Excitatory/Inhibitory (E/I) imbalances as a unifying, treatable, feature of severe autism that cause Cognitive Impairment, Self-Injurious Behavior (SIB) and ultimately seizures in some

 

Autism is a complex condition that manifests in a range of symptoms, from social and communication challenges to sensory sensitivities and repetitive behaviors. Researchers long ago identified a key neurobiological mechanism that underlies many of the core and associated features of autism: excitatory/inhibitory (E/I) imbalances in the brain.

These imbalances, where the delicate interplay between neuronal excitation and inhibition is disrupted, offers a unifying framework to explain certain severe manifestations of autism, including cognitive impairment, self-injurious behavior (SIB), and seizures. Understanding E/I imbalance not only sheds light on the biology of autism but also opens new avenues for targeted therapies.

 

The Role of E/I Balance in the Brain

Neuronal circuits rely on a finely tuned balance between excitatory and inhibitory signals to function properly. Excitatory neurons promote the firing of signals, enabling processes like learning, memory, and sensory integration. Inhibitory neurons, on the other hand, dampen excessive activity, ensuring stability and preventing overstimulation.

In individuals with autism, this balance is often disrupted. Overactive excitatory signaling or insufficient inhibitory control can lead to hyperexcitability in certain brain regions, contributing to behavioral and neurological symptoms. This imbalance is influenced by a range of factors, including:

• Genetic mutations in key synaptic proteins (e.g., SHANK3, SCN1A, GABA receptor subunits).
• Neuroinflammation and oxidative stress.
• Developmental disruptions in synaptic pruning or circuit formation.

 

How E/I imbalances drives severe autism symptoms

 

Cognitive Impairment

E/I imbalance affects the prefrontal cortex and hippocampus, regions critical for cognitive functions like problem-solving, memory, and attention. Disrupted neural signaling in these areas impairs synaptic plasticity—the brain’s ability to adapt and learn—which can manifest as intellectual disability in some individuals with autism.

Studies have shown that restoring E/I balance in animal models can improve cognitive deficits, highlighting its central role in intellectual development.

 

Self-Injurious Behavior (SIB)

Self-injurious behaviors, such as head-banging or skin-picking, are often linked to dysregulated sensory processing and impaired impulse control. Hyperexcitability in brain regions like the amygdala can heighten stress responses, while altered pain thresholds caused by E/I imbalance may make some individuals less sensitive to injury.

Addressing the underlying imbalance can reduce the neural hyperactivity driving these behaviors and improve emotional regulation.

 

Seizures

Seizures are a common comorbidity in autism, affecting up to 30% of individuals. They arise directly from hyperexcitability in neural networks, where excessive excitation leads to abnormal, synchronized firing of neurons. Genetic conditions like Dravet syndrome, linked to mutations in sodium channel genes (e.g., SCN1A), exemplify the connection between E/I imbalance and epilepsy.

Therapies that stabilize E/I balance, such as GABA-enhancing drugs or ion channel modulators, have shown promise in reducing seizure frequency and severity.

 

Targeting E/I Imbalance: A Path Toward Better Treatments

Given its central role in severe autism symptoms, E/I imbalance represents a promising target for therapeutic intervention. Approaches to restore balance include:

 

Pharmacological Therapies

Bumetanide

Bumetanide is a diuretic that also affects neuronal chloride homeostasis by inhibiting the NKCC1 transporter. In autism, elevated intracellular chloride levels impair the function of GABA, shifting its action from inhibitory to excitatory. Bumetanide lowers intracellular chloride, restoring GABA’s inhibitory effect and reducing hyperexcitability. Clinical trials have shown improvements in social behaviors and reduced severity of core autism symptoms in some individuals.

 

L-Type Calcium Channel Blockers

L-type calcium channels play a role in synaptic plasticity and neuronal excitability. Excessive calcium influx can contribute to hyperexcitability and oxidative stress. Blockers like nimodipine and verapamil may help stabilize neuronal activity and have shown potential in reducing seizures and hyperactivity in preclinical studies.

 

T-Type Calcium Channel Blockers

T-type calcium channels are involved in regulating burst firing and thalamocortical oscillations. Dysregulation of these channels can contribute to sensory processing abnormalities and seizures. Agents like zonisade, traditionally used for absence seizures, may also offer benefits in addressing E/I imbalances in autism.

 

Memantine

Memantine is an NMDA receptor antagonist that modulates glutamatergic signaling. By dampening excessive excitatory activity, it can reduce hyperexcitability and improve cognitive and behavioral symptoms. Clinical studies have shown mixed results, with some individuals experiencing notable benefits in areas like communication and social interactions.

 

Low-Dose Clonazepam

Clonazepam, a benzodiazepine, enhances GABAergic inhibition by increasing the activity of GABA-A receptors. At low doses, it can stabilize neural circuits without causing significant sedation. It has been used off-label to manage anxiety, hyperactivity, and seizures in autism.

 

Valproate

Valproate is an anticonvulsant and mood stabilizer that enhances GABAergic signaling and reduces excessive excitation. It has shown efficacy in managing seizures and may also improve irritability and aggression in some individuals with autism.

 

Baclofen and R-Baclofen

Baclofen is a GABA-B receptor agonist that enhances inhibitory signaling. It can modulate overactive NMDA receptor activity, which may be beneficial in cases of excitatory dysfunction. Baclofen has been studied for its role in reducing repetitive behaviors and improving social interaction in preclinical models.

 

Taurine

Taurine is an amino acid with inhibitory properties that can enhance GABAergic activity and reduce excitatory signaling. It also acts as an antioxidant, mitigating oxidative stress linked to hyperexcitability.

 

Pioglitazone

Pioglitazone, a PPAR-gamma agonist, has anti-inflammatory effects that can indirectly stabilize neural circuits by reducing neuroinflammation associated with E/I imbalances. Preliminary studies suggest it may have benefits for behavioral symptoms in autism.

Other agents including

• Anti-inflammatory Drugs: Minocycline and mefenamic acid reduce neuroinflammation, which can exacerbate E/I imbalances.
• Ion Channel Modulators: Sodium channel blockers like lamotrigine and carbamazepine stabilize hyperexcitable neurons and may reduce both seizures and behavioral dysregulation.

 

Neuromodulation Techniques

• Transcranial Magnetic Stimulation (TMS): A non-invasive method to modulate cortical excitability.
• Transcranial Direct Current Stimulation (tDCS): Targets specific brain regions to enhance or suppress neural activity.

 

 

The Role of NMDA and GABA Receptors in E/I Imbalance

Excitatory NMDA receptors and inhibitory GABA receptors play central roles in maintaining E/I balance. NMDA receptor dysfunction, characterized by either hyperactivity or hypoactivity, is implicated in autism. Overactive NMDA receptors can amplify excitatory signaling, while underactive NMDA receptors can impair synaptic plasticity. Both scenarios disrupt neural communication and contribute to autism-related symptoms.

GABA receptors, particularly GABA-A and GABA-B subtypes, are essential for inhibitory control. Dysfunctional GABAergic signaling reduces the brain’s ability to counterbalance excitation, leading to hyperexcitability.

Baclofen’s modulation of GABA-B receptors exemplifies how targeting these systems can restore balance. By reducing NMDA receptor overactivation and enhancing GABAergic inhibition, baclofen addresses multiple aspects of E/I dysregulation.

 

NMDA receptor dysfunction

Addressing NMDA receptor dysfunction requires a nuanced approach because the receptor can be either hypoactive/underactive or hyperactive/overactive in autism, depending on the individual and the specific neural circuits involved. Treatments vary based on the direction of dysfunction:

 

Treating NMDA Hypofunction

In cases where NMDA receptors are underactive, excitatory signaling is insufficient, leading to impairments in synaptic plasticity, learning, and memory. Strategies to enhance NMDA receptor activity include:

1. D-Cycloserine
• Acts as a partial agonist at the glycine site of the NMDA receptor.
• Enhances receptor activity without overactivation, making it useful for improving social and cognitive functions in some individuals with autism.
2. Sarcosine
• A glycine transport inhibitor that increases synaptic glycine levels, promoting NMDA receptor activation.
• Preclinical studies suggest potential improvements in behavioral symptoms.
3. Glycine Supplements
• Directly increase the availability of a co-agonist required for NMDA receptor activation.
• May improve signaling in circuits where glycine levels are suboptimal.

 

Treating NMDA Hyperfunction

Excessive NMDA receptor activity can lead to excitotoxicity.  When there is too much glutamate or an overactive NMDA receptor, the influx of calcium ions into the neuron becomes excessive. This causes a series of harmful processes contributing to neuronal damage, increased oxidative stress, and seizures. Strategies to dampen NMDA receptor overactivity include:

1. Memantine
• An NMDA receptor antagonist that reduces overactivation without completely shutting down receptor function.
• Clinical trials in autism have reported mixed results but some individuals benefit in areas like hyperactivity and irritability.
2. Magnesium Supplements
• Magnesium acts as a natural blocker of the NMDA receptor under resting conditions.
• Supplementation can stabilize receptor activity and reduce hyperexcitability.
3. Low-Dose Ketamine
• At sub-anesthetic doses, ketamine modulates NMDA receptor activity and enhances synaptic plasticity.
• Emerging research suggests potential benefits for specific autism symptoms, although risks and side effects must be carefully managed.
4. Antioxidants (e.g., N-Acetylcysteine, Vitamin E)
• Reduce oxidative stress caused by NMDA receptor hyperactivity.
• Support neuronal health and may mitigate excitotoxicity.

 

Balancing NMDA Dysfunction

In some cases, the same individual may show hypoactivity in some circuits and hyperactivity in others.

Combining treatments tailored to the specific functional state of NMDA receptors in different brain regions. For example, Low-dose ketamine or memantine may help dampen excessive NMDA activity in the amygdala or basal ganglia, while D-cycloserine might be used to enhance NMDA function in areas like the prefrontal cortex.

  

Calcium, Sodium and Potassium Channels

Calcium signaling is critical for excitatory neurotransmission, as calcium ions mediate glutamate release and synaptic plasticity. Dysregulated calcium channels, such as overactive L-type or T-type channels, contribute to hyperexcitability and sensory abnormalities.

Sodium channelopathies, involving mutations in genes like SCN1A, directly impact neuronal firing rates. Excessive sodium influx leads to hyperactive neurons, causing seizures and other excitatory-driven symptoms. While calcium channels influence neurotransmitter release, sodium channel dysfunction primarily affects action potential generation.

Potassium channels, responsible for repolarizing neurons after firing, also play a key role in maintaining neural stability. Mutations in potassium channel genes can prolong neuronal firing and contribute to hyperexcitability.

 

Conclusion

While E/I imbalance is not the sole cause of autism, it is a key unifying feature that connects many severe symptoms. By targeting this imbalance, clinicians can develop more precise and effective treatments tailored to the individual’s needs. Early intervention, particularly during critical periods of brain development, holds the greatest potential for improving outcomes.

As we continue to unravel the complexities of autism, the concept of E/I imbalance serves as a key nexus to understand, and more importantly, treat the challenges faced by individuals with severe autism and their families. By restoring balance, to the extent possible, both in the brain and in daily life, we can empower those with severe autism to reach their full potential. 

People with mild autism are likely affected by less extreme E/I imbalances, but they may be more aware of them. They are likely easier to treat. The principles are the same. 

The issue of sound sensitivity can affect autism from level 0 (including self-diagnosed and ADHD) all the way to level 3; it is complex because it involves both an E/I imbalance and further issues. There will be a summary post on this subject. 

 

Update on Oxytocin and Vasopressin in Autism

A nebulizer as a better means of delivering vasopressin?

 

Previous posts: 

https://www.epiphanyasd.com/search/label/Oxytocin

https://www.epiphanyasd.com/search/label/Vasopressin

One key, often unaddressed feature of autism is hormonal dysfunction in the brain. Oxytocin and vasopressin are two closely related hormones that significantly affect social behavior, an area frequently disrupted in those with autism. Interestingly, this challenge is often most troubling in individuals with milder forms of autism, as they are more acutely aware of their differences in social interactions. While serotonin dysfunctions also play a key role, today’s post focuses on the impact of oxytocin and vasopressin.

 

 Today we are in the top right - central hormonal dysfunction

Here is a very recent article on a Vasopressin trial:

Vasopressin Boosts Social Skills Without Aggression in Autism

Summary: New research shows that supplementing vasopressin levels in low-social rhesus monkeys improves social behavior and facial recognition without triggering aggression. The findings suggest vasopressin deficiency may underlie social difficulties seen in autism spectrum disorder (ASD).

Monkeys given vasopressin became more responsive to prosocial cues and better at remembering faces, critical skills often impaired in ASD. This work opens new avenues for precision therapies aimed at addressing core social deficits in autism rather than just managing symptoms.

Key Facts:

·    Social Gains Without Aggression: Vasopressin improved prosocial behavior and facial memory without increasing aggression.

·    Biological Link to ASD: Low-social monkeys naturally mirror some social impairments seen in humans with autism.

·    Therapeutic Potential: Vasopressin supplementation could offer a future targeted treatment for core social deficits in ASD.

For years, Florida Tech’s Catherine Talbot, an assistant professor of psychology, has worked to understand the sociality of male rhesus monkeys and how low-social monkeys can serve as a model for humans with autism.

Her most recent findings show that replenishing a deficient hormone, vasopressin, helped the monkeys become more social without increasing their aggression—a discovery that could change autism treatment. 

In a research paper published in the journal PNAS, Talbot and researchers with Stanford, the University of California, Davis and the California National Primate Research Center explored vasopressin, a hormone that is known to contribute to mammalian social behavior, as a potential therapeutic treatment that may ultimately help people with autism better function in society.

Previous work from this research group had found that vasopressin levels are lower in their low-social rhesus monkey model, as well as in a select group of people with ASD.

Previous studies testing vasopressin in rodents had found that increased hormone levels caused more aggression. As a result, researchers warned against administering vasopressin as a treatment, Talbot said.

However, she argued that in those studies, vasopressin induced aggression in contexts where aggression is the socially appropriate response, such as guarding mates in their home territory, so the hormone may promote species-typical behavior.

She also noted that the previous studies tested vasopressin in “neurotypical” rodents, as opposed to animals with low-social tendencies.

“It may be that individuals with the lowest levels of vasopressin may benefit the most from it—that is the step forward toward precision medicine that we now need to study,” Talbot said.

In her latest paper, Talbot and her co-authors tested how low-social monkeys with low vasopressin levels and high autistic-like trait burden responded to vasopressin supplementation to make up for their natural deficiency. They administered the hormone through a nebulizer, into which the monkeys could opt.

For a few minutes each week, the monkeys voluntarily held their faces up to a nebulizer to receive their dose while sipping white grape juice—a favorite among the monkeys, Talbot said.

After administering the hormone and verifying that it increased vasopressin levels in the central nervous system, the researchers wanted to see how the monkeys responded to both affiliative and aggressive stimuli by showing them videos depicting these behaviors.

They also compared their ability to recognize and remember new objects and faces, which is another important social skill.

They found that normally low-social monkeys do not respond to social communication and were better at recognizing and remembering objects compared to faces, similar to some humans diagnosed with ASD. When the monkeys were given vasopressin, they began reciprocating affiliative, pro-social behaviors, but not aggression.

It also improved their facial recognition memory, making it equivalent to their recognition memory of objects.

In other words, vasopressin “rescued” low-social monkeys’ ability to respond prosocially to others and to remember new faces. The treatment was successful—vasopressin selectively improved the social cognition of these low-social monkeys.

“It was really exciting to see this come to fruition after pouring so much work into this project and overcoming so many challenges,” Talbot said of her findings.

One of Talbot’s co-authors has already begun translating this work to cohorts of autism patients. She expects more clinical trials to follow.

 

The original paper: 

Nebulized vasopressin penetrates CSF and improves social cognition without inducing aggression in a rhesus monkey model of autism

  

  

A review/update of all the previous posts on vasopressin and oxytocin: 

Plasma vs CSF Levels of hormones

It is relatively straightforward to measure hormone levels in a blood sample. However, plasma levels of oxytocin and vasopressin do not reliably reflect the levels in the brain. Brain hormone levels are best measured via cerebrospinal fluid (CSF), which requires a lumbar puncture. Studies have consistently shown that both oxytocin and vasopressin levels are reduced in the CSF of individuals with autism. These reductions highlight potential deficiencies in the central signaling pathways of these hormones.

 

Dysfunctional Receptors

The dysfunction in autism may not only involve reduced hormone levels but also abnormalities in their receptors.

• Oxytocin Receptors (OXTR): Variations in the oxytocin receptor gene have been linked to autism, potentially leading to reduced receptor sensitivity or signaling efficiency. Dysfunctional oxytocin receptors can impair bonding, trust, and other social behaviors.
• Vasopressin Receptors: Vasopressin exerts its effects through several receptor subtypes:
• V1a Receptors: Involved in social behavior regulation.
• V1b (also known as V3) Receptors: Primarily located in the anterior pituitary, these receptors influence the release of adrenocorticotropic hormone (ACTH) and are implicated in stress responses.
• V2 Receptors: Regulate water retention in the kidneys.

Alterations in these receptors, especially V1a and V1b, may contribute to the social and stress-related symptoms observed in autism.

 

Therapeutic Options and Their Limitations

Addressing these hormonal and receptor dysfunctions offers promising avenues for therapeutic intervention, though challenges remain:

• Increasing Hormone Levels in the Brain. Enhancing oxytocin or vasopressin concentrations in the brain could improve social behaviors. Measuring the efficacy of these interventions is difficult because CSF sampling is invasive.
• Receptor Activation. Drugs designed to activate oxytocin or vasopressin receptors directly could bypass issues with hormone levels. However, such therapies need precise targeting to avoid side effects and ensure effectiveness.

 

Delivery Methods

Various delivery methods have been explored to introduce oxytocin or vasopressin into the body:

Intranasal Spray: Widely researched, intranasal delivery targets the brain directly via the nasal mucosa. However, this method is challenging because the drug is not meant to be inhaled into the lungs. Instead, it must cross the nasal membrane or travel along the olfactory or trigeminal nerves directly to the brain. Only specific molecules can effectively cross the blood-brain barrier, typically those that are small and lipophilic. Stanford University has conducted groundbreaking work using intranasal vasopressin in autism, demonstrating potential improvements in social behavior. However, many commercially available nasal sprays may lose their effectiveness because the active hormones degrade during transit if not properly chilled.

Nebulizer: Recent studies have investigated the use of nebulized vasopressin, delivering the hormone in aerosol form for inhalation. This method may offer more consistent dosing and better absorption while avoiding the challenges of nasal delivery.

Tablet by Mouth: Oral administration faces challenges because these hormones can degrade in the digestive system and may not cross the blood-brain barrier effectively. Vasopressin, for instance, cannot be taken orally due to rapid degradation. However, desmopressin, a synthetic analog of vasopressin, is orally bioavailable and can be used to treat conditions like diabetes insipidus.

Interestingly, desmopressin appears to help some individuals with autism, possibly due to its effects on water retention and central nervous system signaling. The nasal spray form of desmopressin offers rapid absorption compared to tablets, but tablets provide more convenient and consistent dosing.

Probiotic by Mouth. Human research suggests that specific strains of Lactobacillus reuteri can stimulate oxytocin production. These probiotics may offer a novel and non-invasive therapeutic option to enhance oxytocin levels naturally. Biogaia Protectis is one such oxytocin-stimulating probiotic.

 

Recent Advances: Nebulized Vasopressin for Social Deficits in Autism

Research conducted by scientists from Florida Institute of Technology, Stanford, and other institutions has revealed that supplementing vasopressin in low-social rhesus monkeys improves social behaviors and facial recognition without increasing aggression. These findings highlight the potential of vasopressin as a precision therapy for addressing core social deficits in autism.

The study focused on low-social rhesus monkeys, which exhibit behaviors similar to certain social impairments observed in humans with autism. The researchers used a nebulizer to administer vasopressin, a non-invasive and targeted delivery method. The monkeys voluntarily inhaled the hormone while drinking grape juice, ensuring an effective and stress-free administration. The point to note is that monkeys need to breath through their nose for the therapy to work, hence the drink.

Key findings include:

• Improved Prosocial Behavior. Vasopressin enhanced affiliative behaviors and facial recognition memory in low-social monkeys without increasing aggression, addressing a common concern from earlier studies in neurotypical animals.
• Precision Medicine Potential. Researchers observed that individuals with the lowest vasopressin levels derived the greatest benefit, suggesting the importance of tailoring treatments to specific biological deficiencies.
• Successful Central Nervous System Targeting. The study verified that nebulized vasopressin reached the central nervous system, a critical factor for its efficacy in enhancing social cognition.

These results offer a promising path forward, especially since one of the study’s co-authors is already working on translating these findings to human trials. If successful, this approach could modernize autism treatment by targeting an underlying hormonal deficiencies.

 

Why approved therapies remain elusive

Despite the promising science, no therapies targeting oxytocin or vasopressin have yet gained widespread approval for treating autism. The reasons for this include:-

• Challenges in Delivery Systems. Ensuring that sufficient amounts of oxytocin or vasopressin reach the brain remains a significant hurdle. Many delivery systems, such as nasal sprays, face degradation of the active hormone during transit or storage, limiting their effectiveness.
• Variable Responses. Hormonal therapies may yield inconsistent results due to genetic differences, baseline hormone levels, or receptor functionality among individuals.
• Complexity of ASD. Autism is a highly heterogeneous condition with diverse underlying causes, making it challenging to develop a one-size-fits-all treatment.

 

Over-the-counter (OTC) therapies also face criticism for their lack of rigorous testing and quality control. Many users report limited or no benefits, likely due to suboptimal dosing, poor bioavailability, or degraded products. These failures underscore the need for precision medicine approaches and robust clinical evidence to guide treatment.

 

Conclusion

While hormonal and receptor dysfunctions involving oxytocin and vasopressin present significant hurdles, they also offer unique opportunities for targeted interventions. Current therapies and delivery methods are promising but require further refinement to maximize their effectiveness. Recent advances, such as the use of nebulized vasopressin, demonstrate the potential for precision therapies to address core social deficits in autism. Future research into the relationship between these hormones and autism may unlock more personalized and effective treatments, bringing hope to those affected by these challenges. 

Many people have a nebulizer at home - we have had one for 15 years. They are very simple to use, even with a young child with severe autism. If the vasopressin, or oxytocin therapy was once a week for 5 minutes it would be a simple process. The trick would be ensuring breathing through the nose, rather than mouth, which you would normally be encouraging for drugs to reach the lungs. With the monkeys they added a straw and a favourite drink.

Vasopressin has to be kept between 2 and 8 celsius (36-46F). So you would get it from the local pharmacy, measure the dose, add saline solution and turn on the nebulizer. Do not try to buy it online, it will not work! It looks they have already started using this method at Stanford.  

If it works on a rhesus monkey, there is a good chance it will work on your own little monkey—and, of course, for our many adult Aspie readers.