Telmisartan as a useful biological “nudge-therapy,” particularly in bumetanide-responsive autism

 

A nudge is usually better than the sledgehammer !

 

Today’s post is another one most appropriate for people living in autism treatment-friendly counties (Russia, Ukraine, India, USA, Italy, Poland etc). Others will likely see this as from an alternative reality! The post is a bit long, just skip through it. 

My trial dose continues to be 20mg in a 65kg person. Doses trialed in schizophrenia have been much higher. Low doses are always the safest.

The post started life not as a review of any peer-reviewed clinical trials, but rather as an observational report, showing that revisiting the basic science can pay off. I made my initial review several years ago for my own purposes, but shared it in my blog.

I see that in fact the research has partially caught up:

Feinstein Institutes’ scientists find common blood pressure drug could be beneficial in some cases of autism

Scientists at Northwell Health’s Feinstein Institutes for Medical Research have made a significant discovery in autism spectrum disorder (ASD): a widely used blood pressure medication, captopril, can restore healthy function to the brain’s immune cells and reverse ASD-like behaviors in a preclinical animal model. This invaluable research focuses on a specific type of ASD believed to be triggered by a mother’s immune system during pregnancy, and could better understand autism and autism-like symptoms.

 

The full paper is here: 

Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG

 

What this now means - research from 2025 supports Peter’s 2017 idea to use telmisartan for autism

In 2025, researchers at the Feinstein Institutes for Medical Research published a preclinical study showing that modulation of the brain’s renin–angiotensin system (RAS) can reverse autism-like features in a specific immune-primed mouse model. In this model, prenatal immune exposure led to persistent microglial activation, synaptic abnormalities, and altered social behavior — changes that were significantly improved by treatment with captopril, an ACE inhibitor capable of crossing the blood–brain barrier.

Importantly, the study demonstrated that central (brain) RAS signaling is biologically relevant to neurodevelopmental plasticity, and that immune-driven alterations are not necessarily fixed. The benefit was not seen with ACE inhibitors lacking brain penetration, highlighting the importance of central rather than purely peripheral effects.

While captopril was used as a proof-of-concept tool, the underlying mechanism strongly supports the rationale for angiotensin receptor blockers (ARBs) — particularly telmisartan — which offer several advantages. Telmisartan directly blocks AT1 receptors, preserves potentially beneficial AT2 signaling, has a long half-life, and exerts additional anti-inflammatory, metabolic, and mitochondrial effects that are highly relevant to common autism subtypes involving neuroinflammation, behavioral rigidity, fatigue, and impaired stress resilience.

Thus, although the 2025 study does not establish a clinical treatment for autism, it independently validates the systems-level reasoning behind using telmisartan as a chronic “nudge” therapy in carefully selected autism phenotypes. The research supports the mechanism Peter proposed years earlier: that gently modulating regulatory systems such as the brain RAS can restore function in plastic but dysregulated neurodevelopmental circuits.

 

The keep it simple approach

I set out a very simple of framework of classic (Level 3) autism many years ago in this blog. It is also in my book and some presentations.

 

Today’s post falls in to the “central hormonal dysfunction” category.

Renin and angiotensin are both hormones

For the brain, angiotensin (especially angiotensin II) is the one that really matters. Renin is mostly just the upstream trigger.

The brain has its own local renin–angiotensin system, partly independent of the circulating one.

 

A recap for the science lovers - Angiotensin II in the brain

Angiotensin II is the active signalling molecule that actually does things in neural tissue:

• Acts as a neuromodulator
• Shapes excitatory–inhibitory balance
• Influences dopamine, GABA, glutamate
• Regulates stress, threat detection, motivation
• Affects neuroinflammation, oxidative stress
• Alters plasticity and myelination

All of that happens via angiotensin receptors, mainly AT1 and AT2.

 

In the brain, which receptor is activated matters more than how much angiotensin is around:

AT1 receptor (problematic when dominant)

• Increases stress signalling
• Promotes neuroinflammation
• Increases sympathetic tone
• Worsens cognitive rigidity

AT2 receptor (generally protective)

• Promotes neurite growth
• Supports learning and repair
• Anti-inflammatory
• Pro-plasticity

This is why ARBs (especially telmisartan) are interesting neurologically:

• They block AT1
• They shunt signalling toward AT2
• They act inside the brain, not just on blood pressure

 

Back to the more readable stuff

When treating broader autism you can consider the 150-200 possible therapies as ranging from small nudges in the right direction, to a precise hit with a mallet that corrects a precise dysfunction (a specific ion channel dysfunction, a lack of folate in the brain) to a sledge hammer that affects the entire brain (potassium bromide, as an example).

If you have epilepsy and severe aggression then a sledgehammer may well be what you need.

When I first trialed Telmisartan many years ago, I saw that it had an immediate effect, but back then I did not see it as being big enough. It certainly was a nudge, but I was still looking for that mallet, or indeed a sledgehammer. So I moved on.

Last year I revisited Telmisartan and now it is a core therapy. I am happy to include nudge therapies.  

If you have mild autism then a nudge or two maybe all that you need to overcome troubling issues.

If you follow my polytherapy approach for severe autism, then you might select a few nudge therapies and some stronger ones to create a personalized optimization.

 

Telmisartan

Telmisartan is an ARB (angiotensin II type-1 receptor blocker) commonly used to lower blood pressure. But, Telmisartan is thought of best understood not as a single-target drug, but as a system-level regulator.

Telmisartan is highly fat soluble (lipophilic) so it can penetrate the brain and even your bones. Bones matter for old people and all people with level 3 autism.  

Bones are a weak point in severe autism due to the side effects of drugs commonly used, poor diet, lack of exercise and specific genetic issues (in some monogenic autisms).

Bone is not inert. It has active RAAS signalling, telmisartan reaches bone tissue and blocks local AT₁ signalling, reduces inflammatory and oxidative tone in bone microenvironments. Via PPAR-γ, can influence osteoblast/osteoclast balance improving bone density

So an unexpected nudge towards stronger bones. 

The core actions

• AT₁ receptor blockade (RAAS modulation)
  Reduces chronic angiotensin II signalling, lowering background stress, sympathetic drive, and neurovascular strain.
• PPAR-γ partial agonism
  Improves metabolic efficiency, mitochondrial function, and lipid–glucose handling; contributes to anti-inflammatory effects.
• Autonomic calming
  Lowers sympathetic tone and stress reactivity without sedation. This a nudge effect towards better sleep, in some people
• Anti-inflammatory and antioxidant effects
  Indirectly reduces microglial activation and oxidative stress signalling. Microglia are the brain’s immune cells and can be in state of constant activation, which blocks them doing their basic housekeeping duties.
• Neurovascular effects
  Improves cerebral blood flow regulation and oxygen–nutrient delivery. In many types of severe autism, and also in dementia, the brain is unable to produce enough fuel (ATP). While there are many possible factors involved a key one is delivery of glucose and oxygen from your blood.

 

Indirect downstream effects (relevant to neurodevelopment)

• Improved cellular energy status
  Supports ion-pump function and transporter regulation. This is a nudge by improving the environment, Telmisartan does not force the ion-pumps directly
• Stabilisation of chloride homeostasis (indirect)
  Biases the NKCC1–KCC2 balance toward better chloride extrusion in vulnerable circuits, without forcing a gradient shift.

This is the big plus for bumetanide responders

Neuronal chloride levels are set by the balance between NKCC1 (chloride import) and KCC2 (chloride extrusion).

In some with autism the GABA development switch failed to activate after birth and so NKCC1 is overexpressed and KCC2 is under expressed

Stress, inflammation, and high activity increase NKCC1 influence and chloride loading.

KCC2 function is energy- and redox-dependent, and degrades under metabolic strain.

Telmisartan does not directly block NKCC1 or activate KCC2.

By reducing RAAS-driven stress signalling, it lowers pressure toward chloride accumulation.

Improved metabolic and redox conditions stabilise KCC2 membrane function.

Reduced autonomic overdrive lowers activity-dependent chloride loading.

The net effect is a bias toward more reliable chloride extrusion in vulnerable circuits.

This stabilises inhibition without forcing a chloride gradient shift, which KBr the sledgehammer would do. 

• Reduced excitability pressure
  Lowers the likelihood that inhibitory signalling becomes destabilised under stress.

 

Theoretical functional consequences (when it works)

• Lower baseline arousal and irritability
• Improved mood stability
• Increased behavioural flexibility
• Greater tolerance of sensory and cognitive load
• Enhanced availability for learning and interaction

 

My experience

When I conducted my review of “all autism” several years ago I did look at angiotensin. It looked to me that Telmisartan ticked many of the boxes for a cheap generic drug that could be repurposed for autism.

I did trial it and noted an immediate mood improvement with the strange effect of making Monty want to sing.

Several years later trialing it again. Again mood improved, there was no singing, but there was a desire to dance.

It also makes him less rigid. The best example is that when he empties the dishwasher he very clearly now puts things back in different places. You could argue this is negative, or you could see that as expressing his will rather than robotically following a pattern. More on that in the basal ganglia section.

The Basal Ganglia

The basal ganglia is the part of the brain that drives conditions like Tourette syndrome and PANS-PANDAS.

In PANS-PANDAS the immune system temporarily hijacks basal ganglia signalling. This is reversable, with prompt treatment.

The basal ganglia do not generate behaviour.

They gate behaviour.

When basal ganglia inhibition is stable:

• unwanted actions are quietly suppressed  (no tics)
• chosen actions feel voluntary
• habits can be overridden (no autistic rigidity)
• novelty is possible (try new foods, or watch a different cartoon) 

When basal ganglia function is disrupted (by genetics, inflammation, chloride instability, dopamine imbalance, Purkinje cell loss):

• the repertoire of behaviours is still there
• the motor programs still exist
• the thoughts still arise

What is lost is control over which ones fire. This manifest in autism as

Rigidity and stereotypies

• Repetitive behaviours are not “added”
• They become locked in
• Alternative actions cannot pass the gate

The system defaults to what feels safe and known.

This links to 2 further subjects of interest:

·        Purkinje cell loss in severe autism
·        ARFID (Avoidant/Restrictive Food Intake Disorder)

 

Purkinje cell loss as one possible driver of basal ganglia dysfunction

Purkinje cells are the very large, energy-intensive output neurons of the cerebellar cortex, providing continuous inhibitory timing signals to the deep cerebellar nuclei.

During the first two years of life, rapid brain growth creates extreme ATP demand, and transient mitochondrial or metabolic shortfalls can cause brief “power outages.” Because Purkinje cells are among the largest and most metabolically demanding neurons, they are selectively vulnerable and may be lost early, in a patchy and permanent manner. This a classic finding in port-mortem brain studies of people who had severe autism.

Purkinje cell loss leads to clumsiness and dyspraxia, because the cerebellum’s output signal loses timing precision, causing movements to be poorly planned, sequenced, and adjusted despite normal muscle strength. It does not lead to paralysis.

The resulting noisy cerebellar output propagates via thalamocortical loops to the basal ganglia, where it destabilizes action-selection and gating, particularly in the context of immature chloride regulation and weakened GABAergic inhibition.

Although the original cerebellar injury cannot be reversed, downstream circuits remain plastic, allowing pharmacological “nudges” such as bumetanide, atorvastatin, and telmisartan to partially restore inhibitory precision, improve basal ganglia gating, and reopen a window of motor-cognitive flexibility.

 

ARFID (Avoidant/Restrictive Food Intake Disorder)

ARFID can be the feeding expression of the same underlying circuit problem.

The framework explains ARFID extremely well, especially the autism-associated form of ARFID. In fact, it explains it better than sensory-only models. 

ARFID through the basal ganglia “gate” lens

Repetitive behaviours are not added — they become locked in.
Alternative actions cannot pass the gate.
The system defaults to what feels safe and known.

That description fits ARFID almost perfectly. 

In autism and related neuroimmune states, ARFID often acts as a behavioural marker of basal ganglia gating dysfunction, reflecting loss of choice rather than loss of appetite.

ARFID is not always basal ganglia–driven.

There are other ARFID subtypes:

• trauma-based (choking/vomiting)
• primary sensory aversion
• gastrointestinal pain–avoidance
• appetite dysregulation from meds or illness

But in autism-associated ARFID, especially when it:

• fluctuates with stress or illness
• coexists with rigidity, tics, OCD traits
• improves alongside mood and flexibility

the basal ganglia model fits extremely well. 

Blunt pharmaceutical treatment (sledgehammer) of ARFID does not work. Nudges seem a better choice. Nudges can be behavioral, or biological. 

Beyond telmisartan, the most promising pharmaceutical nudges for ARFID are likely those that reduce immune and autonomic stress on basal ganglia circuits while preserving motivation and behavioural flexibility, rather than suppressing output.

Many autism interventions provide a nudge to better functioning of the basal ganglia (NAC, ALA, low dose clonidine, atorvastatin etc).

Indeed one notable immediate effect of atorvastatin on Monty 14 years ago, was that he starting to come downstairs from his bedroom by himself, and not get “stuck” at the top of the stairs awaiting instructions.

I used to call this cognitive inhibition, but perhaps the gating model explains it better.

 

What the behaviour actually shows

“Stuck at the top of the stairs awaiting instructions”
is not a strength or balance problem.

It reflects:

• failure of self-initiated action
• dependence on external cueing (prompt dependence, in ABA terminology)
• intact ability, but blocked execution

That already points away from motor cortex and toward action-selection systems.

 

Basal ganglia explanation

Basal ganglia = action gating, not movement generation

The basal ganglia decide:

• when an action is allowed to start
• whether it is safe to proceed without prompting

In autism (and related neuroimmune states), this gate can become over-conservative:

• “wait”
• “don’t move”
• “need instruction”

So the child:

• knows how to go downstairs
• but cannot release the action independently

 

Why stairs are a perfect stress test

Descending stairs requires:

• motor sequencing
• balance prediction
• suppression of fear/uncertainty
• confidence in outcome

Basal ganglia dysfunction often shows up first in:

• transitions
• initiation
• descending movements
• unprompted actions

So “stuck at the top of the stairs” is a classic gating failure.

 

Why atorvastatin could change this quickly

Atorvastatin did not:

• teach a new skill
• strengthen muscles
• improve coordination

What it plausibly did was reduce a state constraint.

Immune / inflammatory relief

If there was:

• low-grade neuroinflammation
• immune-driven basal ganglia noise

Then dampening that can:

• lower threat signalling
• stabilise dopamine–GABA balance
• relax excessive inhibitory gating

When that happens:

actions that were already available suddenly “go.”

That can be rapid.

 

Reduced “protective inhibition”

In stressed systems, the brain sometimes actively prevents independence:

• to avoid risk
• to avoid uncertainty

Once the stress signal drops, the system stops applying the brake.

This feels like:

• confidence
• initiative
• independence

 

Why instruction dependence disappears

Needing instruction is a workaround:

• the external cue substitutes for internal gating
• the basal ganglia borrow cortical direction

When gating improves:

• the workaround is no longer needed
• behaviour becomes self-initiated

This is not just basal ganglia

Other systems likely contributed:

Cerebellum

• prediction of movement outcome
• timing and sequencing
• fear of misstep

Cerebellar function improves when:

• inflammation drops
• prediction error decreases

Autonomic system

• high sympathetic tone increases “freeze”
• calming allows movement initiation

Confidence loop

• once one successful descent occurs
• future attempts are easier
• habit loop updates

But the gatekeeper is still basal ganglia.

 

Conclusion

The basal ganglia are not “movement centres” in the simple sense.
They are action–selection and state–selection systems.

They decide:

• which action to initiate
• when to initiate it
• whether to repeat the same pattern or explore a new one
• how much reward, pleasure, and motivation is attached to action

They sit at the junction of:

• movement
• mood
• motivation
• habit
• flexibility

That is why basal ganglia changes show up as movement + emotion + novelty, all together.

 

Basal ganglia are especially sensitive in autism

Basal ganglia circuits:

• are GABA-heavy
• are chloride-sensitive
• rely on finely balanced inhibition
• are vulnerable to stress, inflammation, and metabolic strain

When inhibition in these circuits is unstable:

• action initiation becomes effortful
• behaviour becomes repetitive and rigid
• novelty feels unsafe
• mood flattens or becomes anxious

What changed biologically (without forcing anything)

When inhibition becomes more reliable (not stronger, just more predictable):

• neurons fire when they should, not erratically
• “gating” improves and actions can pass through more smoothly
• reward signals are no longer drowned out by noise

 

Why did Monty become happier

Mood is not just cortical thought, it is basal ganglia tone.

With better inhibitory stability:

• dopamine signalling becomes cleaner
• reward prediction improves
• the background “threat” signal drops

The result is:

• spontaneous positive affect
• relaxed facial expression
• joy without obvious cause

This is state change, not learned happiness.

 

Why the urge to dance appears

Dancing is a near-perfect basal ganglia readout.

It requires:

• effortless movement initiation
• rhythmic pattern generation
• reward linked directly to motion

When basal ganglia output is constrained:

• movement feels heavy
• initiation is delayed
• spontaneous rhythm disappears

When the constraint lifts:

• movement becomes intrinsically rewarding
• the body “wants” to move
• rhythm emerges without instruction

That is why dancing appears before language or cognition improves.

 

Why he emptied the dishwasher differently

Changing how a familiar task is done means:

• the brain is no longer locked into a single motor–habit template
• alternative action sequences are now selectable
• exploration feels safe

This is classic basal ganglia flexibility.

Nothing taught him that new method.

The system simply allowed another option to pass through the gate.

 

 

 

Brain repair, protection, or optimization: what is biologically possible in level 3 autisms?

 

Piano tuning vs Brain tuning

Discussions about brain repair often mix together very different biological processes. This leads to confusion, unrealistic expectations, and unhelpful metaphors—most notably the idea that autism reflects “miswired” brains that must somehow be rewired. A more useful approach is to distinguish between construction, protection, repair, and optimization, and to recognise that each dominates at different stages of life and in different conditions.

This discussion focuses primarily on level 3 autism, where early developmental vulnerability, high support needs, and biological stressors play a central role in shaping long-term outcome.

 

Why “brain wiring” is a misleading analogy — and why fine-tuning is better

Autism is frequently described using the language of wiring: faulty circuits, miswired connections, or incorrect neural networks. While intuitively appealing to some, this metaphor is biologically misleading and ultimately unhelpful when discussing development, intervention, or long-term outcome.

The brain does not contain fixed wires. Neurons are living cells embedded in a biochemical, metabolic, and immunological environment that is in constant flux. Synapses strengthen and weaken, receptors are trafficked in and out of membranes, ion gradients shift, myelination adapts to activity, and neuromodulators continuously reshape how information is processed. Even in adulthood, neural networks are not static structures but dynamic systems.

The problem with the wiring metaphor is not that it is entirely wrong, but that it implies permanence and rigidity. Wires, once laid incorrectly, must be physically replaced. This framing naturally leads either to pessimism (“the brain is miswired and cannot be fixed”) or to unrealistic repair narratives (“we must rewire it”). Neither reflects how brains actually function.

A more accurate analogy is fine-tuning or calibration.

In many forms of autism—particularly outside of early severe neuronal loss—the core issue is not missing connections, but suboptimal parameter settings within otherwise intact networks. These include excitatory–inhibitory balance, timing and synchrony, sensory gain control, neuromodulatory tone, and signal-to-noise ratios. These parameters are continuously adjustable across the lifespan.

Fine-tuning implies adjustment rather than reconstruction, optimization rather than replacement. It explains why meaningful improvement remains possible in adulthood, while also acknowledging that early developmental constraints can limit what is achievable later.

In level 3 autism, early neuronal loss or failure of maturation can impose hard structural constraints. In such cases, fine-tuning cannot recreate missing cell populations or replay early construction. But even here, the remaining networks still require calibration. Early protection raises the ceiling; later tuning determines how close that ceiling is reached.

This distinction underlies the rest of this discussion.

 

Neuroblasts: builders, not repair workers

Neuroblasts play a central role during early development. They generate neuronal populations, migrate to appropriate regions, and differentiate into specific cell types. In doing so, they establish the cellular and developmental context in which later plasticity operates.

Outside of development, however, their role is limited. In adulthood, neuroblast generation is sparse and restricted to specific niches, and their contribution to functional recovery after injury (such as stroke) is modest and local. Neuroblasts are therefore best understood as developmental builders, not as the primary agents of ongoing brain repair or optimization.

This distinction matters, because many neurodevelopmental conditions arise from a developmental vulnerability during periods of rapid growth and high metabolic demand.

 

Early vulnerability, degeneration, and plateau

Several severe neurodevelopmental disorders share a common pattern: early disruption or selective neuronal loss followed by long-term stability rather than ongoing degeneration.

Examples include Rett syndrome, CASK-related disorders, certain mitochondrial diseases, and some forms of regressive autism. In these conditions, neurons are lost or fail to mature during early life, when metabolic demand is high and protective systems are immature. Once development slows, the system stabilises and a plateau is reached.

This pattern is often misinterpreted as neurodegeneration. In reality, it reflects failure to complete development under stress, not a progressive destructive process.

 

Mild autism: intact structure, altered tuning

In contrast, many individuals diagnosed with milder forms of autism show preserved gross brain structure, intact cellular populations, and no widespread neuronal loss. Here, the challenge is not repair in the sense of replacing lost neurons, but optimization—particularly of inhibitory timing, neuromodulatory balance, sensory gain control, and network signal-to-noise.

Because the underlying structure is intact, interventions can remain effective across the lifespan without implying reconstruction of early development.

 

The problem with an ever-broadening autism spectrum

The autism spectrum has value as a descriptive and administrative category. However, as it has broadened, it has become increasingly biologically heterogeneous. Conditions with very different mechanisms, trajectories, and therapeutic constraints are now grouped under a single label.

 

Why timing matters in level 3 autism

In level 3 autism, timing is as important as mechanism. This group is enriched for syndromic, regressive, epileptic, and metabolically vulnerable forms of autism, all of which place exceptional stress on the developing brain. Early life combines high energetic demand with immature antioxidant defenses, immune regulation, and microglial control.

For this reason, the earlier developmental stress is reduced, the better the long-term functional ceiling is likely to be. Interventions that reduce oxidative stress, dampen maladaptive neuroinflammation, support mitochondrial function, and stabilize microglial behavior are most likely to have their greatest impact when introduced early—before cumulative stress fixes a lower developmental plateau.

The goal is not to reverse development or guarantee recovery, but to preserve functional substrate. Earlier protection raises the ceiling for later fine-tuning.

 

How developmental stress leads to neuronal loss

In level 3 autism, neuronal loss is not random and not degenerative in the adult sense. It reflects convergence of several stress-driven mechanisms.

 

·        Calcium dysregulation

Excess calcium influx via NMDA receptors and voltage-gated channels overwhelms immature buffering systems, disrupts mitochondria, activates destructive enzymes, and triggers apoptotic pathways.

·        Mitochondrial failure

Calcium overload impairs ATP production and increases reactive oxygen species. Falling ATP worsens ion pump failure, reinforcing calcium toxicity.

·        Oxidative stress

Developing neurons have weak antioxidant defenses. Excess ROS damages membranes, ion channels, and DNA, further impairing energy and calcium control.

 

·        Neuroinflammation and microglia

Microglia guide normal synaptic pruning, but under inflammatory conditions they amplify excitotoxicity and misdirect refinement. Even low-grade, episodic inflammation during critical windows can have lasting effects.

Why loss plateaus

These mechanisms are most dangerous during early development. Once growth slows and protective capacity improves, neuronal loss largely halts, producing a stable—but impaired—plateau.

 

Examples of biologically distinct subtypes currently grouped under “autism”

Condition / subtype	Primary biological issue	Timing of disruption	Neuronal loss	Developmental course	What “repair” realistically means
CASK-related disorders	Early cerebellar vulnerability; impaired synaptic and metabolic support (especially Purkinje cells)	Prenatal / early infancy	Yes, selective and early	Early impairment → plateau	Protection and optimization of remaining circuits
Rett syndrome (MECP2)	Failure of activity-dependent maturation and gene regulation	Infancy / early childhood	Minimal true degeneration	Regression → long-term stability	Restoring plasticity conditions, not cell replacement
Mitochondrial disease with autistic features	Energy failure during periods of high developmental demand	Variable, often early	Often selective	Stress-related regression → relative stability	Metabolic protection and stress reduction
Regressive autism (non-syndromic)	Disrupted synaptic refinement under immune or metabolic stress	Toddler years	Usually no widespread loss	Regression → plateau	Stabilization and plasticity optimization
Mild / non-regressive autism	Altered inhibitory balance, neuromodulation, network noise	Early development, subtle	No	Lifelong, non-degenerative	Optimization and tuning
Stroke (contrast)	Acute focal neuronal loss in mature brain	Adulthood	Yes, focal	Partial recovery	Compensation and plasticity, not rebuilding
Dementia (contrast)	Progressive neuronal loss and toxic protein accumulation	Late adulthood	Yes, progressive	Ongoing decline	Protection and slowing progression

 

Intervention strategies aligned with underlying biology

Biological context	Primary therapeutic goal	What helps most	What has limited value	Why this matters
CASK-related disorders	Preserve remaining function	Neuroprotection, metabolic support, seizure control, supportive therapies	Neurogenesis-based repair narratives	Early cell loss is irreversible
Rett syndrome	Improve functional plasticity	Neuromodulation, activity-dependent therapies, metabolic/redox support	Structural repair strategies	Neurons are present but constrained
Mitochondrial disease	Reduce energetic stress	Metabolic optimization, pacing, stress avoidance	Forcing high-demand plasticity	Energy limits learning capacity
Regressive autism	Stabilize development	Reducing excitotoxicity/inflammation, inhibitory balance, structured learning	Assuming ongoing degeneration	Regression ≠ progressive loss
Mild autism	Network optimization	Inhibitory tuning, sensory modulation, learning-based plasticity	Repair or replacement framing	Structure largely intact
Stroke	Functional recovery	Task-specific training, neuromodulation	Expectation of neuronal replacement	Compensation dominates
Dementia	Slow decline	Neuroprotection, risk reduction	Plasticity-driven optimization	Degeneration overwhelms repair

 

Core biological mechanisms and intervention logic

Core mechanism	What goes wrong developmentally	Downstream consequence	Intervention logic (conceptual)	Why timing matters
Excitatory–inhibitory imbalance	Excess excitation or delayed inhibitory maturation	Network noise, seizures, impaired synaptic refinement	Improve inhibitory timing and reduce excessive excitation	Early imbalance amplifies developmental stress
Calcium dysregulation	Excess Ca²⁺ influx via NMDA and voltage-gated channels	Mitochondrial overload, enzyme activation, cell injury	Reduce excitotoxic stress and improve buffering capacity	Developing neurons have limited calcium buffering
Mitochondrial dysfunction	ATP production cannot meet developmental demand	Energy collapse, impaired ion homeostasis	Support mitochondrial function and reduce energy demand	Energy failure during development causes irreversible loss
Oxidative stress	ROS exceed immature antioxidant defenses	Lipid, protein, and DNA damage	Improve redox balance and reduce ROS generation	Early oxidative damage compounds over time
Neuroinflammation	Maladaptive cytokine signaling and glial activation	Synaptic mis-pruning, excitotoxic amplification	Dampen maladaptive inflammatory signaling	Microglia are most influential during early refinement
Microglial dysregulation	Abnormal synaptic pruning and immune signaling	Long-term circuit instability	Stabilize microglial state and timing	Early pruning errors cannot be fully undone
Sleep and circadian disruption	Reduced restorative and clearance processes	Increased metabolic and oxidative stress	Stabilize sleep–wake rhythms	Sleep is critical for early brain resilience
Metabolic stress (systemic)	Illness, fever, nutrient insufficiency	Regression or stalled development	Reduce cumulative physiological stress	Repeated stress fixes lower developmental plateaus

An example - Phase 1 intervention in CASK: protection before optimization

In CASK-related disorders, early selective neuronal vulnerability—especially of Purkinje cells—imposes hard limits on later outcome.

A hypothetical Phase 1 approach does not aim to replace neurons or reconstruct development. Its goals are to:

• Reduce excitotoxic and metabolic stress
• Support mitochondrial and redox balance
• Stabilize microglial behavior
• Preserve remaining neuronal populations

My thinking suggested

• NAC
• Magnesium
• Atorvastatin 
• Pioglitazone or telmisartan
• Verapamil

Phase 1 targets these upstream injury pathways simultaneously. N-acetylcysteine (NAC) Provides foundational redox protection by restoring glutathione, the brain’s primary antioxidant. This reduces oxidative damage, dampens inflammation, and indirectly limits excitotoxic injury. NAC has also been trialed in autism for irritability and agitation, consistent with reduced neuronal stress. Magnesium acts as an excitotoxicity buffer by modulating NMDA receptor activity and limiting pathological calcium influx. Magnesium supports network stability and sleep, and reduces calcium-driven mitochondrial injury. Verapamil complements magnesium by directly blocking L-type voltage-gated calcium channels, acting as a gatekeeper against intracellular calcium overload. This protects mitochondria, reduces neuronal hyperexcitability, and targets one of the fastest pathways to neuron injury. Atorvastatin is included for its pleiotropic anti-inflammatory effects, not lipid lowering. Statins suppress microglial activation, reduce pro-inflammatory cytokines, and improve endothelial and mitochondrial function—mechanisms relevant to chronic neuroinflammation observed in severe autism.  Pioglitazone or Telmisartan (PPAR-γ axis) targets metabolic-inflammatory signaling at the transcriptional level. Pioglitazone provides full PPAR-γ activation and has been trialed in autism, while telmisartan offers gentler, chronic partial PPAR-γ agonism with CNS penetration. This pathway suppresses microglial activation, improves mitochondrial efficiency, and reduces inflammation-driven excitotoxic vulnerability. 

Phase 1 is therefore protective, not reparative. By lowering early stress, it raises the ceiling for later optimization, even though it cannot undo early loss.

Can past critical periods be revisited?

Critical periods in brain development do not simply disappear; they are actively closed by inhibitory maturation, perineuronal nets, myelination, and epigenetic repression.

Early structural events—migration, layering, cell fate—cannot be replayed. What can be revisited, partially, are the rules governing plasticity. Improving inhibitory balance, metabolic support, and network stability can temporarily create a more permissive learning state.

This is functional reopening, not developmental replay.

 

A unifying perspective

Whether the brain can be repaired, protected, or optimized depends less on diagnostic labels and more on timing, cell loss, and the state of plasticity. Neuroblasts are crucial during construction, marginal during adult recovery, and largely irrelevant once degeneration becomes progressive.

In level 3 autism, early reduction of oxidative, inflammatory, microglial, and metabolic stress is likely to improve long-term outcome by preserving developmental capacity—even if it cannot entirely prevent disability. Later intervention remains valuable for fine-tuning within the biological constraints that remain.