**2. Autonomic function and autism**

The autonomic nervous system has been implicated in symptoms that resemble those seen in autism. ASD has been associated with abnormal findings in autonomic related structures including the insula [23, 24] and the amygdala [25–27]. Autonomic related changes such as increases in basal heart rate [28–31] and diminished heart rate variability due to psychosocial challenges [32, 33] are seen in autism. The autism-autonomic linkage is exemplified by the consequences of respiratory sinus arrhythmia (RSA) that includes difficulties with socialization [30, 34], language difficulties [34, 35], and delays in cognitive development [35].

Kushki [19] hypothesized a chronically over activated autonomic system is a correlate of autism based upon the exaggerated levels of anxiety that attend autism [33], physiologic hyperarousal [36–38], and other correlates. Anxiety is perhaps the greatest co-morbidity associated with autism which may drive other features of the disease [39, 40], and has been associated with central nervous system structures that are linked to autonomic function [41, 42]. Phenotypically autism and anxiety both present with stereotyped repetitive and limited interests, avoidance behaviors and speech problems [43–45]. The relationship between anxiety and reported autonomic symptoms of elevated heart rate, perspiration, and other sequelae of the "fight or flight" reaction reveal a role for the peripheral nervous system function in autism [36–38]. However, this may be secondary to central autonomic activation. Central functions may manifest as elevated emotional responsiveness and exaggerated threat perception or diminished inhibition of fear responses [36], which are associated with the central structures mentioned above in which autonomic responsiveness and emotional responsiveness overlap.

There is a considerable body of evidence, which will not be reviewed here, that associates autism with cholinergic function in the central nervous system, specifically with various α-subtype nicotinic receptors, notably in the cerebellum. However, as autonomic function is classically considered to be a balance of cholinergic and catecholaminergic systems, perceived increases or decreases in cholinergic function may be manifestations of change in the dynamic balance of these systems with catecholaminergic tone. It may be possible to effect therapeutic change through manipulation of either acetylcholine-based manipulations or the counterbalancing of dopamine, norepinephrine, or epinephrine mediated mechanisms.
