THE NEUROTOXICOLOGY OF ATTENTION DEFICITS

1. THE NEUROTOXICOLOGY OF ATTENTION DEFICITS Francis M. Crinella, Trinh Tran & Joey Trampush University of California, Irvine University of California, Davis

2. REVIEW OF ADHD • CURRENT STATUS • BIOLOGICAL THEORIES OF ADHD • NEUROIMAGING EVIDENCE • MOLECULAR BIOLOGICAL EVIDENCE • COGNITIVE NEUROPSYCHOLOGY • ADHD AS DISORDER OF EXECUTIVE FUNCTION • FEATURES OF EXECUTIVE FUNCTION • CNS EF NETWORK

3. ADHD SYMPTOMS AND TOXIC EXPOSURES • Pb • PSE • Mn • SHARED MECHANISMS • EXPERIMENTAL MODEL OF Mn-INDUCED ATTENTION DEFICITS • EF DEFICITS

4. Historic Overview of Attention Deficit Hyperactivity Disorder (ADHD)

9. 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 DSM-IV SYMPTOMS OF ADHD

10. PSYCHOPHARMACOLOGY OF ADHD • CNS STIMULANTS • DEXTROAMPHETAMINES • METHYLPHENIDATES • EFFECTS: • Improved classroom behavior • Improved academic productivity • Improved peer/adult interactions • Less frequent oppositional conduct • Reduced aggression

11. BIOLOGICAL BASES OF ADHD • MOLECULAR BIOLOGY • CATECHOLAMINE HYPOTHESIS --GENETIC VARIATION IN NEUROTRANSMITTER FUNCTION (WENDER, 1971) • SUBSENSITIVE DOPAMINE HYPOTHESIS; DRD4 GENE (LaHOSTE, SWANSON, WIGAL, et al, 1996) • BRAIN IMAGING • MBD (Clements, 1963) • VARIATIONS IN SIZE AND SYMMETRY (Filipek et al, 1997) • FRONTO-STRIATAL • CAUDATE • BASAL GANGLIA

14. RECENT BRAIN IMAGING STUDIES IN ADHD

15. Attention operates by changing the relative activity within specified anatomical areas that perform computations

16. 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

17. ADHD and EF • ADHD is a disorder of Executive Function (Barkley)

18. 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

19. 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).

23. BRAIN STRUCTURES COMPRISING THE RODENT EF SYSTEM • SUPERIOR COLLICULUS • MEDIAN RAPHE NUCLEI • VENTRAL MESENCEPHALIC AREA • SUBSTANTIA NIGRA • PONTINE RETICULAR FORMATION • CAUDATOPUTAMEN • VENTREAL LATERAL THALAMUS • GLOBUS PALLIDUS

24. EXECUTIVE FUNCTION DEFICITS ASSOCIATED WITH LESIONS IN THE RODENT EF SYSTEM • Shifting cognitive sets • Selective attention • Procedural knowledge • Planning behavioral sequences • State control • Inhibition of motor reactivity • Response flexibility • Transfer strategies • Working memory

25. Attention deficits associated with prenatal stimulant exposureEghbalieh, B., Crinella, F. M., & Hunt, L., & Swanson, J. M. Journal of Attention Disorders, 2000, 4, 5-13.

26. PRENATAL STIMULANT EXPOSURE: TOXIC MECHANISM (COCAINE) • cocaine crosses placenta,affecting fetal dopaminergic and serotonergic systems, which play key roles in regulating attention and arousal. • Cocaine permanently alters development of DA-innervated cortical areas, predominantly the anterior cingulate cortex (ACC) • Long lasting structural and functional changes in the ACC • ADHD imaging studies shown ACC dysmorphology (Filipek et al., 1997)

27. PRENATAL STIMULANT EXPOSURE: TOXIC MECHANISM (AMPHETAMINE) • Amphetamine crosses placenta, affecting fetal dopaminergic and serotonergic systems, which play key roles in regulating attention and arousal. • Target areas for toxic effects are catecholaminergic • The precise mechanism of toxicity is somewhat different from cocaine • More evidence of permanent damage to neurons (Seiden and Kleven, 1988).

28. A

29. X

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

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

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

33. DEVELOPMENTAL NEUROTOXICOLOGY OF Pb

35. MECHANISMS OF PB-INDUCED NEUROTOXICITY • NEURAL CELL ADHESION MOLECULE (N-CAM) IMPAIRED • METABOLIC UNCOUPLING IN IMMATURE BRAIN •  GLIAL DIFFERENTIATION •  SYNAPTOGENESIS •  NEURAL PRUNING •  PATHWAYS WITH NO SYSTEMATIC RELATIONSHIP TO PROJECTING CELLS • DOPAMINE RECEPTOR DOWNRETULATION IN MESOLIMBIC SYSTEM • PREFRONTAL CORTEX • HIPPOCAMPUS RESPONSE DISINHIBITION • NUCLEUS ACCUMBENS

36. SOIL LEADCONCENTRATIONS AND PREVALENCE OF HYHPERACTIVE BEHVIOR AMONG SCHOOL CHILDREN IN OTTAWA, CANADA Jonathan E. Ericson & Shiraz I. Mishra Environmental International, 1990, 1, 247-256

39. ATTENTIONAL CORRELATES OF DENTIN AND BONE LEAD LEVELS IN ADOLESCENTSDavid Bellinger, Howard Hu, Libby Titlebaum & Herbert NeedlemanArchives of Environmental Health, 1994, 49, 98-105

40. IMPERSISTENCE

41. DISTRACTIBILITY

42. OVERDEPENDENCE

43. DISORGANIZED

44. HYPERACTIVE

45. IMPULSIVE

46. LOW FRUSTRATION TOLERANCE

47. UNABLE TO FOLLOW DIRECTIONS

48. POOR SEQUENCING ABILITY

49. LOW OVERALL FUNCTIONING

50. SOCIAL PROBLEMS-AGE 7