Showing posts with label anxiety. Show all posts
Showing posts with label anxiety. Show all posts

Friday, 26 April 2019

The Autonomic Nervous System (ANS), Heart Rate Variability (HRV), Performance Anxiety, Propranolol, Vagus Nerve Stimulation and Autism

Performance anxiety symptoms may include:
·       Racing pulse and rapid breathing.

·       Dry mouth and tight throat.

·       Trembling hands, lips, and voice.

·       Sweaty and cold hands.

·       Nausea 

·       Vision changes.

Today’s post started out to be all about Propranolol, a very old and widely prescribed drug that lowers your blood pressure, but does other interesting things as well. It is used to treat several psychiatric disorders and has been widely trialled in autism. As I started researching I decided to broaden the post to bring in Heart Rate Variability (HRV), which one reader of this blog suggested as a useful measure of the effect of supplements.   HRV is actually a good indicator of a dysfunction in the Autonomic Nervous System (ANS). 

The Autonomic Nervous System (ANS) is a control system that acts largely unconsciously and regulates bodily functions such as the heart rate, digestion, respiratory rate, pupillary response and urination.
Within the brain, the autonomic nervous system is regulated by the hypothalamus. Autonomic functions include control of respiration, cardiac regulation, vasomotor activity (actions upon a blood vessel which alter its diameter) and certain reflex actions such as coughing, sneezing, swallowing and vomiting.
Dysfunctions in the Autonomic Nervous System (ANS) are known to be a common feature of autism.  Propranolol is known to affect the Autonomic Nervous System (ANS) and has been shown in numerous trials and case studies to improve some cases of autism.
Performance anxiety is a well-known off-label use of Propranolol.
Vagus Nerve Stimulation (VNS) is known to affect the Autonomic Nervous System (ANS) and is sometimes used to treat performance anxiety.

Vagus nerve stimulation (VNS) using an implanted device can have profound benefits in severe epilepsy. Less invasive VNS can be achieved transcutaneously and in particular via a branch of the vagus nerve that extends to your ear.
The vagus nerve has many roles including sending inflammatory signalling from the gut to the brain. We saw how this was proved, at least in mice, by severing the vagus nerve. Stimulating the vagus nerve can have significant anti-inflammatory effects, which is why it is being developed to treat a wide range of conditions ranging from arthritis to COPD (severe asthma).

We also saw in a post last year that drinking sodium/potassium bicarbonate has an effect that is very similar to VNS, in that it tamps down your immune system in a very similar way.

The Propranalol Autism Research
Fortunately, in 2018 a review of all Propranolol-related autism research was published. I found this out after having started to trawl through the old research.  The issue of Heart Rate Variability (HRV) as potential marker for propranolol responders that I focused in on, was also picked up in the review paper.

We can start with review paper, which happens to be from England, which still has not fully recovered from the Wakefield saga.  There is a real stigma about treating autism, better call it encephalopathy and treat that!

To date, there is no single medication prescribed to alleviate all the core symptoms of Autism Spectrum Disorder (ASD; National Institute of Health and Care Excellence, 2016). Both serotonin reuptake inhibitors and drugs for psychosis possess therapeutic drawbacks when managing anxiety and aggression in ASD. This review sought to appraise the use of propranolol as a pharmacological alternative when managing emotional, behavioural and autonomic dysregulation (EBAD) and other symptoms.
This review indicates that propranolol holds promise for EBAD and cognitive performance in ASD. Given the lack of good quality clinical trials, randomised controlled trials are warranted to explore the efficacy of propranolol in managing EBAD in ASD.

From the 16 articles identified, propranolol dosages ranged from 7.5 mg to 360 mg per day across a range of patients. All studies had a range of outcome measures for those diagnosed with ASD, including a focus on cognitive enhancement, management of social behaviours, EBAD, SIBs, and aggression.

Summary of evidence

Across multiple domains, propranolol had significant benefits in the treatment of adults and children diagnosed with ASD. Propranolol improved cognitive performance, with individuals with ASD demonstrating an improvement in verbal problem solving (Beversdorf et al., 2008; Zamzow et al., 2017), semantic processing (Beversdorf et al., 2011) and working memory (Bodner et al., 2012). No changes in cognitive performance for individuals without ASD were reported (Beversdorf et al., 2008, 2011). Additionally, propranolol exhibited greater functional connectivity in individuals with ASD (Hegarty et al., 2017; Narayanan et al., 2010). Not only does this provide evidence for the ability of propranolol to improve functional connectivity in those with ASD, but also that central and peripheral blockade is more effective than just peripheral blockade as seen by nadolol (Hegarty et al., 2017). It is important to note that a non-significant difference for functional connectivity between placebo and propranolol conditions can be attributed to other hemodynamic factors, such as differences in blood pressure, confounding the effects on blood-oxygen-level-dependent responses during fMRI sessions (Narayanan et al., 2010). Moreover, propranolol decreased functional connectivity in various subnetworks where high baseline functional connectivity was observed. Conversely, for those with low baseline functional connectivity, functional connectivity in these subnetworks increased after the introduction of propranolol, irrespective of diagnostic group (Hegarty et al., 2017). These differences suggest that propranolol, and other beta-adrenergic antagonists may have a greater role in maintaining appropriate patterns of functional connectivity, allowing for more efficient integration of functional networks (Hegarty et al., 2017). These findings also highlight the potential for propranolol to support cognitive processing. Indeed, by modulating noradrenaline, greater associative processing and integration of subnetworks may be achieved. Subsequently, potential improvements in attention-shifting, sensory processing, language communication, and the processing of social information could be observed in those with ASD (Hegarty et al., 2017). Furthermore, propranolol reduced mouth fixation, improving facial scanning at a global level (Zamzow et al., 2014). Although, non-significant findings were reported when investigating the efficacy of single-dose propranolol treatment for eye contact, this may be attributable to the sample used. The majority of subjects fulfilling diagnostic criteria for ASD were high functioning, suggesting that scores for eye contact may have already been at a ceiling prior to the administration of propranolol. Therefore, none or only marginal improvements would be attained from post administration of propranolol leading to non-significant results when compared with controls. Moreover, non-verbal communication improvements (Zamzow et al., 2016) and reductions in hypersexual behaviours (Agrawal, 2014) were also observed. These improvements were reported in studies using a 40 mg dose of propranolol, with just one study utilising a low dose of 20 mg (Agrawal, 2014). However, it may be noteworthy to consider that for this case, the hypersexual behaviours did not decrease while the patient was alone, but the patient was able to manage behaviours more appropriately in the presence of others. This may indicate an improved ability to understand and interpret social contexts, rather than a reduction in hypersexual behaviours. Indeed, social cues and social situations are a challenge for those with ASD, and these findings highlight potential clinical implications for propranolol. In light of this, both studies by Sagar-Ouriaghli et al. (2017) and Santosh et al. (2017) highlight again that on average, a 40 mg dose is suitable for children and adolescents in managing symptoms associated with ASD and EBAD. Furthermore, Santosh et al. (2017) and Zamzow et al. (2017) provide supporting evidence for the use of wearable technologies in measuring biomarkers such as HRV and skin conductance in order to identify treatment responders and monitoring the impact of propranolol on therapeutic outcomes. Alongside these benefits, propranolol significantly helped manage SIBs and aggressive outbursts in those with ASD (Knabe and Bovier, 1992; Lyskowski et al., 2009; Ratey et al., 1987). Two cases reported no significant improvement when using propranolol (Connor, 1994; Luiselli et al., 2000). One case was required to change propranolol due to hypotension and bradycardia despite a decreasing trend in aggressive behaviours (Luiselli et al., 2000). Across these cases, dosing ranged from 7.5 mg–360 mg, indicating a higher dose may be required for SIBs and aggression, in comparison with cognitive performance (20 mg–40 mg). In summary, these results and a subsequent overview by Fleminger et al. (2006) conclude that β-blockers have the best evidence for the management of such symptoms and that propranolol improves impulse control and subsequent violence associated with brain dysfunction of diverse aetiologies.

You can read the original 16 studies referred to if you are seriously interested in Propranolol. I have just highlighted some I found interesting.  It is interesting that beneficial effects are reported across the spectrum from severe autism to Asperger’s. 

People with intellectual disability often exhibit various behavioral problems, which are referred to as “challenging behaviors.” Aggression is among the commonest of these, affecting about 7% of this population. The management of aggression in these patients involves both behavior therapy and medications. Various medications, such as lithium, anticonvulsants, and antipsychotics, have been used, but their evidence base is limited and recent research suggests that antipsychotics, in particular, should not be routinely used
Propranolol is a centrally acting β-adrenergic antagonist used in a variety of medical conditions. It has also been used to manage aggression in various neuropsychiatric conditions, including organic brain syndromes, schizophrenia, dementia, and intellectual disability. Doses used in these studies have been as high as 520 mg/d, but some authors have reported benefits at much lower doses. The following is the case of a young man with intellectual disability, epilepsy, and severe aggression who responded remarkably to low-dose propranolol.
Case report. Mr A, a 20-year-old man diagnosed as having moderate intellectual disability and generalized epilepsy, presented to our clinic with severe aggression, both verbal and physical, occurring with little or no provocation over the past 3 years. These episodes would last up to several hours and often led to food refusal. Before this, he could attend to his personal needs, helped his mother in household tasks, and could communicate in short sentences despite an articulation defect. However, after the onset of his aggression, it was difficult to engage him in any activities, including basic self-care. There was no evidence of a mood disorder or psychosis or of seizures either preceding or following the episodes of aggression. He was seizure-free for the past 4 years on carbamazepine 1,000 mg/d and diazepam 10 mg/d, and he had never exhibited postictal aggression in the past. He had already received trials of olanzapine (up to 15 mg/d for 6 weeks) and chlorpromazine (up to 400 mg/d for 3 months) without significant improvement and was currently on olanzapine 10 mg/d and chlorpromazine 300 mg/d in addition to his medications for epilepsy.

As his mother reported features of autonomic arousal—such as increased perspiration, motor agitation, and rapid breathing—during each episode, he was given a trial of propranolol, starting at 20 mg/d and increased by 20 mg every week. At 40 mg/d, there was a significant reduction in his aggression, and his food intake was better. On further increasing the dose to 60 mg/d, his mother reported that he was essentially “normal,” with no significant episodes of aggression. Over the next year, olanzapine and chlorpromazine were tapered and stopped, and he remained stable. He has been well on carbamazepine 1,000 mg/d, propranolol 60 mg/d, and diazepam 10 mg/d for the past 3 months with no recurrence of either seizures or aggression, and it is now possible to engage him in household tasks and speech therapy.
The management of aggression in the intellectually disabled is a clinical challenge. The best evidence suggests that antipsychotics are of limited use, and the evidence for other medications is even more limited. Behavioral management is valuable, but may not be feasible in a very violent or uncooperative patient, and pharmacotherapy may be required initially in such cases.
Propranolol is effective in reducing aggression in a variety of neurologic and psychiatric conditions. Its exact mechanism of action is unknown, but may involve central β-adrenergic blockade, peripheral effects on the sympathetic nervous system, or serotonergic blockade. It may be effective not only in aggression, but also in the self-injurious behavior commonly seen in the intellectually disabled. Recent evidence suggests that it may improve some aspects of learning in patients with autism. Given these properties, and the uncertainties surrounding other treatment options, low-dose propranolol may be a valuable treatment option in the management of aggression in intellectually disabled adults, even if they do not respond to other drugs.

Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder


Although the autonomic hyperactivity hypothesis of aggression in ASD partially explains the behavior of our patient, aggression likely stems from multiple sources beyond just peripheral autonomic arousal. The rapid improvement with propranolol at a fairly low dose suggests that a subpopulation of patients may benefit from non-selective beta blockers. As beta blockers have hemodynamic side effects that include hypotension and bradycardia, clinicians should record baseline vitals and monitor for orthostasis, dizziness, and syncope. Overall, beta blockers may serve as an important therapy for aggression but should not replace a multimodal interventional plan that encompasses pharmacology, psychotherapy, and social support. It will be beneficial to validate the utility of propranolol and other beta blockers for ASD in future randomized controlled trials.
·       Though autism spectrum disorder (ASD) is primarily a disorder of language and social functioning, there may also be significant autonomic dysfunction that could contribute to aggression and impulsivity often seen in the disorder.
·       Beta-adrenergic blocking agents have been shown to reduce aggression in patients with traumatic brain injury and adult-onset neuropsychiatric disorders, but evidence is still limited in patients with ASD.
·       The non-selective beta-blockers propranolol and nadolol may significantly alleviate aggression, echolalia, and vital sign derangements in autistic patients; it is unknown whether β1-selective antagonists would have similar effects.

Here we have the effect on high functioning autism:-


Autism is characterized by repetitive behaviors and impaired socialization and communication. Preliminary evidence showed possible language benefits in autism from the β-adrenergic antagonist propranolol. Earlier studies in other populations suggested propranolol might benefit performance on tasks involving a search of semantic and associative networks under certain conditions. Therefore, we wished to determine whether this benefit of propranolol includes an effect on semantic fluency in autism.


A sample of 14 high-functioning adolescent and adult participants with autism and 14 matched controls were given letter and category word fluency tasks on 2 separate testing sessions; 1 test was given 60 minutes after the administration of 40 mg propranolol orally, and 1 test was given after placebo, administered in a double-blinded, counterbalanced manner.


Participants with autism were significantly impaired compared with controls on both fluency tasks. Propranolol significantly improved performance on category fluency, but not letter fluency among autism participants. No drug effect was observed among controls. Expected drug effects on heart rate and blood pressure were observed in both the groups.


Results are consistent with a selective beneficial effect of propranolol on flexibility of access to semantic and associative networks in autism, with no observed effect on phonological networks. Further study will be necessary to understand potential clinical implications of this finding.

This paper is interesting because it looks at how you can identify people who are likely to respond to Propranolol:-

Autism spectrum disorders are a group of developmental disorders, which display significant heterogeneity of symptoms. Besides the core symptoms, various comorbidities are common for individuals with autism. A growing body of evidence suggests dysfunction of autonomic nervous system within the ASD population. The detection of autonomic abnormalities could help in more personalized approach, which takes into account individual etiologic differences. It has also been suggested that interventions focused on autonomic function could possibly be beneficial for treatment of aggression, anxiety, as well as the core symptoms of autism.
Detection of autonomic alterations in autism spectrum disorders

Invasive methods 
The measurement of circulating catecholamines belongs to most common methods of assessment of sympathetic nervous system function (SNS) (Zygmunt & Stanczyk 2010). Activity of the SNS can be assessed using the measurement of the plasma or urine concentration of norepinephrine, or its metabolites. Measurement of catecholamines provides useful information about the activity of SNS, however, they are determined by location of vessel used for blood collection and therefore do not reflect the whole amount of neurotransmitter secreted from axon terminal (Sinski et al 2006). Acetylcholine, neurotransmitter released by postganglionic fibers of the parasympathetic system, is very quickly inactivated by acetylcholinesterase, so its plasma levels cannot be used as a marker of parasympathetic nervous system activity (McCorry 2007). Interestingly, plasma norepinephrine concentrations have been reported to be elevated in autism (Launay et al 1987). However, blood and urine samples acquisition represent extremely stressful stimuli for children with autism spectrum disorders and thus pose a challenge for researchers in obtaining such samples from both ethical and methodological reasons. Therefore, various non-invasive methods of ANS activity detection have been developed. 
Non-invasive methods 
To assess autonomic nervous system activity, various non-invasive methods are used. For example, measurement of sympathetic skin response is used frequently (Claus & Schondorf 1999, Kucera et al 2004). This method is based on determination of the alterations in skin electrical resistance in response to activation of sweat glands which are stimulated by impulses conducted by cholinergic postganglionic sympathetic fibers. However, it is important to note, that in general, skin conductance level are not stable and therefore it is difficult to define baseline values and there are large intra- and inter-individual differences (Boucsein et al 2012). Another widely used method has become pupillometry, biomarker of LC-NE system. Several studies found both dysregulated tonic pupil responses to various stimuli (e.g. Anderson et al 2006, Martineau et al 2011) and greater skin conductance level (Prince et al 2016) in children with ASD. One of the most reliable methods for measurement of ANS activity, namely cardiac autonomic responses, has become heart rate variability (HRV). HRV refers to beat-to-beat variations of the heart rate that is determined by autonomic nervous system. In resting conditions, the variability of beat-to-beat intervals remains large and becomes more regular when influenced by stressful environmental factors (Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology 1996). Because of the fast degradation of acetylcholine by acetylcholinesterase, the influence of parasympathetic activation is quick and thus accounts for fast changes in heart rate. Sympathetic influence changes more slowly, its effect is observable as a change in heart rate after longer period, and thus is responsible for slower oscillations. HRV has been found to be decreased in autism spectrum disorders in number of studies (Daluwatte et al 2013, Ming et al 2005). These data

Interventions affecting vagal activity for adjuvant treatment of children with ASD 

In the light of above mentioned findings, several new treatment options are now being explored. Vagus nerve stimulation, which involves surgical implantation of electrodes around cervical portion of the vagus nerve, was found to increase HRV. Study of Hull et al (2015) showed decreased severity and duration of seizures in children with refractory epilepsy and autism after stimulation of vagus nerve. Moreover, they found the improvement in ASD symptoms not related to epilepsy, such as communication skills, or stereotyped behavior. Furthermore, considerable improvement in regulation of aggressive behavior and receptive communication skills were noted and maintained over 1 year. The biggest drawback of vagus nerve stimulation method is cost and requirement of invasive neurosurgery. However, recent studies confirmed the possibility of noninvasive transcutaneous stimulation of the vagus nerve with electrodes located in the auricular concha area that is densely innervated by branches of the vagus nerve (Fang et al 2016). Electrical stimulation of the cervical vagus nerve with handheld device represent another non-invasive method (Schoenen et al 2016). In preterm infants or high-risk infants, kangaroo care or massage therapy may increase vagal tone and promote optimal neurodevelopment (Feldman & Eidelman 2003). Similar preliminary data were obtained on children with ASD, as well (Escalona et al 2001).

This new clinical trial looks very interesting because it includes looking at predictors for responders:-

The specific aim of this study is to examine the effects of serial doses of propranolol on social interaction, and secondarily on language tasks, anxiety, adaptive behaviors, and global function in high functioning adults and adolescents with autism in a double-blinded, placebo-controlled trial. The investigators will also examine whether response to treatment can be predicted based upon markers of autonomic functioning, such as skin conductance, heart rate variability (HRV), and the pupillary light reflex (PLR), and whether anxiety can predict treatment response. The hypothesis is that social functioning and language abilities will benefit from serial doses of propranolol, and that those with the greatest degree of autonomic dysregulation, or the lowest functional connectivity, will demonstrate the greatest benefit from the drug.

Propanolol will be given on a titration schedule in which participants will begin with small doses (single capsules) of the drug and increase to a larger dosage (divided over 3 capsules) over the course of three weeks. Participants aged 15-24 years will undergo an MRI.

 Autonomic Dysfunction in Autism


Objective: To report a case series of clinically significant autonomic dysunction in ASD. 
Background:Autonomic nervous system (ANS) impairment has been increasingly recognized in autism spectrum disorders (ASD). Abnormalities in pupillary light reflex, resting heart rate, heart rate response to social cognitive tasks, respiratory rhythm, and skin conductance suggest that autonomic dysfunction is common in ASD and may play a role in the social, behavioral, and communication problems that are the hallmark of this neurodevelopmental disorder. This case series confirms the presence of clinically significant multisystem ANS dysfunction in ASD. 
Methods: Patients with a history of ASD who underwent an evaluation for ANS dysfunction at our institution were identified. Clinical features, findings on autonomic testing, and laboratory results were reviewed.
Results: Six patients with ASD underwent clinical and autonomic evaluation, ranging in age from 12 to 28, and autonomic symptom duration ranging from 10 months to 6 years. All reported postural lightheadedness, near-syncope, and rapid heart rate. Five reported significant gastrointestinal (GI) symptoms including constipation, diarrhea, and early satiety. Autonomic testing revealed an excessive postural tachycardia with head-up tilt (HUT) in all patients, with a mean heart rate (HR) increment of 50 bpm, mean maximum HR on HUT of 118 bpm, absence of orthostatic hypotension on HUT. Abnormal blood pressure profile with the Valsalva maneuver was identified in three patients. All five patients were diagnosed with orthostatic intolerance. Supine norepinephrine (NE) was low in three of the four patients tested and an inadequate rise in standing NE was noted in two of these patients. GI motility testing was performed in two patients, and suggested gastroparesis in one patient.
Conclusions: Clinically significant ANS dysfunction may occur in ASD, with symptoms suggestive of orthostatic intolerance and gastrointestinal dysmotility, and findings on autonomic testing demonstrating an excessive postural tachycardia.

Functional autonomic nervous system profile in children with autism spectrum disorder


Autonomic dysregulation has been recently reported as a feature of autism spectrum disorder (ASD). However, the nature of autonomic atypicalities in ASD remain largely unknown. The goal of this study was to characterize the cardiac autonomic profile of children with ASD across four domains affected in ASD (anxiety, attention, response inhibition, and social cognition), and suggested to be affected by autonomic dysregulation.


We compared measures of autonomic cardiac regulation in typically developing children (n = 34) and those with ASD (n = 40) as the children performed tasks eliciting anxiety, attention, response inhibition, and social cognition. Heart rate was used to quantify overall autonomic arousal, and respiratory sinus arrhythmia (RSA) was used as an index of vagal influences. Associations between atypical autonomic findings and intellectual functioning (Weschler scale), ASD symptomatology (Social Communication Questionnaire score), and co-morbid anxiety (Revised Children’s Anxiety and Depression Scale) were also investigated.


The ASD group had marginally elevated basal heart rate, and showed decreased heart rate reactivity to social anxiety and increased RSA reactivity to the social cognition task. In this group, heart rate reactivity to the social anxiety task was positively correlated with IQ and task performance, and negatively correlated with generalized anxiety. RSA reactivity in the social cognition task was positively correlated with IQ.


Our data suggest overall autonomic hyperarousal in ASD and selective atypical reactivity to social tasks.

The Vagus nerve as a means to affect the ANS 

Vagal Nerve Stimulation in Autonomic Dysfunction – A Case Study

Background: Autonomic nervous system function is influenced by the balance of the parasympathetic and sympathetic systems. Management for imbalance of these components causing dysfunction is largely focused on medications primarily improving cardiovascular tone. However, there appears to be an opportunity for therapy by modulating neurotransmission. Methods: Our patient is a nine year old female with history of intractable epilepsy and developmental delay related to confirmed genetic abnormalities and also complaints of episodic pallor, fatigue, light-headedness and headaches concerning for dysautonomia. Results: Our patient underwent vagal nerve stimulator (VNS) implantation for treatment of epilepsy and showed improvement of these symptoms at typical settings. Headup tilt test (HUTT) was subsequently performed and revealed normal findings and no subjective symptoms of autonomic dysfunction. A repeat HUTT was performed five months later with VNS output currents set to zero and revealed cardiovascular changes and clinical symptoms consistent with dysautonomia. With resumption of previous VNS settings, clinical symptoms resolved.

Conclusions: Neurotransmission from vagal afferents to brainstem nuclei is increased during VNS affecting multiple brainstem areas and the cerebral cortex, including regions controlling autonomic function. Studies have suggested a role for VNS in patients with clinical signs of autonomic dysfunction showing improvement in sympathovagal balance after VNS implantation. In our patient, we observed subjective and objective improvement in autonomic function. This initial case demonstrates a phenomenon that requires further study, may lead to improved understanding of autonomic function and the response to vagal nerve stimulation, and possibly a new indication for VNS therapy.

The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to the maintenance of cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant, and this change in dominance is negatively correlated with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that the extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be attributable to activation of the afferent branch of the vagus and, potentially, other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

The Vagus Nerve as a target to reduce inflammation
Regardless of its effects on the autonomic nervous system (ANS), we know from the research in earlier blog posts that vagus nerve stimulation can significantly reduce inflammation.  Here is an easy to read article as a reminder.

Vagus Nerve Stimulation Dramatically Reduces Inflammation

Stimulating the vagus nerve reduces inflammation and the symptoms of arthritis.

Healthy vagal tone is indicated by a slight increase of heart rate when you inhale, and a decrease of heart rate when you exhale. Deep diaphragmatic breathing—with a long, slow exhale—is key to stimulating the vagus nerve and slowing heart rate and blood pressure, especially in times of performance anxiety.
A higher vagal tone index is linked to physical and psychological well-being. Conversely, a low vagal tone index is associated with inflammation, depression, negative moods, loneliness, heart attacks, and stroke.

There are many ways put forward to  stimulate the vagus nerve simply without electrical devices. Here is one list I came across:-

1.     Slow deep breathing. An example would be to breathe in slowly for a count of 4 and out for a count 6 to 8. The average normal breathing rate is between 12 and 14 per minute. This slow breathing reduces it to 6 to 7 per minute.
2.     Any exposure to cold. eg rinse your hands and face in cold water.
3.     Singing, chanting, gargling and humming
4.     Laughter
5.     Restorative yoga postures such as the cat cow posture and downward dog
6.     Meditation.
7.     Evoking the emotions of love, compassion and empathy.
8.     Exercise
9.     Massage/acupuncture, acupressure
10. Intermittent fasting

I found re-reading this old post interesting

Drinking Baking Soda for Vagal Nerve Stimulation?

It prompted me to order some potassium bicarbonate.


I think when you read about what the Autonomic Nervous System (ANS) does in your body you are likely to be able to judge whether or not it may be dysfunction. Hopefully the research will identify reliable markers, whether it is heart rate variability (HRV) or pupillary light reflex (PLR).
I do not think Autonomic Nervous System (ANS) dysfunction is a cause of autism, but it may be a consequence of it. Correcting any such dysfunction may have an impact ranging from trivial to profound.
I know that some readers of this blog have been using Propranolol for some time already. It has been very well researched, by the standards of autism. Being a cheap generic drug, there is little interest to spend $8 million in Europe to have it approved for autism, or the $20 million needed in the US. 
It should be noted that while Propranolol is a very widely used drug it does have side effects and interactions. Some other autism drugs used off-label do reduce blood pressure.
Propranolol is a competitive antagonist of beta-1-adrenergic receptors in the heart. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to beta 1 receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA production. This results in less calcium influx to cardiac myocytes through voltage gated L-type calcium channels meaning there is a decreased sympathetic effect on cardiac cells, resulting in antihypertensive effects including reduced heart rate and lower arterial blood pressure.

One side effect of Propranolol is low heart rate (bradycardia), but some people do have too high a heart rate.
Propranolol is a so-called negative inotropic agent, meaning it reduces the strength of contractions of heart muscle. This is why it reduces blood pressure.
Negative inotropic effects can be additive, which means not surprisingly if you take another negative inotropic agent, like an L-type calcium channel blocker, you have to be careful.
There are medical conditions for which the combined use of Propranolol and Verapamil has been suggested, but at the high doses often used this looks rather unwise.
There are interactions between Propranolol and many drugs; note that Verapamil will raise the serum level of propranolol.
The good news is that the dosage often effective in autism is quite low.

The adult dose for Migraine Prophylaxis is up to 240mg a day.  Some of the regular pediatric doses are also huge, compared to the “autism dosage” which can be 40mg of even less.
The initial paper we looked at in this post, from ultra-sceptical that autism can be treated England, concluded:

 “… randomised controlled trials are warranted to explore the efficacy of propranolol in managing EBAD (emotional, behavioural and autonomic dysregulation) in ASD”
Are severe headaches that occur in some autism another possible predictor of Propranolol responders?

Is stuttering another symptom to look out for?

Wednesday, 30 August 2017

Acid-sensing Ion Channels (ASICs) and Autism – Acid in the Brain

Acid sensing ion channels (ASICs) are another emerging area of science where much remains known.  It would seem that ASICs have evolved for a good reason, when pH levels fall they trigger a reaction to compensate.  (The lower the pH the higher is the acidity)  In some cases, like seizures, this seems to work, but in other cases the reaction produced actually makes a bad situation worse.

Research is ongoing to find inhibitors of ASICs to treat specific conditions raging from MS (Multiple Sclerosis), Parkinson’s and Huntington’s to depression and anxiety. Perhaps autism should be added to the list.
NSAIDs like ibuprofen are inhibitors of ASICs.
The complicated-looking chart below explains the mechanism.  The ASIC is on the left, also present is a voltage-gated calcium channel (VGCC) and an NMDA receptor. We already know that VGCCs can play a key role in autism and mast cell degranulation. Similarly we know that in autism there is very often either too much or too little NMDA signaling. Here we have all three together.

The role of ASICs is to sense reduced levels of extracellular pH (i.e. acidity outside the cell) and result in a response from the neuron. Under increased acidic conditions, a proton (H+) binds to the channel in the extracellular region, activating the ion channel and opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions.

All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization.

Voltage-gated Ca2+ channels are then activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released.

NMDA receptors are also activated and this results in more influx of calcium into the cell.

This calcium inflow then triggers further reactions via CaMKII (calmodulin-dependent protein kinase II).

The overall effect is likely to damage the cell.

There is also an important effect on dendritic spines:-

“ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca2+]i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures”

In general the research is looking to inhibit ASICs to improve a variety of neurological conditions.

Acid in the Brain

ASICs only become activated when there is acidity (low pH).  When the pH is more than 6.9 they do nothing at all.
Unfortunately, in many neurological disorders pH is found to be abnormally low and that includes autism.
ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca2+permeability and an inward flow of Ca2+. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death.
However in the case of epilepsy, ASIC1a channels can be helpful.  Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. 

Changes in the brain pH level have been considered an artifact, therefore substantial effort has been made to match the tissue pH among study participants and to control the effect of pH on molecular changes in the postmortem brain. However, given that decreased brain pH is a pathophysiological trait of psychiatric disorders, these efforts could have unwittingly obscured the specific pathophysiological signatures that are potentially associated with changes in pH, such as neuronal hyper-excitation and inflammation, both of which have been implicated in the etiology of psychiatric disorders. Therefore, the present study highlighting that decreased brain pH is a shared endophenotype of psychiatric disorders has significant implications on the entire field of studies on the pathophysiology of mental disorders.

This research raises new questions about changes in brain pH. For example, what are the mechanisms through which lactate is increased and pH is decreased? Are specific brain regions responsible for the decrease in pH? Is there functional significance to the decrease in brain pH observed in psychiatric disorders, and if so, is it a cause or result of the onset of the disorder?. Further studies are needed to address these issues.

The following paper is mainly by Japanese researchers and is very thorough; it will likely make you consider brain acidosis as almost inevitable in your case of autism. 

Lower pH is a well-replicated finding in the post-mortem brains of patients with schizophrenia and bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding  reflects a primary feature of the diseases or is a result of confounding factors such as medication, post-mortem interval, and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies.  In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar  disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then  utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis  that lower brain pH exists in these brains compared to controls due to the underlying pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific  calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and  one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same post-mortem interval and agonal state at death. Upon post-mortem examination, we observed  significantly lower pH and higher lactate levels in the brains of model mice relative to controls. There was a significant negative correlation between pH and lactate levels. These results suggest that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather than mere artefacts.
A number of postmortem studies have indicated that pH is lower in the brains of patients with schizophrenia and bipolar disorder. Lower brain pH has also been observed in patients with ASD. In general, pH balance is considered critical for maintaining optimal health, and low pH has been associated with a number of somatic disorders. Therefore, it is reasonable to assume that lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of various psychiatric disorders.            

Researches have revealed that brain acidosis influences a number of brain functions, such as anxiety, mood, and cognition. Acidosis may affect the structure and function of several types of brain cells, including the electrophysiological functioning of GABAergic  neurons and morphological properties of oligodendrocytes. Alterations in these types of cells have been well-documented in the brains of patients with schizophrenia, bipolar disorder, and ASD and may underlie some of the cognitive deficits associated with these disorders. Deficits in GABAergic neurons and oligodendrocytes have been identified in the mouse models of the disorders, including Shn2 KO mice. Brain acidosis may therefore be associated with deficits in such cell types in schizophrenia, bipolar disorder, and ASD.

Interestingly, we observed that Wnt- and EGF-related pathways, which are highly implicated in somatic and brain cancers, are enriched in the genes whose expressions were altered among the  five mutant mouse strains.

These findings raise the possibility that elevated glycolysis underlies the increased lactate and pyruvate levels in the brains of the mouse models of schizophrenia, bipolar disorder, and ASD.

Dysregulation of the excitation-inhibition balance has been proposed as a candidate cause of schizophrenia, bipolar disorder, and ASD. A shift in the balance towards excitation would result in increased energy expenditure and may lead to increased glycolysis.

University of Iowa neuroscientist John Wemmie is interested in the effect of acid in the brain (not that kind of acid!). His studies suggest that increased acidity—or low pH—in the brain is linked to panic disorders, anxiety, and depression. But his work also indicates that changes in acidity are important for normal brain activity too.

“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, associate professor of psychiatry in the UI Carver College of Medicine. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.
“Brain activity is likely different in people with brain disorders such as bipolar or depression, and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day: Could this signal be abnormal or perturbed in human psychiatric disease? And if so, might it be a target for manipulation and treatment?”

Panic attacks as a problem of pH

An easy to read article from the Scientific American

Dendritic Spines and ASICS

The present results and previous studies suggest that ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca2+]i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures (Xiong et al., 2004; Yermolaieva et al., 2004; Gao et al., 2005; Friese et al., 2007; Ziemann et al., 2008). Interestingly, one previous report suggested increased ASIC2a expression in neurons surviving ischemia, although the functional consequence of those changes are uncertain (Johnson et al., 2001). Moreover, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation (Bernardinelli et al., 2007; Girirajan et al., 2007; Stone et al., 2007). Thus, we speculate that ASIC1a and ASIC2, working in concert, may regulate neuronal function in a variety of disease states  

ASICs in neurologic disorders

Role of ASICs
Parkinson’s disease
Lactic acidosis occurs in the brains of patients with PD.
Amiloride helps protect against substantia nigra neuronal degeneration, inhibiting apoptosis.
Parkin gene mutations result in abnormal ASIC currents.
Huntington’s disease
ASIC1 inhibition enhances ubiquitin-proteasome system activity and reduces huntingtin-polyglutamine accumulation.
ASIC3 is involved in: 1) primary afferent gastrointestinal visceral pain, 2) chemical nociception of the upper gastrointestinal system, and 3) mechanical nociception of the colon.
Blocking neuronal ASIC1a expression in dorsal root ganglia may confer analgesia.
NSAIDs inhibit sensory neuronal ASIC expression.
Cerebral ischemia
Neuronal ASIC2 expression in the hypothalamus is upregulated after ischemia.
Blockade of ASIC1a exerts a neuroprotective effect in a middle cerebral artery occlusion model.
Most dural afferent nerves express ASICs.
Multiple sclerosis
ASIC1a is upregulated in oligodendrocytes and in axons of an acute autoimmune encephalomyelitis mouse model, as well as in brain tissue from patients with multiple sclerosis.
Blockade of ASIC1a may attenuate myelin and neuronal damage in multiple sclerosis.
Intraventricular injection of PcTX-1 increases the frequency of tonic-clonic seizures.
Low-pH stimulation increases ASIC1a inhibitory neuronal currents.
Malignant glioma
ASIC1a is widely expressed in malignant glial cells.
PcTx1 or ASIC1a knock-down inhibits cell migration and cell-cycle progression in gliomas.
Amiloride analogue benzamil also produces cell-cycle arrest in glioblastoma.

One logical question is whether the brain ASIC connection with autism connects to the common  gastrointestinal problems, some of which relate to acidity and are often treated with H2 antihistamines and proton pump inhibitors (PPIs).

Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.

It looks like it is still early days in the research into ASICs and GI problems. Best look again in decade or two.  

Too Much Lactic Acid – Lactic Acidosis 
One theory is that panic attacks are cause by too much lactic acid.
In earlier posts of mitochondrial disease and OXPHOS, we saw that when the mitochondria have too little oxygen they can continue to produce ATP, but lactate accumulates and this leads to lactic acidosis.
So people with mitochondrial disease might have some degree of lactic acidosis that would reduce extracellular pH and activate ASICs.
So perhaps along with those prone to panic attacks, people with regressive autism and high lactate might benefit from an ASIC inhibitor?
Aerobic exercise is suggested to reduce excess lactate, although extreme exercise like running a marathon will actually make more.  Moderate exercise has the added advantage of stimulating the production of more mitochondria.
So moderate exercise for panic disorders and regressive autism (mitochondrial disease).   Moderate exercise is then an indirect ASIC inhibitor, because it should increase pH (less acidic). 

ASICs in panic and anxiety?

Acid sensing ion channels (ASICs) generate H+-gated Na+ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Recent genome-wide studies have associated SNPs near ASIC2 with autism (Stone et al., 2007), panic disorder (Gregersen et al., 2012), response to lithium treatment in bipolar disorder (Squassina et al., 2011) and citalopram treatment in depressive disorder (Hunter et al., 2013), and have implicated a copy number variant of ASIC2 with dyslexia (Veerappa et al., 2013). However, little is currently understood about whether ASIC2 is required for normal behavior.

The goals of this study were to better understand the role of ASIC2 in brain function. Thus our first aim was to localize ASIC2 subunits. Because ASIC2 subunits multimerize with ASIC1 subunits, we hypothesized that the distribution of the two subunits would show substantial overlap. In addition, given that ASIC channels in central neurons missing ASIC2 have altered trafficking and biophysical properties, we hypothesized that disrupting expression of ASIC2 would impact behavior. Therefore, we asked if mice missing ASIC2 would have altered behavioral phenotypes, and whether disrupting both ASIC1 and ASIC2 would have the same or greater behavioral effects than disrupting either gene alone. Because we found that ASIC2, like ASIC1, was highly expressed in brain regions that coordinate responses to threatening events, we focused on tests that evaluate defensive behaviors and reactions to stressful and aversive stimuli.
These results suggest that ASIC channels can influence synaptic transmission. We speculate that pH falls to the greatest extent with intense synaptic activity; the mechanism might involve release of the acidic contents of synaptic vesicles, transport of HCO3 or H+ across neuronal or glial cell membranes, and/or metabolism. The reduced pH could activate ASIC channels leading to an increased [Ca2+]i (Xiong et al., 2004; Yermolaieva et al., 2004; Zha et al., 2006). In this scenario, the main function of ASIC channels would be to enhance synaptic transmission in response to intense activity. This would explain the pattern of abnormal behavior in ASIC null mice when the stimulus is very aversive.

Translating ASIC research into therapy
As you may have noticed in the first chart in this post, there already exist ways to inhibit ASICs, ranging from a diuretic called Amiloride to NSAIDs, like ibuprofen.  The process of translating science into medicine has already begun in multiple sclerosis, as you can see in the following study:-

Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. 

Agmatine and Spermine
In the graphic at the start of this post you might have noticed Agmatine and Spermine.  While ASICs are acid sensing and so activated by protons, they appear to be also activated by other substances.
The arginine metabolite agmatine may be an endogenous non-proton ligand for ASIC3 channels.
Extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.
However, other research shows spermine promotes autophagy and has been shown to ameliorate ischemia/reperfusion injury  (IRI) and suggests its use in children to prevent IRI .  
So nothing is clear cut.
It looks like spermine, spermidine and agmatine all promote autophagy.            
Agmatine gets converted to a polyamine called putrescene.

Personally, I expect polyamines will generally be found beneficial in autism, but there will always be exceptions.  

There is a case to be made for the use of the diuretic amiloride to treat MS and indeed panic disorders.
Will amiloride help autism? You would not want to use it if there is comorbid epilepsy, since ASICs are “seizure protective”. 
If your genetic testing showed an anomaly with the ASIC2 gene, which is known to occur in both autism and MR/ID, then amiloride would seem a logical therapy.
I think we should not be surprised if people with neurological conditions have lower pH brains than NT people, just like we should expect them to show signs of oxidative stress.
If you do indeed happen to have a rather acidic brain, as seems to be quite often the case, damping down the response from ASICs might make things better or worse, or in indeed a mixture of the two. You would hope, at least in some people, that ASICs provide some beneficial response on sensing low pH.
It would be useful if a researcher did a trial of amiloride in different types of autism, then we might have some useful data. You would think the Japanese researchers would be the ones to do this.
One good thing about amiloride is that it increases the level of potassium in your blood and there even is a combined bumetanide/amiloride pill.  Bumetanide has the side effect of lowering potassium.
Many people with autism find NSAIDs beneficial, either long term or for flare-ups. NSAIDs have many beneficial effects; just how important is ASIC inhibition is an open question.
Is the anxiety that many people with autism seem to suffer, sometimes related to ASICs?  Perhaps it is just a minor panic disorder and it relates to ASIC1 and ASIC2.  I think there are numerous different dysfunctions that produce what we might term “anxiety”, among the long list one day you may well find ASICs.
Science has a long way to go before there is a complete understanding of this subject.
Moderate exercise again appears as a simple therapy with countless biological benefits, in this case reducing lactate and thus reducing acidity (increasing pH).