Looking at the Yale perspective on identifying therapies for the downstream effects of a spectrum of autism genes

  

 

Our reader Aleksandra recently sent me a complicated paper by Meilin Fernandez Garcia and colleagues from Yale. The corresponding senior author is Professor Kristen Brennand, whose laboratory is internationally recognised for using human induced pluripotent stem cells (hiPSCs), CRISPR gene editing and neuronal models to study neuropsychiatric disorders.

At least one autism parent is doing something similar to help their child. Instead of engineering mutations into generic cell lines to identify therapies that might benefit many patients, the same approach is being applied to neurons derived from a single individual with autism, allowing researchers to search for drugs that reverse that person's unique cellular abnormalities. You do need money to this.

 

Transcriptomicand phenotypic convergence of neurodevelopmental disorder risk genes in vitroand in vivo

Diverse risk genes have been identified for neurodevelopmental disorders (NDDs), but how these genes converge on similar biological pathways in neurons, and thus give rise to similar phenotypes, is unclear. Here we apply a pooled CRISPR approach to successfully target 23 NDD loss-of-function genes with roles in chromatin biology and examine convergent effects on gene expression across human induced pluripotent stem cell-derived neural progenitor cells, glutamatergic neurons and GABAergic neurons. Points of convergence vary between these cell types, with the greatest number of convergent genes and strongest convergent networks in mature glutamatergic neurons, where they broadly represent synaptic, epigenetic and, unexpectedly, mitochondrial pathways. The most convergent networks were observed between NDD genes with shared biological annotations, clinical associations and co-expression patterns in human post-mortem brain. Drugs that were predicted to reverse convergent transcriptomic signatures and/or arousal and sensory processing behaviors ameliorated behavioral phenotypes in zebrafish NDD gene mutants. These results suggest that convergent effects of NDD risk genes could provide clinically useful insights.

 

As I looked through this paper, I experienced an unusual feeling. The methodology could hardly be more different from the approach I have taken over the past decade, yet many of the conclusions felt surprisingly familiar.

This blog has never had research grants, laboratories, graduate students or sophisticated genomic platforms. It has simply been the product of many years of reading the scientific literature, following developments in genetics, pharmacology and physiology, and trying to understand how apparently unrelated findings might fit together.

The Yale team approached the problem from the opposite direction. Using CRISPR gene editing, single-cell transcriptomics, machine learning and computational drug discovery, they asked a simple question:

Do hundreds of different neurodevelopmental disorder genes converge on a smaller number of common downstream biological pathways that might be therapeutically targetable?

Their answer was yes.

For long-time readers of EpiphanyASD, that conclusion will sound very familiar.

From hundreds of autism genes to common biology

One of the recurring themes of this blog has been that autism is unlikely to require hundreds of completely different treatments simply because there are hundreds of different autism genes.

Many genetic mutations disrupt the same biological systems.

If those downstream pathways can be identified and safely modulated, treatment may become considerably simpler than developing a separate therapy for every mutation.

The Yale investigators reached this conclusion using an extraordinarily sophisticated experimental pipeline.

They used CRISPR to knock out 23 neurodevelopmental disorder genes in human stem-cell-derived neurons and performed single-cell RNA sequencing on more than 118,000 cells. Machine-learning models were then used to extend these findings to more than one hundred neurodevelopmental disorder genes.

Instead of focusing on what made each mutation different, they searched for what they had in common.

The strongest convergence occurred in mature glutamatergic neurons, where many mutations disrupted shared transcriptional programmes involving synaptic function, chromatin regulation and, interestingly, mitochondrial biology.

 

Using AI to identify potential therapies

The next stage of the study was particularly elegant.

Rather than beginning with drugs already proposed for autism, the researchers searched the Connectivity Map database for medicines that produced gene-expression changes opposite to those caused by the convergent neurodevelopmental signatures.

In effect they asked:

Which existing drugs make diseased neurons look genetically more like healthy neurons?

After computational ranking, the most promising candidates were tested in zebrafish models.

Ten of the eleven drug–gene combinations rescued at least one behavioural phenotype.

That does not demonstrate efficacy in people with autism, but it does provide strong proof-of-principle for this approach.

 

Looking beyond the individual drugs

Being a practical sort of person, my first instinct was to examine the supplementary data rather than simply read the discussion section.

With the help of AI, this took only a few minutes.

The Yale analysis compared approximately 520 drug signatures from the Connectivity Map against the convergent transcriptomic changes. Although this represents only a fraction of all approved medicines, it is sufficient to identify the biological pathways most strongly associated with transcriptomic reversal.

I was curious to see how these pathways compared with those that have gradually emerged on EpiphanyASD over more than ten years.

The comparison encouraged me.

Biological Pathway	Yale Computational Hits	Epiphany ASD Approach	Interpretation
Mevalonate / Cholesterol	Pravastatin, Rosuvastatin	Atorvastatin	Independent identification of statin therapy, although different statins were selected.
Renin–Angiotensin System	Valsartan	Telmisartan	Different ARBs targeting the same signalling pathway.
Calcium Signalling	Diltiazem	Verapamil, Amlodipine	Different L-type calcium-channel blockers acting on related pathways.
Histamine / Remyelination	Clemastine	Clemastine	Complete agreement.
mTOR Signalling	Sirolimus	—	Pathway highlighted by Yale and EpiphanyASD. No safe drug.
Immune / Inflammatory Modulation	Corticosteroids	Pioglitazone, NAC	Different therapeutic strategies aimed at immune regulation.
Chloride Homeostasis	—	Bumetanide	Proposed by Ben-Ari and adopted by EpiphanyASD but not identified by the transcriptomic analysis.
Oxidative Stress / Mitochondrial Support	—	NAC, Alpha-lipoic acid, Taurine	Important focus of this blog but not highlighted by the Yale analysis.
Polyamine / NMDA Modulation	—	Agmatine	Outside the principal pathways identified by Yale.

The important point is not that the same drugs were identified.

They were not.

Nor does this study validate any treatment combination discussed on this blog.

The interesting observation is that two completely independent approaches have converged on many of the same biological pathways.

One approach relied on years of reviewing genetics, pharmacology, physiology and clinical reports.

The other relied on CRISPR gene editing, human neuronal models, single-cell transcriptomics, machine learning and computational drug discovery.

When such different methodologies begin pointing towards the same pathways, it increases confidence that those pathways deserve serious attention.

 

Why this matters

One feature of the Yale study particularly resonated with me.

The computational analysis did not identify a single "autism drug."

Instead, it identified multiple interacting biological systems. This mirrors another long-standing theme of EpiphanyASD.

If autism involves disturbances in several interconnected biological systems, then it seems unlikely that one drug alone will restore normal function in many patients.

Instead, carefully chosen combinations of therapies, each targeting a different aspect of the biology, may ultimately prove more effective than monotherapy.

That remains a hypothesis requiring proper clinical evaluation, but the Yale analysis certainly does not argue against such an approach.

 

Where the approaches differ

The Yale study identified sirolimus as an interesting candidate, whereas this has not previously featured prominently on this blog. Some readers have trialed it, but there are side effects, so it is not high on my list of practical therapies.

Conversely, therapies frequently discussed here—including bumetanide, NAC, alpha-lipoic acid, taurine and agmatine—did not emerge from the transcriptomic analysis.

That should not be overinterpreted.

The Connectivity Map used in this study analysed approximately 520 compounds, representing only a subset of approved medicines. Closely related drugs such as atorvastatin, telmisartan and verapamil were either absent from the analysed library or did not emerge as leading transcriptomic reversers.

Transcriptomic reversal is only one method for identifying therapeutic candidates. In the case of a very complex conditional like autism it can likely only solve part of the problem.

Transcriptomic mapping captures gene expression reversal, whereas therapies like Bumetanide (NKCC1 chloride transporter) or NAC (direct antioxidant/glutamate buffer) act primarily through direct protein/ion channel activity, which might not generate a strong early transcriptomic signature in cell culture models.

 

What proportion of effective drugs would be missed by the Yale approach?

 

The 3-Bucket Pharmacological Model

When evaluating how small-molecule drugs work across all FDA-approved therapeutics—and specifically within central nervous system (CNS) and neurodevelopmental disorders—drugs fall into three distinct functional buckets based on their primary Mechanism of Action (MoA):

 

 

A transcriptomic-only screening platform (scRNA-seq + Connectivity Map) is structurally blind to Buckets 2 and 3, meaning it may miss approximately 50% to 60% of effective CNS and neurodevelopmental therapeutics.

 

Breakdown by Bucket

Bucket 1: Primary Transcriptomic & Genomic Modulators (about 40% of drugs)

• Mechanisms: Nuclear receptor agonists/antagonists, chromatin remodelers, HDAC inhibitors, and upstream growth factor/kinase cascades (e.g., mTOR signaling).
• Representative Therapies: Corticosteroids, Pioglitazone (PPAR-gamma), Sirolimus (mTOR), Statins, and ARBs.
• Screening Sensitivity: HIGH. Because these compounds work by intentionally altering mRNA transcription and gene expression programs, scRNA-seq and CMap pick them up effectively. This is where the Yale pipeline excels.
•  

Bucket 2: Electrophysiological & Membrane Modulators (about 40% of drugs)

• Mechanisms: Direct blockade or opening of ion channels, cell-membrane transporters, and fast ligand-gated ion channels. These alter intracellular ion concentrations and membrane voltage within milliseconds to minutes.
• Representative Therapies: Bumetanide (NKCC1 chloride-transporter blocker), Calcium channel blockers (Diltiazem, Verapamil), GABA-A allosteric modulators, and Sodium channel blockers.
• Screening Sensitivity: LOW (High Risk of Being Missed). The primary therapeutic event is electrophysiological (shifting excitation/inhibition balance or hyperpolarizing neurons). While long-term cellular adaptation can produce secondary transcriptional noise, the primary mechanism produces little to no acute transcriptomic signature in cell culture.
•  

Bucket 3: Direct Metabolic & Biochemical Buffers (about 20% of drugs)

• Mechanisms: Direct stoichiometric chemical reactions, free-radical scavenging, direct precursor supply for endogenous enzymatic cycles, or polyamine/receptor modulation that occurs without altering target gene expression.
• Representative Therapies: N-Acetylcysteine (NAC) (direct ROS scavenger and glutathione precursor), Alpha-Lipoic Acid, Taurine, and Agmatine (polyamine/NMDA pathway modulator).
• Screening Sensitivity: VERY LOW (Almost Entirely Missed). These molecules correct cellular redox potential or metabolic fluxes directly. Because they act via direct biochemistry rather than transcriptional reprogramming, a gene expression screen will almost always drop them.

 

Why the "miss rate" is exceptionally high in Autism / NDDs

In fields like oncology, where the goal is altering cell cycle or cell death pathways, Bucket 1 dominates (making transcriptomic matching highly effective).

However, in Neurodevelopmental Disorders (NDDs), core neurobiology relies heavily on:

1.     Intracellular ionic gradients & E/I balance (Bucket 2)

2.     Mitochondrial health, redox balance & oxidative stress (Bucket 3)

Because roughly 50-60% of potential NDD interventions live in Buckets 2 and 3, relying solely on transcriptomic reversal naturally drops more than half of the potential drugs.

To capture those therapies, systems biology must complement transcriptomic screens with Microelectrode Arrays (MEAs) for Bucket 2 and Functional Metabolomics/High-Content Imaging for Bucket 3.

  

Final thoughts

For me, this paper is encouraging for two reasons.

First, it provides compelling evidence that many genetically distinct neurodevelopmental disorders converge on a relatively small number of shared downstream biological pathways.

Second, after more than a decade of independent, unfunded research on EpiphanyASD, it is gratifying to see that a large, well-funded research programme at one of the world's leading universities has independently highlighted many of those same pathways and drugs.

That does not prove that any particular treatment discussed on this blog is correct.

It does suggest that the central idea—that autism should often be approached as a disorder of convergent downstream biology rather than hundreds of isolated gene defects—is increasingly supported by modern systems biology.

If future studies continue to point in the same direction, the prospect of rational, pathway-based precision medicine for autism becomes much more realistic.

 

One final thought. Looking back at my original TRH hypothesis from more than a decade ago, today's technology finally offers a practical way to test it. Rather than immediately embarking on a clinical trial, a logical first step would be to investigate both the direct TRH super-agonist taltirelin (Ceredist) and the indirect TRH-enhancing approach using rifaximin in patient-derived induced pluripotent stem cells (hiPSCs), differentiated into neurons.

The rifaximin story is particularly intriguing because it appears to stimulate endogenous TRH production through the gut–brain axis, rather than replacing TRH pharmacologically. This is exactly the type of experimental platform now being used by groups such as Professor Kristen Brennand's laboratory at Yale to identify drugs that reverse disease-related transcriptomic abnormalities. If either taltirelin or rifaximin were shown to normalize gene-expression patterns or neuronal function in patient-derived neurons, it would provide a much stronger scientific rationale for moving on to carefully designed clinical studies. It would also be fascinating to compare the effects of the two approaches directly, asking whether a TRH super-agonist and a gut-mediated increase in endogenous TRH ultimately converge on the same downstream molecular pathways. If they did, it would represent another example of two completely different therapeutic strategies converging on the same underlying biology—a recurring theme throughout this article

 

Epiphany: TRH and Rifaximin – an alternative to intranasal TRH or oral Taltirelin/Ceredist?

Epiphany: The Peter Hypothesis of TRH-induced Behavioural Homeostasis in Autism

 

Taltirelin sits directly in Bucket 1 as a G Protein-Coupled Receptor agonist that triggers immediate nuclear gene transcription (upregulating BDNF etc), whereas Rifaximin overlaps Buckets 1 and 3 by using gut-microbiome metabolic modulation to indirectly drive central TRH expression via the gut–brain axis.

 

 

TRH and Rifaximin – an alternative to intranasal TRH or oral Taltirelin/Ceredist?

I think this is going to be one of my smarter posts. It may be more for our doctor readers and our motivated home-based researchers. It does remain a hypothesis and while it looks plausible it is certainly not 100% proven – so typical Peter stuff.

Many parents with autism regularly treat their child with the antibiotic Rifaximin. This drug is also the go-to therapy for SIBO (small intestine bacterial overgrowth) and is a key part of the Nemechek autism protocol to increase butyric acid production in the gut (and reduce propionic acid).

Some parents report that their child with completely normal GI function responds well behaviorally to Rifaximin.

Rifaximin is taken orally and stays in the gut, it does not enter the blood stream.

Our long-time reader Maja mentioned that she still uses Rifaximin in her now adult daughter.

I then did a quick Google and was surprised to see Rifaximin linked to the hormone TRH.

And, most surprising, you can use Rifaximin to treat prostate inflammation, via its effect on TRH.

TRH was the subject of an experiment I did 12 years ago. I suggested that an existing Japanese drug, an orally available TRH super-agonist, could be repurposed at a low dose to treat autism.

 https://www.epiphanyasd.com/2014/05/the-peter-hypothesis-of-trh-induced.html

I then noted that a well-known, but a little controversial, doctor in the US used intranasal TRH to treat his patients with chronic fatigue syndrome.

Another doctor had grant funding from the US military to develop intranasal TRH to reduce suicides in veterans.

In my old post I started by wondering why my son and some others with severe autism respond so well to sensory stimulation like standing on the upper deck of a ferry boat in the open sea on a windy day, or sitting in an open-top bus, driving in a convertible car etc.

Without be able to do any testing I looked for “similar” situations that haven been studied. The closest I found was people jumping out of a plan (with a parachute) where one of the key changes was a surge in the level of the hormone prolactin.

How to replicate the open-top bus effect? One of my doctor relatives suggested sitting Monty in front of a fan. Over course I wanted better than that. I found that stimulating TRH receptors in the brain would release prolactin.  It was already known that TRH is disturbed in autism.

It seemed to me that a Japanese orphan drug developed to treat spinocerebellar degeneration (SCD) – a group of progressive neurodegenerative disorders characterized by ataxia (poor coordination, gait disturbance, speech difficulties) could be repurposed.

I did discuss with a Japanese doctor in Osaka and he prescribed it.

It is a very expensive drug, even when bought with a prescription, and it has a very short expiry date. The idea was to use a micro-dose, to avoid undesirable side effects and this would also make the price less scary. I thought it provided a benefit without side effects, but was impractical. At the full dose it is potent and is the only drug I have trialed that had a near immediate profound effect on myself. I suddenly had hyper-acute vision. The micro dose had no effect on me.

Since Ceredist (taltirelin) is a TRH analogue, it could in theory affect the hypothalamic–pituitary–thyroid (HPT) axis.

TRH normally stimulates TSH release from the pituitary, which then increases thyroid hormone (T4/T3) secretion. Taltirelin was designed for CNS activity rather than endocrine use. Its clinical development in Japan for spinocerebellar degeneration focused on neurological symptoms, not thyroid stimulation. Animal studies showed that taltirelin has much weaker TSH-releasing activity than native TRH, but much stronger central nervous system stimulant effects (improved motor coordination, wakefulness).

Human data at therapeutic doses for spinocerebellar degeneration, significant changes in thyroid hormone levels (TSH, T3, T4) have not been a common clinical issue. Monitoring thyroid function is not part of standard Ceredist treatment.

 

So what is TRH?

TRH (thyrotropin-releasing hormone) serves as a master regulator of energy metabolism, mood, arousal, cognition, and immune balance.

Core Endocrine Role

Produced in the hypothalamus (paraventricular nucleus), but also found in other brain regions and peripheral tissues.

Main function is to stimulate the anterior pituitary to release TSH (thyroid-stimulating hormone), this increases thyroid hormone (T3, T4) production in the thyroid gland.

A secondary effect promotes prolactin release from the pituitary. TRH is a significant stimulator, especially when dopamine inhibition is reduced.

 

Effects on Other Hormones

Growth hormone & insulin: Some modulatory effects reported in stress and metabolism, though less central.

ACTH/cortisol: Minor indirect effects; TRH can modulate stress responses via cross-talk with the HPA axis.

 

Mood and Behavior

Antidepressant effects - TRH has rapid mood-elevating and activating effects in both animals and humans, independent of thyroid hormones. Some clinical studies have tested TRH or TRH analogs as rapid-acting antidepressants.

Arousal & vigilance - it increases wakefulness, motivation, and locomotor activity.

Anxiety - can produce mild anxiogenic effects at high doses, but generally associated with improved mood and alertness.

 

Cognition

Neurotransmitter modulation - TRH interacts with cholinergic, dopaminergic, and glutamatergic systems.

Memory & learning - TRH and TRH-like peptides enhance memory consolidation and counteract cognitive decline in animal studies.

Neuroprotection - shown to reduce neuronal injury in models of ischemia and trauma.

 

Inflammation & Immunity

 Anti-inflammatory - TRH dampens pro-inflammatory cytokine production (e.g., TNF-α, IL-1β).

Microglia modulation - TRH reduces microglial over-activation, relevant in neuroinflammation.

Systemic effects: TRH analogs show protective roles in sepsis and multiple organ injury in animal studies, likely via immune regulation and mitochondrial support.

 

Here is the recent study that showed the common antibiotic Rifaximin increases TRH in the brain and in peripheral tissues. Rifaximin itself stays within the gut when taken by mouth, it does not enter the blood stream. It changes the gut microbiota which then sends a signal via vagus nerve to the brain (clever, isn’t it?).

Caveat – rats are not humans.

 

Rifaximin modulates TRH and TRH-like peptide expression throughout the brain and peripheral tissues of male rats

 

The TRH/TRH-R1 receptor signaling pathway within the neurons of the dorsal vagal complex is an important mediator of the brain-gut axis. Mental health and protection from a variety of neuropathologies, such as autism, Attention Deficit Hyperactivity Disorder, Alzheimer’s and Parkinson’s disease, major depression, migraine and epilepsy are influenced by the gut microbiome and is mediated by the vagus nerve. The antibiotic rifaximin (RF) does not cross the gut-blood barrier. It changes the composition of the gut microbiome resulting in therapeutic benefits for traveler’s diarrhea, hepatic encephalopathy, and prostatitis. TRH and TRH-like peptides, with the structure pGlu-X-Pro-NH₂, where “X” can be any amino acid residue, have reproduction-enhancing, caloric-restriction-like, anti-aging, pancreatic-β cell-, cardiovascular-, and neuroprotective effects. TRH and TRH-like peptides occur not only throughout the CNS but also in peripheral tissues. To elucidate the involvement of TRH-like peptides in brain-gut-reproductive system interactions 16 male Sprague–Dawley rats, 203 ± 6 g, were divided into 4 groups (n = 4/group): the control (CON) group remained on ad libitum Purina rodent chow and water for 10 days until decapitation, acute (AC) group receiving 150 mg RF/kg powdered rodent chow for 24 h providing 150 mg RF/kg body weight for 200 g rats, chronic (CHR) animals receiving RF for 10 days; withdrawal (WD) rats receiving RF for 8 days and then normal chow for 2 days.

Results

Significant changes in the levels of TRH and TRH-like peptides occurred throughout the brain and peripheral tissues in response to RF. The number of significant changes in TRH and TRH-like peptide levels in brain resulting from RF treatment, in descending order were: medulla (16), piriform cortex (8), nucleus accumbens (7), frontal cortex (5), striatum (3), amygdala (3), entorhinal cortex (3), anterior (2), and posterior cingulate (2), hippocampus (1), hypothalamus (0) and cerebellum (0). The corresponding ranking for peripheral tissues were: prostate (6), adrenals (4), pancreas (3), liver (2), testis (1), heart (0).

Conclusions

The sensitivity of TRH and TRH-like peptide expression to RF treatment, particularly in the medulla oblongata and prostate, is consistent with the participation of these peptides in the therapeutic effects of RF. 

 

It turns out that other researchers have looked at Rifaximin’s effects on the brain, but they never understood the mechanism.

 

Effects of Rifaximin on Central Responses to Social Stress—a Pilot Experiment

Probiotics that promote the gut microbiota have been reported to reduce stress responses, and improve memory and mood. Whether and how antibiotics that eliminate or inhibit pathogenic and commensal gut bacteria also affect central nervous system functions in humans is so far unknown. In a double-blinded randomized study, 16 healthy volunteers (27.00 ± 1.60 years; 9 males) received either rifaximin (600 mg/day) (a poorly absorbable antibiotic) or placebo for 7 days. Before and after the drug intervention, brain activities during rest and during a social stressor inducing feelings of exclusion (Cyberball game) were measured using magnetoencephalography. Social exclusion significantly affected (p < 0.001) mood and increased exclusion perception. Magnetoencephalography showed brain regions with higher activations during exclusion as compared to inclusion, in different frequency bands. Seven days of rifaximin increased prefrontal and right cingulate alpha power during resting state. Low beta power showed an interaction of intervention (rifaximin, placebo) × condition (inclusion, exclusion) during the Cyberball game in the bilateral prefrontal and left anterior cingulate cortex. Only in the rifaximin group, a decrease (p = 0.004) in power was seen comparing exclusion to inclusion; the reduced beta-1 power was negatively correlated with a change in the subjective exclusion perception score. Social stress affecting brain functioning in a specific manner is modulated by rifaximin. Contrary to our hypothesis that antibiotics have advert effects on mood, the antibiotic exhibited stress-reducing effects similar to reported effects of probiotic

 

Effects of the antibiotic rifaximin on cortical functional connectivity are mediated through insular cortex

It is well-known that antibiotics affect commensal gut bacteria; however, only recently evidence accumulated that gut microbiota (GM) can influence the central nervous system functions. Preclinical animal studies have repeatedly highlighted the effects of antibiotics on brain activity; however, translational studies in humans are still missing. Here, we present a randomized, double-blind, placebo-controlled study investigating the effects of 7 days intake of Rifaximin (non-absorbable antibiotic) on functional brain connectivity (fc) using magnetoencephalography. Sixteen healthy volunteers were tested before and after the treatment, during resting state (rs), and during a social stressor paradigm (Cyberball game—CBG), designed to elicit feelings of exclusion. Results confirm the hypothesis of an involvement of the insular cortex as a common node of different functional networks, thus suggesting its potential role as a central mediator of cortical fc alterations, following modifications of GM. Also, the Rifaximin group displayed lower connectivity in slow and fast beta bands (15 and 25 Hz) during rest, and higher connectivity in theta (7 Hz) during the inclusion condition of the CBG, compared with controls. Altogether these results indicate a modulation of Rifaximin on frequency-specific functional connectivity that could involve cognitive flexibility and memory processing.

  

Probing gut‐brain links in Alzheimer's disease with rifaximin

Gut‐microbiome‐inflammation interactions have been linked to neurodegeneration in Alzheimer's disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut‐specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open‐label trial, we treated 10 subjects with mild to moderate probable AD dementia (Mini‐Mental Status Examination (MMSE) = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament‐light levels (P < .004) and a significant increase in fecal phylum Firmicutes microbiota. Serum phosphorylated tau (pTau)181 and glial fibrillary acidic protein (GFAP) levels were reduced (effect sizes of −0.41 and −0.48, respectively) but did not reach statistical significance. In addition, there was a nonsignificant downward trend in serum cytokine interleukin (IL)‐6 and IL‐13 levels. Cognition was unchanged. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo‐controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

 

Rifaximin and the prostate

For some reason one of the main areas where Rifaximin triggers the production of TRH is in the prostate, in males. There are studies showing how Rifaximin can be used to treat prostatitis (prostate inflammation).

Symptom Severity Following Rifaximin and the Probiotic VSL#3 in Patients with Chronic Pelvic Pain Syndrome (Due to Inflammatory Prostatitis) Plus Irritable Bowel Syndrome

This study investigated the effects of long-term treatment with rifaximin and the probiotic VSL#3 on uro-genital and gastrointestinal symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) plus diarrhoea-predominant irritable bowel syndrome (D-IBS) compared with patients with D-IBS alone. Eighty-five patients with CP/CPPS (45 with subtype IIIa and 40 with IIIb) plus D-IBS according to the Rome III criteria and an aged-matched control-group of patients with D-IBS alone (n = 75) received rifaximin and VSL#3. The primary endpoints were the response rates of IBS and CP/CPPS symptoms, assessed respectively through Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) and The National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and performed at the start of therapy (V0) and three months after (V3). In IIIa prostatitis patients, the total NIH-CPSI scores significantly (p < 0.05) decreased from a baseline mean value of 21.2 to 14.5 at V3 , as did all subscales, and in the IIIb the total NIH-CPSI score also significantly decreased (from 17.4 to 15.1). Patients with IBS alone showed no significant differences in NIH-CPSI score. At V3, significantly greater improvement in the IBS-SSS and responder rate were found in IIIa patients. Our results were explained through a better individual response at V3 in IIIa prostatitis of urinary and gastrointestinal symptoms, while mean leukocyte counts on expressed prostate secretion (EPS) after prostate massage significantly lowered only in IIIa cases. 

Since SIBO is treated by rifaximin, some researchers linked SIBO with prostatitis: 

Chronic prostatitis and small intestinal bacterial overgrowth: is there a correlation?

Background: Clinical management of chronic inflammation of prostate and seminal vesicles is very complex. Among the causes of recurrent chronic prostatitis (CP), a possible malabsorption, such as lactose intolerance, in turn related to small intestinal bacterial overgrowth (SIBO), should be considered.

Methods: We have performed lactose and lactulose breath test (BT) in 42 patients with CP, in order to evaluate the prevalence of SIBO in this kind of patients and the concordance of the two tests.

Results: A positive lactulose BT was present in 33/42 patients and in 73% (24/33) was associated to lactose malabsorption. Five patients had positive response after lactulose, while only 4 had both negative tests.

Conclusions: Our data showed an association between lactose and lactulose BT positivity. They also indicated high prevalence of bacterial colonization of small bowel in patients with CP, possibly related to recurrence or chronicity of genitourinary tract inflammation. The research for these phenomena could be relevant in diagnostic route of infertile patients in whom slight gastro-enteric symptoms can be underestimated.

 

For those of you who still read books:

 

Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders
This seminal work presents Dr. Goldstein's theory that CFS and fibromyalgia result from dysfunctions in neural networks. It integrates neuroscience research into the pathophysiology and treatment of these conditions.

A Companion Volume to Dr. Jay A. Goldstein's Betrayal by the Brain: A Guide for Patients and Their Physicians
Authored by Katie Courmel, this companion guide simplifies Dr. Goldstein's theories and treatment protocols for a broader audience, aiding patients and physicians in understanding and applying his methods.

 Tuning the Brain: Principles and Practice of Neurosomatic Medicine

In this book, Dr. Goldstein outlines the principles of neurosomatic medicine, a field he developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses.

In Tuning the Brain: Principles and Practice of Neurosomatic Medicine, Dr. Jay A. Goldstein discusses the use of thyrotropin-releasing hormone (TRH) in treating chronic fatigue syndrome (CFS) and related disorders. He describes TRH as a neuropeptide that can modulate neural network activity, particularly through the trigeminal nerve, which is involved in sensory processing. By stimulating this pathway, TRH may help "re-tune" the brain's response to sensory input, potentially alleviating symptoms associated with CFS and similar conditions.

The book outlines the principles of neurosomatic medicine, a field Dr. Goldstein developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses. It emphasizes the rapid modulation of neural networks through pharmacological means, aiming to restore normal sensory processing and alleviate symptoms.

 

Conclusion

It does look like Rifaximin has interesting effects beyond where it can reach itself.

Rifaximin → modifies gut microbiota → activates vagus nerve

Vagus nerve → signals to brainstem → hypothalamus → TRH release 

According to that rat study, TRH and TRH-like peptides are present in the prostate, and their levels change in response to rifaximin. The TRH (or TRH-like peptides) in the prostate is produced locally in the prostate tissue itself, not delivered there from the brain via the bloodstream. the level of production can be modulated by gut–brain signaling, such as after rifaximin treatment.

I have to say that this reminds me of using L-Reuteri probiotic bacteria to send a signal via the same vagus nerve to release oxytocin in the brain. Seems a better approach than intranasal oxytocin.

I think the study showing Rifaximin improves the response to social stress fits with Dr Goldstein’s use of intranasal TRH to “retune” the brain in the conditions he studied and the potential use to reduce suicide initiations. It is enough for me to see TRH as a possible common factor.

I think Goldstein and the US DoD scientists should have used the TRH super-agonist Taltirelin/Ceredist. It is 30x more potent and yet does not affect thyroid function. It also has a far longer half-life. The other alternative, we now see, would have been to use Rifaximin.

Goldstein has passed away and the US DoD gave upon TRH. Research indicates that intranasal esketamine can rapidly reduce suicidal thoughts. Esketamine was FDA approved in 2019.

Taltirelin was approved for use in humans in Japan in 2000 for spinocerebellar degeneration (SCD).

Note that spinocerebellar degeneration (SCD) has no drug therapy in the US/Europe, even though one has existed in Japan for 25 years. Looks pretty odd to me. In a perfect world low dose Taltirelin could be a useful add-on therapy for many neurological conditions and potentially even for prostatitis! Don’t hold your breath.

Taltirelin is now being researched in animal models of Parkinson’s and fatigue syndromes.

Unless you live in Japan and have a pal who is a doctor, I think autism parents are best off with Rifaximin.

As Maja just pointed out “Rifaximin is still very helpful. I repeat a ten-day course (2x400 mg) every two to three months”, in her adult daughter. We can never know for sure if increased TRH is mechanism, or reduced SIBO, or increased butyric acid, or something else. If it works, stay with it!

The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism

This is a repost  from last year - the original got deleted.  TRH is another area that you will not find much if you Google "autism plus ......".  But, since writing this post, I did find other people using it for various neurological conditions.  It is another hormone/drug that seems to have a good effect when used in very small doses.










Abstract

Based on observation of a single boy with autism, thorough desk research, and one simple experiment, it is hypothesized that the hormone TRH (thyrotropin-releasing hormone) can induce a brief period of behavioural homeostatis.  During this period, behaviours appear to be modified to near normal.  It is further hypothesized that a TRH analog, Taltirelin, could induce prolonged periods of behavioural homeostatis.

Due to the very short half-life of TRH in plasma, it is necessary to use an analog of TRH.  The proposed TRH analog is Taltirelin hydrate, already licensed for human use since 2000 in Japan, under the trade name Ceredist.  Not only does Taltirelin hydrate have a substantially longer half-life, but it is also it induces a dramatically lower stimulating effect on the thyroid.

It has already been established (Ben-Ari, Lemmonier, Peter) that autistic behaviours are mediated by malfunctions in channelopathy. Ben-Ari’s work focused on the chloride importer NKCC1 and the chloride exporter KCC2. 

Peter drew parallels between the Autistic Sensory Overload (ASO), frequently observed in autism, and the channelopathy diseases hypokalemic periodic paralysis (HypoPP) and Hypokalemic Sensory Overstimulation (HypoSO).  Experimental evidence (Peter) supported the connection, since administration of oral potassium was shown to be a remedy in ASO, as it has already been proved to be in HypoSO and  HypoPP.

The effect of TRH on the central nervous system (CNS) is via receptors TRHR1 and TRHR2.  The exact function of TRHR1 and TRHR2  is not fully understood in the literature; but it appears to involve blocking the flow of K⁺ ions through certain channels.

Clearly only neurons with TRH receptors would be affected and it would be useful to study this in depth.

In the literature, TRH has been shown to have wide ranging benefits in numerous neurological disorders ranging from depression to motor neuron disease. The role of TRH was nicely summarized as “TRH broadly increases the coping capacity of the organism” and “the effects of TRH are not diagnosis specific, but neither are behavioural deficits.”

TRH has also even been demonstrated to help mitigate suicidal tendencies.  Suicide is currently a major problem in the US military.  In August 2012, a leading TRH researcher, Michael Kubek, from Indiana University was awarded a $3 million contract to develop a nasal spray that dispenses TRH. It is not clear whether it is TRH itself, or an analog.

Initial Observations

Having established that autism is at least partially reversible (Peter2012), an investigation was launched under the broad umbrella of Applied Neurological Analysis (Peter).  ANA combines real observations of odd behaviours in autism with the appliance of neuroscience from the literature.

The most important observation investigated was:-

      i.        Neurotypical behaviour during and following a period of extreme sensory exhilaration.

Two further observations were subsequently investigated:

     ii.        Reduction of autistic-like behaviours during fever

    iii.        Effect of oral potassium on Autistic Sensory Overload (ASO)

Neurotypical behaviour during and following extreme sensory exhilaration

This is an observation by Peter; I did not find any similar observations documented by others.  Only the carer would be able to note such behaviours and carers are highly prone to a lack of objectivity.

It was noted that whenever Monty was exposed to extremely windy and sunny conditions his behaviour and manner became decidedly neurotypical.  A perfect example is when riding on the open top deck of a city sightseeing tour bus; others include the open top deck of a large ferry boat crossing the open sea, or running along an exposed beach in windy conditions.

Being a keen photographer, I have learnt how to get great photos will good eye contact and happy facial expressions; this is not always easy with typical children, but is especially hard with an autistic child.  An autistic child like Monty, will not pose smiling for his photo.

Yet, if we go on the open top deck of a City tour bus, and I sit in the row in front of him, I can shoot great photos of Monty one after the other.  Even more interesting is that when the tour ends and we disembark, for a few minutes the neurotypical behaviour and mannerisms continue.

Last summer in Lisbon, Portugal, I had final proof, if it was needed.  The bus stopped, the tour was over and we were in Marques do Pombal Square.  Monty was with his Aunty and I was planning to take a few photos.  Then something totally bizarre happened; Monty walked towards me, stopped about 5 metres (15 feet) in front of me and posed for a photo.  This had never happened before and has not happened since.  He stood still and made a big grin with his mouth closed and the photo is unlike any other of the thousands that I have taken.

I have other less extreme examples, like swimming under water with Monty when I am rewarded with near constant direct eye contact; riding on a big motorbike or in a noisy/shaky old convertible Triumph Spitfire seems to have a similar effect.

Now to Applied Neurological Analysis

In late January 2013, I decided to turn detective and look for clues in the literature that would explain my observations.  It did not take me long.

I found a study from 1976 that investigated hormonal changes in an adult version of my son’s sensory exhilaration - parachute jumping.

Prolactin, thyrotropin, and growth hormone release during stress associated with parachute jumping (Noel Gl et al, May 1976, Aviat Space Environ Med)

I subsequently found a second, more recent and rigorous study of the same effect.

Hormonal Responses to Psychological Stress in Men Preparing for Skydiving (Chatterton RT et al 1997 Clinical Endocrinology and metabolism)

In both studies blood samples taken just after completing the parachute jump showed a spike in prolactin and growth hormone (GH).  The 1976 study also measured TSH, which also showed a spike; the 1997 study measured luteinizing hormone (LH) which also showed a spike.

Anterior Pituitary Gland and Hypothalamus Hormones

The anterior pituitary gland secretes at least eight hormones, of which six seem to be well understood

1.    Follicle stimulating hormone  (FSH)

2.    Luteinizing hormone (LH)

3.    Growth hormone (GH)

4.    Thyroid-stimulating hormone (TSH)

5.    Prolactin 

6.    Adrenocorticotropic hormone (ACTH)

7.    Beta-lipotropin

8.    Beta-endorpin

The basic roles of 1 to 6 seem understood.  Understanding of the role of prolactin, particularly in men, seems incomplete. The role 7 and 8 in human physiology remains unclear.

The anterior pituitary gland is itself is controlled by chemical messengers from the Hypothalamus.

It is not disputed that TSH is itself controlled by TRH (Thyrotropin-releasing Hormone) from the nearby hypothalamus.  In the textbooks (Vander’s Human Physiology 12^th Edition) Prolactin is controlled by Dopamine (DA), but in the footnotes and in the literature, Prolactin is actually controlled by TRH.  

What cannot be disputed is that a spike in TSH can only be caused by a spike in TRH and most likely the spike in prolactin was also caused by the spike in TRH.

The role of TRH

As long ago as 1975 it was established in the literature (Shambaugh et al) that the hormone TRH had functions beyond the control of thyrotropin (TSH) synthesis and secretion and therefore control over the important thyroid gland.  40 years later many people remain unaware of this.

Also in 1975, at the 5th International Congress of the International Society of Psychoneuroendocrinology a remarkable paper was presented, by Arthur Prange from the University of North Carolina (interestingly in 2007 he was still publishing papers on this subject):-

Behavioural Effects of Hypothalamic Releasing Hormones in Animals and Men

In this paper he points out the rapid, though brief, antidepressant effect of TRH in humans.  He comments on the reduced thyroid-stimulating response to thyrotropin releasing hormone in people with depression.

He comments further:-

“We have not been astonished to find that the apparent benefits of TRH are not specific to a single diagnostic group.  TRH is hormone, not a drug.  It probably influences a variety of functions, the alteration of which have behavioral consequences that can reasonably be regarded as improvements, or aggravation, in any diagnostic entity in which that function is involved. 

The effects of TRH are not diagnosis specific but neither are behavioral deficits….”

And

“TRH broadly increases the coping capacity of the organism”

Reduced thyroid-stimulating response to thyrotropin releasing hormone in ASD

Not only is there a reduced thyroid-stimulating response to thyrotropin releasing hormone in depression, but also in most types of mental illness. In 1991 this was established to be the case in autism (Hashimoto et al).

In 2003 Gary et al (including Mr Prange) produced their own hypothesis regarding the role of TRH in Homeostatic Regulation.

In 2007 there was a follow up, this time Yarborough et al (including Mr Prange), but by now Yarborough has set up his own Micro-Pharma called TRH Therapeutics LLC, and patents start getting filed.

 

The short summary of the research is that TRH appears to be a kind of “wonder” hormone that could be used to treat mental illness of most types, brain/spine trauma etc.

Clinical reports of therapeutic benefits with TRH

·         Antidepressant effects in major depression

·         Behavioral vigilance/motivational EEG activation in depression

·         Therapeutic effects in amyotrophic lateral sclerosis/motoneuron disease

·         Anticonvulsant actions in certain intractable epilepsies

·         Therapeutic effects in Alzheimer’s disease

·         Attenuation of scopolamine-induced memory impairment

·         Protective effect on ECT impairment of delayed memory recall

·         Therapeutic effects in spinal muscular atrophy

·         Effective to reduce post-stroke pathogenic emotional liability

·         Decrease in schizophrenic psychotic symptoms

·         Antagonism of ethanol inebriation

·         Neurological improvements post-stroke and head trauma

·         Reversal of benzodiazepam-induced sedation

·         Improved cognition in short-duration alcoholism

·         Therapeutic effects in spinal cord injury

·         Metabolic improvements in protracted critical illness

·         Improves urinary bladder function in spinal shock

·         Stimulates respiration post-general anesthesia

·         Hemodynamic stimulation in vegetative or brain-dead patients

·         Increases cerebral blood flow in cerebellar atrophy and in childhood acute encephalitis or encephalopathy

·         Therapeutic effects in central pontine myelinosis

·         Improves ‘disturbances of consciousness’ post-brain trauma

·         Therapeutic effects in spinocerebellar degeneration

·         Attenuates mania and alcohol withdrawal dysphoria

·         Clinical benefit in juvenile Alexander disease

Some suggested clinical indications for TRH analogs

·         Depression, especially accompanied by hypersomnolence

·         Chronic fatigue syndromes

·         Excessive daytime sleepiness (including narcolepsy), neurasthenia,

·         and lethargy

·         Sedation secondary to drugs, chemotherapy, or radiation therapy

·         Sedative intoxication/respiratory distress (ER setting)

·         Recovery from general anesthesia

·         Attention deficit/hyperactive disorder

·         Disturbances of circadian rhythm (e.g. jet lag)

·         Bipolar affective disorder as a mood stabilizer

·         Anxiety disorders

·         Alzheimer’s disease and other dementias with cognition deficits

·         Seizure disorders

·         Motor neuron disorders

·         May be particularly effective as adjunctive therapy

 Reduction of autistic-like behaviours during fever

It has been observed (Peter) that autistic behaviours diminish during fever.  This phenomenon has recently been tested and proven by Curran (Behaviors associated with fever in children with autism spectrum disorders . Curran, L. 2007, Pedriatics).  In trying to explain the results, five mechanisms were proposed.  The fifth mechanism is “stimulation of the hypothalamic-pituitary-adrenal axis leading to modifications of neurotransmitter production and interaction”; the paper adds “should any of these mechanisms be proved to effect behaviour changes in individuals with ASDs, this would stimulate research on potential treatments focused on these pathways”.

Well I am no Endocrinologist, but it would seem to me that TRH is most definitely involved in stimulation of the hypothalamic-pituitary-adrenal axis and I think I have proved (along with Mr Prange) that TRH affects behaviour changes in autism.

Effect of oral potassium on Autistic Sensory Overload (ASO)

One of the most glaring of autistic behaviours (Peter) is the apparent hypersensitivity to loud sound in general and certain sounds in particular. An autistic child will often cover his ears with his palms or index fingers.  There are many other noted sensory problems and entire books and indeed businesses have created around so-called Sensory Integration Therapy and Auditory Integration Training. Gomes (Auditory Hypersensitivity in Children and Teenagers with Autistic Spectrum Disorder. Gomes, E. 2004, Arq Neuropsiquiatr.)  has investigated auditory hypersensitivity in autism and concluded that, that the behavioral manifestations to sounds are not associated to hypersensitivity of the auditory pathways, but rather to difficulties in the upper processing at the level of the cerebral cortex, involving systems that usually are impaired in autistic spectrum patients, such as the limbic system. Identical results occur with other changes in sensitivity and their associated behaviors, as fear and reality distortions, which are complex interactions originated from upper processings, instead of specific hypersensitive pathways.

There is a known condition called Hypokalemic Sensory Overstimulation (HypoSO) with virtually identical symptoms.

“Hypokalemic sensory overstimulation is a condition characterized by similarities to ion channel disorders such as hypokalemic periodic paralysis. The symptoms of hypokalemic sensory overstimulation and that of sensory integration disorder and attention deficit disorder are quite the same. The relation between the three conditions is yet to be established” (Illnessopedia)

The sensory overstimulation in HypoSO goes away abruptly after taking an oral dose of potassium.

A study by Segal (Hypokalemic Sensory Overstimulation. Segal, M. 2007, Journal of Child Neurology) of two generations of a family with symptoms of sensory overstimulation draws parallels to subtypes of attention deficit disorder that have a peripheral sensory cause and suggests the possibility of novel forms of therapy.

It could be hypothesized that in autism the endogenous level of TRH is reduced this in turn reduces the blockade of K+ channels that linked to TRH receptors. This ion channel dysfunction then induces a kind of hypokalemic sensory overload.  This clearly needs further research.

It would be reasonable to test sound hypersensitivity when trialling oral TRH analog on autistic subjects. Indeed it would be useful to test for sound hypersensitivity in autistic subjects before and after giving an oral dose of potassium.  

Update

Between 7-11 March 2013 we did our own trial with oral potassium and we published the result on my blog.

http://epiphanyasd.blogspot.com/2013/03/nom-de-guerre-mon-frere-manchopathy.html

We demonstrated that an oral dose of potassium reduced sound sensitivity in our autistic subject, but not in his “normal” brother. QED

TRH in practice

Due to its very short half-life (5 minutes in plasma) there has not been much clinical use of TRH.  It was used to test thyroid function, before a modern test was developed.

Researchers seem to have done plenty of self-experimentation.

TRH has also been demonstrated to help mitigate suicidal tendencies.  Suicide is currently a major problem in the US military.  In August 2012, a leading TRH researcher, Michael Kubek, from Indiana University was awarded a $3 million contract to develop a nasal spray that dispenses TRH. It is not clear whether it is TRH itself or an analog.  Prior to this funding Kubek, had grants from an Epilepsy charity for his TRH research.  Kubek has been researching TRH much of his career.

The most interesting case is in Japan, where TRH was used for many years as a therapy for the degenerative disease Spinocerebellar Ataxia (SCA).  This disease (perhaps like ASD) has multiple types, each of which could be considered a disease in its own right.

In Japan there are approximately 30,000 patients with SCA.  Whereas in Western medicine this disease is seen as untreatable, in Japan, the Mitsubishi Tanabe Pharma Corporation developed an oral analog of TRH to replace the previous injections of TRH into the spine. The TRH analog is Taltirelin hydrate and the trade name Ceredist.  It has been licensed for use since 2000.  The drug is very slightly different to the hormone TRH, but these advantages are extremely important:-

·         Much longer half-life (a few hours as opposed to a few minutes)

·         Can cross both through the gut and blood brain barrier, allowing for an oral tablet

·         Substantially (50x ?) reduced releasing impact on the Anterior Pituitary Gland, so that TSH is not overproduced and the thyroid does not become overactive and hyperthyroidism is therefore avoided.

I did already contact the Mitsubishi Tanabe Pharma Corporation in Japan and Mr Junya Namba wrote back saying that Ceredist is only available in Japan.

I also obtained from Japan the Post-Marketing Surveillance of Ceredist Tablets on Spinocerebellar Degeneration (in Japanese).  The drug was well tolerated.

Taltirelin hydrate is currently produced and sold freely as a generic chemical.