Research Avenues Tracker

This document tracks promising research leads discovered during the systematic review of Anthony's interconnected conditions. Each avenue is rated by evidence strength and clinical relevance.

Rating Key

Symbol Evidence Strength
A Strong — multiple RCTs or large meta-analyses
B Moderate — cohort studies, systematic reviews, consistent findings
C Emerging — case reports, animal models, plausible mechanism but limited human data
D Hypothesis-generating — theoretical links, single studies, needs validation

Active Research Avenues

Updated as research progresses. Avenues are added here as they are discovered during paper review.

Neurodevelopmental

# Avenue Evidence Relevance Status
1 Late-diagnosed autism as distinct phenotype B Direct — recent diagnosis Complete
2 AuDHD (autism + ADHD) shared neurobiology B Direct — dual diagnosis Complete
3 ADHD-PI with internal hyperactivity / CDS overlap B Direct — his presentation Complete
4 Stimulant-mediated autistic unmasking C Direct — his experience Complete
5 Masking/camouflaging cognitive cost and burnout B Direct — fatigue driver Complete

Trichotillomania / BFRBs

# Avenue Evidence Relevance Status
6 Trichotillomania as neurodevelopmental (not OCD) B Direct — reclassification Complete
7 BFRBs in autism — stimming/self-regulation B Direct — dual diagnosis Complete
8 BFRBs in ADHD — understimulation/dopamine-seeking C Direct — ADHD link Complete
9 Puberty-onset trich — hormonal triggers C Direct — onset at 12 Complete
10 NAC for trichotillomania A Direct — treatment option Complete
11 CBT failure in undiagnosed neurodivergent people C Direct — his experience Complete

Iron / Mineral Metabolism

# Avenue Evidence Relevance Status
12 Iron overload and repetitive behaviours (basal ganglia iron) C Potential link Complete
13 Copper-iron-dopamine triangle (DBH pathway) B Direct — low copper Complete
14 Iron and myelination in neurodevelopment B Mechanistic link Complete
15 NTBI and brain iron toxicity B Direct — TSAT 60% Complete
16 Zinc deficiency and BFRBs C Direct — low zinc Complete

Genetics

# Avenue Evidence Relevance Status
17 HFE variants and neurodevelopmental outcomes C Direct — compound het Complete
18 MTHFR and folate metabolism in AuDHD B Takes folate Complete
19 Dopamine pathway genes (COMT, DAT1, DRD4) B ADHD genetics Complete
20 Serotonin genes and trichotillomania B Trich genetics Complete
21 Shared GWAS loci autism-ADHD A Dual diagnosis Complete

Gut-Brain Axis

# Avenue Evidence Relevance Status
22 Gut dysbiosis in autism B Potential undiagnosed Complete
23 Gut microbiome and ADHD C Emerging field Complete
24 Iron overload effects on gut microbiome B Direct — iron status Complete
25 Serotonin (gut-derived) and trich/repetitive behaviours C Mechanistic Complete
26 Gut permeability and neuroinflammation B Systemic link Complete

Treatment / Intervention

# Avenue Evidence Relevance Status
27 NAC supplementation (glutamate, trich, oxidative stress) A Multi-target Complete
28 Inositol for OCD-spectrum/BFRBs B Treatment option Complete
29 Specific probiotic strains for AuDHD C Emerging Complete
30 Phlebotomy benefits beyond iron (mineral recovery, neuro) B Direct — planned Complete
31 Dietary interventions for AuDHD B Practical Complete
32 Iron chelation for brain iron (deferiprone) C Speculative Complete
33 Vitamin D deficiency and TTM (OR 4.2) B Untested — high priority Complete
34 Tryptophan-kynurenine pathway in autism B Iron-inflammation-serotonin link Complete
35 Creatine for brain energy in AuDHD B Already supplementing Complete
36 Ferroptosis in neurodevelopmental conditions C Mechanistic — iron overload Complete
37 MTHFR genotyping to optimise folate form B Takes folate — form matters Complete
38 Cognitive Disengagement Syndrome in AuDHD B 32% prevalence in autism Complete

Sleep

# Avenue Evidence Relevance Status
39 Poor sleep as central amplifier of AuDHD + HFE pathways B Direct — all pathways converge Complete
40 Sleep deprivation → ferroptosis (GSH/GPX4 depletion) B Direct — iron overload + sleep loss synergy Complete
41 Glymphatic impairment from poor sleep → brain iron retention B Direct — NTBI clearance failure Complete
42 Sleep deprivation → gut dysbiosis → inflammation → IDO B Direct — double hit with iron overload Complete
43 Sleep loss → PFC dysfunction → TTM disinhibition B Direct — executive depletion model Complete
44 Elvanse timing and sleep architecture B Direct — 70mg long-acting Complete
45 Sensory-driven insomnia in autism ↔ sleep-amplified sensory reactivity B Direct — bidirectional cycle Complete

Sleep Interventions

# Avenue Evidence Relevance Status
46 Melatonin dosing for AuDHD adults (IR 0.5mg + PR 2-5mg) B Direct — treatment protocol Complete
47 CBT-I/ACT-i adapted for neurodivergent adults C Direct — standard CBT-I fails Complete
48 Chronotherapy (bright light + melatonin) for ADHD-DSPS B Direct — 73-78% ADHD have DSPS Complete
49 Weighted blankets for insomnia in psychiatric populations B Direct — large effect size d=1.90 Complete
50 Elvanse timing optimisation for sleep B Direct — pharmacokinetic reasoning Complete

Body Systems

# Avenue Evidence Relevance Status
51 Interoception in AuDHD — accuracy-sensibility mismatch B Direct — alexithymia ~50% in autism Complete
52 Interoception and BFRB urge detection failure C Direct — insula-basal ganglia pathway Complete
53 Iron deposition in insula → impaired interoception C Direct — TSAT 60%, brain iron Complete
54 Autonomic dysfunction / vagal tone in AuDHD B Direct — HRV, gut-brain, sensory Complete
55 HRV biofeedback for ADHD B Direct — intervention option Complete

Endocrine

# Avenue Evidence Relevance Status
56 Iron overload and hypogonadism (pituitary iron) B Direct — fatigue, age 37, recovery window Complete
57 Iron overload and thyroid function C Low prevalence in HFE-HH but worth screening Complete
58 Iron overload and insulin resistance / diabetes B Direct — ferritin 380 in risk zone Complete
59 Phlebotomy and hormone recovery <age 40 B Direct — documented case match at age 37 Complete

Exercise

# Avenue Evidence Relevance Status
60 Exercise and ADHD executive function A Direct — meta-meta-analysis SMD=0.42 Complete
61 Exercise and iron metabolism (hepcidin, muscle sink) B Direct — therapeutic for HFE Complete
62 Exercise and dopamine/BDNF B Direct — complements Elvanse Complete
63 Exercise barriers in AuDHD (sensory, fatigue, motivation) B Direct — practical prescription Complete

Neuroprotection

# Avenue Evidence Relevance Status
64 HFE and Parkinson's/ALS/Alzheimer's risk (meta-analyses) A Reassuring — no increased risk for carriers Complete
65 Brain QSM imaging for baseline iron mapping B Direct — TSAT correlates with nigral iron r=0.78 Complete
66 Deferiprone failure in neurodegenerative trials A Important negative — chelation is not the answer Complete
67 NAC safety and benefit in iron overload B Direct — thalassemia RCT NNT=4.8 Complete
68 NAC as ferroptosis inhibitor via GSH/GPX4 B Direct — bypasses System Xc- Complete

Testing

# Avenue Evidence Relevance Status
69 UK pharmacogenomics testing (COMT, MTHFR, CYP2D6) N/A Direct — medication and supplement optimisation Complete
70 UK endocrine panel (testosterone, thyroid, HbA1c, vitamin D) N/A Direct — rule out treatable fatigue causes Complete

Completed Avenues

Moved here after full investigation with vault note created.

# Avenue Outcome Vault Note
1-5 Late-diagnosed autism, AuDHD, ADHD-PI, masking, unmasking Distinct genetic subtype confirmed (Nature 2025); CDS overlap 32% Late-Diagnosed Autism - Distinct Profile, ADHD-PI and Internal Hyperactivity
6-11 TTM as neurodevelopmental BFRB, NAC, CBT limitations NAC 56% response in adults; understimulation model; CBT fails without ND awareness Trichotillomania and Neurodevelopmental Links
12-16 Iron-mineral-brain links, basal ganglia, myelination Basal ganglia iron disrupts OCD circuits; NTBI crosses BBB; zinc modulates NMDA research/Iron and OCD-Spectrum Repetitive Behaviours, research/Iron and Myelination
17-21 Genetic architecture, COMT, MTHFR, GWAS Shared loci confirmed; MTHFR form check needed; pharmacogenomic relevance Genetic Architecture of AuDHD
22-26 Gut-brain axis, iron-gut dysbiosis, serotonin Iron overload fuels pathogens, depletes Lactobacilli; kynurenine shunt active Gut-Brain Axis and Neurodevelopment, Tryptophan-Kynurenine Pathway
27-32 Treatments: NAC, inositol, probiotics, phlebotomy, diet, chelation Full protocol developed; NAC highest priority add; vitamin D testing urgent Diet and Supplement Strategy
39-45 Sleep as central amplifier: ferroptosis, glymphatic, gut, PFC, sensory, Elvanse Sleep is a hub connecting all major pathways; melatonin + chronotherapy high priority research/Poor Sleep and AuDHD-HFE Interactions
46-50 Sleep interventions: melatonin, ACT-i, chronotherapy, weighted blankets, Elvanse timing Staged protocol developed; melatonin + sensory environment Phase 1 research/Sleep Intervention Protocols for AuDHD Adults
51-55 Interoception + autonomic: accuracy mismatch, urge detection, vagal tone, HRV Insula iron deposition may impair interoception; HRV biofeedback promising neurodevelopment/Interoception in AuDHD - Research Review, research/Autonomic Nervous System and Vagal Tone in AuDHD
56-59 Endocrine: hypogonadism, thyroid, insulin resistance, phlebotomy recovery Age 37 within documented recovery window; Medichecks panel recommended research/Endocrine Effects of HFE Iron Overload, research/UK Testing Guide - Pharmacogenomics and Endocrine
60-63 Exercise: EF (SMD=0.42), hepcidin, dopamine/BDNF, practical barriers Cognitively engaging exercise 3x/week best; start 30min after Elvanse research/Exercise as Medicine for AuDHD-HFE
64-68 Neuroprotection + NAC: HFE-neurodegeneration meta-analyses, QSM, NAC safety No carrier risk increase for PD/ALS/AD; NAC safe and beneficial; chelation harmful research/HFE and Long-Term Neurodegeneration Risk, research/NAC and Iron Metabolism
69-70 UK testing: pharmacogenomics + endocrine panel options and pricing Best combo: myDNA £170 + Methylation £289 + Medichecks £249 = £708 total research/UK Testing Guide - Pharmacogenomics and Endocrine

Cross-References