You’re basically asking:

“How do we stop doing 1997-style blind hammering and use TMS like a precision, state-dependent drug with tunable waveform parameters?”

Good. Annoying, but good.

I’ll break it into the logic chain:

1. What closed-loop TMS gives you

2. What controllable-pulse TMS (cTMS / PWM TMS) can actually change

3. How to connect them: state → pulse selection → metaplastic stacking

4. Concrete therapeutic strategies this enables (for depression, OCD, etc.)

5. What’s missing to make this real

1. What closed-loop TMS actually buys you

Closed-loop = you don’t just fire TMS on a schedule; you condition it on brain state or behavior in real time. Typically:

• EEG-triggered TMS

  • Phase-locked to specific oscillations (e.g. frontal alpha phase, theta in ACC).

  • Sample: M/EEG-triggered M1 pulses during specific phases produce phase-dependent plasticity (some phases strongly increase MEPs, others don’t, and the difference can be 2–3×).

• TMS-EEG response-based adaptation

  • Deliver a pulse → record TEP → adapt subsequent pulses based on amplitude, latency, connectivity, etc.

• Behavioral / symptom triggers

  • Eg, in OCD: cue-provoked symptom spike → deliver stimulation when the pathological network is “online.”

What closed-loop gives you:

• State-dependent plasticity estimates

  • You can empirically see: “when oscillation X is in phase φ, a pulse produces bigger or smaller N100 / P60 or MEP changes.”

• Per-subject response curves

  • Instead of “10 Hz at 120% RMT for everyone,” you start learning: “for this person, DLPFC TEP amplitude saturates at Y% RMT, and inhibitory components kick in past Z%.”

• Online measures of metaplasticity

  • You can see when the system is “primed” vs “fatigued” during accelerated sessions. For example, TEP amplitude or MEPs dropping across blocks shows homeostatic pushback.

On its own, closed-loop TMS lets you time and dose pulses better.

Now combine that with…

2. What controllable-pulse TMS (cTMS / PWM TMS) can change

Controllable TMS lets you treat the pulse like a parameterized object:

• Pulse shape: nearly rectangular vs damped sinusoid, monophasic vs (pseudo) biphasic.

• Pulse width: from ~20–30 µs to > 300 µs main phase.

• Direction & balance of phases: AP vs PA direction, relative amplitudes.

• Energy vs intensity tradeoffs: same neural effect at lower coil heating / discomfort.

And we know from M1 and TMS-EEG work:

• Changing shape/width changes:

  • Which interneuron populations you hit (I-wave composition, layer bias).

  • The sign and magnitude of after-effects (LTP-like vs LTD-like).

• You can, in principle, define a “pulse family” for each subject:

  • Pulse A: strong, excitatory bias

  • Pulse B: more inhibitory / local-circuit recruiting

  • Pulse C: minimal net plasticity, mostly a probe

So cTMS = ability to dial the microscopic “drug” properties of each pulse.

3. The link: closed-loop as the 

controller

, cTMS as the 

actuator

You want:

brain state → algorithm decides which waveform / width / intensity to use next → deliver pulse → measure response → update policy.

In more concrete steps:

1. Baseline mapping for each person

   • Use cTMS + TMS-EEG / MEP:

     • Sweep intensity × pulse width × shape at a given target (e.g. left DLPFC).

     • Measure TEP components (N45, P60, N100), MEPs (if M1), and maybe connectivity metrics (source-localized DLPFC → sgACC).

   • Identify:

     • A set of excitatory-leaning pulses (maximally increase excitability / DLPFC→sgACC inhibition).

     • A set of inhibitory-leaning pulses (engage local inhibition / dampen hyperactive nodes).

     • A neutral or low-impact probe pulse for ongoing readout.

2. Define steering variables

   • For depression: TEP metrics that correlate with “healthy” DLPFC-sgACC dynamics, e.g. enhanced long-latency inhibition, normalized frontal theta, or reduced hyperconnectivity to sgACC on perturbation.

   • For OCD: maybe ACC theta / beta dynamics, or TMS-EEG markers of error-monitoring hyperactivation.

   • You decide: “When variable V is too low / high, we want to drive it in direction D.”

3. Closed-loop policy

   • At each mini-block or even on single-pulse scale:

     • Measure current brain state (EEG phase, power, or TEP from probe pulses).

     • Compare to desired band (“therapeutic manifold”).

     • Choose pulse type:

       • State is hypoactive → choose excitatory pulse family (monophasic, longer width, AP direction, etc.).

       • State is hyperactive or overshooting → choose more inhibitory / shorter-width / different direction pulses.

       • State is near optimal → mostly probe pulses with minimal plasticity.

4. Metaplastic scheduling

   • Across an accelerated schedule (e.g. 10 blocks/day), monitor:

     • Diminishing TEP amplitude = possible saturation.

     • Shift toward more inhibition = homeostatic response.

   • Then:

     • Adjust inter-block spacing.

     • Switch from strong excitatory pulses in early blocks to softer or mixed pulses later, to avoid homeostatic “LTD backlash.”

So closed-loop decides when and how aggressively to push, and cTMS gives you the knobs to modify what each push does.

4. Specific therapeutic strategies this combo unlocks

Here’s how this maps to real conditions instead of abstract control theory.

A. Depression (DLPFC–sgACC circuit)

Goal: strengthen top-down DLPFC control over sgACC, normalize network dynamics, avoid “burnout” over a dense SAINT-style course.

Potential approach:

1. Initial mapping day

   • For this patient’s left DLPFC site (fcMRI-guided anti-correlated to sgACC):

     • Find pulses that maximally:

       • Increase DLPFC TEP early components without overshooting N100.

       • Strengthen DLPFC-to-sgACC functional/inferred effective connectivity in TMS-EEG / concurrent fMRI.

2. During accelerated sessions

   • Use EEG to phase-lock pulses to fronto-midline theta or target specific slow-wave phases associated with better sgACC inhibition.

   • Start blocks with maximally excitatory pulse shape/width when cortical network is “cold.”

   • As TEP amplitudes climb or sgACC activity drops, gradually:

     • Shorten pulse width / switch to a slightly more balanced or less aggressive waveform.

     • Increase inter-train interval when markers suggest metaplastic fatigue.

3. Guardrails

   • If TEP markers of hyperexcitability appear (e.g. excessive early components), shift to more inhibitory-biased pulses for a block, then recheck.

You effectively get dose-adapted SAINT rather than “18,000 identical biphasic pulses no matter what your brain is doing.”

B. OCD / anxiety: ACC / pre-SMA focused

Goal: modulate pathological error / conflict monitoring loops.

• Use symptom provocation + EEG to identify when ACC/pre-SMA is in hyper-error mode.

• Deliver inhibitory-biased pulses (pulse shapes / widths known to produce LTD-like after-effects in that target) only during those states.

• For maintenance, use weaker pulses or neutral probes to track whether circuit re-hyperactivates over days.

Closed-loop gives the “only stimulate when the pathological pattern is online” aspect; controllable pulses let you fine-tune whether you’re gently damping vs strongly quenching.

C. Personalized “plasticity windows” in accelerated protocols

In dense schedules:

• Use probe pulses to estimate how much plasticity reserve is left in that day:

  • If response to standard probe is shrinking across blocks → you’re saturating.

  • Then:

    • Lower intensity,

    • Shorten pulse width, or

    • Shift to maintenance-style stimulation for the remaining blocks.

The upshot: instead of blindly giving everyone 10 identical blocks/day, you adapt the waveforms and intensities so that each block actually does something neuroplastic, instead of just adding side effects.

5. What this needs that we don’t quite have yet

You’re basically sketching the next decade of TMS development. What’s missing:

1. Robust, individual markers of “good plasticity”

   • We need TEP / EEG signatures where we can confidently say:

     “Increasing this feature over sessions predicts symptom improvement for this diagnosis.”

   • Very early, noisy, but there are hints (e.g., TMS-EEG markers of cortical inhibition / excitation balance, sgACC response normalization in depression).

2. cTMS hardware integrated with real-time EEG

   • Some labs have bits of this: cTMS devices + closed-loop phase-locked stimulation on M1. But:

     • It’s rare in clinical settings.

     • Integrations are custom / research-only.

3. Control policies tested in humans, not just sims

   • Need trials where you compare:

     • Standard iTBS vs

     • Closed-loop timing only vs

     • Closed-loop timing + waveform adaptation (full state-to-pulse control).

   • That’s the experiment you actually want.

4. Regulation & usability

   • Clinics will not adopt a system that requires a PhD in control theory at the console.

   • So all of this has to be wrapped into a simple, device-level “adaptive mode”, where the algorithm chooses pulses internally and the operator just sets safety and target ranges.

Condensed version for your internal model

• Closed-loop TMS = learns when and how much to stimulate based on brain state & response.

• Controllable-pulse TMS = lets you change what each pulse actually does at the circuit level.

Combine them and you get:

State-dependent choice of pulse family (shape/width/direction/intensity) that steers a targeted network toward a desired dynamical regime, while monitoring metaplasticity and avoiding saturation.

That’s “maximum therapeutic effect” in a serious sense: not more pulses, but better-placed, better-shaped ones, matched to the patient’s actual brain state instead of a spec sheet written in 2006.