How might an area of the brainstem influence empathy in Autism?

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How might an area of the brainstem

influence empathy in Autism?

Isac Sehlstedt Student nr: 10436022

MSc in Brain and Cognitive Sciences: Cognitive Neuroscience University of Amsterdam

Supervisor: Anke Scheeren

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Abstract

The social problems found in autism spectrum disorder (ASD) are considered the core aspect of ASD (Farmer, Thurm, & Grant, 2013). A recent hypothesis suggests that a key structure in autonomic function that mediates incoming sensory information from the viscera to the brain (nucleus tractus solitarii or NTS) may be of paramount importance in the development of some ASDs. Although many aspects of ASD are covered in that hypothesis, it does not consider how the NTS might be involved in empathy. A hallmark of successful social interaction is empathy. The NTS is involved in interoception (sensing internal visceral states) and interoception has been associated with emotional awareness and empathy. Therefore, the main hypothesis of the current thesis will be the following: Individuals with a deviant functioning NTS might receive invalid signals from visceral sensory afferents (i.e. flawed interoception), and as interoception and empathy is related, flawed interoception mediated by the NTS may be related to ASD traits (including deficiencies in empathy) and comorbidities. Therefore, therapeutic methods targeting the NTS might be considered for individuals with ASD.

Keywords (Key abbreviations): Autism Spectrum disorder (ASD), Nucleus Tractus Solitarii (NTS), interoception, Bayesian Framework of Autism (BFA and BFAtocin), Vagus Nerve Stimulation (VNS).

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Introduction

“… the wise or temperate man, and he only, will know himself, and be able to examine what he knows or does not know, and to see what others know and think that they know and do really know; and what they do not know, and fancy that they know, when they do not. No other person will be able to do this. (Plato, Charmides).”

Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions characterized by difficulties in social interaction, impaired communication skills, and a restricted range of interests and activities (American Psychiatric Association, 2013). The result is

difficulties in everyday life and the disorder can become a burden for the individual, family, and friends. ASD has a clear genetic component, approximately 1% of the world population are diagnosed, and it has a higher prevalence amongst males when compared to females (Mattila et al., 2011; Muhle, Trentacoste, & Rapin, 2004). In addition, comorbidities are common (>70%) with gastrointestinal problems and anxiety being highly prevalent (Lai, Lombardo, & Baron-Cohen, 2014). The social problems found in ASD are considered the core aspect of ASD (Farmer et al., 2013) and will therefore be the focus of the current thesis.

Empathy is essential for social communication (de Waal, 2008)and can be defined by three main points: (1) Being able to share emotions with other people, (2) being emotionally affected by another person, (3) and having the capability to realize and adapt your perspective to another individual (de Waal, 2008). Empathy, like ASD, can manifest itself in a multitude of manners and a universal definition is yet to be defined. Two commonly used aspects of empathy are affective empathy (AE) and cognitive empathy (CE). AE is defined as similar visceral, affective reactions in response to others’ emotions (Decety & Meyer, 2008) and emotional

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contagion is used synonymously to AE (Jean Decety & Svetlova, 2012; Quattrocki & Friston, 2014). CE can be described as the inference of others’ thoughts and feelings without engaging in similar feelings (Blair, 2005).ToM (or mentalizing) is the ability to separate and understand own and others’ mental states (Schreiter, Pijnenborg, & Aan Het Rot, 2013)and is therefore

considered closely related to CE.

Many neurology based (A. Bailey et al., 1998; Hutt, Hutt, Lee, & Ounsted, 1964; Porges & Porges, 1995; Williams, Whiten, Suddendorf, & Perrett, 2001) and cognitively based (Baron-Cohen, Leslie, & Frith, 1985; Frith & Happé, 1994) theories have been put forth to explain ASD. However, the underlying reason still remains obscure. The current thesis will now introduce three theories of ASD and suggest that these three theories may benefit from being considered together.

First, a Bayesian Framework of Autism (BFA) has recently suggested that ASD individuals are less biased by previous experiences when inferring the state of the world around them (Pellicano & Burr, 2012).In essence, the BFA states that predictive coding (by means of prediction error and allows for the construction of meaningful associations between sensory modalities. These associations (or predictions) are subsequently used as templates to guide future behavior. The BFA suggest that individuals with ASD have weak predictions, resulting in a less subjective perception of the world. Therefore, the BFA can provide an explanation for many of the nonsocial symptoms (savant qualities, hypersensitivity to stimuli, and reduced vulnerability to visual illusions) of ASD (Pellicano & Burr, 2012; Quattrocki & Friston, 2014). The nonsocial account for ASD by the BFA is extended by the social account of ASD in the following paragraph.

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Second, an extension of the BFA (here referred to as BFAtocin), has suggested that a failure of the oxytocin system early in development could result in the social symptoms of ASD (Quattrocki & Friston, 2014). Oxytocin is a neuropeptide that has been associated with

recognition of acquaintances, social and sexual behavior, reduction of anxiety, and has been named the “facilitator of life” (Lee, Macbeth, Pagani, & Young, 2009). Empirical studies

regarding oxytocin have found that oxytocin increases AE (Domes et al., 2013; Hurlemann et al., 2010; Olff et al., 2013) making oxytocin a possible powerful mediator of social ability

(Quattrocki & Friston, 2014). The BFAtocin emphasizes the importance of being able to avert attention from one’s own sensory input (i.e. sensory attenuation) in order to develop pro-social behavior. However, the next paragraphs (and the current thesis) suggest that instead of lacking sensory attenuation, individuals with ASD might not have a clear link to their own emotions.

Last, a recent hypothesis has outlined the importance of the nucleus tractus solitarii (NTS) in nonsocial and social symptoms of ASD (e.g. attention, memory, motivation, decision-making, and emotions (McGinnis, Audhya, & Edelson, 2013). Although the NTS hypothesis of ASD (i.e. NTS-ASD) reviews empirical evidence linking the NTS to many of the core and comorbid disorders of ASD (including social interaction problems), it does not explain how (or if) the NTS, an area of the brainstem, can be involved in empathy (McGinnis et al., 2013). However, as an essential hub for reciprocal signaling between visceral sources and evolutionary higher brain areas, the NTS is likely to be an important part of emotional awareness (Craig, 2002). Additionally, the NTS is involved in regulation of the autonomic nervous system. A malfunctioning NTS might provide an account for many of the autonomic dysfunctions observed in ASD (McGinnis et al., 2013).

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With the three accounts of ASD above in mind, a deeper consideration of the NTS-ASD within the BFAtocin might provide a more elaborate framework for future studies and possible therapeutic interventions. The BFAtocin suggests that the social ASD symptoms may be related to an inability to attenuate information from the viscera. However, the current thesis wants to suggest that lack of interoception (and not a lack of control of interoceptive signals) may be a factor in the development of ASD. In line with the BFAtocin, an early disruption of the NTS might hamper the creation of clear predictions between own bodily (interceptive) signals and external (exteroceptive) cues. The lack of these types of predictions may result in an inability to regulate NTS mediated homeostasis, a lack of (experience based) attention to socially relevant stimuli, and a deficient understanding of own emotions. In addition, these interoceptive-exteroceptive predictions may lay the foundation for more complex cognition as CE and ToM. Therefore, deficient predictions because of faulty interoception may impede the development of social skills. The current thesis will complement the BFAtocin and the NTS-ASD and review the NTSs involvement in the core symptoms of ASD with a focus on empathy. However, it is

important to note that the current thesis will likely only pertain to a subgroup of ASD due to the heterogeneous manifestation of the disorder.

The current thesis will start with brief a review of the NTS-ASD. Some of the essential parts of BFAtocin will then be revised and related to the NTS-ASD. The necessary explanation of how “knowing your own emotions precedes knowing others’ emotions” will then be covered. The crucial connection between ASD, interoception, and empathy will then follow. The final section will be devoted to a discussion of how direct stimulation of the NTS might mitigate remediation of the proposed interoception error in ASD.

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The NTS-ASD

A couple of necessary steps are needed to be explained in order to get an appreciation of the possible involvement of the NTS in ASD. The paragraphs below will cover the following topics: The autonomic nervous system, hypothesis of the NTS-ASD, vulnerability of the NTS, and ASD (and NTS) related genetics.

Neurons in the autonomic nervous system (ANS) control the cardiovascular system (e.g. the heart), effectors of the skin (e.g. sweat glands), and visceral organs (e.g. lungs). The sympathetic component allows the body to prepare the “fight-or-flight” response and the parasympathetic component is involved in “rest-and-digest” activities (Porges & Porges, 1995). The function of the ANS is to regulate and keep visceral organs in advantageous states in relation to both visceral and external environments. The parasympathetic nervous system can be

considered to revolve around the vagus nerves. Brain to body (or “efferent”) signals and body to brain (or “afferent”) information are transmitted through the left and right vagus nerves (cranial nerve 10) (Howland, 2014). However, the vagus nerve is considered a predominantly sensory pathway with 80% of the fibers being afferents from visceral targets (e.g. larynx, heart, lungs, and gastrointestinal tract) (Foley & DuBois, 1937; Howland, 2014). Afferent signals of the vagus nerves origin at visceral targets and predominantly terminate at the NTS and afferent connections from the NTS indirectly (and directly) connect to higher level brain areas (e.g. amygdala,

hypothalamus, insula, and prefrontal cortex) (Craig, 2002; Krahl, 2012; van der Kooy et al., 1984). In sum, well-functioning signaling from the vagus nerves via the NTS is important for maintaining visceral organs in an optimal state in response to signals from higher cognitive functions.

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Based on both human and animal studies the NTS-ASD implicates local lack of oxygen (hypoxia) and toxic impairment of a brainstem locus (the nucleus tractus solitarius, nucleus of the solitary tract, nucleus tractus solitarii, or NTS) as a potential reason behind ASD (McGinnis et al., 2013). In essence, the hypothesis states the following: Blunted information flow (mediated via a deficient NTS) from viscera to brain areas at higher levels might contribute to core and comorbid disorders associated with ASD (McGinnis et al., 2013).

A subregion of the NTS situated in parts of the commissural and dorsomedial subnuclei (named permissive NTS or pNTS) is particularly susceptible to hypoxia during early development, and to toxins throughout life due to fenestrated Blood –Brain-Barrier (BBB) protection (McGinnis et al., 2013). This vulnerability to hypoxia and toxins seems to be a result of the close proximity of the NTS to the Area Postrema (AP), a Circumventricular organ (CVO) that lacks BBB protection (Borison, 1989).

The suggested vulnerability of the NTS to hypoxia is a combination of various factors. The vulnerability of the NTS is supported by human autopsy reports where hypoxia and hypertension have shown symmetrical NTS infarcts (De Caro, Parenti, Montisci, Guidolin, & Macchi, 2000; Porzionato, Macchi, Morsut, Parenti, & De Caro, 2005).The amount of cell death as a result of hypoxia has also been shown to be highest in the NTS when comparing to adjacent brainstem structures (Porzionato et al., 2005).Additionally, the small vasculature (or

microvasculature) of the NTS has a significantly lower vascular density than an adjacent

brainstem area (Porzionato et al., 2005) and the full development of the microvasculature within the pNTS might not occur during gestation (Gross, Wall, Wainman, & Shaver, 1991; McGinnis et al., 2013). Furthermore, the AP is known for retaining oxygen deprived blood (or venous blood) (Gross et al., 1991; Roth & Yamamoto, 1968) and venous blood from the AP is

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reintroduced to the NTS (Fodor, Palkovits, & Gallatz, 2007). The selective sensitivity of the NTS to hypoxia may in part be because of its high density of N-methyl-D-aspartate (NMDA) receptors (Choi & Rothman, 1990; McGinnis et al., 2013). NMDA density has been correlated with brain regions sensitivity to oxygen shortage (Choi & Rothman, 1990). Vagal afferents connect heavily to the pNTS (Zhang, Fogel, & Renehan, 1992). Almost half (ca.40 %) of both the vagus nerve terminals and dendrites within the NTS have NMDA receptors (Aicher, Sharma, & Pickel, 1999). In sum, the NTSs vulnerability to hypoxia is supported by brainstem infarctions selectivity to the NTS, the low microvascular density that is not fully developed at birth, the venous blood that the NTS receives from the AP, and its high NMDA receptor density. Therefore, even in absence of infarcts, it is suspected that the NTS might still be impaired in distressed newly born babies (Sarnat, 2004).

The pNTS has been found to amass dye that does not penetrate the BBB (Gross et al., 1990, 1991). Injection of bacterial lipopolysaccharide (an agent that is blocked by the BBB) selectively and acutely affected the pNTS (and CVOs) (Breder & Hazuka, 1994). These results suggest that the pNTS is vulnerable to toxins that are blocked by the BBB.

Amount of available oxygen the pNTS has at a given moment may be affected by toxins (for a review see Yasuda & Tsutsui, 2013). The amount of blood that is transferred through any vasculature is limited by the ability of the vasculature to expand (i.e. vasodilation). Nitrous oxide (NO) is the main and very effective cerebral vasodilator (Lee et al., 2011). Two modulatory neurotransmitters of vasodilation are Acetylcholine (ACh) and Norepinephrine (NE). ACh decreases and NE increases the amount of NO that is released (Lee et al., 2011).

Additionally, acethylcholinherase (AChE) acts by eliminating ACh, inducing a pro-NO effect and increasing vasodilation. The pNTS has been shown to have high amounts of AChE in

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comparison to nearby structures (Fodor et al., 2007). Toxins that have a negative effect AChE function are known to gather in the pNTS (McGinnis et al., 2013). Ionic cadmium (Pari & Murugavel, 2007), ionic mercury (Frasco et al., 2007), and insecticides based on

organophosphate (Pari & Murugavel, 2007) have been shown to inhibit AChE. Cadmium and mercury are also known to disrupt the balance between vasodilation and vasoconstriction (Wolf & Baynes, 2007).

Treatments with monosodium glutamate (MSG) has been shown to remove AChE from the pNTS and debilitate neuronal signaling at axon terminals pertaining to the pNTS (Fodor et al., 2007). AChE activity in rats is reduced after consumption of sodium nitrite (Hassan, Hafez, & Zeghebar, 2010). Furthermore, nitrite has the capacity to decrease the amount of oxygen that is carried in the blood stream and thereby contribute to hypoxia (McGinnis et al., 2013). Nitrite has the ability to permeate the placenta (Gruener, Shuval, Behroozi, Cohen, & Shechter, 1973). Preservatives based on sodium nitrite are common in bacon, ham, meat, hotdogs, sausages, and baby food (Shuval & Gruener, 1972; Varraso & Camargo, 2014). It is ASD individuals have been shown to have elevated levels of nitrite (Sweeten, Bowyer, Posey, Halberstadt, & McDougle, 2003; Söğüt et al., 2003; M. Yu et al., 2003). Therefore, hypoxic effects in pNTS may follow by toxins.

Furthermore, increased uptake of cadmium and mercury has been associated with ASD in a range of studies (Desoto & Hitlan, 2007; Geier & Audhya, 2010; Palmer, Blanchard, & Wood, 2009; Roberts et al., 2013; Windham, Zhang, Gunier, Croen, & Grether, 2006; for a review see Yasuda & Tsutsui, 2013). Higher atmospheric densities of mercury (Palmer et al., 2009; Roberts et al., 2013; Windham et al., 2006; for a recent metanalysis see Yoshimasu, Kiyohara, Takemura, & Nakai, 2014) and cadmium (Windham et al., 2006) have been related

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with the occurrence of ASD. Young boys (4-7 years old) with ASD have strongly elevated levels of mercury in their hair (Fido & Al-Saad, 2005). Increased levels of mercury (Desoto & Hitlan, 2007; Geier et al., 2010) and cadmium (Vergani et al., 2011) in blood has also been found in ASD. In a study including almost 2000 individuals with ASD (and pertaining hair sample analyses) researchers found very high levels of aluminum, lead, arsenic, cadmium, mercury in early infancy (0-3 years of age) (Yasuda, Kobayashi, Yasuda, & Tsutsui, 2013). Noteworthy, cadmium has been found to induce genetic instability and epigenetic changes (Filipič, 2012; for a review see Jin et al., 2003). In sum, toxic levels of metals may provide an account for ASD.

Due to the genetic component of ASD, genes that affect the brainstem need to be reviewed. ASD is associated with genes that bring about vascular abnormalities (Tan et al., 2007) and genes that are related to hindbrain (Brielmaier et al., 2012) and brainstem (Muscarella et al., 2010) development. There are also unexplored genetic factors that might be related to ASD. For instance, genes that are intimately related to the development of the NTS (Dauger et al., 2003; Qian, Shirasawa, Chen, Cheng, & Ma, 2002), and cerebral blood-flow (Kim et al., 2010).

BFAtocin: Predictive coding, interoception, and emotions

A BFA is presented in a recent review (Quattrocki & Friston, 2014). In essence, the review implicates a faulty oxytocin system to the development of ASD (i.e. a Bayesian Framework of Autism based on Oxytocin or BFAtocin). Many of the arguments put forth in the BFAtocin review is of paramount importance for the current thesis and the most essential parts will be revised below by integrating the NTS-ASD into the BFAtocin.

The contemporary understanding of cerebral processing suggests that predefined internal models of environmental states are matched to incoming sensory information (Dayan, Hinton, Neal, & Zemel, 1995; Friston, 2002; Gregory, 1968, 1980). The necessary continuous

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updating process of such internal models most viably involves predictive coding (Mumford, 1992; Rao & Ballard, 1999; Srinivasan, 1982). Predictive coding implies that top-down predictions of environmental states are compared to online bottom-up feedback. Incongruence between the top-down predictions and the bottom-up feedback is commonly referred to as prediction error. By use of the prediction error, higher cognitive functions are able to update the internal models and adapt to the environmental stimuli (Quattrocki & Friston, 2014). Therefore, the necessity for well-functioning bottom-up feedback in estimation of the prediction error is apparent.

Bottom-up feedback used in predictive coding constitutes three separate but related concepts: First, information from external sources (i.e. touch, smells, sound, and light) is termed exteroception. Second, our ability to sense proprioceptive and kinesthetic states of the body is termed proprioception. Last, information signaled from remaining internal visceral (e.g. gut, respiratory and cardiac) sources is termed interoception.

Predictive coding have already been used to explain perceptual inference in exteroception (Rao & Ballard, 1999), proprioception (Adams, Shipp, & Friston, 2013), and interoception (Seth, Suzuki, & Critchley, 2011). As already stated above, the ANS is responsible for keeping the body in a state optimal for the currently active goals. Interoception involves direct signals from the viscera with accompanying indirect signals from itch, temperature, sleepiness, nausea which are ultimately used to engage in homeostatic activity, engage behaviors, and infer emotional states (Quattrocki & Friston, 2014). Therefore, as interoception refers to the ability to sense ones internal visceral states, it is easy to appreciate that the ANS and interoception are intimately related (Quattrocki & Friston, 2014).

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Even though visceral information concerning homeostasis is basal in nature, it is thought to significantly contribute to emotions (Craig, 2002; Quattrocki & Friston, 2014; Seth, 2013). Faulty interoceptive feedback in calculation of prediction error could possibly be the most debilitating of the three bottom-up sources in relation to emotional processing (Critchley & Seth, 2012; Gu, Hof, Friston, & Fan, 2013; Seth et al., 2011). The interoceptive signals mediated via the NTS is consequently joined with exteroceptive and proprioceptive information at higher cognitive areas (such as the amygdala, hypothalamus, the insula, cingulate cortex, and ventromedial prefrontal cortex) (Apps & Tsakiris, 2013; Craig, 2002; Damasio & Carvalho, 2013). By means of predictive coding, top-down predictions may be compared to interoceptive information which are presumed to be an essential part of emotional salience (Craig, 2002; Critchley & Seth, 2012; Quattrocki & Friston, 2014; Seth et al., 2011; Seth, 2013).

The fulfillment of predictions through action is termed active inference (Friston, 2010). Active inference relating to interoception (or interoceptive inference) is the process of initializing internal models that provide the necessary actions required to reach a (homeostatic or emotional) goal state. The main top-down projecting areas associated with interoceptive

inference and autonomic control is the anterior insular cortex and the ACC (Kaada, Pribram, & Epstein, 1949; Nimchinsky et al., 1999; Seth, 2013). In particular, large descending connections from the anterior insula to lower structures (such as the NTS and the hypothalamus) constitute a necessary pathway for interoceptive inference(Adams et al., 2013; Craig, 2002; Nimchinsky et al., 1999)allowing for top-down predictions to be tested and realized (Seth, 2013).

The BFAtocin states that insignificant interoceptive, exteroceptive, and proprioceptive events have to be disregarded in order for predictive coding to function in an optimal manner (Quattrocki & Friston, 2014). The measure of ability to ignore insignificant

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events is called sensory attenuation (Brown, Friston, & Bestmann, 2011; Sommer & Wurtz, 2008). A real life example of sensory attenuation would be of the lack of visual sensations when performing saccadic movements (Wurtz, Joiner, & Berman, 2011).

Modulation of homeostasis has been suggested to require a transient increase in sensory attenuation to allow for top-down predictions to alter the general state of the ANS (Quattrocki & Friston, 2014). For instance, one empirical study supporting this claim used a paradigm where one arm is “detached” by removing it from sight and replacing it with a dummy arm (i.e. the rubber-hand illusion). The rubber-hand illusion was shown to evoke sub-optimal autonomic thermoregulation of the "detached" arm (Moseley et al., 2008) suggesting that the top-down sense (or prediction) of body ownership is able affect the ANS (Quattrocki & Friston, 2014). Evolutionary higher brain areas (such as anterior cingulate cortex and fronto-insular cortex) have been implicated with the ability to perform these body ownership predictions (Butti, Santos, Uppal, & Hof, 2013; Diamond, Fagundes, & Butterworth, 2012). Furthermore, sensory attenuation might be essential for both regulating homeostasis and social interactions (Quattrocki & Friston, 2014). In order to act upon the world and engage in social behaviors, interoceptive sensory attenuation might be necessary to avert attention from the self, to another individual (Quattrocki & Friston, 2014). In turn, becoming less attentive to one's own internal states might, through emotional contagion, lead to ToM and CE (Quattrocki & Friston, 2014).

In summary, the BFAtocin states that sensory attenuation is a prerequisite for being able to accurately process prediction errors and ultimately distinguish self from others

(Quattrocki & Friston, 2014). In other words, learning meaningful associations between exteroceptive signals (e.g. a friendly face) and internal states (e.g. joy) would be hampered by lacking sensory attenuation (Quattrocki & Friston, 2014).

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The BFAtocin when considering the NTS-ASD

Neurotransmitters and neuropeptides have previously been associated with predictive coding due to their essential role in neural processing and close to ubiquitous presence throughout the human body (Corlett, Frith, & Fletcher, 2009; Friston, Adams, Perrinet, & Breakspear, 2012; Friston & Kiebel, 2009; Hirayama, Yoshimoto, & Ishii, 2004; Quattrocki & Friston, 2014; A. J. Yu & Dayan, 2005). The BFAtocin states that ASD is a result of lacking sensory attenuation (i.e. failure to inhibit autonomic responses). This may not be true in all cases. In light of the NTS-ASD, there is reason to assume that the NTS might be compromised in ASD. The NTS (and especially the pNTS) is a key mediator of interoceptive signals from the viscera. If the pNTS is compromised in any way, interoceptive ability might decrease. Additionally, the calculation of interoceptive prediction error might become erroneous leading to a sub-optimal adjustment of internal models. Therefore, miscalculation of interoceptive prediction error might not depend on sensory

attenuation of interoceptive information, but rather the ability to prevent information flow from sources other than interoception (i.e. exteroception and proprioception). Alternatively, it might also depend on faulty interoception. In either case, interoceptive attenuation when the NTS is deficient might not assist the integration of extero-, proprio-, and interoceptive information. Therefore, it may be wise to briefly consider how a deficient NTS would fit into a BFA.

A description of the NTSs involvement in interoception and ASD may be described in the following (BFAtocin influenced) ontogenetic perspective:

 Disruption of the NTS interferes with interoceptive inference early in development.

 A hypoxic/toxic impairment of the NTS impairs the perception of interoceptive signals

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 Learning of context-sensitive associations between interoceptive and exteroceptive cues is

hampered. In turn, this results in a reduction in ability to perceive socially and emotionally relevant stimuli.

 The lack of interoceptive ability leads to an inability to form higher level representation of one’s own emotions and ultimately, others’ emotions. In addition, emotions pertaining to either self or others become indistinguishable.

 The hampered sense of self, due to lack of interoceptive ability brings on a cascade of

impoverished homeostatic and behavioral modulations resulting in a lack of ToM and CE.

With this sequence in mind, the current thesis wants to suggest that lack of interoception (and not a lack of control of interoceptive signals) may be a factor in the development of ASD.

Alexithymia, interoception and empathy

Predictive coding is a way to understand the importance of interoception for the development of emotional awareness. The current thesis began with a classical quote from Plato. In sum, the quote states “know yourself and then you shall know others”. When considering the ontological

sequence of ASD stated above, interoception seems to be connected to the ability to understand the emotions that other individuals experience (Critchley, 2009). Ergo, an understanding of our own emotions might precede the understanding of others’ emotions. Scientific research

supporting that claim is found in individuals with alexithymia. The text below will briefly review what alexithymia is, and the connection between interoception and empathy.

Alexithymia is defined as (“no words for feelings”), has a clinical prevalence of ten percent, and is slightly more common amongst males compared to females (Cook, Brewer, Shah, & Bird, 2013; Levant, Hall, Williams, & Hasan, 2009). The psychological traits associated with

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alexithymia are difficulties in sensing and distinguishing one’s own emotions (Vorst & Bermond, 2001). The construct of alexithymia is classically regarded as one-dimensional; however, the contemporary opinion is that alexithymia should be considered both for an affective dimension and a cognitive dimension for the comprehension of one’s own emotions (Vorst & Bermond, 2001). The affective dimension is regarded as the ability to become aroused by one’s own emotions and to (without necessarily having emotional valance) day-dream (Vorst & Bermond, 2001). The cognitive dimension is regarded as the ability to identify one’s own emotions, explain one’s own emotional reactions and verbalize one’s own emotions (Vorst & Bermond, 2001).

Both the cognitive and affective dimensions can be measured by the Bermond-Vorst Alexithymia Questionnaire (BVAQ) (Vorst & Bermond, 2001), and a measurement on solely the cognitive dimension of alexithymia is measured by the Toronto alexithymia scale (TAS-20) (Bagby, Parker, & Taylor, 1994).

The overlap between empathy and interoception is beginning to take form in light of recent neurophysiological studies. In other words, the brain regions related to sensing own emotional states are also involved in the ability to empathize with others (J Decety &

Sommerville, 2003; Singer & Lamm, 2009). Thus, the ability to sense own vicarious states effectively aids understanding of others (Hooker, Verosky, Germine, Knight, & D’Esposito, 2008). Since the actual result of alexithymia is lack of insight towards own emotions, the

outcome is that individuals with a high level of alexithymia (compared to individuals with a low level) have less insight into others’ emotions (Silani et al., 2008).Therefore, it seems logical to assume that a lower alexithymia levels (i.e. increased insight into own emotions) should be related to an increased awareness of others’ emotions (Bird et al., 2010; Moriguchi et al., 2007).

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alexithymia (Feldmanhall, Dalgleish, & Mobbs, 2013). Lower alexithymia levels is also related to increase in empathic response to emotional facial expressions (Lockwood, Bird, Bridge, & Viding, 2013). Higher alexithymia levels has been associated with lower activity in areas associated with empathy in response to others that are experiencing pain (Bird et al., 2010; Moriguchi et al., 2011). Therefore, there is reason to believe that alexithymia (and introspection) is related to both the ability to understand (i.e. CE) and to experience (i.e. AE) or share others’ emotional states (i.e. AE or CE).

Autism and deficiencies in interoception

The central role in autonomic regulation, a key part of the BFAtocin, and a close relationship to emotions makes the NTS essential for interoception. What are then the empirical evidence for a compromised interoceptive ability in ASD? A number of ASD symptoms that might be explained by interoceptive deficiencies will now be reviewed.

Emotions

The inability of ASD individuals to describe their feelings have been related to measures of alexithymia (Bird & Cook, 2013; Silani et al., 2008). Individuals with ASD that show lower alexithymia levels show greater ease in emotional recognition (Bird et al., 2010), interpreting facial expressions (Cook et al., 2013), and making eye-contact (Bird, Press, & Richardson, 2011). Several studies have also found that individuals with ASD have difficulties naming emotions in an appropriate way, even when disregarding language disabilities (Hill, Berthoz, & Frith, 2004; Samson, Huber, & Gross, 2012).

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Homeostatic regulation

ASD has been associated with sub-optimal activity of the parasympathetic nervous system (i.e. reduction in parasympathetic tone)(Ming, Julu, Brimacombe, Connor, & Daniels, 2005; Porges & Porges, 1995; Vaughan Van Hecke et al., 2009). This deficient ANS activity in ASD has been demonstrated by increase of skin conductance measures (i.e. increase of sympathetic activity) (Hirstein, Iversen, & Ramachandran, 2001), stomach upset and constipation (Mazefsky,

Schreiber, Olino, & Minshew, 2013; Peeters, Noens, Philips, Kuppens, & Benninga, 2013), and reduction in an indirect measure of parasympathetic tone (Respiratory Sinus arrhythmia or RSA)(Ming et al., 2005; Vaughan Van Hecke et al., 2009). Furthermore, animals with selective lesion in the pNTS has been shown to increase water (and salt) consumption (Ogihara et al., 2009) and children with ASD have been reported to have an increased water consumption (Terai, Munesue, & Hiratani, 1999).

Stress response

Anxiety is a highly occurring comorbidity (ca. 40 % prevalence) in ASD (van Steensel, Bögels, & Dirksen, 2012). A predictive model has been put forth to provide an account for this high prevalence of anxiety in light of interoception (Paulus & Stein, 2006). The model predicts that a large interoceptive prediction error might result in a rise in sympathetic activity which might give rise to panic like behavior. Therefore, anxiety in ASD may be a result of faulty interoception that generates heightened stress activity (Paulus & Stein, 2006) and anxiety might be a result of failure to extrapolate interoceptive signals (Quattrocki & Friston, 2014).

Empathy

The BFAtocin suggests that the faulty interoception would impact affective empathy (AE) to a lesser extent compared to cognitive empathy (CE) (Quattrocki & Friston, 2014). In order to

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understand other individuals, it is important to have great insight into your own persona (Gallese, 2003) and an accurate sense of interoception (Quattrocki & Friston, 2014). This is corroborated by studies finding a relationship between the ability to regulate emotional responses and lack of empathic acts (Jean Decety & Jackson, 2004; Jean Decety & Lamm, 2006). In light of individuals with ASD, empathy has been shown to be comparable to typically developing individuals in AE but not in CE (Blair, 2005; Cox et al., 2012). In lack of clear interoception, own emotions become harder to distinguish. Without strong connections to own emotions, ability to discern others’ emotions might become harder, especially if the emotion is difficult to distinguish. In line with that reasoning, individuals with ASD seem to have problems with emotions that are complex and that have low emotional salience (for a review see Bons et al., 2013).

Remediation of the lack of empathy

As already stated in the introduction, the NTS has been implicated in emotional awareness. It is speculative and intriguing to contemplate if the NTS might contribute to the visceral aspects of emotions (e.g. “butterflies in the stomach” or “a broken heart”). The paragraphs above outline a relationship between interoception and empathy in ASD. Since the NTS seems to be intimately related to the ability to be empathic, treatment methods focusing on the NTS seems to be unexplored. One treatment that is able to have a close to direct effect on the NTS is vagus nerve stimulation (VNS). However, no published article has investigated, and no review has considered autonomic treatment methods to remediate the empathic issues in ASD. The current thesis will now briefly review the physiology and proposed effect of VNS.

Vagus nerve stimulation

VNS has been used for over 100 years in animals but the method has only been used in humans for the last 30 years. The method has two versions, VNS and transcutaneous VNS (or tVNS). VNS

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requires a surgeon (in human studies) or a researcher (in animal studies) to wrap a wire around one of the vagus nerves. The wire is wrapped around the vagus nerve in such a way that it avoids stimulation of visceral connections of the vagus (M. S. George & Aston-Jones, 2010). The wire is connected to a battery that is implanted (similar to that of a pacemaker) on the chest. The battery allows stimulation of the attached vagus nerve in a predefined stimulation pattern (M. George et al., 2000). Although, there have been incidences where the wrapping of the wire has been

suboptimal, no major adverse effects have been observed (Daban, Martinez-Aran, Cruz, & Vieta, 2008; Howland, 2014).

The vagus is made up out of different nerve types (i.e. myelinated and

unmyelinated) and vagal afferents and efferents being intertwined. Microsurgical techniques have been suggested to aid the focality of VNS (M. S. George & Aston-Jones, 2010). Researchers are attempting to stimulate specific nerve types to improve the VNS treatments but it has proven difficult. Variation of stimulation parameters adds further complexity of VNS resulting in recruitment of different neural networks (Mu et al., 2004). Therefore, stimulation parameters have been suggested to be disorder (or even patient) specific (Lomarev et al., 2002).

Research and clinical findings

The effects of VNS are well-documented on a cortical level. VNS stimulation has been shown to activate the orbito frontal cortex (OFC) in cats (P. Bailey & Bremer, 1938). Regions related to the NTS (i.e. insula, hippocampus, and amygdala) show greater neuronal activation after VNS (Radna & MacLean, 1981a, 1981b). Changes in brain areas following VNS develop with time (Nahas et al., 2007) and neural changes in humans have been observed in the cingulate cortex, insula, OFC, thalamus, hippocampus, and amygdala following VNS (Henry et al., 1998, 1999;

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Lomarev et al., 2002; Mu et al., 2004). It has been suggested that the Anterior cingulate cortex (ACC), OFC, anterior insula, and amygdala are key regions involved in processing emotions originating from the viscera and processing others emotional state (Jean Decety & Svetlova, 2012). This suggests that VNS can stimulate areas implicated in emotional awareness (Craig, 2002) and empathy (Bernhardt & Singer, 2012) further implicating interoception in both of the aforementioned.

Behavioral and cognitive effects have also been found with VNS (Vonck et al., 2014). Some of the positive effects that have been observed are improvement in working

memory, executive functions and verbal recognition memory (Sackeim, Keilp, et al., 2001). With the stimulation parameter dependent specificity of VNS in mind, clinical outcome has been shown to vary with stimulation parameters and which vagus nerve (left or right) that was stimulated (Howland, 2014). For instance, higher stimulation groups seem to have a better response to VNS compared to lower stimulation (Ben-Menachem et al., 1994; Handforth & DeGiorgio, 1998) and VNS stimulation to the left vagus nerve is common and effective in epilepsy (Howland, 2014).

In light of ASD, VNS has been shown to have positive effects. Subjects with severe ASD showed major improvements after VNS (for control of seizures) (Murphy, Wheless, & Schmoll, 2000). Long term effects show that VNS can improve cognitive performance (Park, 2003). These results are encouraging. However, the effect of VNS on empathy has not been investigated.

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Adverse effects of VNS

Negative effects of the surgical intervention and the stimulation procedures do exist. The surgical risks are very small (O’Reardon, Cristancho, & Peshek, 2006). The immediate side effects of the VNS (e.g. coughing, hoarseness, and dyspnea) are mostly related to stimulation parameters and can be corrected (O’Reardon et al., 2006). Predominantly, the side effects of VNS decrease with time (Sackeim, Rush, et al., 2001). However, one affirmed risk of VNS is that it has been shown to increase respiratory related disorders in those already affected by the aforementioned (Ebben, Sethi, & Conte, 2008; Marzec, Edwards, Sagher, Fromes, & Malow, 2003; Papacostas,

Myrianthopoulou, Dietis, & Papathanasiou, 2007; Parhizgar, Nugent, & Raj, 2011). Therefore, caution is always advised when utilizing VNS but most certainly in respiratory related disorders.

Future directions

The position and size of the NTS makes it problematic to study directly. It might be applicable to acquire alexithymia and empathy ratings from individuals that already have had VNS devices implanted. As stated earlier, the positive effect of VNS seems to increase with time. It would also be easy and cost effective to collect empathy and alexithymia measures for all future patients that receive VNS before the VNS is implanted, thereby building a potentially essential collection of data that can guide future research on the topic.

Although empathy and alexithymia measures for ASD individuals that have had VNS implanted are currently lacking, many findings can be informative in the absence of pre-VNS measures. For instance, one indirect hypothesis that the current thesis has is that

interoceptive signals may be needed early in life. If interoception is faulty, sub-optimal

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formation of this connection has a “sensitive period” that necessitates a reliable interoceptive-exteroceptive connection to be formed before a certain age. For instance, it is possible that neuronal tracts that transmit signals from visceral sources may be weakened by the hypoxic impairments of the pNTS. Since the vagus nerve is (to a large degree) reliant on hypoxia sensitive NMDA receptors, permanent negative effects on the vagus nerve may increase with the amount and duration of hypoxia in the NTS. VNS has the ability to increase microvascular blood flow (Mihaylova et al., 2012). Therefore, VNS can induce anti-hypoxic effects and might therefore assist the recuperation of the deficient NTS. However, due to the invasiveness of VNS, tVNS should be thoroughly evaluated to provide a less invasive method of affecting the NTS.

In light of the BFAtocin, early treatment with oxytocin for infants with ASD has been conducted (Dawson et al., 2012). It seems logical to assume that if this treatment is successful in remediating the lack of CE in ASD, then the NTS-ASD is less likely and the

BFAtocin receives additional support for its sensory attenuation account ASD. Conversely, if the oxytocin treatment is ineffective (or provides many benefits but does not affect CE), then the current thesis receives support for its faulty interoception account of ASD. Noteworthy,

researchers wanting to investigate oxytocin treatment in early development should be aware that oxytocin treatments might have adverse effects on the child’s development (Wahl, 2004).

Finally, relatively simple genetic screening of unexplored NTS genes (Dauger et al., 2003; Qian et al., 2002), and genes coding for cerebral blood-flow (Kim et al., 2010) should be investigated in ASD. The results of such genetic screening might also provide an important future database in ASD research.

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Limitations and considerations

One of the most prominent issues with a circum ventricular organ (CVO) affecting the pNTS is that a key structure of the oxytocin system is classified as a CVO and lack Blood-brain-barrier (for a review see Carson, Guastella, Taylor, & McGregor, 2013). This suggests that any effects of toxins on the pNTS might also affect the oxytocin system. Additionally, the NTS is a part of the oxytocin system. Therefore, negative effects on the NTS will also affect the oxytocin system. This is a major reason for the inclusion of the BFAtocin in the NTS-ASD in the current thesis. The relationship between BFAtocin and the NTS-ASD can be considered as an analogy to the sensori-motor system (that is essential for prorioception and goal directed behavior). As sensory input and motor signals are related, so is the oxytocin system and the NTS. Bottom -up sensory input from proprioception guides top-down motor signals to the entire body. Bottom-up sensory input from visceral sources (mediated via the NTS) guides the oxytocin systems construction of top-down internal predictions.

Why the coupling between NTS and empathy has been overlooked might be the common misconception of autonomic functions to be too rudimentary or phylogenetically old to play a part in empathy. However, the paragraphs above have clearly shown that the ANS and interoception are intimately related and key aspects of emotion and empathy. Another reason for not implicating the NTS in empathy is the technical limitation of imaging quality. For instance, differences in activations in the brainstem (e.g. in the periaqueductal gray) have been shown to be nearly invisible in fMRI scanners with lower magnetic strength (i.e. 3 Telsa) when compared to higher magnetic strength (7 Tesla) (Hahn et al., 2013). However, 7 Tesla might not be applicable for highly cognitive functions (perhaps as empathy) due to the larger increase in physiological noise at higher magnetic strengths.

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It is important to note that many of the findings supporting the NTS-ASD are from animal studies (McGinnis et al., 2013). However, the subnuclei of the NTS have been shown to correspond closely between mammals with regard to function, neurochemistry, and connectivity (Hyde & Miselist, 1992).

Inconsistencies in the research of emotion perception in ASD has brought about a new hypothesis where alexithymia (difficulties in interpreting own and others’ emotional states) has become a possible highly prevalent comorbid disorder (Cook et al., 2013). Similar to ASD pronounced alexithymia has been related to psychiatric syndromes such as anxiety and mood disorders (Onur, Alkın, Sheridan, & Wise, 2013). The overlap between alexithymia and ASD is troublesome and the clinical definition of both disorders might be in need of revision (Cook et al., 2013). The current thesis reviewed ASD research with the newly found alexithymia/ASD debate in mind. Additionally, the current thesis is not suggesting that the interoceptive problem seen in alexithymia without ASD is the same as with ASD. Investigation of the neurophysiological substrates of alexithymia has been inconclusive. Although many studies have tried to correlate various brain areas to alexithymia measures using the TAS-20 only very few studies have investigated the neural correlates of alexithymia when considering both the affective and cognitive dimension by use of the BVAQ (e.g. Goerlich-Dobre, Bruce, Martens, Aleman, & Hooker, 2014; Pouga, Berthoz, de Gelder, & Grèzes, 2010; van der Velde et al., 2013, 2014). In light of that fact, the current thesis would like to state the ACC might be involved in both the affective and cognitive dimension of alexithymia (Goerlich-Dobre et al., 2014; Pouga et al., 2010; van der Velde et al., 2014) and that more research is needed before firm conclusions can be drawn. An investigation of alexithymia on its own should be conducted in the future.

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Conclusion

The current thesis emphasizes the importance of an uncompromised NTS in the perception of interoceptive signals by means of an alternative interpretation of the Bayesian accounts of Autism. A deficient sense of internal states results in poor understanding of own emotions. A deficient sense of own emotions debilitates the understanding of others’ emotions. One precursor of empathy may therefore be a clear connection to internal states, and a lack thereof may disturb the ability to enjoy the full scope of empathy. One popular idiom that fits the current thesis is “Build from the ground up.” When lacking proper interoceptive neuronal circuitry (i.e. well-functioning NTS), introduction of neurotransmitters that modulates interoception (e.g. oxytocin) might not remediate the underlying issue in an effective way. In other words, there is a need to (re-)establish a steady foundation (e.g. with a well-functioning NTS) in order to develop

architectonically (cognitively and emotionally) advanced buildings (cerebra). Therefore, it may be necessary to remediate a deficient NTS in order for individuals with ASD to enjoy the full scope of empathy. Future investigations of genetic and neurophysiological relationships between the NTS and empathy for individuals with ASD are warranted.

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How might an area of the brainstem influence empathy in Autism?