Showing posts with label Autonomic. Show all posts
Showing posts with label Autonomic. 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?

Tuesday 13 May 2014

“Spray Fire in my Head” and how putting it out with Verapamil links Histamine, IL6, Mast cells, Calcium Channel Cav1.2, and even the Vagus Nerve

After 18 months of researching autism, things are falling nicely into place.  For regular readers of this blog, it may seem that we have uncovered a bewildering number of issues/dysfunctions that need to be addressed by the science.  In fact, when you look closer still, you will see that many of these issues are interrelated and you do not need to treat each one.  Also, it is clear that many different methods can be used to treat the same dysfunction.  The best methods though would be the simplest, safest, cheapest and the ones that address multiple issues at once.

One such little gem is Verapamil, an extremely cheap calcium channel blocker that has been widely used for 30 years for other conditions. 

Spray Fire in my Head

Monty, aged 10 with ASD, suffers from allergies like many children.  I noticed that his pollen allergy provoked a dramatic increase in his autistic behaviors.  Last year I spent time developing a treatment for these summertime autism flare-ups, to avoid summertime misery for all of us.

My final secret weapon was not a commonly known allergy drug; in fact almost nobody would even consider it for this purpose, except those who read the old research.

Where we live, last the weekend the air was full of tree pollen and it was 280 C/ 820 F; so I was expecting a response from Monty.

He soon had red eyes, briefly rolled about on the floor and declared “spray fire in my head”.

In anticipation of the pollen season, for the last few weeks I have been giving him some mast cell stabilizing treatments, but clearly they were not sufficient; so I mixed up some extra verapamil, and as expected, a few minutes later peace was fully restored.

I have told you about channelopathies in previous posts.  Verapamil blocks the calcium channel called Cav1.2, but I did not tell you that in addition to this Cav1.2 channel affecting behavior and heart disease, it also appears to directly affect allergies and even the vagus nerve.

It would seem that one cheap little pill can address all of these issues.

The take-home points from the literature are these:-

Verapamil is very widely prescribed calcium channel blocker, used to lower blood pressure; but in the literature it is shown that:-
  • Verapamil inhibits mast cells and is shown to successfully treat asthma
  • Verapamil is more potent than the allergy drug Azelastine (the best mast cell stabilizing anti-histamine drug available)
  • Verapamil will reduce histamine release and therefore inflammatory cytokine Interleukin-6 (IL6), already elevated in autism
  • Verapamil activates the Gene for IL6
  • Verapamil alters the balance between parts of the autonomic nervous system's function, with a shift toward decreased sympathetic tone and increased parasympathetic (vagus nerve) tone
  • Autism is associated with an atypical autonomic response to anxiety that is most consistent with sympathetic over-arousal and parasympathetic under-arousal.  So increasing the parasympathetic (vagus nerve) tone is desirable.
Verapamil, Allergies and Asthma

Pollen allergies are a common trigger for asthma, and since every year many people die from asthma, the underlying science is well researched/understood.

This study has demonstrated, for the first time, that mast cell tryptase potentiates the contractile response to histamine in human isolated airways. Moreover, this potentiation occurs only in tissues derived from patients whose bronchi exhibit a contractile response to antigen, i.e. which are sensitized. The potentiation was not observed in nonsensitized tissue. The mechanism underlying the tryptase-induced potentiation is related to Ca2+ flux through voltage-dependent channels, since it was inhibited by verapamil.

Inhibition of rat mast cell degranulation by verapamil.

Calcium antagonists, e.g. verapamil, prevent exercise-induced asthma. This protective effect may proceed from inhibition of contraction of bronchial smooth muscle, release of mediators by primary effector cells, e.g. mast cells, or both. Therefore, we studied the inhibitory effect of increasing concentrations of verapamil on both in vitro antigen-induced degranulation and ionophore A23187-induced release of labelled serotonin by rat peritoneal mast cells. There was a dose-dependent inhibition by verapamil of both ovalbumin-induced degranulation of mast cells passively sensitized by incubation with mice IgE-rich serum and ionophore-induced release of tritiated serotonin by mast cells previously incubated with (3H)-5HT; the 50% inhibiting concentration was 1.4 X 10(-4) mol I-1 and 5.2 X 10(-5) mol I-1, respectively. An attractive explanation of our results is that verapamil inhibits the antigen-induced release of mediators by mast cells through its calcium antagonist effect. Our results also suggest that the preventing effect of calcium antagonists on asthma may be multi-factorial since other authors have clearly shown that these drugs inhibit contraction of guinea-pig tracheal smooth muscle in vitro.


The inhibition of mediator released by Azelastine may help to explain their protective action in anaphylaxis. Our observations are in agreement that Azelastine exerts inhibitory effect on synthesis and release of chemical mediators from mast cell (Chand et al., 1983), including the leukotrienes (Hamasaki et al., 1996).

 Azelastine is a second-generation antihistamine approved for treatment ofallergic conditions. This randomized, double-blind, placebo- and active-controlled, parallel group clinical trial evaluated the efficacy and safety of Azelastine in patients with moderate to-severe seasonal allergic conditions (Shah et al., 2009).  Reussi et al. (1980) have demonstrated the inhibition of release of chemical mediators from mast cells by Ca++ channel blocker in animals in vivo and demonstrate the inhibition of antigen-induced brocho-constriction by Verapamil in sheep, allergic to ascaris sum antigen but Verapamil failed to block in the same non-sensitized animal. It is speculated that calcium channel blocker protect against the allergic broncho-constriction predominantly by preventing the release of chemical mediators from the mast cells.

Fig. 2. Graph shows dose dependent inhibitory effect of Azelastine and Verapamil with the treatment of EC50 ovalbumin. Line in the box indicates the ovalbumin EC50 induced contraction (Control). Each point represent mean of six observationsSyed Saud Hasan et al. 49  On the other hand Henderson et al. (1983) found significant inhibition of allergic response with Nifedipine and Lee at al. (1983) also supported the finding, which observed inhibition of mediator release from human lung in vitro by Verapamil.

   Verapamil in concentration 10-10 g/ml did not exhibit any inhibition but as the concentration increases to 10-9 g/ml showed marked inhibition in contractile effect of ovalbumin EC50 (0.3x10-6). Further increases in concentration of Verapamil i.e. 10-8 g/ml completely antagonized the ovalbumin induced contraction. Azelastine in concentration of 10-9 g/ml (1ng/ml) did not exhibit any inhibition as the concentration increase to 10-8 g/ml showed mark inhibition i.e. 20% contraction to EC50 (0.3x10-6) ovalbumin, when compared before treatment with Azelastine and the concentration 10-7 g/ml antagonized the effect of EC50 (Table and Figure 2).

CONCLUSION It can be inferred from the observations that response produced by antigen can be controlled better with Verapamil than Azelastine and emerging with similar activity regardless of exact mechanism involved.

Verapamil and the IL-6 Gene

Conclusions—The results demonstrate that CCB of all 3 subclasses are capable of activating NF-IL6 and NF-kB. CCB may thus directly regulate cellular functions by affecting the activity of transcription factors independent of changes of intracellular calcium concentrations, an observation that is of interest considering the biological effects induced by CCB.

A major result of our investigations is the discovery of the activation of  transcription factors resulting from CCB treatment. In general, CCB are postulated to exert their biological effects by decreasing the intracellular concentration of calcium ions.1–4 Experimentally, this effect is usually achieved at micromolar concentrations of the drugs. However, accumulating evidence suggests that CCB, used at therapeutically effective doses (ie, at the nanomolar range), activate calcium in dependent signal transduction pathway(s) altering gene expression.14–17 Here, we show that CCB directly activate the transcription factors NF-IL6 and NF-kB in human VSMC, independent of intracellular calcium levels. This is supported by the existence of multiple regulatory regions within the intracellular part of the L-type calcium channel. It remains to be investigated, however, along which signal transduction pathway this action of CCB occurs.

Verapamil and the Vagus Nerve

Two of the most popular subjects on this blog are “autism and allergies” and “autism and the vagus nerve”.

The vagus nerve connects many parts of the body and seems to be a conduit for inflammatory signaling within the body.  It is deeply involved the process leading to arthritis and epilepsy; by stimulating this nerve with electrical signals, both epilepsy and arthritis can be reduced markedly in certain people.  It is often suggested that the GI problems in many autistic people and linked to aberrant behaviors via the vagus nerve, what some call the “gut brain connection”.

To understand what is going on and why is does affect autism we need to introduce something new, the autonomic nervous system.  For those who already know about this, the interesting finding is that:-

Verapamil alters the balance between parts of the autonomic nervous system's function  with a shift toward decreased sympathetic tone and increased parasympathetic (vagus nerve) tone.

The source of this statement is:

and their sources were:-

We learned in an earlier post about autism and the Vagus Nerve that it seems to link many strange things in autism.

We learned from Professor Porges that, for example, the neural mechanism for making eye contact is shared with those needed to listen to the human voice; people with autism struggle with both.  Anything that can “wake up” the vagus nerve system could be interesting.

In the complicated science we will see that the vagus nerve is also called the parasympathetic nervous system.  The paper below shows how this parasympathetic (Vagus) system is out of balance with the opposing sympathetic nervous system, this then leads to anxiety commonly found in autism.

Assessment of anxiety symptoms in autism spectrum disorders (ASD) is a challenging task due to the symptom overlap between the two conditions as well as the difficulties in communication and awareness of emotions in ASD. This motivates the development of a physiological marker of anxiety in ASD that is independent of language and does not require observation of overt behaviour. In this study, we investigated the feasibility of using indicators of autonomic nervous system (ANS) activity for this purpose. Specially, the objectives of the study were to 1) examine whether or not anxiety causes significant measurable changes in indicators of ANS in an ASD population, and 2) characterize the pattern of these changes in ASD. We measured three physiological indicators of the autonomic nervous system response (heart rate, electrodermal activity, and skin temperature) during a baseline (movie watching) and anxiety condition (Stroop task) in a sample of typically developing children (n = 17) and children with ASD (n = 12). The anxiety condition caused significant changes in heart rate and electrodermal activity in both groups, however, a differential pattern of response was found between the two groups. In particular, the ASD group showed elevated heart rate during both baseline and anxiety conditions. Elevated and blunted phasic electrodermal activity were found in the ASD group during baseline and anxiety conditions, respectively. Finally, the ASD group did not show the typical decrease in skin temperature in response to anxiety. These results suggest that 1) signals of the autonomic nervous system may be used as indicators of anxiety in children with ASD, and 2) ASD may be associated with an atypical autonomic response to anxiety that is most consistent with sympathetic over-arousal and parasympathetic under-arousal.

The following explanation of the Autonomic Nervous System is edited from Wikipedia.

Autonomic Nervous System (ANS)

The autonomic nervous system (ANS) is the part of the peripheral nervous system that acts as a control system that functions largely below the level of consciousness to control functions,] including heart rate, digestion, respiratory rate, salivation, perspiration, pupillary dilation, micturition (urination), sexual arousal, breathing and swallowing. Most autonomous functions are involuntary but they can often work in conjunction with the somatic nervous system which provides voluntary control.

The ANS is divided into three main sub-systems:

PSNS is often considered the "rest and digest" or "feed and breed" system
SNS is often considered the "fight or flight" system
ENS consists of a mesh-like system of neurons that governs the function of the gastrointestinal system

Depending on the circumstances, these sub-systems may operate independently of each other or interact co-operatively.

In many cases, PSNS and SNS have "opposite" actions where one system activates a physiological response and the other inhibits it. The modern characterization is that the sympathetic nervous system is a quick response mobilizing system and the parasympathetic is a more slowly activated dampening system.

In general, ANS functions can be divided into sensory (afferent) and motor (efferent) subsystems. Within both, there are inhibitory and excitatory synapses between neurons. Relatively recently, a third subsystem of neurons that have been named 'non-adrenergic and non-cholinergic' neurons (because they use nitric oxide as a neurotransmitter) have been described and found to be integral in autonomic function, in particular in the gut and the lungs

Neurotransmitters and pharmacology

At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with other cotransmitters such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla:
  • Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglionic neurotransmitter of parasympathetic neurons.
  • Nerves that release acetylcholine are said to be cholinergic. In the parasympathetic system, ganglionic neurons use acetylcholine as a neurotransmitter to stimulate muscarinic receptors.
  • At the adrenal medulla, there is no postsynaptic neuron. Instead the presynaptic neuron releases acetylcholine to act on nicotinic receptors. Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream, which acts on adrenoceptors, producing a widespread increase in sympathetic activity.

 Circulatory system


β1, (β2): increases
M2: decreases


α2: aggregates
β2: inhibits

Endocrine system

α2: decreases insulin secretion from beta cells, increases glucagon secretion from alpha cells
M3:[ increases secretion of both insulin and glucagon.[16][17]
N (nicotinic ACh receptor): secretes epinephrine and norepinephrine

Nerve "Wiring Diagram"

The PSNS (parasympathetic nerve system) is wired together via the Vagus Nerve
The SNS (sympathetic nerve system) is wired together via the splanchnic nerves.

Autonomic nervous system, showing splanchnic nerves in middle, and the vagus nerve as "X" in blue. The heart and organs below in list to right are regarded as viscera.
The viscera are mainly innervated parasympathetically by the vagus nerve and sympathetically by the splanchnic nerves.


For those of you that made it this far, here are my conclusions.

People who have autism and any kind of allergy, be it pollen, food intolerance, asthma or anything similar, might consider asking their doctor to let them trial a very low dose of Verapamil for a couple of days.  The effect is almost instant and so there is no point trialing it for weeks.  Verapamil will lower your blood pressure, in a dose dependent fashion.  The effective autism dose for a severe allergy case is about 1mg/kg.  The half-life varies person to person, so you might need two doses a day, or you might need three.

If you know an adult with severe asthma, look hard and you may see some very mild signs of autism (need for order, anxiety, lack of flexibility etc).

It appears that in all these cases, the gene CACNA1C is misbehaving to varying degrees in different parts of the body.  This gene produces the calcium channel Cav1.2.

You could check if you have the mutated gene, but I do not see the point.  It would only tell you what might happen.  To know what actually has happened, you would need to use proteomics

This emerging science will ultimately be able to provide biomarkers for neurological conditions like autism, depression, bipolar etc, so that the neurologist will know, with certainly, what specific dysfunctions each individual person has.  At that point, behavioral assessments and psychiatry will finally be consigned to history and people will get “smart drugs”, to treat precisely diagnosed neurological dysfunctions.