Autism Research Merry-go-round Keeps Turning

 

Today’s post again shows that many issues raised in previous posts keep on coming back – is that good news? Only you can decide.

I start with the “old chestnut” (English idiom to imply “a tired old story”) of the Autism Tsunami. 

Then we see what has come up in the world of autism interventions in the research in the last 3 weeks, most of which regular readers will already be aware of.

·        Autism Tsunami – real or not?

·        Vitamin D

·        Bumetanide

·        Ibudilast

·        Niclosamide

·         Non-invasive brain stimulation

·         Simvastatin 

I noted the research about autism incidence coming from Northern Ireland because it was published in the Belfast News Letter.  These days it has a tiny subscription, but I am one of those who know it is the world's oldest English-language general daily newspaper still in publication, having first been printed in 1737. In 1972 a bomb warning was called in to the paper's office and, as people evacuated, an explosion went off nearby killing several people and injuring many more. Back in the early 1990s, when some people in Northern Ireland were still blowing up others with bombs, I made a visit to Northern Ireland to meet the management of this newspaper. 

Their recent article on autism incidence is very well researched considering how only about 8,000 copies are published. Keep up the good work!

Idea that 5% of all Northern Ireland's children are autistic is 'a fantasy' claims international expert

Professor Laurent Mottron was speaking to the News Letter following a claim that the rate of autism in Northern Ireland is double the rate in the rest of the UK.

Back in 2019 Prof Mottron had authored a report warning about a tsunami of over-diagnosis, saying that soon "the definition of autism may get too vague to be meaningful, trivializing the condition"

“If this trend holds, the objective difference between people with autism and the general population will disappear in less than 10 years," he had said then – and has now indicated that this “fuzziness” is what’s helping swell the numbers in Northern Ireland.

Meanwhile Jill Escher, the president of the National Council on Severe Autism, takes a different view.

She says that evidence indicates the "skyrocketing" rate of autism in Northern Ireland is real, adding: "It boggles my mind that it is not the subject of the highest possible alarm and inquiry."

"One in 20 children in Northern Ireland of school age has a diagnosis of autism," he told MPs.

"[It is] one in 57 in the rest of the UK. The need in Northern Ireland is significantly different."

To put that in perspective, that would mean 5% of Northern Irish children are diagnosed with autism, compared with 1.8% in the rest of the UK.

Prof Mottron, a psychiatrist based at Montreal University, told the News Letter "numbers such as 5% are pure fantasy... these numbers correspond to the part of the general population which has less overt socialisation, which has minimally to do with prototypical autism". 

There is a "current fuzziness of autism diagnosis and over-inclusivity," he said, leading to "a situation of perfect confusion between autistic traits and prototypical autism" (that is, mixing up people who exhibit some tendencies of autistic people with people who actually have the full-blown condition). 

"The scientific 'quasi consensus' would be around 1% everywhere on the planet,” he added.

 

So on one side we have Jill Escher and her NCSA and on the other we have a French/Canadian researcher.  This time Laurent Mottron but in my blog posts I quoted Éric Fombonne.

A paper that was mentioned both in my blog and critiqued by Jill about autism incidence and cost just got retracted.  In reality a better word is “cancelled.”  The 3 authors are very much in the politically incorrect camp of the autism debate.

I was surprised it ever got published.  

Controversial ‘cost of autism’ paper retracted 

Citing methodological issues and undeclared conflicts of interest, an autism journal has retracted a paper that forecast the prevalence and cost of autism.

The retraction note, posted last week, comes two years after Spectrum reported on backlash surrounding the paper, which was published in the Journal of Autism and Developmental Disorders in July 2021. A month after publication, the journal added an editor’s note that the study was under investigation because of criticisms of its conclusions. 

“I am glad to see that it was retracted, although at a pace that maybe is a bit frustrating in terms of how long it took. But it was the right choice,” says Brittany Hand, associate professor of health and rehabilitation sciences at Ohio State University in Columbus.

Outside experts who reviewed the paper on the journal’s behalf found that it misrepresented the rise in autism diagnoses and gave “insufficient attention” to some potential causes of the increase, such as improved surveillance and changes to the diagnostic criteria. The authors also used “higher estimates and assumptions that inflated costs,” according to the retraction note.

The authors — Mark Blaxill, Toby Rogers and Cynthia Nevison — all disagree with the journal’s decision, the note also says.

The cancelled paper is here:-

Autism Tsunami: the Impact of Rising Prevalence on the Societal Cost of Autism in the United States

 

I assume Blaxill was the driving force behind all the math, because he is the ex- management consultant, with a son with severe autism that his dad attributes to vaccines.

What I found bizarre in their paper was that they has a prevention scenario, based on what they think has already happened in rich parts of California, where they think autism incidence is falling.  It is not falling, all that is happening is that wealthy Californians are paying for treatment using insurance or their own money, and no longer burdening the State.

The “rainbow” researchers that wanted the paper retracted think that preventing autism is akin to eugenics and Dr Mengele. According to Peter, treating autism is good, while Dr Josef Mengele, byname Todesengel (German: “Angel of Death”) was as bad as you can get.    

Jill Escher and her NCSA think that you cannot prevent autism.  According to Peter, you can both minimize the incidence and severity of autism. 

A bugbear of our reader Tanya is that the NCSA have a pet hate of facilitated communication and in particular the rapid prompting method (RPM). This method worked for Tanya’s son and it opened the door to independent, un-facilitated communication. 

Always keep an open mind.

 

 

 

“our Prevention scenario is based on real rates observed among wealthy white and Asian children in the California DDS.  Severe ASD prevalence has flattened and even declined among these children since birth year 2000, suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD. The Prevention scenario assumes that these parental strategies and opportunities already used by wealthy parents to lower their children’s risk of ASD can be identified and made available rapidly to lower income children and ethnic minorities, who are currently experiencing the most rapid growth in ASD prevalence”

 

New Paper Makes Case that Autism Tsunami May Threaten American Economy

A major weakness in the analysis was the “Prevention Scenario” in which future costs were projected based on “what might be possible if strategies for reducing ASD risk are identified and addressed in the near future.” As I think everyone knows, at this time there is no way to prevent autism. But the authors use the observation that autism in the DDS is declining among wealthier white families, and thus “suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD.” No, it’s far more likely that wealthier families are not entering their children into the system because they access services through insurance and school districts instead.

 

Vitamin D as a cause of autism has been discussed for decades.  As the title below puts it – a never-ending story. Our reader Seth Bittker even wrote a paper about it. He later wrote a paper about the use Acetaminophen/Paracetamol in children under two as a risk factor in developing autism. Good work Seth!

 

Maternal Vitamin D deficiency and brain functions: a never-ending story 

A large number of observational studies highlighted the prevalence rates of vitamin D insufficiency and deficiency in many populations as pregnant women. Vitamin D is well known to have a crucial role in differentiation and proliferation, as well as neurotrophic and neuroprotective actions in brain. Then, this micronutrient can modulate the neurotransmission and synaptic plasticity. Recent results from animal and epidemiological studies indicated that maternal vitamin D deficiency is associated with a wide range of neurobiological disease including autism, schizophrenia, depression, multiple sclerosis or developmental defect. The aim of this review is to provide a state of the art on the effect of maternal vitamin D deficiency on brain functions and development.

4.2.2. Autism

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with repetitive behaviour and difficulties in social interaction, communication and learning. Several murine studies and cohorts have demonstrated that early exposure to low levels of VD during pregnancy could be a risk factor for ASD. In 2019, Ali et al. aimed to find out the impact of a maternal VDD on early postnatal, adolescent and adult offspring. By assessing righting reflex and negative geotaxis, they found out that the pups from deficient dams showed a delay in their motor development. P12 rats from deficient females also exhibited increased ultrasound vocalization indicating an alteration in their vocal communication. Adolescent and young adult rats displayed an altered stereotyped repetitive behaviour as they had a reduced digging behaviour. Adolescent rats had less social interaction with longer latency to interact, which was not found in adult rats; however, adults were more hyperactive but showed no anxiety like behaviour.  In another animal study, maternal VDD induced an increase in the vocalizations of the pups accompanied with a decrease in cortical FoxP2, decrease in social behaviour and impaired learning and memory were observed in adult males (Table 1). Using data from the Stockholm youth cohort, Magnusson et al. examined a population of 4-17-year-old children exposed to low levels of VD during gestation and was able to report a positive association between maternal VDD and ASD. Analysing the same cohort, Lee et al. suggested that high levels of VD during pregnancy were associated with a moderate decrease in risk of ASD in the offspring. A prospective study of a multi-ethnic cohort in the Netherlands (generation R study) has also shown an association between maternal mid-gestation VDD and a two-fold increase in the risk of autism in children (Table 2). Interestingly, VD supplementation seems to clinically improve ASD symptoms of affected children.

 

People do associate this blog with Bumetanide.  Yet another paper has been published showing the benefits of this therapy for autism.

 

EEG-based brain connectivity analysis in autism spectrum disorder: Unravelling the effects of bumetanide treatment 

Highlights

 

·        We investigated the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment.

·        We found statistically significant differences between pre and post intervention in the connectivity patterns using repeated measures analysis of variance (ANOVA).

·        We found that the number of strong connections in response to sad image stimuli seem to be less compared with that of the other two stimuli, especially in the central area.

·        We found that the changes in brain connectivity between pre and post intervention is more significant in response to sad image stimuli.

 

Emerging evidence suggests that cognitive impairment associated with brain network disorders in people with autism could be improved with medications such as bumetanide. However, the extent to which bumetanide is effective in improving brain function in these individuals has not been adequately studied. The main purpose of this study is to investigate the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment. We used electroencephalography (EEG) data of nine participants recorded during the face emotion recognition activity in two stages before and after bumetanide treatment. Brain connectivity matrix was calculated using a neural network-based estimator. Graph criteria and statistical tests have been used to determine the effects of bumetanide treatment on children and adolescents with autism. Bumetanide treatment significantly alters the brain connectivity networks based on stimuli type. Differences in brain connectivity related to the sad stimuli are more significant. The most of the significant changes of the strength graph metric was in the occipital electrodes and electrodes related to the right hemisphere. These results suggest that bumetanide may affect effective connectivity and be used a promising treatment for improving social interactions in patients with autism. It also suggests that brain connectivity patterns can be considered as a neural marker to be used in the development of new therapies. 

I have also covered in sometimes painful details the potential to treat autism and increase cognitive function using PDE (Phosphodiesterase) inhibitors. One of our psychiatrist readers is a huge fan of Pentoxifylline and takes it himself.

I was recently asked how to obtain Ibudilast.  It is approved in Japan as an asthma drug. Sometimes it is called Ketas and you can get it from an “International Pharmacy” in Germany/Switzerland if you have a prescription. 

I also wrote about repurposing Roflumilast, which as Daxas is approved all over the world as a therapy for severe asthma (COPD). This drug at a 1/5^th dose has been patented as a cognitive enhancer.

 

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder

 

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats.

Methods

Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum.

Key findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage.

Conclusions

Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

 

 

I have also written widely about repurposing certain anti-parasite medicines to treat autism. This is not because I think parasites cause autism, it is the secondary modes of action.

 

 

Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis

 

 

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer’s Disease and Parkinson’s Disease, as well as various cancers by targeting ERK/MAPK, it’s efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

 

Note that in earlier posts I explored RASopathies as potentially treatable types of intellectual disability (ID). We also have RAS-dependent cancers as a discrete treatable sub-type of cancer.

The ERK/MAPK pathway is known to interact with multiple genes that have been implicated in autism, and genome-wide association analysis of the same have supported these findings. As such, a dysregulation of this pathway has been found to result in many CNS disorders, including ASD-related syndromes, in many studies. These syndromes are collectively known as Rasopathies, due to the fact that the affected genes include those encoding for elements which function together with Ras, a G-protein responsible for activating ERKs (Levitt and Campbell 2009; Tidyman and Rauen 2009). It has been found that ASD is linked to the occurrence of many Rasopathies, and there have been multiple reports suggesting the possible relation of ERK/MAPK pathway defects with the incidence of ASD (Vithayathil et al. 2018; Aluko et al. 2021)⁠⁠. Moreover, a detailed study has found that single nucleotide polymorphisms (SNPs) in the ERK/MAPK-related genes are more common in subjects presenting with idiopathic ASD.

 

Niclosamide is an FDA-approved antihelminthic drug which is routinely used to treat tapeworm infections by inhibiting their mitochondrial oxidative phosphorylation and ATP production. In addition, it has long been known to have significant immunomodulating activity, and has been shown to inhibit a number of signaling pathways, including the Wingless-related integration site (Wnt)/β-catenin, nuclear factor kappa B (Nf-κB), signal transducer and activator of transcription 3 (STAT3), and mammalian target of rapamycin (mTOR) (Chen et al. 2018). However, while these targets are known to be rather well-characterized in terms of the effect that niclosamide has on them, there are also other targets, including the phosphoinositode 3 kinase/Akt (PI3K/Akt) and ERK/MAPK pathways, that are seen to be downregulated by the agent. Hence, given the possible relation of the ERK pathway in autism, there has been interest in the potential role of niclosamide in the management of the prognosis of ASD. This article aims to discuss the possible therapeutic benefit of niclosamide in the treatment of autism spectrum disorders.

 

Now I know that parents like the idea of treating autism with various gadgets you can strap on to your head – things like Transcranial Magnetic Stimulation (TMS). I must say I liked my old post on Photobiomodulation/cold laser/low level laser therapy.

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

From China we have a new round-up paper, but the full text does not yet seem to be ready.

 

Non-invasive brain stimulation for Patient with Autism： A Systematic Review and Meta-Analysis

Objective: To comprehensively evaluate the efficacy of non-invasive brain stimulation (NIBS) in patients with autism spectrum disorder (ASD) in randomized controlled trials (RCT),providing reference for future research on the same topic.

Methods:Five databases were searched (Pubmed,Web of science,Medline,Embase and Cochrane library) and track relevant references,Meta-analysis was performed using RevMan 5.3 software.

Results: Twenty-two references(829 participants) were included. The results of meta analysis showed that, NIBS had positive effects on repetitive and stereotypical behaviors, cognitive function and executive function in autistic patients. Most of the included studies had a moderate to high risk of bias, Mainly because of the lack of blinding of subjects and assessors to treatment assignment, as well as the lack of continuous observation of treatment effects.

Conclusions: Available evidence supports an improvement in some aspects of NIBS in patients with ASD. However, due to the quality of the original studies and significant publication bias, these evidences must be treated with caution. Further large multicenter randomized double-blind controlled trials and appropriate follow-up observations are needed to further evaluate the specific efficacy of NIBS in patients with ASD.

Unfortunately, the Chinese have concluded that most of these studies are not reliable. So no laser for me to go out and buy just yet.

No need to dent your bank balance with the next therapy.  We are back to one of the world's most prescribed and therefore affordable drugs, its Simvastatin (Zocor). 

There is masses of information in this blog about the potential to treat sub-types of autism with Atorvastatin, Simvastatin or Lovastatin. They are each slightly different.

 

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model 

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway. 

Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting. 

Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p < 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats. 

Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

  

Conclusion

What is the conclusion? Well, I could say give up reading the new research and just read my old posts.  It seems you are not going to miss very much.

Of course, back in the real world, it is true that things do take time to change and after a few decades the leap might be taken from the research to the doctor’s office.

There already is plenty of research on the causes of autism and what steps can be taken by those who want to treat aspects of it.  It is far from a complete picture, but it is enough to get started.  There are no guarantees of success, but if you want 100% certainty you will wait forever.

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

Photobiomodulation underlying mechanisms at the cellular and molecular levels. Light at 600–850 nm is absorbed by the mitochondrial electron transfer chain and leads to upregulation of the neuronal respiratory capacity. The near-infrared light at range of 900– 1100 nm is absorbed by structured water clusters formed in or on a heat/light-gated ion channels. An increase in vibrational energy of water cluster leads to perturb the protein structure and opening the channel which ultimately allows modulation of intracellular Ca2+ levels. The absorption of green light by neuronal opsin photoreceptors (OPN2-5) activates transient receptor potential channels which causes nonselective permeabilization to Ca2+ , Na+ , and Mg2+ . The cryptochromes (a class of flavoprotein blue-light signaling receptors) absorb blue light and seems to activate the transducing cellular signals via part of the optic nerve to the suprachiasmatic nucleus in the brain, which is important in regulation of the circadian clock

  

Today we return to the idea of using low power lasers to treat autism.  This follows on from the original post that reviewed a credible clinical trial that compared laser therapy with a sham red light therapy.  My conclusion was either the researchers cheated, or it really did work.   It is a pity, but experience shows us that cheating does occur in published research. I also pondered whether a cheaper LED device could give the same benefit of an expensive laser.

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

Our reader RD has been busy at home applying the research, first using LEDs to no avail, before moving on to an expensive laser device, which does provide a benefit.  Today we dig a little deeper about what might be going on inside the brains of people treated with such devices. Click below to read RD's extensive comments and interesting links.

https://epiphanyasd.blogspot.com/2018/12/low-level-laser-therapy-lllt-for-autism.html?showComment=1560875374458#c8257042607661710259

Some autism therapies involving the use of expensive gadgets do set alarm bells ringing, but the more you look into Photobio-modulation, which is the new name of Low Level Laser Therapy (LLLT), the more credible it becomes.  There has been a great deal of recent research regarding other neurological conditions, autism only rarely gets a mention. The same therapy has been used on different parts of the body for several decades in Russia and some other countries. Where we live physiotherapists use Photobiomodulation/LLLT to treat numerous types of ache and pain.

It is still early days for Photobiomodulation and the brain. A lot depends on which parts of the brain you want to target; there are even plans for using the mouth, nose and ears as entry points to reach different parts of the brain.

Heat/light sensitive ion channels

Many human diseases are associated with ion channel dysfunctions (channelopathies).  Many people with autism have either genetic or acquired channelopathies of one kind or another.

Today our focus on light introduces us to a class of ion channels activated by heat and/or light.

We should immediately recall the so called “fever effect” in autism where in some people a rise in body temperature improved their autism, sometimes dramatically. The fever effect was replicated by one US researcher having people sit in a hot tub.

HYPERTHERMIA AND THE IMPROVEMENT OF ASD SYMPTOMS

 Five control subjects without a history of fever completed the hyperthermia condition at 102 °F, and demonstrated the safety and feasibility of the study. Ten subjects with ASD and a history of fever response were enrolled and completed the hyperthermia condition (102 °F) and control condition (98 °F) at the aquatic therapy pool. Improvement in social cognition and repetitive/restrictive behaviors were observed at the hyperthermia condition (102 °F) on parent (SRS, RBS-R) and rater (CGI-I) assessments. Pupillometry biomarker and gene expression can be correlated with clinical improvement. Side effects were minimal, and were the same as those observed in a hot tub/sauna (redness, nausea).

Discussion

We demonstrated improvement of socialization and repetitive and restricted behaviors at the hyperthermia condition (102 °F), and that we could reliably and safely increase children’s temperatures into the fever range (mean max temperature of 101.7 °F). This temperature increase was observed to cause significant and convergent improvement on clinician ratings (CGI-I) and parent ratings (SRS, RBS-R), both of which were kept blinded to the temperature of the pool. Interestingly, each child’s fever response history was correlated with the improvements observed at the elevated temperature. Those with a history of marked fever response had the most observable behavior changes. Behavior changes observed for each child were similar to those observed by parents during febrile episodes, including increased cooperation, communication and social reciprocity and decreased hyperactivity and inappropriate vocalizations. Although multiple rationales have been posited, this is the first study looking at the direct effect of temperature on ASD symptomatology.

  

TRPV1 and Autism

There has been a link suggested between TRPV1 and autism.  SHANK3 is a single gene type of autism, often used to study autism.

Autism gene may double as pain processor

  

In control mice, SHANK3 tethers a protein called TRPV1 to the surface of sensory neurons, where it detects heat and chemical signals. Those signals activate TRPV1, causing calcium ions to flood into the cell, leading to a painful sensation.

Neurons from control mice show a robust influx of calcium ions in response to capsaicin, the chemical that gives chili peppers their heat. But the chemical triggers significantly less calcium flow into neurons from SHANK3 mice.

The study stokes curiosity about the connection between autism and TRPV1. This protein aids heart and lung function, and has been linked to addiction, anxiety and depression, says Camilla Bellone, assistant professor of neuroscience at the University of Geneva in Switzerland, who was not involved in the study. “It would be really interesting to see if TRPV1 dysfunction could explain other [features] associated with autism,” she says.

SHANK3 deficiency impairsheat hyperalgesia and TRPV1 signaling in primary sensory neurons

Pain, Rett Syndrome, MECP2 and TRPV1

It appears to be not just SHANK3 autism that has a TRPV1 connection, so does the all-female Rett Sydrome. Here the connection relates to unusual pain sensitivity in Rett Sydrome. Many people with autism have an unusual relationship with pain.

REduced MeCP2 signaling leads to hypoalgesia in a mouse model of Rett syndrome

Although TRPV1 was expressed in MeCP2-positive TG neurons innervating the tongue in both wild-type and Mecp2^+/- mice, a significantly smaller number of TRPV1-positive neurons were observed in the tongues of heterozygotes compared to wild-types. Together, these data suggest that the hypoalgesia observed in this mouse model is induced by the inhibition of TRPV1 expression, and this expression is dependent in part on MeCP2 signaling.

These findings suggest that tongue heat sensitivity and inflammatory hyperalgesia are dependent on TRPV1 expression in TG neurons that innervate the tongue and that this expression is regulated by MeCP2 signaling, supporting a role for MeCP2 in pain modulation. Hypoalgesia is a potentially dangerous condition that may result in more severe tissue damage from burns or other physical trauma due to a blunted pain withdrawal reflex.  Understanding how MeCP2 modulates pain might lead to therapies that improve the pain sensitivity in Rett syndrome patients, as well as treatments that might help to reduce neuropathic pain associated with other genetic or acquired conditions.

TRP ion channels in thermosensation, thermoregulation and metabolism

TRPV Channels in Mast Cells as a Target for Low-Level-Laser Therapy

Low-level laser irradiation in the visible as well as infrared range is applied to skin for treatment of various diseases. Here we summarize and discuss effects of laser irradiation on mast cells that leads to degranulation of the cells. This process may contribute to initial steps in the final medical effects. We suggest that activation of TRPV channels in the mast cells forms a basis for the underlying mechanisms and that released ATP and histamine may be putative mediators for therapeutic effects.

Modulation of TRPV channel gating by light-switched ligand. Putative modulation of an azo-chromophore between cis- and trans-form by light leading to activation of TRPV channel opening. As an example TRPV activation by the cis-form is cartooned.

We have shown in this review that laser irradiation in the visible and IR as well as UV range can modulate the function and expression of TRPV ion channels, and in particular TRPV1, TRPV2, and TRPV4. This may form the basis for effect of LLLT. As Ca²⁺-permeable ion channels, their activation may contribute to the laser-induced increase in intracellular Ca²⁺ that triggers degranulation and endocytotic release of ATP. Such light-induced mechanism may contribute to the basis of the medical effects of LLLT. This hypothesis still needs confirmation in animal tests and clinical trials.

Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy

Photobiomodulation (PBM) also known as low-level laser (or light) therapy (LLLT), has been known for almost 50 years but still has not gained widespread acceptance, largely due to uncertainty about the molecular, cellular, and tissular mechanisms of action. However, in recent years, much knowledge has been gained in this area, which will be summarized in this review. One of the most important chromophores is cytochrome c oxidase (unit IV in the mitochondrial respiratory chain), which contains both heme and copper centers and absorbs light into the near-infra-red region. The leading hypothesis is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential and ATP production. Another hypothesis concerns light-sensitive ion channels that can be activated allowing calcium to enter the cell. After the initial photon absorption events, numerous signaling pathways are activated via reactive oxygen species, cyclic AMP, NO and Ca2+, leading to activation of transcription factors. These transcription factors can lead to increased expression of genes related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, antioxidant enzymes. Stem cells and progenitor cells appear to be particularly susceptible to LLLT.

MOLECULAR MECHANISMS OF PBM

Light sensitive ion channels

The most well-known ion channels that can be directly gated by light are the channelrhodopsins (ChRs), which are seven-transmembrane-domain proteins that can be naturally found in algae providing them with light perception. Once activated by light, these cation channels open and depolarize the membrane. They are currently being applied in neuroscientific research in the new discipline of optogenetics [35].

However, members of another broad group of ion-channels are now known to be light sensitive [36]. These channels are called "transient receptor potential" (TRP) channels as they were first discovered in a Drosophila mutant [36] and are responsible for vision in insects. There are now at least 50 different known TRP isoforms distributed amongst seven subfamilies [37], namely the TRPC (‘Canonical’) subfamily, the TRPV (‘Vanilloid’), the TRPM (‘Melastatin’), the TRPP (‘Polycystin’), the TRPML (‘Mucolipin’), the TRPA (‘Ankyrin’) and the TRPN (‘NOMPC’) subfamilies (see Figure 2). A wide range of stimuli modulate the activity of different TRP such as light, heat, cold, sound, noxious chemicals, mechanical forces, hormones, neurotransmitters, spices, and voltage. TRP are calcium channels modulated by phosphoinositides [38].

Conclusions

Low levels of red/NIR light can interact with cells, leading to changes at the molecular, cellular and tissue levels. Each tissue, however, can respond to this light-interaction differently, although it is well known that the photons, especially in the red or NIR, are predominantly absorbed in the mitochondria [132]. Therefore, it is likely that even the diverse results observed with PBM share the basic mechanism of action. What happens after the photon absorption is yet to be fully described, since many signaling pathways seem to be activated. It seems that the effects of PBM are due to an increase in the oxidative metabolism in the mitochondria [133]. Different outcomes can occur depending on the cell type, i.e. cancer cells that tend to proliferate when PBM is delivered [88]. In this review we have not discussed the response of cells and tissues to wavelengths longer than NIR, namely far IR radiation (FIR) (3 µm to 50 µm). At these wavelengths water molecules are the only credible chromophores, and the concept of structured water layers that build up on biological lipid bilayer membranes has been introduced to explain the selective absorption [134]. Nevertheless FIR therapy has significant medical benefits that are somewhat similar to those of PBM [135], and it is possible that activation of light/heat sensitive ion channels could be the missing connection between the two approaches.

As we have shown, PBM can regulate many biological processes, such as cell viability, cell proliferation and apoptosis, and these processes are dependent on molecules like protein kinase c (PKC), protein kinase B (Akt/PKB), Src tyrosine kinases and interleukin-8/1a (IL-8/1a). The effects of light on cell proliferation can be stimulatory at low fluences (which is useful in wound healing, for instance), but could be inhibitory at higher light doses (which could be useful in certain types of scar formation such as hypertrophic scars and keloids) [131].

The applications of PBM are broad. Four clinical targets, however, are the most common: shining light on injured sites to promote healing, remodeling and/or to reduce inflammation; on nerves to induce analgesia; on lymph nodes in order to reduce edema and inflammation; and on trigger points (a single one of as many as 15 points) to promote muscle relaxation and to reduce tenderness. Since it is non invasive, PBM is very useful for patients who are needle phobic or for those who cannot tolerate therapies with non-steroidal anti-inflammatory drugs [83].

The positive outcomes depend on the parameters used on the treatment. The anti-inflammatory effect of light in low intensity was reported on patients with arthritis, acrodermatitis continua, sensitive and erythematous skin, for instance [136]. With the same basic mechanism of action, which is the light absorption by mitochondrial chromophores, mainly Cox, the consequences of PBM are various, depending on the parameters used, on the signaling pathways that are activated and on the treated tissue. In order to apply PBM in clinical procedures, the clinicians should be aware of the correct parameters and the consequences for each tissue to be treated. More studies have to be performed in order to fill the gaps that still linger in the basic mechanisms underlying LLLT and PBM.

Photobiomodulation improves the frontal cognitive function of older adults.

OBJECTIVES:

The frontal lobe hypothesis of age-related cognitive decline suggests that the deterioration of the prefrontal cortical regions that occurs with aging leads to executive function deficits. Photobiomodulation (PBM) is a newly developed, noninvasive technique for enhancing brain function, which has shown promising effects on cognitive function in both animals and humans. This randomized, sham-controlled study sought to examine the effects of PBM on the frontal brain function of older adults.

METHODS/DESIGNS:

Thirty older adults without a neuropsychiatric history performed cognitive tests of frontal function (ie, the Eriksen flanker and category fluency tests) before and after a single 7.5-minute session of real or sham PBM. The PBM device consisted of three separate light-emitting diode cluster heads (633 and 870 nm), which were applied to both sides of the forehead and posterior midline, and delivered a total energy of 1349 J.

RESULTS:

Significant group (experimental, control) × time (pre-PBM, post-PBM) interactions were found for the flanker and category fluency test scores. Specifically, only the older adults who received real PBM exhibited significant improvements in their action selection, inhibition ability, and mental flexibility after vs before PBM.

CONCLUSIONS:

Our findings support that PBM may enhance the frontal brain functions of older adults in a safe and cost-effective manner.

Brain Photobiomodulation Therapy: a Narrative Review.

Brain photobiomodulation (PBM) therapy using red to near-infrared (NIR) light is an innovative treatment for a wide range of neurological and psychological conditions. Red/NIR light is able to stimulate complex IV of the mitochondrial respiratory chain (cytochrome c oxidase) and increase ATP synthesis. Moreover, light absorption by ion channels results in release of Ca²⁺ and leads to activation of transcription factors and gene expression. Brain PBM therapy enhances the metabolic capacity of neurons and stimulates anti-inflammatory, anti-apoptotic, and antioxidant responses, as well as neurogenesis and synaptogenesis. Its therapeutic role in disorders such as dementia and Parkinson's disease, as well as to treat stroke, brain trauma, and depression has gained increasing interest. In the transcranial PBM approach, delivering a sufficient dose to achieve optimal stimulation is challenging due to exponential attenuation of light penetration in tissue. Alternative approaches such as intracranial and intranasal light delivery methods have been suggested to overcome this limitation. This article reviews the state-of-the-art preclinical and clinical evidence regarding the efficacy of brain PBM therapy.

                                                   

Because neural tissues contain large amounts of mitochondrial CCO, application of red to NIR lights (600–850) for brain PBM therapy is highly attractive. The main problem so far has been getting enough light into the brain to accomplish the beneficial effects. In recent years, irradiation in the wavelength range between 980 and 1100 nm has been growing rapidly, and its different mechanisms of action including stimulation of ion channels and water molecules suggest it might even be combined with red/NIR. Improving cerebral metabolic function, stimulating neurogenesis and synaptogenesis, regulating neurotransmitters, and providing neuroprotection via anti-inflammatory and antioxidant biological signaling are the most important effects of brain PBM therapy (Fig. 4). The overall results from extensive preclinical and clinical studies in the brain PBM field suggest that modest levels of red and NIR light show biostimulatory effects without any thermal damage, and could improve neurobehavioral deficits associated with many brain disorders. Nevertheless, it is still not completely clear whether chronic repetition of brain PBM will be necessary for sustained clinical benefit, especially in psychological and neurodegenerative disorders. Owing to the beneficial impacts of brain PBM therapy in depression and anxiety, new trials for other psychiatric disorders such as schizophrenia autism, , bipolar, attention-deficit hyperactivity, and obsessive–compulsive disorders might well emerge in the future. Development of new techniques for effective light delivery to deeper structures of the brain is crucial, because of involvement of the limbic system and midbrain abnormalities seen in some brain disorders. In this respect, intracranial and intranasal irradiation methods, as well as the oral cavity route, even via the ear canal could be options. Although therapeutic influences of intracranial PBM therapy has been focused on PD researches, it is postulated that developing this technique also potentially effective for those conditions that are associated with limbic system dysfunctions such as anhedonia, anxiety, as well as impaired emotional processing. Preliminary evidence of benefit has been obtained in autism spectrum disorders. There is an epidemic of AD that is expected to hit the Western world as the overall population ages, and there has been a noticeable lack of any effective pharmacological therapies that have been approved for AD. Although the evidence for the effectiveness of PBM in the treatment of AD is still very preliminary, it is possible that PBM will play an even larger role in society in years to come if clinical trials now being conducted are successful. The authors conclude that clinic or home-based PBM therapy using laser or LED devices will become one of the most promising strategies for neurorehabilitation in upcoming years

Conclusion

Our reader RD is well ahead of the curve with his PBM/LLLT investigation. I do not see this kind of therapy being adopted by mainstream Western medicine, even if it did work.  It has been used in other countries for many decades by medical doctors, for all kinds of conditions, but that fact does not cut it with most Western doctors.  There are  practitioners of PBM/LLLT in Western countries, but they tend to be on the fringes of medicine, which puts PBM/LLLT clearly in the crank therapy category for most qualified Western doctors.

On the basis that we should keep an open mind about all kinds of therapies, we should consider PBM further. It is apparently safe at the power levels used. It may look a little strange, but it is non-invasive and the therapy does not take long. A single device could easily be used to treat many people, so the high price should not remain a barrier.

I was very surprised to hear that a local speech therapy company is now offering “neurofeedback therapy” using an expensive machine they have bought. I was very suspicious of a recent study carried out in Florida that was put forward to support this therapy using a commercial device, since of the 42 children in the group that had the actual therapy only 17 completed the 12 week trial and came back for the evaluation.  The trial included a similar sized group who had a sham therapy.  The likelihood of completing the trial was the same in both groups, which also looks odd.

https://www.frontiersin.org/articles/10.3389/fneur.2018.00537/full

Of the 83 subjects that completed the evaluation at the enrollment time, 34 returned for the POST evaluation after the 12 weeks of home based therapy.

If the results were so good, why did the majority of parents walk away during the trial? I was going to suggest to the speech therapist that perhaps those few thousands of euros/dollars might have been better spent on a laser, or perhaps the lottery.

For me, one big question about the laser is about how the device is used. Depending on what you believe the mode of action to be, you would have to use it in completely different ways.

If the benefit relates to improved mitochondrial function, you should really be able to measure this benefit using a PET scan that measures glucose uptake to each part of the brain. This was the method proposed by Polish researchers to show how some people benefit from a ketogenic diet to improve power/ATP output from different parts of the brain.

You would hope other researchers would try and replicate the benefit in autism, but the first group have already patented the laser idea.

Hopefully our reader RD will perfect this therapy and we await his feedback.

I did recently write about the recently discovered lymphatic system within the brain. One proposed benefit of PBM/LLLT is improved drainage of lymph. I thought that was interesting; if it was actually true then this therapy could potentially be used to prevent the onset of Alzheimer’s. We saw in that post that faulty lymph drainage may allow the accumulation of waste products (plaques etc) in aging brains and then Alzheimer's develops. Targeting the relevant lymph node with PBM/LLLT might be an alternative to the drug therapy currently being developed.

I am told that lymphatic drainage is currently "the big thing" in autism in the US, alongside anything to do with CBD (cannabis). Hopefully in the fb world of autism they have noted that in MS the problem with the brain's lymphatic system was not drainage, but the ingress of inflammatory messengers from the body into the brain, suggesting the opposite therapy.