Targeting Dendritic Spines to Improve Cognitive Function and Behavior in Autism; plus Hair Loss/Graying



I have written several posts about dendritic spines and their varying shapes (morphology).  This sounds like a rather obscure subject, but it looks like it may be a key area where both behavior and cognition can be modified, even later in life.



Homer Simson after using a Wnt Activator 

Dendritic spines

In a typical neuron (brain cell) you have dendrites at one end and so-called axon terminals at the other. When neurons connect with each other, an axon terminal connects with a dendritic spine from another close by neuron.  Axons transmit electrochemical signals from one neuron to the dendrites of other neurons.  The junction formed between a dendritic spine and an axon terminal is called a synapse.







One neuron can have as many as 15,000 spines, some of which are picking up signals from axon terminals of other neurons.
The number and shape of these spines is constantly changing and not surprisingly defects in this process affect both cognition and behavior.
The other end of the neuron, with the axon terminals is much less studied.  The myelin sheath deserves a mention. This protective coating is constantly being repaired in a process called remyelination. MS (Multiple Sclerosis) is caused by damage to the myelin coating that does not self repair. A newly identified feature of autism is an abnormally thin layer of myelin. A lack of insulation along the axon will affect the flow of electrical signals.
Many factors are involved in dendritic spine morphology and plasticity. Many of the same factors are known to be disturbed in autism and other related dysfunctions (schizophrenia, bipolar, ADHD etc).
Recall that within autism there are two broad groups; the larger group has �too many� dendritic spines and the smaller group has �too few�. I am writing about the larger group. My post is a simplification of a complex subject.
Factors that influence dendritic spine morphology and plasticity include:- 

        BDNF  (want less)

        Estrogen  (want more)

        Reelin (want more)

        BCL2 (want more)

        PAK1 (want less)

        GSK3 beta (want more)

        PTEN (want more)

All the above seem to work via

        Wnt signaling (want less) 

BDNF is a growth factor within the brain, which tends to be elevated in most autism.
The female hormone estrogen seems to be reduced in male autism and this will have many effects via something called ROR alpha. There is also reduced expression of estrogen receptor beta.
Reelin is a protein that is critical in brain development and maintenance. Reelin is implicated in most brain diseases, including autism. It stimulates dendritic spine development. Reelin is found to be reduced in autism.
BCl2 is a very well-known cancer gene/protein. BCL2 is part of a broader family of genes/proteins that control cell growth/death. BCL2 is anti-apoptotic, meaning it encourages growth rather than cell death. You will find elevated BCL2 in cancers.  BCL2 is implicated in both schizophrenia and autism.
Bax is another key member of the BCL2 family. The BCL2 protein duels with Bax, its counteracting twin. When Bax is in excess, cells execute a death command. When BCL2 dominates, the program is inhibited and cells survive. In cancer you want more Bax.
Modulating BCL2/Bax has been proposed as an autism therapy in Japan.
BCL2 is found to be reduced in autism.
The Japanese proposed the use of Navitoclax, a drug responsible for inhibiting BCL2 production for the treatment of cancer. I think they want to activate BCL2 production. 
I covered PAK1 in some lengthy posts. This was what the Japanese Nobel Laureate at MIT was working on. In summary, a PAK1 inhibitor should be helpful in autism, schizophrenia and some cancer.  Some people with a condition called neurofibromatosis, where non-cancerous tumors grow, use a special kind of bee propolis that contains a substance called CAPE (caffeic acid phenethyl ester), that is a mild PAK1 inhibitor.


GSK3 beta plays a role in several key signaling pathways. Abnormal expression of GSK3 beta is associated with Bipolar disorder. One role played by GSK3 beta is in Wnt signaling, which then affects dendritic spines. A GSK3 beta inhibitor, like lithium, is a Wnt activator which will increase the number of dendritic spines.
PTEN is a tumor suppressor gene/protein that is also an autism gene.
PTEN deficiency results in abnormal arborization and myelination in humans. PTEN-deficient neurons in brains of animal models have increased synaptic spine density.
People with autism and PTEN mutations have large heads because they lacked enough PTEN to reign in cell growth (and head growth).  You would expect them to have increased synaptic spine density.
Note than in both autism/cancer genes (BCL2 and PTEN) the balance is shifted towards growth, which fits in with the broad concept of autism as a growth dysfunction.
Wnt signaling is a complex and only partially understood subject, that has been previously discussed in this blog.  The short version is that most people with autism and particularly the ones with large heads will likely have too much Wnt signaling as the result of their various metabolic �disturbances�. The best way to inhibit their Wnt signaling might be to counter their particular metabolic disturbances, so if you are one of the 2% of autism with a PTEN mutation, then increase your PTEN levels.  If this is not possible than any other way to inhibit Wnt might be effective.
In Bipolar, where GSK3 beta is a known risk gene, you want more dendritic spines and so you want a GSK3 beta inhibitor like lithium. 
I think lithium will have a negative effect on most autism. Within children diagnosed with autism, a minority may well better fit a diagnosis of bipolar.

OBJECTIVE:


Children with autism spectrum disorder (ASD) have higher rates of comorbid psychiatric disorders, including mood disorders, than the general child population. Although children with ASD may experience irritability (aggression, self-injury, and tantrums), a portion also experience symptoms that are typical of a mood disorder, such as euphoria/elevated mood, mania, hypersexuality, paranoia, or decreased need for sleep. Despite lithium's established efficacy in controlling mood disorder symptoms in the neurotypical population, lithium has been rarely studied in children with ASD.

METHODS:


We performed a retrospective chart review of 30 children and adolescents diagnosed with ASD by the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria who were prescribed lithium in order to assess target symptoms, safety, and tolerability. Clinical Global Impressions - Improvement (CGI-I) ratings were performed by two board-certified child psychiatrists with expertise in ASD. CGI-I scores were dichotomized into "improved" (CGI-I score of 1 or 2) or "not improved" (CGI-I score =3).

RESULTS:


Forty-three percent of patients who received lithium were rated as "improved" on the CGI-I. Seventy-one percent of patients who had two or more pretreatment mood disorder symptoms were rated as "improved." The presence of mania (p=0.033) or euphoria/elevated mood (p=0.041) were the pretreatment symptoms significantly associated with an "improved" rating. The mean lithium blood level was 0.70?mEq/L (SD=0.26), and the average length of lithium treatment was 29.7 days (SD=23.9). Forty-seven percent of patients were reported to have at least one side effect, most commonly vomiting (13%), tremor (10%), fatigue (10%), irritability (7%), and enuresis (7%).

CONCLUSIONS:


This preliminary assessment of lithium in children and adolescents with ASD suggests that lithium may be a medication of interest for those who exhibit two or more mood disorder symptoms, particularly mania or euphoria/elevated mood. A relatively high side effect rate merits caution, and these results are limited by the retrospective, uncontrolled study design. Future study of lithium in a prospective trial with treatment-sensitive outcome measures may be indicated.


Hair Growth and Graying 
One surprising observation is the apparent connection between dendritic spine modification and modifying growth/color of human hair.
The same pathway is involved in signaling growth and coloring in the hair on your head and growing the dendritic spines on the neurons inside your head. I have mentioned this once before in a previous post. It is relevant because if a substance is potent enough to affect your dendritic spines you would expect it also to have a visible effect on the hair, of at least some people.
For example one reader of this blog uses a PAK1 inhibitor to treat her case of autism and she found that it has a hair graying effect.

EdnrB Governs Regenerative Response of Melanocyte Stem Cells by Crosstalk with Wnt Signaling

Pigmented hair regeneration requires epithelial stem cells (EpSCs) and melanocyte stem cells (McSCs) in the hair follicle.

Thus far, only a handful of signals that regulate McSCs have been identified, including extrinsic signals, such as transforming growth factor beta (TGFB) and Wnts, which are provided by the epithelial niche. Wnt signaling induces activation of EpSCs to drive epithelial regeneration while coordinately inducing McSCs to proliferate and differentiate to pigment regenerating hair follicle


One known but uncommon side effect of my current favourite Wnt inhibitor, Mebendazole, is hair loss. Hair follicles require Wnt signaling and if there is too little Wnt signaling you will lose some hair.
BCL2 is a very important cancer gene/protein but it also plays a role in autism and in dendritic spine morphology.  Low levels of the protein BCl2 leads to premature graying.

The team then looked at what would happen if they 'knocked out' a gene in mice that is known to be important for cell survival.
Mice lacking this Bcl2 gene went grey shortly after birth.

The scientists believe the same principle might apply in humans, which would explain why some people - such as TV presenter Philip Schofield - go grey in their 20s, while others keep their dark locks into retirement.
  

BCL2 is known to be reduced in the reduced in the brains of people with autism, as is another substance called Reelin.  Both Reelin and Bcl-2 are needed for dendritic spines to develop correctly.  

Autism is a severe neurodevelopmental disorder with potential genetic and environmental causes. Cerebellar pathology including Purkinje cell atrophy has been demonstrated previously. We hypothesized that cell migration and apoptotic mechanisms may account for observed Purkinje cell abnormalities. Reelin is an important secretory glycoprotein responsible for normal layering of the brain. Bcl-2 is a regulatory protein responsible for control of programmed cell death in the brain. Autistic and normal control cerebellar corteces matched for age, sex, and post-mortem interval (PMI) were prepared for SDS-gel electrophoresis and Western blotting using specific anti-Reelin and anti-Bcl-2 antibodies. Quantification of Reelin bands showed 43%, 44%, and 44% reductions in autistic cerebellum (mean optical density +/- SD per 30 microg protein 4.05 +/- 4.0, 1.98 +/- 2.0, 13.88 +/- 11.9 for 410 kDa, 330 kDa, and 180 kDa bands, respectively; N = 5) compared with controls (mean optical density +/- SD per 30 microg protein, 7.1 +/- 1.6, 3.5 +/- 1.0, 24.7 +/- 5.0; N = 8, p < 0.0402 for 180 kDa band). Quantification of Bcl-2 levels showed a 34% to 51% reduction in autistic cerebellum (M +/- SD per 75 microg protein 0.29 +/- 0.08; N = 5) compared with controls (M +/- SD per 75 microg protein 0.59 +/- 0.31; N = 8, p < 0.0451). Measurement of beta-actin (M +/- SD for controls 7.3 +/- 2.9; for autistics 6.77 +/- 0.66) in the same homogenates did not differ significantly between groups. These results demonstrate for the first time that dysregulation of Reelin and Bcl-2 may be responsible for some of the brain structural and behavioral abnormalities observed in autism.  

Abstract

The development of distinct cellular layers and precise synaptic circuits is essential for the formation of well-functioning cortical structures in the mammalian brain. The extracellular protein Reelin through the activation of a core signaling pathway including the ApoER2 and VLDLR receptors and the adapter protein Dab1, controls the positioning of radially migrating principal neurons, promotes the extension of dendritic processes in immature forebrain neurons, and affects synaptic transmission. Here we report for the first time that the Reelin signaling pathway promotes the development of postsynaptic structures such as dendritic spines in hippocampal pyramidal neurons. Our data underscore the importance of Reelin as a factor that promotes the maturation of target neuronal populations and the development of excitatory circuits in the postnatal hippocampus. These findings may have implications for understanding the origin of cognitive disorders associated with Reelin deficiency.

While not everything relating to dendritic spines is variable, and hence potentially can be modified, much seems to be.
Rather like in this blog it took a few years to get a comprehensive view of the factors involved in neuronal chloride and extend the list of potential therapies, getting to the bottom of fine tuning dendritic spin morphology for improved behavior and cognition will be a complex task.
Much is already known.
Our reader AJ is busy looking at GSK3 beta inhibitors.
GSK3 beta is best known as a bipolar gene/protein, but it is becoming seen as an autism gene.


GSK3 is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. Although the inhibition of GSK3-mediated �-catenin phosphorylation is known to be the key event in Wnt-�-catenin signaling, the mechanisms which underlie this event remain incompletely understood. The recent demonstration of GSK3 involvement in Wnt receptor phosphorylation illustrates the multifaceted roles that GSK3 plays in Wnt-�-catenin signaling. In this review, we will summarize these recent results and offer explanations, hypotheses, and models to reconcile some of these observations.
Recent advances indicate that GSK3 also plays a positive role in Wnt signal transduction by phosphorylating the Wnt receptors low density lipoprotein receptor-related protein (LRP5/6) and provide new mechanisms for the suppression of GSK3 activity by Wnt in �-catenin stabilization. Furthermore, GSK3 mediates crosstalk between signaling pathways and �-catenin-independent downstream signaling from Wnt.


it is known that glycogen synthase kinase 3� (GSK-3�) regulates both synaptic plasticity and memory. 
GSK-3� overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased.


Over the past 2 decades, neuroscientists have built a body of evidence that links not only bipolar disease, but other psychiatric disorders including autism and schizophrenia to abnormal brain development. In particular, they have found abnormalities in the numbers of synapses and in the shape of neurons at the points where they form synapses. Their studies have often implicated abnormal signaling in a brain pathway called Wnt, which is involved both in early brain development and later, more complex, refining of brain connections. The role of Wnt could help explain why lithium is effective: It blocks an enzyme called GSK-3 �, which is an inhibitor on the Wnt pathway. By boosting Wnt signaling, lithium could produce a therapeutic effect in psychiatric diseases in which the Wnt pathway is underpowered.

They then treated the mutant mice with lithium. Although the researchers acknowledge that rodents are an imperfect proxy for human mood disorders, they did observe that the animals� symptoms markedly improved; studies of their brains also revealed normal numbers of spines. �That�s the key finding,� Cheyette says. �It suggests that lithium could have its well-known therapeutic effect on patients with bipolar disorder by changing the stability of spines in the brain.�







GSK3 has numerous effects.

Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. However, this serine/threonine kinase is now known to regulate numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, malfunction of this kinase is also known to be involved in the pathogenesis of human diseases, such as nervous system disorders, diabetes, bone formation, inflammation, cancer and heart failure. Therefore, GSK-3 is recognized as an attractive target for the development of new drugs. The present review summarizes the roles of GSK-3 in the insulin, Wnt/�-catenin and hedgehog signaling pathways including the regulation of their activities. The roles of GSK-3 in the development of human diseases within the context of its participation in various signaling pathways are also summarized. Finally, the possibility of new drug development targeting this kinase is discussed with recent information about inhibitors and activators of GSK-3.  

Estradiol


The present study demonstrates that estradiol may trigger formation of new dendritic spines by activation of a cAMPregulated CREB phosphorylation. Induction of the CREB response requires activation of NMDA receptors, increased intracellularcalciumconcentrationsandcAMP-activatedPKA.These systems together then contribute to the CREB response, which in turn leads to the morphological changes seen with estradiol�i.e., spine formation. The biochemical and cellular routes leading from activated CREB to the morphological change in dendritic spine density are still uncharted.

Dendritic spines of the medial amygdala: plasticity, density, shape, and subcellular modulation by sex steroids.

The medial nucleus of the amygdala (MeA) is a complex component of the "extended amygdala" in rats. Its posterodorsal subnucleus (MePD) has a remarkable expression of gonadal hormone receptors, is sexually dimorphic or affected by sex steroids, and modulates various social behaviors. Dendritic spines show remarkable changes relevant for synaptic strength and plasticity. Adult males have more spines than females, the density of dendritic spines changes in the course of hours to a few days and is lower in proestrous and estrous phases of the ovarian cycle, or is affected by both sex steroid withdrawal and hormonal replacement therapy in the MePD. Males also have more thin spines than mushroom-like or stubby/wide ones. The presence of dendritic fillopodia and axonal protrusions in the MePD neuropil of adult animals reinforces the evidence for local plasticity. Estrogen affects synaptic and cellular growth and neuroprotection in the MeA by regulating the activity of the cyclic AMP response element-binding protein (CREB)-related gene products, brain-derived neurotrophic factor (BDNF), the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and the activity-regulated cytoskeleton-related protein (Arc). These effects on signal transduction cascades can also lead to local protein synthesis and/or rearrangement of the cytoskeleton and subsequent numerical/morphological alterations in dendritic spines. Various working hypotheses are raised from these experimental data and reveal the MePD as a relevant region to study the effects of sex steroids in the rat brain.

PTEN 


CNS deletion of Pten in the mouse has revealed its roles in controlling cell size and number, thus providing compelling etiology for macrocephaly and Lhermitte-Duclos disease. PTEN mutations in individuals with autism spectrum disorders (ASD) have also been reported, although a causal link between PTEN and ASD remains unclear. In the present study, we deleted Pten in limited differentiated neuronal populations in the cerebral cortex and hippocampus of mice. Resulting mutant mice showed abnormal social interaction and exaggerated responses to sensory stimuli. We observed macrocephaly and neuronal hypertrophy, including hypertrophic and ectopic dendrites and axonal tracts with increased synapses. This abnormal morphology was associated with activation of the Akt/mTor/S6k pathway and inactivation of Gsk3�. Thus, our data suggest that abnormal activation of the PI3K/AKT pathway in specific neuronal populations can underlie macrocephaly and behavioral abnormalities reminiscent of certain features of human ASD.  


Mutations in phosphatase and tensin homolog deleted on chromosome ten (PTEN) are implicated in neuropsychiatric disorders including autism. Previous studies report that PTEN knockdown in neurons in vivo leads to increased spine density and synaptic activity. To better characterize synaptic changes in neurons lacking PTEN, we examined the effects of shRNA knockdown of PTEN in basolateral amygdala neurons on synaptic spine density and morphology using fluorescent dye confocal imaging. Contrary to previous studies in dentate gyrus, we find that knockdown of PTEN in basolateral amygdala leads to a significant decrease in total spine density in distal dendrites. Curiously, this decreased spine density is associated with increased miniature excitatory post-synaptic current frequency and amplitude, suggesting an increase in number and function of mature spines. These seemingly contradictory findings were reconciled by spine morphology analysis demonstrating increased mushroom spine density and size with correspondingly decreased thin protrusion density at more distal segments. The same analysis of PTEN conditional deletion in dentate gyrus demonstrated that loss of PTEN does not significantly alter total density of dendritic protrusions in the dentate gyrus, but does decrease thin protrusion density and increases density of more mature mushroom spines. These findings suggest that, contrary to previous reports, PTEN knockdown may not induce de novo spinogenesis, but instead may increase synaptic activity by inducing morphological and functional maturation of spines. Furthermore, behavioral analysis of basolateral amygdala PTEN knockdown suggests that these changes limited only to the basolateral amygdala complex may not be sufficient to induce increased anxiety-related behaviors. 


Aberrant regulation of WNT/�-catenin signaling has a crucial role in the onset and progression of cancers, where the effects are not always predictable depending on tumor context. In melanoma, for example, models of the disease predict differing effects of the WNT/�-catenin pathway on metastatic progression. Understanding the processes that underpin the highly context-dependent nature of WNT/�-catenin signaling in tumors is essential to achieve maximal therapeutic benefit from WNT inhibitory compounds. In this study, we have found that expression of the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), alters the invasive potential of melanoma cells in response to WNT/�-catenin signaling, correlating with differing metabolic profiles. This alters the bioenergetic potential and mitochondrial activity of melanoma cells, triggered through regulation of pro-survival autophagy. Thus, WNT/�-catenin signaling is a regulator of catabolic processes in cancer cells, which varies depending on the metabolic requirements of tumors.

BDNF
A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p?=?0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

Dendritic spines are major sites of excitatory synaptic transmission and changes in their numbers and morphology have been associated with neurodevelopmental and neurodegenerative disorders. Brain-derived Neurotrophic Factor (BDNF) is a secreted growth factor that influences hippocampal, striatal and neocortical pyramidal neuron dendritic spine density. However, the mechanisms by which BDNF regulates dendritic spines and how BDNF interacts with other regulators of spines remain unclear. We propose that one mechanism by which BDNF promotes dendritic spine formation is through an interaction with Wnt signaling. Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.


Other Wnt inhibitors

Yet another anti-parasite drug, Niclosamide,  turns out to be a Wnt inhibitor. 


Not surprisingly, Niclosamide is now a candidate drug to treat several different types of cancer.  It is also thought to have great potential in suppressing the metastatic process of prostate cancer. Another extremely cheap drug, not available in the US.
Even the flavonoid quercetin can inhibit Wnt. 

Therapeutic Avenues

There certainly are many potential ways to fine tune dendritic spine morphology.
Some readers of this blog are already doing just that, perhaps not all realizing it. 
        BDNF  (want less - TrkB inhibitor)

        Estrogen 

        Reelin (want more � statin via RAS activation)

        BCL2 (want more � statin)

        PAK1 (want less � PAK inhibitor, BIO30)

        GSK3 beta (want more � GSK3 activator)

        PTEN (want more � statin)

All the above seem to work via

        Wnt signaling (want less � Mebendazole/Niclosamide etc)

If you inhibit GSK3 beta you activate Wnt. You need get things the right way around. 
Statins promote RAS signaling which appears to increase Reelin expression. 


Conclusion

Fine tuning dendritic spine morphology seems like a good target for those with MR/ID and also those with any kind of neurological disorder.
There appear to be many ways to achieve this.
It seems a plausible idea and in many ways seems more credible than the idea of a diuretic (bumetanide) raising some people�s IQ.
The big issue is which substances have sufficient potency, once they have crossed the blood brain barrier, to do anything at all.  This is an issue with all therapies targeting the brain, including bumetanide.
At least substances that can affect hair growth and color are making it through to the bloodstream, which is a start.
Does this mean that tuning your dendritic spines will inevitably make your hair turn grey or begin to thin?  I don�t think so. I think this will happen in people who have low to normal Wnt signaling to start with.
Do some people with naturally premature graying, or thinning, hair have low levels of Wnt signaling? Quite possibly. Are they more likely to have traits of bipolar/creativity? Look for actors with gray or thinning hair.
Do people with autism tend to have full heads of thicker hair, as well as bigger heads?
Do the minority of people with autism and small heads have thinning hair?
Some readers of this blog are already using statins to treat autism. As has been pointed out in earlier posts, other than lowing cholesterol, statins have potent anti-inflammatory effects and they also affect expression of RAS, PTEN and BCL2, all of which are implicated in autism and all affect dendritic spines. It seems plausible that these readers are already modifying dendritic spine morphology.




Electro Convulsive Therapy (ECT) and Cannabidiol (CBD) in Autism


Today�s post is another one to fill in some of the gaps in this blog.
Psychiatrists have long been using electric shocks, of one kind or the other, to treat their patients. There is even a special school in the US (the Judge Rotenberg Center) where they used electric shocks as aversive therapy, until very recently.  


Cannabis, in the form of Cannabidiol (CBD), is currently the subject of an autism trial in Israel, home to some very innovative people.


Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT), formerly known as electroshock therapy, and often referred to as shock treatment,is a psychiatrictreatment in which seizuresare electrically induced in patients to provide relief from mental disorders. The ECT procedure was first conducted in 1938 is often used as a last line of intervention for major depressive disorder, mania, and catatonia.
As of 2001, it was estimated that about one million people received ECT annually.
Several hundred people with autism have been treated with ECT in the US. 

Transcranial Magnetic Stimulation (TMS)
Do not confuse ECT with Transcranial Magnetic Stimulation (TMS).
Transcranial magnetic stimulation (TMS) is a magnetic method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. This is rather similar to the way the base station of a rechargeable electric toothbrush works.
A big fan of TMS is Manuel Casanova, a neurologist and Autism blogger. 

A while back I watched a BBC documentary following an autistic girl adopted from a Serbian orphanage by a US family. All was going well until she later developed a serious problem with aggression and self-injury that was being treated by monthly visits to the hospital for electroconvulsive therapy.  The shocks did indeed seem to do the trick and suppress her aggressive tendencies. She is an example of what I call double tap autism, where an autistic person later suffers a profound setback for some reason. 

Video:- 

My Child, ECT (electric shock) and Me (click the picture below)



Long article from Spectrum News:- 


What I found interesting was that you could see that when you took away the SIB, the girl was pretty high functioning. She could read, write and do math.

This made me recall a previous idea of mine that you might grade people�s autism in terms of both their good days and their bad days.  So on a scale of 100, this girl might have been 30/100.  On a bad day she was a major danger to herself and those around her and so she scored 100, but on a good day she was able to be part of the family and be educated.  She clearly had autism but not such a severe kind, so she might score a 30.
The point missed by the BBC was that in this example, electric shock therapy was not an autism therapy, it was an SIB therapy and it appears to have been a pretty effective one.
Many people with autism do not have flare-ups, they do not have SIB; they are pretty constant in their behavior, so they might be a constant 30/30.  

Cannabis 

Much is written on the internet about the use of cannabis for all kinds of conditions, the ones relevant to this blog are autism and epilepsy.  There is a study currently underway in Israel where they are using CBD oil, the non psychoactive part of cannabis, as an autism therapy.
As you might expect they had no difficulty recruiting people to participate in the study, which is still ongoing. 




Dr. Aran is the Director of the Neuro-pediatric unit in Shaare Zedek Medical Center and his latest research involves treating the symptoms of autism using medical marijuana. �So far,� Aran tells NoCamels, �our impression is that it�s working.�

The clinical study began in January 2017 in Jerusalem at the Shaare Zedek Medical Center. There are 120 participants, including children and young adults, diagnosed with various degrees of ASD ranging from mild to severe. Dr. Aran hopes to have final results by December 2017.

According to Dr. Aran, �there are theories� for why medical cannabis can alleviate symptoms of autism, �but we don�t know exactly how. There are theories and models but we don�t know. It can�t be explained.�

This is worrisome given that cannabis is being given to children with little knowledge of why or how it may help. Of course, �We are worried with children because of the long-term impact. But it is considered mostly safe and we have already tested it with epilepsy.� Other studies, like the one published in Seizure: European Journal of Epilepsy 2016, conducted in Israel, successfully demonstrated that cannabis reduced the number of seizures of children with epilepsy. Nonetheless, Aran admits that �There are always worries that something will happen that we don�t know about.�

It is key to note that the participants are receiving cannabidiol (CBD), a non-psychoactive compound, as opposed to the more commonly known tetrahyrdrocannabinol (THC), which creates the �high� feeling. Therefore, the benefits they seem gain from the treatment �help the children cooperate more,� reduce behavioral problems, and �improve their functioning.�

While the study offers much hope for the children and families affected by ASD, Aran warns that �It won�t cure the symptoms, that�s for sure. It will never cure autism. But it certainly can help the quality of life of the families.� 

The lead researcher recently made some revealing comments, he suggested that the results so far are very positive and that it seems that the quality of life has been improved but it does not cure the symptoms. That made be draw the connection to the adopted child in the US; the therapy does indeed seem to be helpful because it is treating the �100� in the 30/100. So it may not improve cognition or reduce stereotypy, but it makes life better, just like the girl receiving the electric shocks.  Hopefully when they publish the results Dr Aran will be much more precise as to the effect of his therapy, since perhaps I am inferring too much from his comments. 

Why does any of this matter?

Well if you want to solve a problem, you have to define it and the more precisely you can define it, the more likely you are to find a solution.
If you have a girl who is a stable 30/30 with no SIB and no epilepsy, it might well be shown that neither electric shocks nor CBD oil will help here.
If you have a girl who is 30/100 with SIB and epilepsy it might well be the case that both electric shocks and CBD oil might help here; but it appears that neither will improve her core autism (which is the 30).


Mode of Action

Neither the doctors using electric shocks nor CBD oil claim to fully understand the mode of action. There are of course various plausible theories.
In the case of CBD it is an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It has also been shown to act as a 5-HT1A receptor partial agonist, and this action may be involved in the antidepressant, anxiolytic, and neuroprotective effects of cannabidiol. It is an allosteric modulator of the �- and d-opioid receptors as well.  Cannabidiol's pharmacological effects have additionally been attributed to PPAR? agonism and intracellular calcium release.

  

Do the therapies �work�?

What we have seen in this blog to date is that there are very many things that do seem to help specific people.  It is sometimes hard to figure out for sure the mode of action; but if high doses of biotin, or vitamin B6, or anything else consistently improve someone�s condition over years of use you have to take note.
The electric shocks did indeed seem to successfully control SIB for 3-4 weeks.  Maybe someone clever might figure out the biological cause triggering her SIB and so provide an alternative  drug therapy, but for now it seems she will go once a month for more shocks.
There are people who think long term use of CBD oil will have negative effects and I guess monthly electric shocks may also have some unforeseen consequences.
The Israeli researchers seem pretty keen on pursuing CBD oil and so they may well end up with a large enough clinical trial to make people take notice.
I do not see hundreds of parents signing up to a clinical trial of electric shock therapy, so it looks likely to be a niche therapy used by one or two clinicians.
CBD oil is the sort of therapy that will appeal to many parents and it is being trialed on so many different people we will soon know if there are harmful long term effects.
  

My Take

It looks to me that electroconvulsive therapy is rather crude and while it does evidently help some people, it might not be without serious risk. If the person has uncontrollable SIB, it looks a risk worth taking.
Short term use of CBD oil looks a safer bet, but if the effect required is just calming/sedating there may be other ways to achieve this.  Many parents are already using CBD oil as a home autism therapy.
There are hundreds of clinical trials completed, or in progress, using CBD to treat everything from ulcerative colitis to anxiety. It is being trialed in schizophrenia and even Dravet Syndrome and other kinds of epilepsy.  There is even a trial of a CBD chewing gum to treat Irritable Bowel Syndrome. CBD actually now has designated orphan drug status with the FDA for Dravet Syndrome.
I have no plans to use either therapy; I seem to have addressed the variable nature of my case of autism.  I am more interested in treating the core autism symptoms, the �30� in the 30/100; it is clear that much more remains possible.  

Tackling the �30�

An interesting recent finding came from a study on Oxytocin at Stanford. This time researchers had the good sense to actually measure the level of the oxytocin hormone in the blood of the trial participants before and after they started having oxytocin squirted up their noses. 

Not surprisingly it was people with low natural levels of oxytocin who were the favorable responders and interestingly those in the placebo group who also responded actually increased their natural level of oxytocin production.
As we know there are other ways to increase you level of oxytocin, one of which is via certain L. reuteri probiotic bacteria.
Oxytocin would fit in the tackling the �30� category, for those with naturally lower levels of this hormone.
The Stanford researcher is again Dr Hardan, from that interesting phase 2 trial of the antioxidant NAC.  He is now planning a larger oxytocin trial. Has he forgotten about making a phase 3 trial of NAC?   

Self Injurious Behavior (SIB)

You do wonder why some clinician does not compile a list of all the known causes and therapies for self-injurious behavior (SIB) in autism.  There is even a study planned at Emory University to test the efficacy of NAC to treat SIB, but with only 14 participants, I do not really see the point.
We do know that a small number of people with SIB respond well to NAC. If just 10% are responders, you would need a really large trial prove anything at all. With 14 participants you should have just one, but as luck might have it, it could be none.
With a more scientific/engineering approach you might identify five sometimes effective SIB therapies, and then go systematically through testing each therapy on each person with SIB. Then you would have some useful data.    
As I mentioned in a recent comment, the late Bernie Rimland from ARI, was a big believer in high dose vitamin B6 to treat SIB.  For some people it is a nicotine patch, for my son in summer it is an L-type calcium channel blocker.
The reality is that numerous complex dysfunctions can lead to SIB, but so do some simple things like untreated pain and inflammation, which could be from IBS/IBD or even tooth eruption/shedding or just tooth decay.






Neurodiversity or the Truth?


This blog is about the science behind autism and does try to avoid political agendas, which may make it seem somewhat cold and unemotional. Thanks to the internet, there are plenty of places to go and read about other views on autism.
I was reading one of the few scientific blogs about autism recently and I was surprised how much time was spent attacking neurodiversity and in the end it detracts from the science part of the blog.
Political agendas, like �America first�, or �Brexit means Brexit� and indeed �Neurodiversity� usually start with some truth and then everything gets lost in gross over-simplification. The more we move away from getting our information from serious considered sources and move to catchy snippets of information, the more people there are that think they have the knowledge to form a considered opinion, but the less valid those opinions may be.
Neurodiversity sounds like a nice idea; people are all a little bit different. Anyone who went to a non-selective school will already know just how different people can be. By studying the gene expression of people with autism, schizophrenia and bipolar we know just how varied people are and that almost everyone has an element of one observational behavioral diagnosis or another.
Neurodiversity only gets a bad name when one group at the extreme, that is defined by the lack of empathy and understanding for others, starts to hijack the debate; just like some intelligent person with Asperger�s may want to talk endlessly about his pet subject.
Fortunately, science and scientists clearly pay little attention to neurodiversity and so in countries like China, Canada and the US autism is very much seen as a medical disorder in need of potential treatments;  that is why thousands of research papers have been published. However many people there are out there adamant that autism is just a difference, and does not need treating, has no effect whatsoever. Science is elitist rather than democratic, you have to prequalify to get a say.
Not all doctors are scientists and so clearly they do absorb some of the background autism chatter. You will find doctors who are adamant that autism will remain untreatable.
Politicians, who often associate more with agendas rather than values/truths, are of course a different matter and they do count because they determine where your tax money gets spent. So the uninformed public debate can often lead to poor decision making and allocation of resources.
The truth sometimes can be boring and sometimes even dangerous, and is unlikely to win you an election or a referendum, but in the long run the truth is usually the best strategy. So ideally you want a politician with genuine values, compensated for by a good PR team to generate those memorable sound  bites.
Many people writing about autism, even award winning authors, not surprisingly seem to have mild autism themselves and so while they may have strong opinions, they may lack the ability to take in new information that might cause them to modify their opinions. So while you might want to check your math homework with one of these people, best not to try and debate anything with them.
In spite of the wave of autism awareness, most vaguely neurotypical people have little interest in the subject and so rarely express an opinion. That seems pretty much the way it should be.
Everyone is entitled to their opinion. Some people with mild autism are happy the way they are, but many people with disabling autism need help. Some people with mild autism also chose to seek help. Some people do not seek help until it is too late.
If this blog has an agenda, it is to promote the better use of the scientific research that has already been published and to take more control over your own health, just how much more and who should decide the limits are debatable points.









Ketones and Autism Part 4 � Inflammation, Activated Microglia, CtBP, the NLRP3 Inflammasome and IL-1�

This series of posts on ketones and the ketogenic diet (KD) is nearly finished and I am glad that I made favourable comments about the KD ea...