Genetic Epilepsy Team Australia’s 2024 Genetic Epilepsy Conference

Thank you all. I’m amazed that I can sit here and hear these families spout off a dozen different genes. When I finished my training in 1990 at Boston Children’s and the Beth Israel Hospital, where David spent some time in the sleep program, the most famous in the world. We spoke to parents about the most specific diagnosis they would give would be Lennox Gastaut syndrome. You’ve heard of that? In fact, William Lennox started the first seizure unit in the world, at Boston Children’s Hospital in the 1920s. And I have the Lennox chair, so I’ve got to know his family, and we could talk about him for an hour, but it’s amazing to me that all we ever had back then was Lennox Gastaut, and focal seizures versus generalized seizures. And now, you’re sitting here telling us these genes. As Sarah said, we’re living in a turbulent time. And part of that has been the mapping of the human genome, which has allowed us to find these genes and discover the causes of these diagnoses. And hopefully that’ll lead to treatments, specific, targeted, personalized treatments in the form of gene therapy, gene editing, mRNA therapy, antisense oligonucleotides. And it turns out, if you can spend the whole day here, you’re going to hear about a lot of these things. And I think they’re going to be very relevant to you. I’m the introductory speaker, and I’m not going to be talking about genes and epilepsy, although someone had GAMP deficiency here, right? My research is in metabolic disorders, and that incluDEEs the creatine deficiency. So I’m very interested in talking to that family. But I’m going to be talking about how the brain handles creativity. And Sarah talked about this a little bit, you’re cracking the code. That story about Helen Keller, it was amazing, and Annie Sullivan, and Helen Keller’s mother. I never heard of, but you’re talking about symbols and it turns out the brain is differentiated for most people, the left hemisphere is the language one where words are processed and the right hemisphere is thought to be the symbol one. So it starts getting you thinking, right? Different parts of the brain are handling different things. It’s called the neuro visual process. I’ll talk about three different processes. Now, that’s for right handed person. I happen to be left handed, so there’s a 50 percent chance things are switched in my brain. Who else here is left handed? So things could be a little switched in your brain to 50 percent chance. But in general we talk about the left hemisphere is being language dominant and the right is being symbol dominant. But it’s not that simple. Let’s talk about, for a moment, the neurology of creativity and then I’m going to segue into autism and the brain and music.

The science of creativity has become a very popular topic. The kinds of questions that are addressed are these. What is the neurological substrate of creativity? Why does the brain seek it? How do we acquire it? What factors disrupt it? Can creativity be learned? I think you have proven through your children with disabilities that it can be learned. Because, and you’re having to be creative to do it.

Now, studies have shown that if you put someone in an fMRI scan, a functional MRI, the parts of the brain that are active when listening to music are not one area. There’s not one music area. They’ve studied people listening to music and compared the brain activity to listening to silence. And they found that both sides of the brain were very involved. The temporal lobe down at the temple, the orbitofrontal lobe at the front, the insula, which is the deep insulated cortex, the more back areas called the posterior fusiform, and occipital way in the back. Here’s the temporal lobe on the side, here’s the frontal lobe, here’s the parietal lobe, back here would be an example of the occipital lobe. So if you wanted to summarize the vast literature of the human brain mapping when it comes to music, it would this slide here. Music activates widespread bilateral, meaning both sides of the brain, as well as the cerebellum way in the back, the kind of balance center, and listening and even just imagining music. You don’t even have to hear it. You could just think about it. This shows you the power of the imagination. Even that activates similar areas and those are different areas. And when you’re imagining, say prose or literature or poetry or visual art, like a great piece of art, that’s more of the back, the occipital lobes, the visual areas. Musical perception does begin at what’s called primary auditory cortex. That’s the top gyrus or the superior gyrus of the temporal lobe. But it turns out there are different neuronal clusters or different cells that handle different aspects of music, like pitch, like a higher frequency versus a lower frequency. They activate different neurons, not just different, like different, same neuron differently, but different neurons and different timbres or quality of sound or duration or volume.

It’s funny. You’d think that a louder sound would activate more neurons. Then a softer sound. It turns out it’s different neurons that are activated for louder sounds versus softer sounds. Now, there’s a lot more to music, of course, than the sound, right? There’s like patterns. If I play a pattern for you and you hear me play us a common Bach fugue, or a Beethoven piece, you’re going to anticipate what I’m going to play next because the pattern recurs and recurs. You’re activating your orbitofrontal cortex. It’s up in the frontal lobes. So that’s not the temporal lobe where music’s living where auditory perception’s living. It’s the frontal lobes where your higher executive functions are living.

The same functions that allow you to plan something complex, initiate it, maintain it, Stay at it. Persevere at it. Self check. Make sure you’re doing the right thing. That’s your frontal lobe. So exercise your frontal lobes right now by listening to the patterns and anticipating the next pattern.

Now, didn’t you know what was coming next? Cause you’ve heard it so many times. That’s coming from those higher executive functions in your brain. But there’s also emotional reactions to music, right? Like certain songs might remind you of something and bring a tear to your eye. That’s a different area of the brain. That’s mainly the amygdala, the anxiety area. Which is deep in the brain and right next to the hippocampus, the memory area. Why do you remember things better that you have an emotional attachment to? Because your amygdala is tucked in right next to your hippocampus. So there’s a logic to all this. It also turns out that, there are areas that are involved in expectation to music that actually deactivate with music. They get quieter. It’s almost like our brain is always running or in some kind of idling mode. And then actually it’s active, always going. But then when you hear music they get quieter. It allows your brain to soak it in. So a lot of music has to do with the brain. Not being active but relaxing, and that seems to be happening when one improvises, by the way.

Now, there’s another set of studies besides functional MRI. For example, DTI, Diffusion Tractography Imaging, is looking at the volume of parts of the brain. So here, for example, there’s this blue area you can see here and here. It’s connecting basically the frontal lobe to the temporal lobe.

Here it’s connecting the front to the back, it connects the expressive to receptive language areas. Singers have the thickest of those structures, because they’re, because they’re constantly working on pitch, and hearing it, and producing it. So that also goes to show you there’s plasticity in the brain. And the more you use it, the more it develops. And that’s going to become really important to us in this discussion. So the volume of the arcuate fasciculus correlates with musical experience. For example,this graph here is showing non musicians, that’s in the dark, versus instrumentalists in the hatch brown, versus singers or plain.

So we have the left dorsal and the left ventral arcuate fasciculi compared to the right. And notice how thick, in cubic millimeters, the left dorsal and ventral arcuate fasciculi are in singers compared to other musicians or compared to non musicians. There’s something really significant about how the brain reacts to its input.

But there’s also other aspects of metaplasticity that are really important. For example, this study here was done in a music institute in Hanover, Germany, and they found that there’s a part of the brain that correlates with age of onset of playing piano. They took Classical piano, professional pianists, concert pianists. And they studied them and they found that those who started piano lessons before the age of nine had two important things. One is they were relatively protected against musicians dystonia. The whole area of performance arts medicine is about kids that we train to use their fingers in a way the human hand wasn’t meant for. And they can develop dystonia so stiff that you can no longer play once you’re an adult. Some of the most famous musicians in history, Leon Fleischer, the great pianist. Robert Schumann, the poster child of the romance area in music. They had terrible musicians dystonia. They found that if people started piano lessons at a younger age than nine or by nine, they were relatively protected as if their brain learned how to overcome that. And they also found that one area of the brain, the putamen, was actually a little smaller in that area as if it was more efficient and trained better.

But here’s another really important thing. remains throughout life. One of my favorite studies is this one. At the bottom, this was published in the Annals of the New York Academy of Sciences just in 2022. They took a group of musically naive older adults from the ages of 64 to 76, and they gave half of them six months of piano lessons. And the control group was the other half. They put in music, culture, listening course, where they sat around and listened to music and talked about it and appreciated it, but didn’t actually learn to play it. And after six months, they found that the adults who took piano lessons had increased thickness of the temporal lobe cortex where music and sounds are starting. So even in the ages of 64 to 76, you can improve your brain by practicing. It’s never too late, by the way, to start piano lessons. On the other hand, what happens if things go bad? Remember one of the questions I asked at the beginning was what can disrupt creativity? So this is a patient of mine who has musicogenic epilepsy. That means when he hears music, he has a seizure. It tips off a seizure. Anybody know what part of the brain is going to be the seizure focus? It’s almost always the right temporal lobe. Same thing if a person has a stroke, the adult neurologist knows this, and they develop amusia, or loss of appreciation of music the stroke’s almost always in the right temporal lobe. So here, we have him in the EEG lab, and you can see he’s hooked up to the EEG. And here’s his EEG. Now right now the EEG looks fine. You’re probably maybe not used to looking at EEGs. But all over the world, the odd numbers are left hemisphere, the even numbers are right hemisphere. His brain waves are going along fine. But then, we say, give me a piece of music that gives you a seizure. And he says, there’s this one band called, Aha,

It’s called take on me. Have you heard of this song? It’s it’s a popular junk song. It’s not like Beethoven or Brahms or some, but it’s pretty good. Anyway, he says, if this song always gives me a seizure and it’s actually the rhythm in the beginning, it has this like pulsating rhythm, so we start playing the song and wouldn’t you know it 20 seconds into the song, look at his right temporal lobe, do you see the rhythmic pattern there? That’s a seizure. A seizure is an electrical storm of the brain. The rest of the brain looks okay. The left hemisphere is not involved at this point. But here in the right frontal lobe and all over the right temporal lobe, here and down here, he is having a rhythmic buildup boom, spike and wave, goes into a massive grand mal seizure when he doesn’t take his medication. But even when he takes his medication, when he hears this pulsating rhythm, he goes into a seizure. That’s pretty fascinating that music produces that right temporal lobe seizure.

Let’s talk about the science of improvisation. So you might think of music as over learned versus improvised. Like over learned is stuff you repeat over and over again because you’re taking piano lessons and you have to memorize it for your recital. Improvising is more about what? It’s about immediacy, being involved, unpredictability. And you may have noticed at the beginning, I quoted these questions by a Dr. Charles Limb. He is a very good, excellent pianist as well as an otolaryngologist. And he created this keyboard that’s MRI compatible at the top. You could put someone in the MRI and have them play the keyboard. So he had them play the keyboard, and he had them play to this piece of music here. By the way, this is going to be published in a book coming in of my own, called The Neurobiology of Creativity, under contract with Cambridge University Press. So he had the piano players play that little ditty at the top, straight. And then he had them improvise to the same little riff. And he studied what parts of the brain were active when they were playing it straight versus what parts were improvised. Let me play it straight

and then I’m going to improvise to it. This is what the piano players did. And then we’re going to see how the fMRI changed between the two things. So I’ll play it straight.

That’s what he had them do, thank you. And what he found is when they were playing The straight music, the more lateral aspect on the side of the frontal lobes was more active. And when they were playing the improvised music, this is a subtraction scan, the more medial or right in the middle sides were more active. So even though it’s all part of the frontal lobe, higher executive function area of the brain, different areas are active depending on whether you’re improvising or not. This is mind boggling work. In summary, over learned performance seemed to activate the lateral prefrontal cortex, improvised performance seemed to activate the medial prefrontal cortex.

In summary, improvisation seems to activate a different network. Now that we have all these fancy imaging studies, we think about diseases like epilepsy as network diseases, not just a single seizure focus, not just an active focus and a surrounding number of inhibition, but different areas network to each other, causing all kinds of havoc over time, getting worse and worse.

That’s really the underlying basis of the epileptic encephalopathy. Or you might say the developmental and epileptic encephalopathy, because it’s not just the seizures, it’s the underlying developmental problem, like the genetic disorder you’re all dealing with. Improvisation seems to activate the default mode network, the one that we’re relaxing, we’re hanging out, we’re chilling, versus effortful playing seems to activate the central executive network, very important for learning and academics. And there are other networks involved. For example, there’s a salience network that lets you know what in the environment is salient. Or you have to focus on, or you gotta get rid of the noise, right? What happens if all you hear is noise and you can’t filter the signal from the noise? You need your salience network to do that. We’re gonna get into that shortly with autism, right? So that’s what’s happening.

Now, here’s a slide. One of my favorites of me playing at some meeting in California for KCNQ2. And the kids absolutely love the music. And as Sarah was talking to me about speaking to you this morning, and I was saying I could talk about epilepsy or metabolic epilepsy. Those are my areas. I could talk about all sorts of things, but I like to talk about creativity in the brain because it’s really interesting and she said these kids with autism, they just love music and music resonates with them.

I said, yeah, I have this slide where I’m playing music and the KCNQ2 kids, they just wake up. It’s like going into a nursing home, and you have people who have Alzheimer’s dementia, and all of a sudden you play music and they just start moving, they get happy, they get stimulated in a way you haven’t seen in years.

So it’s very powerful. So what’s the basis of this? That inspired me to prepare this talk for you today. It’s actually the first time I’ve given this talk, so I’m excited about it. So what did I do? I am a musician, I am a neuroscientist, but frankly I didn’t really know what I was going to come up with before today. So I went to the literature. So here I put in a PubMed search for two words, music and autism. Now you see on the left is the graph. Here’s a close up of the graph. In the last 70 years, from 1953 to 2004, look at the explosion of literature and scientific studies published on the combination of music and autism in the last couple of years. Really the last five to ten years there’s been an explosion of interest in the neuroscience of the combination between music and autism. But notice this. Who first described autism? Does anybody know the history of autism? It’s a fascinating history. Autism was first described by a child psychiatrist at Johns Hopkins Hospital in Baltimore, Maryland, my hometown. Dr. Leo Kanner, a very famous child psychiatrist, who in 1943 wrote the first paper called Autistic Disturbances of Affective Contact in the journal Nervous Childhood, Volume 2. 1943. Okay. That’s when autism was first described The word autism refers to auto self being engrossed with the self and not others. And in the very first case study ever published, look at the description by Dr. Kanner himself at the age of one year, he could hum and sing many tunes accurately. Before he was two years old, he had an unusual memory for faces and names. He knew the names of a great number of houses in his hometown. He was encouraged by the family in learning and reciting short poems and even learned the 23rd Psalm and 25 questions and answers of the Presbyterian Catechism. The parents observed that he was not learning to ask questions or to answer questions unless they pertain to rhymes or things of this nature. And often then, he would ask no question, except In single words, his enunciation was clear. He became interested in pictures, et cetera, et cetera. You get the idea that from the first patient ever described with autism, there was something about their proclivity toward rhyme and music.

Now look at the DSM 5 diagnostic criteria for autism. That’s the Diagnostic and Statistical Manual of the American Psychiatric Association. That’s how every physician in the United States, at least, and probably all over the world diagnoses autism spectrum disorder. Now, the DSM has gone from 1 to 5 and revisions, but here’s the latest and the diagnosis of autism is done by the presence of persistent deficits in two categories here. A, social communication and B, restricted, repetitive behavioral patterns. And notice the fourth one in B. Hyper, meaning increased, or hypo, decreased reactivity to sensory input, including responses to specific sounds. So the connection between music and autism is even manifest in the diagnostic criteria used to make the diagnosis. Research has shown that people with autism seem to have a higher tendency to perfect pitch. Which is the ability to instantly and effortlessly identify the pitch of a tone without a reference tone. For example, if I said to you just sitting here, what note is this?

Now, if you’re a musician, you may have relative pitch. Do you know what that is? Or, perfect fifth perfect fourth, or minor third. You know how Beethoven used the major third and the minor third 750 times in the first movement of the fifth symphony? Major third, minor third, the whole fifth symphony. Alright, so we were playing. An E, pretty close to an A. There’s this one school of thought that says, people with autism have higher perfect pitch. This hasn’t been completely consistently proven, but it’s an interesting observation. There are basically two models to explain unusual auditory performance in autism spectrum disorder. One’s called the weak central coherence theory. The other is called the enhanced perceptual functioning theory, but there’s sort of two sides of the same coin. The first theory is that the person with autism, remember I talked about the salience network where you have to figure out the signal from the noise. The person with autism may over focus on details. I’m sure you’ve seen this in your kids. This is true of any preschooler, but the person with autism does it their whole life. Over focused on details at the expense of the global, context dependent, big picture. In other words, they miss the forest for the trees. But that may have to do with better perceptual performance to certain stimuli like hearing, or touch, or other things too. It also can cause hypersensitivity to sounds, like they hate the sound of a vacuum cleaner or something, because they can’t really filter it out.

The second theory is, enhanced perceptual functioning theory, which is the same thing, I think, increased perceptions without the global processing of stimuli affecting their pragmatic language, like prosody is the emotional content of language. It’s not what you say, but how you say it. That’s prosody. And the thinking is that they have such increased sensitivity to perception that they can’t really sort out things enough to understand the prosody of language.

What have the studies shown? In general, studies in autism, and I showed you how many studies there have been like hundreds and hundreds of studies. I can’t tell you about every one, but I’m going to summarize them in this talk. It seems that children with autism have enhanced memory for pitch. They remember pitch way better than language. It seems they prefer non speech to speech sounds. And it also seems like they have impaired pitch imitation in speech, but not non speech. In other words, they can imitate music better than they can imitate language. Here’s a paper that was published in the journal Autism in 2014. And they found that in children with Autism Spectrum Disorder, pitch discrimination was significantly better than typically developing children. Number two, even in the melodic part of the task, children with Autism Spectrum Disorder perform better indicating a tie between pitch discrimination and short term memory. Because they had to remember the pitches over time and three children with autism spectrum disorder had better ability at recognizing patterns and were more accurate at recognizing sharper flat notes than melodies. This is a picture of their data. And it’s basically showing that in the autistic group, they had a higher memory scores for melodies than in the typical developing group. Now here’s another study that was published in 2016. And they were testing children with autism for absolute or perfect pitch. What I just explained to you at the piano as opposed to relative pitch. And they found, this is amazing to me, 37 out of 38 individuals with autism, almost 100%, were able to match pitch on a piano. But only half of neurotypical participants had this ability. I don’t know if, this isn’t exactly perfect pitch, but they were able to match it, the way they hummed it back. So here’s a study that was done. looking at auditory pitch perception and autism. A systematic review was called a meta analysis of multiple studies. They looked at six major electronic databases and they found 22 studies that met their criteria. Basically, they identified over 460 patients or subjects research subjects with autism spectrum disorder and what they found was just a small to medium but a positive effect size of higher pitch perception in the children with autism compared to controls with a statistically significant p value. Now they suspected some publication bias. In other words, if the studies were negative, probably they weren’t published. But they also found that the ones with better pitch perception also had higher nonverbal IQ. IQ is divided into verbal, left hemisphere, nonverbal like visual perception, right hemisphere. And so their theory was maybe it’s not the music. Maybe it’s just the ones with a higher IQ, the nonverbal IQ were better. And their conclusion was disappointing, I think. Further research employing neurophysiological and brain imaging techniques with a longitudinal design is needed.

So let’s go to a better example. You’ve all heard of musical savants, right? There are certain people who are just unbelievably musically gifted. One syndrome of autism is associated with musical savant skills. It’s known as Williams Syndrome. Now these are the faces of Williams Syndrome. This is due to a gene deletion at chromosome 7, locus Q11. 23. And it’s been said for years and years, that children with Williams Syndrome are the most musical of all. Is this really true? Here’s a paper published by Daniel Levitin, who wrote a very popular book for the lay press, called This is Your Brain on Music. And he found studying musical behavior in a neurogenetic developmental disorder, evidence from Williams Syndrome, that those with Williams Syndrome, based on a questionnaire at least, are more musically involved when compared to others, and have heightened sensitivity to sounds. And via functional MRI, they found that imaging showed increased activity in the right amygdala, now that’s the emotional center, anxiety center really, of individuals with Williams Syndrome, and more sides activity to auditory stimulants overall. So there’s something to be said about the increased musicality that’s been observed for years, decades in Williams Syndrome. Now, let’s really study this. It turns out there’s an animal model for Williams Syndrome. Sometimes it’s called Williams Buren syndrome after another scientist, as far as I know, but we usually call it Williams syndrome. Anyway, there’s a mouse model. There’s the mouse in the middle, and it turns out the mouse model created by the gene deletion has auditory hyperacuity. So that’s not just the kids. Even the mouse is more sensitive to sounds. And so this is the way we can really make discoveries about how the brain handles music. They in fact found that there is haploinsufficiency, which means less representation of a gene, of a certain gene, that I never even heard of before. It’s down here as GTF2. All these crazy gene names that don’t really mean anything. But what they found is that haploinsufficiency leads to down regulation of a certain protein. They’re calling VIPR1. But anyway, they think that’s the basis, of the increased sensitivity to sound of the animal model. All I’m trying to share with you this morning is this is a way for us to unravel the science behind music and autism. Now here’s a very important paper because one, it’s published in Brain, which is a very prestigious journal. It’s like New England Journal of Medicine, Lancet, and Brain. These are the top journals in our fields. And this study found, I think the most important lesson from today, is that neural systems, meaning functional MRI, show that individuals with autism had more activation in the left inferior frontal gyrus. Now you might recognize that as Broca’s area, that’s the speech area, with musical stimulation when compared to neurotypical children. In contrast, those with autism have less activation in these areas with speech stimulation. What I’m trying to say here is, in the autistic brain, music and speech are switched. This music is activating the speech area in the autistic child’s brain, and the speech is not. And this is their actual data. It’s hard to explain in a busy slide. They looked at the controls, the normal, and they looked at the kids with autism. Speech was appropriately activating the speech areas in the typical kids, but not the autistic kids. Whereas the song didn’t activate the speech area in the typical kids, but it activated the speech area in the autistic kids. They have language and music mixed up. And this is showing the same thing. Speech, they looked at the control patient had more language. Autistic patient, they had that for song. And this is comparing speech versus song. When they gave speech to the control, the speech areas activated, and the autistic nothing really showed up. Whereas when they looked at song, the autistics showed the higher activation of the language areas. Fascinating work. Here’s a study that’s hot off the press. Notice the publication date, 2024. You can’t get any more recent than that. It’s somewhere up here. See, it says 2024 in the Journal of Autism and Developmental Disorders. They did what I would call a qualitative study where they basically interviewed adults who have autism about their quality of life. The title, look at the title of the paper. Quote, it is more important than food sometimes, meanings and functions of music in the lives of autistic adults through a hermeneutic phenomenological lens. Now hermeneutic really, it is a philosophical term. It’s usually used about how one interprets meanings from scripture. Like the Talmud, something like that. Phenomenological. Basically it’s a qualitative study, not a quantitative study. But look what they found in the table. Table 1. Of the themes and sub themes. Because that’s how qualitative research is done. They found that for well being, the auditory involvement was number three on the list. And they also found, in the bottom, negative experiences. If the music was something they didn’t like, or the sound, like that vacuum cleaner, that was very much a negative impact. That had very much of a negative impact on their quality of life. So this is the reporting of adults living with autism. Here’s a study showing that music improves social communication and auditory motor connectivity in children with autism. They randomized 51 children from the age of 6 to 12 years with autism spectrum disorder into music therapy. And they put half the kids into non music behavioral intervention. And they did this for 8 to 12 weeks, 2 or 3 months. And they found that the music therapy provided benefits in their communication skills. And the children with autism spectrum disorder demonstrated more connectivity between primary auditory cortex and subcortical and motor regions after the music intervention. The red group had music therapy. The blue group had no music therapy, just some other kind of behavioral therapy. And after the intervention, there was better connectivity between the right Heschel’s gyrus, which is temporal lobe, and subcortical areas of the brain. There were better brain correlations. They also found, and this is for both the right and the left side, after music therapy, better networking between language areas and other important areas of the brain having to do with movement and enunciating speech and all those things. Another thing they found, which I hadn’t expected, the kids with autism had over connectivity. In other words, parts of their brain are overly connected. The auditory and the visual areas. They need less connection. And they found that after music therapy, the connections decrease. The inappropriate excessive connections between the language areas and the occipital or visual areas decrease. So the music therapy is doing something very interesting to correct their wiring or their networking. So here’s a study of the effectiveness of music therapy in children with autism spectrum disorder. A systematic review and meta analysis. They looked at eight randomized controlled trials. That’s important. You have to have controls, you have to randomize people into different groups to be able to assess the validity of the data and consider it valid. And they found, overall, that music therapy was associated with increased social reactions. Okay, but it didn’t actually improve social adaptive behavior or language. And they concluded there was no consensus on the persistence of these effects because the studies were all relatively short term.

Here’s my last slide. There’s always a Cochrane review. Cochrane is a name of a big database out of McMaster University in Canada where they do a lot of systemic reviews. They have hundreds of statisticians and epidemiologists, and they just published in 2022 a systematic review about music therapy for autism. They looked at 26 studies with over 1100 subjects with autism spectrum disorder, and what did they find? Now they use typical statistician speak. Which means everything’s about how much certainty there is in the conclusion. And they found with moderate certainty, which is positive, although it’s not marked, that music therapy was associated with global autism improvement. How much did it help? Now, as clinicians, this one statistical parameter we’re looking for when we read a study, among others, is the number needed to treat. The number needed to treat is how many patients do I have to give a drug before one of them has the benefit? When they published the original paper about using cannabidiol in Dravet syndrome, SCN1A people don’t realize that the number needed to treat was six, which meant you had to treat six kid with Dravet for the one to have benefit from the cannabidiol in the outcome measures.

Everybody flocked to Colorado when the Charlotte’s Web story hit the news. I had patients moved from the East Coast to Colorado to get that medical marijuana when it was illegal everywhere but Colorado. But those people were crazy. They call it the Rocky Mountain High for a reason. Anyway, But the studies show the number needed to treat was six.

All right, they found in this Cochrane review for at least immediate post intervention after music therapy improvement, the number needed to treat was somewhere between six and 11 based on how good the study was or what the risk of dropouts were. If you take the average of that six to 11, it’s what say maybe eight, maybe nine. But what we’re saying is that you had to give music therapy based on all this amalgamation of studies to about 8 kids with autism for one to show the improvement. And there was a small increase in quality of life, but there was an increase. There was a reduced autism severity score from music therapy, but long term benefits are unclear. That’s where the science stands. My personal rendition of music is it helps the kids in some global way that we are still studying. And that’s where we are with the neurology of creativity and autism. I thank you for your attention.