattention subgroup.

A series of prenatal, perinatal, postnatal and parental psychopathology variables were examined. Using multivariate statistical modeling, a series of variables showed significant risk for high levels of ADHD symptoms (variable and adjusted odds ratio):

male gender 2.15
low birth weight 2.11
nonintact family 1.85
maternal tobacco exposure 1.93
younger maternal age at birth 1.78
paternal history of antisocial behavior 1.78
maternal depression 1.38

These findings suggest specific research design strategies in the primary and secondary prevention of ADHD. Studies aimed at reducing risk of low birth weight (i.e. early prenatal care, nutritional support, surveillance for prenatal infections and treatment of drug and nicotine dependence) may provide primary prevention in ADHD.

Secondary intervention strategies could include a structured ADHD symptom assessment at about 18 months of age. Children with high ADHD symptoms at 18 months age with several of the risk factors outlined above might benefit most from early educational, psychological or psychopharmacological interventions.

An additional risk factor for ADHD in children in the U.S. appears to be geographic location. The Canadian study enrolled children from Quebec limiting the ability to assess the effect of geographic variability.

The state by state variability in ADHD rates in the U.S. in 2007 has been estimated by the Center for Disease Control (CDC) (figure above). The highest rate states show a southern U.S. pattern. Some of this geographic variability may be due to higher rates for the risk factors identified in the Canadian study.

The authors note "Early development is a particular period of vulnerability but also plasticity, when influences on programming processes and on the developing brain are subject to modification". Their study helps in identifying high-risk children most likely to benefit from additional support and monitoring.

Figure of U.S. ADHD prevalence rates from Wikipedia Commons file authored by CDC.

Galera, C., Cote, S., Bouvard, M., Pingault, J., Melchior, M., Michel, G., Boivin, M., & Tremblay, R. (2011). Early Risk Factors for Hyperactivity-Impulsivity and Inattention Trajectories From Age 17 Months to 8 Years Archives of General Psychiatry, 68 (12), 1267-1275 DOI: 10.1001/archgenpsychiatry.2011.138

Brain Correlates of Emotional Intelligence

2011-12-06T10:26:00.001-06:00

Insula Cortex Highlighted in Blue

Emotional intelligence (EI) is a concept that has received more attention in the lay press than in the field of neuroscience research.

EI has been defined an individual's ability to be aware of their own emotions as well as the emotions of others. Using this information to guide thinking and action is felt to be important in a variety of interpersonal situations.

Individuals with limited EI faces challenges in the social aspects of work, friendship and marriage. EI overlaps with the concept of social cognition.

EI has been proposed to involve integrated network function in somatic marker circuit and the social cognition network. The somatic marker circuit is felt to involve the vetromedial prefrontal cortex, insula and amygdala. The social cognition network is felt to involve the medial prefrontal cortex and the region of the superior temporal sulcus.

Takeuchi and colleagues from Tohoku University in Sendai Japan have recently published a study of white matter structure and EI using diffusion tensor imaging (DTI). One hundred eighteen healthy young adults were imaged and completed a measure known at the Emotional Intelligence Scale.

The EI Scale is a 65-item self-report questionnaire composed of three factors:

Intrapersonal factor: insight into one's own emotional state, self-control and self-motivation
Interpersonal factor: insight into the emotional state of others, empathy, altruism and interpersonal control
Situation management factor: ability to have insight and control social situations

DTI measures white matter integrity in various brain regions. The Japanese research team examined correlations between measures of white matter function with the factors in the EI scale. The major correlates documented in their analysis were:

Intrapersonal factor scores correlated with white matter indices in the right anterior insula area
Interpersonal factor scores correlated with white matter indices in the right inferior longitudinal fasciculus

The insula is a brain structure that has received increased research attention. It's functions have been found to include gut and body perception as well as emotional awareness. I have previously posted a summary of the function of the insula and clinical disorders that may have links to dysfunction of the insula (autism, ADHD and anorexia nervosa).

The inferior longitudinal fasciculus connects the temporal lobe and the occipital lobe. This area has been linked to facial recognition skills, emotional processing and linguistic processing.

The authors note their findings are consistent with growing evidence for EI as a distinct cognitive function separate from general intelligence. EI appears related to measures of function of brain regions related to the somatic marker circuit and the social cognition network.

Screen shot of the brain insula cortex from the Brain Tutor HD iPad app from the author's collection.

Takeuchi, H., Taki, Y., Sassa, Y., Hashizume, H., Sekiguchi, A., Nagase, T., Nouchi, R., Fukushima, A., & Kawashima, R. (2011). White matter structures associated with emotional intelligence: Evidence from diffusion tensor imaging Human Brain Mapping DOI: 10.1002/hbm.21492

Obesity Linked to Brain White Matter Pathology

2011-12-05T11:55:00.001-06:00

Brain Corpus Callosum Highlighted in Brown

Obesity influences a variety of body organ systems including the cardiovascular, endocrine and hepatic function.

There is a growing body of evidence that the brain may also be a target for adverse effects in obesity. White matter hyperintensities occur at a higher rate in obesity compared to normal weight controls. I have previous highlighted some of the effects of white matter intensities in posts here and here.

Obesity appears linked to an increase risk for dementia including Alzheimer's and vascular types of dementia.

Brain white matter function is important in brain connectivity--communication between various brain regions in coordinating complex processes.

White matter volume studies in obesity have suggested increased white matter volumes relative to normal weight controls although these findings have not be universal.

Brain diffusion tensor imaging (DTI) provides a relatively new tool to examine function of brain white matter. Using complex imaging algorithms, indicies of white matter function can be estimated by measuring the diffusion of water in multiple directions.

A few small studies of DTI in obesity suggest a decrease in white matter function in the brain corpus callosum. The corpus callosum represents a major pathway for communication between the brain right and left hemisphere.

Xu and colleagues at Yale University recently published an additional study on this topic in Human Brain Mapping. They examined the DTI data in a cohort of fifty-one individuals with a wide range of BMI. Although not specifically noted, data suggests about a third of the subjects had a BMI over 30, the cutoff for obesity.

When BMI was correlated with measures of white matter function, three statistically significant findings were noted with higher BMI:

White matter changes in the fornix and splenium (posterior corpus callosum) in patterns typically seen with traumatic brain injury
White matter changes in the left corpus callosum in patterns typically seen acutely in stroke
White matter changes in the right corpus callosum in patterns typically seen in minor white matter fiber loss without gross tissue changes

Fornix Shown as Brown Loop Structure

The new finding in this most recent study is extension of white matter abnormalities to the fornix and suggestion that more than one type of white matter pathology may be involved with obesity. On the right you will see the brain fornix structure as a brown loop structure. The fornix links the brain hippocampus and the hypothalamus. The hippocampus plays a key role in memory function.

The authors note these types of cross-sectional studies have limited generalizability. Longitudinal studies of white matter function and dysfunction linked to neuropsychological function would be very informative. Longitudinal studies will be needed to examine the potential specific contribution of obesity to brain white matter pathology and dysfunction.

3D Brain images of corpus callosum and fornix are screenshots from the iPad app from the author's personal collection.

Xu, J., Li, Y., Lin, H., Sinha, R., & Potenza, M. (2011). Body mass index correlates negatively with white matter integrity in the fornix and corpus callosum: A diffusion tensor imaging study Human Brain Mapping DOI: 10.1002/hbm.21491

Perinatal Risk Factors for Autism

2011-11-28T11:39:00.001-06:00

Matt Holliday Batting in 2011 Spring Training

Literature review studies provide summaries of the current knowledge in an area of clinical research. A recent literature review of prenatal, perinatal and neonatal risk factors in autism has been published online at Acta Obstetricia et Gynecologica Scandinavica. For simplicity, I have grouped these studies under a broader definition of perinatal risk factors.

The authors of this study collected and reviewed 85 case-control studies of autism. Included studies needed to meet specific quality-related criteria to be included in the review.

The authors summarize their results in three tables that include an estimate size of the specific risk (larger number indicates larger effect of the risk factor). Here is a summary of the findings from this review-risk factor followed by estimated range of effect estimates:

Prenatal Risk Factors (Effect estimate, i.e. 2.0 equal double risk with presence of risk factor):
Advanced maternal age (1.6-2.1)*
Advanced paternal age (1.3-3.1)*
Mother born abroad (1.6-2.2)*
Parity (first child risk compared to third or later child) (1.6)
Diabetes in pregnancy (1.2-3.5)
Bleeding in pregnancy (1.1-2.9)*
Psychotropic drug use in pregnancy (1.1-2.0)
Preeclampsia in pregnancy (1.5-1.7)*

Perinatal Risk Factors:
Preterm birth (before 33 weeks) (2.8-5.4)*
Preterm birth (33 to less than 37 weeks) (1.4-2.6)
Breech presentation (1.6-2.1)*
Scheduled caesarean section (1.2-1.8)*
Labor induction (1.2)
Fetal distress (1.4-1.5)

Neonatal Risk Factors:
Low birth weight (1.3-7.1)*
Small for gestational age (1.9-2.1)*
Low birth Apgar score (2.0-3.2)*
Hyperbilirubinemia (1.3-9.0)
Encephalopathy (3.1-5.6)*

The authors note that some individual risk factors have not been replicated in other studies. In a global review of all the studies, the authors highlighted risk factors with "the most robust results". I have highlighted these risk factors by placing an asterisk (*) after the effect estimate range.

Risk factors do not indicate causality. A risk factor may be related another variable that directly increases risk for a disorder. These types of studies do not tend to provide information specific to pathological mechanisms.

The authors note the variety of risk factors suggests future studies should be designed to investigate combinations of multiple factors rather than a single risk factor.

The authors provide some thoughts about how temporal trends may be contributing to the increased rates of autism. Improvement in obstetrical and high-risk pregnancy may boost survival rates for infants with some element of brain compromise and increased risk for autism and other developmental disorders.

Additionally, delaying the parental age of conception appears to be increasing in many areas of the world. This may also be increasing the number of children born with autism and autism spectrum disorders.

This review was helpful to me in providing an overview of the perinatal risk factors in autism. Genetic and environmental factors contributing to autism deserve additional funding and research efforts.

Photo of St. Louis Cardinal Matt Holliday batting in 2011 from the author's collection.

Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, & Cohen D (2011). Pre-, peri-, and neonatal risk factors for autism. Acta obstetricia et gynecologica Scandinavica PMID: 22085436

Circadian Rhythm Alterations in Adult ADHD

2011-11-28T10:28:00.001-06:00

Sleep problems are encountered frequently in the clinical management of attention-deficit hyperactivity disorder (ADHD). Children with ADHD sleep fewer hours than children without ADHD. ADHD symptoms often decrease in severity with development but may persist in to adulthood.

The sleep patterns of adults with ADHD are less well studied than those in children. However, research evidence exists for disruption of sleep and circadian rhythms in adult ADHD including: evening preference (being a night owl), delayed sleep onset, reduced efficiency of sleep (% of time in slow wave sleep) and reduced time spent in rapid eye movement (REM) sleep.

Baird and colleagues from the National University of Ireland recently published results of a study examining a series of variables related to sleep and circadian rhythms in a group of subjects with adult ADHD and controls. As the title of their study suggests, these variables can be divided into three domains:

Behavioural: sleep onset latency, physical activity during the night, sleep efficiency and morning versus evening preference
Endocrine: absolute melatonin and cortisol levels and rhythmicity of these levels
Molecular: rhythmic expression of the clock genes BMAL1 and PER2

Thirteen adult subjects with ADHD were compared to nineteen controls over a seven day period. Behavioural data was collected using actigraphy and questions. Endocrine and molecular data was collected using buccal swabs and saliva samples collected every 4 hours over a 24 hour period.

Multiple sleep and circadian rhythm differences emerged in the study of the ADHD group. Adult ADHD subjects were statistically different from controls in the following variables:

Behavioural: 53% of the ADHD group typically took one hour or more to fall asleep compared to none of the controls, nocturnal physical activity levels were higher, sleep duration and sleep efficiency were lower, preference for evening over morning was higher
Endocrine: amplitude of melatonin rhythm was lower, cortisol rhythm was phase delayed
Molecular: loss of circadian rhythm for the clock genes BMAL1 and PER2

The authors note cortisol rhythm appears to be controlled by a brain region known as the suprachiasmic nucleus (SCN) and that their results suggest a "deficit of entrainment of the master circadian clock in adult ADHD to appropriate environmental and social stimuli". The SCN is a small structure the size of only a grain of rice located close to visual brain pathways and sensitive to environmental light levels.

Several limitations of this sample and study are outlined in the manuscript. Adults with ADHD have higher rates than those without ADHD of mood and anxiety disorders. Controlling for the specific effect of ADHD on sleep and circadian rhythm is complicated by this comorbidity. Thirty percent of the subjects with ADHD in the sample took atomoxetine or a stimulant medication during the study. The medication effect on sleep and circadian rhythm could not be controlled due to the small sample size.

However this study highlights the importance of assessment of sleep in adults with ADHD. Cognitive behavioral interventions hold promise for improving the sleep patterns in this population. Pharmacologic interventions might also be helpful but need to be studied specifically in those with ADHD.

Figure of the suprachiasmic nucleus (SCN) from Wikipedia Commons file with unknown author/creator.

Baird, A., Coogan, A., Siddiqui, A., Donev, R., & Thome, J. (2011). Adult attention-deficit hyperactivity disorder is associated with alterations in circadian rhythms at the behavioural, endocrine and molecular levels Molecular Psychiatry DOI: 10.1038/mp.2011.149

Zolpidem (Intermezzo) for Middle of Night Insomnia

2011-11-23T15:38:00.001-06:00

Molecular Model for the Drug Zolpidem

Hypnotic medications have provided assistance to millions of people around the world. Some use them for brief periods while some are used chronically. Typically targeted to assist in getting six to eight hours of sleep with limited morning hangover effect.

However, there are several situations where typical hypnotic agents fail. Let me describe three clinical scenarios.

Scenario #1: I only use hypnotics on an as needed basis. Typically I sleep well without medication but occasionally use them when travelling or after a stressful day. Tonight I thought I would be able to fall asleep on my own, but now it's three hours after bedtime and I am not sleeping. I can't take my hypnotic now because I have an important early morning appointment and can't afford to be groggy at 8 am.
Scenario #2: I don't typically have any problem falling asleep. I go to bed at 10 pm and am asleep within 10 minutes. But, I have been waking up every night at 2 am. I toss and turn and can't fall back to sleep. By 8 am I am exhausted as I get out of bed for the day.
Scenario #3: I use a sleeping pill every night. Tonight, I am not getting to bed until 2 am due to a night at the opera and dining out late. I need to sleep well but have a 8:30 am meeting that I must attend. If I take my usual hypnotic, I will be too groggy to get to my morning meeting.

Now in the U.S., the Food and Drug Administration (FDA) has approved a formulation of the drug zolpidem specifically for middle of the night insomnia (FDA press announcement is located here.

Zolpidem is already marketed in the U.S. for insomnia under the trade name Ambien and Ambien CR. Typically used at doses between 5 mg and 12.5 mg for full night insomnia treatment, the new formulation uses a rapidly dissolvable sublingual (under the tongue) tablet with a lower dose of 1.75 mg for women and 3.5 mg for men.

Sublingual zolpidem produces more rapid absorption than the tablet form. Research supports superiority of the sublingual form of zolpidem in reduced time to onset of sleep.

Use of hypnotics should be done only under the direction of a physician. One concern I have with a middle of the night hypnotic is the potential to miss an underlying mood disorder that might need to be treated. Waking up in the middle of the night and not being able to go back to sleep is a common sign in major depression. Antidepressant treatment or other depression approaches may be better interventions for some individuals with middle of the night insomnia.

Non-drug approaches are increasingly showing efficacy in the treatment of insomnia. Cognitive behavioral therapy for the treatment of insomnia is gaining evidence-based support in adults and in geriatric patient groups. I have previously summarized some research in CBT for insomnia here and here.

Sublingual zolpidem offers a new option for the management of insomnia. There will likely be additional studies of the potential use of this pharmacologic agent in a variety of clinical settings.

Molecular model of the drug zolpidem from the Wikipedia Commons file authored by

Staner C, Joly F, Jacquot N, Vlasova ID, Nehlin M, Lundqvist T, Edenius C, & Staner L (2010). Sublingual zolpidem in early onset of sleep compared to oral zolpidem: polysomnographic study in patients with primary insomnia. Current medical research and opinion, 26 (6), 1423-31 PMID: 20397964

Dang A, Garg A, & Rataboli PV (2011). Role of zolpidem in the management of insomnia. CNS neuroscience & therapeutics, 17 (5), 387-97 PMID: 20553305

Can Antihypertensive Choice Reduce Dementia Risk?

2011-11-22T15:26:00.001-06:00

Odds Ratio For Dementia in Drug Class Users

Genetic factors contribute to the risk of Alzheimer's dementia. However, other lifestyle risk factors appear to contribute to modifying the risk.

Hypertension and cerebrovascular disease may influence dementia risk via adding a vascular component to cognitive decline. It is also possible, cerebrovascular disease may directly influence the risk of Alzheimer's disease progression.

Control of hypertension may reduce dementia risk. It has typically been felt that any class of antihypertensive drug that sufficiently lowered blood pressure would produce a lower risk for cerebrovascular disease, stroke and dementia related to vascular factor.

However, a recent study of rates of Alzheimer's dementia, vascular dementia and other dementia has produced an intriguing finding. Neil Davies and colleagues from the University of Bristol examined a group of 9,000 subjects with dementia compared to a group of controls.

They examined the association of specific classes of antihypertensive drugs with rates of dementia. The key findings from the study are summarized in the figure above. Two classes of antihypertensive drugs appeared to be associated with a lower rates of dementia. These two classes of agents and prominent members of the classes include:

Angiotension reuptake blockers (ARBs): losartan (Cozaar), valsartan (Diovan), irbesartan (Avapro), olmesartan (Benicar) and candasartan (Atacand)
Angiotension-converting enzyme inhibitors (ACE-I): captopril (Capoten), enalapril (Vasotec), lisinopril (Zestril), ramipril (Altace) and benzipril (Lotensin)

Subjects in the study taking ARBs had a odds ratio of .47 for also having a diagnosis of Alzheimer's disease. For vascular dementia, this odds ratio was .70. These figures correspond to an approximate 30 to 50% reduction compared to controls.

The lower rates of dementia in the ACE-Inhibitor groups were not quite as low with odds ratios of .76 for Alzheimer's disease and .70 for probable vascular dementia.

The authors note that the angiotension-converting enzyme (ACE) appears to be involved in the metabolism of the protein linked to Alzheimer's disease, beta amyloid. ACE may degrade beta amyloid protein reducing risk of Alzheimer's-associated pathology in the brain. The authors note "ARBs protect against the cognitive deficits and beta amyloid related pathology in animal models of AD".

They also other studies have suggested lower rates of Alzheimer's disease and slower progression is subjects treated with ARB antihypertensive drugs compared to agents such as the beta blocker atenolol.

There are significant limitations to generalizability of this type of study. Association does not mean causality. Randomized prospective studies are needed to identify a causal relationship. Such studies might be quite informative in those with a high risk for Alzeimer's disease or evidence of mild cognitive impairment.

Nevertheless, this study is exciting because it suggests a new strategy to potentially prevent or delay the onset of more than one type of dementia. Preventive strategies in Alzheimer's and other dementias are crucial given the increased prevalence and morbidity associated with these disorders.

Chart is original from the author using data supplied in the Davies et al study cited below.
Davies NM, Kehoe PG, Ben-Shlomo Y, & Martin RM (2011). Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. Journal of Alzheimer's disease : JAD, 26 (4), 699-708 PMID: 21709373

Heart Effects in Severe Anorexia Nervosa

2011-11-22T13:00:00.001-06:00

3D Image of Heart Using Echocardiography-Details Below

The physical manifestations due to extreme weight loss in anorexia nervosa include effects on the heart.

Cardiac effects can contribute to the risk of death in anorexia nervosa. Electrolytye abnormalities increase the risk of cardiac conduction defects and increase the risk of potentially fatal cardiac arrhythmias.

One tool to study the effects of weight loss on the heart in anorexia nervosa is echocardiography. Echocardiography is a safe non-invasive technique that can provide information about both the heart's structure as well as function. Three dimensional echocardiograpy provides a real-time image of the heart compiled from scanning across multiple planes. The figure above gives an idea about what types of heart images can be produce from 3D echocardiography.

Kastner and colleagues from the Freie University in Berlin, Germany have recently published a study of echocardiography in anorexia nervosa. Images were taken from a group of over 100 young female patients early in the course of hospitalization. Second images were taken after weight recovery. This provides the ability to determine cardiac effects that might be weight dependent compared to effects that might be weight independent.

The research team identified a series of cardiac effects found in underweight young individuals with anorexia nervosa including:

Reduced left ventricular end-diastolic volume
Reduced left ventricular end-systolic volume
Presence of a "clinically silent" pericardial effusion in 34.7% of the anorexia nervosa sample compared to 0% of controls

Pericardial effusion can be due to a variety of causes including infection, trauma, congestive heart failure or metastatic cancer. These causes could be ruled out in the anorexia nervosa group so the exact mechanism is unclear. Those with pericardial effusion tended to have lost the most weight, have prolonged hospitalizations and to show subtle thyroid function abnormalities that might contribute to cardiac dysfunction.

The authors note that following weight gain, pericardial effusion resolved in almost 90% of cases. Other abnormalities noted above did not completely resolve although they may have normalized with further study at a later date.

This study may aid clinicians treating anorexia nervosa who find pericardial effusion in the course of clinical care. This finding appears to relatively common and benign if weight can be restored. If weight is not restored, the potential for adverse cardiac effects may be a significant clinical problem.

Image is from Wikipedia Commons file showing a GIF-animation of a moving echocardiogram; a 3D-loop of a heart viewed from the apex, with the apical part of the ventricles removed and the mitral valve clearly visible. Authored by Kjetil Lenes.

Kastner S, Salbach-Andrae H, Renneberg B, Pfeiffer E, Lehmkuhl U, & Schmitz L (2011). Echocardiographic findings in adolescents with anorexia nervosa at beginning of treatment and after weight recovery. European child & adolescent psychiatry PMID: 22086424

Sleep Disorders and Cognition in Older Men

2011-11-21T14:11:00.001-06:00

Sleep Stage Architecture Figure with REM Sleep in Red

Sleep contributes to brain function through a variety of mechanisms. Sleep functions change over the life cycle with older adults showing a greater amount of time in light sleep phases (stage 1 and stage 2 sleep). Less time is typically spent among older adults in restorative or deep sleep (slow-wave sleep) and rapid age movement sleep.

Since dementia risk increases with age, it is natural to wonder how age-related sleep changes might interact with cognitive function.

One method of examining the sleep-cognition relationship is to perform sleep studies and neuropsychological testing in a cohort of individuals. Large samples of elderly subjects with such association studies are limited.

A recent study of a large correlational study of sleep and cognition has been recently published in the Journal of the American Geriatrics Society. This data set analysis is a secondary study as the data was collected originally for the Osteoporotic Fractures in Men Study (MrOS). Nearly 6,000 men aged 65 and older from six centers in the U.S. Subjects needed to be ambulatory not had have had bilateral hip replacement. The sleep and cognitive function variables collected in the study included:

Sleep parameters (from ambulatory polysomnography testing): sleep stages duration (Rapid eye movement sleep, i.e. dreaming sleep--REM, Stages 1-4, Non-rapid eye movement sleep--NonREM), arousal index (number of EEG arousals per hour of sleep), apnea-hypopnea index (measure of sleep-disordered breathing) and arterial oxygen saturation.

Cognitive function testing: Trail Making Test Part B (measure of psychomotor speed and visuospatial functioning, modified Mini-Mental State Exam (screening test of orientation, memory, comprehension, speech), Digital Vigilance Test (testing of attention and memory).

Spending more time during sleep in light sleep (stage 1) and spending less time in REM sleep correlated with decreased cognitive function. Surprisingly, sleep apnea measures did not associate many of the cognitive function variables tested in this population. Severe levels of sleep hypoxia were related to decreased vigilance scores but no change was found on other cognitive function variables.

Reduced REM sleep time was linked to a variety of clinical characteristics including: hypertension, history of stroke or transient ischemic attack (TIA), coronary artery disease, current antidepressant use, higher current Geriatric Depression Scale score, less education, lower physical activity and lower self-rated health.

The authors note that a primary weakness of their study is the correlational analysis--direction of effect is unknown. From this study it is impossible to know if having a sleep problems contributes to risk or vice versa--cognitive decline may produce sleep changes. It is also possible a third unknown pathway may be in operation.

This study is not sufficient to change clinical practice. However, it seems prudent to monitor cognitive function in older adults and consider the potential for sleep problems (and sleep disorders) to contribute to process of mental decline in the elderly.

Sleep architecture from Wikipedia Commons file authored by Petitemontagnedujura

Blackwell, T., Yaffe, K., Ancoli-Israel, S., Redline, S., Ensrud, K., Stefanick, M., Laffan, A., Stone, K., & , . (2011). Associations Between Sleep Architecture and Sleep-Disordered Breathing and Cognition in Older Community-Dwelling Men: The Osteoporotic Fractures in Men Sleep Study Journal of the American Geriatrics Society DOI: 10.1111/j.1532-5415.2011.03731.x

Smell Function as an Early Parkinson's Clue

2011-11-21T13:03:00.001-06:00

Basal Ganglia Including Substantia Nigra Key In Parkinson's Disease

Early identification of neurodegenerative disorders plays a key role in prompt intervention and surveillance. A great deal of research is being conducted in the early identification of Alzheimer's disease. Less attention has been placed on early identification of Parkinson's disease.

Early Parkinson's disease identification may be more valuable given the spectrum of pharmacological options for treatment.

One clinical finding in Parkinson's disease is an early loss of smell (olfactory) function. The predictive value of an abnormal loss of olfactory function on Parkinson's disease diagnosis is unknown. Tyler Rolheiser and colleagues at Dalhousie University and Innsbruck Medical University in Austria have recently published their research on this topic in the Journal of Neurology.

In their study fourteen subjects with early stage Parkinson's disease were matched with subjects of similar age and gender. Subjects completed the University of Pennsylvania Smell Identification Test (UPSIT). This test uses a series of scratch and sniff booklets with subjects provided four options to choose from whether they sense an odor or not.

The cases and controls then underwent sensitive MRI brain imaging scan that focused on several brain areas including the substantia nigra (known to be a region of dysfunction in Parkinson's) and the brain anterior olfactory structure.

The brain MRI method used in this study is diffusion tensor imaging. This technique focuses on brain white matter structure and function. A previous post on the use of DTI in memory exercise has been posted here.

The UPSIT smell function test successfully discriminated the Parkinson's disease group from the control group. Parkinson's disease patients showed either complete loss of ability to identify smells or marked impairment in smell function.

The study found several measures of DTI in the substantia nigra region that distinguished the Parkinson's disease group from control. In the anterior olfactory structures, DTI differed between groups in the measure known as factional anisotropy.

The authors note that loss of sense of smell may precede clinical Parkinson's disease by two to five years. Their study supports research looking at the UPSIT or other smell function tests as a first-stage screening test followed by brain MRI DTI imaging of the substantia nigra and anterior olfactory structure.

The advantage of the further testing of olfactory function in early Parkinson's disease is that it is an easy and inexpensive test to administer. Brain imaging is much less available and very costly. Finding and using lower cost screening options is important.

Any use of a smell test for screening is likely to have some false positive and false negatives. The magnitude of these errors in general population screening is unknown. Nevertheless, further exploration of smell testing with other markers of early Parkinson's may soon give clinicians more tools for screeing for this neurodegenerative disorder.

3D Brain image of brain substantia nigra from screen shot in author's collection.

Rolheiser TM, Fulton HG, Good KP, Fisk JD, McKelvey JR, Scherfler C, Khan NM, Leslie RA, & Robertson HA (2011). Diffusion tensor imaging and olfactory identification testing in early-stage Parkinson's disease. Journal of neurology, 258 (7), 1254-60 PMID: 21287185

CBT and Exercise Reduce Pain in Fibromyalgia

2011-11-16T13:10:00.001-06:00

Cognitive Behavior Therapy or (CBT) is a form of psychotherapy originally developed for the treatment of major depression. Modifications of CBT for a variety of other neuropsychiatric disorders quickly emerged and now the demand for CBT exceeds the supply of trained therapists. Efforts to extend the benefits seen with CBT now includes telephone and internet-based methods.

CBT hold promise in management of pain from a variety of medical conditions. This promise requires the development of novel strategies to move CBT into primary care settings. John McBeth and colleagues in Scotland and England, recently published a large study of telephone-delivered CBT in primary care patients identified with chronic widespread pain found in fibromyalgia.

This study randomized patients with widespread chronic pain to one of four treatment options:

Treatment as usual--a control intervention
Telephone-based CBT for six months
Graded exercise training for 6 months
Both telephone-based CBT and graded exercise training for 6 months

The telephone-based CBT included an initial assessment of one hour followed by seven weekly sessions lasting 30 to 45 minutes. A booster session was held at 3 months and at 6 months. Elements of the CBT therapy included:

Assessment included selection of two to three patient-defined goals
A CBT manual developed for the study was provided
Behavioral activation--changing level of activity and the pace it is completed
Cognitive restructuring--identifying thinking styles that might contribute to pain or reaction to pain
Lifestyle changes--modifying lifestyle to improve sleep, reduce fatigue and reduce irritability

The exercise group received an exercise assessment from a fitness training followed by monthly appointments with their trainer. They were encouraged to get to the gym on their own at least twice per week and on other days participate in brisk walking or other activities that might improve cardiorespiratory fitness.

The primary outcome for this study was a patient global assessment at six months where individual subjects were asked to rate change in health since beginning the trial. Those who rated their health as "much better" or "very much better" were considered responders to the intervention. The response rates at six months for each of the interventions were:

Treatment as usual--8%
Telephone-based CBT for six months--30%
Graded exercise training for 6 months--35%
Both telephone-based CBT and graded exercise training for 6 months--37%

All intervention groups were superior to treatment as usual. A second global health rating at 9 months found a small increase in response rate in the CBT group.

This study suggests that telephone-based CBT is worthy of consideration as a mainstream intervention for the chronic pain associated with fibromyalgia. It would have been nice to see a little higher response rates in the active interventions. However, chronic pain is a treatment-resistant condition where any new pathways to improvement are welcomed.

Photos of butterflies from author's private collection.

McBeth, J., Prescott, G., Scotland, G., Lovell, K., Keeley, P., Hannaford, P., McNamee, P., Symmons, D., Woby, S., Gkazinou, C., Beasley, M., & Macfarlane, G. (2011). Cognitive Behavior Therapy, Exercise, or Both for Treating Chronic Widespread Pain Archives of Internal Medicine DOI: 10.1001/archinternmed.2011.555

Mirtazapine Linked to Reduced Methamphetamine Use

2011-11-14T10:52:00.001-06:00

Molecular Model of Mirtazapine

Methamphetamine abuse and dependence are often resistant to treatment intervention with high relapse rates. Pharmacological augmentation of behavioral treatments may provide one strategy to improve the outcome of methamphetamine addiction.

Potential mechanisms for pharmacological augmentation in methamphetamine abuse include reduction id drug craving, blocking the hedonic effect of drug use, reducing dysphoria during methamphetamine withdrawal or treatment of underlying psychiatric disorders such as anxiety and mood disorders.

No drug is currently approved for methamphetamine abuse--this is unfortunate given that pharmacological options exist for alcohol, nicotine and opioid abuse.

Mirtazapine, a generically available antidepressant drug (Trade name Remeron) facilitates the release of several CNS monoamines including norepinephrine, serotonin and dopamine. It has relatively low impact on sexual function. It's primary drawback has been a tendency to increase appetite and increase weight. Since many methamphetamine abusers are underweight, this adverse effect may be less problematic.

Colfax and colleagues recently published a small randomized placebo-controlled clinical trial of mirtazapione in methamphetamine abuse. The key elements of the clinical trial include:

Diagnosis: methamphetamine dependence by DSM-IV-TR criteria
Urine drug testing positive for methamphetamine metabolites
No acute medical or psychiatric illness
No current major depression
No recent use of antidepressant drugs
Clinical trial drug: mirtazapine 30 mg or placebo for 12 weeks
Outcome measure: methamphetamine urine drug tests

This clinical trial focused on a group of male methamphetamine abusers who have sex with men. This demographic group is known to have increased risk for sexually transmitted disease including HIV making treatment advances important.

Methamphetamine-positive drug urine sample rates in the active mirtazapine drug assigned group dropped from 73% at baseline to 44% at study end. The placebo group had no significant change with 67% positivity at baseline and 63% positivity at study end.

The research team noted that the efficacy of mirtazapine for methamphetamine use seemed to be independent of any antidepressant effect. The study participants reported only fair adherence to the study drug during the trial. The authors note this might indicate the effect of mirtazapine might be greater in groups with higher adherence. The mediocre adherence does underscore a hurdle for any pharmacologic intervention in those with methamphetamine abuse.

This clinical trial was relatively small with thirty subjects in the mirtazapine group and thirty subjects in the placebo group. Additionally, generalizability is limited due to the restricted demographic profile of the study group. However the magnitude of reduction in methamphetamine-positive drug rates in the mirtazapine is impressive. Mirtazapine holds promise as a potential new strategy for methamphetamine abuse, but the results of this study will need confirmation before wide adoption in clinical practice.

Molecular model of mirtazapine from the Creative Commons file at Wikipedia authored by Ben Mills.

Colfax GN, Santos GM, Das M, Santos DM, Matheson T, Gasper J, Shoptaw S, & Vittinghoff E (2011). Mirtazapine to reduce methamphetamine use: a randomized controlled trial. Archives of general psychiatry, 68 (11), 1168-75 PMID: 22065532

Testosterone Boosts Sexual Function in Men on SSRIs

2011-11-11T10:28:00.001-06:00

Selective serotonin reuptake inhibitor antidepressants (SSRIs) such as fluoxetine (Prozac) continue to be a common first-line treatment for major depression and a variety of anxiety disorders. Although generally well tolerated, sexual side effects are common in both men and women taking SSRIs.

There are a variety of options for managing sexual side effects. These can include reducing the dose of the SSRI, switching (or augmenting) with antidepressants without sexual side effects or in men considering a trial of an erectile dysfunction drug such as sildenafil (Viagra).

Now a small clinical trial suggests that testosterone gel may be another option for men with SSRI-related sexual dysfunction.

A team of researchers from Israel and the United States combined to perform a randomized placebo-controlled trial of testosterone gel in men with low or low-normal serum testosterone levels. The key elements of this randomized trial published in The Journal of Sex and Marital Therapy include:

Male subjects with DSM-IV major depression currently or within last year
Taking one of eight SSRI drugs
Current HAM-D depression severity rating scale of twelve or greater
Morning total testosterone levels less than or equal to 350 ng/dl
Randomized to receive testosterone gel (5 gram/day) versus placebo gel
Primary sexual function outcome measured by the International Index of Erectile Function (IIEF)

It should be noted this present study was a secondary analysis from data collected to determine if testosterone augmentation would improve depression in men partially responsive to SSRI treatment. This explains the requirement that at least moderate depressive symptoms were required for participation in the study. The second reference below is the results manuscript for the testosterone augmentation in depression study. This study found limited support for testosterone augmentation in depression.

The testosterone augmentation group showed an improvement in IIEF scores in a variety of domains compared to the placebo group. This included improvement in subscales in the domains of sexual desire, erectile function and orgasmic function.

The authors were unable to demonstrate a correlation between testosterone levels and improved sexual functioning ratings. Of note, some of the participants with low screening testosterone on more accurate testing later on admission samples showed normal testosterone levels. These individuals appeared to have as much improvement in sexual function measures as men with low serum testosterone levels.

The authors note they were unable to distinguish whether impaired sexual function in this sample of subjects was due to SSRI treatment, major depression or a pre-existing hypothalamic-pituitary-gonadal functioning. Nevertheless, they note their study supports "the need for systematic clinical research to determine the therapeutic utility--including the effect on sexual function--of androgen replacement in depressed men, and the proper sequence of treatment".

It should be noted that although testosterone gel is approved for use in hypogonadism in men, it is not approved for sexual dysfunction in men with normal serum testosterone levels. Testosterone therapy poses significant risk and should only be considered in the context of a medical evaluation by a physician. Testosterone supplementation may increase risk for prostate cancer. Subjects in the study described here were required to have normal prostate specific antigen levels (PSA less than 4.0 ng/ml) to participate in the study.

Photo of green sea turtle from Loggerhead Marinelife Center of Juno Beach, Florida from author's personal file.

Amiaz R, Pope HG Jr, Mahne T, Kelly JF, Brennan BP, Kanayama G, Weiser M, Hudson JI, & Seidman SN (2011). Testosterone gel replacement improves sexual function in depressed men taking serotonergic antidepressants: a randomized, placebo-controlled clinical trial. Journal of sex & marital therapy, 37 (4), 243-54 PMID: 21707327

Pope HG Jr, Amiaz R, Brennan BP, Orr G, Weiser M, Kelly JF, Kanayama G, Siegel A, Hudson JI, & Seidman SN (2010). Parallel-group placebo-controlled trial of testosterone gel in men with major depressive disorder displaying an incomplete response to standard antidepressant treatment. Journal of clinical psychopharmacology, 30 (2), 126-34 PMID: 20520285

Neuropsychology and the Cerebellum: Part II

2011-11-08T14:06:00.003-06:00

Cerebellum in Purple from Inferior View of Brain

In a previous post I summarized some of the recent understanding of the role of the cerebellum in a variety of neuropsychological domains.

The recent review by O'Halloran and colleagues also included a discussion of the cerebellum in several neuropsychiatric disorders. I will highlight the key components from the review in autism spectrum disorder, ADHD and schizophrenia/mood disorders.

Autism Spectrum and the Cerebellum

Individuals with Asperger's disorder demonstrated soft cerebellar dysfunction signs including posteral instability, pointing accuracy deficits and timing deficits
Autism in children is associated with smaller cerbellar vermis lobes
Diffusion tensor imaging (DTI) brain white matter imaging studies show decreased axonal density emanating from the right cerebellum
These findings suggest that in autism "the reduction in cerebellar feedback to supratentorial regions may play a key role in these individuals' difficulty in appreciating social cues"

ADHD and the Cerebellum

Individuals with ADHD also show some soft neurological signs of cerebellar dysfunction including gait and postural deficits
Boys and girls with ADHD show reduced cerebellar volumes in vermis lobes (different from the lobes decreased in autism spectrum disorder)
Greater decrease in cerebellar volumes are seen in children with ADHD not treated with stimulants suggesting stimulant medication may reduce cerebellar abnormalities in ADHD
The medial cerebellum appears to contribute to the regulation of attention and this area of the cerebellum may contribute to attentional deficits in ADHD

Schizophrenia, Mood Disorders and the Cerebellum

Reduced cerebellar white and gray matter volumes have been found in multiple studies of schizophrenia
Reduced cerebellar vermis volumes have been found in both unipolar and bipolar affective disorder
Bipolar disorder has been linked to reduced white matter volume in the left cerebellar hemisphere

The potential for treatment interventions involving the cerebellum is intriguing and worthy of further exploration. The authors note one study of implantation of a device to stimulate the cerebellar vermis reduced psychotic symptoms in a small sample of eleven subjects. Transcranial magnetic stimulation over the lateral cerebellum stimulates the prefrontal cortex on the opposite side.

I hope that better understanding of the role of the cerebellum in a variety of neuropsychiatric disorders provides opportunities for novel treatment development.

O'Halloran CJ, Kinsella GJ, & Storey E (2011). The cerebellum and neuropsychological functioning: A critical review. Journal of clinical and experimental neuropsychology PMID: 22047489

Neuropsychology and the Cerebellum: Part I

2011-11-07T14:59:00.001-06:00

Cerebellum Highlighted in Purple

When in medical school I remember memorizing the functions of the cerebellum with the acronym ETC standing for equilibrium, tone (motor) and coordination.

I won't mention how long ago that was but I will note that until about the last 20 years or so, this was the common view of the limits of the cerebellum.

Within the last twenty years, the function of the cerebellum is being understood to expand to a much more complex list of domains.

This increased understanding of the role of the cerebellum stems from study of patients with hereditary cerebellar disorders, i.e. spinocerebellar ataxia, localized strokes involving the cerebellum, advances in neuroanatomy and brain imaging studies related to brain function such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET).

Christopher O'Halleran and colleagues from Australia have recently reviewed the neuropsychological functions linked to the cerebellum in an article published in the Journal of Clinical and Experimental Neuropsychology. Additionally, they have pointed out this brain region appears linked to several clinical neuropsychiatric conditions including: autism, ADHD and schizophrenia.

The cerebellum appears to have "localization of discrete cognitive processes". The anterior cerebellum contributes to sensory and motor function while the posterior cerebellum is involved in cognitive processes. Medial portions of the cerebellum participate in emotional regulation.

Here are some of the neuropsychological domains of emerging knowledge associated with the cerebellum:
Visuospatial: The cerebellum appears to influence a variety of visuospatial functions. The right cerebellum seems to crucial in visual attention while the left cerebellum contributes to visuospatial processes.
Learning and memory: The cerebellum seems important in many learning and memory functions including those related to procedural, associative and declarative domains.
Language: The left cerebellum participates in articulation while the posterior right cerebellum contributes to cognitive elements of language.
Executive functioning: The review noted that patients with spinocerebellar ataxia have "a wide range of deficits in executive functioning such as concept formation, abstract reasoning, mental flexibility, sensitivity to interference, planning and organization, set shifting, and sequencing". Cerebellar infarction can produce dysfunction in working memory--a key component of executive function.
Social, emotional and regulatory behavior: In addition to effects in dorsolateral prefrontal cortex function, the cerebellum appears important prefrontal cortex known to modulate affective regulation. Patients with cerebellar pathology commonly show evidence of impaired prefrontal cortex function including anxiety, agressive outbursts and impaired judgement. Imagining the mental states of others is a key emotional skill that appears to be part of the role of the right cerebellar hemisphere.

The is an excellent review of what is known about the neuropsychological domains linked to the cerebellum. In the next post, I will focus on the second part of this review: the cerebellum and neuropsychiatric disorders.

Screen shot of the cerebellum from the iPad app 3D Brain from the author's personal file.

O'Halloran CJ, Kinsella GJ, & Storey E (2011). The cerebellum and neuropsychological functioning: A critical review. Journal of clinical and experimental neuropsychology PMID: 22047489

Brain White Matter Changes Increase Dementia Risk

2011-10-27T10:30:00.002-05:00

Diffuse White Matter Hyperintentsity in CADASIL

Approximately a year ago, I reviewed some of the growing evidence of the clinical significance of brain white matter intensities or lesions. Magnetic resonance imaging identifies these types of lesions but their significance had been unknown.

The review noted that white matter hyperintensities appear to increase future risk for several disorders including stroke and dementia. Additionally, these lesions have increase mortality rates in some follow up studies.

Now an additional study has examined the effect of these lesions on dementia. Inaba and colleagues examined the progress of cognitive decline in a group of elderly individuals participating in the Honolulu-Asia aging study.

The study followed 267 men between the ages of 74 and 95. At baseline, brain MRI scans were rated for the presence and grade level of white matter lesions. A cognitive function test (Cognitive Abilities Screening Instrument) was obtained at baseline and five years later repeated. Significant cognitive decline was defined as a drop of 12 points or more over the five year period.

Subjectives with significant white matter lesions had higher rates of cognitive decline (34.4%) compared to the control group without these lesions (22.4%).

Men with the lesions were more likely at baseline to have a diagnosis of hypertension and show evidence of a small infarct (stroke) on MRI. They did not differ on rates of depression or smoking history. Baseline differences on potential confounding variables were controlled in this study using multivar

The effect of white matter lesions on cognitive decline appeared to be stronger in those without the gene known to be associated with Alzheimer's disease risk (ApoE).

The authors propose that white matter lesions may reflect damage to brain connectivity tracts. This could result in slowing speed of neural transmission. This may be the mechanism for neuropsychological studies linking white matter lesions to reduced cognitive processing speed, attention and executive function.

Further research is needed to identify potential preventive interventions to reduce the risk of these lesions.

MRI brain image showing white matter hyperintensities in a frontal to occipital distribution from a patient with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). From the Wikipedia Commons file authored by Bohlega S, Al Shubili A, Edris A, Alreshaid A, Alkhairallah T, AlSous MW, Farah S, Abu-Amero KK.

Inaba M, White L, Bell C, Chen R, Petrovitch H, Launer L, Abbott RD, Ross GW, & Masaki K (2011). White matter lesions on brain magnetic resonance imaging scan and 5-year cognitive decline: the Honolulu-Asia aging study. Journal of the American Geriatrics Society, 59 (8), 1484-9 PMID: 21718274

The IQ of Steve Jobs

2011-10-25T22:50:00.000-05:00

I've been distracted from my review of Google Reader neuroscience feeds for a few days reading the Walter Isaacson biography of Steve Jobs.

I don't buy many books right after publication. I typically wait until they arrive at my local Tulsa Public Library or until an electronic version is available free for download from the library. OK, I admit I have a reputation for being frugal.

But I have to admit this book is a book I wanted to read really bad. So I rationalized and said I will spend the money to read this biography as soon as possible. Some of the money will go to the family of Steve Jobs. My life has been changed by this man and his products.

I have purchased so many Apple products and they have influenced me in many ways. Here is a partial list:

Apple II: I wrote my first scientific paper on this computer and that led me to a career in academic medicine
Macintosh and derivatives: I was introduced to Excel and the power to manage data and to perform statistical analysis
iPod: I have spent hundreds of hours listening to music on the iPod and use the iPod Touch to access medical information to provide medical care
iPad: I used this Apple product to make brain imaging accessible and understandable

So I went to my iPad and preordered the Jobs biography on iBooks where my bank account was seamlessly deleted to bring the book magically to my iPad. A morning later I was reading the book without getting out of my pajamas. Thank you Steve Jobs!

From a brain science perspective, I found an indirect answer to a question I had wondered about, "How smart was Steve Jobs?"

The biography does not state results of an IQ test score from testing of Steve Jobs. But it does present information for a reasonable estimate.

When in the fourth grade his teachers were impressed by his intelligence and had his cognitive ability tested. They found his performance was equal to that of a tenth grade student.

One way to measure IQ is to compare mental age to chronological age. So a tenth grade student would have a mental age of 16. A fourth grade student would have a chronological age of ten. So that would produce an IQ estimate of 160.

An IQ estimate of 160 would put Steve Jobs at the 99.99%tile (or higher) of IQ.

I am not surprised by this estimate. This genius found a way to extract tens of thousands of dollars from me-a penny pinching man who loved technology and the possibilities technology provided.

I just wish Steve had given me a more direct message on the wisdom of buying Apple stock. If I had taken the $4000 I spent on the Macintosh (and printer) in 1986 I would have over $1,000,000 today.

If you think you have a better estimate of the IQ of Steve Jobs, post your estimates in the comments section.

Photo of Steve Jobs from a Wikipedia Commons file authored by Matt Yohe.

Preterm Birth and Epilepsy Risk

2011-10-24T12:22:00.000-05:00

Albert Pujols Spring Training 2011

Infants born preterm and with low-birth weight have increased risk of a variety of neuropsychiatric problems including autism, ADHD and epilepsy.

The link between preterm birth and adolescent and early adulthood epilepsy has been demonstrated. But few studies have examined the link between preterm birth and epilepsy later in life.

Crump and colleagues recently published results of their research on this topic in the journal Neurology.

This study used the Swedish Birth registry for individuals born between 1973 and 1979 (age at study 27 to 42 years of age). Subjects were group into those born between 23-31 weeks, 32-34 weeks, 35-36 weeks, 37-42 weeks (normal pregnancy duration) and 43 weeks or more (post-term).

Epilepsy cases were identified by those with a hospitalization for epilepsy or the prescription of one of three anti-epileptic drugs: phenytoin, phenobarbital or levetiracetam. Other drugs used for epilepsy were excluded as many have indications for non-epileptic disorders.

Using a multivariate model, the research team corrected for potential confounding variables including fetal growth (deviation from expected weight at gestational age), gender, single versus twin pregnancy, birth order, maternal age, maternal marital status, maternal education, family income and family history of epilepsy.

Using the epilepsy hospitalization case identification resulted in the following odds ratio after adjustment for confounding variables:

23-31 weeks Odds ratio 4.98
32-34 weeks Odds ratio 1.98
35-36 weeks Odds ratio 1.76
37-42 weeks Odds ratio 1.00
>=43 weeks Odds ratio 0.89

Estimates for those identified by antiepileptic risk were similar although this group showed a statistically increased odds ratio for those born post-term (43 weeks or more).

So this study estimates that adults born most preterm have approximately a five fold increase in epilepsy as an adult. This risk appears to diminish with increasing maturation.

The authors note their study highlights the need for continued efforts to reduce the risk of preterm birth. Preterm birth is linked to a variety of potential modifiable factors: smoking, alcohol or illicit drug use, poor nutrition, low or high pre-pregnancy BMI and infections during pregnancy.

Additionally, efforts to improve neonatal care in those born preterm may also contribute to lowering of adulthood epilepsy and other neuropsychiatric disorders.

Photo of Albert Pujols from the author's private collection. Pujols recently joined Babe Ruth and Reggie Jackson as hitters with three home runs in a single World Series game.

Crump C, Sundquist K, Winkleby MA, & Sundquist J (2011). Preterm birth and risk of epilepsy in Swedish adults. Neurology, 77 (14), 1376-82 PMID: 21968843

Shift Work Linked to Multiple Sclerosis Risk

2011-10-19T15:34:00.001-05:00

Fiery Skipper Butterfly

Multiple sclerosis (MS) is a neurological disorder characterized by t cell-mediated inflammation involving the myelin sheath that covers neurons. The inflammation can occur in the brain or peripheral nervous system.

When inflammation damages the myelin sheath, the axons become less efficient in function. Since the inflammation associated with MS can occur nearly anywhere axons are found, the variety of types of neurological symptoms is diverse.

The rates of MS vary across geographical locations and across racial and cultural groups. A common estimate of the prevalence of MS is one per thousand individuals . But a variety of risk factors appear to increase risk.

Some of the important risk factors associated with MS include:

Age between 20 and 40
Female gender
First degree relative with MS (increases risk 10 to 30 fold)
Other autoimmune disorder, i.e. thyroiditis, type 1 diabetes mellitus, inflammatory bowel disease (Crohns disease, ulcerative colitis)
Caucasian race
Obesity
Living in a temperate climate
Northern European family of origin, i.e. Scandanavian
History of viral infections, i.e. Ebstein-Barr (mononucleosis) virus
Cigarette smoking
Vitamin D deficiency

Now a epidemiological study from Sweden has reported that doing shift work early in life may also increase risk for later development of MS. The authors of this study report that shift work has been implicated in several other conditions including immune thyroid problems, heart disease and cancer.

Shift work was defined this research as "permanent or alternating working hours other than ordinary day work". This would include evening and night shift workers and workers beginning work before 7 am. The researchers looked at two independent Swedish study samples and examine age of performing shift work and as well as duration/intensity of shift work.

Potential confounding variables controlled in the analysis included: gender, ancestry, smoking status, sun exposure habits and serum vitamin D levels.

Using a case-control design, the research team found both samples demonstrated a link between early age shift work and risk of later development of MS. There did appear to also be a duration effect---those beginning shift work as a teenager and working three or more years in shift work by age 20 showed the largest effect with a two-fold increase in rates of MS

The authors propose this shift work association may be due to interaction between circadian rhythms and immunological system function. Proinflammatory cytokines peak during the night when cortisol is typically low and melatonin levels high. Additionally, shift workers may have impairment in sleep. Sleep deprivation appears to have significant negative effects on immune function via changes in "number of circulating lymphocytes, natural killer cells and antibody titers".

This is an important study that needs replication. It does support further study of the potential role of shift work on sleep and immune function and a variety of clinical neuroscience disorders. The study suggests if shift work is necessary, it may be best to delay it until individuals pass through the adolescent developmental period.

Photo of Fiery Skipper butterfly from the author's collection.

Risk factor list from factors listed in manuscript as well as from the Mayo Clinic website on MS.

Hedström, A., Åkerstedt, T., Hillert, J., Olsson, T., & Alfredsson, L. (2011). Shift work at young age is associated with increased risk for multiple sclerosis Annals of Neurology DOI: 10.1002/ana.22597

Elite Tennis Performance: Gender and Age Effects

2011-10-18T14:05:00.000-05:00

Elite tennis performance is attained by development of a complex set of cognitive and musculoskeletal skills. Understanding some of the patterns for development of elite tennis performance may provide insight into some of the effects of gender and age on adolescent and early adult development.

A research team from France recently published a study of elite tennis performance by studying top 10 ranked world tennis players beginning in 1968. They examined each elite tennis players performance over the lifespan of their career.

The goals of the research was to examine the timing of reaching peak performance, the length of peak performance, the differences between male and female tennis players and any changes that might have occurred over the last 40 years.

A key variable in this study was the match winning percentage during each year of the elite tennis players career. Here is a summary of some of the key findings from the study:

Female elite number one ranked tennis players reach peak performance earlier then men (21.5 years versus 23.7 years of age)
Female elite players reaching the highest world rank of 2 to 10 reach peak performance earlier than similarly ranked male players (22.7 years versus 24.2 years)
Female and male elite tennis players have similar career lengths (15.5 years versus 14.7 years)
More recent elite female and male tennis players (first professional played after 1985) are younger at their first match as well as their last match

Tennis players appear to have an earlier peak performance than other athletes--25 years of age seems to be the year of peak performance for several other sports compared to an average of about 22 to 23 for elite tennis players.

The manuscript has an interesting figure comparing the percentage victory rates by age for Stefanie Graf and Pete Sampras. The figure demonstrates an effect found for the entire sample: number one women have a higher winning percentage at peak than their male counterparts and their peak is reached at an earlier age.

The authors noted that although elite tennis players are getting younger, their total career tennis performance (tennis capital) does not seem to be declining. Starting younger is leading to earlier retirement but not any decline in career generation.

Earlier adolescent growth spurts in girls compared to boys appears to translate into an earlier peak performance within the gender group for tennis and a variety of other sports.

The authors note that the majority of tennis players have a career that resembles a parabola with an ascent phase, a plateau phase and a decline phase. Some individuals deviate this pattern based on career-ending injuries, pregnancy or other factors.

This is an interesting study. It poses a question to be answered in a few more decades. Is the trend for earlier elite performance continuing and how long can this trend last?

Photo of monarch butterfly from the author's collection.

GUILLAUME, M., LEN, S., TAFFLET, M., QUINQUIS, L., MONTALVAN, B., SCHAAL, K., NASSIF, H., DESGORCES, F., & TOUSSAINT, J. (2011). Success and Decline Medicine & Science in Sports & Exercise, 43 (11), 2148-2154 DOI: 10.1249/MSS.0b013e31821eb533

Family History of Alzheimer's: Biomarker Findings

2011-10-17T13:53:00.000-05:00

West Coast Lady Butterfly

Family history provides patients and clinicians valuable information about risk for a variety of clinical neuroscience diseases. Alzheimer's disease is one of the dementing disorders that appears to run in families and has had a gene (APOE4) identified with increased risk.

Whether family history of Alzheimer's disease is simply a reflection of increased risk for the APOE4 risk gene is unclear.

Chengjie Xiong and colleagues at Washington University in St. Louis recently published an informative study of the effect of a family history of Alzheimer's disease on several biomarkers of the disorder.

They studied 269 cognitively normal adults between the ages of 43 and 76 years of age. All subjects were classified as Alzheimer's disease family history positive or negative based on the following criteria:

Positive family history-at least one biological parent diagnosed with Alzheimer's disease by the age of 80
Negative family history-both biological parents living to 70 without Alzheimer's disease

Using this classification, 160 subjects were classified as having a positive family history of Alzheimer's with 109 classified as having a negative family history.

Subjects in the study underwent a series of studies looking for biomarkers of Alzheimer's disease risk:

Cerebrospinal fluid tau protein levels
Pittsburgh Compound B levels in the brain assessed by positron emission tomography
Brain volume assessment using MRI imaging
White matter connectivity estimates using diffusion tensor imaging

Subjects were genotyped to assess APOE4 risk status. This allowed the research team to tease out the role of family history independent of APOE4 status.

In this cognitively normal cohort, positive family history of Alzheimer's independent of APOE4 status was linked to several biomarkers of Alzheimer's: cerebrospinal fluid proteins tau and alpha beta 42, brain Pittsburgh compound B binding levels and diffusion tensor white matter defects in the brain corpus callosum.

The authors conclude that their findings "point to the likelihood of non-APOE susceptibility genes for Alzheimer's disease, consistent with recent reports of multiple risk genes (PICALM, CR1 and CLU).."

So knowing your family history for Alzheimer's disease is important. It will become more important when future research provides evidence for effective prevention and early intervention strategies.

Butterfly photo from the author's collection.

Xiong, C., Roe, C., Buckles, V., Fagan, A., Holtzman, D., Balota, D., Duchek, J., Storandt, M., Mintun, M., Grant, E., Snyder, A., Head, D., Benzinger, T., Mettenburg, J., Csernansky, J., & Morris, J. (2011). Role of Family History for Alzheimer Biomarker Abnormalities in the Adult Children Study Archives of Neurology, 68 (10), 1313-1319 DOI: 10.1001/archneurol.2011.208

Pedophilia and the Progranulin Gene

2011-10-12T15:03:00.000-05:00

Solution Structure Model of Peptide Subdomain of Granulin

The development of pedophilic urges among pedophiles typically occurs during sexual maturation in adolescence. However, in a minority of cases, pedophilic urges may emerge later in life. An interesting case report has been published in the journal Biological Psychiatry describing a case of late-onset pedophilia.

In the case description a 49 year old married man presented to a neurology clinic in with recent onset of pedophilic urges toward girls. His wife confirmed that these types of urges had not been present until approximately the last 12 months.

At the time of initial presentation, neurological and neuropsychological testing was normal. A brain CT scan showed "mild assymetric frontal atrophy". The patient was placed on olanzapine (an atypical antipsychotic) and fluoxetine (a selective serotonin reuptake inhibitor). This treatment appeared to reduce the pedophilic urges.

Over a period of follow up, the patient demonstrated increased increase in aggressive personality and personality changes. He had mild memory impairment but was able to continue working, Six years later he was admitted to the hospital due to increased behavioral and clinical deterioration.

At this assessment, brain MRI showed increased bilateral frontal atrophy with decreased blood flow to the frontal lobe on SPECT imaging. Neuropsychological testing showed selective impairment in frontal lobe function with a normal score on the Minimental Status Exam, a screening test for Alzheimers dementia.

The patient at this time met criteria for the diagnosis of frontotemporal dementia (FTD). This type of dementia has recently been linked to the progranulin gende (PGN). The patient in the case report had genetic analysis completed with evidence of a point mutation in the progranulin gene.

The authors reviewed a growing literature suggesting progranulin is a key neurotrophic protein that appears important in sexual behavior development. With frontotemporal dementia, the loss of frontal lobe function in the disease contributes to behavioral disinhibition and social inappropriateness.

Although case reports have limited generalizability, this report suggests that late-onset pedophilic urges and behaviors should prompt suspicion of frontotemporal dementia.

Model of Granulin from the Wikipedia Creative Commons file authored by Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute.

Rainero, I., Rubino, E., Negro, E., Gallone, S., Galimberti, D., Gentile, S., Scarpini, E., & Pinessi, L. (2011). Heterosexual Pedophilia in a Frontotemporal Dementia Patient with a Mutation in the Progranulin Gene Biological Psychiatry DOI: 10.1016/j.biopsych.2011.06.015

B12, Cognition and Brain Aging

2011-10-11T12:55:00.001-05:00

Molecular Model of B12-cyanocobalamin

Vitamin B12 is known to be important in the preservation of cognitive function in elderly populations. I have previously reported on a study suggesting B vitamin supplementation may be related to reduction in the rate of brain atrophy associated with aging.

A study of vitamin B12-related markers, cognition and brain MRI measures was recently published in the journal Neurology. This study lends support to the importance of B12 and brain aging. Additionally, the study suggests testing simply for blood vitamin B12 blood levels may not be the most sensitive method of assessing B12 status.

Tangney and colleagues from Rush University Medical Center collected serum B12-related markers in a series of 112 elderly individuals. An average of 4.5 years later, this cohort had standardized cognitive testing and brain MRI structural assessments.

B12-related serum markers assessed at baseline in this study included:

vitamin B12 levels
homocysteine levels
methylmalonic acid (MMA) levels
cystathionine levels
2-methylcitric acid

Cognitive function tests obtained at follow up included:

perceptual speed
visual working memory
semantic memory
episodic memory
perceptual organization/visuospatial
global cognition

MRI measurements included total brain volume, presence of cerebral infarcts and volume of brain abnormalities known as white matter hyperintensities. The clinical significance of brain white matter hyperintensities is unclear. However, in a previous post I reviewed a study suggesting these lesions are linked to higher rates of stroke, dementia and mortality.

The authors found global cognitive function was linked to all B12-related serum markers except for serum B12 levels itself. Performance on several specific cognitive tests was impaired with specific B12-related markers (MMA levels with perceptual speed and episodic memory impairment, cystathionine and 2-methyl citric acid with impaired episodic and semantic memory).

As for the brain MRI measurements, elevated homocysteine levels were linked to decreased brain volume and increased volume of white matter hyperintensities.

Homocysteine levels increase with vitamin B12 deficiency. However, there are other pathways to elevated homocysteine. In contrast, elevated MMA levels are specific to vitamin B12 deficiency.

The authors of this study suggest vitamin B12 deficiency may have adverse brain effects in more than one pathway--through increased MMA levels and cognitive impairment and through increased homocysteine levels and increased white matter hyperintensities and reduced brain volume. They note "Marginal vitamin B12 status in older age is frequently missed by measurement of serum vitamin B12 levels alone".

Molecular model of vitamin B12 cyanocobalamin from Wikipedia Commons file authored by Ben Mills.

Tangney, C., Aggarwal, N., Li, H., Wilson, R., DeCarli, C., Evans, D., & Morris, M. (2011). Vitamin B12, cognition, and brain MRI measures: A cross-sectional examination Neurology, 77 (13), 1276-1282 DOI: 10.1212/WNL.0b013e3182315a33

Cannabis Use Linked to Lower Obesity Rates

2011-10-10T11:28:00.001-05:00

Anecdotal evidence supports a temporary increase in appetite following the use of cannabis. However, there is very limited clinical research directed at the association of chronic cannabis use and body weight.

Endogenous endocannabinoid compounds are popular targets of research to improve understanding the pharmacology of appetite and weight regulation.

Rimonabant, a selective antagonist/inverse agonist for the CB1 receptor was briefly approved for weight reduction before being removed because of safety concern. Research on cannabanoid drugs and receptors continues in a hope to develop an effective and safe drug for the treatment of obesity.

However, a new study published in The American Journal of Epidemiology suggests the association of cannabis and body weight may be more complex than thought. Le Strat and Le Foll examined two United States general population surveys (NESARC and NCS-R) for reported prevalence of obesity and frequency of cannabis use.

Subjects in each of these surveys were split into four groups with prevalence in (men and women):

No cannabis use in last 12 months (94.3%, 97.3%)
Cannabis use more than once a year to less than once a month (2.0%, 1.2%)
Cannabis use once a month to two days per week (1.9%, 0.8%)
Cannabis use three days per week to daily (1.8%, 0.7%)

When obesity rates (BMI level of >30) were compared between the four groups, the rates were surprising to me. The odds ratios found in the study are plotted below. The rates of obesity are set a one for non-users and odds ratios for obesity for both surveys by frequency of cannabis use. The results show approximately 33% reduction in rates in obesity in the cannabis user groups.

The odds estimates in the figures in this blog are an average of adjusted odds ratios controlling for potential confounding variables such age, gender, cigarette smoking status, education, income and other non-cannabis drug use.

The authors note their study is limited by reliance on self-report for height, weight and frequency of cannabis use. They also note their study was unable to control for potential diet and physical activity confounding issues.

I would wonder if there may be additional confounders that explain this association at the general population. This association study does not show that obesity in cannabis abstainers will be reduced by initiating cannabis use.

Nevertheless, I think this finding is counterintuitive to what most have assumed to be the effect of cannabis on appetite and weight. We will likely see more pre-clinical and clinical research on this topic.

Photo of flowers, moth and lady bug from the authors collection. Figure is produced by the blog author from data provided in the following manuscript:

Le Strat, Y., & Le Foll, B. (2011). Obesity and Cannabis Use: Results From 2 Representative National Surveys American Journal of Epidemiology, 174 (8), 929-933 DOI: 10.1093/aje/kwr200