Heart Mind

REVIEW ARTICLE
Year
: 2017  |  Volume : 1  |  Issue : 2  |  Page : 78--83

Autism spectrum disorders: Autonomic alterations with a special focus on the heart


Bart A Ellenbroek, Hatice K Sengul 
 School of Psychology, Behavioural Neurogenetics Group, Victoria University Wellington, Wellington 6041, New Zealand

Correspondence Address:
Bart A Ellenbroek
School of Psychology, Behavioural Neurogenetics Group, Victoria University Wellington, PO Box 600, Wellington 6041
New Zealand

Abstract

Autism spectrum disorders (ASD) is a heterogeneous group of developmental disorders characterized by stereotyped behaviors and thoughts, and deficits in social behavior, interactions, and communication. The epidemiological evidence shows an increase in the prevalence of ASD although the etiology and pathology of ASD are still largely unknown. In addition to the core symptoms, patients with ASD show emotional and cognitive deficits, and are thought to suffer from abnormal levels of arousal and therefore increasingly studies have been performed to investigate alterations in the autonomic nervous system. The aim of the review is to focus on the changes in the cardiovascular system. Overall, the literature provides some evidence for an increase in baseline heart rate (HR) and a decrease in HR variability (HRV), specifically for high-frequency respiratory sinus arrhythmia. However, the review also illustrates the large variability in results. This is in part due to differences in methodology, but also to the heterogeneity of ASD per se. Moreover, as ASD already occurs at a very young age, differences in the age of the patients are also likely to play a role. Therefore, we propose a more systematic analysis of autonomic dysfunction in well-defined patient populations. In addition, given the plethora of genetic and environmental animal models for ASD that have been developed in recent years, we argue that investigation of HR and HRV could substantially improve the translational validity of these models.



How to cite this article:
Ellenbroek BA, Sengul HK. Autism spectrum disorders: Autonomic alterations with a special focus on the heart.Heart Mind 2017;1:78-83


How to cite this URL:
Ellenbroek BA, Sengul HK. Autism spectrum disorders: Autonomic alterations with a special focus on the heart. Heart Mind [serial online] 2017 [cited 2019 Aug 23 ];1:78-83
Available from: http://www.heartmindjournal.org/text.asp?2017/1/2/78/218520


Full Text



 Autism Spectrum Disorder



Autism spectrum disorder (ASD) is a pervasive neurological disorder with a very early age of onset [1] and typically persists into adulthood. With an average age of onset of symptoms between 1 and 2 years of age, it is one of the earliest of the major psychiatric disorders. Patients with ASD suffer from three core deficits: Reduction in social interaction and in communication and an increase in stereotyped, repetitive behaviours (which extends into the cognitive domain as well). In addition to those core symptoms, many patients with ASD also suffer from complications in a wide range of domains, such as behavioral (aggressive and self-injurious behavior), psychiatric (anxiety and depression), gastro-intestinal (gastro-esophageal reflux, food selectivity), neurological (epilepsy, sleep disruption), and developmental (language deficits, motor delay) symptoms. Many of these symptoms are common in ASD patients. For instance, approximately 50% of the patients suffer from seizures, constipation, and low blood pressure, and up to 75% of the patients experience anxiety and sleep disturbance.

Although the Diagnostic Statistical Manual of Mental Disorders - V (DSM-V) groups all patients with ASD together, three different subtypes of ASD are often identified: Autism (sometimes referred to as “true autism”), Asperger syndrome (sometimes referred to as “high-functioning autism”) and pervasive developmental disorders not otherwise specified. Of these three subtypes, autism is the most severe [1] with an earlier onset, and severe intellectual disability (IQ usually below 60). Autism occurs in both genders, though it is more prevalent in boys than girls, with ratios ranging from 4:1 to 8:1.[2],[3]

One of the most intriguing aspects of ASD it that its incidence seems to have risen over the last years, as indicated by epidemiological studies that were conducted in several different countries including Denmark,[4] Finland,[5] the UK [6] and Australia.[7] Recently the centre for disease control and prevention in the USA reported a 4 fold increase in ASD prevalence (http://www.cdc.gov/mmwr/pdf/ss/ss6302.pdf), in the period between 2000 and 2010. The exact reasons for this increase are still unclear, with some suggesting changes in diagnostic criteria or in detection as the main cause, while others have argued for a real increase in ASD cases. While there has clearly been increased recognition of ASD over the years, it seems unlikely that this is the only reason. In a recent study in the Republic of Korea, two thirds of all cases of ASD were from mainstream schools, undiagnosed and untreated,[2] suggesting that even in this day and age, many ASD cases go unnoticed.

Given the early onset and chronicity of the disorder, the rising prevalence and the fact that virtually no effective treatment currently exists, it is not surprising that ASD comes at a tremendous cost for patients, their families and society as a whole. Recent estimates have calculated the total costs in the USA at US$ 2.4 million for ASD patients with an intellectual disability and US$ 1.4 million for ASD patients without,[8] leading to an aggregated societal costs of US$ 175 billion.

 Autism Spectrum Disorder and Emotional Regulation



In addition to the core symptoms of ASD, there is an increasing realization that patients with ASD have problems with emotional regulation.[9] This is, among others, evident from the high psychiatric co-morbidity seen in these patients. For instance a study in 5 – 16 year old children with ASD found much higher levels of hyperactivity, emotional and conduct problems compared to a cohort of typically developing (TD) children.[10] Moreover, this pattern did not substantially change during the course of the illness. Thus a study in young adults with Asperger syndrome found that 70% had suffered from a major depressive episode, while 50% suffered from recurrent depression and 50% from anxiety disorders.[11] Likewise, in one study, on average adults with ASD met criteria for at least three co-occurring psychiatric disorders, most specifically ADHD, major depressive disorder and generalized anxiety disorders.[12]

Emotional dysregulation is often associated with, if not directly linked to alterations in psychological and physiological arousal.[9] In line with this, many patients with ASD show abnormal patterns of arousal, especially in relation to social stimuli. However, the exact nature of the deficit is still hotly debated. In fact, there is evidence for both hyper- and hypo-arousal. For instance, in a review paper discussing abnormal eye contact in patients with ASD, both hypotheses were proposed. The “hyper-arousal” model is based on the idea that the eyes and face are strongly aversive stimuli for patients with ASD and hence are avoided as a means to reduce overarousal.[13] This theory is actually quite old and dates back to the pioneering work of Tinbergen and Tinbergen.[14] The “hypo-arousal” model, on the other hand, suggests that a hypo-activation of the amygdala leads to a reduced perception of the rewarding value of face and eye contact. It is perhaps illustrative of the complexity and heterogeneity of ASD that evidence in favor of both opposing theories has been reported over the years. Irrespective of these conflicting results, they strongly suggest that ASD is associated with alterations in arousal, both at the psychological and physiological levels.

 Autonomic Dysregulation in Autism Spectrum Disorder



While the majority of research papers has focused on the traditional behavioural and psychiatric symptoms, the realization that patients with ASD have abnormal levels of arousal (see above) and that these may actually be directly linked to the core symptoms of the disorder, has led to an increase in studies investigating the autonomic nervous system (ANS). Porges' polyvagal theory has, in this respect, been of pivotal importance.[15] In this theory, Porges proposed that the ANS is crucial for promoting and maintaining social and communicative behaviour. More specifically, the theory states that the vagus nerve (a crucial component of the parasympathetic nervous system, PNS) affects facial expression and vocalizations, and therefore, increases in PNS activity are essential for approach behaviour. On the other hand, the sympathetic nervous system (SNS) is engaged predominantly in a “flight or fight” response, leading to a “threat-like” response during social encounters. Thus, adaptive social engagement would be associated with an increase in PNS and a decrease in SNS. Since both PNS and SNS also affect cardiac activity, the changes in several cardiac parameters can be used as a proxy for the relative activity of the PNS and SNS.

Studies conducted in the patients with ASD have focused on alternations in the heart rate (HR), heart rate variability (HRV), respiratory sinus arrhythmias (RSA) and cardiac pre-ejection period (PEP). [Table 1] describes the different parameters in more detail. Studies investigating cardiac activity in ASD patients been performed both at rest, as well as during tasks, of during exposure to sensory or social stimuli. Unfortunately, most studies have used a unique design and few results have actually been confirmed in independent studies. Moreover, as mentioned before, ASD is inherently heterogeneous. Thus some studies have focussed on children, others on adolescents or on adults. Likewise, some have incorporated all patients with ASD, while others have focussed on specific subgroups (such as high functioning patients). As a result of this, it is not surprising that results have been very mixed and more rigorous research is needed to identify the exact nature of the ANS disturbances in patients with ASD.[16]{Table 1}

Heart rate

Probably the most studied variable in ASD is basal HR. In general, most studies have reported a higher HR both at rest [17],[18],[19],[20],[21],[22] and during sleep,[23] although some studies failed to find a significant effect [24] and one report even found a reduction in baseline HR.[25] However, these latter two studies were relatively small (8 or 10 patients and controls), which may explain the anomalous finding.

Perhaps more interesting than differences in baseline HR, several studies have reported that exposure to external stimuli leads to a blunted HR response in ASD patients. Thus Smeekens and colleagues found a reduced HR response to social role playing,[21] a finding similar to that observed by Kushi et al in response to public speaking,[18] and by Mikita et al, who used an adaptation of the Trier Social Stress Test, which include, among others, a 5 minute public speech.[17] Even in the study that found reduced baseline HR levels in patients with ASD,[25] a blunted HR response to physical exercise was observed. These same authors also reported a blunted day/night difference in HR in high functioning ASD children.[26] On the other hand, no differences were seen between children with ASD and TD children while performing the Stroop Color Word task,[19] or during exposure to social or nonsocial pictures.[27] Overall, these data suggest that HR response in ASD patients is blunted, but that the effect is most pronounced during active social engagement, rather than during passive exposure to (non) social stimuli. However, the situation may actually be more complex. In a recent study, the HR response to both familiar and unfamiliar social interactions was studied in 18 boys with ASD and compared to 18 typically developed (TD) boys.[20] While the authors did not find a difference in response to an unfamiliar partner, they found that while HR reduced over time in TD boys when interaction with a familiar partner for 5 min, ASD boys showed a small increase in HR during the same period. In an interesting correlative study, in forty older ASD patients (average age, 22 years), correlations were found between HR response to social video clips and both levels of autism and empathy: the higher the autistic score or the lower the empathy score, the greater the decrease in HR.[28] Thus these latter two studies, while showing effects that seem opposite to some of the previously mentioned studies, further add to the overall idea that HR and HR response to (especially social) stimuli is altered in ASD. While the results of the Stroop color word test would suggest that the ANS response to a cognitive challenge is unaltered in ASD children, a replication using other cognitive tests would be required to confirm this hypothesis.

Respiratory sinus arrhythmia

While alterations in HR and HR response suggests abnormalities within the ANS, they do not allow to distinguish between the two branches, as both SNS (increase) and PNS (decrease) affect HR. In other words an increase in baseline HR, as seen in ASD patients could be due to an increase in SNS or a decrease in PNS activity (or a combination of both). In order to differentiate between the two branches of the ANS, several different techniques have been developed. RSA, see [table 1] for more details, is generally thought to be influenced virtually exclusively by the PNS.[29] The RSA refers to the variations in the HR during the respiratory cycle. Typically, the PNS influence decreases during inhalation, leading to a corresponding increase in breathing during this phase. When RSA is measured during the resting state, an increase is usually regarded as a sign of physiological flexibility, while a reduction in RSA is often considered mal-adaptive and an indication of a reduced vagal (PNS) tone. Although there are different ways to measure RSA, most commonly this is done by extracting the high-frequency (HF) domain (0.15–0.4 Hz) of HRV (see below for more details). In line with the increase in baseline HR, several studies have reported decreases in baseline RSA, in both Caucasian and Asian patients with ASD,[20],[30],[31],[32],[33] although the same results were not observed in all studies.[18],[34] Interestingly, two studies have evaluated the level of RSA during sleep with contradictory results. Thus, in line with the baseline studies, Harder et al. found a reduction in HF-HRV,[23] while Pace et al. found a significant increase.[35] It is currently unclear why the results of the two studies differed. In addition, a study by Harder et al. found that the reduction in the level of RSA in patients with ASD was only observed in the N3 and rapid eye movement sleep phase, while all the phases were combined in the study conducted by Pace et al.[25],[26]

Although various data on the changes in RSA existed, most studies reported a reduced RSA in patients with ASD. As RSA is a primary indicator of the PNS, these data seem to support a reduced parasympathetic tone in patients with ASD. Several functional studies have linked low RSA with dysfuntioning at a social level, in line with Porges' polyvagal theory (as described above). For instance, it was shown that during social interactions with a familiar adult, RSA increases in typically developing children, indicating better social skills. Yet this increase was absent in patients with ASD.[20] In a previous study, these authors and others had already shown that the RSA levels at baseline were correlated with social skills and internalizing.[30],[32]

With respect to the RSA response to stimuli, a picture similar to that seen for HR (see above) emerges. Thus, while some found that the RSA response to social stressors was blunted,[21] others found that there were no differences between ASD and TD in the RSA response to (stressful) stimuli.[18] A possible explanation of the differences is that the first study was done in adults (mean age, 23.5 years) while the second was performed in children (mean age, 12 years). Comparatively, a study that was conducted in slightly older children (12–18 years) also found that the RSA responses to different stressful stimuli were similar between patients with ASD and children with RD.[32] However, the RSA responses to stress were negatively correlated with social problems in patients with ASD.

Preejection period

The cardiac PEP is often regarded as a relatively pure sympathetic parameter based on its sensitivity to beta-adrenergic drugs.[36],[37] It refers to the delay between the onset of the left ventricular depolarization and the opening of the aortic value that allows the influx of blood into the aorta. The increases in the SNS would lead to an increase in blood flow and in HR and a reduction in PEP. Compared to RSA and certainly to HR, relatively few studies examined PEP in patients with ASD. In a study by Schaaf et al.,[34] 59 children with ASD were compared to 29 TD (mean age around 7.5 to 8.2 years, with the ASD group significantly younger). The authors found that both baseline PEP and the response to sensory stimuli did not differ between both groups. On the other hand, in a study with a similar age group PEP was found to be enhanced in ASD patients.[20] Moreover, a differential response to social interaction was found: whereas in ASD patients PEP decreased during social interaction (with both a familiar and an unfamiliar adult), this did not occur in TD. Since PEP is inversely related to activation of the SNS, this suggests a reduced baseline SNS tone and increased recruitment during social interaction, indicative of a “threat-like” response in ASD individuals. However, apart from the two papers, very little is known about potential differences in PEP in patients with ASD.[16]

Heart rate variability

Heart rate variability refers to the beat to beat variation HR and is usually considered to represent both sympathetic and parasympathetic components. There are multiple different ways of calculating HRV, most of which are either in the time or the frequency domain, but more specific, non-linear methods have also been developed.[38] In the time domain, the most often used parameter is the RMSSD (root mean square of successive differences). As indicated in [Figure 1], the RMSSD can be easily calculated by taking the square root of all the differences between successive R-R peaks in the electrocardiogram and dividing it by the total number of differences. Other parameters used in the time analysis are the standard deviation of RR intervals (SDNN), NN50, and pNN50 (the total number [or percentage, p] of successive RR pairs that differ by more than 50 ms).{Figure 1}

In addition to a time analysis, most HRV studies also investigated the changes in the frequency domain, after applying a fast Fourier transformation. Several bands can be discerned, with the two most prominent ones being a low frequency (LF) band, in the range between 0.04 and 0.15 Hz, and a HF band, in the range between 0.15 and 0.4 Hz. In addition, a very LF (VLF, between 0.0033 and 0.04 Hz) and even an ultra-LF (ULF [21] while Cohen and colleagues found an increase in the LF/HF ratio,[33] although this may have been secondary to decreases in HF-HRV. In the two already mentioned sleep studies, increase in LF were reported,[23] as well as increases in RMSSD.[35] However, other studies did not consistently found deficits.[16] In an interesting study, the behavioural and physiological response to regional transcranial magnetic stimulation (rTMS) was investigated in 33 children with ASD (mean age 13 years).[39] Focussing on stereotypy, the authors found that stimulation over the dorsolateral prefrontal cortex significantly reduced all aspects of stereotypic behaviour (including self-injurious, compulsive and ritualistic behaviour as well as restricted interest) over a period of 12 weeks of once weekly stimulation. Interestingly, the authors also found that, in parallel with the clinical improvement, HRV increased. This was apparent in the time domain (SDNN, NN50 and pNN50) and the frequency domain (HF, but not LF), and points to the usefulness of HRV as a parameter for assessing clinical improvement.

 Discussion and Summary



ASD represents a group of related neurodevelopmental disorders, and is primarily characterized by deficits in social communication, interaction, and an increase in stereotyped thoughts and behaviors. In addition to these core symptoms, most patients also display emotional and cognitive deficits with signs of altered arousal. In the study, we focused on the changes in the autonomic system, especially in relation to the cardiovascular system.

Overall, the data show strong evidence for an increase in baseline HR with a concomitant reduction in RSA. Likewise, although less consistently, the HR response to stressors seems to be blunted in patients with ASD. However, perhaps one of the most consistent findings in this review has been the inconsistency of results from study to study. Unfortunately, this is not atypical for studies in psychiatric populations and is especially prominent in ASD research.[40] There are several explanations for these inconsistencies. First and foremost, ASD is a very heterogeneous disorder (or spectrum of disorders). As discussed in the introduction, previously, different variations (such as true autism and Asperger syndrome) were distinguished. Given the obvious clinical differences between these subtypes,[1] ANS differences are also likely. In addition, ASD has a very early onset in life, and generally persists into adulthood. However, signs and symptoms differ between children, adolescents and adults.[41] In addition, the relative contribution of the SNS and PNS in regulating ANS reactivity seems to develop over time,[16] Thus upon exposure to stressful stimuli, younger children (3 – 6 years) seem to respond predominantly with a co-inhibition of both the SNS and PNS, while older children (8 and over) seem to show predominantly a reciprocal pattern (increase in SNS, decrease in PNS). Finally, methodological differences are apparent between different studies. These range from differences in the definition of “baseline” or “resting” state, to differences in the type of stimuli presented to the participants. These include simple sensory stimuli,[24],[31] pictures or video of social interactions,[27],[28],[33] interactions with adults,[20] cognitive tests,[19],[42] public speaking, and role playing.[17],[18],[32]

This diversity of methods and patients clearly indicates the need for more systematic investigations of ANS alterations in ASD patients, especially in response to external stimuli. In particular studies that combine both simple sensory stimulations with exposure to more cognitively or emotionally demanding stimuli may shed important light on the ANS abnormalities in ASD. Moreover, the vast majority of research into ANS abnormalities in ASD has been performed with Caucasians. It will therefore be important to extend these findings to other ethnicities, including Asians.

In addition, a large number of animal models for ASD has been developed over the years including genetic models,[43],[44] early environmental models [40],[45] and even models based on gene– environment interactions.[46] Most of these models have been rigorously studied with behavioural methods and deficits in emotional behaviour (especially anxiety) have been observed in many cases. However, to the best of our knowledge, none of the models have investigated aspects of ANS abnormalities. HR and HRV can be readily measured in freely moving rats and mice,[47],[48] and that, also in these species, HRV has been directly related to emotion and anxiety.[49],[50] Given the fact that HR and HRV can be assessed in humans and animals with identical methods, the assessment of ANS abnormalities in animal models for ASD may substantially improve the translational value and may provide a parameter that can be effectively used in drug development.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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