Why Pushing Harder on the Brake Fails
The companion document to the mechanism — this one is about the unlock
When the Signal Cannot Get Through established the mechanism: somatostatin locks adenylyl cyclase via Gαi inhibition, the ATP/adenosine inverse relationship reinforces that lock, and PDE4 upregulation degrades whatever cAMP briefly escapes. The six breaking points together create a system where the regulatory peptides that should carry the reset signal — VIP, secretin, oxytocin — cannot transmit durably even when the peptides themselves are present and the receptors are intact.
This document addresses the next question: how do you release the lock?
The instinctive answer is to stimulate harder — to administer more of the peptide, at higher doses, more frequently. The biology of the locked cascade tells us precisely why this approach fails and ultimately makes things worse. It is blocking the signal because chronic neuroinflammation is holding it elevated. The brake is engaged because the immune system is still in crisis mode — not because somatostatin is unaware that secretin or VIP is trying to get through. Pressing harder on a peptide reset against an actively maintained somatostatin block does not release the brake — it desensitizes the receptors trying to send the signal, consuming the very biological capacity that would be needed once the brake is eventually released.
The somatostatin lock is a biological response to neuroinflammatory conditions. It can only be released by addressing those conditions. This is the fundamental strategic reorientation that four decades of peptide trials failed to make — not because the researchers were wrong about the biology, but because the upstream driver had not yet been assembled into a coherent intervention target.
The Distinction That Changes Everything
There is a precise difference between two biological situations that look identical from the outside:
Situation A: Absent peptide
The signaling peptide (secretin, VIP, oxytocin) is genuinely deficient. Administration of the peptide restores the signal. More peptide = more signal, durably.
Situation B: Locked infrastructure
The peptide is present. The receptor is present. But the second messenger infrastructure is locked. Administration of the peptide produces a brief, partial response. Repeated administration desensitizes receptors.
The secretin trial literature documents Situation B. The initial responses were real — the biology is responsive, the pathway works. The rapid attenuation was not a failure of the peptide; it was the signature of a locked infrastructure that could not sustain the signal it briefly generated. Distinguishing these two situations determines whether the intervention target is the peptide supply or the signaling infrastructure.
What the Published Evidence Shows
The secretin trial literature and clinical neuroimmunology converge on the same infrastructure failure pattern
The G-protein cascade failure framework is not constructed from theory alone. The published clinical and biochemical literature provides convergent evidence for each breaking point — and the secretin trial record, read through an infrastructure-failure lens rather than a simple efficacy lens, provides the clearest available clinical signal that the failure is in the second messenger system, not in the peptides themselves.
The key evidence comes from three distinct bodies of research: the secretin and oxytocin trial literature documenting initial response with rapid attenuation; neuroimmunological characterization of the NK cell and T-cell activation phenotype present in a subset of autism cases; and established biochemistry linking chronic neuroinflammation to each of the six breaking points through independent mechanisms.
The Secretin Trial Record: A Success Misread as a Failure
Horvath and colleagues (1998, Journal of Pediatrics) reported striking improvements in three children with autism following intravenous secretin during routine endoscopy — improvements in eye contact, alertness, and expressive language that prompted a wave of controlled trials. The controlled trials found that the improvements did not sustain across repeated administrations and did not reach statistical significance in blinded protocols. The field concluded: secretin does not work.
The infrastructure-failure framework reframes what those trials actually showed. The consistent pattern in the early observational literature — genuine multi-domain improvement on first or early administration, progressive attenuation with repetition — is precisely the clinical fingerprint of a signaling system that can respond to a stimulatory input but cannot sustain the response. This is receptor desensitization in a context of inadequate downstream infrastructure: the GPCR receives the secretin signal, Gαs activates, adenylyl cyclase is briefly stimulated — but the somatostatin lock, PDE4 upregulation, and ATP depletion mean the resulting cAMP pulse is too brief and too small to complete PKA-dependent downstream work. Repeated stimulation without infrastructure repair leads to receptor internalization — a rational cellular adaptation to a signal the downstream system cannot process.
The secretin trials did not fail to show an effect. They showed an effect that attenuated — which is a different finding. The field asked "does it work?" The infrastructure-failure framework asks "why did it stop working?" The second question has a precise mechanistic answer.
The Neuroimmune Phenotype: What NK Cell Elevation Tells Us
A consistent finding in neuroimmunological characterization of autism subgroups is elevated NK cell activity and skewed T-cell activation profiles — a chronic immune activation pattern distinct from classical immunodeficiency. Vargas et al. (2005, Annals of Neurology) documented neuroinflammatory markers in post-mortem brain tissue including activated microglia and elevated cytokines. Connolly et al. and others have documented aberrant NK cell activity in subgroups of children with autism spectrum conditions.
This chronic neuroimmune activation is the upstream driver of the somatostatin lock. TNF-α, IL-1β, and IL-6 — the primary cytokines of this inflammatory state — each independently upregulate PDE4 through NF-κB signaling. The same cytokine burden drives microglial activation, depletes the cellular ATP pool through immune cell metabolic demand, and generates the adenosine accumulation that constitutes the second independent inhibitory input to adenylyl cyclase. The neuroimmune phenotype is not a parallel finding to the signaling failure — it is the upstream driver of it.
Chronic NK cell and T-cell activation → elevated TNF-α/IL-1β/IL-6 → simultaneous upregulation of PDE4 (degrades cAMP), depletion of ATP (removes AC substrate), and accumulation of adenosine (adds second Gαi inhibitory input to AC). Three convergent mechanisms, one upstream source.
The Convergence Across Breaking Points
Each of the six breaking points described in When the Signal Cannot Get Through is independently supported by published biochemistry:
- BP1 — Membrane oxidation: Glutathione depletion and oxidative membrane damage in autism have been documented by Chauhan & Chauhan (2006) and James et al. (2004, 2006). GSTP1 variant prevalence and its role in reduced Phase II detoxification capacity is established in the pharmacogenomics literature.
- BP2 — GTP depletion: Mitochondrial dysfunction in autism is one of the most replicated biochemical findings in the field; Frye & Rossignol (2011, Molecular Psychiatry) provide a systematic review. GTP availability as a downstream constraint on G-protein activation follows directly from established purine biochemistry.
- BP3 — Somatostatin lock and adenosine accumulation: SST elevation under chronic inflammatory conditions is established in the neuroendocrinology literature. Adenosine A1 receptor-mediated adenylyl cyclase inhibition is fundamental receptor pharmacology (Fredholm et al., 2001, Pharmacological Reviews).
- BP4 — PDE4 upregulation: Cytokine-driven PDE4 upregulation via NF-κB is well established (Souness et al., 2000; Jin & Bhatt, 1996). The self-reinforcing loop between NF-κB, PDE4, and cAMP-mediated NF-κB suppression is mechanistically documented in the inflammation literature.
- BP5 — PKA ATP limitation: ATP as the obligate phosphate donor for PKA is fundamental biochemistry. Mitochondrial ATP depletion under inflammatory conditions is independently documented.
- BP6 — BDNF Val66Met: The Val66Met variant's impairment of activity-dependent BDNF secretion is extensively characterized (Egan et al., 2003, Cell; Chen et al., 2006). Exercise-driven BDNF enhancement in Met carriers is documented by Leckie et al. and others.
Six Layers of the Unlock — Infrastructure Repair by Breaking Point
Each breaking point has a specific repair logic — and several share common interventions
The six breaking points identified in When the Signal Cannot Get Through each have a corresponding repair target. The unlock strategy is not a single intervention — it is a layered approach where each layer addresses a specific node of the cascade failure simultaneously. The power of the approach comes from the convergence: several of the interventions address multiple breaking points at once, meaning the infrastructure repair compounds rather than requiring six separate parallel tracks.
The Convergence: Why Sulforaphane Carries Triple Weight
Several interventions address multiple breaking points simultaneously, which is why the protocol compounds rather than requiring parallel independent tracks. Sulforaphane is the most striking example of this convergence:
- BP1 (membrane coupling): Nrf2 activation upregulates GSTP1 → increased glutathione conjugation → reduced membrane lipid peroxidation → restored GPCR coupling efficiency
- BP3 (adenosine axis): NF-κB suppression reduces neuroinflammatory ATP demand → less ATP depletion → less adenosine accumulation → reduced secondary A1-mediated adenylyl cyclase inhibition
- BP4 (PDE4 loop): NF-κB suppression reduces TNF-α/IL-1β/IL-6 production → reduced PDE4 upregulation → longer cAMP signal duration
- Blood-brain barrier penetration: Unlike most anti-inflammatory compounds, sulforaphane crosses the BBB to act on neuroinflammation directly at the central level where the somatostatin brake is engaged
This is why sulforaphane ranks as the highest-priority addition to any protocol targeting the somatostatin lock — it is not one tool for one breaking point but a single compound engaging three of the six simultaneously.
Caffeine as Adenosine Antagonist — and the Methylation Cycle Connection
Two converging mechanisms that generate excess adenosine — and why the methylation cycle is a largely overlooked source
Caffeine's pharmacological mechanism is well established: it is a competitive non-selective antagonist at adenosine A1 and A2A receptors (Fredholm et al., 2001, Pharmacological Reviews). At A1 receptors — which couple to inhibitory Gαi proteins — adenosine suppresses adenylyl cyclase, reducing cAMP production. Caffeine blocks this inhibitory input, partially restoring adenylyl cyclase responsiveness to stimulatory inputs. At A2A receptors in striatum and prefrontal circuits, caffeine enhances dopaminergic signaling through the cAMP pathway, with well-documented effects on attention, processing speed, and executive function (Fisone et al., 2004, European Journal of Pharmacology).
The relevance to the somatostatin brake is direct: adenosine is one of the two simultaneous inhibitory inputs holding adenylyl cyclase suppressed at Breaking Point 3. The somatostatin Gαi lock is the first; accumulated adenosine activating A1 receptors is the second. Caffeine addresses the second of these two locks. It does not touch the somatostatin lock, the PDE4 upregulation, or the membrane oxidation at BP1. This is why caffeine's benefit, while real, is partial — it lifts one of three simultaneous brakes on adenylyl cyclase, leaving the other two in place.
Where Adenosine Comes From: The Two Sources
Understanding the unlock strategy for the adenosine axis requires understanding that adenosine excess in neuroinflammatory conditions has two distinct generating mechanisms — and both converge on the same adenylyl cyclase inhibitory node.
Source 1 — ATP catabolism under inflammatory ATP depletion: The well-characterized degradation chain ATP → ADP → AMP → adenosine. Chronic neuroinflammation drives elevated ATP consumption by activated immune cells and stressed neurons, simultaneously impairing mitochondrial ATP regeneration. The result is a state of chronic adenosine excess from the energy side of purine metabolism.
Source 2 — The methylation cycle: SAH hydrolysis to adenosine + homocysteine. This source is less widely discussed in the neuroinflammation context but is biochemically significant. S-adenosylhomocysteine (SAH) — the byproduct of every methylation reaction — is hydrolyzed by adenosylhomocysteinase (AHCY) to produce adenosine and homocysteine. When the methylation cycle is burdened — elevated SAM turnover, impaired SAH clearance, or constitutional AHCY insufficiency — SAH accumulates, and the AHCY-generated adenosine load increases proportionally.
The methylation cycle generates adenosine as a direct byproduct of every methyltransferase reaction. In individuals with impaired SAH clearance — whether from AHCY variants, MTRR impairment, or high methylation demand — this represents a constitutionally elevated adenosine load that adds to the neuroinflammatory adenosine burden at the same A1 receptor node. Two independent sources, one shared inhibitory target.
The Methylation Cycle as an Adenosine Source — The Biochemistry
The mechanistic chain is well established in the methylation literature (Cantoni, 1975; Chiang et al., 1996, FASEB Journal). SAM (S-adenosylmethionine) donates its methyl group in any methyltransferase reaction, producing SAH. SAH is then hydrolyzed by AHCY:
The reaction is thermodynamically reversible and strongly favors SAH synthesis — meaning efficient clearance of both adenosine and homocysteine is required to drive it in the hydrolysis direction. When adenosine is not cleared efficiently (e.g., adenosine deaminase insufficiency, impaired cellular uptake) or homocysteine remethylation is blocked (MTRR variants, B12 insufficiency), SAH accumulates. Elevated SAH is itself a potent inhibitor of virtually all methyltransferase enzymes — creating a methylation stall that further elevates SAH, which further inhibits clearance, in a self-reinforcing loop first described by Cantoni and elaborated by James et al. in the autism methylation literature (James et al., 2004, American Journal of Clinical Nutrition; James et al., 2006, American Journal of Medical Genetics).
The adenosine generated by this pathway contributes directly to A1 receptor activation and adenylyl cyclase inhibition. In individuals with constitutionally elevated methylation cycle throughput — or impaired SAH clearance — the methylation cycle is generating a baseline adenosine load that operates independently of the neuroinflammatory ATP catabolism source. Both sources arrive at the same inhibitory receptor.
The therapeutic implication: supporting SAH clearance — through adequate AHCY cofactors (Mg²⁺, zinc), methylation cycle support (hydroxy-B12, low-dose methylfolate, TMG for BHMT backup) and avoiding agents that push SAH accumulation further — addresses the methylation-origin adenosine source, complementing the anti-inflammatory strategy targeting the ATP catabolism source.
The Partial Benefit Problem — and What Full Restoration Requires
Caffeine's documented benefit in autism-spectrum neuroinflammatory phenotypes is consistent with what the model predicts from partial adenosine antagonism. A 2021 review by Bhatt et al. (Journal of Caffeine and Adenosine Research) summarized the mechanism through which adenosine A2A receptor blockade improves prefrontal dopaminergic signaling via cAMP/PKA — the same pathway the somatostatin lock suppresses. Caffeine's benefit is real and pharmacologically coherent, but it is upstream-receptor-level compensation, not infrastructure repair.
The critical limitation: caffeine blocks the receptor that adenosine activates, but it does not reduce adenosine generation. The neuroinflammatory ATP catabolism continues generating adenosine. The methylation cycle SAH hydrolysis continues generating adenosine. The A1/A2A receptors are blocked from signaling — but the biochemical conditions that make adenosine excess a chronic problem are unchanged. This is why caffeine's benefit, though sustained over years, is partial rather than complete, and why it cannot substitute for the upstream interventions that address the adenosine generation itself.
Full restoration requires both: reducing adenosine generation (sulforaphane/anti-inflammatory to reduce ATP catabolism; methylation cycle support to reduce SAH-origin adenosine) and restoring the AC substrate pool (magnesium for myokinase salvage, mitochondrial support for ATP regeneration). Caffeine remains a rational bridging strategy while these upstream interventions are being established — but the upstream work is what the brake ultimately requires.
Both pathways converge on the same adenosine pool. Caffeine blocks the downstream receptor. Infrastructure repair addresses both upstream sources.
Where in the Chain Each Intervention Acts
The degradation chain, and where each compensatory intervention acts, maps as follows:
Caffeine acts at the rightmost node — the receptor. It blocks where adenosine signals, but leaves adenosine production from both upstream sources (ATP catabolism and SAH hydrolysis) entirely unchanged. The sulforaphane/magnesium strategy acts at the leftmost node — reducing the neuroinflammatory ATP demand that generates the excess adenosine in the first place. The deeper the intervention in the chain, the more complete the compensation — but the further upstream the intervention, the longer the timeline to effect. This is why bridging with caffeine while building the upstream infrastructure is a rational transitional approach rather than an either/or choice.
Reduces ATP demand → Less ATP
depleted → Mg²⁺ Myokinase
2ADP→ATP+AMP → Less
adenosine → Less A1/A2A
inhibition of AC
Upstream repair addresses the source. Caffeine addresses the receptor. Both are valid positions in the chain — the upstream work is what produces lasting change.
Strategic Sequencing: Infrastructure First, Then Signal
Why the order of interventions matters as much as the interventions themselves
The six-layer unlock strategy described in Section 02 is not a list of parallel independent interventions — it is a staged sequence where earlier layers create the conditions that make later layers more effective. Understanding the sequencing argument is critical, because attempting to push through peptide-based signaling before the infrastructure is prepared repeats the failure mode of the secretin trials.
Reduce upstream neuroinflammation — the SST driver
Somatostatin rises in response to chronic immune activation. The upstream immune cascade — gut dysbiosis → mucosal immune failure → systemic immune activation → IDO1-driven tryptophan depletion → kynurenine/QUIN burden — is what is holding somatostatin elevated. Addressing gut ecology (butyrate, zinc carnosine, Bifidobacterium repletion, Vitamin D for VDR-driven sIgA restoration) reduces the chronic antigen translocation that feeds systemic immune activation. This is the foundational layer — without addressing it, every downstream intervention operates against an ongoing inflammatory signal that continuously reasserts the somatostatin lock.
Repair the glutathione/membrane layer — the GPCR coupling foundation
NAC + glycine + sulforaphane running simultaneously addresses membrane oxidation (BP1) and begins reducing the neuroinflammatory cytokine burden driving PDE4 (BP4). This layer can begin immediately — it does not require waiting for gut restoration. It also directly addresses any constitutional glutathione impairment from GSTP1 variants, which makes it both foundational and genetically targeted.
Restore the adenine nucleotide pool — the AC substrate and salvage layer
Magnesium (myokinase cofactor, Mg²⁺-ATP activator) and mitochondrial support address Breaking Points 2, 3, and 5 simultaneously. This layer becomes increasingly effective as Step ① reduces the inflammatory ATP demand that is depleting the pool in the first place. The two layers are mutually reinforcing: less inflammation means less ATP consumed by immune cells, means magnesium-supported myokinase salvage can do more with what is available.
Break the PDE4/NF-κB self-reinforcing loop
As the neuroinflammatory burden begins to reduce through Steps ① and ②, the PDE4 loop progressively weakens. This is not a separate intervention — it is the downstream consequence of the anti-inflammatory layers above. The practical effect: cAMP signals generated by whatever stimulatory peptide activity is present begin to last longer. The cascade starts transmitting partial signals where previously it generated none.
The brake releases — regulatory peptides can now transmit
As somatostatin tone falls with reduced neuroinflammatory pressure, as adenosine accumulation is reduced, and as PDE4 upregulation recedes, the adenylyl cyclase becomes progressively more responsive to stimulatory inputs. The body's own VIP, secretin, and oxytocin — which were never absent, merely unable to transmit — begin to carry their signals. This is the restoration of the reset system the body already has.
Add exercise to address BDNF consolidation (BP6)
With signaling infrastructure now partially restored, the gains that begin to emerge can begin to consolidate — but BDNF Val66Met limits activity-dependent BDNF secretion, reducing structural encoding. Aerobic exercise, specifically, has been shown to enhance BDNF secretion in Val66Met carriers through an exercise-driven pathway that partially compensates for the variant's impairment of the secretion mechanism. Structural gains become more durable as exercise-driven BDNF supplements the constitutionally limited activity-dependent pathway.
Why This Sequence Cannot Be Shortcut
It is tempting to attempt Step ⑤ directly — to administer the peptide reset signals while bypassing the infrastructure repair. The secretin trial experience documents precisely why this fails: administering stimulatory peptides against an actively maintained somatostatin lock, into a system where PDE4 immediately degrades whatever cAMP the peptide generates, does not produce durable benefit. It produces brief transient improvement followed by receptor desensitization that reduces even the brief transient response over time.
The sequence is not slow caution — it is mechanistic necessity. Steps ① through ④ are not preparatory niceties; they are the conditions that determine whether Step ⑤ can work at all. An infrastructure prepared by Steps ① through ④ responds to peptide signaling the way a functional cascade should. An unprepared infrastructure responds the way 1998–2002 did: briefly, partially, and with progressive desensitization.
Preparing for IMIG: Infrastructure Repair as a Prerequisite
Why the supplement protocol is not just concurrent support — it is mechanistically preparatory to immunological intervention working at all
Intramuscular immunoglobulin (IMIG) therapy targets the upstream neuroimmune dysregulation that drives the locked cascade — the chronic NK cell and T-cell activation that maintains the neuroinflammatory cytokine burden responsible for the somatostatin lock, the PDE4 upregulation, and the ATP-depleting immune activation that generates adenosine accumulation. Where the supplement protocol addresses the cascade from the intracellular level upward, IMIG addresses it from the immune regulatory level downward. They are complementary, not alternatives.
This creates a strategic question that is rarely asked in clinical trial design: what is the relationship between the supplement protocol and IMIG? If a patient enters an IMIG trial with a fully intact, compromised second messenger infrastructure — depleted ATP, adenosine accumulation, PDE4 upregulation, oxidized GPCR membranes — will the downstream signaling benefits of IMIG's immune modulation be attenuated by the same infrastructure failure that attenuated the secretin signal in 1998?
The G-protein cascade framework gives a precise answer: yes.
The Preparation Argument
IMIG modulates the upstream immune activation, but its downstream effects operate through the same second messenger pathways that the cascade failure has compromised. The anti-inflammatory effect of IMIG — the reduction in neuroinflammatory cytokine burden — will only produce improved downstream peptide and regulatory signaling if the infrastructure that signaling depends on has been prepared to receive it.
Consider the parallel with the secretin trials directly: IMIG-generated immune modulation reduces TNF-α and IL-1β — the same cytokines that upregulate PDE4. But if PDE4 is already constitutively elevated because the underlying ATP depletion and membrane oxidation have not been addressed, the reduction in cytokine-driven PDE4 upregulation will only partially restore cAMP duration. The intracellular conditions still attenuate every signal the improved immune environment generates.
The preparation argument is not slow caution — it is mechanistic sequencing. Running NAC + sulforaphane + magnesium before and concurrently with IMIG restores the glutathione/oxidative axis (BP1), partially restores the adenine nucleotide pool (BP3, BP5), and begins breaking the NF-κB/PDE4 self-reinforcing loop (BP4). These are the intracellular conditions that determine whether IMIG's upstream immune modulation can propagate into durable downstream functional benefit.
The supplement protocol is not a separate pathway running in parallel with IMIG — it is infrastructure preparation that determines the gain coefficient of whatever immune modulation IMIG achieves. The same infrastructure failure that made secretin trials look like failures would attenuate IMIG-generated signaling improvements if left unaddressed.
The IMIG Target Phenotype — Defined Without Reference to Any Single Case
IMIG, as developed by Fourie & Armstrong (2024) and the emerging clinical literature on immunoglobulin therapy in autism, targets a specific biological phenotype — not the behavioral diagnosis of autism broadly, but the neuroimmune dysregulation subgroup characterized by:
- Elevated NK cell activity — documented across multiple autism cohort studies as a consistent finding in a neuroimmune-dysregulated subgroup (Connolly et al.; Enstrom et al., 2009, Brain, Behavior, and Immunity)
- Aberrant T-cell activation profiles — skewed Th1/Th2/Th17 balance, reduced regulatory T-cell function, documented in the autism neuroimmunology literature (Ashwood et al., 2011, Journal of Neuroimmunology)
- Chronic neuroinflammatory cytokine elevation — TNF-α, IL-1β, IL-6, IL-17 persistently elevated in cerebrospinal fluid and peripheral blood in neuroimmune-dysregulated autism subgroups (Vargas et al., 2005; Careaga et al., 2017)
- Impaired antibody-mediated immune responses — suboptimal vaccine-antibody titers despite adequate vaccination history, consistent with immune dysregulation impairing normal B-cell response regulation
- Peptide signaling desensitization history — the rapid attenuation of benefit from secretin, oxytocin, or other cAMP-pathway peptides, which is the functional signature of the locked infrastructure that IMIG targets upstream
Families and clinicians seeking to evaluate IMIG candidacy should work from this phenotypic profile — not from behavioral symptom severity alone. The relevant laboratory assessments are NK cell and lymphocyte subset panel, inflammatory cytokine markers, and immunoglobulin subclass levels, interpreted in the context of the cascade model and reviewed with a clinician experienced in neuroimmune dysregulation.
The Integrated Three-Pathway Strategy
The supplement protocol, mucosal immune restoration, and IMIG are not alternative approaches — they are complementary layers of a single integrated strategy, each addressing the locked cascade from a different level:
- Supplement protocol addresses the intracellular infrastructure: glutathione/oxidative axis (BP1), ATP/adenosine pool (BP3, BP5), PDE4 loop (BP4), BDNF consolidation (BP6). Timeline: immediate, ongoing. No clinical trial enrollment required.
- Mucosal immune restoration addresses the gut-origin driver of systemic immune activation: sIgA restoration, Bifidobacterium repletion, butyrate production, tight junction integrity. Reducing antigen translocation reduces the chronic immune activation that holds somatostatin elevated. Timeline: months to years.
- IMIG addresses the systemic neuroimmune dysregulation directly — the NK cell/T-cell activation that drives the cytokine burden the supplement protocol and mucosal restoration are working to reduce from below. Timeline: clinical evaluation, then treatment cycles.
The strategic sequence: begin supplement protocol immediately → initiate mucosal restoration concurrently → obtain NK/lymphocyte subset panel and current stool analysis within 30–60 days to establish baseline → pursue IMIG evaluation if the neuroimmune dysregulation phenotype is confirmed. Run all three pathways simultaneously once IMIG is initiated — the supplement protocol and mucosal restoration enhance the cellular environment in which IMIG operates, and IMIG addresses the upstream driver that the other two pathways cannot fully reach on their own.