10th September 2014, v1.0 draft Assessing Cognition

Assessing Cognition © Cambridge Cognition All rights reservedPage 2 Aims of this resource This presentation provides an overview of the assessment of cognition, and has been designed for post-graduates and PhD students.

Assessing Cognition © Cambridge Cognition All rights reservedPage 3 Summary of contents Discussion of different reasons for assessing cognition – perspective of society/groups and of individuals, with examples: Understanding relationships between cortico-subcortical circuitry, neuromodulators, and behaviour Study gene by environment interactions Identify and treat cognitive problems across a multitude of disorders Occupational uses: impact of sleep deprivation in military personal; enhancing cognition in sleep-deprived doctors Individual level: early detection of dementia Consideration of what would make an ‘ideal’ set of cognitive tests Pros and cons of different methods of cognitive assessment (clinician rated versus self-report; pen & paper versus computerized) Introduction to the CANTAB method of cognitive assessment, exemplified with the CANTAB ADHD battery

Assessing Cognition © Cambridge Cognition All rights reservedPage 4 Why assess cognition? Cognitive assessment refers to the objective measurement of distinct cognitive abilities, such as working memory, inhibition, cognitive flexibility, and executive planning Cognitive functioning is critical for day-to-day life, governing our thoughts and actions Reasons for assessing cognition can be considered from different vantage points: -Perspective of society (and of groups) -Perspective of the individual

Assessing Cognition © Cambridge Cognition All rights reservedPage 5 Why assess cognition? Perspective of society Understand key aspects of human and animal behavior, and how this arises from distinct circuits and neurotransmitters in the brain 1 1 Arnsten et al., Bio Psych, 2011 neuromodulators

Assessing Cognition © Cambridge Cognition All rights reservedPage 6 Why assess cognition? Perspective of society Understand how genetic and environmental factors can influence brain function across the lifespan Genetic factors Gene variants Gene expression Environmental factors e.g. Stress Trauma Inflammation Diet and drug use

Assessing Cognition © Cambridge Cognition All rights reservedPage 7 Why assess cognition? Perspective of society Example: studies have identified negative effect of maternal smoking on subsequent cognitive abilities in infancy / early childhood, which can be influenced by genes 1 Genetic factor Environmental factor Maternal smoking 1 Morales et al., Int J Epidem, 2009 GSTM1 polymorphism (codes for enzyme involved in breakdown of tobacco by-products) Maternal smoking in women with a defective form of GSTM1 gene polymorphism was associated with worse cognition in children, when assessed four years after birth.

Assessing Cognition © Cambridge Cognition All rights reservedPage 8 Why assess cognition? Perspective of society Example: the Apolipoprotein E4 gene (APOE4) is involved in lipid metabolism and is widely studied as a risk factor for cognitive decline in older age (including dementia) 1 Genetic factor Environmental factor Cortisol level (stress axis) 1 Lee et al., Am J Psych, 2008 APOE4 gene Higher levels of cortisol were associated with worse cognition in community dwelling older adults; however, this relationship was particularly strong in individuals with at least one APOE4 allele

Assessing Cognition © Cambridge Cognition All rights reservedPage 9 Why assess cognition? Perspective of society Cognitive assessment is invaluable for understanding the role of brain dysfunction across a multitude of disorders/syndromes Examples of conditions in which cognitive impairment can occur: These impairments represent key treatment targets 1 Alzheimer's disease Mild cognitive impairment Depression ADHD Schizophrenia Pain Sleep disorders Down's syndrome Parkinson's disease Diabetes Traumatic brain injury Substance abuse Cancer Huntington's disease Epilepsy Autism Fragile X Bipolar disorder Multiple sclerosis Impulse-control disorders Allergic diseases Genetic disorders Cardiovascular disease Eating disorders Obesity Respiratory disorders Anxiety disorders/stress Stroke 1 e.g. Chamberlain et al., Bio Psych, 2011

Assessing Cognition © Cambridge Cognition All rights reservedPage 10 Why assess cognition? Perspective of society Cognitive assessment is widely used in occupational contexts “Psychometric Testing” to screen potential employees Use of “cognitive rehabilitation” and “cognitive (re)training” e.g. in children with special educational needs, in people with Traumatic Brain Injury (TBI) Explore the impact of environmental factors on cognitive function, and safety, in sensitive occupations (e.g. military, truck drivers, doctors)

Assessing Cognition © Cambridge Cognition All rights reservedPage 11 Why assess cognition? Perspective of society 1 Lopez et al., J App Res Mem Cog, 2008 Example: impact of sleep deprivation on cognition in US Air Force Pilots 1 Sleep deprivation was associated with a variety of cognitive deficits, shown here in relation to deterioration in sustained attention more attentional lapses sleep deprivation begins 1pm 4pm 7pm 10pm 1am 4am 7am 10am 1pm 4pm

Assessing Cognition © Cambridge Cognition All rights reservedPage 12 Why assess cognition? Perspective of society Cognitive assessment allows measurement of effects of interventions This includes both unwanted effects: psychomotor slowing, impaired attention, impaired ability to undertake goal-directed planning (important: e.g. driving abilities) and desired effects: cognitive enhancement, remediation of cognitive deficits These effects may be unexpected

Assessing Cognition © Cambridge Cognition All rights reservedPage 13 Why assess cognition? Perspective of society Example: synergistic effect of benzodiazepine and antipsychotic medication on reaction time slowing 1 1 Internal Camcog data deterioration equivalent to BAC>0.05% equivalent to BAC>0.1% Reaction Times Combination of benzodiazepine and antipsychotic medication had a synergistic unwanted effect on reaction times in volunteers The combination was equivalent to being over the drink-driving limit in virtually all jurisdictions, in terms of effects on cognition BAC = Blood alcohol concentration

Assessing Cognition © Cambridge Cognition All rights reservedPage 14 Why assess cognition? Perspective of society 1 Sugden et al., Ann Surg, 2012 Example: effect of modafinil on cognition in sleep-deprived doctors 1 Modafinil improved the ability of sleep-deprived doctors to solve difficult trials on an executive planning task (p<0.05) slower problem solving

Assessing Cognition © Cambridge Cognition All rights reservedPage 15 Why assess cognition? Individual level Cognitive assessment also has many applications at the level of the individual person An individual’s performance can be compared to normative data Clinicians and researchers can quantify to what extent an individual’s cognition is impaired (or better than expected), in which domains, and to what extent Objective quantification of cognitive impairments can inform early detection, diagnosis, and treatment

Assessing Cognition © Cambridge Cognition All rights reservedPage 16 Why assess cognition? Individual level Example: early detection of memory problems requiring further investigation in General Practice Patient undertakes brief assessment using medical device in GP surgery One-page report generated for GP Software indicates where further medical investigations are needed; and reassures where no problems were detected

Assessing Cognition © Cambridge Cognition All rights reservedPage 17 Characteristics of an ‘ideal’ set of cognitive tests Capture the spectrum of different cognitive functions and separate them Good psychometric properties Reliability (consistency, test-retest) Validity (face, content, discriminant) Sensitive: able to maximize detection of cognitive impairments in disorders/syndromes; and effects of interventions Translational: can be directly related to neural circuitry and neurochemical systems Respected by scientific community Availability of a large normative database

Assessing Cognition © Cambridge Cognition All rights reservedPage 18 Methods of cognitive assessment: pros and cons Clinician-rated (or supervised) cognitive assessment refers to trained individuals assessing cognition by asking questions/tasks of patients, or overseeing the testing process For example, Mini Mental State Examination (MMSE), widely used in clinical practice as a broad composite measure of cognition, and to detect possible dementia 1 e.g. “What year is it?” “What is this?” [point to object] “Please copy this figure” Clinician-rated versus self-rated 1 Folstein et al., J Psych Res, 1975 Takes about 10 minutes to complete Measures orientation, registration, short-term memory, and language Scores (maximum 30): normal mild impairment moderate impairment <10 severe impairment

Assessing Cognition © Cambridge Cognition All rights reservedPage 19 Methods of cognitive assessment: pros and cons Self-rated cognitive assessment refers to individuals doing tests themselves, typically following written instructions, such as from their own homes or over the Internet For example, the Self-Administered Geocognitive Examination (SAGE), designed to detect signs of dementia 1 e.g. “What is today’s date?” “Name the following pictures” “Copy this picture” Clinician-rated versus self-rated 1 Scharre et al., Alz Dis Assoc Dis, 2010 Takes about minutes to complete Four pages long Measures various cognitive functions Score (maximum 22) <17 suggests cognitive impairment

Assessing Cognition © Cambridge Cognition All rights reservedPage 20 Methods of cognitive assessment: pros and cons Clinician-rated (or supervised) assessment - Greater objectivity - Greater control over testing environment and test administration - Less ‘statistical noise’ and superior data control But, - Requires training - Potential inconvenience (supervisor and person being assessed together at the same site) Self-rated assessment - Convenience (can be done from home) - No need to train and employ testers But, - Limited control over testing environment and test administration - Difficult to quantify or record various confounding factors Clinician-rated versus self-rated

Assessing Cognition © Cambridge Cognition All rights reservedPage 21 Methods of cognitive assessment: pros and cons Cognitive assessment initially relied on pen/paper tests, before the advent of computer technology Computerized assessment is now the gold standard, with potential advantages: - Objectively tease apart distinct cognitive abilities - Automated data collection and processing; quality control - Accuracy (such as in measurement of response latencies) - Can be made less reliant on complex motor skill; special interface technology - Translational: neuroimaging, animal models Pen/Paper versus Computerized assessment

Assessing Cognition © Cambridge Cognition All rights reservedPage 22 Computerized assessment: CANTAB Comprehensively captures all important cognitive domains Established validation including excellent psychometric properties Proven sensitivity to drug and disease effects where cognition is a factor Comprehensively validated by >30 years of global translational research, and >1300 peer-reviewed papers Used in over 700 academic research institutions worldwide Extensive normative and clinical data

Assessing Cognition © Cambridge Cognition All rights reservedPage 23 Psychomotor speed AttentionMemory Social cognition Executive function Reaction Time Visual Information Processing Paired Associates Learning Spatial Working Memory CompulsivityEmotion RecognitionVerbal Recall Alzheimer's disease DepressionADHDSchizophreniaAbuse Liability Parkinson's disease PainSleep Down’s syndrome Multiple sclerosis Cardiovascular disease Huntington’s disease Traumatic brain injury AutismCancer Validated touchscreen tests Measuring effects across cognitive domains Applied to research of disorders and syndromes Drug SafetyDrug Efficacy

Assessing Cognition © Cambridge Cognition All rights reservedPage 24 Stop Signal Task Verbal Recall / Recognition Memory Reaction Time Task Delayed Matching to Sample Paired Associates Learning Spatial Working Memory Stockings of Cambridge Attention Switching Task Pattern or Spatial Recognition Memory Affective Go/No-go Emotion Recognition Test Rapid Visual Information Processing CANTAB Cognitive Tests and Brain Regions

Page 25Assessing Cognition © Cambridge Cognition All rights reserved CANTAB Cantab detects effects in smaller sample sizes over shorter periods of time (large effect sizes versus placebo for drug manipulations, even in healthy volunteers) 1 The high sensitivity, and established validation of Cantab enables research that is lower cost and lower risk for your academic research Cantab is sensitive to the discovery of effects that other tests would miss 2 1 Turner et al., Psychopharm, 2003; Deakin et al., Psychopharm, 2004; 2 Greig et al., Curr Alz Res, 2005

Page 26Assessing Cognition © Cambridge Cognition All rights reserved CANTAB The translational bridge from pre-clinical research increases chance of success with grant applications, and maximises the scientific impact of your research 2 Enables you to pinpoint cognitive deficits in syndromes/disorders, and effects of drug manipulations and interventions (high precision) 1 Computerized, language-independent delivery enables easy deployment, and maximises signal-to-noise 3 1 Chamberlain et al., Bio Psych, 2011; 2 Robbins et al., Neurosci Biobehav Rev, 2013; 3 e.g. Yurko-Mauro et al., 2010; Shiina et al., 2010

Page 27Assessing Cognition © Cambridge Cognition All rights reserved CANTAB Core Cognitive Battery Research key aspects of cognitive performance using computerized tests that have proven sensitivity to pharmacological manipulation Dementia Battery For measuring the severity of impairment in patients with prodromal Alzheimer’s disease and those functioning within the dementia range Schizophrenia Battery Accurately research cognitive effects in schizophrenia and related syndromes ADHD Battery Reliably study the cognitive effects in conditions characterized by excessive impulsivity and the inability to control behaviors Depression Battery For research into cognitive impairment associated with depression (including treatment resistant depression) and related mood disorders during acute mood episodes and periods of remission Or create your own test combination Tailored packages

Page 28Assessing Cognition © Cambridge Cognition All rights reserved Example: CANTAB ADHD Battery Fast, reliable and highly sensitive, the CANTAB ADHD Battery allows accurate quantification of cognitive problems in ADHD, and effects of interventions Attention / reaction time Rapid Visual Information Processing (RVP) Spatial Working Memory (SWM) Executive Function Response Control Stop Signal Task (SST)

Page 29Assessing Cognition © Cambridge Cognition All rights reserved CANTAB ADHD Battery Impairment (Cohen’s D) in ADHD v Controls 1 From Chamberlain et al., Bio Psych, 2011; and Gau & Huang, Psych Med, 2014; see also Fried et al., Journ Atten Disorders, 2012; 2 Dowson et al., Acta Psych Scand, 2010; Lipszyc & Schachar, J Int Neuropsych Soc, 2010 greater impairment Maximize scope for detecting cognitive benefits of intervention, and enrich samples, with large baseline deficits in ADHD 1 significant clinical impairment CANTAB discriminates the cognitive profile of ADHD from other conditions including 2 -Anxiety/Depression -Personality Disorder -Conduct Disorder Sensitive to cognitive impairments

Page 30Assessing Cognition © Cambridge Cognition All rights reserved CANTAB ADHD Battery 1 Tseng & Gau, J Child Psychol and Psych, 2013; 2 Clark et al., J Child Psychol and Psych, 2002; Kofler et al., J Abnorm Child Psychol, 2011 CANTAB predicts day-to-day function in ADHD 1,2. In path modelling, CANTAB SWM significantly mediated the relationship between ADHD and social problems 1 Cognitive impairment in ADHD contributes to functional impairment across multiple areas (including academic, work, and social domains) 2 ADHD Executive Dysfunction Social Problems p<0.01 Functionally relevant

Page 31Assessing Cognition © Cambridge Cognition All rights reserved CANTAB ADHD Battery 1 Aron et al., Nat Neurosci, 2003; see also Aron et al., Trends Cog Sci, 2014; 2 Chamberlain et al., Bio Psych, 2009; 3 Shang et al., Psych Med, 2013 CANTAB SST detects the effects of ADHD medications on brain function, even following a single dose 2 CANTAB SST is sensitive to frontal lobe damage, especially to the right inferior frontal gyrus (correlation p<0.001) Volume of damage (cm 3 ) Stop Signal Reaction Time (SST) worse inhibitory control more cortex damage Enhanced brain activation in the right inferior frontal gyrus following atomoxetine treatment, detected using CANTAB 2 CANTAB performance correlates with structural and functional brain abnormalities in ADHD, such as with disorganized white matter tracts 3 Translational

Page 32Assessing Cognition © Cambridge Cognition All rights reserved CANTAB ADHD Battery CASE STUDY: CANTAB SWM showed dose-dependent improvement from single-dose methylphenidate treatment in N=26 patients with ADHD 1 1 Bedard et al., J Am Child Adolesc Psych, Chamberlain et al., Bio Psych, 2007 better inhibitory control CASE STUDY: CANTAB SST detected cognitive benefits of atomoxetine (selective norepinephrine reuptake inhibitor) following just a single- dose in N=22 patients with ADHD 2 Stop Signal Reaction Time (SST) * p < 0.05 Errors (SWM) better working memory higher dose * p < 0.05 significant linear reduction in errors with increasing methylphenidate dose Sensitive to cognitive enhancing effects of interventions

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