Scientific Update of ADHD Russell Schachar The Hospital for Sick Children Department of Psychiatry Brain and Behaviour Programme University of Toronto.

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Scientific Update of ADHD Russell Schachar The Hospital for Sick Children Department of Psychiatry Brain and Behaviour Programme University of Toronto Slide 2 Affiliations CIHR CIHR Barr, Kennedy, Ickowicz, Crosbie, Pakulak, Ornstein Barr, Kennedy, Ickowicz, Crosbie, Pakulak, Ornstein Noseworthy, Chevrier Noseworthy, Chevrier Robaey, Perusse Robaey, Perusse NINDS NINDS Levin, Dennis, Barnes Levin, Dennis, Barnes Lilly Lilly Purdue Frederick Purdue Frederick Shire Shire Slide 3 Outline Summary and overview current understanding Summary and overview current understanding Neuroscience 101 Neuroscience 101GenesProteins Brain structure Cognitive function Behavior Caveats Caveats Slide 4 g 1 g 2 g 3 Cell membranes, transmitters, assemblies Proteins function hyp-impinattention ADHD environment Slide 5 Genetics Slide 6 What are genes? DNA is specific sequence of nucleotide bases that encode instructions for proteins DNA is specific sequence of nucleotide bases that encode instructions for proteins Genome is complete set of DNA Genome is complete set of DNA Slide 7 How do genes function? Many changes evident and passed on Most changes cannot be seen by microscope Most base pairs are not involved in genes and are not functional Can be used to track functional changes May regulate gene expression or function Epigenetic factors affect gene function Many hereditary effects may be outside of genes Slide 8 Neurotransmitter systems Dopamine transporter Serotonin Noradrenalin Glutamate GABA Transporters and receptors variably distributed Slide 9 Dopamine D4 48bp Repeat Variants: Pharmacologic differences not linearly correlated with number of repeats EC 50 2R4R 7R10R Asghari et al, 1995 Jovanovic et al, 1999 Implication: the 7R allele has a blunted response to dopamine Slide 10 SNAP-25 Critical for controlled release of neurotransmitters into the synaptic cleft Loss of expression of a single copy of the gene results in dysregulation in the controlled release of glutamate, dopamine, and serotonin in select brain regions SNAP-25 Slide 11 Genes, proteins and neural development Slide 12 Neural development Stem cells differentiate Stem cells differentiate Growth factors (sonic hedgehog, notch, BDNF) Growth factors (sonic hedgehog, notch, BDNF) Half survive Half survive Development depends of where they end up, activity there (use it or lose it!) Development depends of where they end up, activity there (use it or lose it!) Rate of division/survival depends on experience, formation of synapses, integration into networks Rate of division/survival depends on experience, formation of synapses, integration into networks Loss of neurons normal (exaggerated in some diseases) Loss of neurons normal (exaggerated in some diseases) Neurons likely regenerate and affected by experience (can teach old dog new tricks) Neurons likely regenerate and affected by experience (can teach old dog new tricks) Environment can affect gene expression Environment can affect gene expression Slide 13 Brain tour Slide 14 Phineas Gage Slide 15 Prefrontal cortex Not involved in specific tasks Not involved in specific tasks Executive control of behaviour, thought and affect Executive control of behaviour, thought and affect Organization and planning for future action and social goals Organization and planning for future action and social goals Balances perceptual, instinctual and motivational input Balances perceptual, instinctual and motivational input Reflective: guided by internal states and intentions Reflective: guided by internal states and intentions Control subordinate attention and motor processes Control subordinate attention and motor processes Slide 16 Prefrontal subcortical circuits Begin and end in frontal cortex Begin and end in frontal cortex Pass through subcortical structures Pass through subcortical structures Reciprocal and interacting connections Reciprocal and interacting connections Excitatory and inhibitory neurotransmitters Excitatory and inhibitory neurotransmitters Separate yet overlapping and interacting Separate yet overlapping and interacting Specific and intermingled mixture of deficits Specific and intermingled mixture of deficits Evident in individuals with massive lesions Evident in individuals with massive lesions Slide 17 Dorsolateral circuit Organization, planning, attention Organization, planning, attention Lesions generate concrete thinking, inability to stop, shift set, filter and ignore distractions, plan and organize Lesions generate concrete thinking, inability to stop, shift set, filter and ignore distractions, plan and organize Slide 18 Orbitofrontal circuit Mediates socially appropriate behaviour Mediates socially appropriate behaviour Lesions lead to marked personality change, social disinhibition, explosiveness, tactlessness, lability, lack of interpersonal sensitivity Lesions lead to marked personality change, social disinhibition, explosiveness, tactlessness, lability, lack of interpersonal sensitivity Slide 19 Anterior cingulate circuit Motivation, balancing competing demands, performance monitoring Motivation, balancing competing demands, performance monitoring Lesions result in akinetic mutism, apathy, lack of motivation, insensitive to errors Lesions result in akinetic mutism, apathy, lack of motivation, insensitive to errors Slide 20 Frontal/ executive processes wave of attention Encoding, maintaining, retrieving in working memory Encoding, maintaining, retrieving in working memory Preparing and anticipating Preparing and anticipating Interference management Interference management Withholding of response tendency Withholding of response tendency Maintain set Maintain set Retract or inhibition Retract or inhibition Error detection Error detection Error correction Error correction Slide 21 Summary Considerable understanding of brain development and function Considerable understanding of brain development and function Differentiation in structure and function Differentiation in structure and function Cognitive deficits Cognitive deficits Genetic risks Genetic risks Structural and functional anomalies Structural and functional anomalies Slide 22 ADHD genetics Highly genetic Highly genetic Not simple Mendelian inheritance Not simple Mendelian inheritance Multigenic Multigenic Non-genetic factors contribute separately and through various combinations Non-genetic factors contribute separately and through various combinations Disorder occurs when combination of genetic and non-genetic factors exceeds some threshold Disorder occurs when combination of genetic and non-genetic factors exceeds some threshold Nature of risk and mode of inheritance unknown Nature of risk and mode of inheritance unknown Slide 23 Genetics of ADHD % risk to family% concordance Slide 24 D19S229D19S247D19S204D19S221D19S179D19S248D19S178D19S246D19S180D19S254 Genome Scan Systematically screen all of the chromosomes for linkage using DNA markers spaced at regular intervals Slide 25 Genome scans for ADHD Fisher et al., 2002 Fisher et al., 2002 UCLA 126 affected sib pairs UCLA 126 affected sib pairs no regions met genome-wide significance levels no regions met genome-wide significance levels suggestive 5p12, 10q26, 12q23, 16p13 (Smalley, 2002) suggestive 5p12, 10q26, 12q23, 16p13 (Smalley, 2002) Ogdie et al., 2003 Ogdie et al., 2003 expansion of Fisher et al., sample + 144 sib pairs expansion of Fisher et al., sample + 144 sib pairs 17p11 (LOD 2.98), 16p13 17p11 (LOD 2.98), 16p13 Bakker et al., 2003 Bakker et al., 2003 164 Dutch affected sib pairs 164 Dutch affected sib pairs regions with LOD scores > 3, 15q15.1, 7p13 regions with LOD scores > 3, 15q15.1, 7p13 LOD score > 2, 9q33.3 LOD score > 2, 9q33.3 Slide 26 Candidate gene study Case-control Case-control Compare samples Compare samples Ethnicity Ethnicity Associated characteristic or disorder Associated characteristic or disorder Family-based Family-based Compare children and their parents or siblings Compare children and their parents or siblings Slide 27 Dopamine, cognition and behaviour Neurotoxin reduces DA in rats Neurotoxin reduces DA in rats hyperlocomotion, learning problems hyperlocomotion, learning problems DA depletion impairs working memory DA depletion impairs working memory Impulsiveness associated with low extracellular DA Impulsiveness associated with low extracellular DA Blocking DA reuptake makes DA more available and improves executive control Blocking DA reuptake makes DA more available and improves executive control Slide 28 Drugs and ADHD Slide 29 54 75 % adults and children with ADHD responds to methylphenidate (0.6 mg/kg) (Spencer et al 2001) The behavioural modifications induced by stimulants occurs with the reaching of peak plasma level Psychostimulants and ADHD Slide 30 Dopamine Transporter Some individuals with ADHD, have higher expression of the dopamine transporter. Some individuals with ADHD, have higher expression of the dopamine transporter. Possible mechanism of genetic susceptibility is over expression of the DAT protein Possible mechanism of genetic susceptibility is over expression of the DAT protein Stimulants blockade dopamine transporter and temporarily correct the levels of dopamine. Stimulants blockade dopamine transporter and temporarily correct the levels of dopamine. DAT Knock Out mouse DAT Knock Out mouse difficulty shifting - perseverative errors difficulty shifting - perseverative errors novelty-driven hyperactivity novelty-driven hyperactivity spatial learning deficit spatial learning deficit Slide 31 1) hyperactive 2) responsive to dextroamphetamine 3) not responsive to methylphenidate 4) delayed in some developmental milestones Rationale: mouse irradiation mutant strain Coloboma has a single copy of the SNAP-25 gene. The other copy has been deleted. Synaptosomal-Associated Protein of 25 kDa (SNAP-25) Slide 32 A number of Genes Identified as linked to ADHD What now? Confirm linkage in larger samples Determine how these genes contribute to ADHD Additional candidates e.g., neurotrophic factors Slide 33 Neuroimaging Computed tomography (CT) Series of x rays from different angles Positron emission tomography (PET) Inject radioisotope that emits positrons Water labelled with oxygen-15 measure changes in blood flow Deoxyglucose labelled with florine-18 which accumulates in active cells Magnetic resonance imaging (MRI) Magnets detect magnetic molecules fMRI detects changes in magnetic properties of hemoglobin as it carries O 2 to active brain cells Slide 34 Slide 35 Brain structure and ADHD Slide 36 Inhibitory control Withholding and withdrawing of responses if intention or circumstances change or error is made Withholding and withdrawing of responses if intention or circumstances change or error is made Failure of inhibition results in errors & impulsiveness Failure of inhibition results in errors & impulsiveness Slide 37 Inhibition and ADHD Activates orbital, DLPF and basal ganglia Activates orbital, DLPF and basal ganglia Rich in DA Rich in DA Disruption of DA by knock out or neurotoxins affects executive control Disruption of DA by knock out or neurotoxins affects executive control DA tone associated with executive control DA tone associated with executive control Impulsiveness associated with low extracellular DA Impulsiveness associated with low extracellular DA Blocking DA (mostly in basal ganglia) reuptake makes DA more available and improves executive control Blocking DA (mostly in basal ganglia) reuptake makes DA more available and improves executive control Slide 38 500 ms 1000 ms Inter-trial interval = 3000 ms Stop Signal Task motor response * X/O fixation point go stimulus: choice reaction time task Slide 39 * X/O 500 ms 1000 ms Stop Signal Task stop signal delay (variable) RED SCREEN or TONE 500 ms stop signal Slide 40 Latency of inhibition (SSRT) in ADHD and controls SSRT (ms) Schachar et al., 2001 Slide 41 Inhibition & psychopathology Osterlaans et al., 1999 IQ, age, aggression, speed, reading Slide 42 Impulsive Personality Slide 43 Inhibition and Methylphenidate Response Tannock, Schachar & Logan, 1995 T-score (Mean = 50, SD = 10) Slide 44 Slide 45 Inhibition in concordant and discordant siblings ConcordantDisconcordantControls SSRT ms Slide 46 Evidence of performance monitoring Introspection Introspection Slowing following errors Slowing following errors Slowing following correct responses Slowing following correct responses Self-detected action slips or errors due to faulty knowledge (external feedback) Self-detected action slips or errors due to faulty knowledge (external feedback) Pattern seen in range of tasks Pattern seen in range of tasks Speeded choice response tasks Speeded choice response tasks Memory tasks Memory tasks Inhibition tasks Inhibition tasks Slide 47 Relevance of performance monitoring to ADHD Poorly regulated behaviour Poorly regulated behaviour often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities Inaccurate and variable task performance Inaccurate and variable task performance Slide 48 Slowing after non-stopped responses in ADHD and controls ms Slide 49 Executive control summary New breed of measures of specific processes New breed of measures of specific processes Cognitively and neurally distinct, multiple deficits characteristic of ADHD Cognitively and neurally distinct, multiple deficits characteristic of ADHD Functional assessment warranted Functional assessment warranted Slide 50 What do you mean Cognitive tests are not diagnostic? Clinic sample (N = 100) Clinic sample (N = 100) ADHDcontrols 50/2550/5 Of 30 cases with diagnostic marker, 25/30 =83% will be ADHD General population (N = 100) General population (N = 100) ADHDcontrols 5/2.595/19 Therefore, of every 21.5 cases with the diagnostic marker, 19/21.5 = 88% will be controls! Slide 51 Environmental causes of ADHD/cognitive deficit Traumatic Traumatic closed head injury closed head injury prematurity prematurity radiation radiation Toxic Toxic alcohol (FAS) alcohol (FAS) smoking smoking Social / stress (alteration in DA, NA, S release in PFC) Social / stress (alteration in DA, NA, S release in PFC) in animals & humans disrupts complex cognitive function in animals & humans disrupts complex cognitive function maternal stress during pregnancy maternal stress during pregnancy disrupted early caregiving disrupted early caregiving Slide 52 School policy dilemma ADHD is a learning problem associated with cognitive deficits and academic underachievement ADHD is a learning problem associated with cognitive deficits and academic underachievement Slide 53 Approach differs from RD But is handled differently than learning disability Accommodation in classroom Slide 54 Summary Heritable Heritable Genetic risks Genetic risks Structure Structure Function Function Non-genetic factors Non-genetic factors Educational system Educational system Slide 55 Opportunities for participation Children 6 -16 years Children 6 -16 years Presumptive diagnosis of ADHD Presumptive diagnosis of ADHD Two affected children and both parents Two affected children and both parents Willing to give blood Willing to give blood No exclusions No exclusions Teju Pathare(416) 813-8291 Teju Pathare(416) 813-8291 One affect, sibling unaffected One affect, sibling unaffected Tracee Francis(416) 813-6568 Tracee Francis(416) 813-6568