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Highlights in clinical autonomic neuroscience: New insights into autonomic dysfunction in autism
Autonomic Neuroscience: Basic and Clinical 171 (2012) 4–7
Contents lists available at SciVerse ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
HIGHLIGHTS IN CLINICAL AUTONOMIC NEUROSCIENCE: NEW INSIGHTS INTO AUTONOMIC DYSFUNCTION IN AUTISM Prepared by: William P. Cheshire ⁎ Mayo Clinic, College of Medicine, United States
Section editor: Dr. Roy Freeman a r t i c l e
i n f o
Section editor: Dr. Roy Freeman Keywords: Autistic Disorder Autonomic Nervous System Diseases Vagus Nerve Pupil, Questionnaires
a b s t r a c t Investigations of autonomic nervous system biomarkers in autism have been sparse relative to its prevalence. Recent studies of children with autism spectrum disorders (ASD) have increasingly drawn correlations between autonomic findings and psychosocial behavior. Studies of heart rate variability, pupil size, salivary alpha-amylase, and electrodermal responsiveness have shown that children with ASD differ from normally developing children in their autonomic responsiveness to visualizing human faces and other mental tasks. While some results have conflicted, much of the data appears to support the theory of a hypersympathetic state in autism insufficiently attenuated by vagal parasympathetic influences. To what degree these differences in autonomic physiology might influence cognitive processing and behavior rather than simply being epiphenomena of a pervasive disorder of brain development is as yet unclear. © 2012 Elsevier B.V. All rights reserved.
Introduction Autism spectrum disorders (ASD) comprise a group of developmental disorders characterized by impairments in social interaction and communication and by restricted, repetitive, stereotyped patterns of behavior. Along the autistic spectrum are autistic disorder, pervasive developmental disorder, Asperger disorder, and atypical autism. Autism is also more frequent in patients with tuberous sclerosis, fragile X syndrome and Rett syndrome. Multiple interacting genetic factors predominate in autism pathogenesis. The Centers for Disease Control and Prevention has estimated the prevalence of ASD to be as high as 11.3 per 1000 children (Centers for Disease Control and Prevention, 2012).
that explored symptoms of autonomic instability, secretomotor and sensory integration, visceral dysfunction involving gastrointestinal, urinary, cardiopulmonary and thermoregulatory systems. The average time needed to complete the survey was 15 min. The pediatric autonomic symptoms scale succeeded in distinguishing both groups of patients from age-matched controls. Children with familial dysautonomia scored higher on scales of visceral symptoms, whereas children with ASD scored higher on scales of psychosocial symptoms, which evaluated symptoms of autonomic dysfunction associated with mood, behavior and emotions.
Commentary Ming, X., Bain, J.M., Smith, D., et al. (Newark, NJ, USA). 2011. Assessing autonomic dysfunction symptoms in children: a pilot study. Journal of Clinical Neurology 26, 420–427. Article summary These investigators piloted a comprehensive autonomic symptom screening tool administered to parents of children with familial dysautonomia (7 patients) and ASD (18 patients: 7 with autistic disorder, 10 with pervasive developmental disorder, and 1 with Asperger disorder). The pediatric autonomic symptoms scale consisted of 80 questions ⁎ Tel.: +1 904 953 2000; fax: +1 904 953 0757. E-mail address: [email protected]. 1566-0702/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2012.08.003
This is the first study to utilize a comprehensive symptom scale to evaluate autonomic dysfunction in children with ASD. The findings indicate that autonomic dysfunction, although not the cause of psychosocial dysfunction, is pervasive as well as heterogeneous in children with ASD. Autonomic symptom surveys may not improve upon neuropsychological evaluations in ascertaining a diagnosis of autism, but they may become useful clinically in identifying autonomic symptoms amenable to interventional strategies in children with ASD. Further validation studies are needed. An autonomic questionnaire for adults with autism would require a different methodology.
Kaartinen, M., Puura, K., Mäkelä, T., et al. (Tampere, Finland). 2012. Autonomic arousal to direct gaze correlates with social impairments
W.P. Cheshire / Autonomic Neuroscience: Basic and Clinical 171 (2012) 4–7
among children with ASD. Journal of Autism and Developmental Disorders 42, 1917–1927. Article summary These authors investigated whether autonomic arousal, as measured by skin conductance responses, during eye contact was related to impairment in social skills among children with ASD. Subjects consisted of 15 children of ages 8–16 years with ASD and 16 controls matched for age and IQ. Subjects were asked to determine the direction of gaze of a model who sat 110 cm from the subject separated by a liquid crystal shutter that could be switched between an opaque and a transparent state. The models were young women who successively directed their gaze directly, averted their gaze, or kept their eyes closed, in each case maintaining a neutral facial expression. A positive skin conductance response was defined as an amplitude change of greater than 0.05 μS from baseline recorded from the left hand. They found, interestingly, that the level of autonomic arousal in response to direct gaze did not correlate directly with measurements of social skill or distinguish ASD patients from controls. However, when autonomic responsiveness to direct gaze was compared to that when faces were not looking directly ahead, increased autonomic arousal was positively associated with impaired social skill in children with ASD. No correlation to social skill was observed in children without ASD.
5
and norepinephrine-modulated connections within cortical regions responsible for higher-order processing of social responsiveness and communication. On that basis they hypothesized a therapeutic role for β-adrenergic antagonists in improving task performance, anxiety, irritability and aggression in ASD. Commentary Previous research has shown that children with ASD as compared to age-matched controls have a larger tonic pupil size and decreased pupillary responses when looking at human faces (Anderson and Colombo, 2009). Biobehavioral research has increasingly incorporated measurements of sAA into study designs as a noninvasive biomarker for sympathetic nervous system activity. Previous studies have shown that sAA increases in response to stress and exhibits a diurnal profile with a pronounced decrease shortly after awakening and a steady increase during the course of the day (Nater et al., 2007). The release of α-amylase is, however, also dependent on glands that are parasympathetically innervated, on synergistic sympathetic–parasympathetic effects on protein secretion, and on salivary flow rate. For these reasons the use of sAA as a valid and reliable measure of sympathetic nervous system activity has not attained universal support (Bosch et al., 2011). The findings in this small study should be interpreted provisionally given the limitations of the methodology.
Commentary Eye contact, which is essential to social interaction, is impaired in children with ASD. Children with ASD are atypical in how they process visual information about faces. Functional neuroimaging has shown that gaze cues elicit less activity in the right fusiform gyrus, which is responsible for facial visual processing, and in frontoparietal regions associated with orienting attention, in ASD children as compared to those who develop normally (Greene et al., 2011). ASD children also preferentially explore details of the lower parts of people's faces and are less attentive to the eyes (McPartland et al., 2011). This study expands on previous research that found that ASD children, unlike normally developing children, did not show a larger electrodermal skin response when looking at their mother's face as compared to looking at a cup (Hirstein et al., 2001). Kaartinen and colleagues attribute their findings to disturbances in arousal-related motivational systems in ASD. They reason that, since children with ASD do not find eye contact rewarding, they may be more likely to avoid eye contact when autonomic arousal to direct gaze increases. Since gaze condition was only weakly related to autonomic arousal in this study, it is reasonable to conclude that ASD children avoid direct gaze on a basis other than perceiving eye contact to be threatening.
Anderson, C.J., Colombo, J., Unruh, K.E. (Lawrence, KS, USA). 2012. Pupil and salivary indicators of autonomic dysfunction in autism spectrum disorder. Developmental Psychobiology epub ahead of print.
Martineau, J., Hernandez, N., Hiebel, L., et al. (Tours, France). 2011. Can pupil size and pupil responses during visual scanning contribute to the diagnosis of autism spectrum disorder in children? Journal of Psychiatric Research 45, 1077–1082. Article summary This study investigated pupil size and reactivity in 19 children with ASD and 38 controls (19 matched for chronological age and 19 matched for mental age) during visual scanning of neutral faces, virtual faces (avatars), and various objects presented on a computer monitor. A black slide was presented between stimuli. The investigators found that the ASD group had a significantly smaller pupil size (mean 4.11 mm) while gazing at the black slide between stimuli as compared to pupil sizes in mental age-matched (5.35 mm, p=0.00002) or chronological age-matched (5.46 mm, p=0.000004) controls. Analysis of pupil reactivity waveforms over time during the presentation of visual stimuli found no significant difference among groups in maximum changes of pupil size, but there was a significant difference in the time course of pupil size change. Whereas pupil waveforms over time did not vary according to the stimulus used for ASD or mental age-matched controls, pupil size was significantly greater (p = 0.0006) for age-matched controls when the stimuli were faces rather than avatars or objects. Discriminant analysis correctly classified 89% of the ASD group. Commentary
Article summary This study correlated pupil size with levels of salivary α-amylase (sAA), a putative correlate of norepinephrine, in 12 children with ASD. As compared to age-matched controls, children with ASD were found to have a larger tonic pupil size (5.573 versus 4.304 mm, p b 0.001), and this correlated with lower sAA levels (r = − 0.404, p = 0.018). The ASD group also lacked the diurnal variation in sAA that was seen in controls. The authors reasoned that ASD entails dysregulation of a feedback loop between hypothalamic systems
Interpretation of changes in pupil size is more complex than first meets the eye. Although pupil diameter is just one dimension plotted over time, it represents the summation of the combined influences of inhibitory and excitatory sympathetic and parasympathetic activity due to light stimuli as well as levels of emotional arousal and mental alertness, and these have elaborate central nervous system connections. Of interest in this study is an autonomic correlate in autism of the impaired psychological response to visualizing the human face.
6
W.P. Cheshire / Autonomic Neuroscience: Basic and Clinical 171 (2012) 4–7
The findings of this study conflict with those of Anderson and colleagues, who found a larger tonic pupil size in ASD. A possible explanation for the discrepancy is the difference in methodology. When measuring baseline tonic pupil size, Martineau and colleagues utilized a black slide (0.1 lx), whereas Anderson and colleagues utilized a gray slide (3.0 lx), which would have cast more light on the retina. A relative parasympathetic deficit or sympathetic excess might be less apparent in more dimly lit conditions.
Bal, E., Harden, E., Lamb, D., et al. (Chicago, IL, USA). 2010. Emotion regulation in children with autism spectrum disorders: relations to eye gaze and autonomic state. Journal of Autism and Developmental Disorders 40, 358–370.
Article summary These investigators correlated baseline respiratory sinus arrhythmia (RSA) and heart rate with the accuracy and latency of recognition of facial emotions in 33 children with ASD ages 7–17 in comparison to 45 controls. They found that children with ASD had significantly lower amplitude RSA and faster heart rates than typically developing children. ASD children with higher amplitude RSA at baseline recognized emotions more quickly but not more accurately. They concluded that children with ASD have a less effective “vagal brake,” (Porges et al., 1996) with the consequence that sympathetic influences may not be sufficiently attenuated.
Commentary These findings are in harmony with Porges's polyvagal theory Porges et al., (1996), which propounds that vagal outflow is functionally linked to attentional and emotional processing, influencing temperament and emotional reactivity. Accordingly, RSA as a measure of cardiovagal tone has been interpreted as a psychophysiological marker of behavioral functioning (Beauchaine, 2011). Lending further support to this theory, Patriquin and colleagues found that ASD children with higher baseline RSA amplitudes showed greater RSA reactivity during attention-demanding tasks and demonstrated better social behavior (Patriquin et al., 2011). Others have found in ASD a decrease in central vagal tone without impairment in vagal gain or sympathetic responsiveness during an attention-demanding task (Althaus et al., 2004; Ming et al., 2005). Paradoxically, Toichi and Kamio found that in half of their autistic subjects cardiovagal activity increased during mental arithmetic, suggesting that they may be less stressed when engaged in certain mental tasks in comparison to normally developing children, who show a decrease in heart rate variability during mental stress (Toichi and Kamio, 2003). If this model is a valid framework for distinguishing ASD from typically developing children, then ASD children may be in a hypersympathetic state with diminished capacity for calm behavior, which may contribute to their impaired ability to engage in social interactions, anxiety, and behaviors in response to anxiety. A small but relevant body of literature has found that β-adrenergic antagonists may be helpful in managing impulsivity, aggression and self-injurious behavior in ASD (Aman, 2004).
Lioy, D.T., Wu, W.W., Bissonnette, J.M. (Portland, OR, USA). 2011. Autonomic dysfunction with mutations in the gene that encodes methyl-CpG-binding protein 2: Insights into Rett syndrome. Autonomic Neuroscience 161, 55–62.
Article summary These authors review recent advances in human and animal studies in Rett syndrome, which is an X-linked autism spectrum disorder that affects one in 10,000–15,000 girls. Rett syndrome presents in the first year of life with developmental arrest, regression of language, seizures, ataxia, respiratory dysfunction and repetitive stereotypic hand movements. Cardiovascular autonomic dysfunction has been suspected to be the cause of the sudden, unexpected death that occurs in a quarter of women with Rett syndrome. A handful of studies have found prolonged QT intervals in 30–55% of patients. Spectral analysis studies have found evidence of reduced heart rate variability, suggesting inadequate vagal counterbalancing of cardiac sympathetic overactivity, possibly as the result of insufficient GABAergic transmission. Additionally, the finding of lower plasma levels of serotonin has prompted suggestions that serotoninergic influences may be awry. Rett syndrome is caused by mutations in the gene that encodes methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor highly expressed in neurons and important for neuronal function and brain development (Amir, 2000). A significant discovery was reversal of the MeCP2 deficiency phenotype by gene therapy in mouse models of Rett syndrome (Guy et al., 2001). Activation of a conditionally functioning transgene promoter upstream from the MeCP2 locus delayed or prevented the progression of neurologic symptoms in mice with deletions in MeCP2 exons (Luikenhuis et al., 2004; Giacometti et al., 2007). Commentary Delineation of the genetic basis of Rett syndrome represents a major landmark in deciphering the pathophysiology of one form of autism. This advance also holds promise for the prospect of gene therapy, pending the development of a safe and effective gene delivery vehicle for human clinical use (Gray, 2012). Altogether these studies indicate that the relationships between the autonomic nervous system and aberrant central nervous system development in autism are complex. Beauchaine draws an analogy to planetary motion, which eluded a satisfactory mathematical explanation before astronomers recognized that the Earth is a noncentral component of a larger solar system (Beauchaine, 2011). Autism research is disclosing many interesting details of altered autonomic tone and responsivity. Analogous to cosmology, some findings may turn out to be noncentral components in the constellation of intricate developmental processes in the central nervous system. Interpretation of associated autonomic phenomena is most meaningful when viewed also from the complementary perspectives of molecular neuroscience, structural and functional neuroimaging, and developmental psychopathology. References Centers for Disease Control and Prevention, 2012. Prevalence of autism spectrum disorders — Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1–19. Greene, D.J., Colich, N., Iacoboni, M., et al., 2011. Atypical neural networks for social orienting in autism spectrum disorders. Neuroimage 56, 354–362. McPartland, J.C., Webb, S.J., Keehn, B., Dawson, G., 2011. Patterns of visual attention to faces and objects in autism spectrum disorder. J. Autism Dev. Disord. 41, 148–157. Hirstein, W., Iversen, P., Ramachandran, V.S., 2001. Autonomic responses of autistic children to people and objects. Proc. R. Soc. Lond. 268, 1883–1888. Anderson, C.J., Colombo, J., 2009. Larger tonic pupil size in young children with autism spectrum disorder. Dev. Psychobiol. 51, 207–211. Nater, U.M., Rohleder, N., Schlotz, W., et al., 2007. Determinants of the diurnal course of salivary alpha-amylase. Psychoneuroendocrinology 32, 392–401. Bosch, J.A., Veerman, E.C., de Geus, E.J., Proctor, G.B., 2011. Alpha-amylase as a reliable and convenient measure of sympathetic activity: don't start salivating just yet! Psychoneuroendocrinology 36, 449–453. Porges, S.W., Doussard-Roosevelt, J.A., Portales, A.L., Greenspan, S.I., 1996. Infant regulation of the vagal “brake” predicts child behavior problems: a psychobiological model of social behavior. Dev. Psychobiol. 29, 697–712.
W.P. Cheshire / Autonomic Neuroscience: Basic and Clinical 171 (2012) 4–7 Beauchaine, T., 2011. Vagal tone, development, and Gray's motivational theory: toward an integrated model of autonomic nervous system functioning in psychopathology. Dev. Psychopathol. 13, 183–214. Patriquin, M.A., Scarpa, A., Friedman, B.H., Porges, S.W., 2011. Respiratory sinus arrhythmia: a marker for positive social functioning and receptive language skills in children with autism spectrum disorders. Dev. Psychobiol. (epub ahead of print). Althaus, M., Van Roon, A.M., Mulder, L.J.M., et al., 2004. Autonomic response patterns observed during the performance of an attention-demanding task in two groups of children with autistic-type difficulties in social adjustment. Psychophysiology 41, 893–904. Ming, X., Julu, P.O.O., Brimacombe, M., et al., 2005. Reduced cardiac parasympathetic activity in children with autism. Brain Dev. 27, 509–516. Toichi, M., Kamio, Y., 2003. Paradoxical autonomic response to mental tasks in autism. J. Autism Dev. Disord. 33, 417–426.
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Aman, M.G., 2004. Management of hyperactivity and other acting-out problems in patients with autism spectrum disorder. Semin. Pediatr. Neurol. 11, 225–228. Amir, R.E., 2000. Rett syndrome: methyl-CpG-binding protein 2 mutations and phenotype– genotype correlations. Am. J. Med. Genet. 97, 147–152. Guy, J., Hendrich, B., Holmes, M., et al., 2001. A mouse MeCP2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326. Luikenhuis, S., Giacometti, E., Beard, C.F., Jaenisch, R., 2004. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl. Acad. Sci. U. S. A. 101, 6033–6038. Giacometti, E., Luikenhuis, S., Beard, C., Jaenisch, R., 2007. Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc. Natl. Acad. Sci. U. S. A. 104, 1931–1936. Gray, S.J., 2012. Gene therapy and neurodevelopmental disorders. Neuropharmacology (epub ahead of print).
Contents lists available at SciVerse ScienceDirect
Autonomic Neuroscience: Basic and Clinical journal homepage: www.elsevier.com/locate/autneu
HIGHLIGHTS IN CLINICAL AUTONOMIC NEUROSCIENCE: NEW INSIGHTS INTO AUTONOMIC DYSFUNCTION IN AUTISM Prepared by: William P. Cheshire ⁎ Mayo Clinic, College of Medicine, United States
Section editor: Dr. Roy Freeman a r t i c l e
i n f o
Section editor: Dr. Roy Freeman Keywords: Autistic Disorder Autonomic Nervous System Diseases Vagus Nerve Pupil, Questionnaires
a b s t r a c t Investigations of autonomic nervous system biomarkers in autism have been sparse relative to its prevalence. Recent studies of children with autism spectrum disorders (ASD) have increasingly drawn correlations between autonomic findings and psychosocial behavior. Studies of heart rate variability, pupil size, salivary alpha-amylase, and electrodermal responsiveness have shown that children with ASD differ from normally developing children in their autonomic responsiveness to visualizing human faces and other mental tasks. While some results have conflicted, much of the data appears to support the theory of a hypersympathetic state in autism insufficiently attenuated by vagal parasympathetic influences. To what degree these differences in autonomic physiology might influence cognitive processing and behavior rather than simply being epiphenomena of a pervasive disorder of brain development is as yet unclear. © 2012 Elsevier B.V. All rights reserved.
Introduction Autism spectrum disorders (ASD) comprise a group of developmental disorders characterized by impairments in social interaction and communication and by restricted, repetitive, stereotyped patterns of behavior. Along the autistic spectrum are autistic disorder, pervasive developmental disorder, Asperger disorder, and atypical autism. Autism is also more frequent in patients with tuberous sclerosis, fragile X syndrome and Rett syndrome. Multiple interacting genetic factors predominate in autism pathogenesis. The Centers for Disease Control and Prevention has estimated the prevalence of ASD to be as high as 11.3 per 1000 children (Centers for Disease Control and Prevention, 2012).
that explored symptoms of autonomic instability, secretomotor and sensory integration, visceral dysfunction involving gastrointestinal, urinary, cardiopulmonary and thermoregulatory systems. The average time needed to complete the survey was 15 min. The pediatric autonomic symptoms scale succeeded in distinguishing both groups of patients from age-matched controls. Children with familial dysautonomia scored higher on scales of visceral symptoms, whereas children with ASD scored higher on scales of psychosocial symptoms, which evaluated symptoms of autonomic dysfunction associated with mood, behavior and emotions.
Commentary Ming, X., Bain, J.M., Smith, D., et al. (Newark, NJ, USA). 2011. Assessing autonomic dysfunction symptoms in children: a pilot study. Journal of Clinical Neurology 26, 420–427. Article summary These investigators piloted a comprehensive autonomic symptom screening tool administered to parents of children with familial dysautonomia (7 patients) and ASD (18 patients: 7 with autistic disorder, 10 with pervasive developmental disorder, and 1 with Asperger disorder). The pediatric autonomic symptoms scale consisted of 80 questions ⁎ Tel.: +1 904 953 2000; fax: +1 904 953 0757. E-mail address: [email protected]. 1566-0702/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.autneu.2012.08.003
This is the first study to utilize a comprehensive symptom scale to evaluate autonomic dysfunction in children with ASD. The findings indicate that autonomic dysfunction, although not the cause of psychosocial dysfunction, is pervasive as well as heterogeneous in children with ASD. Autonomic symptom surveys may not improve upon neuropsychological evaluations in ascertaining a diagnosis of autism, but they may become useful clinically in identifying autonomic symptoms amenable to interventional strategies in children with ASD. Further validation studies are needed. An autonomic questionnaire for adults with autism would require a different methodology.
Kaartinen, M., Puura, K., Mäkelä, T., et al. (Tampere, Finland). 2012. Autonomic arousal to direct gaze correlates with social impairments
W.P. Cheshire / Autonomic Neuroscience: Basic and Clinical 171 (2012) 4–7
among children with ASD. Journal of Autism and Developmental Disorders 42, 1917–1927. Article summary These authors investigated whether autonomic arousal, as measured by skin conductance responses, during eye contact was related to impairment in social skills among children with ASD. Subjects consisted of 15 children of ages 8–16 years with ASD and 16 controls matched for age and IQ. Subjects were asked to determine the direction of gaze of a model who sat 110 cm from the subject separated by a liquid crystal shutter that could be switched between an opaque and a transparent state. The models were young women who successively directed their gaze directly, averted their gaze, or kept their eyes closed, in each case maintaining a neutral facial expression. A positive skin conductance response was defined as an amplitude change of greater than 0.05 μS from baseline recorded from the left hand. They found, interestingly, that the level of autonomic arousal in response to direct gaze did not correlate directly with measurements of social skill or distinguish ASD patients from controls. However, when autonomic responsiveness to direct gaze was compared to that when faces were not looking directly ahead, increased autonomic arousal was positively associated with impaired social skill in children with ASD. No correlation to social skill was observed in children without ASD.
5
and norepinephrine-modulated connections within cortical regions responsible for higher-order processing of social responsiveness and communication. On that basis they hypothesized a therapeutic role for β-adrenergic antagonists in improving task performance, anxiety, irritability and aggression in ASD. Commentary Previous research has shown that children with ASD as compared to age-matched controls have a larger tonic pupil size and decreased pupillary responses when looking at human faces (Anderson and Colombo, 2009). Biobehavioral research has increasingly incorporated measurements of sAA into study designs as a noninvasive biomarker for sympathetic nervous system activity. Previous studies have shown that sAA increases in response to stress and exhibits a diurnal profile with a pronounced decrease shortly after awakening and a steady increase during the course of the day (Nater et al., 2007). The release of α-amylase is, however, also dependent on glands that are parasympathetically innervated, on synergistic sympathetic–parasympathetic effects on protein secretion, and on salivary flow rate. For these reasons the use of sAA as a valid and reliable measure of sympathetic nervous system activity has not attained universal support (Bosch et al., 2011). The findings in this small study should be interpreted provisionally given the limitations of the methodology.
Commentary Eye contact, which is essential to social interaction, is impaired in children with ASD. Children with ASD are atypical in how they process visual information about faces. Functional neuroimaging has shown that gaze cues elicit less activity in the right fusiform gyrus, which is responsible for facial visual processing, and in frontoparietal regions associated with orienting attention, in ASD children as compared to those who develop normally (Greene et al., 2011). ASD children also preferentially explore details of the lower parts of people's faces and are less attentive to the eyes (McPartland et al., 2011). This study expands on previous research that found that ASD children, unlike normally developing children, did not show a larger electrodermal skin response when looking at their mother's face as compared to looking at a cup (Hirstein et al., 2001). Kaartinen and colleagues attribute their findings to disturbances in arousal-related motivational systems in ASD. They reason that, since children with ASD do not find eye contact rewarding, they may be more likely to avoid eye contact when autonomic arousal to direct gaze increases. Since gaze condition was only weakly related to autonomic arousal in this study, it is reasonable to conclude that ASD children avoid direct gaze on a basis other than perceiving eye contact to be threatening.
Anderson, C.J., Colombo, J., Unruh, K.E. (Lawrence, KS, USA). 2012. Pupil and salivary indicators of autonomic dysfunction in autism spectrum disorder. Developmental Psychobiology epub ahead of print.
Martineau, J., Hernandez, N., Hiebel, L., et al. (Tours, France). 2011. Can pupil size and pupil responses during visual scanning contribute to the diagnosis of autism spectrum disorder in children? Journal of Psychiatric Research 45, 1077–1082. Article summary This study investigated pupil size and reactivity in 19 children with ASD and 38 controls (19 matched for chronological age and 19 matched for mental age) during visual scanning of neutral faces, virtual faces (avatars), and various objects presented on a computer monitor. A black slide was presented between stimuli. The investigators found that the ASD group had a significantly smaller pupil size (mean 4.11 mm) while gazing at the black slide between stimuli as compared to pupil sizes in mental age-matched (5.35 mm, p=0.00002) or chronological age-matched (5.46 mm, p=0.000004) controls. Analysis of pupil reactivity waveforms over time during the presentation of visual stimuli found no significant difference among groups in maximum changes of pupil size, but there was a significant difference in the time course of pupil size change. Whereas pupil waveforms over time did not vary according to the stimulus used for ASD or mental age-matched controls, pupil size was significantly greater (p = 0.0006) for age-matched controls when the stimuli were faces rather than avatars or objects. Discriminant analysis correctly classified 89% of the ASD group. Commentary
Article summary This study correlated pupil size with levels of salivary α-amylase (sAA), a putative correlate of norepinephrine, in 12 children with ASD. As compared to age-matched controls, children with ASD were found to have a larger tonic pupil size (5.573 versus 4.304 mm, p b 0.001), and this correlated with lower sAA levels (r = − 0.404, p = 0.018). The ASD group also lacked the diurnal variation in sAA that was seen in controls. The authors reasoned that ASD entails dysregulation of a feedback loop between hypothalamic systems
Interpretation of changes in pupil size is more complex than first meets the eye. Although pupil diameter is just one dimension plotted over time, it represents the summation of the combined influences of inhibitory and excitatory sympathetic and parasympathetic activity due to light stimuli as well as levels of emotional arousal and mental alertness, and these have elaborate central nervous system connections. Of interest in this study is an autonomic correlate in autism of the impaired psychological response to visualizing the human face.
6
W.P. Cheshire / Autonomic Neuroscience: Basic and Clinical 171 (2012) 4–7
The findings of this study conflict with those of Anderson and colleagues, who found a larger tonic pupil size in ASD. A possible explanation for the discrepancy is the difference in methodology. When measuring baseline tonic pupil size, Martineau and colleagues utilized a black slide (0.1 lx), whereas Anderson and colleagues utilized a gray slide (3.0 lx), which would have cast more light on the retina. A relative parasympathetic deficit or sympathetic excess might be less apparent in more dimly lit conditions.
Bal, E., Harden, E., Lamb, D., et al. (Chicago, IL, USA). 2010. Emotion regulation in children with autism spectrum disorders: relations to eye gaze and autonomic state. Journal of Autism and Developmental Disorders 40, 358–370.
Article summary These investigators correlated baseline respiratory sinus arrhythmia (RSA) and heart rate with the accuracy and latency of recognition of facial emotions in 33 children with ASD ages 7–17 in comparison to 45 controls. They found that children with ASD had significantly lower amplitude RSA and faster heart rates than typically developing children. ASD children with higher amplitude RSA at baseline recognized emotions more quickly but not more accurately. They concluded that children with ASD have a less effective “vagal brake,” (Porges et al., 1996) with the consequence that sympathetic influences may not be sufficiently attenuated.
Commentary These findings are in harmony with Porges's polyvagal theory Porges et al., (1996), which propounds that vagal outflow is functionally linked to attentional and emotional processing, influencing temperament and emotional reactivity. Accordingly, RSA as a measure of cardiovagal tone has been interpreted as a psychophysiological marker of behavioral functioning (Beauchaine, 2011). Lending further support to this theory, Patriquin and colleagues found that ASD children with higher baseline RSA amplitudes showed greater RSA reactivity during attention-demanding tasks and demonstrated better social behavior (Patriquin et al., 2011). Others have found in ASD a decrease in central vagal tone without impairment in vagal gain or sympathetic responsiveness during an attention-demanding task (Althaus et al., 2004; Ming et al., 2005). Paradoxically, Toichi and Kamio found that in half of their autistic subjects cardiovagal activity increased during mental arithmetic, suggesting that they may be less stressed when engaged in certain mental tasks in comparison to normally developing children, who show a decrease in heart rate variability during mental stress (Toichi and Kamio, 2003). If this model is a valid framework for distinguishing ASD from typically developing children, then ASD children may be in a hypersympathetic state with diminished capacity for calm behavior, which may contribute to their impaired ability to engage in social interactions, anxiety, and behaviors in response to anxiety. A small but relevant body of literature has found that β-adrenergic antagonists may be helpful in managing impulsivity, aggression and self-injurious behavior in ASD (Aman, 2004).
Lioy, D.T., Wu, W.W., Bissonnette, J.M. (Portland, OR, USA). 2011. Autonomic dysfunction with mutations in the gene that encodes methyl-CpG-binding protein 2: Insights into Rett syndrome. Autonomic Neuroscience 161, 55–62.
Article summary These authors review recent advances in human and animal studies in Rett syndrome, which is an X-linked autism spectrum disorder that affects one in 10,000–15,000 girls. Rett syndrome presents in the first year of life with developmental arrest, regression of language, seizures, ataxia, respiratory dysfunction and repetitive stereotypic hand movements. Cardiovascular autonomic dysfunction has been suspected to be the cause of the sudden, unexpected death that occurs in a quarter of women with Rett syndrome. A handful of studies have found prolonged QT intervals in 30–55% of patients. Spectral analysis studies have found evidence of reduced heart rate variability, suggesting inadequate vagal counterbalancing of cardiac sympathetic overactivity, possibly as the result of insufficient GABAergic transmission. Additionally, the finding of lower plasma levels of serotonin has prompted suggestions that serotoninergic influences may be awry. Rett syndrome is caused by mutations in the gene that encodes methyl-CpG-binding protein 2 (MeCP2), which is a transcriptional repressor highly expressed in neurons and important for neuronal function and brain development (Amir, 2000). A significant discovery was reversal of the MeCP2 deficiency phenotype by gene therapy in mouse models of Rett syndrome (Guy et al., 2001). Activation of a conditionally functioning transgene promoter upstream from the MeCP2 locus delayed or prevented the progression of neurologic symptoms in mice with deletions in MeCP2 exons (Luikenhuis et al., 2004; Giacometti et al., 2007). Commentary Delineation of the genetic basis of Rett syndrome represents a major landmark in deciphering the pathophysiology of one form of autism. This advance also holds promise for the prospect of gene therapy, pending the development of a safe and effective gene delivery vehicle for human clinical use (Gray, 2012). Altogether these studies indicate that the relationships between the autonomic nervous system and aberrant central nervous system development in autism are complex. Beauchaine draws an analogy to planetary motion, which eluded a satisfactory mathematical explanation before astronomers recognized that the Earth is a noncentral component of a larger solar system (Beauchaine, 2011). Autism research is disclosing many interesting details of altered autonomic tone and responsivity. Analogous to cosmology, some findings may turn out to be noncentral components in the constellation of intricate developmental processes in the central nervous system. Interpretation of associated autonomic phenomena is most meaningful when viewed also from the complementary perspectives of molecular neuroscience, structural and functional neuroimaging, and developmental psychopathology. References Centers for Disease Control and Prevention, 2012. Prevalence of autism spectrum disorders — Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1–19. Greene, D.J., Colich, N., Iacoboni, M., et al., 2011. Atypical neural networks for social orienting in autism spectrum disorders. Neuroimage 56, 354–362. McPartland, J.C., Webb, S.J., Keehn, B., Dawson, G., 2011. Patterns of visual attention to faces and objects in autism spectrum disorder. J. Autism Dev. Disord. 41, 148–157. Hirstein, W., Iversen, P., Ramachandran, V.S., 2001. Autonomic responses of autistic children to people and objects. Proc. R. Soc. Lond. 268, 1883–1888. Anderson, C.J., Colombo, J., 2009. Larger tonic pupil size in young children with autism spectrum disorder. Dev. Psychobiol. 51, 207–211. Nater, U.M., Rohleder, N., Schlotz, W., et al., 2007. Determinants of the diurnal course of salivary alpha-amylase. Psychoneuroendocrinology 32, 392–401. Bosch, J.A., Veerman, E.C., de Geus, E.J., Proctor, G.B., 2011. Alpha-amylase as a reliable and convenient measure of sympathetic activity: don't start salivating just yet! Psychoneuroendocrinology 36, 449–453. Porges, S.W., Doussard-Roosevelt, J.A., Portales, A.L., Greenspan, S.I., 1996. Infant regulation of the vagal “brake” predicts child behavior problems: a psychobiological model of social behavior. Dev. Psychobiol. 29, 697–712.
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