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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 Affiliations CIHR NINDS Barr, Kennedy, Ickowicz, Crosbie, Pakulak, Ornstein Noseworthy, Chevrier Robaey, Perusse Levin, Dennis, Barnes Lilly Purdue Frederick Shire Outline Summary and overview current understanding Neuroscience 101 Genes Proteins Brain structure Cognitive function Behavior Caveats ADHD hyp-imp inattention function environment Cell membranes, transmitters, assemblies… Proteins g1 g2 g3 Genetics What are genes? DNA is specific sequence of nucleotide bases that encode instructions for proteins Genome is complete set of DNA 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 Neurotransmitter systems Dopamine transporter Serotonin Noradrenalin Glutamate GABA Transporters and receptors variably distributed Dopamine D4 48bp Repeat Variants: Pharmacologic differences not linearly correlated with number of repeats EC50 Asghari et al, 1995 Jovanovic et al, 1999 2R 4R 7R 10R Implication: the 7R allele has a blunted response to dopamine Critical SNAP-25 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 Genes, proteins and neural development Neural development Stem cells differentiate Growth factors (sonic hedgehog, notch, BDNF) Half survive 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 Loss of neurons normal (exaggerated in some diseases) Neurons likely regenerate and affected by experience (can teach old dog new tricks) Environment can affect gene expression Brain tour Phineas Gage Prefrontal cortex Not involved in specific tasks Executive control of behaviour, thought and affect Organization and planning for future action and social goals Balances perceptual, instinctual and motivational input Reflective: guided by internal states and intentions Control subordinate attention and motor processes Prefrontal subcortical circuits Begin and end in frontal cortex Pass through subcortical structures Reciprocal and interacting connections Excitatory and inhibitory neurotransmitters Separate yet overlapping and interacting Specific and intermingled mixture of deficits Evident in individuals with massive lesions Dorsolateral circuit Organization, planning, attention Lesions generate concrete thinking, inability to stop, shift set, filter and ignore distractions, plan and organize Orbitofrontal circuit Mediates socially appropriate behaviour Lesions lead to marked personality change, social disinhibition, explosiveness, tactlessness, lability, lack of interpersonal sensitivity Anterior cingulate circuit Motivation, balancing competing demands, performance monitoring Lesions result in akinetic mutism, apathy, lack of motivation, insensitive to errors Frontal/ executive processes “wave of attention” Encoding, maintaining, retrieving in working memory Preparing and anticipating Interference management Withholding of response tendency Maintain set Retract or inhibition Error detection Error correction Summary Considerable understanding of brain development and function Differentiation in structure and function Cognitive deficits Genetic risks Structural and functional anomalies ADHD genetics Highly genetic Not simple Mendelian inheritance Multigenic Non-genetic factors contribute separately and through various combinations Disorder occurs when combination of genetic and non-genetic factors exceeds some threshold Nature of risk and mode of inheritance unknown Genetics of ADHD % risk to family % concordance 100 30 25 75 20 50 15 10 MZ DZ 25 5 0 0 ADHD families Control families Stevenson (1992) Gillis et al. (1992) Levy et al. (1997) Genome Scan D19S229 D19S247 D19S204 D19S221 D19S179 D19S248 D19S178 D19S246 D19S180 D19S254 Systematically screen all of the chromosomes for linkage using DNA markers spaced at regular intervals Genome scans for ADHD Fisher et al., 2002 Ogdie et al., 2003 UCLA 126 affected sib pairs no regions met genome-wide significance levels suggestive 5p12, 10q26, 12q23, 16p13 (Smalley, 2002) expansion of Fisher et al., sample + 144 sib pairs 17p11 (LOD 2.98), 16p13 Bakker et al., 2003 164 Dutch affected sib pairs regions with LOD scores > 3, 15q15.1, 7p13 LOD score > 2, 9q33.3 Candidate gene study Case-control Compare samples Ethnicity Associated characteristic or disorder Family-based Compare siblings children and their parents or Dopamine, cognition and behaviour Neurotoxin reduces DA in rats hyperlocomotion, learning problems DA depletion impairs working memory Impulsiveness associated with low extracellular DA Blocking DA reuptake makes DA more available and improves executive control Drugs and ADHD Psychostimulants and ADHD 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 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 Stimulants blockade dopamine transporter and temporarily correct the levels of dopamine. DAT Knock Out mouse difficulty shifting - perseverative errors novelty-driven hyperactivity spatial learning deficit Synaptosomal-Associated Protein of 25 kDa (SNAP-25) Rationale: mouse irradiation mutant strain Coloboma has a single copy of the SNAP-25 gene. The other copy has been deleted. 1) hyperactive 2) responsive to dextroamphetamine 3) not responsive to methylphenidate 4) delayed in some developmental milestones 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 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 O2 to active brain cells Brain structure and ADHD Inhibitory control Withholding and withdrawing of responses if intention or circumstances change or error is made Failure of inhibition results in errors & impulsiveness Inhibition and ADHD Activates orbital, DLPF and basal ganglia Rich in DA Disruption of DA by knock out or neurotoxins affects executive control DA tone associated with executive control Impulsiveness associated with low extracellular DA Blocking DA (mostly in basal ganglia) reuptake makes DA more available and improves executive control Stop Signal Task * fixation point X/O go stimulus: choice reaction time task 500 ms motor response 1000 ms Inter-trial interval = 3000 ms Stop Signal Task * X/O 500 ms stop signal delay (variable) RED SCREEN or TONE 1000 ms 500 ms stop signal Latency of inhibition (SSRT) in ADHD and controls SSRT (ms) 350 300 250 200 SSRT 150 100 50 0 ADHD Normal Control Schachar et al., 2001 Inhibition & psychopathology SSRT (ms) 500 400 300 200 100 us An xi o D HD +C AD du ct Co n HD AD No rm al 0 • IQ, age, aggression, speed, reading Osterlaans et al., 1999 Impulsive Personality Logan, Schachar & Tannock, 1997 650 Mean RT in MS 550 450 SSRT Go RT 350 250 150 0 2 4 6 Impulsivity Score 8 Inhibition and Methylphenidate Response T-score (Mean = 50, SD = 10) 65 60 55 ssrt % still 50 45 40 35 placebo low medium high Tannock, Schachar & Logan, 1995 Inhibition & Family History for ADHD % Percent of Family History for ADHD 60 50 48.1 40 30 18.5 20 7.7 10 0 Poor Inhibition Good Inhibition Normal Control Crosbie & Schachar (2001) Inhibition in concordant and discordant siblings SSRT ms 350 300 250 200 150 100 50 0 Concordant Disconcordant Controls Evidence of performance monitoring Introspection Slowing following errors Slowing following correct responses Self-detected action slips or errors due to faulty knowledge (external feedback) Pattern seen in range of tasks Speeded choice response tasks Memory tasks Inhibition tasks Relevance of performance monitoring to ADHD Poorly regulated behaviour “often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities” Inaccurate and variable task performance ms Slowing after non-stopped responses in ADHD and controls 80 60 40 20 0 ADHD Normal Control Executive control summary New breed of measures of specific processes Cognitively and neurally distinct, multiple deficits characteristic of ADHD Functional assessment warranted What do you mean “Cognitive tests are not diagnostic”? Clinic sample (N = 100) ADHD 50/25 controls 50/5 Of 30 cases with “diagnostic marker”, 25/30 =83% will be ADHD General population (N = 100) ADHD 5/2.5 controls 95/19 Therefore, of every 21.5 cases with the “diagnostic marker”, 19/21.5 = 88% will be controls! “Environmental” causes of ADHD/cognitive deficit Traumatic closed head injury prematurity radiation Toxic alcohol (FAS) smoking Social / stress (alteration in DA, NA, S release in PFC) in animals & humans disrupts complex cognitive function maternal stress during pregnancy disrupted early care–giving School policy dilemma ADHD is a learning problem associated with cognitive deficits and academic underachievement Approach differs from RD But is handled differently than learning disability Accommodation in classroom Summary Heritable Genetic risks Structure Function Non-genetic factors Educational system Opportunities for participation Children 6 -16 years Presumptive diagnosis of ADHD Two affected children and both parents Willing to give blood No exclusions Teju Pathare (416) 813-8291 One affect, sibling unaffected Tracee Francis (416) 813-6568