Chlorzoxazone for sound sensitivity (hyperacusis) and hyper-excitable neural circuits in Fragile X and broader autism – an alternative to Ponstan? Why is Gallic acid beneficial in Autism? Varenicline and other nicotinic therapies, revisited

  

 

Today’s post covers some practical interventions raised recently either in the research, or in the comments section.

 

·         Chlorzoxazone (via Potassium channels – BKCa, SKCa) an old muscle relaxant first approved in 1958

·         Varenicline a drug approved in 2006 that targets nicotinic receptors in the brain

·         Nicotine

·         Tropisetron, an anti-nausea drug that also targets nicotinic receptors in the brain; it was approved in 1992 in Switzerland and is available in the Europe but not the US.

·         Gallic acid, a component of numerous plants/foods (grapes, pomegranates, green tea, red wine etc) that have been used in traditional medicine across different cultures

 

The common link between the first four is the sensory problems usually found across all severities of autism, and some forms of ADHD/autism-lite. It can be either sound sensitivity (hyperacusis) or misophonia (impaired sensory gating), both of which often co-occur in the same person.

We will refer to some of the excellent research into Fragile X syndrome. This is the most common single gene type of autism; most autism is polygenic and some is not of genetic origin at all (hypoxia during birth, sepsis etc).

 

Let’s start with the easiest topic.

 

Gallic acid

I saw the recent study below and wondered what is gallic acid.

 

Vitamin C and Gallic Acid Ameliorate Motor Dysfunction, Cognitive Deficits, and Brain Oxidative Stress in a Valproic Acid‐Induced Model of Autism

Autism, a developmental‐neurodegenerative disorder, often manifests as social communication difficulties and has been correlated to oxidative stress in the brain. Vitamins C and gallic acid (GA) possess potent antioxidant properties, making them potential candidates for addressing autism‐related issues. This study examined the influence of vitamin C (Vit C) and GA on behavioral, motor, and cognitive performance, along with the assessment of brain oxidative markers, using an experimental model of autism.

Finding

The prenatal VPA‐induced autism model increased nociceptive threshold, heightened anxiety‐like behaviors, impaired balance power, delayed spatial learning, elevated malondialdehyde, and decreased glutathione and catalase levels in the brains of the male offspring. Administration of Vit C and GA effectively mitigated these anomalies.

Conclusions

Vit C and GA could potentially alleviate anxiety‐like behaviors, motor and cognitive deficits, and brain oxidative stress markers in a prenatal rat autism model. This underscores their viability as potential pharmacological interventions for treating autistic dysfunction.

 

Gallic acid is a naturally occurring organic acid widely found in various plants, fruits, and foods. It is notable for its antioxidant, anti-inflammatory, and antimicrobial properties, making it of interest in health and medicine.

For no obvious reason, gallic acid has never been commercialized as a supplement, but gallic acid is one of the reasons a glass of red wine a day may well be good for you.  It can give a you a 20 mg dose of gallic acid.

Red wines made from grape varieties with higher tannin content, such as Cabernet Sauvignon or Pinot Noir, tend to have higher levels of gallic acid because tannins contain gallic acid. Longer aging, especially in oak barrels, can increase gallic acid due to the extraction from the wood.

The new study suggests that gallic acid is a potential pharmacological intervention for treating autism.  It joins an already very long list! 

 

Varenicline and other nicotinic therapies

Our reader Dragos in Romania recently asked for help obtaining Varenicline, which is also sold as Chantix. This drug is similar to using a nicotine patch, but different in some important ways.

DAN doctors in the US used to prescribe nicotine patches to children with autism.

There is a lot of research to support the use  of therapies that target a specific nicotinic receptor in the brain called the alpha 7 nicotinic acetylcholine receptor (α7 nAChR).

Nicotine itself activates all nicotinic receptors, not just α7 nAChR.

Dragos want to trial the smoking cessation drug Varenicline, which targets α7 nAChRs and a little bit the one called α4β2 nAChR.

 

α7 nAChRs

These receptors are well known to be implicated in diseases such as Alzheimer's, schizophrenia, autism, and epilepsy.

They affect:

Cognition and memory

·        α7 nAChRs are involved in synaptic plasticity, learning, and memory formation due to their role in calcium signaling and modulation of neurotransmitter release.

·        Highly expressed in the hippocampus, which is critical for memory processing.

Neuroprotection

·        Calcium influx through α7 nAChRs activates signaling pathways that promote cell survival and neuroprotection.

·        Involved in reducing neuroinflammation and protecting against excitotoxicity.

Modulation of Neurotransmitter Release

·        Regulate the release of dopamine, glutamate, GABA, and serotonin, impacting mood, arousal, and reward mechanisms.

Inflammatory Regulation

·        Present on immune cells, where they regulate the release of pro-inflammatory cytokines like TNF-α via the cholinergic anti-inflammatory pathway.

Sensory Gating

·        α7 nAChRs are crucial for sensory filtering, preventing sensory overload. Dysfunction in these receptors is linked to conditions like autism and schizophrenia.

 

α4β2 nAChRs

These play a role in:

Cognitive function

·        Involved in attention, learning, and memory.

·        Enhances synaptic plasticity in brain regions like the hippocampus.

Dopamine release

Pain modulation

Mood regulation

 

Research has shown reduced expression of both α7 nAChRs and α4β2 nAChRs in the brains of people with autism.

Dragos has good reason to trial Varenicline; not only has another young adult in Romania with severe autism recently responded well, but there are published case reports to give further support.

 

Varenicline in Autism: Theory and Case Report of Clinical and Biochemical Changes

Objective: To explore the potential benefits of varenicline (CHANTIX^®), a highly specific partial agonist of neuronal α4β2 nicotinic acetylcholine receptors (nAChR), for autistic symptoms, and present resulting biochemical changes in light of dopamine-related genotype.

Methods: The clinical and biochemical changes exhibited by a 19-year-old severely autistic man following the use of low-dose varenicline in an ABA experiment of nature, and his genotype, were extracted from chart review. Clinical outcome was measured by the Ohio Autism Clinical Impression Scale and 12 relevant urine and saliva metabolites were measured by Neuroscience Laboratory.

Results: With varenicline, this patient improved clinically and autonomic biochemical indicators in saliva and urine normalized, including dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), epinephrine, norepinephrine, taurine, and histamine levels. In addition, with varenicline, the dopamine D1 receptor (DRD1) antibody titer as well as the percent of baseline calmodulin-dependent protein kinase II (CaM KII) activity dropped significantly. When varenicline stopped, he deteriorated; when it was resumed, he again improved. Doses of 0.5, 1, and 2 mg daily were tried before settling on a dose of 1.5 mg daily. He has remained on varenicline for over a year with no noticeable side effects.

Conclusion: This report is, to the best of our knowledge, only the second to demonstrate positive effects of varenicline in autism, the first to show it in a severe case, and the first to show normalization of biochemical parameters related to genotype. As with the previous report, these encouraging results warrant further controlled research before clinical recommendations can be made.

 

Varenicline vs Nicotine 

Let’s compare the mechanisms of action:

Varenicline

• Partial agonist at the α4β2 nicotinic acetylcholine receptor (nAChR) and a full agonist at α7 nAChRs.
• Modulates neurotransmitter release (e.g., dopamine, glutamate), which may improve cognitive function and reduce repetitive behaviors in ASD.
• FDA-approved for smoking cessation.

 

Nicotine Patches

• Deliver nicotine, a full agonist at nAChRs.
• Broadly activate multiple nAChR subtypes, leading to enhanced cholinergic signaling.
• Typically used for smoking cessation

 

Other Considerations

Varenicline

·         Offers more targeted modulation of nAChRs with less widespread cholinergic activation.

• Varenicline’s mechanism prevents full desensitization, maintaining its effects over time.

·         May be preferred if minimizing side effects like overstimulation is important.

 

Nicotine Patches:

• Easy to administer and widely available but less specific in its action, which may lead to more off-target effects.
• Nicotine can lead to rapid receptor desensitization and tolerance, especially with continuous delivery via patches.

 

Alternatives

There are some theoretical alternatives, such as:

 

ABT-126 (Pozanicline)

·         Type: Selective α7 nAChR agonist.

·         Status: Investigated for Alzheimer's disease and schizophrenia.

·         Cognitive enhancement and improved sensory gating.

 

RG3487 (MEM 3454)

·         Type: Partial α7 nAChR agonist and modulator of glutamate receptors.

·         Status: Investigated for schizophrenia and cognitive impairment.

·      Improves cognition and reduces symptoms like sensory gating deficits.

 

The one that caught my attention previously when writing about this subject was Tropisetron.

 

Tropisetron:

• Already approved as an antiemetic but also acts as a weak α7 nAChR agonist.
• Potential benefits in cognitive and inflammatory disorders.

 

Clinical Evidence with Tropisetron

Schizophrenia

Early studies show cognitive and sensory gating improvements in schizophrenia patients treated with tropisetron.

One-day tropisetron treatment improves cognitive deficits and P50 inhibition deficits in schizophrenia

Not to forget Vagus Nerve Stimulation (VNS)

The vagus nerve activates α7 nAChRs on immune cells, reducing inflammation without immunosuppression.

The vagus nerve indirectly affects α7 and α4β2 nAChRs in the brain by modulating acetylcholine release.

Vagus nerve stimulation is already used in epilepsy, depression, and inflammatory disorders.

 

It is worthwhile highlighting the effect on people with some types of GI disorder. There is a known association between Asperger’s and ulcerative colitis.

 

Nicotine and Ulcerative Colitis (UC)

·         Smoking appears to have a protective effect on ulcerative colitis.

·         Smokers are less likely to develop UC, and those who quit smoking are at higher risk of developing the condition.

·         Current smokers with UC may experience milder disease with fewer flares and less severe symptoms.

The suggested mechanism

·         Dysregulated inflammation in the colonic mucosa leads to ulcerations, diarrhea, and abdominal pain.

·         α7 nAChR activation may reduce this inflammation, aiding in mucosal healing and symptom improvement.

·         Nicotine’s anti-inflammatory effects may play a role by modulating cytokine release (e.g., reduced IL-8 and TNF-α).

·         Nicotine also stimulates mucus production and increases colonic blood flow, potentially improving mucosal healing.

·         Smoking-induced changes in the microbiome may also reduce UC severity.

 

Note that for Crohn's Disease (CD) and Irritable Bowel Syndrome (IBS) smoking makes the symptoms worse.

 

So, it would make sense to use vagal nerve stimulation for inflammatory bowel disease?

 

Here are results from 2023

 

Vagus nerve stimulation reduces inflammation in children with inflammatory bowel disease

 

Bioelectronic medicine researchers at The Feinstein Institutes for Medical Research and Cohen Children’s Medical Center published results today, in the journal Bioelectronic Medicine, from a proof-of-concept clinical trial that showed non-invasive, non-pharmacological transcutaneous auricular vagus nerve stimulation (ta-VNS), or stimulating in the ear, significantly reduced inflammation in more than 64 percent of pediatric patients with IBD. 

Dr. Sahn and his team used a commercially available transcutaneous electrical nerve stimulator (TENS) unit (TENS 7000) and sensor probe for the trial. Two earbuds on the probes were placed on a small area of the external ear called the cymba conchae, where the vagus nerve is most accessible. For five-minute intervals, the patients received the stimulation for a total of 16 weeks.

 Finally to BKCa and SKCa channels in Fragile X syndrome (FXS) and broader autism !

 

Let’s have a quick recap on Fragile X.

 

Fragile-X

Fragile X (FXS) is the most common single gene cause of intellectual disability (IQ less than 70).

FXS affects approximately 1 in 4,000 males and 1 in 8,000 females.

The condition is very well studied and the Fragile X gene (FMR1) is considered an autism gene.

I am surprised how rarely (never?) FXS parents comment in this blog. They are actually the ones who stand to benefit the most, given how well-studied their syndrome is and how many treatment options exist. I was recently discussing this exact point with an autism therapist with an FXS patient – why do parents remain passive and not react?

 

More severe in males than females

Males have one copy of the FMR1 gene, while females have two.

In females with the full mutation, symptoms are generally less severe than in males due to what is called random X-inactivation. Since females have two X chromosomes, one of the X chromosomes in each cell is randomly inactivated. In cells where the X with the mutation is inactivated, FMRP is produced normally, and in cells where the normal X is inactivated, no FMRP is produced. The severity of symptoms often correlates with the proportion of cells in which the mutated X is active.

In a strange twist of fate females with the milder form of FXS, called premutation, have the greatest chance of being infertile. This is due to Fragile X-associated primary ovarian insufficiency (FXPOI).

 

Testing

The ability to conduct genetic testing began in the 1990s, became more widespread by the mid-1990s, and became integrated into routine clinical practice in the early 2000s. Today, genetic testing for Fragile X is a standard tool used to diagnose FXS, assess carrier status, and inform genetic counselling.

You can also identify Fragile X based on facial features and this is a common practice, especially in the early diagnosis of individuals with the syndrome.

BKCa and SKCa channels in autism and Fragile X

Ion channel dysfunctions play a key role in all neurological conditions. A great deal is known about them, making them an excellent target for intervention.

Fragile X is such a well-studied condition that you can access all the information very easily.

For other single gene autisms and the more common idiopathic (unknown cause) autism it is more a matter of guesswork. 

This recent paper is excellent: 

Channelopathies in fragile X syndrome

The paper lists all the proven ion channel dysfunctions and suggests how to treat some of them.

Potassium channels – BKCa, SKCa, Kv1.2, Kv3.1, Kv4.2,

Calcium channels – Cav1.3, Cav2.1, Cav2.3,

Misc – HCN, NKCC1, AMPAR, NMDAR, GABA_AR

 

Targeting BKCa, SKCa in Fragile X and for hyperacusis in broader autism

In FXS, hyperexcitability in brain circuits is thought to contribute to cognitive and behavioral symptoms.

Preclinical studies suggest that SKCa and BKCa channel activators may correct this hyperexcitability and improve neural network function.

The therapeutic effects of a cheap drug called chlorzoxazone in FXS models are believed to stem from its ability to enhance BKCa channel activity. These channels play a pivotal role in regulating neuronal firing rates and neurotransmitter release. By activating BKCa channels, chlorzoxazone may counteract the neuronal hyperexcitability observed in FXS, leading to improved behavioral and sensory outcomes.

BKCa channels are indispensable for hearing, as they regulate frequency tuning, temporal precision, and signal transmission in both cochlear hair cells and auditory neurons. Dysfunctions in these channels are linked to hearing impairments like frequency discrimination deficits, tinnitus, and hyperacusis (sound sensitivity). Modulating BKCa activity offers a promising avenue for treating auditory disorders.

 

Therapeutic efficacy of the BKCa channel opener chlorzoxazone in a mouse model of Fragile X syndrome

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and autistic-like symptoms such as social deficits. Despite considerable efforts, effective pharmacological treatments are still lacking, prompting the need for exploring the therapeutic value of existing drugs beyond their original approved use. One such repurposed drug is chlorzoxazone which is classified as a large-conductance calcium-dependent potassium (BKCa) channel opener. Reduced BKCa channel functionality has been reported in FXS patients, suggesting that molecules activating these channels could serve as promising treatments for this syndrome. Here, we sought to characterize the therapeutic potential of chlorzoxazone using the Fmr1-KO mouse model of FXS which recapitulates the main phenotypes of FXS, including BKCa channel alterations. Chlorzoxazone, administered either acutely or chronically, rescued hyperactivity and acoustic hyper-responsiveness as well as impaired social interactions exhibited by Fmr1-KO mice. Chlorzoxazone was more efficacious in alleviating these phenotypes than gaboxadol and metformin, two repurposed treatments for FXS that do not target BKCa channels. Systemic administration of chlorzoxazone modulated the neuronal activity-dependent gene c-fos in selected brain areas of Fmr1-KO mice, corrected aberrant hippocampal dendritic spines, and was able to rescue impaired BKCa currents recorded from hippocampal and cortical neurons of these mutants. Collectively, these findings provide further preclinical support for BKCa channels as a valuable therapeutic target for treating FXS and encourage the repurposing of chlorzoxazone for clinical applications in FXS and other related neurodevelopmental diseases.

  

·        Chlorzoxazone

In the FXS research they repurpose a drug called chlorzoxazone to activate BKCa channels, with positive results

 

·        Mefenamic acid (Ponstan)

In this blog Ponstan has shown promise to treat hyperacusis. Ponstan is a known activator of both BKCa and SKCa channels.

 

Which is “better” chlorzoxazone or Ponstan?

According to the science chlorzoxazone is more potent than Ponstan in affecting both BKCa and SKCa channels.

Ponstan has more effects on Kv channels like Kv7. Kv7 is implicated in autism and epilepsy.

In terms of gene expression Ponstan has more direct effects on gene expression due to its modulation of inflammatory pathways and inhibition of prostaglandin synthesis.

Chlorzoxazone primarily acts on ion channels, and its effects on gene expression are secondary and less pronounced.

In conclusion the two drugs are very different, both potentially useful, and some of their actions, such as on hyperacusis, are overlapping.

  

Conclusion

Chlorzoxazone an inexpensive drug used to treat muscle spasms is also known for its effects on calcium-activated potassium channels (BKCa and SKCa).

Some claim that Chlorzoxazone may affect GABAa and/or GABAb receptors, but that appears not to be the case.

The research suggests that Chlorzoxazone should have a beneficial effect in FXS and very likely would have a benefit in some broader autism and in hyperacusis specifically.

The effects of Chlorzoxazone are likely to overlap with the effects of Ponstan. Ponstan is quite possibly also going to be effective in FXS, as it is in broader autism.

There are many suggested therapies for FXS (Metformin, Lovastatin, Baclofen, Acamprosate, Gabapentin, Minocycline, Memantine, Rapamycin, L-carnitine, Omega 3 etc). None, when taken alone, are game-changers.

Every parent of a child with Fragile X should read the paper I have linked to in this post.

 

Channelopathies in fragile X syndrome

 

It is full of excellent ideas. If NKCC1 is overexpressed, as is suggested, trial bumetanide.

As in all autism, polytherapy is going to be key. No single therapy can be highly effective with so many dysfunctions present. To quote from the above paper:-

 “Ultimately, the most effective treatment strategies are likely to be multifactorial.”

This means do not be surprised if you need 5 different drugs, with 5 different targets to produce a game-changing effect. Better 5 cheap old re-purposed generic drugs than a single brand-new drug with little overall effect and that costs a king’s ransom, each and every year.

Unfortunately, a personalized approach will need to be used to find such a polytherapy. What works at one age may not be beneficial at another age. Even within single gene autisms, treatment response can vary widely from person to person.

At a conference, I did ask a clinician who is an “expert” in Fragile X, does she apply any of the existing therapies from the research, to her patients. She was rather taken aback by the idea and said “no, we have to follow the protocols.” So, an expert in exactly what then? An expert would make the protocols, if none existed.

Educating children with level 3 Autism

 

Some people do not like South Park, but it is a good example of genuine inclusion

The number of children with autism and intellectual disability continues to rise and this is putting a strain on government resources in many parts of the world. Increasing budgets can never match the increased perception of needs.

In spite of the vast amounts of money being spent very little attention is given to evaluating what gives the best results.

In the US it has long been put forward that the earlier the intervention starts the better the results will be and often it is stated that 40 hours a week of one-to-one therapy is needed.  This view is generally limited to the US.    

ABA therapy became a big business in the US and many providers are now owned by private equity investors.

I did point out that in the book the Politics of Autism, the author recounts her discussions with the founding father of ABA, Ivar Lovaas, that revealed he had rigged his clinical studies by excluding those children who did not respond to his 40 hours a week therapy from the final results. He just dropped them before the end of the trial. This would totally invalidate his conclusions.

There is a recent study on this very subject.

Rethinking the Gold Standard for Autism Treatment

Research shows some autistic children may get more treatment hours than needed.

The JAMA Pediatrics study looked at the relationship between the amount of intervention provided (hours per day, duration, and cumulative intensity) and the outcomes for young autistic children. Researchers analyzed data from 144 studies involving more than 9,000 children, making it one of the most comprehensive analyses of its kind.

Contrary to what many have long believed, the study found no significant association between the amount of intervention and improved developmental outcomes. As the authors write, “health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.”

Determining Associations Between Intervention Amount and Outcomes for Young Autistic Children A Meta-Analysis

A total of 144 studies including 9038 children (mean [SD] age, 49.3 [17.2] months; mean [SD] percent males, 82.6% [12.7%]) were included in this analysis. None of the meta-regression models evidenced a significant, positive association between any index of intervention amount and intervention effect size when considered within intervention type.

Conclusions and Relevance  Findings of this meta-analysis do not support the assertion that intervention effects increase with increasing amounts of intervention. Health professionals recommending interventions should be advised that there is little robust evidence supporting the provision of intensive intervention.

Some parents in the US get to the bizarre situation where their child can receive 40 hours of ABA for free, but if they say they want only 20 hours because they have other activities for the rest of the week, this is refused.  It is the full 40 hours or none.   

School segregation

Segregation is a word with negative connotations, but it is used when it comes to the merits of inclusive education versus special schools.

There are many ways in which schools are segregated, including

By sex

It is still very common to have separate boys' schools and girls' schools in many countries

By religion

Religious schools are common in both public and private sectors

By ethnicity

This was widely practiced in the United States and South Africa. The legacy of these policies is still evident today.

By ability

Selecting pupils by academic level is very common.

By disability

Segregation of those with learning disabilities into special schools or special classes within a mainstream school is widespread.

By socioeconomic status

Segregation by the ability to pay is common all over the world. In parts of the world there is no schooling for those whose family cannot afford it.

Homeschooling

In parts of the world homeschooling is legal and thriving. The US has by far the largest contingent, with 6% of children home-schooled.  In Germany it is illegal.

What is the best type of school for level 3 autism?

There is no “best” choice.

From the parents' perspective, some are desperate for their child to attend a special(ist) school and some are desperate not to attend such a school.

Some parents choose to home school.

Some parents look for some kind of hybrid solution.

Most parents just take what is given to them.

Inclusion vs segregation

The key issue here is whether the child is “includable”. It is fashionable in Western countries to be anti-segregation and pro inclusion.

Some children are not includable and some school environments are hostile rather than welcoming.  Even some children with level 1 autism struggle to cope in mainstream school.

Monty was lucky and completed all his schooling in a mainstream school with very small class sizes, about 12 pupils. He had his own teaching assistant throughout. Two of his former assistants later became class teachers at his school. We paid for the school and the assistants.

Had Monty attended a school with 30 children in the class with 3 other special needs kids, each with their own teaching assistant, the result would not have been so good.

As you can see it is a question of “inclusion in what” versus “segregation in what”.

What is the purpose of “school”

If you talk to parents of older children you will discover that over the years their view of schooling changes. It is an illusion, one grandfather told me. For many schooling is just daycare for the pupil and respite care for the parents.

Some parents do not want their child to be just taught daily living skills, they want the academic curriculum.

Some schools teach non-verbal children an alternative method of communication, whereas other do not bother.

It is not surprising that the result is often nobody is satisfied.

Peter’s idea about schooling for level 3 autism

I would require all children with level 3 autism to be taught at primary/elementary school a means of communication. Remarkably this is not done.

Proactive parents have been doing this for decades at home, but what if your parents are not proactive?

I read the other day that a mother commented that her non-verbal 7 year old daughter would greatly benefit from an augmentative communication device, but that the council/municipality did not want to provide one. In previous decades these were expensive devices, but nowadays these are just apps that you install on an iPad, or android device. Some of these apps are even free !!

Clearly, I would ensure all pupils with level 3 autism were screened and treated for any type of treatable intellectual disability, the most common one being elevated chloride inside neurons, which was the case for Monty.

I recently was contacted by a parent who, after trying to help his son for 7 years, has finally had success by increasing his dose of leucovorin (calcium folinate). Now his son responds to verbal instructions like "wash your hands".

Some of these children, once under medical treatment, will be able to follow much of the core academic curriculum and be genuinely included in mainstream classes. That was the outcome for Monty, now aged 21.

Children who remain with a lower IQ should not be in classes that teach academic concepts far above their level of understanding. This is pointless and will just lead to frustration.

One non-verbal child I know, who cannot read or write is “taught” a second language at school. How about teaching him a first language?

Children should be taught in groups of similar ability/functioning level, rather than grouping them by age. I thought this would be just common sense, but not in the world of education.

If the material has not been mastered there is no point moving forward, just repeat it. After 15 years at school there should have been measurable progress.

Beware of prompt-dependence and assistant-dependence. Skills learned at school need to be such that the child can apply them independently and can generalize them to new situations. Some wealthy schools provide very high levels of support and this risks that the child will become an adult dependent on a similar level of support. This is an example of “too much of a good thing”.

 

The services “cliff-edge”

Some people with autism, and their families, receive very considerable support for two decades and become dependent on it. At some point in early adulthood these supports may get abruptly withdrawn.

In other parts of the world, there was only ever very minimal support and the family became more self-reliant and so do not experience such a cliff-edge. The family and the young adult learnt to cope.

Level 1 autism / Asperger’s

This post is about level 3 autism, but I am always surprised how many people with level 1 autism write to me so here are some thoughts on them.

You would think that all people with level 1 autism should be able to thrive in mainstream education these days. There is so much in the media, or social media, about accommodating differences and promoting the “able disabled” who are featured everywhere, so how come kids at school are still bullying/tormenting their classmates who are 1% different. Times have not really changed as much as we might have thought.

Most kids with level 3 autism love going to school.  Monty adored it.

Many kids with level 1 autism clearly hate it.

During my time helping to run my children’s school one of the things teachers told me was that kids are actually very supportive of those who are clearly disabled but will delight in picking on kids who are a tiny bit different.

The net result is that many children with level 1 autism thoroughly enjoyed their on-line education during the pandemic away from all that awkwardness at school.

Many parents whose child goes to a special school for autism or Down syndrome are completely unaware that there are also some special schools for level 1 autism. It greatly surprised me.

 

Conclusion

The idea of trying to educate children with level 3 autism is relatively new. In the recent past they were just put aside in institutions and forgotten about.  Today much is possible, but a lot comes down to who the parents are and where they happen to live.

The Education for All Handicapped Children Act (EAHCA) of 1975 (later renamed the Individuals with Disabilities Education Act, or IDEA, in 1990) was the major turning point in the US. This ultimately opened the door to a flood of ABA, paid for by private health insurance, but only in the US.

My doctor mother once commented to me that we had shown that such children can be taught and can genuinely learn. This was a combination of personalized medicine and personalized learning.

Good things don’t just happen, you have to make them happen.

The outcome in level 3 autism is hugely variable and that is rather sad.

Big heads, the Car wash, Transcranial pulse stimulation, GABA alpha 5 and Potassium channel Kv3.1

Today’s post is a review of some interesting new research that relates to the scope of this blog.  It ranges from training young people with autism/ID to work at the car wash, to more complex science.

Let’s start with the easiest paper. Somewhat bizarrely it was carried out in Japan by researchers from India. I am a fan of teaching kids to wash cars but I was surprised to see that it would be covered in a published research study.

One often forgotten item to teach teenagers and young adults with autism or ID is how to safely use public transport, so they might travel independently to and from any future job. We have had a lot of success with this recently. Monty, now aged 20, can get all the way from home to various different locations across the city using public transport, including changing buses and with journey times more than one hour.

 

Increasing car washing competency in adolescents with autism and intellectual disabilities: Researching visual task evaluation

This study looked at how well visual task evaluation helped teenagers with autism and intellectual disabilities become more competent at car washing. For disabled people to promote their independence and employment chances, car washing skills are crucial. The goal of this study was to ascertain whether training techniques that include visual task evaluation can improve car washing proficiency in teenagers with autism and intellectual disabilities. 30 participants, ranging in age from 12 to 18, participated in a pre-test/post-test design. Randomly chosen groups of participants were put into the evaluation group for the visual task or the control group. According to the findings, the visual task evaluation group outperformed the control group in terms of car washing ability. Adolescents with autism and intellectual disabilities can learn skills more quickly and become more independent by including visual task evaluation into their teaching strategies. These results demonstrate the potential for such treatments to enhance their quality of life and employment chances.

 

Car washing with a pressure washer is great fun for most people and washing a car thoroughly has many individual steps to master, so it is good practice.

  

Head size

It has been known for decades that big heads (macrocephaly) and small heads (microcephaly) are a tell-tale sign of a neurodevelopment problem. Normally, big heads are linked to intellectual disability, but very small heads are also a warning sign.

Readers may recall the Zika virus epidemic in Brazil in 2015. This mosquito-borne virus caused pregnant women to give birth to children with microcephaly. Zika virus infection caused intellectual disability in babies. The severity of the intellectual disability varied from mild to severe. Babies with Zika virus infection may have difficulty learning and communicating. They may also have problems with problem-solving and abstract thinking. Hearing and vision can be impaired and growth is retarded.  

Head size parts autism into two major subtypes

Essentially opposite paths in fetal brain development may explain two major subtypes of autism. In one of these subtypes, an unusually high number of excitatory neurons in a key brain region leads to large heads, or macrocephaly, which affects roughly 20 percent of people with autism; in the other, a decreased number of the same cells in that area leads to more typical head sizes, a new study finds. 

This fundamental biological difference suggests that “therapeutic avenues may be drastically different for these subtypes,” says lead investigator Flora Vaccarino, professor of neuroscience at Yale University. “That in turn could explain why drug treatments for autism so far are failing.”

 

The opposite brain development paths found in this research may both lead to autism because they are each a case of imbalance, says investigator Alexej Abyzov, associate professor of biomedical informatics at the Mayo Clinic in Rochester, Minnesota. 

The full paper:- 

Modeling idiopathic autism in forebrain organoids reveals an imbalance of excitatory cortical neuron subtypes during early neurogenesis

Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.

 

Head circumference at birth is a useful measurement, but what really matters is how it changes over time.  Hyperactive pro-growth signaling affects more than just brain growth, it also affects muscle development, which is easy to notice.  I have highlighted the graphic below several times in this blog and in my book.  It is a good summary of what is going on.

 

Kv3.1

Regular readers will know that I like ion channels. The reason is that dysfunctions in these channels really should be treatable.  Usually we are looking for channel blockers, but today with Kv3.1 we are looking for channel enhancers.

Ion channel enhancers increase the activity of ion channels without directly opening them. They do this by increasing the number of open channels, increasing the opening time of each channel, or decreasing the closing time of each channel.

  

Grant aids drug discovery for autism, schizophrenia

At the heart of the study is a type of inhibitory neuron called GABAergic interneurons, which connect brain regions, playing vital roles in coordinating high-frequency brain activity. As a potential source of the excitatory/inhibitory imbalance in ASD and schizophrenia, evidence now points to malfunction of a type of potassium channel, Kv3.1, special to GABAergic interneurons. Denton and his team will aim to develop Kv3.1 enhancers and test their efficacy in restoring the balance of neural activity in a mouse model of ASD. In latter stages of this work, they’ll focus on key brain areas, using various lab techniques to carefully fill in neurological details surrounding any targeted drug effects.

“This grant creates opportunities for developing critically needed tool compounds to explore the role of Kv3.1 potassium channels in autism spectrum disorder and schizophrenia,” said Denton, professor of Anesthesiology and Pharmacology. “These are some of the most challenging and costly disorders going, and we’re excited to have this opportunity to take this work forward.”

 

Japanese researchers from the RIKEN Brain Science Institute are also thinking along the lines of targeting Kv3.1 to “correct aberrant developmental trajectories”. 

K_v3.1 channels regulate the rate of critical period plasticity 

The emergent function of fast-spiking PV-cell circuits during postnatal life may hold the key to a deeper understanding of critical periods in brain development (Reh et al., 2020) and the etiology of related mental illnesses as well (Do KQ and Hensch, 2015). The human neocortex notably shows a decrease in K_v3.1b channel protein in schizophrenia, a deficit that is restored by anti-psychotic drugs (Yanagi et al., 2014). Moreover, individuals with a KCNC1 loss-of-function variant can present intellectual disability without seizure and epilepsy (Poirier et al., 2017; Park et al., 2019). Our work points toward a prophylactic psychiatry that may target these particular channels to correct aberrant developmental trajectories.

 

As with head size, the “when” is also important with correcting Kv3.1.  The idea is to intervene at a very early age to redirect the developmental trajectory, rather than just to improve today’s functioning.

The logical question is what drugs will Professor Denton come up with to explore the benefit of targeting Kv3.1.  Perhaps someone can beat him to it and save us all a couple of decades?

If you look up Kv3.1 or the gene that encodes it called KCNC1 you can read all about it.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNC1

 

As expected, there is no shortage of channel blockers – Nifedipine (used a calcium channel blocker), Miconazole (an antifungal), Capsaicin (an active component of chili peppers), Fluoxetine (better known as Prozac, which is vitamin P to many people) plus many more.

Professor Denton is hunting for a channel enhancer.  Keep an eye on what he comes up with. He has $2.7 million over 4 years to play with. 

 

Transcranial pulse stimulation

Many autism parents do not like drug therapies, but often like the idea of zapping the brain from outside. I liked the idea of Photo biomodulation (PBMT) a form of light therapy that utilizes light sources including lasers or LEDs.

 

Low Level Laser Therapy (LLLT) for Autism – seems to work in Havana

Home/Clinic based Photobiomodulation/Laser Therapy in Autism - acting on Light Sensitive Ion Channels, Mitochondria, Lymph Nodes and more

 

You could potentially do Low Level Laser Therapy (LLLT) at home.

Professor Manual Casanova is a fan of transcranial magnetic stimulation (TMS).

Today’s paper below is about transcranial pulse stimulation, which I suppose we can just call TPS.

Transcranial pulse stimulation (TPS) is a non-invasive brain stimulation technique that uses pulsed electrical or magnetic fields to stimulate the brain. It is a relatively new technique, but it has the potential to be used for a variety of purposes, including:

• Treating neurological disorders such as Parkinson's disease, Alzheimer's disease, and depression
• Enhancing cognitive function, such as memory and attention
• Improving mood and well-being
• Reducing pain
• Promoting neuroplasticity, the ability of the brain to change and adapt

 

 

Effects of transcranial pulse stimulation on autism spectrum disorder: a double-blind, randomized, sham-controlled trial

 

Transcranial pulse stimulation has been proven effective to improve cognition, memory and depressive symptoms of Alzheimer’s disease, but supporting evidence on other neurological diseases or neuropsychiatric disorders remains limited. This study aimed to investigate the effects of transcranial pulse stimulation on the right temporoparietal junction, which is a key node for social cognition for autism spectrum disorder, and to examine the association between transcranial pulse stimulation and executive and social functions. This double-blinded, randomized, sham-controlled trial included 32 participants (27 males), aged 12–17 years with autism spectrum disorder. All eligible participants were randomized into either the verum or sham transcranial pulse stimulation group, on a 1:1 ratio, based on the Childhood Autism Rating Scale screening score. Sixteen participants received six verum transcranial pulse stimulation sessions (energy level: 0.2–0.25 mJ/mm2; pulse frequency: 2.5–4.0 Hz, 800 pulse/session) in 2 weeks on alternate days. The remaining 16 participants received sham transcranial pulse stimulation. The primary outcome measure included Childhood Autism Rating Scale score changes, evaluated by parents, from baseline to 3-month follow-ups. Secondary outcomes included a self-reported questionnaire responded to by parents and cognitive tests responded to by participants. A licensed mental health professional evaluated clinical global impression severity, improvement, efficacy and total score. Results revealed significant interactions in Childhood Autism Rating Scale and other secondary outcomes. Significant group and time effects were found in most secondary outcomes. Additionally, significant differences were found between the transcranial pulse stimulation and sham transcranial pulse stimulation groups in Childhood Autism Rating Scale and clinical global impression improvement and total score immediately after 2 weeks of transcranial pulse stimulation intervention (all P < 0.05), and effects were sustainable at 1- and 3-month follow-up, compared with baseline. The effect size of Childhood Autism Rating Scale (d = 0.83–0.95) and clinical global impression improvement (d = 4.12–4.37) were large to medium immediately after intervention and sustained at 1-month post-stimulation; however, the effects were reduced to small at 3-month post-stimulation (d = 2.31). These findings indicated that transcranial pulse stimulation over right temporoparietal junction was effective to reduce the core symptoms of autism spectrum disorder, as evidenced by a 24% reduction in the total Childhood Autism Rating Scale score in the verum transcranial pulse stimulation group. Additionally, the clinical global impression total score was reduced by 53.7% in the verum transcranial pulse stimulation group at a 3-month follow-up, compared with the baseline. Participants in the verum transcranial pulse stimulation group had shown substantial improvement at 1- and 3-month follow-ups, compared with baseline, although some of the neuropsychological test results were deemed statistically insignificant. Future replication of this study should include a larger sample derived from multi-nations to determine transcranial pulse stimulation as an alternative top-on treatment option in neuropsychiatry

 

TPS looks pretty impressive, based on the above study. TPS is available today, but it does need a lot of visits to the therapist. The effects are not permanent so you would have to keep going back for more.

People are doing transcranial direct current stimulation (tDCS) at home. 

People are zapping their brains at home to improve focus and clear brain fog. But is it safe?

For any kind of zapping therapy to be viable, it would have to be possible to do it yourself at home.

 

Targeting alpha 5 subunit of GABA_A receptors

Some earlier posts in this blog did get rather complicated.  One field that I looked at in rather painful detail was the GABA_A receptor. Some readers of this blog have children whose autism is entirely caused by a defect in this receptor, many other readers just see the effects of a GABA_A malfunction caused by a problem with NKCC1/KCC2 expression resulting from the GABA developmental switch failing to occur.

I looked to me that targeting alpha 3 and alpha 5 subunits could well enhance cognition.

Alpha 3 is targeted by low dose Clonazepam, thanks to Professor Catterall.

Alpha 5 was targeted to treat Down syndrome, using a new drug called Basmisanil (an inverse agonist of alpha 5 subunit of GABA_A). That work failed. I wrote about Cardiazol/ Pentylenetetrazol (PTZ) a drug that was widely used in the 1930s in mental hospitals to trigger seizures that were supposed to treat people with schizophrenia.  At much lower doses, it found a new purpose decades ago as an ingredient in cough medicine. 

The alpha 5 subunit is one of several subunits that can make up a GABA_A receptor. GABA_A receptors containing the alpha 5 subunit are thought to be involved in cognitive function, learning and memory, and mood regulation.

PTZ has been shown to block the action of GABA at alpha 5-containing GABAa receptors in animal studies.  

Variable Expression of GABRA5 and Activation of α5 -  a Modifier of Cognitive Function in Autism?

 

Sodium Benzoate and GABRA5 - Raising Cognitive Function in Autism 

Cardiazol, a failed Schizophrenia treatment from the 1930s, repurposed at low doses as a Cognitive Enhancer in Down Syndrome and likely some Autism

 

The logical human trial would be to use the cough mixture, Cardiazole that is already used in children. 

“We actual have quite a few readers from India and that is the only other country using this drug.  In India the producer is Nicholas Piramal and the brand name is Cardiazol Dicodid, it cost 30 US cents for 10ml.  So for less than $1, or 70 rupees, you might have a few months of cognitive enhancement, that is less than some people pay for 1 minute of ABA therapy.

If a few drops of this children’s cough medicine improves cognition please lets us all know.”

 

Back to recent research on alpha 5 that caught my attention.

 

An alpha 5-GABAa receptor positive allosteric modulator attenuates social and cognitive deficits without changing dopamine system hyperactivity in an animal model for autism

 Autism Spectrum Disorders (ASD) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABA_A receptors (α5-GABA_ARs) SH-053-2’F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in a rat model for autism based on in utero VPA exposure. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2’F-R-CH3 could attenuate these changes. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2’F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Male and female adult VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2’F-R-CH3. Despite sex differences, our findings indicate α5-GABA_ARs positive allosteric modulators may effectively attenuate some core ASD symptoms

 

Fine tuning alpha 5, perhaps you need more, perhaps less?

 

Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors

Despite being a genetically heterogeneous disorder, the potential utility for mechanism-based GABAAR pharmacologic treatment with ASDs is supported by shared pathologies both in patients and related mouse models.

  

PAM α5 GABAAR Therapeutic Applications

Neurodevelopmental Disorders

Mouse models of neurodevelopmental disorders that present with insufficient inhibitory tone show improvement with positive modulators of GABAAR signaling. In the Scn1a+/− mouse model of Dravet syndrome, a severe childhood epileptic encephalopathy syndrome with hyperactivity and autism behaviors, abnormal social behaviors and fear memory deficits were rescued following treatment with a benzodiazepine, clonazepam (Han et al., 2014). In an ASD mouse model with reduced GABAAR-mediated inhibition, the BTBR T+tf/J mouse, the α2,3 and 5 PAM L-838,417, improved deficits in social interaction, repetitive behaviors, and spatial learning (Han et al., 2014).

 

Postweaning positive modulation of α5GABAA receptors improves autism‐like features in prenatal valproate rat model in a sex‐specific manner 

Autism spectrum disorder (ASD), as a common neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still awaits an effective treatment strategy. The involvement of GABAergic neurotransmission, and especially a deficit of GABA A receptors that contain the α5 subunits, were implicated in pathogenesis of ASD. Therefore, we tested MP‐III‐022, a positive allosteric modulator (PAM) selective for α5GABAA receptors, in Wistar rats prenatally exposed to valproic acid, as an animal model useful for studying ASD. Postweaning rats of both sexes were treated for 7 days with vehicle or MP‐III‐022 at two doses pharmacokinetically determined as selective, and thereafter tested in a behavioral battery (social interaction test, elevated plus maze, spontaneous locomotor activity, and standard and reverse Morris water maze). Additional rats were used for establishing a primary neuronal culture and performing calcium imaging, and determination of hippocampal mRNA levels of GABRA5, NKCC1, and KCC2. MP‐III‐022 prevented impairments in many parameters connected with social, repetitive and restrictive behavioral domains. The lower and higher dose was more effective in males and females, respectively. Intriguingly, MP‐III‐022 elicited certain changes in control animals similar to those manifested in valproate animals themselves. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, assessed with calcium imaging, and also in expression changes of three genes analyzed. Our data support a role of α5GABAA receptors in pathophysiology of ASD, and suggest a potential application of selective PAMs in its treatment, that needs to be researched in a sex‐specific manner. Lay Summary In rats prenatally exposed to valproate as a model of autism, a modulator of α5GABAA receptors ameliorated social, repetitive and restrictive impairments, and, intriguingly, elicited certain autism‐like changes in control rats. Behavioral results were mirrored in GABA switch and spontaneous neuronal activity, and partly in gene expression changes. This shows a role of α5GABAA receptors in pathophysiology of ASD, and a potential application of their selective modulators in its treatment.

 

Note the researchers actually know about the GABA switch and so measured mRNA levels of NKCC1 and KCC2.

Note also that the lower dose of MP‐III‐022 was more effective in males and the higher dose in females.

We even have the recent associated PhD thesis from Anja Santrač:-

 

The influence of positive modulation of GABAA receptors containing the alpha5 subunit on behavioral changes of mice and rats in models of autistic disorders

The role of α5 GABAA receptors in learning and memory is well known. Therefore, we decided to examine the effect of the selective positive allosteric modulator (PAM) MP-III-022 on learning and memory of healthy animals, as well as GABRA5 expression. After demonstrating the needed tolerability and potential procognitive effects, the ligand would be used in an animal model of autism spectrum disorders (ASD). ASD is a neurodevelopmental disorder that encompasses impairments in social communication and interaction, as well as repetitive and restrictive behavior, still without an effective treatment. In this context, animal models that imitate specific disease’s symptoms are an excellent tool of translational research. Some of the most frequently used models are BTBR T+ tf/J mouse strain (BTBR) and valproate prenatal model (VPA). Our experiments have shown that the variability of α5GABAA receptors’ roles depends on its level of expression and localization, on the type and protocol of cognitive tasks, the timing of testing and intensity of pharmacological modulation. Obtained results proved potential beneficial effects of MP-III-022 in cognitive tasks. The BTBR model failed to express sufficient face validity, while VPA demonstrated adequate face validity and in part construct validity. Thus, we decided to subacutely apply MP-III-022 to juvenile VPA rats. In control animals, treatment led to GABRA5 decrease and to impairments similar to ones seen in ASD, suggesting the possible role of this receptor in the pathogenesis of the disease. Most importantly, our results demonstrated the potential of α5 GABAA receptor PAMs in secondary prevention and treatment of ASD, with the caveat that the drug development program would require adaptations tailored to sex-specific differences revealed.

 

Good job Anja. For our Serbian speaking readers, here is the link to her thesis:-

https://nardus.mpn.gov.rs/bitstream/handle/123456789/21424/Disertacija_13513.pdf?sequence=1&isAllowed=y

Perhaps we should connect her with Professor Ben-Ari?

  

Conclusion

Fine tuning alpha 5 subunits of GABA_A receptors really should be followed up.  I think you need both options - a little bit more and a little bit less. It did not work for Roche in Down syndrome, but the potential remains.

Kv3.1 is another focused target for research, that very likely will become actionable. 

Transcranial pulse stimulation, like all the other zapping therapies, looks interesting, but it needs to be packaged in way that can actually be implemented every day at home.

In the meantime, at least getting your kid to wash the car is something we can all do.