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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.

Discussion 
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


Conclusions

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:-

OBJECTIVE AND BACKGROUND:


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.

METHODS:


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.

RESULTS:


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.

CONCLUSIONS:


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

Abstract


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

         
           Background

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.

Methods

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.

Results

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.

Conclusions

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.

Conclusion

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?












35 comments:

  1. Hi Peter, started with 20 mg propanolol, he takes also tizanidine at night, do you know of any interaction?
    Valentina

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  2. Hi Peter. I've given Propranolol to my son in the past. The problem I've noted is that the effect ceases too fast (about 4 hours). So, wouldn't it be better to give 10 mg every 4 hours, instead of 40 mg once a day ? (I really don't know, and would like to know your opinion and from the rest of folks). Thanks.

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  3. Luis, the quoted half life is 10 hours, but some people metabolize drugs differently. You could try giving 10mg every 4 hours and see if the effect is better.

    There is an extended release version.

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    Replies
    1. HI Peter, thanks for these recent posts on Propranolol and the JHU/KK article on Bumetanide/Azosemide. So helpful as always. We are continuing with 2 mg bumetanide every morning and still happy with the greater connectedness this brings us - a big relief and improvement in quality of life. Here is my question: you have written about the positive effects in some kids of propranolol, but it does not appear to be part of the Polypill. I am wondering why that is - does it conflict with other elements of the polypill, or am I misreading the polypill information? Did you perhaps chose the Verapamil instead of propranolol because of lesser-supposed side effects? Thanks, Mira

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    2. Mira, different people will require their own tailor-made PolyPill. I am just sharing in my PolyPill what works for my one specific case.

      Some Bumetanide responders also respond well to Propranolol and some non-responders to Bumetanide also do very well with Propranolol.

      There are different biological causes of the anxiety often observed in autism and in the extreme case they lead to aggression and self-injury. You can be either, neither or both verapamil responsive to anxiety/aggression and propranolol responsive to anxiety/aggression.

      Doctors are taught not to combine Propanolol with Verapamil, but a small number actually now recommend it in certain specific circumstances.

      Many off-label drugs for autism affect heart rate and/or blood pressure. The individual person's reaction needs to be monitored to each drug and combinations. A combination might be perfectly safe in one person and harmful in another case.

      In my specific case I think there are multiple causes of anxiety, the primary one responds well to Verapamil. I think that Propranolol does provide some extra benefit, but not a profound one like for Luis, or Valentina. This is what should be expected. By looking at the behaviors of the child you probably can predict who the big responders will be.

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  4. Thank you, Peter. I'll try it.

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  5. Peter, what I found is contradictory information about propranolol and tizanidine, some say serious interaction, other places say less,could you give me your opinion?
    Valentina

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    Replies
    1. Valentina, tizanidine has many interactions. With propranolol it is stated that:

      Propranolol: (Moderate) Concurrent use of tizanidine with antihypertensive agents can result in significant hypotension. Caution is advised when tizanidine is to be used in patients receiving concurrent antihypertensive therapy.

      Many drugs repurposed for autism lower blood pressure and so you need to measure it and keep a record.

      The lower the dosage used the weaker any interaction will be.

      Delete
  6. Peter, you wrote about Butyrate and Miyairi previously. Any thoughts on AURX (https://www.tessmed.com/product/aurx/)

    Thanks

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    Replies
    1. SM, Al Czap who is behind this company is one of the people that has written to me in the past. I have no idea if his products are more effective than the other products. In my opinion the best products are prescription medications, many of which are very cheap and are all subject to strict quality controls, which supplements are not.

      Delete
  7. Ouch, feedbucket looks like it just stopped working. Maybe it is temporary, but it doesn't look like that.
    Peter, have you had thoughts on moving your blog to some other platform, or just adding new scripts for searching comments? What kind of help would you need?
    /L

    ReplyDelete
    Replies
    1. Was wondering about that too. I love Peter's blogspot.

      Delete
    2. Feedbucket is working again.

      http://feedbucket.com/?src=http%3A%2F%2Fepiphanyasd.blogspot.com%2Ffeeds%2Fcomments%2Fdefault%3Falt%3Drss

      Delete
  8. I love this post, it breaks down the thinking behind analyzing the ANS and options. Thank you for this Peter. What can be concerning to me as a parent weighing implanted VNS is that these implants are programmed to fire at intervals which effects HRV. These newer implants are suppossed to gauge HRV and be adaptive. The question to ask here is how does this adaptive mechanism work? It is also important to consider biophysics and engineering when considering implanted devices.

    I asked my son's neurologist more questions in regards to how VNS is impacted by nnEMF's in our environment she had no answer. I asked her about heart rate variability in response to exposures in the environment and was told that it is not as important in children. I asked why and was told I needed to take courses in Neuroscience.

    She ordered a 5 day EEG study and I had to decline as the EEG study would put a hot spot in our home. Why are we allowing pulsed nnEMFs in our homes and expecting to get accurate testing results?

    Yes HRV is important in the ANS and it is important regardless of your age. I don't understand the downplay of serious biological oxidative stressors that contribute to gliosis.


    https://www.npr.org/2018/01/17/578562873/are-implanted-medical-devices-creating-a-danger-within-us

    ReplyDelete
  9. Interesting drug for some people:
    Pimavanserin
    "Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A [5] receptors with high binding affinity (Ki 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki 0.44 nM). Pimavanserin shows low binding to σ1 receptors (Ki 120 nM) and has no appreciable affinity (Ki >300 nM) to serotonin 5-HT2B, dopamine (including D2), muscarinic acetylcholine, histamine, or adrenergic receptors, or to calcium channels."
    (Wikipedia)

    /Ling

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  10. Hello Friends and Community,

    Hope everyone is doing well!

    I just found the following "PR" for an expensive report on the Autism drug pipeline, and thought I would share the link as it at least provides the names of the relevant companies for reference:

    https://www.businesswire.com/news/home/20190429005912/en/Autism---Pipeline-Review-H1-2019--

    I'm also providing the link to a new paper on the connection between Shank3 mutations and sleep issues:

    https://elifesciences.org/articles/42819

    Have a great night everyone - and don't stay up late reading the above, it can wait until tomorrow ;)

    AJ

    ReplyDelete
  11. Here is some interesting research on Toxoplasmosis Gondii infection in mammals where negative behavioral symptoms such as cognitive impairment, hyperactivity, and lack of fear were successfully treated with a drug called Guanabenz:

    Press Release:

    https://www.sciencedaily.com/releases/2019/04/190430141627.htm

    Paper:

    https://mbio.asm.org/content/10/2/e00381-19

    What is interesting and relevant to autism is that the researchers found that even though the drug reduced the number of cysts in the brain, the improvements in behavior were the result of the anti-neuroinflammatory properties of Guanabenz.

    Here is one of the most important paragraphs in the paper:

    "Guanabenz reduces chronic inflammation in infected BALB/cJ mice.

    As our previous experiment showed that reduced brain cyst burden is not linked to the reversal of hyperactivity, we examined other aspects of neurophysiology that may explain the effect of guanabenz. It is well established that guanabenz exhibits anti-inflammatory properties in vitro and in vivo (22–24). In vitro, guanabenz has been shown to decrease the expression of proinflammatory cytokines, including IFN-γ, IL-6, and TNF-α (23, 24). Using RT-qPCR, we determined the mRNA expression levels of these inflammatory cytokines in J774.1 cells, a BALB/c-derived macrophage line (Fig. 4A to E). Stimulation of these cells using LPS resulted in increased expression of IFN-γ, TNF-α, IL-6, IL-1β, and COX-2; however, guanabenz blocked this effect. These results are consistent with the abovementioned studies showing that guanabenz has immunomodulatory properties."

    All of these cytokines that Guanabenz impacts are of course very relevant to the "activated microglia" theory of autism, among many other ideas concerning neuroinflammation in general and autism severity.

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  13. Hello Peter,

    My nick is Un tio and I told you about this time ago. I think it could be better bisoprolol than propanolol, as it is newer and perhaps have some less side effects. I read a person in internet who said he was changed forever (for worse) just by one pillof propanolol, probably is false but I don't know.

    I have taken bisoprolol for a time. And I can tell you some things:

    It has a relaxing effect. But if you take it everyday it could have some side effects, such as some tics which might appear (I mean involuntary movements on the eyelid.

    On the other hand, here they talk about vitamin D and serotonin. It could be interesting:

    https://www.ihcan-mag.com/solving-autism-vitamin-d-and-serotonin-synthesis/

    Regards

    ReplyDelete
    Replies
    1. Un tio, can you share a link to the propranolol bad effect after one pill? Was it a person with autism? Do you remember what changed for worse? I would really appreciate more details on this.

      Delete
    2. Hi Agnieszka and Un tío, my son is doing excellent with propranolol, he takes 20 mg twice a day. Improvement in motor and speech.
      Valentina

      Delete
  14. Hi everyone,

    Hope everyone is doing well!

    I found an interesting paper today that I wanted to share:

    http://bio.biologists.org/content/biolopen/early/2019/04/25/bio.041327.full.pdf

    It again points to Pioglitazone as an interesting option to look at in treating cognitive impairments in ASD, although the research was done in rats. Pioglitazone has already been a molecule of interest in ASD research, but this caught my eye as it was looking at cognition.

    There was a recent study here in Canada using Pioglitazone, and the results looked promising, but they appeared to have been focusing on behavioural measures, so there may have also been cognitive benefits that weren't measured.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258310/

    Finally, there are two new trial results relating to Vasopressin / Vasopressin Receptors Antagonists:

    https://stm.sciencemag.org/content/early/2019/04/30/scitranslmed.aau7356

    https://stm.sciencemag.org/content/early/2019/04/30/scitranslmed.aat7838

    Have a great evening everyone!

    AJ

    ReplyDelete
  15. Hi, again, Peter.
    I'm giving Propranolol, 20 mg as he wake up and 20 mg just before sleep. It's been helping a lot, but there's still a period of the day, between 4:00 PM and before he takes the night dose, when he gets agitated/ irritated. I have to decide between giving another Propranolol dose at 4:00 PM or giving him Risperdal. I know one has nothing to do with the other (oranges and apples). Could you give me your father's opinion, please ? Thank you.

    ReplyDelete
    Replies
    1. Hi Luis. I think you likely only need Propranolol "coverage" during his waking hours, so I would move the just before sleep dose to 4pm, or even slightly earlier.

      So two doses of 20mg (wake up and 4pm). That may be all you need. This would make sense in terms of having coverage during waking hours.

      I would avoid anti-psychotic drugs like Risperdal if at all possible. They are associated with many problems.

      Delete
    2. Peter, the effect that propranolol had on my son has been so notorious, that still can not beleive it and explain it. Tics and stimming are gone, really.No more. His level of conversation and interests are higher. Still has some OCD, but much less, and he is more emotional. From the first 20 mg all changed, it is incredible!
      Valentina

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    3. Valentina, that is great news.

      Delete
    4. Valentina, I should add that people should take note that response is from the first pill, this applies to many other interventions, but not all.

      It seems that many people with autism respond well to propranolol, another cheap generic drug.

      Delete
    5. Peter, imagine that we spend money in many supplements, find a cheap drug with this incredible effect, available in your country without prescription, is like disneyland!
      Valentina

      Delete
  16. Mast cell–glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide

    https://royalsocietypublishing.org/doi/full/10.1098/rstb.2011.0391

    ReplyDelete
  17. Tyler,
    This is interesting. Thank you for posting. Will check into this more. Guanabenz made me laugh, I was thinking Bat Guano and Benzo's and laughing.

    ReplyDelete
  18. We did VNS via the ear with a TENS unit for a few weeks. The first 2 weeks were an unbelievable change of presentation for my 25 yr old son. He was calm and flexible and rages that had been pretty much daily disappeared completely. it was immediate upon the first or second 10 min session.
    But after 2 weeks, all the gains disappeared. It was disheartening.
    Recently, we started 20 mg of propanolol (once in AM and once around 4 PM).
    Some noticeable mood stabilizing but toward the end of the afternoon before the second dose, as well as at waking before the first dose of the day, the rages were back.
    A couple days ago I split the 10 mg tablets in half and started doing 5 mg upon waking, another 5 mg midday, another 5 mg around 4 or 5 PM, then another 5 mg at bedtime. it has made all the difference. I think the calm and flexibility are even more noticeable and reliable and there are no crashes before the next dose.
    Let's see if it lasts. Very few things with my son seems to last long term.
    I am not seeing any other changes beyond mood improvement, however (such as memory or speech or cognition).
    Nancy

    ReplyDelete
    Replies
    1. Nancy, there is a sustained/extended release version of Propranolol which might be easier to use and give a consistent mild dosage.

      Delete
  19. Thank you! If we can keep this positive effect going beyond the 2 week mark, I will definitely look into it.
    Nancy

    ReplyDelete
  20. We are almost in week 4 of propanolol and rages are nearly nonexistant. Even slight agitationscare greatly decreased and end very quickly. My son is far more flexible and happy. We had spread the 20 mg over 4x per day but it seemed cutting out that 3rd dose completely helped even more. It's been a wonderful month at 15mg/day. Oddly, last weekend he started sobbing uncontrollably. He had not cried in years.
    My son was a no responder to bumetanide and propanolol has not seemed to increase cognition. I would love to address this. Can adding something (like propanolol) make something else work that didn't before, possibly?
    Nancy

    ReplyDelete
    Replies
    1. Nancy, that is great news. I am glad propranolol gives such a benefit.

      People do report that it does often matter the order in which you start these off-label autism therapies. So it is quite possible that having solved one issue with Propranolol, something else that failed to help in the past might now work.

      It might well be worth trying bumetanide again for at least a month, at say 2mg per day. The researchers now say you should give it 3 months, before giving up.

      Delete

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