Diagnosis and Treatment of Attention Deficit ... - McLean Hospital

ADHD - OpinionDoesn’texist!Almosteveryonefindsthemselveshere.Drugcompany&APAconspiracy

ADHDYes, it exits!But no, you don’t have it!

DisclaimerDuring the course of this talk I will be discussing patentedtechnologies - the McLean Motion and Attention Test (M-MAT), and certain imaging methods that I invented, orco-invented. These technologies have been licensed toBioBehavioral Diagnostics, Inc. by McLean Hospital,which owns the patents. I have no equity or position inthis company, and receive no consulting fees. I do havethe potential to receive royalties, in keeping with conflict ofinterest policies established by Harvard Medical Schooland Partners Health Care.

Attention-Deficit/Hyperactivity DisorderADHD is recognized world-wide as one of themost common neuropsychiatric disorders ofchildhood. It has been estimated to affectbetween 2% and 9% of school-age children --with most recent studies indicating a prevalence ofapproximately 6%.ADHD accounts for 30% - 50% of child referralsto mental health services.

Assessment

AssessmentHow ADHD is assessed in clinical practice (DMS-IV criteria).What’s wrong with how it is assessed.How might assessment be improved (M-MAT).

InattentionImpulsivityHyperactivity

Diagnostic Criteria - DSM IVA. Either (1) or (2):(1) Six (or more) of the following symptoms of inattentionhave persisted for at least 6 months to a degree that ismaladaptive and inconsistent with developmental level(2) Six (or more) of the following symptoms of hyperactivity -impulsivity have persisted for at least 6 months to a degree thatis maladaptive and inconsistent with developmental level:

Diagnostic Criteria - DSM IVInattention - 6 or more1. Often fails to attend to details2. Often has difficulty sustaining attention3. Often does not seem to listen4. Often fails to finish tasks5. Often has difficulty organizing tasks6. Often avoids sustained mental effort7. Often looses things necessary for tasks8. Is often distracted by extraneous stimuli9. Is often forgetful

Diagnostic Criteria - DSM IVHyperactivity & Impulsivity - 6 or more1. Often fidgets with hands or feet2. Leaves seat in classroom when expected to stay seated3. Often runs about or climbs excessively4. Often has difficulty playing quietly5. Often “on the go” or “driven by a motor”6. Often talks excessively7. Often blurts out answers8. Often has difficulty awaiting turn9. Often interrupts or intrudes

Diagnostic Criteria - DSM IVB. Some hyperactive-impulsive orinattentive symptoms that causedimpairment were present before age 7.C. Some impairment from thesymptoms is present in two or moresettings (e.g., at school and at home).

Diagnostic Criteria - DSM IVD. There must be clear evidence of clinicallysignif icant impairment in social, academic, oroccupational functioning.E. The symptoms do not occur exclusivelyduring the course of a Pervasive DevelopmentalDisorder, Schizophrenia or other Psychoticdisorder, and are not better accounted for byanother mental disorder (e.g., Mood Disorder,Anxiety Disorder, Dissociative Disorder, or aPersonality Disorder).

CriticismsCriteria are entirely behavioralA patient is diagnosed with ADHD if he/shebehaves in a manner in which we expect someonewith ADHD to behave.Some children with ADHD (particularly girls)may not behave enough like the typical ADHDchild to meet diagnostic criteria.

CriticismsCriteria are entirely behavioralSome children who really do not have ADHDmay behave in a manner similar enough to meetdiagnostic criteria (e.g., conduct disorder, bipolar,PTSD, learning disorder, medication side-effect,etc.)

CriticismsCriteria are entirely behavioralNeed to distinguish between children who fail tosit still and pay attention because they lack theability, and those who behave in that manner buthave the ability.

CriticismsCriteria are committee-based and arbitraryCriteria are some what arbitrary, and changeevery several years as the diagnostic criteria arerevised.With each revision the disorder becomes moreprevalent, as criteria becomes less restrictive.

ICD-10 Criteria • Hyperkinetic DisorderICD-10 Inattention (6 or more) + Impulsivity (1 or more) + Hyperactivity (3 or more)DSM-IV Inattention (6 or more) or Hyperactivity-impulsivity (6 or more)1. Fails to attend to details 1. Blurts out answers2. Has difficulty sustaining attention 2. Difficulty awaiting turn3. Does not seem to listen 3. Interrupts or intrudes4. Fails to finish 4. Talks excessively (ICD-10) 4. Talks excessively (DSMIV)5. Has difficulty organizing tasks 5. Fidgets with hands or feet6. Avoids sustained effort 6. Leaves seat in classroom7. Looses things 7. Runs about or climbs8. Is distrated by extraneous stimuli 8. Difficulty playing quitely9. Is forgetful 9. Motor excess ('on the go')

CriticismsThe disorder is misnamed“…the evidence…is that there is no attentiondeficit in this disorder. If what you mean byattention is the following: the ability to perceive,detect, filter and process information”. Barkley

CriticismsThe disorder is misnamed“All the evidence is on the output side of thebrain, the way behavior is being organized,inhibited, planned, executed and protected fromdisruption”. BarkleyDSM-IV committee was going to rename thedisorder ‘Behavioral Inhibition Disorder’.

CriticismsCriteria are not age-adjustedDSM-IV criteria validated in children from 4 - 16years of age.Symptoms (and number of required items) notappropriate for adults (or younger children).

CriticismsCriteria are not gender specificDSM-IV criteria validated mostly in boys (subject pool84% male).DSM-IV requires girls to meet the same requirement forDx as boys.Does not account for the fact that baseline for normalgirls is quite different than the baseline for normal boys.

CriticismsPredominantly Inattentive Subtype is anUnrelated DisorderOpposite symptoms -- instead of beinghyperactive, intrusive, distractible, they’relethargic, slow-moving, hypoactive, spacey,daydreamy, passive, withdrawn, and in a fog.

CriticismsPredominantly Inattentive Subtype is anUnrelated DisorderUnlike Combined or Hyperactive-ImpulsiveSubtype the Inattentive subtype has an“input problem” - difficulty with selectiveattention and speed of processing incominginformation plus they have memoryproblems.

CriticismsPredominantly Inattentive Subtype is anUnrelated DisorderCombined and Hyperactive-Impulsivesubtypes are closely associated withOppositional Defiant Disorder and ConductDisorder. This is not true for children withthe Inattentive subtype. This subtype doesnot fit amongst the ‘disruptive disorders’.

CriticismsPredominantly Inattentive Subtype is anUnrelated DisorderOnly about 20% of the Inattentive subtypeshow good clinical response to stimulants(low doses). 90% of Combined orHyperactive-Impulsive children respondwell to stimulants (moderate to high doses).

CriticismsPredominantly Inattentive Subtype is anUnrelated DisorderOften this is a wastebasket category - somehave this subtype others have depression,anxiety disorders, undiagnosed learningdisorders, substance abuse disorders,borderline IQ.

CriticismsPredominantly Inattentive Subtype is anUnrelated DisorderGirls with ADHD are not usually (contrary to whatyou hear or read) ‘Predominantly Inattentive’.Objective measures show that they are as hyperactiveas boys with ADHD. Teachers rate them as muchmore hyperactive-impulsive than normal girls, but nomore hyperactive-impulsive than normal boys.

Validity of DSM-IV CriteriaThis was assessed by having a panel of ADHD expertsindependently ascertain in their best opinion whether aset of children did or did not have ADHD. They hadaccess to highly detailed transcribed clinicalinformation on each child. They were not required touse any specific criteria for ADHD, but to diagnoseeach child based on their best conceptualization of thedisorder. DSM-IV criteria were then applied to theexact same data set.Concordance was 0.59 (for combined, hyperactive -impulsive subtypes) and 0.47 (inattentive subtype).

Validity of DSM-IV CriteriaDSM-IV was designed to provide a convenient andreliable (i.e., consistent) basis for diagnosis. We knowrelatively little about the validity of these criteria as atrue psychiatric or neurobiological taxonomy.Costellanos and Tannock (2002) have appropriatelysummarized the situation stating that “… ADHD hasbeen reified “as an ontological and psychologicalreality, rather than just a useful clinical construct...”

RecommendationReconceptualize ADHD as a functionaldisability.In children, it would be a diminished orimpaired ability to inhibit motor activity andimpulsive behaviors, and to persist in theperformance of tasks that require selfmotivationand self-regulation.

GOAL: MMATTo develop a rapid and reliablemedical test that can aidclinicians so they can moreaccurately diagnose patientswith ADHD, and can betterevaluate whether selectedtreatments are helpful.

Value of Objective MeasuresYou could assess myopia in children with teacher andparent ratings - do they squint? How close do they sitto the TV?But that would depend on where they sit in class, thesize of the teacher’s writing, or the size of your TVscreen. There is enormous value in standardizedquantitative assessment.

Variability in ADHD Symptoms

MMAT - DevelopmentSigns and symptoms that most accurately distinguishADHD from other disorders (DSM-IIIR, APA, 1987).Often fidgets with hands or feet or squirmsin seatHas difficulty remaining seated whenrequired to do soIs easily distracted by extraneous stimuli

StrategyProvide an office-based assessment instrument for the objectivemeasures of hyperactivity, impulsivity and inattention.HyperactivityThis is a bit of a misnomer. Children with ADHD are no moreactive than normal children during recess. The “hyperactivity”of the ADHD child is an impaired ability to inhibit activity tolow levels (i.e.,to sit still).•Use a high-resolution motion analysis system to capturetheir fidgetiness during a monotonous attention task.

ImpulsivenessImpulsivity in ADHD is a consequence of an impaired ability toinhibit behavioral responses (acting before thinking).•Assess this parameter using an attentional task thatelicits rapid responses.InattentionChildren with ADHD receive and process information normally.Their problem with “attention” stems from distractability(inability to inhibit attending to irrelevant stimuli) andsusceptibility to boredom.•Assess their degree of distraction by using a monotonoustask that provides no feedback or reward.

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Ecological Validity

School Study I n=698Connors Teacher Ratings20151050BoysHyperactiveNot Hyperp < 10 -8 p < 10 -5Girls

ADHD - GirlsGirls with ADHD have activity disturbances on M-MAT that are very similar to those in boys. They moveas often, but cover a slightly smaller area.Humans rating hyperactivity are markedlyinfluenced by the nature of the behaviors observed. Weoverrate aggressive behaviors, underrate sociallyacceptable behaviors.

Adult (M) - Normal ControlAdult (M) - ADHD

Adult (F) - Normal ControlAdult (F) - ADHD

Improved Attention TestIn our original research we used a TOVA-based attentiontest. The TOVA was designed to be useful with dyslexicchildren, and it uses solid squares at either the the inner top orinner bottom of a central rectangle (Square Test) instead ofletters. All previous CPTs had used letters presented at thecenter of the screen.

Improved Attention Test

Improved Attention TestWe created a new CPT using randomly positioned 8 pointed and5 pointed stars as targets / non-targets. This was done to preventcheating, but there was an important additional benefit.Humans have two visual attention systems:1) Highly focused foveal system for detaileddiscrimination. Largely left frontal, dopamine mediated, andslow.2) Global awareness of environment, peripheral fields,sensitive to motion. Largely right parietal, norepinephrinemediated and fast.

Improved Attention TestWe believe that the attention task we createdactivates both attentional systems while previousCPTs only engaged the high definition fovealsystem.

Improved Attention TestTargetNon-TargetTargetNon-Target

Improved Attention TestResults in children with ADHD.On the TOVA children with ADHD tend torespond more slowly than healthy controls, whichmakes little sense given their proclivity to respondimpulsively.On the STAR-CPT children with ADHD oftenrespond more rapidly (but with less accuracy) thanhealthy controls.

MMAT: Fluctuations in AttentionComputerized attention tasks have been used aslaboratory tests to provide composite measures ofattention. However, attention is not a staticparameter, but a dynamic and fluctuant process.Throughout the course of a 15 minute test therecan be many shifts in attention and mental state.

MMAT: Fluctuations in AttentionBetter insight into the nature of theattention disturbance in ADHD, andunderstanding of the effects of drugs on thedisorder may arise from the assessment ofattention as a dynamic temporal process.

MMAT: Fluctuations in Attention

MMAT: Fluctuations in AttentionTable I. Differences between children with ADHD and healthy controls (NL) on CPT measures.MEASURES ADHD (60) NL (8) F(1,66) = p < EFFECT SIZEStandard CPT ParametersErrors of Commision 27.9 ± 19.5 11.6 ± 7.9 5.38 0.03 0.89Errors of Omission 13.1 ± 14.7 1.2 ± 1.3 5.20 0.03 0.87Latency 537 ± 77 619 ± 88 7.68 0.007 1.06Variability (S.D.) 179 ± 58 134 ± 27 4.82 0.03 0.84Signal Detection TheorySensitivity (d') 1.77 ± 1.63 4.02 ± 1.32 13.97 0.0004 1.43Response bias (β) 0.64 ± 0.39 0.16 ± 0.15 11.96 0.001 1.32Attention Shift AnalysisAttention Shifts (#) 12.8 ± 4.3 5.4 ± 5.7 19.22 0.00004 1.67Time on Task (%) 42.6 ± 30.3 82.4 ± 20.4 12.95 0.0006 1.37% Time Impulsive 32.7±18.8 14.8±18.5 6.45 0.02 0.97% Time Distracted 11.0±13.1 1.9±2.8 3.89 0.06 0.75% Time Random 13.6±21.7 0.9±1.7 2.72 0.10 0.63

MMAT: Fluctuations in AttentionOn average, unmedicated children withADHD had 12.8 attention shifts compared toonly 5.4 shifts in controls.Children with ADHD were “On-Task”during only 42.6% of the 30 second epochs vs.an 82.4% “On-Task” rate for normal controls .

MMAT: Fluctuations in AttentionTable 2. Effects of probe-dose methylphenidate (MPH) on CPT performance.MEASURES Baseline MPH F(1,59) p < EFFECT SIZEStandard CPT ParametersErrors of Commision 27.9 ± 19.5 13.6 ± 15.9 53.70 8.00E-10 1.91Errors of Omission 13.1 ± 14.7 5.0 ± 14.9 18.20 0.00007 1.11Latency 537 ± 77 500 ± 69 24.10 8.00E-06 1.28Variability (S.D.) 179 ± 58 123± 50 64.80 5.00E-11 2.10Signal Detection TheorySensitivity (d') 1.77 ± 1.63 3.72 ± 2.00 72.92 7.00E-12 2.22Response bias (β) 0.64 ± 0.39 0.28 ± 0.30 62.38 8.00E-11 2.06Attention Shift AnalysisAttention Shifts (#) 12.8 ± 4.3 7.0 ± 5.5 67.70 2.00E-11 2.14Time on Task (%) 42.6 ± 30.3 75.4 ± 26.3 88.50 2.00E-13 2.45% Time Impulsive 32.7±18.8 18.1±17.2 29.48 1.00E-06 1.41% Time Distracted 11.0±13.1 2.3±4.0 31.78 5.00E-07 1.47% Time Random 13.6±21.7 4.2±14.6 15.52 2.00E-04 1.03

MMAT: Fluctuations in AttentionOn average, unmedicated children withADHD had 12.8 attention shifts compared toonly 5.4 shifts in controls (F1,66 = 19.2, p < 0.0001).Following treatment attention shifted only7.0 times per test (F1,59 = 67.7, p < 10 -10 ), a ratenot significantly different than normal (p > 0.4).

.15DA. Pre-Methylphenidate.11.35.32I.14.44.42.34A.45.04.15.16 .12R.08.25.44

MMAT: Fluctuations in AttentionChildren with ADHD were “On-Task”during only 42.6% of the 30 second epochs vs.an 82.4% “On-Task” rate for normal controls(F1,66 = 12.9, p < 0.001).Following MPH “On-Task” rate increasedto 75.4% (p< 10 -11 ).

Treatment

Effects of MethylphenidatePlacebo0.2 mg/kg bid0.4 mg/kg bid0.75 mg/kg bid

Attention Testing (v1)Accuracy Omission Commission(%) (%) (%)ADHD 79.4 ± 14.5 8.7 ± 8.9 32.8 ± 23.3Normal 89.4 ± 8.8 3.2 ± 6.1 18.3 ± 13.5Difference -11% 170% 80%Group p 0.061 0.057 0.099Age p NS 0.075 NSLatency S.D.(msec) (msec) C.V.ADHD 507 ± 200 316 ± 182 0.59 ± 0.17Normal 389 ± 138 162 ± 65 0.44 ± 0.21Difference 30% 95% 34%Group p 0.007 0.003 0.066Age p 0.00004 0.006 NS

Objective AssessmentA simple composite of activity and attentionmeasures discriminated 11/11 normal controls from16/18 children with ADHD.Of the 2 children with ADHD not identified, 1met ADHD criteria by DSM-IV but not DSM-IIIR,suggesting that this was a questionable case. Theother child had comorbid diagnosis of bipolardisorder, manic phase. (Virtually all children withbipolar mania meet DSM-IV criteria for ADHD. Isthis comorbidity or syndromic overlap?).

Objective AssessmentM-MAT provides objective information thatdistinguishes children with ADHD from normalcontrols.M-MAT provides objective information thatcorrelates strongly with Teacher Ratings, but is alsosubstantially different (approximately 50% sharedvariance).

ADHD - GirlsAccuracy Omission Commission(%) (%) (%)ADHD M 79.4 8.7 32.8F 90.8 6.1 7.6Normal M 89.4 3.2 18.3F 96.8 0.2 7.2Difference M -11% 172% 79%F -6% 2950% 6%Latency S.D.(msec) (msec) C.V.ADHD M 507 316 0.59F 553 216 0.37Normal M 389 162 0.44F 442 129 0.29Difference M 30% 95% 34%F 25% 67% 28%

ADHD - GirlsImmobility Movements DisplacementDuration (per 5 min) (meters)ADHD M 0.138 3088 5.88F 0.156 3224 6.81Normal M 0.406 1345 1.74F 0.238 1653 2.07Difference M -66% 130% 238%F -34% 95% 229%Area Complexity Temporal(cm2) (spatial scale) ScalingADHD M 160.8 1.173 0.840F 135.9 1.153 0.860Normal M 42.2 1.313 0.582F 35.2 1.274 0.549Difference M 281% -45% 44%F 286% -44% 57%

ADHD - GirlsGirls with ADHD have activity disturbances on M-MAT that are very similar to those in boys. Theymove as often, but cover a slightly smaller area.Girls with ADHD have attentional abnormalitieson M-MAT, characterized mostly by excess variabilityand occasional errors of omission. They do not showthe high rate of commission errors observed in boyswith ADHD.

ICD-10Too Restrictive!DSM-IV ADHDToo Loose!M-MATJust Right!!!

MTA - Multimodal Treatment StudyIn a detailed and elaborate study, the MultimodalTreatment Group evaluated the effects of behavioraltherapy versus medication management. Altogether, 579children with ADHD Combined Type, aged 7 to 9.9 years,were assigned to 14 months of medication managementwith methylphenidate (titration followed by monthly visits);intensive behavioral treatment (parent, school, and childcomponents); the two combined; or standard communitycare.

MTA - Multimodal Treatment StudyChildren in the combined treatment and medicationmanagement groups showed significantly greaterimprovement than those given intensive behavioraltreatment or community care.No significant differences were seen on any measurebetween combined treatment and medicationmanagement. Combined treatment may haveadvantages in more complex cases.

MTA - Multimodal Treatment StudyMedication management was vastly superior tocommunity treatment, even though most childrentreated in the community received medications.% Subjects with virtually no ADHD Sx:MTA - Meds. alone or multimodal: 65%Medicated in the community: 25%

MTA - Multimodal Treatment StudyMTA Titration - Monthly contact with teachers,average 8 visits/14 months. Mean dose 35 mgmethylphenidate.Community - Generally no contact with teachers,average 3 visits/14 months. Mean dose 18 mgmethylphenidate.

LessonsMany children with ADHD are not receivingoptimally-effective care.MTA - titration protocol, requiring monthly teachercontact and visits, will not be implemented by mostclinicians in practice.A better way is needed!

Texas AlgorithmMany children with ADHD are not receivingoptimally-effective care.MTA - titration protocol, requiring monthly teachercontact and visits, will not be implemented by mostclinicians in practice.A better way is needed!

MMAT: Fluctuations in AttentionTable I. Differences between children with ADHD and healthy controls (NL) on CPT measures.MEASURES ADHD (60) NL (8) F(1,66) = p < EFFECT SIZEStandard CPT ParametersErrors of Commision 27.9 ± 19.5 11.6 ± 7.9 5.38 0.03 0.89Errors of Omission 13.1 ± 14.7 1.2 ± 1.3 5.20 0.03 0.87Latency 537 ± 77 619 ± 88 7.68 0.007 1.06Variability (S.D.) 179 ± 58 134 ± 27 4.82 0.03 0.84Signal Detection TheorySensitivity (d') 1.77 ± 1.63 4.02 ± 1.32 13.97 0.0004 1.43Response bias (β) 0.64 ± 0.39 0.16 ± 0.15 11.96 0.001 1.32Attention Shift AnalysisAttention Shifts (#) 12.8 ± 4.3 5.4 ± 5.7 19.22 0.00004 1.67Time on Task (%) 42.6 ± 30.3 82.4 ± 20.4 12.95 0.0006 1.37% Time Impulsive 32.7±18.8 14.8±18.5 6.45 0.02 0.97% Time Distracted 11.0±13.1 1.9±2.8 3.89 0.06 0.75% Time Random 13.6±21.7 0.9±1.7 2.72 0.10 0.63

MMAT: Fluctuations in AttentionTable 2. Effects of probe-dose methylphenidate (MPH) on CPT performance.MEASURES Baseline MPH F(1,59) p < EFFECT SIZEStandard CPT ParametersErrors of Commision 27.9 ± 19.5 13.6 ± 15.9 53.70 8.00E-10 1.91Errors of Omission 13.1 ± 14.7 5.0 ± 14.9 18.20 0.00007 1.11Latency 537 ± 77 500 ± 69 24.10 8.00E-06 1.28Variability (S.D.) 179 ± 58 123± 50 64.80 5.00E-11 2.10Signal Detection TheorySensitivity (d') 1.77 ± 1.63 3.72 ± 2.00 72.92 7.00E-12 2.22Response bias (β) 0.64 ± 0.39 0.28 ± 0.30 62.38 8.00E-11 2.06Attention Shift AnalysisAttention Shifts (#) 12.8 ± 4.3 7.0 ± 5.5 67.70 2.00E-11 2.14Time on Task (%) 42.6 ± 30.3 75.4 ± 26.3 88.50 2.00E-13 2.45% Time Impulsive 32.7±18.8 18.1±17.2 29.48 1.00E-06 1.41% Time Distracted 11.0±13.1 2.3±4.0 31.78 5.00E-07 1.47% Time Random 13.6±21.7 4.2±14.6 15.52 2.00E-04 1.03

MMAT: Fluctuations in AttentionChildren with ADHD were “On-Task”during only 42.6% of the 30 second epochs vs.an 82.4% “On-Task” rate for normal controls(F1,66 = 12.9, p < 0.001).Following MPH “On-Task” rate increasedto 75.4% (p< 10 -11 ).

.15DA. Pre-Methylphenidate.11.35.32I.14.44.42.34A.45.04.15.16 .12R.08.25.44

B. Post-Methylphenidate.01c .03 e.18 cDI.18.02 d.71 a.72 e.18 bA.78 a.01.30.13 .04 eR.08.07 d.31

MPH Effects on ActivityMEASURES Baseline MPH F(1,59) p < EFFECT SIZEActivity ParametersMicroevents 2805±1579 1078±913 80.47 1.00E-12 2.34Area 130.1±84.4 37.4±38.5 99.20 3.00E-14 2.59Displacement 5.228±3.927 1.639±1.558 54.39 6.00E-10 1.92Immobility 0.129±0.101 0.557±0.618 31.28 6.00E-07 1.46Activity ScalingTemporal Scaling 0.881±0.125 0.529±0.313 94.10 8.00E-14 2.53Spatial Scaling 1.136±0.279 1.338±0.196 79.66 2.00E-12 2.32

M-MAT Descriptive Report

M-MAT Descriptive ReportM-MATM-MAT

M-MAT Descriptive Report

M-MAT Descriptive Report

M-MAT Descriptive Report

M-MAT - Comparative Reports

M-MAT - Comparative Reportsnone Concerta Straterra

M-MAT - Comparative ReportsnoneConcertaStraterra

none Concerta Straterra

M-MAT - Comparative ReportsBaseline - unmedicated

M-MAT - Comparative ReportsConcerta

M-MAT - Comparative ReportsStraterra

Does Response to Medication on MMAT PredictClinical Response?MH Teicher, A Polcari, CE McGreeneryMethods: Eleven boys (10±2 years of age; range: 6-12), currentlyreceiving treatment with MPH, and meeting DSM-IV criteria for ADHD,participated in this IRB-approved randomized order, triple-blind (parent,child, rater), within-subject, treatment trial.Subjects received one week each of placebo, low (0.4 mg/kg), medium(0.8 mg/kg) and high (1.5 mg/kg) daily doses of MPH (in randomizedorder). During the last day on each regimen children were testedobjectively for degree of hyperactivity and inattention using MMAT.Parents rated weekly response using an index of clinical globalimprovement (CGI).

Does Response to Medication on MMAT PredictClinical Response?MH Teicher, A Polcari, CE McGreeneryResults: In 10/11 instances the dose that produced the bestoverall improvement on objective measures of activity andattention was also the dose rated best by parents (p< 10-6).Similarly, 8/11 parents indicated that their child’s worst weekoccurred in concordance with their worst objective outcome(p=0.00001).Parents rated the week that produced the best overallimprovement in objective response as significantly better than thechild’s response to their customary treatment.

The Brief M-MAT for Pharmacodynamic AnalysisIn collaboration with Kamal Midha, Ph.D., D.Sc. andGordon McKay, Ph.D. we conducted a combinedpharmacokinetic/pharmacodynamic analysis ofmethylphenidate effects on activity and attention, utilizingdifferent dose regimens.In particular, we sought to ascertain if treatmentregimens that produced stable MPH levels, or risingMPH levels had benefits, or if fluctuating levels werenecessary to prevent rapid development of tolerance(tachyphylaxis).

The Brief M-MAT for Pharmacodynamic AnalysisSubject: Boys 8 - 10 years of age with DSM-IVADHD. Prescreened by M-MAT to haveobjective hyperactivity (>25% control), and tohave positive therapeutic response to probedose MPH (0.4 mg/kg).Method: Children were brought to thelaboratory for a 12 hour test day. An i.v. (heplock) was inserted, meds were administeredthroughout the day to produce desiredregimens, and they were tested at hourlyintervals using 5 min M-MAT tests.

The Brief M-MAT for Pharmacodynamic AnalysisRegimens: All children received a total daily dose of 1 mg/kg.CD1 - Small loading dose, then frequent small doses toproduce increasing blood levels for 6 hours, plateau, wearoff.(Similar to Concerta).CD2 - Large loading dose. Relatively stable levels for 8hours, wear-off.PD1 - Large loading dose, followed by decreasing pulses.PD2 - Pulsatile schedule 40%, 40%, 20% - based on myclinical experience.

M-MAT: Pharmacokinetic /Pharmacodynamic Analysis

M-MAT: Pharmacokinetic /Pharmacodynamic Analysis

M-MAT: Pharmacokinetic /Pharmacodynamic Analysis

M-MAT: Pharmacokinetic /Pharmacodynamic Analysis

M-MAT: Pharmacokinetic /Pharmacodynamic Analysis

M-MAT: Pharmacokinetic /Pharmacodynamic AnalysisVolkow & Swanson, Am J. Psychiatry, 2003

Is there a therapeutic window formethylphenidate?Average blood level associated with maximalimprovement in activity - 11.3 ng/ml (68%reduction in activity).Average response to highest blood level -14.2 ng/ml - 44% reduction in activity(beneficial but significantly worse than atoptimal level).

Is there a therapeutic window formethylphenidate?On average poorest response tomethylphenidate occurred at blood level 5.4ng/ml less than optimal dose (71% ofsubjects). Response was 34.7% worse(more hyperactive) than at zero blood level.

M-MAT: Pharmacokinetic /Pharmacodynamic AnalysisM-MAT results correspond well on the individualand group level with measures of d-methylphenidateblood levels.M-MAT indicates that pulsatile dosing producesbetter overall clinical response.M-MAT shows that on average maximal benefitsoccur with plasma levels of MPH around 11 ng /ml.

Brain ImagingImaging studies have identified keybrain regions implicated in thepathophysiology of ADHD.

ADHD and Brain FunctionDopamine System Illustration

Brain ImagingThese include the striatum (caudateand putamen), prefrontal cortex, andmost recently the cerebellar vermis

Brain ImagingInitial findings of brain-baseddifferences between individuals withADHD and healthy controls wereestablished using measures of basalblood flow or metabolism.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)Using 133xenon inhalation, Lou et al (1984) foundhypoperfusion in the caudate-putamen of 7 of 11 childrenwith ADD that was reversed by methylphenidate. Thesefindings were replicated and expanded (Lou et al 1989), toshow that asymetrical hypoperfusion of the right caudateputamenwas more pronounced in pure ADHD group, andthat ADHD comorbid with other neurological symptomsdemonstrated bilateral hypoperfusion. Methylphenidate wasagain found to increase flow to the striatal regions.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)Functional imaging studies using perfusion dependentmeasures such as xenon 133 inhalation and emissiontomography, as well as metabolism dependent measuressuch as fludeoxyglucose F18 PET have implicated thefrontal cortex in ADHD.Lou et al (1984) found hypoperfusion in the frontal lobesof 11/11 children with ADD. Stimulant drugs decreasedblood flow in primary sensory and motor cortex.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)Zametkin et al. (1990) found, using PET, that adults with ahistory of childhood ADHD (who were also parents ofchildren with ADHD) had an overall 8% reduction incerebral glucose metabolism, with a significant reductionsin 30 of 60 cortical regions. The largest decreases were inpremotor and superior prefrontal cortex.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)More recently, Ernst et al. (1994) used PET to comparecerebral blood flow in 20 adolescents with ADHD and 19normal controls. On the whole, there were no significantdifferences in global or regional blood flow. However,there was a substantial interactive effect of gender, andgirls with ADHD had global cerebral blood flow measuresthat were 15% lower than normal girls, and 19.6% lowerthan boys with ADHD.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)In the entire group there was a significant associationbetween diminished regional glucose metabolism in theleft anterior frontal region (frontal premotor region) andseverity of ADHD symptoms (Zametkin et al 1993).Adolescent girls had additional abnormalities in rightfrontal premotor cortex, right temporal cortex, right and leftposterior putamen, and middle cingulate cortex (Ernst etal. 1994).

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)At McLean Hospital – Harvard Medical School wehave recently developed a new imaging procedureto evaluate brain function in children with ADHDunder normal resting conditions. Unlike PET andSPECT, the technique is non-invasive andrequires no drugs, injections or exposure toradiation.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)We call this new technique T2-Relaxometry. Briefly, itprovides a measure of regional blood volume, whichcorrelates with brain activity. Technically, it is based on thefact that deoxyhemoglobin is the primary fluidparamagnetic signal in the brain, and the knowledge thatthe concentration of deoxyhemoglobin in the bloodremains constant under steady-state conditions.

T2-RelaxometryImage IntensityTime (msec)T2 intensity decay curve from single pixel in the putamen

T2-Relaxometry &Dynamic Susceptibility Contrast MRIT2-relaxometry provides a non-invasive indirect measure of restingrelative cerebral blood volume.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)Initial study – 11 boys with ADHD assessed blindly onplacebo, low, medium and high doses of methylphenidatevs. 6 normal healthy boys who received no drugs. Ourinitial focus has been on the striatum (caudate nucleus andputamen) which are brain regions strongly involved in theregulation of motor activity, arousal, and attention.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)No difference emerged between ADHD children andhealthy controls in bilateral T2 relaxation time measuresfor thalamus (p > 0.4), and fell short of significance for thecaudate nucleus (p = 0.14).In contrast, ADHD and controls differed markedly inbilateral putamen T2 relaxation time measures (p = 0.008).These differences were more striking in the left putamenthan the right.

ADHD and Brain Function

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)There were marked and significant correlationsbetween motor activity and T2 relaxation timemeasures for the putamen as a whole. Twomeasures of rest-inactivity (temporal scaling andaverage time spent immobile) correlated -0.730 (p< 0.001) and -.722 (p = 0.001), respectively withT2 relaxation time in putamen.

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)Table I. Correlation between T2 relaxation time and motor behavior during CPT.Regions Rest-Activity Measures Complexity MeasureTemporal Scaling % Time Immobile Spatial ScalingBilateralCaudate -0.057 -0.077 0.024Putamen -0.730§ -0.722§ 0.528‡Thalamus 0.036 -0.074 -0.031UnilateralR. caudate 0.038 0.202 0.034L. caudate -0.121 -0.285 0.012R. putamen -0.721§ -0.659¥ 0.525‡L. putamen -0.658¥ -0.715§ 0.473†R. thalamus -0.245 0.015 0.216L. thalamus 0.367 0.039 -0.327† p = 0.055; ‡ p < 0.05; ¥ p < 0.005; § p < 0.001

ADHD and Brain FunctionFunctional Magnetic Resonance Imaging (T2 –Relaxometry)There were also robust correlations betweenmeasures of CPT performance and T2 relaxationtime measures in the putamen bilaterally.Accuracy on the CPT correlated -0.739 (p =0.0007) with T2 relaxation time, while variability(S.D.) in response latency correlated 0.620 (p =0.008).

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)Table II. Correlation between T2 relaxation time and CPT performance.Region Accuracy Response SDBilateralCaudate -0.144 0.030Putamen -0.739§ 0.620¥Thalamus 0.423† -0.167UnilateralR. caudate -0.082 -0.048L. caudate -0.165 0.087R. putamen -0.754§ 0.629¥L. putamen -0.636¥ 0.538‡R. thalamus 0.171 -0.160L. thalamus 0.518‡ -0.161† p < 0.10; ‡ p < 0.05; ¥ p < 0.01; § p < 0.001

ADHD and Brain Function

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)T2 relaxation time in both right and left putamen weresignificantly altered by ongoing treatment withmethylphenidate (p = 0.006), though the response wasvery strongly tied to the subject’s unmedicated activitystate (Drug x temporal scaling covariate p = 0.008).The magnitude and direction of change in the T2 relaxationtime of the putamen following methylphenidate correlatedstrongly with basal activity level (Right putamen r = 0.821,p = 0.002; Left putamen r = 0.648, p = 0.03).

ADHD and Brain Function

ADHD and Brain FunctionFunctional Imaging (Brain Metabolism / Blood Flow)

Can imaging techniques provide a definitivediagnosis of ADHD?This is an interesting but complex question. The simplestanswer is “No, not yet.” The reason for this is summarizedin the following Table which includes effect-size calculations(Cohn’s d) derived for several recent imaging studies ofADHD.Effect-size is a measure of the magnitude of a statistical difference betweensamples and is useful for comparing different studies, as it is not stronglyinfluenced by sample-size differences. From these effect-size values one canestimate the degree of expected overlap between subjects with ADHD andhealthy controls.

Summary of Imaging Results ADHD vs. Controls

Krause et al., Neurosci Letters 2000 285: 107–110

Can imaging techniques provide a definitivediagnosis of ADHD?The imaging measures reviewed had effectsizesfor their most significant differences thatranged from 0.34 - 1.68. At best none of themeasures used alone would provide more than75% accuracy.

Can imaging techniques provide a definitivediagnosis of ADHD?If we look far into the future to where advanced imaging, behavioraland genetic tools will take us, we can imagine that one day we will beaware of, and able to diagnose, a number of very specificpathophysiological disorders affecting neurotransmission and theintegrity of cortico-striatal-thalamic-cerebellar loops. Some disordersmay involve abnormalities in the molecular structure of receptors fordopamine or norepinephrine, or enzymes such as catechol-O-methyltransferase. Other disorders will be delineated by dysmorphology ofthe lobular structure of the cerebellar vermis or the degree ofmaturation of the prefrontal cortex. These disorders will haveoverlapping symptoms that fit within the broad ADHD syndromecategory, though they may be more homogeneous in their behavioralmanifestations, clinical course and therapeutic response.

Can imaging techniques provide a definitivediagnosis of ADHD?Although imaging studies can not be used at the presenttime to objectively diagnose ADHD, this is good news. Adeeper understanding of the nature of this syndrome willrequire moving beyond the ADHD construct to morediscrete and specific pathophysiological diagnoses.Imaging studies, molecular biology, and precise cognitivebehavioralmeasures are the tools that will enable us tounravel the heterogeneous clinical enigma of ADHD intowell-defined components.

Logistic Regression Analysis: Using Left-Putamen and Right DorsolateralPrefrontal Cortex Distinguishes 11/11 ADHD from 6/6 controls.

ADHD - Circuit Diagram

Dual Attention SystemsLeft Frontal - Striatal (Dopamine)Focused attention - vigilance (filters out distractions).Underactive - ADHDOveractive - “Absentminded professor”Right Frontal - Parietal (NE)Environmental Awareness.Underactive - Depression, “Absentminded professor”Overactive - Some ADHD, Posttraumatic Stress Disorder