Core vs extended Maths? An unexpected dilemma. And yet they say “Autism is untreatable and you should not try to treat it”. Plus Lego

 

This time the “Professor” wears the Dunce’s cap

I had a surprise last month, talking to my son’s 1:1 assistant, this time about maths (or math in US English).

Normally I am trying to simplify school academics, and so if something really is not important, like argumentative writing, I am all for skipping over it.  The idea is that Monty, aged 17 with autism, should focus on useful learning that he has a chance of mastering.

Monty’s international school follows an English curriculum and in that model you have a choice in some subjects of studying the core or the extended version. So a typical child who wants to become a doctor, or an engineer, will have to follow the extended version of all their subjects, but someone who is going to shift boxes in a warehouse might opt for the core/simplified versions. Most people lie somewhere in between.

People with severe autism would not normally follow any of these academic curricula, because it is all way above their heads.  Their school is about life skills and providing day-care, while the parents are out at work, or having some respite. Realistically, “graduation” is often just a photo opportunity - things could and should be better.

There is very little published about literacy and numeracy in severe autism.

I thought an ambitious target for Monty would be to try and sit exams, aged 18, in five subjects, but at the easy level where possible, the so-called “core” version.  These exams are normally taken at the age of 16, which is the minimum school leaving age in the UK.

The maths teacher has been thinking about which of her students should be aiming at core or extended.  She thinks five pupils should be aiming for extended and the others should settle for core.  Monty is one of the group of five.

The assistant was almost apologetic, because she did not want to change my plans for Monty. He is now "too good" for core maths.

I do know Monty’s mathematical abilities very well, because I teach him maths at the weekend.  He is no maths savant, but he works extremely hard and now has a good understanding of what they learn at school. I am just amazed at the other kids, with no disability, who do not keep up with him. Prior to pharmacological autism treatment, starting at the age of nine, Monty could not subtract single digit numbers, like 9 – 2 = 7.

Even more recently Monty’s school assistant proudly announced his results in the half year maths test. He got 68%, making him 3^rd out of the 15 people in class.  68% certainly does not make you an “A student”, but given he was a “basket case” at maths not many years ago, it is truly remarkable. The teacher even told the whole class his score, which you might think would lead to resentment, but the others are actually very supportive. They have seen his progress over the years. They are currently involved in helping him to reliably tell the time. For some people solving algebra is easier than telling the time – who would have thought that?

The other day I skimmed through an article about some Professor who was quoted as saying “Autism is untreatable and you should not try to treat it”. What a fool - more of a dunce than a Professor. 

Literacy and Numeracy Rates in Autism

People rarely talk about literacy or numeracy in autism. I think it is another issue that people do not want to discuss. We would rather hear about people with savant skills, or characters from those TV shows like the Good Doctor, with trivial autism.

It is clear that many people with severe autism currently cannot read or write, so I suppose they are also innumerate.

You can be non-verbal but literate and numerate; there are specific teaching methods.

I was recently asked to present at an autism conference in Russia. I did click on the organisation’s website and I was pleased to see on the first page its message to Russian parents that you can teach people with autism to read and write and indeed that non-verbal kids belong in school. I agree with them, but it may seem like a Herculean task at times.

My last conference presentation was very simple and not controversial, at the request of the US organizer.  Russians like science and they have asked for a long presentation, so they will get the real deal. A big job for the person who has to translate and then dub it into Russian!

 

 Any human brain can be taught to read, write, count

 

One to one teaching, as above in Russia, is the only way to teach those with severe autism.

Reading and writing do matter. Look at the literacy rates by country and guess where you find countries like Afghanistan, Ethiopia, Sudan and Nigeria?

In Afghanistan the male literacy rate is 55% and for females it is 30%.

Even India has 25% illiterate and they tell us it is the world’s largest democracy. In India literacy ranges from about 66% in Andhra Pradesh in the South East to over 95% in Kerala in the South West. In China illiteracy is just 3% and it shows.

In the US 4% are non-literate and the average American adult reads at the 7^th- to 8^th-grade level, i.e. like a 13 year old child; plenty of room for improvement.  The problem is the large group at the bottom who drag down the overall results. This is why countries like Finland do so well in skill assessments; they do not have a forgotten underclass.

  

Why bother with Mathematics?

It is certainly worthwhile reconsidering what to teach people with severe autism. If you cannot cut your own fingernails, or tie your own shoelaces, why do you need to know any maths?

Maths is all about following instructions/rules. If you can follow instructions, you can do maths. Daily living skills are also all about following instructions; before emptying the dishwasher, check the dishes are actually clean! Monty has learnt that lesson.

What do you do when the toothpaste has run out? Find some more and if that does not work, ask for help.

Learning to follow instructions is extremely important to those with learning difficulties; just like practising motor skills helps them overcome their initial challenges with fine and gross motor skills.  In the end, the problems just fade away.

Lego is a great way to combine following instructions with improving fine motor skills. It is a perfect therapy for autism; at the very beginning you can use large bricks to get a young child to replicate simple colour patterns (so-called “block imitation”) by stacking bricks. You can use Lego to develop team skills; one person locates the next bricks, while the other assembles them.

We have a lot of Lego at home, but until recently it was mainly the simple models of planes and helicopters that were of interest to Monty. People would give complicated (expensive) models for birthday presents, when actually what you want are the cheaper, simple ones.

We have now progressed to the point where Monty has completed a model that was intended for people older than himself. All the Lego sets have an age recommendation on them. Yes, Lego has some very complicated Star Wars models meant for those 18 and over.  A Christmas present from big brother, it did have a ridiculous number of pieces (several hundred) and some mistakes were made. 

Monty actually calls it “doing the instructions”, rather than making Lego.

The key seems to be to leave him entirely alone and let him make the occasional mistake.  If a later part does not fit, he asks for help and you then intervene, find the earlier mistake and correct it.  If you hover behind him to prevent any mistake being made, then you are not achieving much.

 

Conclusion

You definitely can treat severe autism, meaning raise IQ and/or improve quality of life.  The evidence is overwhelming and is sitting there in the peer-reviewed science.

It looks like you can avoid/prevent some autism by taking certain steps prior to conception and during pregnancy. This is quite clever.

After birth, can you “cure” severe autism? I think this will only be possible in rare cases, for example correcting an in-born error of metabolism at an extremely young age. One example in this blog was the young Greek boy with biotinidase deficiency, that responds to high dose biotin. Our reader Roger is a rare example of an adult whose central folate deficiency was only treated in adulthood.

You can minimize many troubling features of autism at any age; this applies to Aspies and those with more severe autism.

Learning maths develops much broader skills than might be initially apparent.

Lego is a great activity and a fun therapy.  You can of course re-use it, particularly the most basic sets, which you can use over and over.

Vasopressin, Oxytocin, the Lateral Septum, Aggression and Social Bonding, Autism gene NLGN3 and MNK inhibitors for reversing Fragile-X and likely more Autism

 

The Lateral Septum, in green, turns the volume

 up or down in aggression

Today’s post started by me checking for anything new in the research about the hormone Vasopressin and autism. I was surprised by just how much research continues to be published on the subject – no smoke without fire, perhaps.

We also get another insight into how aggressive raging develops in the brain; we even have a photo.

A novel therapy for Fragile-X is also thrown into the mix, due to a link to oxytocin.

So, what is cooking in the research?

The first thing to note is that you really do have to look at both Oxytocin and Vasopressin, because these two hormones are very closely related.

We have previously looked at the autism gene NLGN3, this gene encodes the cute sounding neuroligin-3.

 

https://epiphanyasd.blogspot.com/search/label/neuroglin

 

The reason people with Fragile-X have autism is because they lack the protein FMRP (Fragile X mental retardation protein).

In healthy neurons, FMRP modulates the local translation of numerous synaptic proteins. Synthesis of these proteins is required for the maintenance and regulation of long-lasting changes in synaptic strength. In this role as a translational inhibitor, FMRP exerts profound effects on synaptic plasticity.

When you look at the interactions of the FMRP protein you can find ways to compensate for this deficiency.  This is nicely illustrated in the graphic below. You just need to find another way to influence elF4E and elF4G.

Some people have told me they find these charts a bit overwhelming, but they precisely show what is going on.  You just have to look up all the terms, you do not know.  In the chart below there is NF1 autism, there is PTEN autism, problems with Ras are called RASopathies and cause MR/ID plus autism. We have at least one reader with TSC (Tuberous sclerosis) type autism. We have readers whose kids lack FMRP, because they have Fragile-X syndrome. 

Today we see that an inhibitor of MnK (in yellow in the chart below) is another via option to treat Fragile-X.

Beyond Fragile-X, we can see that numerous other upstream dysfunctions in the chart can result in miss-expression of neuroligins (NLGNs) in the chart below and then result in autism.

 

 One of the papers below goes further and suggests

“This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses”

“We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis”

“Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome to a non-syndromic model of ASD”

 

Regarding Fragile X 

“Collectively, this work establishes eFT508 (an MNK inhibitor) as a potential means to reverse deficits associated with FXS.”

 

What is the connection to Oxytocin?

A problem with your neuroligins causes an impairment in oxytocin signalling.

 

The role of the Lateral Septum (LS) in both aggression and desirable social behavior 

If you scan through the research on vasopressin and oxytocin you will eventually come across references to the LS.  The LS is a part of your brain called the Lateral Septum.

In the picture below you see a mouse brain and the green part is the Lateral Septum (LS).

 

Source: https://neurosciencenews.com/rage-lateral-septum-3637/ 

“Our research provides what we believe is the first evidence that the lateral septum directly ‘turns the volume up or down’ in aggression in male mice, and it establishes the first ties between this region and the other key brain regions involved in violent behavior”

Both social bonding and offensive aggression involve vasopressin receptors in a part of the brain called the Lateral Septum (LS).  Activity in the Lateral Septum (LS) is regulated by inhibitory GABA, and excitatory glutamate.

There is a notable difference between males and females, at least in rats.  No sex differences were found in extracellular GABA concentrations during social playing; however, glutamate plays a major role in female social playing. When glutamate receptors are blocked in the LS pharmacologically, there is a significant decrease in female social playing, while males had no decrease in playing. This suggests that in the lateral septum, GABA neurotransmission is involved in social play behavior regulation in both sexes, while glutamate neurotransmission is sex-specific, involved in regulation of social play only in females.

 

Aggressive behavior in females 

Neural mechanisms of female aggression: Implications on the oxytocin and vasopressin systems

These models allowed me to investigate the role of the brain oxytocin (OXT) and vasopressin (AVP) systems on aggressive behavior. Both neuropeptides are known to regulate social including aggressive behaviors in males and lactating females.

Taken together this part of my thesis shows that the balance between OXT and AVP release within the LS regulates female aggression in a receptor and region-specific manner via modulating GABAergic neurotransmission.

Overall, this thesis shows that females are able to develop escalated as well as abnormal aggression just like males. In addition, the OXT and the AVP system seem to be main players in regulating aggressive behavior in female Wistar rats, especially, regarding their role in controlling aggression by acting on the LS.

 

The effect of Vasopressin as a therapy

 

Correction of vasopressin deficit in the lateral septum ameliorates social deficits of mouse autism model 

Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.

 

In humans, intranasal administration of AVP increased activity in the LS and reciprocated social collaboration (47). Intranasal OXT administration enhances the suppression of oscillatory activity (8–25 Hz) during execution and observation of social actions (48). Altogether, OXT- and AVP-dependent modulation of neural activity in response to social stimuli directly affect EEG activity, which may have a predictive value for the impact of such treatment in ASD-associated disorders. Furthermore, an imbalance between inhibition and excitation is associated with ASD, and AVP treatment could reset the balance by altering the functions of SST neurons (49).

  

Predicting Autism measuring Neonatal CSF vasopressin concentration 

We have yet another predictor of future autism.

Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder

The Russian paper below is very thorough. At least in the case of autism, I do not agree with the therapeutic implications.  The paper suggests Oxytocin agonists (like oxytocin itself) and Vasopressin antagonists.

I propose Oxytocin agonists and Vasopressin agonists, as a practical solution today.  It is not a perfect solution, but totally doable today.

  

The role of oxytocin and vasopressin dysfunction in cognitive impairment and mental disorders 

Oxytocin (OXT) and arginine-vasopressin (AVP) are structurally homologous peptide hormones synthesized in the hypothalamus. Nowadays, the role of OXT and AVP in the regulation of social behaviour and emotions is generally known. However, recent researches indicate that peptides also participate in cognitive functioning. This review presents the evidence that the OXT/AVP systems are involved in the formation of social, working, spatial and episodic memory, mediated by such brain structures as the hippocampal CA2 and CA3 regions, amygdala and prefrontal cortex. Some data have demonstrated that the OXT receptor's polymorphisms are associated with impaired memory in humans, and OXT knockout in mice is connected with memory deficit. Additionally, OXT and AVP are involved in mental disorders' progression. Stress-induced imbalance of the OXT/AVP systems leads to an increased risk of various mental disorders, including depression, schizophrenia, and autism. At the same time, cognitive deficits are observed in stress and mental disorders, and perhaps peptide hormones play a part in this. The final part of the review describes possible therapeutic strategies for the use of OXT and AVP for treatment of various mental disorders.

 

4.4. Autism

Autism spectrum disorder (ASD) is a group of disorders that are characterized by early disturbances of social communication and limited, repetitive behaviour. Individuals with autism have impaired social cognition and social perception, executive dysfunction, and atypical perceptual and information processing. Additionally, they exhibit atypical neural development at the systems level . Autism is characterized by a disturbance of social interaction first of all, but it is also characterized by cognitive dysfunctions, including working memory impairment. The OXT/AVP system plays a role in such deficits. In male mice with a mutation in the Magel2 gene, social behaviour and cognitive functions are disrupted in adulthood, which makes this model similar to ASD. The lack of Magel2 causes a change in the OXT system. Subcutaneous administration of OXT to mice with this mutation during the first week of life suffices to restore normal social behaviour and learning abilities in adult mice. Exogenous OXT stimulates the release of endogenous OXT and inhibits the accumulation of intermediate forms of OXT (this is observed in OXT neurons in mice with the Magel2 mutation). This was revealed by neuroimaging methods. Human ASD is associated with altered face processing and decreased activity in brain areas involved in this process. OXT enhances the importance of social stimulus in ASD, and probably can stimulate face processing and eye contact in people with ASD. Genetic polymorphisms of the OXT and AVP receptor genes are associated with ASD. Additionally, this review revealed a link between social cognition disorders in autism and some SNPs in the OXTR and V1a receptor genes. The most significant associations between SNPs in OXTR and social cognition were found for rs2254298, rs53576 and rs7632287. SNP rs2254298 has been associated with a diagnosis of ASD. SNP in the V1a receptor gene, rs7294536, is closely associated with a deficit in social interactions. In addition, OXTR rs237887 polymorphism affects facial recognition memory in families with autistic children.

 

 

 

 

Fig 1. The role of oxytocin and vasopressin systems in the pathogenesis of mental disorders. Stress activates the HPA axis and rises in plasma glucocorticoid levels, which leads to social through the cortisol release. HPA axis activation increases the risk of development of psychopathologies. OXT and AVP regulate emotional behaviours, multiple aspects of social behaviour and cognitive functions. Negative environment, including stress factor, causes an imbalance of the OXT/AVP system, which also leads to psychopathological behaviour: aggression, social impairment, anxiety, emotional and cognitive disorders. At the same time, the OXT/AVP system forms a reaction to stress oppositely. OXT inhibits the HPA axis stress induced activity (anxiolytic effect). AVP activates the HPA axis (anxiogenic effect). OXT and AVP can be used as the treatment of mental diseases associated with social and cognitive dysfunctions. OXT – oxytocin; AVP – arginine-vasopressin; iOXT – intranasal oxytocin; iAVP – intranasal arginine-vasopressin; ACTH - adrenocorticotropic hormone; CRH – corticotropin releasing hormone; HPA axis - hypothalamic-pituitary-adrenal axis.

 

 

5. OXT and AVP systems in mental disorder treatments in recent years, interest in the usage of OXT as the treatment of various psychiatric diseases is growing. OXT and AVP systems that exist in balance produce the contrary effect on emotional behaviour. Positive social stimuli and/or psychopharmacotherapy can shift this balance towards OXT and can help to stimulate emotional behaviour and restore mental health through this shifting. OXT produces an effect on several neurobiological systems, including the HPA axis, limbic system, neurotransmitters, and immune processes related to stress disorders. The exact effects of iOXT still remain unclear; nevertheless, it is known that iOXT action depends on individual sensitivity. Data from functional magnetic resonance imaging demonstrated that iOXT induces temporary activation of some cortex areas and prolonged activation of hippocampus and forebrain areas. These structures are characterized by a high density of OXT receptors. At the same time, iAVP causes stable deactivation in the parietal cortex, thalamus, and mesolimbic pathway. Importantly, the intravenous administration of OXT and AVP does not repeat activation patterns caused by intranasal administration of OXT and AVP. Nevertheless, it is possible that a small amount of OXT which crosses the blood-brain barrier may lead to an additional central OXT release since OXT is able to bind to brain OXT ergic neurons and cause its own release. Generally, OXT doses administered in studies vary from 15 IU to more than 7000 IU. As the table indicates, the results of these studies are very different. The most frequently used dose is 24 IU. Many studies are focused on the capability of OXT in the treatment of depressive disorders. It was demonstrated that iOXT reduces the time of concentration on aggressive facial expressions and increases the time of concentration on happy faces in men and women with chronic depression. Therefore, iOXT regulates emotion recognition in depression. iOXT can be used in combination with antidepressants, enhancing antidepressant efficiency. iOXT administration positively affects mother-child relationship in mothers with postpartum depression (PPD). iOXT activates the protective behaviour of mothers with PPD towards their children. Similar results were found in animal experiments. In rats, iOXT reduced the depressive-like behaviour in adult animals subjected to early maternal separation. Moreover, the research of specific neurogenesis markers Ki67 and BrdU demonstrated that iOXT promotes hippocampal neurogenesis, which is impaired in depressed rats. Many studies investigate the therapeutic properties of iOXT and iAVP for the treatment of schizophrenia and autism. It is known that schizophrenia disturbs social behaviour; and cognitive function. iOXT has the potential for usage as a therapeutic tool to restore impaired functions during schizophrenia. Some data suggest that iOXT reduces the negative symptoms of schizophrenia, improves working memory, verbal memory and cognitive function, and also improves social function in patients with schizophrenia and schizoaffective disorder. Although many studies indicate a positive effect of iOXT on cognitive function in people with schizophrenia, the neuropeptide has a very selective action on behaviour. The exact mechanism of iOXT action is also indefinite; therefore, its therapeutic potential requires further research. Eventually, iOXT can be used as an additional therapeutic agent in traditional schizophrenia treatment. iOXT can also be applied to ASD treatment. It was found that iOXT improves social abilities in children and emotionality in adult men with ASD. Moreover, the improvement of emotional state was observed in adults after an 8 IU dose, but not after 24 IU. The study of iOXT's therapeutic properties was also carried out using a mouse valproate autism model. iOXT improved social behaviour in that model, and reduced anxiety, depressive-like behaviour, and repetitive behaviour. iOXT has some positive effects in the ASD treatment. Despite this, studies of the potential therapeutic usage of iOXT are still at an early stage, and doctors have insufficient data to prescribe iOXT to patients. A few data indicate the therapeutic possibilities of AVP compared to OXT. It is known that iAVP was used in the treatment of the first episode of schizophrenia, in addition to the traditional benzodiazepine treatment. Cognitive functions (namely the memorization process, long-term and short-term memory) improved in patients. iAVP treatment ameliorated social ability in children with ASD. Additionally, iAVP treatment reduced anxiety and repetitive behaviors in these children. These data indicate the necessity of further investigation of AVP's treatment potential.

 

 

Rescue of oxytocin response and social behaviour in a mouse model of autism

A fundamental challenge in developing treatments for autism spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of cases^1-3. Subsets of risk genes can be grouped into functionally related pathways, most prominently those involving synaptic proteins, translational regulation, and chromatin modifications. To attempt to minimize this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin^4-6, which regulate aspects of social behaviour in mammals⁷. However, it is unclear whether genetic risk factors predispose individuals to autism as a result of modifications to oxytocinergic signalling. Here we report that an autism-associated mutation in the synaptic adhesion molecule Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and in altered behavioural responses to social novelty tests in mice. Notably, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3-knockout mice with a new, highly specific, brain-penetrant inhibitor of MAP kinase-interacting kinases resets the translation of mRNA and restores oxytocin signalling and social novelty responses. Thus, this work identifies a convergence between the genetic autism risk factor Nlgn3, regulation of translation, and oxytocinergic signalling. Focusing on such common core plasticity elements might provide a pragmatic approach to overcoming the heterogeneity of autism. Ultimately, this would enable mechanism-based stratification of patient populations to increase the success of therapeutic interventions. 

Social recognition and communication are crucial elements in the establishment and maintenance of social relationships. Oxytocin and vasopressin are two evolutionarily conserved neuropeptides with important functions in the control of social behaviours, in particular pair-bonding and social recognition7,8 . In humans, genetic variation of the oxytocin receptor (OXTR) gene is linked to individual differences in social behaviour9 . Consequently, signalling modulators and biomarkers for the oxytocin or vasopressin system are being explored for conditions with altered social interactions such as autism spectrum disorders (ASDs)5,6 . In mice, mutation of the genes encoding oxytocin or its receptor results in a loss of social recognition and social reward signalling10–14. Mutation of Cntnap2, a gene linked to ASD in humans, resulted in reduced levels of oxytocin in mice, and the addition of oxytocin improved social behaviour in this model15. However, the vast majority of genetic risk factors for autism have no known links to oxytocinergic signalling. 

Thus, modification of translation homeostasis in Nlgn3KO mice by MNK inhibition restores oxytocin responses and social novelty responses. This work uncovers an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, oxytocinergic signalling, and social novelty responses. Although loss of Nlgn3 impairs oxytocin responses in VTA DA neurons, the behavioural phenotype does not fully phenocopy genetic loss of oxytocin. Oxytocin knockout mice exhibit impaired habituation in the social recognition task10, whereas Nlgn3KO mice habituate normally but exhibit a selective deficit in the response to a novel conspecific. This is probably due to differential roles of Nlgn3 and oxytocin across several neural circuits and over development. Moreover, Nlgn3 loss-of-function also affects signalling through additional GPCRs23. We propose that pharmacological inhibition of MNKs may provide a new therapeutic strategy for neurodevelopmental conditions with altered translation homeostasis. Notably, MNK loss-of-function appears to be overall well tolerated. MNK1/2 double-knockout mice are viable46 and several MNK inhibitors are entering clinical trials for cancer therapy47. Previously available MNK inhibitors were greatly limited by specificity and brain penetrance. Our work not only highlights a new class of highly-specific, brain-penetrant MNK inhibitors but also expands their application from fragile X syndrome41 to a non-syndromic model of ASD. The common disruption in translational machinery and phenotypic rescue in two very different genetic models indicate that genetic heterogeneity of ASD might be reduced to a smaller number of cellular core processes. This raises the possibility that pharmacological interventions targeting such core processes may benefit broader subsets of patient populations.

 

A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice 

Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS.

  

Conclusion

I think I have written enough about Oxytocin and Vasopressin.

The research is not entirely consistent regarding Vasopressin, but my assumption is that for my kind of autism I want an Oxytocin Agonist and a Vasopressin Agonist, some people might think it would be a Vasopressin Antagonist.

The good news is that there is significant research in humans, reported in previous posts, to support the use of both Oxytocin Agonist and a Vasopressin Agonist

I also think there will be both short-term, or immediate effects, from both treatments but also potentially different long-term effects from continued therapy, that is indeed suggested by the animal research models.  For example, neurite outgrowth is stimulated by oxytocin.  It is suggested that oxytocin may contribute to the regulation of scaffolding proteins expression.

Is it worth using oxytocin as a therapy to generate some extra hugs? You can argue both ways, but the longer-term benefits of correcting low oxytocin levels may be more profound.

The effects of vasopressin and oxytocin are somewhat overlapping. We know that low levels of vasopressin in spinal fluid are a good marker for autism, so putting a little extra vasopressin in the brain does not seem unreasonable.

As usual with the human body, the effects of oxytocin and vasopressin are different within the brain and in the rest of your body.  Also, the levels of these hormones in your blood are not a good predictor of their levels within the brain.  This is a reoccurring problem.  Because taking a spinal fluid sample is an invasive procedure, it is rarely taking place and then endless time and money is wasted on blood tests that may well send the doctor in the wrong direction, or just no direction.

It is highly likely that increasing Oxytocin and Vasopressin in the brain is going to affect aggressive behaviors, via actions in the Lateral Septum (LS).  Due to the role of GABA potentiating activity in the Lateral Septum (LS) you might expect a possible difference in bumetanide-responders and bumetanide non-responders (because GABA is acting as excitatory).

I would consider Oxytocin and Vasopressin as fine-tuning autistic behavior and you would have to personalize the dosage. In some people it might be a case of either or, rather than both.

Using MNK inhibitors to treat human Fragile-X looks a great idea and hopefully a commercialized therapy could then be trialed in broader autism.

 

Autism and the Police – challenging behaviors leading to restraint

 

Today’s post is about an issue that seems to cause a problem in some countries far more than others. While some people with mild autism (Asperger’s) may feel anxiety when dealing with the police, the big problem occurs when the police are called in to restrain someone with severe autism and particularly someone who is also non-verbal with MR/ID.  Most people with untreated severe autism actually have MR/ID, even if it was never diagnosed.

It would never occur to me to call the police to restrain my own son, but in North America this is a regular occurrence.  It sometimes does not end well, often it was the parents who called the police, when it is not the parents it is likely to be the school. The research shows that most often the police in the US do successfully resolve the incident.

I did ask my son’s assistant what she knows about the police dealing with aggressive autistic people. She knows lots of people with autism and parents. She initially did not understand my question, because where we live nobody would think to call the police to deal with their autistic son/daughter. You would just deal with it yourself, as best as you could.  Even if you did call the police, there is nowhere for them to take an aggressive person with autism.

Schools have a difficult job dealing with people with autism who exhibit challenging behaviors.  They have a range of options that do include restraint and indeed seclusion.  Monty, now aged 17 with autism, used to have a male 1:1 assistant for a couple of years.  The assistant was training to be a speech therapist and also worked at a special school. Because he was a male in his mid-twenties and athletic, he was the first option when a child in the school got aggressive and needed restraining. In some schools this restraint involves several staff and it is not without risks to all involved.

 

A Dreaded Part Of Teachers' Jobs: Restraining And Secluding Students

Earlier this year, an NPR investigation with WAMU and Oregon Public Broadcasting found deep problems in how school districts report restraint and seclusion. Following that investigation, NPR reached out to educators about their experiences with these practices. 

The view of some unhappy UK parents:-

Disabled children ‘constantly’ physically restrained and left with bruises and trauma, parents say

Small children are sometimes placed in a supposedly safe room and left alone to calm down. 

Our son was always in school with his own 1:1 assistant and never required any intervention from the school’s staff, even when he had extremely “challenging” behaviors as an 8 year old. At that time he only went to school in the morning and his assistant at that time, though female, was very tall, young and sporty and so well able to take care of physical behaviors, so keeping the peace in the classroom.

 

Challenging Behaviors as Children get Bigger

Young children with autism do have meltdowns for numerous reasons, but these are not usually difficult to deal with.  As children get bigger and stronger, challenging behaviors can become so severe that parents struggle to cope.

When Monty had his 9 months of raging, he was only eight years old; I could easily pick him up and hold him upside down, which was his “reset button”. At his current age of 17 years old, I could still do this …  but I might drop him if he wriggled.

Hopefully, parents figure out and treat challenging behaviors in childhood and so are not left with an aggressive autistic adult to deal with.  It is these adult-sized people with challenging behavior who are at risk if they encounter the police. Given the difficulty special schools have dealing with aggressive autistic kids; it is hardly surprising that many police officers lack the skills to safely restrain an aggressive adult-sized person with autism. In my opinion an untrained police officer is entirely the wrong people to be involved.

One piece of advice I was given shortly after Monty was diagnosed with autism, was from my doctor mother, “make sure he does not get aggressive, as he gets older”.  This is very wise advice, perhaps rather easier said than done, but was based on her seeing what actually happens to adults with a psychiatric diagnosis.

Here is a study from Canada exploring families living with a child with autism and challenging behaviors.

 

Home Sweet Home? Families’ Experiences With Aggression in Children With Autism Spectrum Disorders

Although not inherent to the diagnosis, many individuals with autism spectrum disorders (ASD) display aggressive behavior. This study examined the experiences of families living with individuals with ASD who also demonstrate aggressive behaviors. Using a qualitative approach, semi structured interviews were conducted with parents of nine males with autism and aggression. Eight families’ homes also were observed. Through constant-comparison analysis of interview data, triangulated with home observations, three central processes were identified: deleterious impact on daily routines and well-being of family members, limited supports and services, and financial strain. Emergent themes included isolation, exhaustion, safety concerns, home expenses, respite needs, and limited professional supports and alternative housing. Examination of families’ experiences living with someone with ASD who is aggressive, and the impact of aggression on the supports and services that families receive, constitutes an important step in tailoring resources to best meet families’ needs.

 

The families who participated in this study demonstrated great resiliency in the face of adverse living situations. Many families of individuals with ASD become more optimistic and accepting of their children’s diagnoses over time, relying less on formal supports and services. Unfortunately, this optimism was not expressed by the families who participated in this study because aggression presented significant and pervasive challenges to their families, for which adequate knowledge, supports, and services were not in place. Many of the families in this study received ASD specific medical, home- and community-based services in a geographic location known to have a relatively high level of service for individuals with ASD; however, parents perceived that none of these services were equipped to deal with aggression

 

Canada is one of the better countries when it comes to dealing with severe autism.

In the United Kingdom, when it comes to autism and the police, it appears that neither party is satisfied.

Experiences of Autism Spectrum Disorder and Policing in England and Wales: Surveying Police and the Autism Community 

An online survey gathered the experiences and views of 394 police officers (from England and Wales) regarding autism spectrum disorder (ASD). Just 42 % of officers were satisfied with how they had worked with individuals with ASD and reasons for this varied. Although officers acknowledged the need for adjustments, organisational/time constraints were cited as barriers. Whilst 37 % of officers had received training on ASD, a need for training tailored to policing roles (e.g., frontline officers, detectives) was identified. Police responses are discussed with respect to the experiences of the ASD community (31 adults with ASD, 49 parents), who were largely dissatisfied with their experience of the police and echoed the need for police training on ASD.

 

I came across a very detailed study from the US, with very many links to other papers, for those interested in this topic. In the US it seems that most parents are satisfied with encounters with the police.  Given the bad impression of the American police given by much of the media, this is very noteworthy and encouraging. 

Correlates of Police Involvement Among Adolescents and Adults with Autism Spectrum Disorder

This study aimed to describe police interactions, satisfaction with police engagement, as well as examine correlates of police involvement among 284 adolescents and adults with autism spectrum disorder (ASD) followed over a 12- to 18-month period. Approximately 16% of individuals were reported to have some form of police involvement during the study period. Aggressive behaviors were the primary concern necessitating police involvement. Individuals with police involvement were more likely to be older, have a history of aggression, live outside the family home, and have parents with higher rates of caregiver strain and financial difficulty at baseline. Most parents reported being satisfied to very satisfied with their children's police encounters. Areas for future research are discussed in relation to prevention planning.

 

Similar to past studies concerning emergency service use among individuals with ASD (e.g., emergency department and psychiatric in-patient services; Kalb et al. 2012; Lunsky et al. 2015; Mandell 2008), aggression was the primary presenting concern resulting in police contact in the current study. A significant proportion of police resources are expended on resolving mental health crises in the community (de Tribolet-Hardy et al. 2015; Short et al. 2014). The appropriateness of such police involvement has been questioned due to the time, cost, and lack of adequate mental health training provided to police (Clifford 2010; Fry et al. 2002). Research concerning more effective solutions to responding to psychiatric crises, such as the use of crisis intervention teams (Franz and Borum 2011; Compton et al. 2008), is promising and should be extended to include individuals with ASD. A history of aggression differentiated individuals who did and who did not interact with police in the observation period. Aggressive behaviors commonly occur in ASD (Kanne and Mazurek 2011; Matson and Rivet 2008; Mazurek et  al. 2013), with rates reported to occur in up to 68% of affected individuals at some point in their lives (Lecavalier 2006). These behaviors can result in negative physical, emotional, and financial consequences for family members (Hartley et  al. 2012; Hodgetts et  al. 2013). Despite a high need and the recognized existence of effective empirically based interventions, there is often a lack of professional knowledge and community-based resources to assist individuals with ASD and their families deal with aggressive behaviors (Hodgetts et  al. 2013; White et  al. 2012). In the current study, an individual’s history of aggressive behavior, caregiver strain and police contact were associated with each other, further highlighting the need for appropriate community-based family supports. Police contact in the observation period was more likely among older individuals with ASD, those living outside of the family home, and individuals without structured day activities at baseline. Age, family involvement, service use and/or community involvement have similarly been shown to predict involvement with police and the greater criminal justice system among typically developing youth (Greenberg and Lippold 2013; Ryan and Yang 2005; Williams et al. 2007). There is a recognized decline in service availability in the adult service sector for individuals with ASD; a phenomenon referred to as a “service cliff” in past ASD research (Shattuck et al. 2011; Turcotte et al. 2016). Findings from the current study emphasize the importance of developing supports and service models to meet the needs of this population. Autism spectrum disorder symptom severity and ID status were not associated with police contact in this convenience sample. Similarly, Rava et al. (2017) found no association between individuals’ conversation ability and police contact. The diversity of individuals’ presentations emphasizes the broad training police may need to properly understand and interact with all individuals with ASD. To this effect, ASD support and advocacy organizations have initiated various tools to assist individuals with ASD disclose their diagnosis and individualized communication needs to law enforcement officers (e.g., information cards; Debbaudt 2006). The efficacy of these tools from the perspectives of the individual with ASD and law enforcement officials is an area for future research. Most police interactions did not result in criminal charges being brought against the individual with ASD. This replicates Rava et al.’s (2017) increased rate of police contact compared to convictions. In the current study, police contact resulted in a variety of outcomes, including crisis resolution, transportation to the emergency department, and/or physical restraint. Additionally, parents reported that police involvement had a calming effect in nearly half of all incidents and reported, on average, being somewhat satisfied with their children’s interactions with police. This is in contrast with a recent U.K. based study where almost three-quarters of surveyed parents of adults with ASD reported unsatisfactory ratings of their interactions with police officers (Crane et  al. 2016). In addition to being from a different jurisdiction, that study included only retrospective reports from caregivers who had police involvement, whereas our study followed a larger group of families forward, some of whom had police involvement in the observation period.

 

In the study below from Australia, it concludes that more training and awareness is needed by the local police when called in to deal with autistic people being violent at home. Not surprisingly, it is the parents who usually get attacked by the autistic person – so better keep in shape! 

Domestic violence events involving autism: a text mining study of police records in New South Wales, 2005-2016

Highlights

·      Text mining was applied to domestic violence police records in Australia.

·      Domestic violence involving autism most commonly involves parent-child relationships.

·      Autistic domestic violence more commonly involves intellectual disability.

Background

Recent research and high-profile media cases have suggested an association between autism spectrum disorder and violent behaviour. Whilst certain characteristics of autism may make individuals vulnerable to increased involvement with the police, either as a victim or person of interest, evidence regarding this is scant. The present study used a population-based dataset to describe the characteristics of domestic violence events involving autistic and non-autistic adults.

Methods

Text mining and descriptive statistics were applied to police-recorded data for 1,601 domestic violence events involving autism and 414,840 events not involving autism in the state of New South Wales, Australia from January 2005 to December 2016.

Results

The relationship between autistic victims and perpetrators was predominantly familial or carer whereas events not involving autism were predominantly involved intimate partners. Abuse types and injuries sustained were similar for both autistic and non-autistic events. The most common mental conditions present in autistic perpetrators were developmental conditions and intellectual disability, whilst non-autistic perpetrators most commonly reported psychoactive substance use or schizophrenia.

Conclusions

These results highlight the need to further understand the risk factors for strain and violence in relationships between autistic adults and their family members or carers, especially for those with comorbid behavioural developmental conditions. Given the uniqueness of domestic violence involving autism found in this study and the potentially unique nature of the circumstances surrounding these events, appropriate police awareness and training in relation to autism is needed.

Unfortunately, calling for help, whether from the police or a psychiatric hospital can lead to a quick downward spiral of events, from which there may be no return. 

In the US there are residential places at Kennedy Krieger where they try and treat children with extremely challenging behaviour – good luck to them!  The idea is that after a few weeks the child gets sent home. There are very limited places and I wonder who pays for them.

Where we live, there still are some residential mental institutions.  One boy we know of got very aggressive towards his mother and he was sent to live in such a facility, surrounded by adults with schizophrenia and other conditions.  This boy actually likes living there, it is very structured and there are activities, so he is not trying to escape home.

 

France and Belgium

I did meet a French former classmate of mine a few years ago and she told me all about her nephew with severe autism. Life got so bad with his aggression at home that, as a young boy, he was sent to live in an institution in Belgium.

I always remember this because I thought it extremely odd that a large country like France would send its disabled children across the border to live in little Belgium. I also wondered who paid for this.

The family were in no rush for the boy to come home and in fact feared the day when he would age out of the Belgian facility for children.

Across the world mental hospitals for adults have been shut down and they have not really been adequately replaced with alternatives. So there may be nowhere to go.

The French sending kids with autism to Belgium has actually been going on for years, as you can read below.

Disabled French Alone – or Sent to Belgium

For years France has been sending disabled citizens to Belgium. This kind of “forced exile”, denounced by the paper Libération, applies especially to adults. Problems are a bit different for children: certain parents are themselves addressing Belgium because it proposes education methods, especially for autistic children, which still do not exist in France. 

In his latest report, the EU Commissioner for Human Rights reproached the French government for depriving an estimated 20 000 disabled children of school education. 

 

Conclusion

The research suggests that 2 in 3 people with autism will engage in aggressive behaviors at some point in their life. These tend to be learned behaviors, meaning once they develop they are likely to reoccur.  Once the "beast within" has been discovered, it is really a case of controlling it, rather than banishing it forever; it is likely both biological and behavioral.

For children with challenging aggressive behavior, there should be an urgency to resolve the issue as much as possible, otherwise the future will not be bright.  Psychiatric drugs are unlikely to be the answer, they are just a band-aid with troubling side effects.

Calling the police to deal with an aggressive adult-sized person with autism does seem to be asking for even more trouble. In the US, it may work well for some people, some of the time, if they happen to have extremely understanding and well-trained first responders, but I think their luck will eventually run out.

Without aggressive behavior there would be no need for institutionalization, in a strict setting.

The medical literature and parent reports are scattered with many clues and ideas of how to resolve challenging aggressive behavior in autism; you just have to look and the sooner the better. It may well take time to find the optimal solution, but the sooner you start looking, the sooner you will find it.  Verapamil is an effective solution in my case, but yours is very likely to be different.  Nobody keeps a comprehensive list to refer to.

Based on the studies I reviewed, the police in the US are doing a better job dealing with autism than the police in some other countries. This is not the impression you get from media reporting, which makes it seem that the cops will just shoot you, or suffocate you, if you are autistic and aggressive. So a pat on the back is deserved.