Keynote at Duke ACE

 

Excitation/Inhibition Imbalance in Autism Rodent Models

E/I IMBALANCE AND AUTISTIC-LIKE BEHAVIORS:

• Optogenetic stimulation of pyramidal neurons in the medial prefrontal cortex in mice induces social deficits associated with enhanced gamma oscillations.
• Increased neocortical E/I ratio caused by malfunctions of PV-expressing interneurons induces excessive gamma oscillations and autistic-like behaviors.

Factors Contributing to E/I Imbalance

• E/I balance at the circuit level involves the interplay between GABAergic interneurons and target pyramidal neurons, modulating long-range connections.

Excitatory Synapse Development

• Neuroligin and neurexin genes play critical roles in synapse and circuit development.
• Knockout of 4E-BP2 in mice upregulates neuroligins, increases hippocampal synaptic E/I ratio, and induces autistic-like behaviors.
• Pharmacologic inhibition of eIF4E or knockdown of neuroligin-1 normalizes the E/I ratio and rescues autistic-like behaviors.

AMPAR 

• Ampakine rescues impaired long-term potentiation and long-term memory in Ube3a-deficient mice, a model of Angelman syndrome.
• Various gene mutations affect AMPAR transmission and synaptic functions in different mouse models.
• IGF-1 treatment rescues reduced excitatory transmission in Shank3 and Mecp2 mice.

NMDAR

• Mutations in genes like Nlgn1, Shank2, and Tbr1 lead to NMDAR hypofunction and social deficits in mice.
• Both hypo- and hyperfunction of NMDARs can cause autistic-like behaviors in animal models.
• mGluR5 hyperfunction in Fmr1 and BTBR mice is implicated in ASDs.

Signaling Pathways

• The mTOR pathway and actin-modulatory pathways play crucial roles in rescuing autistic-like phenotypes in animal models.
• Dopamine receptor agonists/antagonists and 5-hydroxytryptamine rescue behaviors in various mouse models.

Inhibitory Synapse Development and Function

• Deletion of inhibitory synapse-specific Nlgn2 leads to decreased inhibitory synapse density and cognitive deficits.
• Mutations in genes like Nlgn3 and Cntnap2 affect GABAergic transmission in different brain regions.
• Deficiencies in GABA A receptor subunits and altered tonic GABAergic transmission are observed in ASD model animals.

Interneurons

• PV interneurons are crucial for regulating gamma oscillations and are associated with psychiatric disorders.
• Defects in PV, SST, and NPY interneurons lead to various phenotypes in mouse models.
• Reduced interneuronal firing and GABAergic output contribute to social and cognitive deficits in ASD models.

Glial Cells

• Astrocytes and nonastrocytic glial cells like microglia and oligodendrocytes play roles in regulating excitatory synapse structure and function.
• Re-expression of MeCP2 in glial cells can restore disease-related phenotypes in ASD models.

Intrinsic Neuronal Excitability

• Deficits in dendritic ion channels and intrinsic excitability are observed in various mouse models.
• Neuregulin-ErbB4 signaling modulates the intrinsic excitability of PV interneurons.Homeostatic 

Synaptic Plasticity

• Fmr1 mice show altered synaptic scaling in different brain regions.
• GKAP/DLGAP1/SAPAP1 scaffold regulates bidirectional synaptic scaling in the hippocampus.

Temporal E/I Regulation

• Temporal changes in E/I balance are crucial for normal brain development.
• Early interventions with specific inhibitors can normalize E/I balance and rescue abnormal phenotypes in animal models.
• Delayed restoration of certain genes can also rescue abnormal phenotypes in ASD models.

Perspectives

• Careful interpretation of rescue results is necessary to understand the fundamental correction of pathogenic mechanisms.

Lee, E., Lee, J., & Kim, E. (2017). Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biological psychiatry, 81(10), 838-847.

Systematic Desensitization

 

Listen at: https://www.dailycal.org/2018/03/15/first-transitions

MTT Mental Time Travel

Mental Time Travel (MTT) refers to the cognitive ability to mentally project oneself backward in time to recall past events or forward in time to anticipate future scenarios. In relation to autism, MTT research explores how individuals with autism may experience differences in episodic memory and future-oriented thinking, potentially leading to challenges in recalling specific personal events or imagining detailed future scenarios. [ Read in more detail on MTT]

PlainSpeak: Mental Time Travel (MTT) is our brain’s way of thinking back to past memories or imagining what might happen in the future. For people with autism, MTT might work differently, sometimes making it harder to remember personal events or imagine future plans. [Read in more detail, a PlainSpeak Version]

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Related Posts: [Autism Theories], [Sensorimotor], [Neuroscience of Autism]

No passion or urgency for solutions

Why is there NO PASSION OR URGENCY in seeking ACTUAL SOLUTIONS for Autism in the myriad conversations around autism?

I’m been waiting 2.5 decades for solutions, there is still NO MOVEMENT.

Monotropism and Special Interests in Autism - a Neurocognitive Perspective

Monotropism and special interests are closely related yet distinct constructs within the context of autism. Both concepts elucidate how autistic individuals exhibit profound engagement with specific domains, yet they underscore different facets of this phenomenon.

Monotropism is a cognitive model positing that autistic individuals exhibit a narrowed attentional focus on a limited set of interests, in contrast to the broader attentional distribution observed in neurotypical individuals. This heightened attentional focus facilitates deep expertise and significant enjoyment in specialized areas. However, it also results in attentional inflexibility, making it challenging for individuals to shift focus to other tasks or interests that do not align with their core interests. Monotropism provides a framework for understanding why autistic individuals often demonstrate exceptional proficiency in their areas of passion but may face difficulties with tasks that are outside these focal points.

Special Interests refer to the specific topics or activities that elicit intense focus and enthusiasm in autistic individuals. These interests often manifest as lifelong passions and serve as sources of comfort, identity, and competence. While special interests contribute positively to an autistic individual's life, they may be misunderstood or undervalued by others who fail to recognize their significance.

Neurocognitive explanations for both monotropism and special interests suggest that these behaviors are underpinned by fundamental differences in brain function and information processing in autistic individuals. Monotropism is thought to involve an atypical allocation of cognitive resources, where autistic individuals preferentially allocate their cognitive bandwidth to areas of high personal significance. This preferential allocation can be understood through the lens of predictive coding theories, particularly those emphasizing 'slow-updating' and 'high-precision' or 'hypoprior' mechanisms. These theories propose that autistic individuals maintain highly precise and stable internal models for their areas of interest, leading to profound engagement and expertise in these domains but also to challenges in adapting to new or less predictable tasks.

Special interests, on the other hand, may be conceptualized as emergent properties of these underlying neurocognitive mechanisms. The intense focus and enthusiasm associated with special interests reflect the heightened precision and stability of the predictive models governing these interests. The sustained engagement with special interests can be further understood through the framework of neural reward pathways, where dopaminergic activity reinforces behaviors that align with these precise internal models, thereby enhancing the salience and reward value of special interests.

Understanding both monotropism and special interests from a neurocognitive perspective can inform the development of supportive environments that leverage the strengths of autistic individuals. By recognizing and building upon their focused cognitive styles, educators, clinicians, and caregivers can implement strategies that accommodate attentional inflexibility while fostering opportunities for growth and adaptation. This approach not only acknowledges the unique cognitive profiles of autistic individuals but also promotes their overall well-being and societal inclusion.

Here are the different versions to help understand Monotropism and Special Interests 

• Neurocognitive explanation
• Plain Language
• A Short Definition

Special Interests

Special interests in autism are intense and highly focused areas of interest that individuals may pursue with great enthusiasm and expertise, often serving as a source of comfort and a means of coping with sensory and social challenges.

PlainSpeak: Special interests are topics or activities that autistic people are extremely passionate about and know a lot about, which can be both a hobby and a way to feel comfortable.

Read more about Special Interests 

• Neurocognitive explanation
• Plain Language

Monotropism

 Monotropism in autism refers to a cognitive tendency toward deep focus on specific interests or tasks, often leading to intense concentration and reduced awareness of broader contexts or multiple stimuli.

PlainSpeak: Monotropism is when someone, often an autistic person, focuses deeply on one thing, making it hard to pay attention to other things around them.

Read more about Monotropism 

• Neurocognitive explanation
• Plain Language

Privilege of choice

Many of us with very visible autism disability DO NOT HAVE THE PRIVILEGE OF CHOICE, 

“to-disclose” or “not-to-disclose” our autism dx to ask for accommodations.

In fact, a very visible disability means many doors of opportunity are slammed shut in your face even before you have a chance to cross the doorway, or before you come to asking for accommodations on the other side. You are held to a much higher bar to even get anywhere close to the door. The question of choice does not even arise.

We desperately need SOLUTIONS, so ALL autistics get to access doors of opportunities.

Stress and Anxiety in Autism: The Role of the HPA Axis

Understanding Stress and Anxiety in Autism: The Role of the HPA Axis

Stress and anxiety are common experiences for everyone, but for individuals with autism, these feelings can be particularly intense and challenging. Understanding why this happens involves delving into the body’s stress response system, known as the hypothalamic-pituitary-adrenal (HPA) axis.

What is the HPA Axis?

The HPA axis is a complex network of interactions among three glands: the hypothalamus, the pituitary gland, and the adrenal glands. When we encounter a stressful situation, the hypothalamus releases a hormone called CRH (corticotropin-releasing hormone). This hormone signals the pituitary gland to release another hormone, ACTH (adrenocorticotropic hormone), into the bloodstream. ACTH then prompts the adrenal glands to produce cortisol, often referred to as the "stress hormone."

Cortisol helps our body manage stress by increasing energy levels, suppressing non-essential functions (like digestion), and preparing the body for a "fight or flight" response. Once the stressful situation is resolved, cortisol levels drop, and the body returns to a state of balance.

Stress and Anxiety in Autism

In Autism, the HPA axis can often be more reactive, leading to heightened stress and anxiety. Several factors contribute to this increased reactivity:

1. Sensory Sensitivities: Many autistics have heightened sensory perceptions. Everyday noises, lights, or textures can be overwhelming, triggering a stress response more frequently.
2. Social Interactions: Social situations, which can be difficult to navigate, often cause significant stress and anxiety. The effort required to interpret social cues and respond appropriately can be exhausting.
3. Routine and Change: Many autistics thrive on routine and predictability. Unexpected changes or disruptions can cause considerable anxiety, activating the HPA axis.

The HPA Axis in Autism

Research suggests that the HPA axis in autistic individuals may function differently. Autistic people can have higher baseline levels of cortisol, indicating a chronic state of stress. Additionally, their cortisol levels might not return to normal as quickly after a stressful event, prolonging the period of anxiety and stress.

This heightened and prolonged stress response can have several implications:

• Mental Health: Chronic stress and anxiety can contribute to other mental health issues, such as depression.
• Physical Health: Elevated cortisol levels over long periods can affect physical health, leading to issues like weakened immune function and digestive problems.
• Daily Functioning: High stress levels can interfere with daily activities, making it harder to concentrate, learn, and interact with others.

Supporting Stress Management

Understanding the role of the HPA axis in autism can help in developing strategies to manage stress and anxiety. Here are a few approaches:

• Sensory Management: Creating environments that minimize sensory overload can help reduce stress.
• Routine and Predictability: Maintaining a predictable routine can provide a sense of security and reduce anxiety.
• Relaxation Techniques: Practices like deep breathing, mindfulness, and other relaxation techniques can help manage the body's stress response.
• Professional Support:  **** See Caveat 

By recognizing the unique ways the HPA axis operates in autism, we can better support autistics

[*** Caveat from my personal experience as autistic is that most of autism therapy is geared towards maximizing profits and fame, and less about the autistic progressing, because lack of progress can easily be attributed as fault of the autistic, it's never the therapy or therapist. So why spend more and more $$$$ on therapy].

We need SOLUTIONS

We need action on ACTUAL SOLUTIONS for Autism.

Communication,  Biomedical physiology (physical/mental health), Precision Pharma, Healthcare, Sensorimotor, Policy Priorities, Funding Priorities, Supports services, myriad equity of access issues.

Lets work on leveling the playing field.

QUALITY OF LIFE means ALL Autistics get to avail of opportunities

The Pervasive Loneliness of Autism

 "It was a thought provoking read about an angle that I hadn’t thought of. It is also beautifully written."

https://time.com/6551520/loneliness-autism-essay/

The Access Ramp to Volunteering

https://www.dailycal.org/2018/04/05/access-ramp-volunteering