Welcome to From the Spectrum Podcast. This is a podcast about autism. It is my goal to
explain what is autism. I plan to use a mixture of scientific literature, personal experience,
and opinion. With opinion, I will explain why, I will show the way I do and give examples.
I will provide links to various references for each episode. For each episode, we will
discuss various aspects of autism. The From the Spectrum Podcast will mostly avoid causes
of autism and I will try to avoid the increase of diagnoses of late. This is like playing tug-of-war
with barbed wire and I don't think I want to travel down that path. For today's episode,
we will parse out the medial, prefrontal cortex and common connections and the roles in autism.
The medial part of the prefrontal cortex is just a subdivision. The prefrontal is just behind the
forehead extending up and back to about the top of the head. We have discussed the medial prefrontal
and today we will expand on those discussions, expand on the functions, the implications,
the metabolic demands, and talk more about some excitation and inhibition imbalance.
And mention some familiar genes and proteins and other so-called disorders that share these
biological implications. Remember, problems upstream in our biology can have different
presentations downstream. For example, problems in the medial prefrontal could cause autism,
schizophrenia, OCD, epilepsy, ADHD, etc. There are many variables and variations.
We will explore more of these later. For today's episode, we will primarily discuss
three areas. The medial prefrontal cortex, the interior cingulate cortex, or ACC, and the insula.
Just a heads up, we will discuss other regions. This will be a deep discussion into our biology.
The goal is seeing how this is entangled with autism. Also, we will cover a couple of scientific
papers related to these regions and functions of autism. First, the medial prefrontal cortex.
Prefrontal cortex. Some basics. The medial prefrontal cortex is 80 to 90% excitatory,
and 10 to 20% inhibitory. Already, you should see with the excitation and inhibition phenomenon
of autism how this is a region of interest. The medial prefrontal cortex has the highest
resting metabolic rate. Remember the bank account episode. Some genes or proteins involved include
the CNT, NAP2, shank 3, and neuro ligand. Remember which is post-synaptic. Neurorexin is pre-synaptic.
Neuro ligand is post-synaptic. And P10, phosphorus and tinsin. The first component covered in episode
3. Common genetic and proteins associated with autism. A brief recap. And sidebar. We have covered
all of those areas previously. But to expand on P10, P10's overall goal is regulating cell division.
No. Cells divide. Remember the discussion on rapamycin or mTOR, mammalian target of rapamycin.
P10 regulates cells from growing and dividing too quickly or in an uncontrollable rate.
So cell growth. If you thought about tumors or cancer, that was a correct association.
P10 regulates that. How this is related to autism. That role with tumors or cancer is unclear to me.
I have not pursued that data. Only P10's role of cells related to development, migration, and so
forth. A key function of P10. The increased and strengthening of a connection. The medial prefrontal
cortex to the basal lateral amygdala. Remember the amygdala from autism and anxiety. The basal
lateral is a hotspot for learned anxiety. Or fear. It is a subdivision of the amygdala.
Which, remember, is well known for anxiety, fear, some forms of motivation, and social cognition.
A side note. Oxytocin. We still plan on having an episode on oxytocin and vasopressin. Because of the roles in social inputs.
Oxytocin has long range projections to the amygdala. The medial prefrontal cortex.
And to the basal ganglia. Discussed in the first episode. Our go-no-go area is the basal ganglia.
Which involves the striatum. Where motivation and motor movements converge.
These long range projections were just published by Levery et al. in 2024.
Also remember the cortico striatal thalamic loop. Mentioned in episode 1. This is OCD.
And these subdivisions discussed today are deep dives into that loop.
Okay, some functions of the medial prefrontal cortex. Cells in the medial have robust responses to motor and sensory cues.
We have three basic types of cells. Trillions of cells. But, essentially, there are three types.
It's amazing. The three types are motor, sensory, and interneurons.
The medial prefrontal cortex has a role with mentalizing and processing social information.
About the self. And about others in the environment.
Briefly.
Conflict monitoring. Air detection. Executive control. Reward guided learning.
Decision making about risk and reward. Adaptive responses. So this is a good item to dissect.
Warned a connection from a midline thalamus. Remember the thalamus is a central area for sensory processing.
This connection to the medial prefrontal creates silency enhancing. Or stress is enhancing.
Whereby, when we face fears, when we face threats, face those unwanted or challenging stimuli.
This connection equals rewarding arousal. Rewarding stress.
You have probably heard of fight, flight, or freeze. Which describes the sympathetic side
of the central nervous system. This side with stress. This connection promotes more. Fight.
And not limited to physical fight is my interpretation. But more of a tenacity.
Grit. Determination role. The Navy seal attitude. Normal or adaptive responses. The pathway is
the medial prefrontal cortex to the ACC and insula. Discussed later. When we have fear, anxiety, panic,
and so forth. The medial prefrontal cortex is controlled by the ACC and insula.
Remember the need to lead with the prefrontal. It allows us to understand things.
So we can properly evaluate things. One of those overall higher order roles.
Of the prefrontal. And what makes humans the dominant species on earth.
Adaptive responses also include specialized autonomic or emotional control.
As we just discussed. Controlling actions. And includes pain perception.
And it works downstream with the lateral habinula. Remember that serotonergic area.
Involved in passive versus active coping. That's a few ways of basically explaining
the same thing. Adaptive responses. Now if you are listening to those functions.
You can connect autistic phenotypes to all of them. Also the medial prefrontal cortex works
alongside the hypothalamus to mediate homeostatic roles such as hunger, thirst, an autonomic and
endocrine functions. Finally the medial prefrontal cortex is involved in recent memory.
Disrupting the medial prefrontal cortex. Just after a learning bout. Implicates memory consolidation.
Or said differently. How or if you remember something.
A sub area of the medial. The ventral medial. This is important. Remember the excitation
and inhibition balance. And the metabolic demands. The ventral medial prefrontal cortex connects to
neuromodulatory systems. All of them. Remember episode 5. Part 2 of the excitation inhibition
balance. And the raffae for serotonin. The ventral tegmental area for dopamine. And remember valence
2. From the VTA. From autism and anxiety episode. The locus serilius for brain adrenaline.
Epinephrine and or nor epinephrine. And the medial or the ventral medial prefrontal cortex
connects to acetylcholine. Which modulates our focus. In 2022, Hugh and Bayer show the
medial prefrontal cortex relies on a delicate balance of those neuromodulatory inputs.
Okay. The anterior cingulate cortex. Or ACC. The cingulate wraps around. It is entangled
around white matter. It's very unique. When blocked or interfered with. Or shut off.
Catatonic behaviors follow. And the ACC is involved in dissociative data. Dissociation
is when one is completely separate from reality. Catatonic and dissociation are not included
in our autism discussion. But worthy of mentioning how powerful the cingulate is.
To some of these more severe potential behaviors. Some functions of the ACC. Motivation.
Decision making. Conflict and air calculating. Emotion regulation.
Pain perception. Cognitive control. You can see. It helps modulate or help.
How and where we send our attention. The medial prefrontal cortex and the ACC
receives direct inputs from those lower level sensory regions. Essentially those lower level
sensory regions ask the medial prefrontal cortex and the ACC. What should we do? And what do we need?
This is what's going on in the outside world. What and how should we handle it? The medial
prefrontal cortex and the ACC recruits different brain regions based on that information. This
is what we're going to do. The medial prefrontal cortex and the ACC lead the way. In addition,
the medial prefrontal cortex and the ACC have massive bi-directional connections to those
neuromodulator systems and all the the sensory processing systems so they can be updated and
understand what is working, what is not working and of course how to adapt. An interesting and
related study shows during passive listening during dissonance listening when we are passively
dislistening to things in the background. The medial prefrontal cortex and the ACC are lit up.
They are active during passive listening. In other words, when there's noise going on in the
background, the medial prefrontal cortex and the ACC are active and listening. These two regions
are always on call, always ready. And now you can see that metabolic demand here as well.
And you can see autistics typically prefer being within ourselves. And you can remember me saying,
the outside world is chaotic. The ACC is hyperactive and hyperconnected with other brain areas under
baseline or said differently under resting state. And when stimulated, two different scenarios,
resting and stimulated. NMDA are involved here. Remember the glutamate receptor.
Remember glutamate is excitation. This area, data show involvement in autism, developmental delay,
intellectual disability, epileptic encephalopathy, cephala, our brains are like an extended versions.
Several thousand modifications of cephalopods. Those less complex creatures living underwater.
Also involvement in ADHD, schizophrenia and OCD. All things we've discussed.
This biology assist with synaptic development and plasticity. So more neuro plasticity,
learning and shaping who we are. A study on theory of mind, which is understanding others,
based on looking at them created by Sir Simon Baron Cohen in 1985. It's also called mentalizing or
cognitive empathy. These are super deficits in autism. Duval et al. in 2023 show during a theory of
mind task while using neuro imaging, autistic subjects had reduced activity in the ACC,
the medial prefrontal cortex and another area temporal parietal junction. We won't dissect
that area. In a second study, we'll discuss from Lee et al. in molecular psychiatry from 2024.
The ACC show stronger responses to sensory stimuli and they can do this on mice. Remember mice are
modeled organisms. They can use foot shocks and whisker stimulation for example. Two good
sensory processing tools. The ACC and thalamus and the BNST, the bad neculus of the striaterminalis.
Remember from the autism and anxiety episode. And some areas responsible for memory, the hippocampus
and the interior rhino cortex. These areas were hyper activated. In addition, the study normalized
the ACC with chemogenetic creating a normalized sensory processing sensitivity and normal connection
of those areas. In other words, they helped the connection to and from these areas that helped
with sensory processing. Okay, we'll discuss the insula and then review a few more studies.
The insula was a buzzword in neuroscience since about 12 years ago or so. And later, we'll review
a paper by maybe the top scientist on the insula. The insula is a hub, a meeting spot for interpreting
bodily responses or bodily states and brain. So things like cognition, thoughts and feelings
and how those are entangled with the current environmental situation. It has three large
sources of data, the brain, body and environment. It receives and processes this data and helps recruit
proper responses. Proper responses or normal responses is extremely subjective to that person.
Defining the insula officially. The insula is central for applying defensive and behavioral
strategies, processing bodily states involved in interoception, self awareness, emotional
regulation, consciousness, social anxiety. It connects with cortical and sub cortical areas,
including being co-activated with the amygdala during fear and anxiety. Now let's break it down.
The interior insula, discussed more in detail shortly, contains spindle neurons. Spindle
neurons are new in mammalian history and they are only found in humans, bonobos, chimps,
gorillas and orangutans. This was discovered about 25 years ago. Interesting and a side note
with frontal temporal dementia. These areas that we're discussing today and these spindle neurons
or a hot topic, they are a region of interest with this type of dementia. The right interior insula,
a subdivision, coordinates the executive network and the default mode network. These are opposite
networks or functioning depending on if you have a task or if you have no task. Having a task,
you recruit the executive functioning, skills led by the prefrontal. Remember the rule sets
and the prefrontal being a flexible rule setting and execution machine. Turning areas and systems on
and off, activating and inactivating areas and systems across the entire body. What is needed
for that task demand? It's a conductor or orchestrator or director, whatever you want to call it.
Typically, when nothing is abnormal, typically the executive network and the default mode network
do not operate simultaneously. They are anti-correlated. During anxiety or fear, the circuitry can
reverse. If someone has maladaptive responses or that passive coping or they stay afraid, panicked,
so on. The insula alongside with the ACC leads the prefrontal, leads the entire prefrontal cortex,
including the medial. Then we lose that so-called executive functioning. Remember, this is crucial
reason why humans are the dominant species when we lead with the prefrontal cortex.
Okay, let's review some data. Let's go in with a recent one from Neuron published in
2024 by Fan et al. To start, the dorsal medial area of the prefrontal has a role with mentalizing
and representing social information about the self and about others. Fan et al found the dorsal
medial prefrontal cortex and the ACC gyrus show neural representations for gaze fixations
directed toward the eyes and face of con-specific partner during contact-specific neutral eye
contact. Okay, so that was a lot, but this has some obvious interest with autism and the eye gaze
and the eye contact. The study shows that these areas are involved here.
And last week, a cool paper came out about eye gaze as an infant improving specificity and
sensitivity on later autism assessments. We plan to discuss eye gaze in a future episode.
In Fan et al, the question asked is, do these areas contribute to our social attention?
Combined with the orbital frontal cortex, remember, nothing singular is the cause
or responsible for any one thing. These areas, the orbital frontal cortex, the medial
prefrontal cortex and the ACC have bidirectional connections to the amygdala, a region sharing
interest with social cognition. Remember the autism and anxiety episode.
Social gaze might be or could be critical for observational learning and social decision-making.
Two huge components with autism. In socialness, gaze timing, adapting with increases or decreases
of eye gaze depending on the social context are important. Remember, because social norms
and humans say so. This guides social interaction and social learning. And we can think about this
as a young child all the way through adulthood and the implications with autism.
Okay, the next two studies come from 2009. Interestingly, these are old relative to autism
research, but both feature Lucena Euden, one of the foremost researchers and neuroscientist on the
Insula. One is a review and one is a meta-analysis. The meta-analysis show hyperactivation in the ACC
in social task and non-social task. Important with autism research and important for exploring
specific regions of the brain. The social task show a hypoactivation in the peridinual ACC.
Whereas non-social task is highlighted in the dorsal ACC. Confirming the roles the ACC have
in both social task and non-social task. Additionally, the right anterior insula
hypoactive during social task. In the autistic group during non-social task,
autistics have greater activation in a completely different area, the rostral ACC,
an area typically suppressed in the comparison group.
In the review study, there is a suspicion that hypoactive or a disconnected region
of the insula is a result of projections to and from sensory and limbic areas.
Thus, causing errors in attentional resources and subsequent guiding of adaptive responses
in socialness. Sounds familiar. Sounds like autism.
Okay, last one. Published in Communications Biology in April of 2024.
Sang et al. Studying six-week-old infants with a high risk of autism, a family history of autism.
If we step back for a moment, infants, a primary visual input for them are faces
and specifically smiling and happy faces. Everyone wants to see the baby smile and or laugh.
This study is brilliant whereby they used six-week-old infants and studied
attentional biases and sensory motor processing. The high likelihood group as the study defined
have higher connectivity with sensory motor regions whereas typical likelihood
have a stronger connectivity to prefrontal regions. And if you think about that critical age
that we've discussed, if autism manifest in this critical age where we learn the outside world is
chaotic from all that sensory overload, that age where there is a lot of sensory going on and
neuroplasticity going on, is it learned that the outside world is chaotic and then we learn to
withdraw, we learn to avoid. In addition, the higher connected sensory motor group,
the high likelihood group had lower connections to the prefrontal areas. And this ought to suggest
that the prefrontal cortex is not recruited as much or as needed compared to the typicals.
As we wrap up today, we covered a lot of biology and a lot of different studies. However,
mostly they are all directed towards certain areas of the body or the brain and certain behaviors.
I think we funneled this down into a few certain behaviors and causes of autism. I hope you can
see that people with autism have these biological implications and this can help explain our why
this can help you understand autism. If you are listening and enjoy the episode and enjoy the podcast,
please feel free to leave a review or rating. In podcasting, reviews, ratings and downloads are
huge and I very much appreciate your feedback. You can contact me if you wish at info.fromthespectrum.com
and thank you for listening to From the Spectrum podcast.