Neuroimaging and ADHD: The Neurobiological Basis of ADHD and Pharmacological Treatment

Transcription

1 Neuroimaging and ADHD: The Neurobiological Basis of ADHD and Pharmacological Treatment Jeffrey H. Newcorn, MD Icahn School of Medicine at Mount Sinai

2 Neurobiological Basis of ADHD NE enhances relevant signal Modulators Nicotinic/ Cholinergic 5-HT 1A, 1B H 3 Posterior Parietal Cortex NET, ɑ 2A Synthesis/ metabolism DƁH COMT MAO (A) Cerebellum D3, D 4 Sensory input Striatum DAT, D 2 Locus Coeruleus VTA Substantia Nigra Prefrontal Cortex D1, D4, D5 NET, ɑ 2A NE enhances relevant signal; regulates DA DA suppresses irrelevant signal Interface with: Glutamate NMDA/ AMPA GABA Newcorn, NCDEU, 2008

3 Objectives of This Presentation Discuss different types of imaging techniques and their application to ADHD Examine results of studies using neuroimaging to elucidate the neurobiological basis of ADHD Show results of studies examining effects of medications for ADHD on brain function Present our own work on mechanisms of action and differential response to methylphenidate and atomoxetine

4 What Can PET Studies Tell Us? Opportunities Receptor binding to confirm hypothesized activity Glucose utilization (proxy for regional brain activity) while performing a task Disadvantages Single dose challenge - does not study actual clinical utility; better for stimulants than other drugs; still there are issues Desired radioligand often not available (e.g., NET) Expensive (multiple scans; cost of radioligand development; may require a cyclotron)

5 DA Transporters and Receptors in ADHD *In children DA DA DA DA DA DA DA DA Synapse DA Transporters DA D2 Receptors DAT: Increased: 70% Dougherty et al, % Krause et al, % Dresel et al, % McGough et al., % Cheon et al, 2003* 34% Spencer et al., % Spencer et al., 2007 No Change: van Dyck et al, 2002 Jucaite et al., 2005* (striatum) Volkow et al., 2007 (putamen) Decreased: 16% Jucaite et al., 2005* (midbrain) 13% Volkow et al, 2007 (caudate) DA D2: Increased: Ilgin et al., 2001* No Change: Jucaite et al., 2005* Decreased: Volkow et al., 2007

6 Striatal Dopamine Transporter Alterations in ADHD: Pathophysiology or Adaptation to Psychostimulants? Fusar-Poli et al., Am J Psychiatry. 2012;169(3):

7 Density of DAT and D2/D3 in Adults With ADHD vs. Healthy Controls D2-Raclopride DAT-Cocaine [ 11 C]raclopride distribution volume ratio images revealed 1 cluster with lower D 2 /D 3 availability in ADHD participants than controls in the left hemisphere. This cluster included brain regions of the dopamine reward pathway ventral caudate, accumbens, and midbrain regions, as well as the hypothalamic region Volkow et al., JAMA, 2009 Sep 9;302(10):

8 Relationship Between Trait Motivation and DA Transporter and D2/D3 Receptor Availability Scattergram showing the regression between the measures of DA D2/D3 receptor and of DAT availability in the NAcc and in the midbrain regions and Trait Motivation (MPQ Achievement scale) in ADHD participants (circles) and in controls (x). Volkow et al., Mol Psychiatry, 2010 Sep 21

9 What Can MRI and fmri Tell Us? Potential uses Pharm MRI: document site of activity (in animals) Structural MRI: regional brain volume and white matter connections; good for longitudinal studies fmri: demonstrate regional activity in relation to task performance (animals; humans) fmri: connections between brain regions/networks Limitations fmri highly task dependent; task-based scans are lengthy; hard to obtain data on multiple tasks Difficulty scanning children

10 Developmental Trajectories of Cerebellum & Caudate Nucleus in ADHD Normalization of reduced caudate volume in ADHD by mid-adolescence Reduced cerebellar volume in ADHD persists through adolescence Castellanos et al. JAMA. 2002;288:

11 Delayed Cortical Maturation in ADHD Age (yr) Kaplan-Meier curve showing fraction of cortical points that had reached peak thickness at each age >2 yr delay Delay of 0 to 2 yr Regions where the ADHD group had delayed cortical maturation Based on 824 magnetic resonance scans of 223 children with ADHD and 223 controls; longitudinal data; mean interval between scans 2.8 years Shaw et al. Proc Natl Acad Sci U S A. 2007;104:

12 Normal ADHD Adult vs Normal Controls (fmri During Perceptual Task)* Adults with ADHD process information less efficiently Normal Controls ADHD *Stroop task utilized. MGH-NIMR Center & Harvard-MIT CITP, Bush G, et al. Biol Psychiatry. 1999;45(12):

13 fmri Studies of Inhibition and Attention in ADHD ADHD vs. healthy controls Inhibition tasks. Decreased activation in right IFC extending into the insula, SMA and cognitive division of the ACC; left caudate extending into the putamen and insula; and right mid-thalamus. Attention tasks. Decreased activation in right DLPFC, left putamen and globus pallidus, right posterior thalamus (pulvinar), caudate tail extending into the posterior insula, right inferior parietal lobe, and the precuneus and superior temporal lobe. Decreased activation - red and orange; Increased activation blue Increased activation in left cuneus and right cerebellum. Hart et al., JAMA Psychiatry, 2013 Feb;70(2):

14 Meta-analysis Showing Ventral Striatal Hypo-responsiveness in ADHD During Reward Anticipation Plichta & Scheres, Neurosci Biobehavioral Rev, 38: , 2014

15 Resting State MRI: What Can We Learn About Pathophysiology and Treatment? Efficient method to study changes in and across networks, rather than individual regions Scans are short; larger n studies possible Instrumental in developing a new model of what ADHD is Possible to test in large numbers of subjects Excellent for hypothesis generation Excellent for cross-site studies and building larger data based

16 Default Mode Network: Functional Connectivity of ACC, Precuneus, PCC and VMPFC ACC Seed: A robust negative or antiphasic relationship was noted between the ACC seed region and default-mode network components (i.e., an increase in ACC activity predicts a decrease in default-mode activity). ADHD related decreases in functional connectivity were noted between the ACC and precuneus. Precuneus Seed: ADHDrelated decreases in precuneus/acc connectivity, and among precuneus and other default-mode network components, including VMPFC and anterior portions of PCC. Castellanos et al., Biol Psychiatry, 2007

17 Anti-correlated Task-Positive and Task- Negative Networks Sonuga-Barke and Castellanos, Neurosci Biobehav Rev, 31: , 2007

18 Summary: Using Imaging and ADHD Pathophysiology Studies have both confirmed hypothesizd neurobiological bases of ADHD and also generated new hypotheses about the disorder Current conceptualizations include a greater number of inter-digitating brain regions and an expanding array of neural circuits Moving away from region of interet analyses toward a broader conceptualization focusing on communication across regions

19 Imaging ADHD Treatment

20 % DAT Occupancy Dopamine Transporter Occupancy by Methylphenidate 100 Placebo 20 mg 40 mg Typical Dose (0.5 mg/kg) At typical therapeutic doses ( mg/kg), MPH occupies >50% of DATs Dose (mg/kg) Volkow et al; J Neurosci, 2001 Volkow et al., Synapse, 2002

21 MPH Occupancy of NET at Clinically Relevant Doses in Humans Demonstrates activity of an established treatment in a different neurotransmitter system; examines differences in activity across multiple brain regions Hannestad et al., Biol Psychiatry, 2010

22 Meta-Analysis of fmri Findings and Normalization with MPH Main areas implicated in ADHD are right inferior frontal (increased activity) and right rostral/doral anterior cingulate (decreased activity) Rubia et al., Biol Psychiatry, 2013

23 MPH Increases Suppression of Default-mode Activity in Precuneus and mpfc in Children with ADHD Peterson et al., Am J Psychiatry 2009

24 MPH Normalizes OFC Activation for Reward Processing in Medication-naïve Children with ADHD Rewarded non-rewarded target trials on CPT: MPH (single dose challenge) enhanced activation in mesial frontal cortex (above), and anterior cingulate and caudate (not shown) Rubia et al., Neuropharmacology, 57: , 2009

25 MPH Attentuation of mpfc Activity During an Emotional Stroop Task* Positively valenced distraction interactions *Using a different task to show an alternative effect of a treatment Negatively valenced distraction interactions Posner et al., Psychiatry Research: Neuroimaging, 2011

26 Atomoxetine Increases Right IFG Activation: Association with Improved Inhibitory Control Chamberlain et al., Biol Psychiatry, 2009;65:

27 Guanfacine Enhances Activation of dl-pfc During a Cued Alerting Task* Single dose challenge with guanfacine and placebo in healthy adults Clerkin et al., Biol Psychiatry, 2009

28 Summary: Using Brain Imaging to Study ADHD Pathophysiology and Treatment Convergent evidence re: change in brain structure or function in association with treatment Several methods; each providing different information Receptor binding; metabolism (PET) Regional volume (MRI) acutely and over time; Regional activation (fmri); Regional blood flow (pharm MRI) Connectivity (fmri; Resting state); DTI (MRI) Methodologic issues in how to use/study medication Single dose challenge vs. clinical trial Acute discontinuation designs Common and unique effects of medications (discussed later)

29 Methylphenidate Atomoxetine Crossover (MACRO) Study Common and Unique Effects of Methylphenidate and Atomoxetine: Understanding Mechanisms of Action and Predicting Differential Response

30 MACRO Study Methylphenidate 6-8 wks Methylphenidate 6-8 wks 2 wk washout Randomize 2 wk washout Open-label treatment Baseline fmri N = 56 Atomoxetine 6-8 wks EOT fmri N = 36 Atomoxetine 6-8 wks ATX MPH MPH ATX

31 fmri Scan Procedures 3.0 Tesla Siemens Allegra headonly MRI scanner with Echo Planar Imaging (EPI) hardware Stimuli projected via LCD system onto rear projection screen at head of MRI bore Fiber optic response pad on right hand Image Acquisition Spin-echo T2-weighted structural image 2D EPI sequence depicting BOLD signal

32 Schematic of Go/No-go Task * GO GO GO NOGO GO Time (Seconds) Participants instructed to focus on the center of the screen; press the button for all Spiderman pictures and do not press for Green Goblin pictures. * Adapted from go/no-go test in Durston et al., Neuroimage, 2002.

33 Sample Characteristics Variable MPH (n = 18) ATX (n = 18) p Age (mean ± SD yrs) 11.0 ± ± 3.0 >.10 Gender Male N (%) Female N (%) 15 (83%) 3 (17%) 15 (83%) 3 (17%) >.10 ADHD Subtype Combined N (%) Inattentive N (%) Hyperactive N (%) 10 (56%) 7 (39%) 1 (5%) 10 (56%) 7 (39%) 1 (5%) >.10 Comorbid ODD N (%) 8 (44%) 7 (39%) >.10 Baseline ADHD-RS-IV (mean ± SD) 38.0 ± ± 10.6 >.10 Prior stimulant treatment N (%) 8 (44%) 5 (28%) >.10 Required washout N (%) 5 (28%) 3 (8%) >.10

34 Second-Level (Group) Analysis General linear model (GLM) Multiple regression Regressor 1: Medication (MPH vs. ATX) Regressor 2: ADHD-RS-IV change score Regressor 3: Interaction term Threshold: p < 0.01, kappa = 100 voxels Variable centered on zero

35 Differential Activation Profiles in Association with Response to MPH and ATX - Pre and post-treatment (7 weeks) scans in 18 subjects treated with MPH and 18 subjects treated with ATX in randomized clinical trials - Regression analysis incorporates change in regional activation and change in ADHD-RS ratings in the same model Schulz et al., Arch Gen Psychiatry, 2012

36 Conclusions First evidence of common and distinct frontoparietal therapeutic mechanisms of action for stimulant and nonstimulant treatments in youth with ADHD Common therapeutic mechanisms for MPH and ATX in motor cortex Possible attenuation in prepotency of inhibited GO responses Cannot rule-out practice and other non-specific factors MPH and ATX had divergent therapeutic actions on taskpositive and task-negative brain regions Divergent effects on inferior frontal activation indicate therapeutic actions not solely attributable to promiscuous NET

37 Conclusions Atomoxetine drives mental effort Enhances inferior frontal inhibitory mechanisms Enhances cognitive control mechanisms in anterior cingulate cortex Homeostatic gains in posterior cingulate activation Amelioration of oft-reported prefrontal hypoactivation Methylphenidate increases neural efficiency Posterior cingulate deactivation reduces distracting mental processes Reduces need for inferior frontal inhibitory effort Reduces need for anterior cingulate control effort Amelioration of poster cingulate hyperactivation

38 Acknowledgements Collaborators: Mount Sinai Clinical Translational ADHD Program Kurt Schulz, PhD Jin Fan, PhD Suzanne Clerkin, PhD Jeffrey Halperin, PhD Anne-Claude Bédard, PhD Iliyan Ivanov, MD Special Thanks to: Beth Krone, PhD Hanna Oltarzewska Robyn Palmero, PhD