9/13/2018. Neurobiological Aspects of Attention Deficit Hyperactivity Disorder (ADHD) DSM-5 Diagnostic Criteria

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1 DSM-5 Diagnostic Criteria Neurobiological Aspects of Attention Deficit Hyperactivity Disorder (ADHD) Neil P. Jones 7th Annual Conference on ADHD and Executive Function September 14, 218 Diagnosis Child (<17 yrs. old): 6 in either inattention of hyperactivity/impulsivity domains, or both. Adult ( 17 yrs. old): 5 in either domain. 3 Presentations Inattentive Hyperactive Inattentive & Hyperactive Road Map Clinical Overview Neural Circuits Underlying ADHD Basic Neuroanatomy Structural MRI: ADHD as a function of delayed neural maturation Functional MRI: Inhibitory Control, Sustained Attention, & Reward Processing Impact of stimulant medication on neural function in ADHD Conclusions ADHD is associated with significant impairment across the lifespan. Academic Impairment Social Functioning Addiction Poor Economic Outcomes Incarceration Clinical Features of ADHD Worldwide prevalence % Age of onset by 17 years Characterized by age-inappropriate inattention, hyperactivity, and impulsivity. Diagnosed more in males than females (2-4:1) 5% of cases persist into adulthood Emotion dysregulation is an associated clinical feature Emotion Dysregulation Aggressive behavior Emotional lability Poor frustration tolerance Excessive excitability Estimated Prevalence in ADHD 25-45% of Children 3-7% of Adults Associated with worse occupational and social outcomes above and beyond inattention and hyperactive and impulsive symptoms. 1

Terminology & Basic Neuroanatomy Basial Ganglia Subthalamic Nucleus (STN) vmpfc =

perigenual Anterior Cingulate adacc = anterior dorsal Anterior Cingulate pdacc = posterior

Nucleus Accumbens Lateral (Ventral Striatum) Substantia Nigra Medial Striatum =,,

Brain Regions Active During Attention M1a: Default Mode Network Spontaneous thought M1b:

Fields Inferior Parietal Lobe Inferior Frontal Junction S1: Intrinsic Processing M1c:

Attention Network Somatasensory Auditory Precuneus Angular gyrus S2: External Processing

, 211 An automated meta-analysis of 168 studies (term=attention network) from Neurosynth.

2 Terminology & Basic Neuroanatomy Basial Ganglia Subthalamic Nucleus (STN) vmpfc = Ventromedial Prefrontal mpfc = Medial Prefrontal dmpfc = Dorsomedial Prefrontal pgacc = perigenual Anterior Cingulate adacc = anterior dorsal Anterior Cingulate pdacc = posterior dorsal Anterior Cingulate SMA/preSMA = Supplementary Motor presma = Presupplementary Motor Nucleus Accumbens Lateral (Ventral Striatum) Substantia Nigra Medial Striatum =,, Accumbens Intrinsic brain networks identified in the resting brain. Brain Regions Active During Attention M1a: Default Mode Network Spontaneous thought M1b: Fronto-Parietal Network Inner maintenance and manipulation of information Frontal Eye Fields Inferior Parietal Lobe Inferior Frontal Junction S1: Intrinsic Processing M1c: Salience Network Detection of salient events Switching between other networks M2a: Dorsal Attention Network Somatasensory Auditory Precuneus Angular gyrus S2: External Processing M2b: Visual Network Doucet et al., 211 An automated meta-analysis of 168 studies (term=attention network) from Neurosynth.org Brain Regions Active During Sustained Attention Insula SMA/dACC MPFC Precuneus Brain regions and functional networks of critical interest in ADHD DLPFC IFJ Frontal Eye Fields IPL Fortenbau et al., 217 2

Brain Regions Active During Inhibition Brain Regions Active During Emotion

Amygdala sgacc dacc Lateral An automated meta-analysis of 61 (term= Inhibition)

org An automated meta-analysis of 137 (term=emotion) studies from Neurosynth.

Scanning Environment Primary motor cortex (M1) Inferior Frontal Presupplementary

Nucleus Thalamus Brain Regions Active During Reward Processing dacc vmpfc/ofc

3 Brain Regions Active During Inhibition Brain Regions Active During Emotion Processing Inferior Frontal /Anterior Insula dmpfc Dorsolateral PFC Amygdala pgacc Amygdala sgacc dacc Lateral An automated meta-analysis of 61 (term= Inhibition) Studies from Neurosynth.org An automated meta-analysis of 137 (term=emotion) studies from Neurosynth.org Neural Network Underlying Inhibitory Control Reactive Selective Stop The Scanning Environment Primary motor cortex (M1) Inferior Frontal Presupplementary Motor Dorsolateral Prefrontal pars externa (GPe) pars interna (GPi) Subthalamic Nucleus Thalamus Brain Regions Active During Reward Processing dacc vmpfc/ofc Review of Structural MRI Studies of ADHD Striatum Ventral Tegmental Area Substantial Nigra An automated meta-analysis of 922 (term=reward) Studies from Neurosynth.org 3

What are we measuring with structural MRI? We can measure volume, thickness, and surface area.

corrected for age, sex, intracranial volume and site.

for subcortical volumes corrected for age, sex, intracranial volume and site (continued).

, 217; Scientific Reports, 7, Article number: 5547 Age bins (years) Age bins (years) Age bins (years) Age

Meta- and mega-analysis of cortical volume ENIGMA study 23 Sites: 1713 ADHD vs.

4 What are we measuring with structural MRI? We can measure volume, thickness, and surface area. Volume = surface area * thickness Pial Surface White Surface Moving averages for subcortical volumes corrected for age, sex, intracranial volume and site. Hippocampus Amygdala 2mm 3mm Age bins (years) Key subcortical brain structures of interest Moving averages for subcortical volumes corrected for age, sex, intracranial volume and site (continued). Accumbens Amygdala Brain Stem Thalamus Pallidum Hippocampus Nucleus Accumbens Shen et al., 217; Scientific Reports, 7, Article number: 5547 Age bins (years) Age bins (years) Age bins (years) Age bins (years) ADHD is associated with reduced volume in the amygdala, hippocampus, and striatum in childhood. Meta- and mega-analysis of cortical volume ENIGMA study 23 Sites: 1713 ADHD vs. 15 Controls Median Age: 14 years Range: 4-63 years Measures: Intracranial volume Average bilateral volumes of the hippocampus, amygdala, thalamus, caudate, accumbens, putamen, pallidum Cortical Development in the context of ADHD Hoogman et la., 217 4

Prospective study of cortical thickness development in ADHD. Sampling of cortical thickness across 4 time points spaced on average 2.

each scan ADHD Typically Developing Time Age SD Age SD 1 1.2 (-3.2) 1.6 (-3.5) 2 12.8 (-3.6) 13.3 (-4) 3 15.3 (-3.7) 14.8 (-3.6) 4 17.9 (-3.

3) ADHD significantly lag in the time it takes for the all cortical points to reach peak thickness, especially true in the prefrontal

8 years Middle Prefrontal : 5 year delay Superior & Medial Prefrontal: 2 year delay (Shaw et al., 27) (Shaw et al.

Prospective study of cortical thickness and ADHD persistence into adulthood.

5 Prospective study of cortical thickness development in ADHD. Sampling of cortical thickness across 4 time points spaced on average 2.9 years apart (SD=1.5yrs). Sample: 223 Children with ADHD (92 Combined Presentation; 13 Inattentive, 5 Hyperactive). 223 typically developing controls No. of subjects at each wave of scan acquisition # of Subjects Time ADHD Typically Developing Mean age at each scan ADHD Typically Developing Time Age SD Age SD (-3.2) 1.6 (-3.5) (-3.6) 13.3 (-4) (-3.7) 14.8 (-3.6) (-3.6) 16.1 (-3.3) ADHD significantly lag in the time it takes for the all cortical points to reach peak thickness, especially true in the prefrontal cortex. 5% all cortical regions reaching peak thickness: ADHD=1.5 years; TDCs = 7.8 years Middle Prefrontal : 5 year delay Superior & Medial Prefrontal: 2 year delay (Shaw et al., 27) (Shaw et al., 27) ADHD is associated with early cortical maturation in the motor cortex. Prospective study of cortical thickness and ADHD persistence into adulthood. ADHD Sample 92 ADHD with childhood and adult assessments Childhood: M(SD) age = 1.7(3.3) years Adulthood: M(SD) age = 23.8(4.3) years Healthy Controls 184 Typically Developing Controls 5% of regions within the primary motor cortex reach peak thickness in ADHD=7 years and TDCs = 7.4 years (Shaw et al., 27) ADHD is associated with slower maturation of cortical thickness. Greater inattention symptoms in adulthood associated with faster rate of cortical thinning in the sustained attention network SMA/dACC 4% Persistence of ADHD into Adulthood Precuneus R. IPL R. DLPFC L. Postcentral gyrus (Shaw et al., 27) 5

6 Persistent ADHD associated with faster rate of cortical thinning relative to TDC. Remitters showed cortical thickening and converge with adults. Functional neuroimaging studies of ADHD have predominately examined cognitive and motivational functioning. 1. Cognitive Sustained Attention Inhibitory Control 2. Motivation Reward Processing 3. Cognitive x Motivation Interactions Reward x Inhibitory Control Interactions Summary of structural findings in ADHD ADHD is a marked by delayed maturation of the striatum, amygdala, and hippocampus in childhood that normalizes in by adolescents. Implications for reward processing, motor control, emotion processing, and memory ADHD is marked by advanced development in the motor cortex. Implications for hyperactivity ADHD is marked by a 2-5 year delay in prefrontal cortical development. Implications of inattention, inhibition, emotion regulation, impulsivity. Persistence of ADHD inattention symptoms into adulthood is associated with faster rate of cortical thinning. Sustained Attention in ADHD fmri paradigms assessing sustained attention. Review of Functional MRI Studies in ADHD 6

Brain Regions Active During Sustain Attention fmri Paradigms assessing Inhibitory control Insula SMA/dACC Stop Signal Task Go/NoGo Task MPFC Precuneus DLPFC IFJ Frontal Eye Fields IPL Fortenbau et al.

Meta-Analysis of Studies Examining Functional Activation Associated with Inhibitory Control and Sustained Attention Attention: 13 Studies; 171 patients with ADHD; 178 Controls Age: 2 Studies in

7 Brain Regions Active During Sustain Attention fmri Paradigms assessing Inhibitory control Insula SMA/dACC Stop Signal Task Go/NoGo Task MPFC Precuneus DLPFC IFJ Frontal Eye Fields IPL Fortenbau et al., 217 Meta-analyses indicate that ADHD is associated with decreased activation in frontoparietal network supporting sustained attention. Meta-Analysis of Studies Examining Functional Activation Associated with Inhibitory Control and Sustained Attention Attention: 13 Studies; 171 patients with ADHD; 178 Controls Age: 2 Studies in Adults > 18; 1 Studies in Adolescents Brain Regions Active During Inhibition Inferior Frontal /Anterior Insula Red = Healthy Controls > Patients Blue = Patients > Healthy Controls Dorsolateral PFC dacc Lateral Hart et al., 213; JAMA Psychiatry An automated meta-analysis of 61 (term= Inhibition) Studies from Neurosynth.org Meta analyses indicate that ADHD is associated with decreased inferior frontal cortex, supplementary motor area, and, basal ganglia (putamen & caudate) activation. Meta-Analysis of Studies Examining Functional Activation Associated with Inhibitory Control and Sustained Attention Inhibition: 21 Studies; 287 patients with ADHD; 32 Controls Age: 7 Studies in Adults > 18; 14 Studies in Adolescents Inhibitory Control in ADHD Red: Healthy Controls > Patients Hart et al., 213; JAMA Psychiatry 7

Decrease right inferior frontal cortex activation is associated with persistence of ADHD symptoms into adulthood, whereas abnormal caudate functioning likely reflects a scar from childhood.

8 Decrease right inferior frontal cortex activation is associated with persistence of ADHD symptoms into adulthood, whereas abnormal caudate functioning likely reflects a scar from childhood. Approximate M(SD) age = 24.3(4) Left Inferior Frontal Successful Inhibition: Childhood ADHD < Never Affected Cohen s d=.37* Inhibition failure: Childhood ADHD > Never Affected Cohen s d= -.36* Reward Processing in ADHD Right Inferior Frontal r= -.33, p=.9 Szekely, et al., 217 Neural Network Underlying Inhibitory Control Reactive Selective Stop Primary motor Inferior Frontal Presupplementary cortex (M1) Motor fmri paradigms assessing reward processing Monetary Incentive Delay Task Dorsolateral Prefrontal pars externa (GPe) pars interna (GPi) Subthalamic Nucleus Thalamus Black = Impaired in ADHD Limitations Early studies based on small sample sizes (Mean N = 17 per group). Studies included in meta-analysis of sustained attention were almost exclusively conducted in males. Limited number of adult studies examining sustained attention in ADHD preventing examination of age as a moderator of effects sizes across identified brain regions. Brain Regions Active During Reward Processing dacc vmpfc/ofc Striatum Ventral Tegmental Area Substantial Nigra An automated meta-analysis of 922 (term=reward) Studies from Neurosynth.org 8

ADHD is associated with hypoactivation in the ventral striatum when anticipating reward.

as reliable as research demonstrating hyperactivation during reward receipt. *** AGE(SD) 14.3(1.6) 32.4(8.1) 23.3(5.

, 214 Results from large study of reward processing in adolescents with ADHD indicates hyperactivation to the receipt

) 92 Unaffected siblings M(SD) Age = 18.5(3.8) 18 control participants M(SD) Age = 17.2(3.

Parameter Estimate Anticipation Receipt Von Rhein, et al.

9 ADHD is associated with hypoactivation in the ventral striatum when anticipating reward. Reward Study Limitations Anticipation of reward is based predominately on studies with small sizes results may not be as reliable as research demonstrating hyperactivation during reward receipt. *** AGE(SD) 14.3(1.6) 32.4(8.1) 23.3(5.2) 38.3(11.3) 27.3(3.8) 33.6(1.3) 15.5(2.2) 33.1(1.7) Plitcha et al., 214 Results from large study of reward processing in adolescents with ADHD indicates hyperactivation to the receipt of reward in the nucleus accumbens and orbital frontal cortex. 15 ADHD; M(SD) Age = 17.3(3.) 92 Unaffected siblings M(SD) Age = 18.5(3.8) 18 control participants M(SD) Age = 17.2(3.) Scanned off of medications (48 hrs) Monetary Incentive Delay Task Emotion Processing in ADHD Nucleus Accumbens Parameter Estimate Anticipation Receipt Von Rhein, et al., 215 Small study seems to corroborate decreased response to reward anticipation and increased response to reward receipt in the striatum in ADHD. 14 ADHD vs 15 Controls M(SD) age = 23(1.4) The current status of the neurobiological underpinning of emotion processing alterations in in ADHD. Inconsistent Results! Furukawa, et al., 214 9

Inhibitory Control Deficits Over the Immediate Impulse for Reward in Adults with a History of Attention Deficit Hyperactivity Disorder Sample.

Integration of Reward processing & Inhibitory Control Childhood ADHD was diagnosed in childhood with research quality assessments (e.g., semi-structured clinical interviews, standardized rating scales).

9 Neural Network Underlying Inhibitory Control Reactive Selective Stop Proactive Selective Stop Primary motor Inferior Frontal Presupplementary Primary motor Inferior Frontal Presupplementary cortex

10 Inhibitory Control Deficits Over the Immediate Impulse for Reward in Adults with a History of Attention Deficit Hyperactivity Disorder Sample. 17 proband and 32 nonadhd HC adults from the Pittsburgh ADHD Longitudinal Study 8 (n=139, age 27-43). Integration of Reward processing & Inhibitory Control Childhood ADHD was diagnosed in childhood with research quality assessments (e.g., semi-structured clinical interviews, standardized rating scales). Adult ADHD symptoms were based on self- and informant-report (parents, 91%) with the BAARS-IV. 9 Neural Network Underlying Inhibitory Control Reactive Selective Stop Proactive Selective Stop Primary motor Inferior Frontal Presupplementary Primary motor Inferior Frontal Presupplementary cortex (M1) Motor cortex (M1) Motor Dorsolateral Dorsolateral Prefrontal Prefrontal pars externa (GPe) pars externa (GPe) Objectives 1. To determine whether adults with an ADHD history (probands) vs. healthy controls (HCs) demonstrate altered behavioral and neural functioning when inhibiting a prepotent response to an immediate reward, in order to obtain a larger delayed reward. 2. To determine, among probands, whether ADHD symptom severity in adulthood is associated with increased deficits in behavioral and neural functioning when inhibiting the prepotent response to immediate reward, in order to obtain a larger delayed reward. pars interna (GPi) Subthalamic Nucleus pars interna (GPi) Subthalamic Nucleus Thalamus Thalamus Adolescents diagnosed with ADHD are hyper-responsive to reward in the VS, stronger VS-Motor connectivity than TDY. 33 TDC, 23 ADHD ~M(SD) age = 15.3(1.6) Functional Connectivity VS Seed Motor The Monetary Incentive (MI) Go/NoGo task. 1

11 2A. 2C. MI Go/NoGo Task Results Inhibition Accuracy (% Correct) ROI Activation d=.8 Condition Effect d=.1 HCs & Probands d=.29* DLPFC S1/M1 Thal OP1 Regions of Interest Reward-NoGo d=.24* d=.27* Neutral-NoGo 2B. Left Y = -23 All NoGo > Go S1/M1 OP1 DLPFC Thal Z score X = -42 Cluster forming threshold p=1x1-6, extent=1 voxel Within probands, recruitment of the primary motor cortex mediated the effects of inattention on inhibition accuracy under conditions of reward. -.35* Inattention S1/M1 C=-.35* C =-.29* Indirect Effect = -.42, SE=.29, 95% CI: * Inhibition Accuracy Probands demonstrated worse inhibition accuracy relative to HCs. No differences in brain activation in key regions were observed. Conclusions Inhibition Accuracy (% Correct) HCs Reward-NoGo Group Effect d=.46* Probands Neutral-NoGo ROI Activation All NoGo vs. Go d=.14 d=-.9 d=.26 d=-.6 DLPFC S1/M1 Thal OP1 Regions of Interest Healthy Controls Probands Probands experiencing greater ADHD symptoms have difficulty engaging neural circuitry supporting proactive inhibitory control needed to facilitate goal attainment. Within probands, ADHD symptoms were associated with decreased inhibition accuracy and decreased activation within proactive inhibitory control regions. Inhibition Accuracy (% Correct) = -.29, SE=.7, p< Inattention S1/M1 NoGo beta estimates OP1 NoGo beta estimates Reward: = -.35, SE=.14, p=.12 Neutral: =.3, SE=.14, p= Inattention Reward: = -.32, SE=.9, p<.1 Neutral: =.7, SE=.9, p= Inattention Thalamus NoGo beta estimates DLPFC NoGo beta estimates Reward: = -.25, SE=.9, p=.8 Neutral: =.2, SE=.9, p= Inattention Reward: = -.17, SE=.1, p=.87 Neutral: =.11, SE=.1, p= Inattention Impact of stimulant medication on neural function in ADHD Neutral-NoGo Neutral-NoGo Reward-NoGo Reward-NoGo 11

Red: Healthy Controls > Patients Hart et al., 213; JAMA Psychiatry racc SMA Blue = Stimulant < Placebo Red = Stimulant > Placebo Right Inferior frontal cortex Insula Rubia et al.

12 The effects of stimulants on brain function in ADHD. Acknowledgements Meta-Analysis of Studies Examining the effects of Stimulants on Inhibitory control 14 Studies 212 children/adolescents with ADHD Tasks: Measuring predominately inhibitory control Red: Healthy Controls > Patients Hart et al., 213; JAMA Psychiatry racc SMA Blue = Stimulant < Placebo Red = Stimulant > Placebo Right Inferior frontal cortex Insula Rubia et al., 214; Biological Psychiatry p<.5 p<.5 Co-Authors/Collaborators Brook Molina, PhD Cecile Ladouceur, PhD Amelia Versace, PhD Rachel Lindstrom, PhD Tracey K. Wilson, BA Elizabeth M. Gnagy, BS William Pelham, Jr., PHD Funding National Institute of Mental Health R1MH1196 (PIs: Molina & Ladouceur) Summary Stimulants appear to normalize deficits associated with reactive inhibitory control. What do we know about the neurobiology of ADHD? Delayed maturation of both subcortical and cortical regions critical for inhibitory control, sustained attention, emotion processing. ADHD persistence into adulthood is marked by decreased cortical thickness and alterations in right inferior frontal cortex (IFC) activation in the context of inhibitory control. Stimulant mediation improves right IFC activation increasing the ability to engage in inhibitory control. Evidence of altered reward processing, hypoactivation when anticipating reward and exaggerated responses to the receipt of reward in the ventral striatum. Alterations in control of motor functioning in the context of proactive inhibitory control. 12

Supplementary Material S3 Further Seed Regions

Supplementary Material S3 Further Seed Regions Figure I. Changes in connectivity with the right anterior insular cortex. (A) wake > mild sedation, showing a reduction in connectivity between the anterior