Submitted my first Grad School abstract to
SfN Society for Neuroscience Conference.
How about that!!
Decoding the Excitatory-Inhibition Imbalance in Autism
Caveat: Always keep in mind there is no single theory that perfectly explains autism.
The Excitatory-Inhibition (E-I) Imbalance hypothesis posits that an imbalance between excitatory and inhibitory signaling in the brain contributes to the sensory, cognitive, and behavioral features of autism.
Factors that contribute to the E-I imbalance.
Elevated Glutamate and Hyperactive Glutamatergic Neurons
Glutamate is the primary excitatory neurotransmitter in the brain, and its excessive release or receptor overactivation can lead to heightened neuronal excitability. Research indicates that autistics have increased glutamate concentrations in certain brain regions, suggesting a hyper-excitable state that disrupts normal neural communication and network dynamics. This over-excitation can manifest in the form of heightened sensitivity to sensory stimuli and difficulties in cognitive processing.
GABAergic Signaling Deficit
GABA is the primary inhibitory neurotransmitter, crucial for counterbalancing excitation. In autism, there is often a reduction in GABAergic signaling, whether through decreased GABA levels, impaired GABA receptor function, or reduced GABAergic neuron activity. This means that the inhibitory 'brake' on neuronal activity is weakened, failing to counteract the excessive excitation from glutamate, thus exacerbating the E-I imbalance.
Imbalance in Pyramidal Neurons and Interneurons
Pyramidal neurons are the primary excitatory cells in the cortex, while interneurons provide the necessary inhibitory control. In autism, there are differences in the density, function, and connectivity of these neuron types eg: alterations in the number or function of specific types of inhibitory interneurons, such as parvalbumin-positive (PV+) interneurons. These changes disrupt the local circuitry, leading to an overall increase in excitation and reduced inhibition.
Critical Developmental Periods
E-I imbalance is particularly impactful during critical developmental periods when the brain is highly plastic and sensitive to changes. Early disruptions in E-I balance can have long-lasting effects on brain development and function. During these periods, the maturation of both excitatory and inhibitory circuits is crucial for establishing proper neural networks. If the E-I balance is skewed, it can impair synaptic plasticity, cortical maturation, and the formation of functional neural circuits, contributing to the developmental trajectory of autism.
Alterations in Synaptic Proteins
Changes in the expression or function of synaptic proteins play a critical role in E-I imbalance. Proteins such as neuroligins and neurexins, which are involved in synaptic adhesion and signaling, have been implicated in autism. Mutations or dysregulation of these proteins can lead to atypical synapse formation and function, contributing to an imbalance between excitatory and inhibitory synapses.
Ion Channel Dysfunction
Ion channels are essential for maintaining the proper function of neurons. Dysfunctions in ion channels, such as those involving sodium, potassium, and calcium, can alter neuronal excitability. In autism, mutations in genes encoding these ion channels (e.g., SCN2A, KCNQ2) have been identified, leading to altered action potential generation and propagation, thereby affecting the E-I balance.
Impaired Synaptic Plasticity
Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is crucial for learning and memory. Long-term potentiation (LTP) and long-term depression (LTD) are key mechanisms of synaptic plasticity that depend on a delicate E-I balance. In autism, impairments in LTP and LTD have been observed, suggesting that the capacity for synaptic change is disrupted, further contributing to cognitive and behavioral challenges.
Role of Astrocytes and Microglia
Astrocytes and microglia, types of glial cells, also play significant roles in maintaining E-I balance. Astrocytes regulate neurotransmitter levels, including glutamate and GABA, by uptake and recycling processes. Dysregulation of astrocyte function can lead to excess glutamate and insufficient GABA, exacerbating E-I imbalance. Microglia, the brain's immune cells, are involved in synaptic pruning during development. Abnormal microglial activity can lead to either excessive or insufficient synaptic pruning, disrupting the E-I balance and normal brain connectivity.
Genetic and Epigenetic Factors
Genetic mutations and epigenetic modifications can influence E-I balance. Numerous genes associated with autism are involved in synaptic function, neurotransmitter systems, and neuronal development. Additionally, epigenetic changes, such as DNA methylation and histone modification, can alter gene expression patterns related to E-I balance. These genetic and epigenetic factors contribute to the heterogeneity observed in autism, affecting the degree and nature of E-I imbalance across individuals.
Environmental Influences
Environmental factors, including prenatal exposure to toxins, infections, and stress, can impact E-I balance. These factors can alter the development of neural circuits and neurotransmitter systems, leading to long-term changes in excitatory and inhibitory signaling. Understanding the interaction between genetic predisposition and environmental influences is crucial for comprehending the full picture of E-I imbalance in autism.
The Excitatory-Inhibition (E-I) Imbalance hypothesis posits that an imbalance between excitatory and inhibitory signaling in the brain contributes to the sensory, cognitive, and behavioral features of autism.
Factors that contribute to the E-I imbalance.
Elevated Glutamate and Hyperactive Glutamatergic Neurons
Glutamate is the primary excitatory neurotransmitter in the brain, and its excessive release or receptor overactivation can lead to heightened neuronal excitability. Research indicates that autistics have increased glutamate concentrations in certain brain regions, suggesting a hyper-excitable state that disrupts normal neural communication and network dynamics. This over-excitation can manifest in the form of heightened sensitivity to sensory stimuli and difficulties in cognitive processing.
GABAergic Signaling Deficit
GABA is the primary inhibitory neurotransmitter, crucial for counterbalancing excitation. In autism, there is often a reduction in GABAergic signaling, whether through decreased GABA levels, impaired GABA receptor function, or reduced GABAergic neuron activity. This means that the inhibitory 'brake' on neuronal activity is weakened, failing to counteract the excessive excitation from glutamate, thus exacerbating the E-I imbalance.
Imbalance in Pyramidal Neurons and Interneurons
Pyramidal neurons are the primary excitatory cells in the cortex, while interneurons provide the necessary inhibitory control. In autism, there are differences in the density, function, and connectivity of these neuron types eg: alterations in the number or function of specific types of inhibitory interneurons, such as parvalbumin-positive (PV+) interneurons. These changes disrupt the local circuitry, leading to an overall increase in excitation and reduced inhibition.
Critical Developmental Periods
E-I imbalance is particularly impactful during critical developmental periods when the brain is highly plastic and sensitive to changes. Early disruptions in E-I balance can have long-lasting effects on brain development and function. During these periods, the maturation of both excitatory and inhibitory circuits is crucial for establishing proper neural networks. If the E-I balance is skewed, it can impair synaptic plasticity, cortical maturation, and the formation of functional neural circuits, contributing to the developmental trajectory of autism.
Alterations in Synaptic Proteins
Changes in the expression or function of synaptic proteins play a critical role in E-I imbalance. Proteins such as neuroligins and neurexins, which are involved in synaptic adhesion and signaling, have been implicated in autism. Mutations or dysregulation of these proteins can lead to atypical synapse formation and function, contributing to an imbalance between excitatory and inhibitory synapses.
Ion Channel Dysfunction
Ion channels are essential for maintaining the proper function of neurons. Dysfunctions in ion channels, such as those involving sodium, potassium, and calcium, can alter neuronal excitability. In autism, mutations in genes encoding these ion channels (e.g., SCN2A, KCNQ2) have been identified, leading to altered action potential generation and propagation, thereby affecting the E-I balance.
Impaired Synaptic Plasticity
Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is crucial for learning and memory. Long-term potentiation (LTP) and long-term depression (LTD) are key mechanisms of synaptic plasticity that depend on a delicate E-I balance. In autism, impairments in LTP and LTD have been observed, suggesting that the capacity for synaptic change is disrupted, further contributing to cognitive and behavioral challenges.
Role of Astrocytes and Microglia
Astrocytes and microglia, types of glial cells, also play significant roles in maintaining E-I balance. Astrocytes regulate neurotransmitter levels, including glutamate and GABA, by uptake and recycling processes. Dysregulation of astrocyte function can lead to excess glutamate and insufficient GABA, exacerbating E-I imbalance. Microglia, the brain's immune cells, are involved in synaptic pruning during development. Abnormal microglial activity can lead to either excessive or insufficient synaptic pruning, disrupting the E-I balance and normal brain connectivity.
Genetic and Epigenetic Factors
Genetic mutations and epigenetic modifications can influence E-I balance. Numerous genes associated with autism are involved in synaptic function, neurotransmitter systems, and neuronal development. Additionally, epigenetic changes, such as DNA methylation and histone modification, can alter gene expression patterns related to E-I balance. These genetic and epigenetic factors contribute to the heterogeneity observed in autism, affecting the degree and nature of E-I imbalance across individuals.
Environmental Influences
Environmental factors, including prenatal exposure to toxins, infections, and stress, can impact E-I balance. These factors can alter the development of neural circuits and neurotransmitter systems, leading to long-term changes in excitatory and inhibitory signaling. Understanding the interaction between genetic predisposition and environmental influences is crucial for comprehending the full picture of E-I imbalance in autism.
- 2 versions of this post:
- For the Scientific/Academic Audience
- PlainSpeak / Plain Language for the Lay Reader
Keynote at Duke ACE
Thank you for such a powerful presentation, Hari! As a mother of an autistic child, I found your insights deeply resonant. I'm grateful for the opportunity to learn from it.
Rewind: Interactions with Planet X
Rewinding to something I wrote many years ago in high school.
=====
Interactions with Planet X
(So you want to help, but have no clue)
My fellow Teens,
You all probably know some people with disabilities. After all, it's fairly commonplace now. Words like Autism, Downs Syndrome and Cerebral Palsy abound in the news. You probably even feel sorry for them. But honestly, even a truckload of pity is not much use.
You probably are also "initially freaked out" at meeting people with disabilities. (This is a direct quote from a high school volunteer I know.) Maybe you want to help, but have no idea how and what.
Consider:- Once upon a time, we were all babies. Our life track was defined - preschool, elementary school, middle school, high school, college, job etc.
A UCSD sophomore was speaking of his college experiences to our SSE class last week. Many of his friends from Cupertino schools are with him in college, so his social circle remained somewhat homogeneous. That had greatly aided his transition from the small school setting to life on an enormous college campus. I imagine it will be the same for most of you. Most of you probably have friends you've known all your life and who will be with you in college.
Some of those babies however, ended up on a path that wandered off into the wilderness of disability. Years of therapy helped some get back onto a more typical path, especially if the right therapy was done at the right time with the right set of people who knew what to do. But there is no set formula and not everyone made a full or even partial turnaround. But biologically, the bodies kept growing and voila, they became Teens with Disabilities!
I speak not just for myself, but for all the others I've observed over the years.
The therapy years are behind most teens, parents are exhausted and most therapists are giving up. Not an attractive picture!
Many are headed into Homes and "residential facilities" after high school. Some are already in Homes. I had 3 classmates in 5th grade who came from a Home. The only time they got to go out, was if the school did outings, as the Home did not do that. All that my classmate Johnny ate at every meal, was cheese pizza - how healthy is that? Others, I know - post 18 and Indian - live at home with their parents.
A few may make it to community college or even a university. A fortunate few may even end up doing a job they like and lead independent lives. But there are always additional hurdles at every step.
Expectations are not high at this point. Job training programs, at most, target low level jobs. How exciting will it be to toss burgers, especially if intellectually you are capable of so much more? Frustration rides high, and this translates into more behavioral issues. As it is, being a Teen is an emotional roller-coaster for most of you. Just add on a whole suitcase of emotional and physical struggles!
Your world will open out as you go into college and beyond, while those of individuals with disabilities, may well narrow down. More doors shut with age. Ironically after age 22, govt. assistance and programs reduce significantly - just when we need it most.
We're surrounded by adults a lot; but most are paid therapists who last just 1-2 years. There is a high turnover of people, which is very emotionally distressing. Working and assisting teens or adults is not considered a desirable profession, so one cannot expect any intelligent company either, going forward.
Quality of Life however, goes beyond just basic care. It becomes a 'Lonely Planet X.’
So what was the point of telling you these depressing scenarios?
It is said that friends influence your character? This is the area that individuals with disabilities really fall short on. It's going to be a bigger problem going forward, as more of this growing population of children with disabilities become adults.
It is less your money that is needed, and more your humanity.
And it is not just about playing board games once a month at a center. That gets real boring by the 3rd month. And irritating by the 6th month, because by then the same games start to feel like therapy. And teens (disabled or not) don't want to be subjected to preschool activities like circle-time! Oh the sheer indignity of having preschool circle-time in some of the Special Ed classrooms, years after our typical peers had stopped doing them. Are you surprised that many adults with disabilities still listen to Barney and Sesame Street?
It is about getting involved in their lives. Being involved does not mean being physically there all the time either. In today's Internet World, there are many avenues of communication - Facebook, email, text, a phone call etc...
Tell them about your own lives so that through you, they can learn and experience more. You will be surprised at the insights you get into your lives when viewed through their eyes. Most are surprisingly sensitive and intelligent despite their outward body mannerisms. A person may have cerebral palsy and be dependent on a wheelchair. They may not even be able to respond. But their minds will eagerly lap up information and conversation. Don't expect responses, especially if the person has limited communication skills - just be there. They will never cease to amaze you or surprise you.
Get to know a few individuals and continue to be in their lives. The key is to be a constant presence over many years. Don't be a therapist who moves onto another client in 1-2 years.
Check in during your school vacations, and during your college vacations. Visit if you can.
Include them in some of your physical activities. Are you or your friends in a musical performance, band, team or play? Invite them to these - you will find no better cheerleaders. Do you belong to a group of some sort – you could find ways to include them at least some of the time. What do you do with your typical friends - do you just "hang out and chill.”? You'd be amazed at how many teens with disabilities long to do this but don't have the opportunity.
Don't assume they don't know academics just because they haven't been formally taught it. Academic subjects are just a matter of perspective sometimes. In light of other challenges, it just seems a lot more straightforward. Tell them about what you do - why you find certain subjects difficult or which teacher is really lousy or good.
It’s pretty hard to abuse drugs, smoke or drink if you are disabled. So you will in fact, be keeping very good company.
Be an advocate for them and watch out for them in their lives. Friends of this disabled adult I know on Facebook, keep tabs on her online activity to watch for online predators and the like. Most individuals will outlast their parents, so friends are important in their lives. As you become an adult, there will be many such opportunities for advocacy. Dealing with bureaucracy is tough for most; imagine the disabled adult who has to face it 24x7.
Consider - Pity is condescending, while Empathy and Friendship is Humanity.
In the end, it's a win-win scenario for both. You will fulfill a real need and make a difference. Man is defined by his character, not by his wealth or his social status. You will be amazed at how these interactions will shape your life.
Bring the Forgotten People on Lonely Planet X, back to the Humane Planet Earth.
You may or may not choose to do something about this issue, or not be able to do so now. But perhaps you will later in your life. All this is Food for Thought.
Words matter: Reframing neurodivergence in science, medicine and society
How we write and think about neurodiversity can have a profound effect on people’s lives; watch the webinar hosted by Cell Press and The Lancet.
Weak Central Coherence Theory of Autism
Autism Lexicon: Weak Central Coherence (WCC) Theory
The WCC Theory is a cognitive theory of autism (cognitive theories try to explain how autistics think).
It suggests that autistics focus on noticing details but might struggle with seeing the bigger picture. This affects how they see and understand the world around them. This unique way of thinking brings both strengths and challenges, affecting everyday tasks, social interactions, and work or hobbies.
Read about WCC in more detail
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Vanderbilt Brain Institute Graduate Student Directory
Just noticed I'm in the Grad Student Directory of Vanderbilt Brain Institute.
https://medschool.vanderbilt.edu/brain-institute/about-us/team-directories/#h2-graduate-student-directory
https://medschool.vanderbilt.edu/brain-institute/about-us/team-directories/#h2-graduate-student-directory
The end of Autism Month
April is Autism Acceptance Month.
On April 30th there is a flood of emails and social media posts - all pointing to the fact that its the last day of autism acceptance month.
Does this mean that autism acceptance is not important for the remaining 11 months? 😔
An endless cycle of labels in autism
Targeted interventions for autism don't need creation of more new labels.
The issues that need help, were present there before the label creation and still exist years after the label.
In another 5-10 years, another new catchy trademarked label will appear
Last Class at Berkeley
This day 2 years ago.
OMG. My very last undergrad class at Berkeley.
Berkeley Haas Scholars at work.
Shoutout from FCAI on my NSF Award
The NSF GRFP is a tremendous achievement and a testament to Hari's hard work, dedication, and innovative research approach. As a neurodivergent individual, Hari brings a unique perspective to the field of Neuroscience, and his work, with its potential to make a significant impact on the lives of the community, is truly inspiring.
At the Frist Center for Autism and Innovation, we are committed to promoting neurodiversity and providing opportunities for individuals like Hari to flourish in science and engineering. We believe that neurodiversity is a strength, and we are proud to support Hari and other neurodivergent researchers in their quest to make a difference in the world.
On behalf of the Frist Center for Autism and Innovation, we would like to extend our heartfelt congratulations to Hari on this well-deserved honor. We are not just proud, but deeply appreciative of all that he has accomplished and look forward to seeing all the amazing things that he will achieve in the years to come. Hari is an inspiration to us all, and we are grateful to have him as a part of our community.
hashtag#Neurodiversity hashtag#Neurodivergence hashtag#ASD hashtag#Autism hashtag#Strength hashtag#SocialModel hashtag#NSF hashtag#GraduateStudent hashtag#Fellowship hashtag#NationalScienceFoundation hashtag#GraduateFellowship hashtag#Congratulations hashtag#Awards
A kinder ABA is a therapist driving you to the point of frustration, then offering to hold your hand
https://link.springer.com/article/10.1007/s40617-023-00833-w
Good grief is all I can say.
Adding the prefix of "Kind" to something does not automatically make anything automatically Kinder. As is peppering a paper with the word "Kind" to sublimely influence you that it must be kind.
And a sample size of 4 autistics in the study makes this a valid method, how?
And what did this "kind" translate to exactly. when a therapist drives you to the point of a tantrum in the first place, then offers to hold your hand, and saying "I can see you are frustrated."
Is this a new marketing strategy by the (massive-profits with no accountability) ABA industry to make even more profits of desperate families.
Please don't joke around with studies trying to whitewash stuff. This is not helping.
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