ADHD and Cognitioncdn.neiglobal.com/content/encore/synapse/2017/slides_at...CANTAB Spatial Working...

Handout for the Neuroscience Education Institute (NEI) online activity:

ADHD and Cognition

Learning Objectives

• Identify conceptual definitions of executive function (EF) and examine the role of EF in ADHD

• Address the importance of using scales in the diagnosis of ADHD

• Examine the most effective treatment options for cognitive dysfunction associated with ADHD

Executive System / Function

"The executive system is responsible for the simultaneous operation of a number of cognitive processes in charge of goal-directed, task-oriented behaviors; self-regulation; and behavior inhibition as well as planning, working memory, mental flexibility, response inhibition, impulse control, and monitoring of action."

Working Memory

Response Inhibition Interference Control

Set Shifting

Seidman LJ. Neuropsychological functioning in people with ADHD across the lifespan. Clinical Psychology Review 2006;26:466-485; Doyle et al. 2000; Nigg et al. 2005; Robinson

S et al. Brain Cognition 2009;71(3):362-368

Executive Dysfunction:ADHD vs. General Population

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60%

ADHD General PopulationSeidman LJ. Neuropsychological functioning in people with ADHD across the lifespan. Clinical Psychology Review

2006;26:466-485.

Defined by neuropsychological testing

Defining Executive Function

• Behavioral rating scales ‒ Self, observer, clinician‒ ADHD scales, EF scales, impairment scales

• Neuropsychological testing ‒ Which tests?‒ Ecological validity concept

• Neuroimaging/functional connectivity• GeneticsOperationalized definition determines the construct.Construct relationships may not align.

Diagnostic Overlap

Intelligence

LearningDisabilitiesADHD

ExecutiveFunction

NeuropsychologicalDiagnoses

SymptomDiagnosis

EF Associated With Other Disorders

Executive Disorder

ADHD30-50% with EF

BipolarDisorder

Autism

Schizophrenia

LearningDisorders

Chronic SUD

MajorDepression GAD

NeurologicalDisorders

TBI, MCI, CVA, CNS tumors,Degenerative

GeneticDisorder

Klinefelter's(47, XXY)

GeneralPopulation

5-10% with EF

Neurocircuitry

• Executive Function‒ Prefrontal (dorsolateral and lateral orbital) regions

• Regulation of affect‒ Orbitofrontal and ventromedial regions

• Attention and inhibitory control‒ Frontostriatal structures (ventrolateral prefrontal cortex, dorsal anterior

cingulate cortex, caudate, and putamen)

Bush et al. Biological Psychiatry 2005;57;1273-1284; Bush G. Biol Psychiatry 2011;69:1160-1167.

EF Predicts Negative Outcomes

• Childhood EF significantly predicted outcomes in academic achievement and employment status

• ADHD/low digit span in childhood had lower follow-up reading scores than ADHD/high digit span (not found in controls)

• ADHD/worse ROCF in childhood was associated with suspensions/expulsions

• Working memory and ROCF were the strongest predictors for young adult outcomes

ROCF: Rey-Osterrieth Complex FigureMiller M. J Abnl Child Psychology 2012;40:657-668.




• Neuroimaging• Genetics

Executive Function Rating Scales

• Behavior Rating Inventory of Executive Function (BRIEF)1

• Behavioral Assessment of the Dysexecutive Syndrome (BADS)2‒ 6 subtests, score out of 4

• Dysexecutive Questionnaire (DEX)2‒ 20 items on everyday executive problems

• Barkley Deficits in Executive Functioning Scale (BDEFS)3‒ 88 items in 5 dimensions of EF

1. Gioia GA. Child Neuropsychol 2002;8(4):249-572. Wilson BA. Neuropsychological Rehabilitation 1998;8:213-2283. Barkley RA. JARD 2010

Neuropsychological Tests for Executive Function

Task Name EF Construct AssessedStop signal reaction time Response inhibitionContinuous Performance Test commissionerrors

Response inhibition

Continuous Performance Test omission errors VigilanceWisconsin Card Sorting Test Set shiftingTrail Making Test Part B Set shiftingTower of Hanoi/London PlanningPorteus Maze PlanningRey-Osterrieth Complex Figure Test Planning/organizationWorking Memory Sentence Span Verbal working memoryDigits Backward Verbal working memorySelf-Ordered Pointing Spatial working memoryCANTAB Spatial Working Memory Spatial working memory

Willcutt EG. Biol Psychiatry 2005;57:136-1346

Psychometric Approach to Assessing EF Relies on Testing Cold Cognition

EF Constructs Typically Assessed by Tests• Inhibition and Interference Tasks

‒ CPT, Go/No-Go, Stop Signal, Stroop Color and Word Test

• Working Memory Tasks (Verbal and Nonverbal)‒ Digit span, mental arithmetic, n-back, spatial memory, sequence

memory, Simon game, Kaufman Hand Movements Test

• Fluency Tasks‒ F-A-S Test, Five-Point Test, ideational fluency

• Planning and Problem Solving Tasks‒ Tower of London, Tower of Hanoi, Wisconsin Card Sorting Task

Slide courtesy of Russell Barkley, PhD

Can EF Tests Detect ADHD?

• These studies examined male and female youth as well as adults and found that most measures of EF have good positive predictive power for ADHD (characterized by adequate sensitivity) but poor negative predictive power (poor specificity)

• That is, abnormal scores on measures of EF are generally predictive of the diagnosis; however, normal scores cannot rule out the diagnosis

Siedman L. Clinical Psychology Review 2006;36:207-226

Problems With the EF Construct

• Lacks any consensus definition (20+ definitions exist)• Considered to be a meta-construct serving as an

"umbrella" term for a set of more specific components (33+)

• Assessment of EF nearly always employs "cold" and relatively brief cognitive psychometric tests

• Test limitations‒ Unreliable and often poorly normed‒ Lack ecological validity

Do not correlate with EF rating scales or observations

‒ Do not predict impairment in major domains of life in which EF is important for effective functioning

Slide courtesy of Russell Barkley, Ph.D

Criteria for a Primary Neurocognitive Deficit

• ADHD groups must consistently exhibit weaknesses on EF measures after controlling for confounding variables

• EF weaknesses must account for a substantial proportion of the variance in ADHD symptoms in the population

• EF weaknesses must be present in most individuals with ADHD

• EF weaknesses and ADHD symptoms must be attributable to common etiological influences

Willcutt EG. Biol Psychiatry 2005;57:136-1346

Clinic-Referred Adults With ADHD

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WCSD: Wisconsin Card Sorting Test. CPT: Conners' Continuous Performance Test.Barkley RA & Murphy KR. Impairment in occupational functioning and adult ADHD: The predictive utility of executive

function (EF) ratings vs. EF tests. Archives of Clinical Neuropsychology 2010;25:157-173

Self-rated

Chart1

Time MgmtTime MgmtTime Mgmt

OrganizeOrganizeOrganize

DisciplineDisciplineDiscipline

MotivationMotivationMotivation

ActivationActivationActivation

Digit SpanDigit SpanDigit Span

StroopStroopStroop

WCST %ErrorsWCST %ErrorsWCST %Errors

WCST Persev.WCST Persev.WCST Persev.

WCST CategoriesWCST CategoriesWCST Categories

CPT OmissionsCPT OmissionsCPT Omissions

CPT CommissionsCPT CommissionsCPT Commissions

CPT Reaction TimeCPT Reaction TimeCPT Reaction Time

CPT VariabilityCPT VariabilityCPT Variability

Five PointsFive PointsFive Points

ADHD

Clinical

Community

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Sheet1

ADHDClinicalCommunity

Time Mgmt98938

Organize898311

Discipline94937

Motivation98987

Activation98987

Digit Span796

Stroop161313

WCST %Errors947

WCST Persev.736

WCST Categories1267

CPT Omissions26228

CPT Commissions27268

CPT Reaction Time957

CPT Variability29217

Five Points27277

To resize chart data range, drag lower right corner of range.

EF Scales and Tests in Adult ADHD

Barkley RA & Fischer M. Predicting impairment in occupational functioning in hyperactive children as adults: Self-reported executive function (EF) deficits vs. EF tests. Developmental Neuropsychology 2001;36(2):137-161.

ADHD-P = Persistent ADHD ADHD-NP = Non-persistent ADHDControl = Community Control Group

All p-values < .001

Self-rated

Kaufman Hand Movements Test

Tower of London

Chart1

Time MgmtTime MgmtTime Mgmt

OrganizeOrganizeOrganize

DisciplineDisciplineDiscipline

MotivateMotivateMotivate

ActivateActivateActivate

Digit SpanDigit SpanDigit Span

SimonSimonSimon

Five PointsFive PointsFive Points

StroopStroopStroop

TOL TotalTOL TotalTOL Total

TOL TimeTOL TimeTOL Time

KHM CorrectKHM CorrectKHM Correct

KHM LongestKHM LongestKHM Longest

ADHD-P

ADHD-NP

Control

Percent of Group Impaired > 93rd %

Comparison of groups on percentage impaired

ADHD-P

ADHD-NP

Control

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Sheet1

ADHD-PADHD-NPControl

Time Mgmt691912

Organize672413

Discipline742911

Motivate621611

Activate763417

Digit Span17197

Simon232310

Five Points17278

Stroop14157

TOL Total201511

TOL Time142111

KHM Correct29234

KHM Longest29188

Ecological Validity of EF Tests

• Virtual reality • Multitasking in a City Test• Virtual supermarket• Virtual library• Multiple Errands Test• Executive Secretarial Task

Ecological Validity of EF Tests

• 92 mixed etiology neurological patients • 216 controls• Assessed 10 neuropsych measures with

6 different tests• Relatives completed questionnaire about

dysexecutive problems• Factor analysis of symptoms suggested

a fractionation of dysexecutive functions into 3 cognitive factors• Inhibition, intentionality, working memory

Burgess PW. J Int Neuropsychol Soc 1998;Nov;(4):547-58

Different tests measure different

cognitive processes, and there may be

limits to the fractionation of the

executive system on the basis of

neuropsychological tests

Testing in a Distraction Setting:Adult ADHD vs. Controls

Pelletier MF et al. Journal of Attention Disorders 2016. 20(4): 306-316.

0102030405060708090

Silence ISE

Controls(n=32)

Rec

all A

ccur

acy

%

Conditions

**

* p>.05

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0.15

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Silence ISE

Controls (n=32)ADHD (n=32)

Prop

ortio

n of

Er

rors

Omissions

*

*

* p>.001

Pelletier MF et al. 2013. Characterisation of Attention and Short Term Memory Processes in Adult ADHD with the Irrelevant Sound Paradigm. Poster Presentation.

Testing in a Distraction Setting:Adult ADHD vs. Controls

Rating Scales vs. Tests: Contribution Variance to Impairment

• EF scales predict up to 45% of variance in global self-rated impairment and 20% in other-rated impairment

• EF tests predict up to 6% in global self-rated impairment and 7% in other-rated impairment

Barkley RA et al. Developmental Neuropsychology 2011;36(2):137-161

Rating Scales vs. Tests: Contribution Variance to Impairment

• EF tests show their best (albeit weak) relationships with academic achievement tests, but not when IQ is removed

• Overall, EF scales predict 2-20% of variance in work history measures, averaging 11%

• Overall, EF tests predict 2-18% of variance in work history measures, averaging 6.8%

• EF scales predict a wider array of occupational problems than EF tests

• If predicting impairment is an index of validity of measurement, EF scales out-predict EF tests

Barkley RA et al. Developmental Neuropsychology 2011;36(2):137-161

ADHD Symptoms Correlate Poorly to Impairments

• Average correlation between symptoms and impairment is less than 10% of the variance

• Symptoms never predicted more than 25% of the variance in impairment

• When the measure of impairment was added to symptoms, the sample size shrunk by 77% for an ADHD diagnosis

• Strongest relationship between symptoms and impairment is between inattention and school functioning

Gordon M et al. Symptoms versus Impairments: A Case for Respecting the DSM-IV CriteriaD. J Atten Disord. February 2006;9(3):465-475




• Neuroimaging• Genetics

Genes and Executive Function

• Evaluate 5 functional SNPs in specific genes related to DA on executive function in a general population

• Use Frontal Assessment Battery (FAB)• Flexibility subset of FAB was associated with

the SNP in COMT after adjusting for confounding variables

• Combination of 2 SNPs in the COMT gene and the dopamine D4 receptor gene had a significant effect on FAB score

Isomura MS et al. Impact of five SNPs in dopamine-related genes on executive function. ActaNeurologica 2013;127:70-76.

Frontal Assessment Battery

FAB composite tool consisting of 6 subtests: • Categorization• Flexibility• Programming• Resistance to interference• Inhibitory control• Forced movement

Genes and ADHD

• Genetic predisposition may be associated with subsequent ADHD symptoms

• Recent study examined the role of glutamate in an animal model for ADHD

• The glutamate transporter GLT1 splice variant, GLT1b was increased, while total GLT1 was reduced in the hippocampus compared to controls

• Pattern is indicative of elevated extracellular glutamate levels• Glutamate is elevated in the prefrontal cortex of patients with

ADHD• Suggest a role for GLT1 in the pathophysiology of ADHD

MacMaster et al. Biological Psychiatry 2016 53:184-187; Sterley et al. Metabolic Brain Disorders 2016. 31:169-182

What Should Be Treated First?

Goodman DW. In: Biederman J, ed. Across the Life-Span: From Research to Clinical Practice—An Evidence-Based Understanding. Veritas Institute for Medical Education; 2006:227-69;

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013.

treatment inadults oftenends here

treatment in children/adolescents oftenbegins here

alcohol / stimulant / substance abuse

anxiety disorders

nicotine dependence

mood disorders

ADHD

Methylphenidate Effects on Cognition in ADHD

• Pietrzak et al. (2006) provides a meta-analysis of the recent literature on placebo-controlled studies of the effects of MP on a variety of neuropsychological tasks and studies comparing effects for more than 1 clinical dose: ‒ Higher doses produced greater improvements than lower doses

on some tasks (attention, vigilance, memory, and working memory), but no additional improvements on others (planning, cognitive flexibility, inhibitory control, naming, and motor speed)

Pietrzak RH, Mollica CM, Maruff P, Snyder PJ. Cognitive effects of immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev

2006;30:1225-1245.

Understanding the Cognitive Effects of Stimulants

• In well-controlled studies using batteries, stimulant-related cognitive enhancements were more prominent on tasks without an executive function component (complex reaction time, spatial recognition memory reaction time, and delayed matching to sample) than on tasks with an executive function component (inhibition, working memory, strategy formation, planning, and set shifting)

Swanson J et al. Understanding the effects of stimulant medications on cognition in individuals with attention-deficit hyperactivity disorder: A decade of progress. Neuropsychopharmacology 2011;36:207-

226.


• These reviews marked a watershed in the literature on cognitive deficits in ADHD Pointed out that few children with ADHD showed

pervasive deficits across tests Concluded that executive function deficits were not

necessary and sufficient causes of ADHD Contributed to the shift from core deficit to multiple

deficit theories


226.


• In addition, this approach has uncovered ADHD–control group differences (deficits) on tests of temporal and parietal lobe function (spatial recognition and span, pattern recognition, and delayed matching to sample) as well as frontal lobe function (working memory, planning and strategy formation, and set shifting)


226.

Regions Where Age of Attaining Peak SurfaceArea Was Delayed by More Than 1 Year: ADHD Compared With Typically

Developing Participants

Shaw P et al. Development of cortical surface area and gyrification in attention-deficit/hyperactivity disorder. Biol Psychiatry 2012;72:191-197

R L


• Dose response studies of stimulant medications suggest that the optimal dose varies across individuals and depends somewhat on the domain of function, with high doses tending to produce greater enhancement of some domains (e.g., vigilance) but not others (e.g., planning), without clear evidence of completely correcting the cognitive deficits associated with ADHD


226

Exercise as Adjunctive Treatment

• Current research status: Physical exercise is beneficial as adjunctive treatment, but there’s not enough evidence to suggest that it is a stand-alone treatment

• Exercise may be particularly effective for youth, potentially preventing or altering the course of ADHD

• The literature is promising; however, the most challenging complications for these types of studies are: random assignment, blinded raters, and adequate control groups

• Comparisons have been made between aerobic/nonaerobic, and acute vs chronic exercise on cognitive and behavioral symptoms

• Exercise has beneficial effects on a variety of cognitive capacities, measured by neuropsychological or EF tasks

• Systematic exercise appears to have beneficial effects on additional functional domains in ADHD (motor skills, social functioning, behavior, affective/emotional domain)

Hoza et al. Current Psychiatry Rep 2016; 18:113: 1-7


Questions that need to be addressed:

• What is the optimal “dose” (individual session duration, frequency, program length)

• Is there an age during development when exercise could be most effective?

• How does exercise compare to established treatments for ADHD? To medication? To behavioral therapy?

• How long do the beneficial effects of exercise last?


• Literature review: 25 published studies on exercise and cognition in children with ADHD, 4 studies on adults with ADHD

• Compared 1) exercise type (aerobic vs nonaerobic)2) effect type (acute vs chronic)3) outcome measure (cognitive/behavioral/socio-emotional,

physical/neurophysiological)

• Aerobic exercise appears to be the most effective for improvements in EF

• Both acute and chronic exercise have beneficial effects on behavioral and cognitive measures in children with ADHD

• Cognitive measures: improved response inhibition, cognitive control, attention allocation, cognitive flexibility, processing speed, and vigilance, when assessed immediately after exercise

Heijer et al. Journal of Neurotrauma 2016, 016: 1593-1597

Exercise, Catecholamines, and ADHD

• Exercise may exert its therapeutic effects by raising levels of catecholamines, similar to the effects of medication for ADHD

• Up to 30% of children do not show a beneficial response to stimulants or are unable to tolerate potential side effects

• Physical exercise induces increased levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in the prefrontal cortex, hippocampus, and striatrum)

• In a study that compared NE, DA, and epinephrine (Epi) levels in children with ADHD vs controls at baseline, during the last 2 minutes of exercise, 30, and 60 minutes post exercise: ‒ Resting NE levels were significantly lower in children with ADHD compared to controls ‒ In response to exercise, the increase in NE and Epi were severely blunted, and there was

no increase in DA

Heijer et al. Journal of Neurotrauma 2016, 016: 1593-1597; Wigal et al., J Atten Dis 2003, 17(4): 279-290

Exercise, Catecholamines, and ADHD

• There are other medical conditions that can result in a blunted catecholamine response to exercise, such as obesity and type I diabetes

• Gender influences • Prolonged exercise programs affect not only the acute

catecholamine response to individual bouts of exercise, but resting systemic rates of catecholamine secretion

• Training reduces the magnitude of catecholamine response to a comparable exercise challenge; however, it increases the basal resting catecholamine levels

• Thus, future research on the effects of prolonged exercise programs on catecholamine levels in patients with ADHD is needed

Zouhal, Jacob, Delamarche, & Gratas-Delamarche, 2008

Exercise and ADHD

• The findings suggest that an exercise “test” could be a diagnostic tool to measure catecholamine levels, and could serve as a biomarker for children with ADHD

• Further research is needed to determine the extent to which catecholamine levels are altered in response to exercise in patients with ADHD compared to controls

• Future studies should examine whether a greater intensity or duration of exercise can increase catecholamine levels in patients not on medication, to the levels that are observed with medication

• For now, it’s best to view exercise as an effective way of managing ADHD symptoms, but not as a stand-alone treatment

Conclusions

• Executive function is conceptually understood but operationally ill defined

• Definitional constructs are poorly correlated with each other (scales vs. tests)

• Positive predictive validity for impairments increases further in the presence of executive dysfunction and learning disorders

• Medications seem to have selective effects in ADHD and executive dysfunction, so…

• Don't overdose your patients!• Explore exercise programs as an adjunctive therapy,

particularly in the case of treatment-resistant patients

Posttest Question 1

Executive function is disrupted in approximately 5-10% of the general population, and what % of patients with ADHD?

1. 15-25%2. 30-50%3. 80-90%4. 50-75%

Posttest Question 2

Which of the following may be useful in diagnosing ADHD?

1. Wisconsin Card Sorting Test 2. Trail Making Test Part B3. Behavior Rating Inventory of Executive Function4. Digits Backward5. None of the above

Posttest Question 3

A meta-analysis on the effects of physical exercise for symptom management in children with ADHD, has demonstrated improvement on what cognitive measures?

1. Response Inhibition2. Visuospatial Tasks3. Cognitive Flexibility4. 1 and 35. None of the above

ADHD and CognitionLearning ObjectivesExecutive System / FunctionExecutive Dysfunction:�ADHD vs. General PopulationDefining Executive FunctionDiagnostic OverlapEF Associated With �Other DisordersNeurocircuitryEF Predicts Negative OutcomesDefining Executive FunctionExecutive Function Rating ScalesNeuropsychological Tests for �Executive FunctionPsychometric Approach to Assessing EF Relies on Testing Cold CognitionCan EF Tests Detect ADHD?Problems With the EF ConstructCriteria for a Primary Neurocognitive DeficitClinic-Referred Adults With ADHDEF Scales and Tests in Adult ADHDEcological Validity of EF TestsEcological Validity of EF TestsTesting in a Distraction Setting:�Adult ADHD vs. ControlsTesting in a Distraction Setting:�Adult ADHD vs. ControlsRating Scales vs. Tests: �Contribution Variance to ImpairmentRating Scales vs. Tests: �Contribution Variance to ImpairmentADHD Symptoms Correlate Poorly to ImpairmentsDefining Executive FunctionGenes and Executive FunctionFrontal Assessment BatteryGenes and ADHDWhat Should Be Treated First?Methylphenidate Effects on Cognition in ADHDUnderstanding the Cognitive Effects of Stimulants Understanding the Cognitive Effects of StimulantsUnderstanding the Cognitive Effects of StimulantsRegions Where Age of Attaining Peak Surface�Area Was Delayed by More Than 1 Year: ADHD Compared With Typically Developing Participants�Understanding the Cognitive Effects of StimulantsExercise as Adjunctive TreatmentExercise as Adjunctive TreatmentExercise as Adjunctive TreatmentExercise, Catecholamines, and ADHDExercise, Catecholamines, and ADHDExercise and ADHDConclusionsPosttest Question 1Posttest Question 2Posttest Question 3

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