1. NEUROPSYCHOLOGICAL CONSIDERATIONS IN THE EVALUATION OF ADHD Francis M. Crinella, Ph.D. Clinical Professor of Pediatrics, Psychiatry & Human Behavior, & Physical Medicine & Rehabilitation Director, Neuropsychology Laboratory Child Development Center University of California, Irvine

2. HISTORICAL OVERVIEW OF ADHD 1920-1937Post-encephalitic syndrome 1937Minimal Brain Damage 1960s Minimal Brain Dysfunction 1968 Hyperkinetic Reaction of Childhood (DSM-II) 1980 Attention Deficit Disorder, with or without hyperactivity (DSM-III) 1987 Attention Deficit Hyperactivity Disorder (DSM III-R) 1994 Attention Deficit/Hyperactivity Disorder (DSM-IV)

3. DSM-IV SYMPTOMS OF ADHD INATTENTION CAN’T ATTEND TO DETAILS CAN’T SUSTAIN ATTENTION DOESN’T LISTEN FAILS TO FINISH CAN’T ORGANIZE TASKS AVOIDS SCHOOLWORK LOSES THINGS EASILY DISTRACTED FORGETFUL HYPERACTIVITY/IMPULSIVITY FIDGETS CAN’T STAY SEATED RUN ABOUT AND CLIMBS CAN’T PLAY QUIETLY IS OFTEN ON THE GO TALKS TOO MUCH BLURTS OUT ANSWERS CAN’T WAIT TURN INTERRUPTS OR INTRUDES

8. METHODS OF ARRIVING AT DIAGNOSIS OF ADHD BEHAVIORAL PSYCHIATRIC INTERVIEW/BIOSOCIAL HISTORY STANDARDIZED RATING TECHNIQUES CHECKLISTS/minimum criteria (e.g., DSM-IV criteria) RATING SCALES/cut-off scores (e.g., Conners, SWAN) DIRECT OBSERVATION BEHAVIOR SAMPLING PSYCHOMETRIC NEUROPSYCHOLOGICAL

9. CRITIQUE OF BEHAVIORAL METHODS PSYCHIATRIC INTERVIEW –Biosocial history--95% of diagnosis is history (Adolf Meyer, 1915) But: Getting adequate history is an extraordinarily lengthy process Focus of history may be based on interviewer experience and/or idiosyncracies (e.g., adaptation level) Interviewee may not be accurate (or even biased)

10. CRITIQUE OF BEHAVIORAL METHODS PSYCHIATRIC INTERVIEW –Biosocial history augmented by in-office observations Artificial setting—symptoms of concern may not be observed

11. CRITIQUE OF BEHAVIORAL METHODS RATING TECHNIQUES CHECKLISTS Minimum criteria for diagnosis (e.g., DSM-IV criteria) Must be observed in more than one setting Problem: Different sets of items will all satisfy Diagnostic Criteria

12. SAMPLE CONFIGURATION OF A CHILD’S DSM-IV SYMPTOMS OF ADHD—CASE MEETS CRITERIA FOR PRIMARILY HYPERACTIVE SUBTYPE INATTENTIONHYPERACTIVITY/I MPULSIVITY 1CAN’T ATTEND TO DETAILS YESFIDGETSYES 2CAN’T SUSTAIN ATTENTION NOCAN’T STAY SEATED YES 3DOESN’T LISTENNORUN ABOUT AND CLIMBS YES 4FAILS TO FINISHYESCAN’T PLAY QUIETLY YES 5CAN’T ORGANIZE TASKS YESIS OFTEN ON THE GO YES 6AVOIDS SCHOOLWORK NOTALKS TOO MUCH NO 7LOSES THINGS EASILY NOBLURTS OUT ANSWERS NO 8DISTRACTEDNOCAN’T WAIT TURN YES 9FORGETFULYESINTERRUPTS OR INTRUDES YES NUMBER OF INATTENTION SYMPTOMS 4NUMBER OF HYPERACTIVITY SYMPTOMS 7

13. SYMPTOM CHECKLISTS FOR TWO CHILDREN WHO MEET CRITERIA FOR ADHD, HYPERACTIVE/IMPULSIVE SUBTYPE HYPERACTIVITY/ IMPULSIVITY CHILD #1 CHILD #2 1 FIDGETS YES NO 2 CAN’T STAY SEATED YES NO 3 RUNS ABOUT AND CLIMBS YESNO 4 CAN’T PLAY QUIETLY YES 5 IS OFTEN ON THE GO YES 6 TALKS TOO MUCH YES 7BLURTS OUT ANSWERSNOYES 8 CAN’T WIAT TURN NO YES 9 INTERRUPTS OR INTRUDES NO YES ∑ “YES” 66

14. NUMBER OF POSSIBLE DSM-IV SYMPTOM CONFIGURATIONS THAT MEET CRITERIA FOR DIAGNOSIS OF ADHD FOR HYPERACTIVE SUBTYPE: –NUMBER OF VARIATIONS ON 9 CRITERIA 9/6 = 84 9/7 = 36 9/8 = 9 9/9 = 1 ∑ = 130

15. CRITIQUE OF BEHAVIORAL METHODS RATING SCALES Score based on sum of scores for individual items (e.g., “fidgety” Always = 3; Often = 2; Sometimes = 1; never = 0) Total score used for cut-off lacks differentiation Profile analysis reveals multiple subtypes Subtype profiles lack external validation

16. RATING ITEM: “FIDGETS”

17. UCI-CDC Parent/Teacher Ratings of Behavioral Competencies 48 items Subjects rated on positive traits Age-based reference group (i.e., “Compared to same-age children, how well is your child able to sit still in class?”) Rating scheme: 1. Very poorly—worse than all but as few children this age 2. Not too well—most children this age do better (well <average 3. Fair—better than quite a few children this age (slightly <average) 4. Fairly well—better than many children this age, (slightly >average) 5. Good—better than most children this age (well >average) 6. Excellent—better than all but a few children this age

18. UCI-CDC PARENT/TEACHER RATINGS OF BEHAVIORAL COMPETENCIES ADVANTAGES: –Multiple dimensions of behavior determined by factor analysis –Inter-rater reliability established for each dimension –Norms for mothers, fathers & teachers –Raw scores converted to percentile rankings

19. TYPICAL DISTRIBUTION OF RATINGS ON UCI- CDC PARENT-TEACHER RATING SCALE

22. UCI-CDC Parent/Teacher Ratings of Behavioral Competencies Major drawbacks: Must clinically account for differences among raters Fails to elucidate neurocognitive processes underlying behavioral competencies

23. NEUROPSYCHOLOGICAL EVALUATION Assumptions: –ADHD has a biological basis –ADHD reflects dysfunction in specific neural networks –Variations in neuropsychological test performance reflect integrity of underlying neural systems –Specific neurocognitive deficits in ADHD reflect impairment of attentional network

24. EVIDENCE FOR BIOLOGICAL BASIS OF ADHD 1.NEUROCHEMICAL 2.GENETIC 3.ELECTROPHYSIOLOGICAL RECORDINGS 4.FUNCTIONAL IMAGING 5.CORRELATIVE NEUROANATOMICAL STUDIES

26. BIOLOGICAL BASIS OF ADHD 1.NEUROCHEMICAL –PSYCHOPHARMACOLOGY MOST EFFECTIVE TREATMENT--CNS STIMULANTS DEXTROAMPHETAMINES METHYLPHENIDATES EFFECTS: –Improved classroom behavior –Improved academic productivity –Improved peer/adult interactions –Less frequent oppositional conduct –Reduced aggression

27. BIOLOGICAL BASIS OF ADHD 2.GENETIC BEFORE MOLECULAR BIOLOGY Catecholamine hypothesis—genetic variations in brain neurochemistry (Wender, 1971) Family genetic studies (e.g., Faroane, Biederman, Chen et al., 1992) AFTER MOLECULAR BIOLOGY Subsensitive dopamine receptor hypothesis; DRD4 gene (LaHoste, Swanson, Wigal, et al., 1996) Dopamine transporter gene (Cook, Stein, Krasowski, et al., 1995)

28. BIOLOGICAL BASIS OF ADHD GENETICS 1.Coding region of DRD4 gene for D4 receptor 2.Located on chromosome 11p 3.High degree of variability in 3 rd cytoplasmic loop 4.48 bp region can be repeated two to eleven times 5.Variants display different pharmacological properties 6.DRD4 mRNA in frontal and prefrontal brain regions

30. BIOLOGICAL BASES OF ADHD 3.FUNCTIONAL BRAIN IMAGING Evidence before modern imaging methods MBD hypothesis (Clements et al, 1963) Neuropsychology of MBD (Crinella, 1972) Evidence from modern imaging methods Methods used: PET; SPECT; fMRI Results: Variations in size and symmetry of brain structures (e.g., Swanson & Castellanos, 1997) Structures involved: FRONTO-STRIATAL NETWORK CAUDATE NUCLEUS BASAL GANGLIA

33. RECENT BRAIN IMAGING STUDIES IN ADHD

34. BIOLOGICAL BASIS OF ADHD 4. ELECTROPHYSIOLOGY Early studies of analog EEG Satterfield, J.H., & Schell, A.M. (1984). Childhood brain function differences in delinquent and non-delinquent hyperactive boys. Electroencephalography and Clinical Neurophysiology, 57, 199-207. Finding: Abnormal maturational effects of auditory event-related potential differentiated ADHD from non-ADHD subjects Recent brain mapping studies Pliszka, S.R., Liotti, M., & Woldorff, M.G. (2000). Inhibitory control in children with attention-deficit/hyperactivity disorder: event related potential identify the processing component and timing of an impaired r right-frontal response-inhibition mechanism. Biological Psychiatry, 48, 238-46.

36. BIOLOGICAL BASIS OF ADHD 5. CORRELATIVE NEUROANATOMY TRADITIONAL APPROACH TO STUDYING BRAIN- BEHAVIOR RELATIONSHIPS Experimental removal of brain structures Observation of effect on specific behavioral functions Necessary to identify functions affected by ADHD

37. DEFINITIONS OF ATTENTION “A special function was instituted which had periodically to search the outer world in order that its data might be already familiar if an urgent inner need should arise: This function was attention. Its activity meets the sense impressions half way, instead of awaiting their appearance. At the same time, there was probably introduced a system of notation, whose task was to deposit the result of this periodic activity of consciousness—a part of which we call memory.”

38. Sigmund Freud “Formulations regarding the two principles of mental functioning.” (1911)

39. Everyone knows what attention is. It is the taking possession of the mind in clear and vivid form of one out of what seem several simultaneous object or trains of thought. William James “The Principles of Psychology,” 1890

40. Attention operates by changing the relative activity within specified anatomical areas that perform computations Michael Posner “Images of Mind,” 1996

41. DISTINCT ANATOMICAL NETWORKS CARRY OUT SPECIFIC ASPECTS OF ATTENTION ALERTING NETWORK –LOCATION: ARAS, ETC. –FUNCTION: ACHIEVE AND MAINTAIN STATE OF READINESS ORIENTING NETWORK –LOCATIONS: PARIETAL LOBE, SUPERIOR COLLICULUS & PULVINAR –FUNCTION: REACT TO SENSORY STIMULI EXECUTIVE NETWORK –LOCATION: ANTERIOR CINGULATE; DORSOLATERAL FRONTAL CORTEX & BASAL GANGLIA –FUNCTIONS: CONTROL NEURAL RESPONSES TO STIMULI GENERATE NEW INFORMATION FROM LONG TERM MEMORY PRIORITIZE OPERATION OF OTHER BRAIN AREAS

42. ADHD and EF ADHD is a disorder of Executive Function (Barkley, 1997)

43. SOME FEATURES OF EXECUTIVE FUNCTION Decision as to just what the problem is that needs to be solved Selection of lower-order components Selection of one or more representations of organizations for information Selection of a strategy for combining lower order components Decision regarding tradeoffs in the speed and accuracies with which various components are executed Solution monitoring STERNBERG, 1985

44. BRIEF DEFINITIONS OF EXECUTIVE FUNCTION Processes used to plan, monitor and revise strategies of information processing (STERNBERG. 1985) Appropriate set maintenance to achieve a future goal (PENNINGTON, WELSH & GROSSIER, 1990) A process which enables the brain to function as many machines in one, setting and resetting itself dozens of times in the course of a day, now for one type of operation, now for another (SPERRY, 1955) A process that alters the probability of subsequent responses to an event, thereby altering the probability of later consequences (Barkley, 1997).

49. EXECUTIVE FUNCTION DEFICITS ASSOCIATED WITH LESIONS IN RODENT DOPAMINE NETWORK Shifting cognitive sets Planning behavioral sequences Inhibition of motor reactivity Response flexibility

50. TESTS OF EXECUTIVE FUNCTION IN THE HUMAN NEUROPSYCHOLOGY LABORATORY By definition, no test can be performed in the absence of executive control Executive functions must be differentiated from other cognitive –abstract reasoning –crystallized problem solving –long term memory –sensory-perceptual processing –motor control systems –Motivational states Which tests do this best?

51. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD WISC-III: 1.PERFORMANCE > VERBAL IQ 2.VERBAL > PERFORMANCE IQ 3.ACID/ACIDS PROFILE 4.FREEDOM FROM DISTRACTIBILITY INDEX 5.PROCESSING SPEED INDEX

52. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD WISC-III 1. PERFORMANCE > VERBAL

53. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD Critique: PERFORMANCE > VERBAL Same pattern occurs in: –English as 2 nd language –Receptive and/or expressive dysphasia –Left hemisphere tumors –Conduct disorder –Specific learning disabilities

54. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD WISC-III 2. VERBAL>PERFORMANCE EVIDENCE OF INATTENTIVE SUBTYPE?

55. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD Critique: VERBAL>PERFORMANCE Same pattern occurs in: –Non-verbal learning disability –Cerebral palsy/fine motor control deficits –Depression –Obsessive compulsive disorder –Visual-spatial defects

56. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD WISC-III 3. “ACIDS” Index: Arithmetic Coding Information Digit Span Symbol Search)

57. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD Critique of ACIDS Index Arithmetic is sensitive to specific learning disabilities (e.g., dyscalculia secondary to developmental Gerstmann syndrome), dysphasias, anxiety states, psychotic states, etc. Coding is sensitive to deficits in motor control, visual perception, anxiety, depression, OCD, etc. Information is sensitive to cultural bias, lack of educational opportunity, specific learning disabilities (e.g., dyslexias), dysphasias, long term memory disorders, etc. Digit Span is affected by anxiety, schizophrenia, bipolar illness, dysphasia, etc. Digits reversed, but not forward, has high correlation with general intelligence. Symbol Search is sensitive to deficits in visual acuity, visual perception, motor control, depression, anxiety, obsessive compulsive disorder, etc.

58. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD WISC-III 4. Processing Speed index Based on Coding and symbol search subtests

59. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD Critique of Processing Speed index: Both Coding and Symbol search are are timed 1.Coding is sensitive to deficits in motor control, visual perception, anxiety, obsessive compulsive disorder, depression, etc. 2.Symbol Search is sensitive to deficits in visual acuity, visual perception, depression, anxiety, obsessive compulsive disorder, etc.

60. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD WISC-III 5.FREEDOM FROM DISTRACTIBILITY Based on Arithmetic and Digit Span

61. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD CRITIQUE OF FREEDOM FROM DISTRACTIBILITY INDEX: 1. Arithmetic is sensitive to specific learning disabilities (e.g., dyscalculia), dysphasias, anxiety states, psychotic states, etc. 2.Digit Span is affected by anxiety, schizophrenia, bipolar illness, dysphasia, etc. 3.Digits Backward, but not forward, has moderately high correlation with general intelligence

62. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD PERFORMANCE DISCREPANCY SCORE Observed academic achievement vs IQ- based academic achievement expectation

63. TRADITIONAL PSYCHOMETRIC APPROACHES TO IDENTIFICATION OF ADHD Critique: Observed vs expected achievement Can reflect specific learning disabilities, low motivation, depression, adjustment disorder, test-taking anxiety, memory defects, etc.

64. MORE SPECIFIC NEUROPSYCHOLOGICAL APPROACHES TO IDENTIFICATION OF ADHD BASED ON LABORATORY MEASURES OF EXECUTIVE FUNCTION CONTINUOUS PERFORMANCE TEST –FOCUSES ON SPECIFIC AREAS OF EXECUTIVE FUNCTION TASK PERSISTENCE VIGILANCE IMPULSE CONTROL REGULATION OF AROUSAL LEVEL

65. MORE SPECIFIC NEUROPSYCHOLOGICAL APPROACHES TO IDENTIFICATION OF ADHD 1. CONTINUOUS PERFORMANCE TEST –FOCUSES ON SPECIFIC AREAS OF EXECUTIVE FUNCTION TASK PERSISTENCE VIGILANCE IMPULSE CONTROL REGULATION OF AROUSAL LEVEL

66. PRESS BUTTON EVERY TIME A LETTER APPEARS A

67. EXCEPT WHEN THE LETTER “X” APPEARS X

68. CONTINUOUS PERFORMANCE TEST SCORING CATEGORIES: Omissions Commissions Overall Processing Speed Overall Attentional Variability Perceptual Sensitivity Risk Taking Perseverations Speed Decrement Over time Variability Over time Activation/arousal

69. HIT REACTION TIME 300 325 350 375 400 425 450 475 500 525 550 575 600 625 650 675 700 MILLISECONDS TYPICAL ADHD 1 SEC 2 SEC 4 SEC

70. STANDARD ERROR OF HIT REACTION TIME 0 10 20 30 40 50 60 70 80 90 100 MILLISECONDS TYPICAL ADHD 1 SEC 2 SEC 4 SEC

71. COMMISSION ERRORS 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 MILLISECONDS CONTROLS ADHD 1 SEC 2 SEC 4 SEC

72. CONTINUOUS PERFORMANCE TEST NON-ADHD CONDITIONS THAT CAN AFFECT SCORES: Commissions: anxiety; toxic exposure Omissions: depression; dyspraxia Overall Processing Speed: depression; anxiety Perceptual Sensitivity: Visual acuity; dyseidetic dyslexia Risk Taking: psychopathy; anxiety Perseverations: psychomotor retardation; frontal lobe damage Speed Decrement Over time: diabetes; hypothyroidism Activation/arousal: schizotypal conditions (blocking)

73. MORE SPECIFIC NEUROPSYCHOLOGICAL APPROACHES TO IDENTIFICATION OF ADHD 2. WISCONSIN CARD SORTING TEST FOCUSES ON SPECIFIC AREAS OF EXECUTIVE FUNCTION: SET FORMATION SET MAINTENANCE SET SHIFTING

74. WISCONSIN CARD SORTING TEST SORT BY COLOR OR SHAPE?

75. MORE SPECIFIC NEUROPSYCHOLOGICAL APPROACHES TO IDENTIFICATION OF ADHD CRITIQUE OF WISCONSIN CARD SORTING TEST Set formation can be affected by depression, lowered motivational states, frank retardation Set shifting difficulties are sometimes seen in anxious people Loss of set is seen in major psychiatric illness, substance abuse, etc.

76. MORE SPECIFIC NEUROPSYCHOLOGICAL APPROACHES TO IDENTIFICATION OF ADHD 3. WIDE RANGE ASSESSMENT OF LEARNING AND MEMORY (WRAML) FOCUSES ON SPECIFIC AREAS OF EXECUTIVE FUNCTION: 1.WORKING MEMORY 2.SEQUENCING AND MENTAL CONTROL 3.RESISTANCE TO INTERFERENCE

78. MORE SPECIFIC NEUROPSYCHOLOGICAL APPROACHES TO IDENTIFICATION OF ADHD CRITIQUE OF WIDE RANGE ASSESSMENT OF LEARNING AND MEMORY (WRAML) AUDITORY WORKING MEMORY DEFICITS MUST BE DIFFERENTIATED FROM AUDITORY PROCESSING DEFICITS, DYSPHASIAS, ANXIETY STATES, ETC. SEQUENCING AND MENTAL CONTROL DEFICITS ARE ALSO CHARACTERISTICS OF THOUGHT AND DISORDERS SUSCEPTIBILITY TO INTERFERENCE MAY BE ASSOCIATED WITH ALMOST ANY NEURODEVELOPMENTAL OR PSYCHIATRIC CONDITIION

79. CONCLUSIONS THE BEST WAY TO ENSURE AN ACCURATE DIAGNOSIS IS TO USE A COMBINATION OF HISTORY, RATING SCALES, DIRECT OBSERVATIONS, AND A CAREFULLY SELECTED BATTERY OF NEUROPSYCHOLOGICAL TESTS NEUROPSYCHOLOGICAL TESTS THAT ARE BASED ON LABORATORY METHODS OF ASSESSING EXECUTIVE FUNCTION PROVIDE INFORMATION THAT IS MOST PERTINENT TO THE COGNITIVE DEFICITS FOUND IN ADHD NEVERTHELESS, PERFORMANCE DEFICITS ON SPECIFIC TESTS MAY BE ATTRIBUTABLE TO ANY NUMBER OF NON-ADHD SYMPTOM COMPLEXES