A layered control-state framework for understanding symptom expression (M1–M3), global load (GLA / ER stress), control sensitivity (SMPDL3B), and time-dependent progression from Phase 1 to Phase 4.
Michael Daniels · GLA Framework · Version 2.4 · December 2025
This document describes disease progression in ME/CFS using a layered control-state model. Rather than proposing a single linear cause, it explains how symptoms emerge, fluctuate, and become persistent through the interaction of multiple physiological layers over time.
To reduce confusion, the framework is introduced one layer at a time, before addressing disease severity and progression.
How to interpret severity: disease severity should be read as a control problem, not a capacity problem. Symptoms emerge when sufficient load is applied to vulnerable terrain within a system that has lost regulatory resilience.
The first layer describes where symptoms express when the system is stressed.
In this framework, symptoms do not arise randomly. Instead, they emerge within specific physiological domains that are predisposed to failure under load. These domains are referred to as symptom amplifiers and are labeled M1–M3.
The three amplifiers represent distinct regions of symptom terrain:
These amplifiers should be understood as stable symptom terrain, not disease stages, disease types, or severity categories. Patients do not progress from one amplifier to another. Instead, the amplifiers define which physiological systems become symptomatic once thresholds are crossed.
As stress on the system rises or falls, different regions of the symptom terrain may become more or less exposed. During recovery or deterioration, patients may therefore experience shifts in which symptom domains dominate their clinical presentation.
Earlier GLA documents referred to this phenomenon as subtype drift. In the present framework, subtype drift should be understood primarily as a change in exposure, not a change in the underlying terrain. Shifts in dominant symptom patterns most often reflect changes in overall system load and/or control bandwidth, which determine which terrains cross threshold at a given time.
In practical terms:
This interpretation preserves the stability of the M1–M3 framework while accurately reflecting clinical observation.
Apparent subtype drift is most commonly observed following step-changes in system state, such as:
By contrast, day-to-day post-exertional malaise typically reflects oscillation within the same symptom terrain rather than a reconfiguration of dominant amplifiers. PEM represents transient rises in stress that expose more of an already vulnerable terrain, not a change in which terrain exists.
Layer 1 does not define disease severity or disease progression.
Symptom amplifiers describe where failure expresses, not:
Those dimensions emerge only when symptom terrain interacts with global load (Layer 2) and control sensitivity (Layer 3), which are addressed next.
Layer 1: This terrain illustrates an M1-dominant pattern with moderate M2 and minor M3 symptom expression at baseline.
The second layer describes how much stress the system is under.
In this framework, Gut–Liver–Autonomic (GLA) burden and ER stress are treated as a single global load variable, analogous to a rising or falling water level across the symptom terrain described in Layer 1. As this load increases, more terrain becomes flooded into active symptom space; as it falls, terrain re-emerges and symptoms may recede.
Crucially, this layer determines how much of the terrain is exposed, not which terrain exists.
Global load integrates multiple upstream pressures into a common physiological stress signal, including:
These inputs converge on ER stress and downstream signaling, which function as a system-wide load integrator. When processing demand exceeds throughput capacity, load rises globally rather than remaining confined to a single organ or pathway.
This integrative role explains why GLA burden behaves like a water level: it rises and falls system-wide, affecting all symptom terrains simultaneously.
Because global load acts broadly, relatively small changes in load can have nonlinear effects.
As the water level rises:
This explains why patients may feel relatively stable at rest yet deteriorate abruptly after modest exertion, and why symptom onset often feels sudden rather than gradual.
A defining feature of global load is that it accumulates and resolves over time, rather than peaking at the moment of exertion.
During activity:
Symptoms often peak after activity because load continues to rise while processing and recovery lag behind demand. This delayed peak is a defining feature of post-exertional malaise and is naturally explained by load accumulation rather than by immediate injury or inflammation.
At rest, global load may remain below activation thresholds for much of the terrain. As a result, standard clinical tests performed under resting conditions often fail to detect abnormalities.
Under exertion or sustained stress:
This disconnect between resting measurements and exertional collapse is a hallmark of ME/CFS and is directly accounted for by the global load layer.
It is important to be precise about the role of Layer 2.
Global load:
Those questions depend on control sensitivity, which is introduced in Layer 3.
Layer 2 answers a narrower but essential question: How much of the symptom terrain is flooded at a given time?
Layer 2: Global load behaves like a water level rising across the same symptom terrain. As load rises, more terrain becomes exposed to symptoms. Delayed peak illustrates why symptoms can worsen after activity rather than during it.
The third layer describes how fragile regulation is.
While Layer 2 determines how much stress (load) is applied to the system, Layer 3 determines how the system responds to that load. This layer governs the distance between stability and collapse — the system’s control bandwidth.
Control sensitivity refers to how easily physiological thresholds are crossed and how effectively stability is restored afterward. In practical terms, it determines:
Two patients may experience similar symptom patterns under similar global load yet differ markedly in tolerance, pacing response, and recovery. These differences arise from control sensitivity, not from symptom terrain or load alone.
Within the GLA framework, SMPDL3B functions as a key regulator of membrane organization and signaling stability, and therefore of control bandwidth.
Variation in SMPDL3B regulation shapes:
Importantly, this layer does not determine where symptoms express — that is fixed by the M1–M3 terrain — nor does it determine how much load is present. It determines how much load the system can tolerate before regulatory control is lost.
Different SMPDL3B phenotypes can produce overlapping symptoms through distinct failure modes. These differences influence pacing tolerance, medication responses, and recovery trajectories.
As disease advances, repeated stress and incomplete recovery can reduce effective control bandwidth across phenotypes. In later stages, this loss of control can make distinct phenotypes appear clinically similar without implying mechanistic convergence or phenotype conversion.
Similarity of symptoms therefore does not imply similarity of underlying control architecture.
A key implication of this layer is that worsening illness does not necessarily reflect permanent loss of physiological capacity. Instead, it often reflects loss of regulatory control.
As control bandwidth narrows:
This explains why patients may feel “weaker” or more reactive over time even in the absence of progressive tissue damage.
Layer 3 explains why repeated exposure to load without full recovery gradually destabilizes the system. When regulatory control is lost before recovery completes, the baseline state itself begins to shift. Thresholds lower, margins shrink, and the system operates closer to failure even at rest.
This process sets the stage for baseline threshold erosion, which defines disease progression over time and is addressed in the next layer.
Layer 3: Control sensitivity determines how easily thresholds are crossed and how completely recovery restores stability. The same global load (Layer 2) can produce mild, contained symptom exposure (wide bandwidth) or steep, runaway exposure with incomplete recovery (narrow bandwidth).
The fourth layer introduces time.
Disease progression in this framework reflects baseline threshold erosion: a gradual loss of regulatory headroom that occurs when physiological stress recurs before full recovery is achieved. Progression is therefore not defined by new pathology or cumulative damage, but by persistent elevation of baseline load combined with narrowing control bandwidth.
Severity reflects how much of the symptom terrain is chronically flooded and how close the system operates to collapse, rather than which amplifier or phenotype a patient has.
Under stable conditions, transient increases in load are followed by recovery that restores baseline stability. In ME/CFS, recovery is often incomplete. When stress recurs before stabilization is complete, the baseline state itself begins to shift.
Over time:
This process does not require continuous inflammation or structural injury. It reflects loss of regulation, not loss of capacity.
The phases below describe control states, not fixed timelines. Movement between phases is possible, particularly in earlier stages, but becomes increasingly constrained as baseline erosion advances.
Most symptom terrain remains unflooded at rest. Thresholds are high, and resilience is relatively preserved.
Residual instability accumulates, gradually raising the baseline and narrowing tolerance to exertion.
Large portions of the terrain are chronically flooded. Different phenotypes and amplifiers may appear clinically similar due to shared loss of control, despite distinct underlying mechanisms.
Phase 4 represents a depolarized control state with extreme baseline threshold erosion. This reflects regulatory failure rather than inevitable irreversible damage, though recovery capacity is severely constrained.
Progression depends on the balance between:
Improvement is possible, especially in earlier phases, but becomes increasingly difficult as regulatory margins erode. Because progression reflects control-state degradation rather than structural injury, reversibility is possible in principle, though increasingly limited in practice.
Layer 4 explains why severity increases over time, why recovery windows shrink, why late-stage disease converges clinically, and why pacing and intervention rules must change by phase.
Disease progression in ME/CFS is therefore best understood as a time-dependent loss of regulatory control emerging from repeated interaction between terrain, load, and sensitivity.
Layer 4: Disease progression is a control-state shift over time. With repeated stress before full recovery, baseline load rises, control bandwidth narrows, and recovery windows shrink—flooding more symptom terrain even at rest.
Baseline threshold erosion refers to the progressive loss of regulatory headroom that occurs when physiological stress repeatedly exceeds the system’s ability to recover.
Within the landscape model, erosion reflects a gradual rise in baseline load combined with narrowing control margins. Over time, more symptom-relevant terrain remains flooded even at rest, and increasingly small perturbations are sufficient to trigger disproportionate symptom escalation.
Crucially, baseline threshold erosion does not imply cumulative tissue damage or continuous inflammation. Instead, it reflects a failure to fully re-establish regulatory stability between episodes. Each incomplete recovery leaves the system operating closer to its activation thresholds, reducing tolerance and compressing recovery windows.
As erosion advances:
Baseline threshold erosion therefore provides the mechanistic link between repeated stress exposure and disease progression, preparing the ground for the integrative interpretation that follows.
Baseline threshold erosion occurs when episodes recur before full recovery completes. Each incomplete recovery leaves a higher baseline, while the headroom band (distance to collapse thresholds) becomes progressively smaller.
This document has framed disease progression in ME/CFS as a layered problem of regulatory control, rather than a linear process of accumulating damage. Symptoms, severity, and progression emerge from the interaction of where failure can express, how much stress is present, how fragile regulation is, and how these interactions unfold over time.
Across the four layers, a coherent picture emerges:
Disease severity is therefore not a property of any single layer. It reflects chronic flooding of symptom terrain combined with diminished control bandwidth, rather than a change in subtype, amplifier, or diagnosis.
This framework explains why ME/CFS can:
It also explains why pacing tolerance, medication responses, and recovery potential vary by phase and control state, rather than by symptom label alone.
This framework does not claim:
The model is descriptive and integrative, not diagnostic, and is intended to clarify interpretation rather than prescribe treatment.
The central implication is that protecting regulatory control and recovery capacity matters as much as reducing symptoms. Early recognition of load intolerance, pacing appropriate to disease phase, and avoidance of repeated incomplete recovery are critical to limiting further baseline threshold erosion.
Viewed through this layered lens, ME/CFS progression becomes interpretable without reduction to a single pathway, trigger, or stage—allowing symptoms, variability, and severity to be understood as expressions of a unified control-state architecture.