ADHD-001
ADHD · Catecholamine PFC / Delayed Maturation Engine · VIZASL v1
MEBICAL · EOSE Fleet · TRB-MEBICAL-HEALTH-DOMAIN-001 · Day 90 · Real data · Cited · Sorries marked
MEBICAL · PSYCH ← RESEARCH
PFC underdeveloped network
DAT transporter (too fast)
θ excess / β suppressed
DMN failing to suppress
γ₁ floor anchor
PHASES
RX
BIOMARKERS
EEG
NPs
Pathophysiology
Catecholamine Deficit in PFC
DA + NE both required for PFC executive function. Optimal D1/α2A stimulation needed for working memory maintenance. Too little (ADHD) → PFC under-activated → distractibility. Too much (stress) → PFC shut-down. Goldilocks mechanism. DAT removes DA too fast in ADHD (DAT1 gene variant).
Arnsten 2011 Nat Rev Neurosci (DA/NE PFC regulation)
Delayed Cortical Maturation
Shaw et al. 2007 PNAS: peak cortical thickness delayed ~3 years in ADHD vs neurotypical. Most pronounced in PFC (right middle frontal, superior frontal). The brain eventually catches up — explains why 60% persist to adulthood (if maturation stays delayed) vs 40% who remit.
Shaw et al. 2007 PNAS (cortical maturation delay) · Castellanos et al. 2002 JAMA (smaller brain volumes)
Genetics: DAT1 + DRD4
DAT1 (SLC6A3): dopamine transporter gene. 10-repeat allele → DAT efficiency increase → DA removed too fast → low synaptic DA. DRD4 7-repeat allele: reduced D4 sensitivity → compensatory mechanism. Both variants relatively common — ADHD is polygenic, common variant architecture.
Faraone et al. 2021 Nat Rev Dis Primers (comprehensive ADHD review)
Executive Function Impairment — Core Deficit
3 core executive functions: (1) Working memory, (2) Inhibition, (3) Cognitive flexibility/planning. All mediated by PFC. ADHD = developmental EF impairment. Not attention per se — "ADHD is not a disorder of knowing what to do, but of doing what you know" (Barkley).
Barkley 1997 (EF model) · Diamond 2013 Annu Rev Psychol
Stimulants — First-Line PROVEN
Methylphenidate (Ritalin/Concerta)
DAT blocker → increased synaptic DA + NE. Most studied drug in child psychiatry (>200 RCTs). Cipriani/Cortese 2018 network meta-analysis: most effective in children. SORRY: full mechanism unknown beyond DAT blockade. Why blocking removal (not adding) produces therapeutic effect is partially understood via D1 optimal stimulation.
Cortese et al. 2018 Lancet Psychiatry (network meta-analysis)
Amphetamine Salts (Adderall/Vyvanse)
DA + NE release AND DAT block. Vyvanse (lisdexamfetamine) = prodrug, smoother profile, lower abuse potential. Slightly higher effect size than MPH in adult ADHD (Cortese 2018). Both PROVEN, similar efficacy.
Cortese et al. 2018 Lancet Psychiatry
Atomoxetine (Strattera)
NE selective reuptake inhibitor (NET blocker). Non-stimulant. Useful for abuse risk, comorbid anxiety, tics. 4–6 weeks for full effect. FDA approved ADHD all ages. PFC NE D1 mechanism like optimal stimulation model.
Michelson et al. 2001 Am J Psychiatry (pivotal trial)
Guanfacine (Intuniv) — α2A agonist
NE α2A agonist. Mimics NE optimal stimulation in PFC D1. Reduces impulsivity + emotional dysregulation. Useful for tics comorbidity. Lower effect size than stimulants but different mechanism.
Sallee et al. 2009 Am J Psychiatry
Biomarker Status CLINICAL DIAGNOSIS ONLY
No Validated Diagnostic Biomarker
SORRY: ADHD is diagnosed entirely by clinical assessment (DSM-5: inattention + hyperactivity/impulsivity criteria for ≥6 months in ≥2 settings). No blood test, brain scan, or EEG test confirms ADHD. The FDA-cleared θ/β ratio tool is controversial (see EEG tab).
SORRY: diagnosis relies on clinical assessment — most subjective in all of neurology
θ/β EEG ratioFDA-cleared (NEBA tool). Theta:beta power ratio. Elevated in ADHD. Lubar 1991. SORRY: contested validity. Not recommended as standalone diagnostic. Specificity poor. See EEG tab
MRI cortical maturationDelayed cortical thickness peak. Group-level finding. Not diagnostic for individuals. Research biomarker.
DAT-SPECTResearch only. Shows DAT elevation in ADHD. Not clinical practice. Too expensive, too invasive for diagnosis.
EEG in ADHD
θ/β ratio ↑ CONTESTEDTheta excess (4–8Hz) frontally + beta deficit (13–30Hz). Lubar 1991 original report. FDA-cleared NEBA system (2013). BUT: Snyder et al. 2015 meta-analysis: insufficient evidence to recommend as diagnostic. SORRY: diagnostic validity widely contested.
P300 latency ↑Longer P300 latency = slower cognitive processing. Attention deficit correlate. Group-level finding, not diagnostic.
CNV ↓Contingent negative variation — anticipatory preparatory response. Reduced in ADHD. Reflects executive readiness failure. Research biomarker.
Neurofeedbackθ/β protocol: train theta down, beta up. EMERGING. Meta-analyses conflict. Cortese 2016: probably efficacious but not sufficient standalone. SORRY: evidence base weak, blinding impossible.
Novel Patterns (8)
PROVENNP-ADHD-001 · Delayed cortical maturation 3yr later than neurotypical (Shaw 2007) — brain eventually catches up in 40% explaining adult remission
PROVENNP-ADHD-002 · Goldilocks mechanism: PFC needs optimal DA/NE stimulation — too little = ADHD, too much (stress) = PFC shutdown · explains why stimulants work at correct dose
PROVENNP-ADHD-003 · MPH: most studied drug in child psychiatry (>200 RCTs) · mechanism = DAT block · full mechanism beyond that = SORRY unknown
PROVENNP-ADHD-004 · ADHD = executive function disorder not attention disorder · "can't do what you know to do" vs "not knowing what to do" · Barkley framing
SORRYNP-ADHD-005 · θ/β ratio FDA-cleared but diagnostic validity widely contested · Snyder 2015 meta-analysis: insufficient evidence · FDA cleared ≠ validated
SORRYNP-ADHD-006 · ADHD in adults massively underdiagnosed — diagnostic criteria developed entirely in children · adult symptom presentation different · adult criteria poorly validated
OPENNP-ADHD-007 · Adult ADHD persistence predictor: unknown · 40% remit, 60% persist · can't predict from childhood which · no biomarker
SORRYNP-ADHD-008 · No diagnostic biomarker · diagnosis entirely clinical · adult underdiagnosis · neurofeedback evidence weak · stimulant mechanism incomplete · no objective test
⚠ OPEN SORRIES · ADHD-001
SORRY-1 · θ/β ratio contested
The NEBA tool is FDA-cleared for ADHD assessment but its diagnostic validity is widely contested. Snyder et al. 2015 meta-analysis concluded there was insufficient evidence to recommend it as a diagnostic tool. FDA clearance and clinical validation are different standards.

SORRY-2 · Adult ADHD underdiagnosis
DSM criteria for ADHD were developed in children. Adult presentations differ (more inattention, less hyperactivity). Age of onset criterion (symptoms before 12) is difficult to apply retrospectively. Adult ADHD is systematically underdiagnosed in clinical practice.

SORRY-3 · Stimulant mechanism incomplete
We know stimulants block DAT and NET, raising synaptic DA and NE. We know they work. The full mechanistic chain from DAT blockade → PFC D1 optimal stimulation → executive function improvement → behavioural change is not fully mapped.

SORRY-4 · No diagnostic biomarker
ADHD diagnosis relies entirely on clinical assessment and rating scales. No objective biomarker — blood, EEG, or imaging — has been validated for individual diagnosis. This creates significant diagnostic variability across clinicians and cultures.
ADHD-001 · DA/NE PFC DEFICIT · DELAYED MATURATION · STIMULANTS PROVEN · θ/β RATIO CONTESTED · NO DIAGNOSTIC BIOMARKER
γ₁ = 14.134725141734693