Approaches to Understanding Multisensory Dysfunction in Autism Spectrum Disorder

“For example, human psychophysical studies have shown that the added visual information of seeing a speaker’s lip movements can facilitate speech intelligibility in a noisy environment [Sumby & Pollack, 1954].”

“In contrast, the mouse and, more recently, the rat allow facile creation of genetic models of disease risk [Nestler & Hyman, 2010].”

“…interpretation is that by utilizing a speaker uttering syllables, there INSARSiemann et al./Multisensory function in ASD1432 may be intrinsic differences between the groups as there is evidence of atypical processing of faces in ASD [Dalton et al., 2005; Dawson, Webb, & McPartland, 2005].”

“There are a variety of cortical regions in the nonhuman primate shown to receive convergent input from multiple sensory modalities, and to demonstrate many of the classical multisensory features [Ghazanfar & Schroeder, 2006; Kajikawa, Falchier, Musacchia, Lakatos, & Schroeder, 2012].”

“, 2005] and the medial superior temporal area [Bruce et al., 1981; Ghazanfar et al., 2008; Gu et al., 2008].”

“…Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007; Miller, 1982; Miller & D’esposito, 2005; Olive et al., 2015; Raab, 1962; Stein, 2012; Stevenson, Ghose, Fister, et al., 2014; Watkins et al., 2006].”

“The interactive index compares multisensory responses to the largest or most effective unisensory response [Meredith & Stein, 1983, 1986a, 1986b].”

“There is clear evidence that sensory processing across multiple modalities (sight, sound, touch, smell, and taste) is impacted in ASD [Baum, Stevenson, & Wallace, 2015a; Robertson & Baron-Cohen, 2017].”

“, 2014; Stein & Stanford, 2008], numerous studies have identified the necessary brain structures, and behavioral/perceptual benefits of multisensory integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassine…”

“…[Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007; Miller, 1982; Miller & D’esposito, 2005; Olive et al., 2015; Raab, 1962; Stein, 2012; Stevenson, Ghose,…”

“…benefits of multisensory integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007; Miller, 1982; Miller &…”

“One of the best-studied models for this work has been the cat [Meredith & Stein, 1983].”

“The spatial and temporal principles specify that stimuli from different sensory modalities presented in close spatial and/or temporal proximity result in greater neural responses and behavioral benefits compared to those presented in a disparate manner [Meredith et al., 1987; Meredith & Stein, 1986a].”

“Importantly, many of these subcortical and cortical findings are similar to those that have been observed in larger animal models (Table 1) [May, 2006; Wallace & Stein, 1996].”

“…Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007; Miller, 1982; Miller & D’esposito, 2005; Olive et al., 2015; Raab, 1962; Stein, 2012; Stevenson, Ghose, Fister, et al., 2014; Watkins et al., 2006].”

“Interestingly, neuroimaging studies have found both structural and functional differences in the STS of those with ASD, and this brain region, which has been shown to be important for the McGurk illusion, has also been established as a neural hub for multisensory integration and social processing [Beauchamp, Argall, B…”

“Beyond studies in the cat; neural, circuit, and behavioral-based studies in the non-human primate have been crucial in understanding the underlying mechanisms of multisensory processing [Cappe et al., 2010; Cappe & Barone, 2005; Maier, Neuhoff, Logothetis, & Ghazanfar, 2004; Rockland & Ojima, 2003].”

“, 2005] and the medial superior temporal area [Bruce et al., 1981; Ghazanfar et al., 2008; Gu et al., 2008].”

“Further, primary unisensory cortices such as visual and auditory cortex have been shown to be modulated by multisensory stimulation, expanding greatly the view of what constitutes a “multisensory” brain region [Foxe & Schroeder, 2005; Ghazanfar et al., 2005; Lakatos et al., 2007; Wang et al., 2008].”

“…of these studies is reinforced by the fact that serotonin has been consistently implicated in ASD [Cook & Leventhal, 1996; Mulder et al., 2004; Muller et al., 2016], has been shown to be important for sensory cortical development [Cases et al., 1996; Gaspar, Cases, & Maroteaux, 2003; Salichon…”

“These include the prefrontal cortex [Fuster et al., 2000; Romanski et al., 2005; Romanski & Goldman-Rakic, 2002; Sugihara et al., 2006], parietal cortex [Avillac et al., 2007; Cohen, 2009; Mullette-Gillman, Cohen, & Groh, 2005; Schlack et al., 2005] and the medial superior temporal area [Bruce et…”

“, 2016], has been shown to be important for sensory cortical development [Cases et al., 1996; Gaspar, Cases, & Maroteaux, 2003; Salichon et al., 2001], and can modulate responses to a variety of sensory stimuli [Esaki et al.”

“…as a tractable target for intervention that would have benefits that have cascading impact across both the processing hierarchy as well as in development [Baum et al., 2015a; Robertson & Baron-Cohen, 2017; Stevenson et al., 2018; Stevenson, Siemann, Schneider, et al., 2014; Thye et al., 2018].”

“…are those studies that then investigate the underlying neurophysiology and multisensory behavior in non-human primates [Angelaki, Gu, & DeAngelis, 2009; Frens & Van Opstal, 1998; Gu et al., 2008; Kayser et al., 2008; Miller et al., 2001], allowing for the mapping of neuron-behavior relationships.”

“…work identifying subcortical (i.e. inferior colliculus - [Dillingham, Gay, Behrooz, & Gabriele, 2017], superior colliculus - [Doykos et al., 2020; Drager & Hubel, 1975a; Drager & Hubel, 1975b] to cortical connections [Lesicko, Hristova, Maigler, & Llano, 2016], cortical–cortical connections…”

“…shown that the combination of information from multiple senses can result in behavioral enhancements, such as increased accuracies and reduced reaction times, when compared to behavioral performances under unisensory (i.e. visual, auditory, or tactile alone) conditions [Stevenson et al., 2014].”

“Interestingly, neuroimaging studies have found both structural and functional differences in the STS of those with ASD, and this brain region, which has been shown to be important for the McGurk illusion, has also been established as a neural hub for multisensory integration and social processing [Beauchamp, Argall, B…”

“While these studies have differed on the variety of stimuli, specific stimulus features, and task, they have all successfully demonstrated multisensory processing in rats, finding similar effects to those found in larger animal species (Table 1) [Carandini & Churchland, 2013; Gleiss & Kayser, 2012; Hirokawa et al., 20…”

“, 2014; Stein & Stanford, 2008], numerous studies have identified the necessary brain structures, and behavioral/perceptual benefits of multisensory integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassine…”

“In addition to the Ayres Sensory Integration intervention, studies have evaluated these sensory-based therapies with mixed results, largely concluding there is little efficacy of these treatments or at least more evidence is still needed [Case-Smith et al., 2015; Lang et al., 2012; Schaaf, Dumont, Arbesman, & May-Bens…”

“, 2014; Stein & Stanford, 2008], numerous studies have identified the necessary brain structures, and behavioral/perceptual benefits of multisensory integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassine…”

“…the original work that evaluated the underlying neurobiology and development of multisensory processing was initially performed in animal models [Murray & Wallace, 2011; Stein et al., 2014; Stein & Stanford, 2008], numerous studies have identified the necessary brain structures, and…”

“In sum, numerous findings, using a variety of approaches, have demonstrated the presence of multisensory and temporal processing deficits in individuals with autism spectrum disorder [Baum et al., 2015b; Brandwein et al., 2015; Collignon et al., 2013; Foss-Feig et al., 2010; Foxe et al., 2015; Irwin et al., 2011; Kwak…”

“The importance of these studies is reinforced by the fact that serotonin has been consistently implicated in ASD [Cook & Leventhal, 1996; Mulder et al., 2004; Muller et al., 2016], has been shown to be important for sensory cortical development [Cases et al., 1996; Gaspar, Cases, & Maroteaux, 2003;…”

“…evaluated the underlying neurobiology and development of multisensory processing was initially performed in animal models [Murray & Wallace, 2011; Stein et al., 2014; Stein & Stanford, 2008], numerous studies have identified the necessary brain structures, and behavioral/perceptual benefits of…”

“Interestingly, neuroimaging studies have found both structural and functional differences in the STS of those with ASD, and this brain region, which has been shown to be important for the McGurk illusion, has also been established as a neural hub for multisensory integration and social processing [Beauchamp, Argall, B…”

“In a study of multiplex ASD families, the Ala56 allele was the most common of a group of rare amino acid coding variants in the serotonin transporter [Sutcliffe et al., 2005].”

“…and behavioral studies have now demonstrated atypical multisensory processing in individuals with ASD [Baum et al., 2015a; Foss-Feig et al., 2010; Iarocci & McDonald, 2006; Kwakye, Foss-Feig, Cascio, Stone, & Wallace, 2011; Marco, Hinkley, Hill, & Nagarajan, 2011; Russo et al., 2010; Stevenson,…”

“…that (multi)sensory function may play a critical role in the establishment and maintenance of more complex functions such as social communication [Baum et al., 2015a; Robertson & Baron-Cohen, 2017; Stevenson et al., 2018; Stevenson, Siemann, Schneider, et al., 2014; Thye, Bednarz, Herringshaw,…”

“…disturbances correlate with greater deficits in social communication, along with the presence of more repetitive behaviors in individuals with ASD [Boyd et al., 2010; Boyd, McBee, Holtzclaw, Baranek, & Bodfish, 2009; Feldman et al., 2019; Foss-Feig, Heacock, & Cascio, 2012; Hilton et al., 2010;…”

“Beyond studies in the cat; neural, circuit, and behavioral-based studies in the non-human primate have been crucial in understanding the underlying mechanisms of multisensory processing [Cappe et al., 2010; Cappe & Barone, 2005; Maier, Neuhoff, Logothetis, & Ghazanfar, 2004; Rockland & Ojima, 2003].”

“Interestingly, neuroimaging studies have found both structural and functional differences in the STS of those with ASD, and this brain region, which has been shown to be important for the McGurk illusion, has also been established as a neural hub for multisensory integration and social processing [Beauchamp, Argall, B…”

“…Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007; Miller, 1982; Miller & D’esposito, 2005; Olive et al., 2015; Raab, 1962; Stein, 2012; Stevenson, Ghose, Fister, et al., 2014; Watkins et al., 2006].”

“…the opportunity to evaluate whether training in animal models can improve multisensory function, which may parallel approaches being developed in humans that seek to capitalize on multisensory training [De Niear et al., 2016; De Niear et al., 2018; Powers 3rd et al., 2012; Powers et al., 2009].”

“…sensory cortices (visual, auditory, somatosensory) that contain a large number of multisensory neurons and demonstrate similar multisensory characteristics to those found in larger animal models [Schormans & Allman, 2019; Schormans, Typlt, & Allman, 2017; Wallace et al., 2004; Xu et al., 2014].”

“…and the relevance to the human population, audiovisual stimuli have been most frequently used to assess multisensory function behaviorally [Carandini & Churchland, 2013; Sakata et al., 2004], despite the fact that rodents tend to have fairly poor vision and more specialized somatosensory…”

“Remarkably, rats are capable of performing classic psychophysical simultaneity judgment (SJ) and temporal order judgment (TOJ) tasks [Schormans, Scott, et al., 2017], generating TBWs that appear to be similar to those found in the human population [Wallace & Stevenson, 2014].”

“…temporal binding window may be abnormally wide in individuals with ASD [Baum et al., 2015a; Baum, Stevenson, & Wallace, 2015b; Foss-Feig et al., 2010; Kwakye et al., 2011; Stevenson, Siemann, Woynaroski, et al., 2014; Wallace & Stevenson, 2014], resulting in degraded perceptual representations.”

“…integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007; Miller, 1982; Miller & D’esposito, 2005; Olive et al.,…”

“, 2014] N/A N/A Gad65 KO Insula: [Gogolla et al., 2014] N/A N/A SERT Ala56 N/A N/A AV detection: [Siemann et al.”

“…addition, the brain region (STS) shown to be critical in the perception of this illusion [McGurk effect) (Beauchamp et al., 2010; Nath et al., 2011; Nath & Beauchamp, 2012], is also a key hub for the processing of social communicative stimuli [Pelphrey, Morris, & Mccarthy, 2004; Stevenson et al.,…”

“…include the prefrontal cortex [Fuster et al., 2000; Romanski et al., 2005; Romanski & Goldman-Rakic, 2002; Sugihara et al., 2006], parietal cortex [Avillac et al., 2007; Cohen, 2009; Mullette-Gillman, Cohen, & Groh, 2005; Schlack et al., 2005] and the medial superior temporal area [Bruce et al.,…”

“, 2014; Stein & Stanford, 2008], numerous studies have identified the necessary brain structures, and behavioral/perceptual benefits of multisensory integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassine…”

“These include the prefrontal cortex [Fuster et al., 2000; Romanski et al., 2005; Romanski & Goldman-Rakic, 2002; Sugihara et al., 2006], parietal cortex [Avillac et al., 2007; Cohen, 2009; Mullette-Gillman, Cohen, & Groh, 2005; Schlack et al., 2005] and the medial superior temporal area [Bruce et…”

“…[Boyd et al., 2010; Boyd, McBee, Holtzclaw, Baranek, & Bodfish, 2009; Feldman et al., 2019; Foss-Feig, Heacock, & Cascio, 2012; Hilton et al., 2010; Kern et al., 2007; Schauder, Muller, Veenstra-VanderWeele, & Cascio, 2015; Stevenson et al., 2017; Stevenson et al., 2018; Watson et al., 2011; Zhou…”

“The use of animal models has been integral in determining the development [Stein, Stanford, & Rowland, 2014; Wallace & Stein, 1997, 2001; Wallace & Stein, 2007], neural mechanisms [Jiang, Wallace, Jiang, Vaughan, & Stein, 2001; Wallace et al., 1992; Wallace & Stein, 2000], and brain regions and…”

“…2004; Muller et al., 2016], has been shown to be important for sensory cortical development [Cases et al., 1996; Gaspar, Cases, & Maroteaux, 2003; Salichon et al., 2001], and can modulate responses to a variety of sensory stimuli [Esaki et al., 2005; Hurley, Thompson, & Pollak, 2002; Waterhouse,…”

“Also, studies, utilizing various psychophysical behavioral measures, have determined that the development of multisensory integration might be delayed in these individuals [Beker et al., 2018; Brandwein et al., 2012; Foxe et al., 2015; Stevenson, Siemann, et al., 2013; Taylor et al., 2010], along with evidence of sex-…”

“In addition to the Ayres Sensory Integration intervention, studies have evaluated these sensory-based therapies with mixed results, largely concluding there is little efficacy of these treatments or at least more evidence is still needed [Case-Smith et al., 2015; Lang et al., 2012; Schaaf, Dumont, Arbesman, & May-Bens…”

“…structures, and behavioral/perceptual benefits of multisensory integration in humans as well (Table 1) [Calvert et al., 1997; Calvert et al., 2001; Colonius & Diederich, 2004; Driver & Noesselt, 2008; Foxe & Schroeder, 2005; Frassinetti et al., 2002; Lakatos et al., 2007; Martuzzi et al., 2007;…”

“Over the past decade, increasing interest has focused on multisensory research in the mouse [Borges-Merjane & INSARSiemann et al./Multisensory function in ASD1436 Trussell, 2015; Hornix, Havekes, & Kas, 2018; Olcese et al., 2013; Radvansky & Dombeck, 2018; Reig & Silberberg, 2014].”

“…has also been established as a neural hub for multisensory integration and social processing [Beauchamp, Argall, Bodurka, Duyn, & Martin, 2004; Boddaert et al., 2004; Calvert, Campbell, & Brammer, 2000; Gervais et al., 2004; Redcay, 2008; Stevenson & James, 2009; Zilbovicius et al., 2006].”

“…compounds have been found to rescue social or repetitive behaviors observed in genetic or behavioral mouse models of ASD [Gogolla et al., 2014; Silverman et al., 2012; Silverman et al., 2015]; however, those compounds that have been tested in translational clinical trials have not yet…”

“Typically developing participants tend to report high proportions of simultaneity for stimuli separated by about 300 ms, depending on the complexity of stimuli [Stevenson & Wallace, 2013].”

“In addition, the brain region (STS) shown to be critical in the perception of this illusion [McGurk effect) (Beauchamp et al., 2010; Nath et al., 2011; Nath & Beauchamp, 2012], is also a key hub for the processing of social communicative stimuli [Pelphrey, Morris, & Mccarthy, 2004; Stevenson et…”

“…Stanford, & Rowland, 2014; Wallace & Stein, 1997, 2001; Wallace & Stein, 2007], neural mechanisms [Jiang, Wallace, Jiang, Vaughan, & Stein, 2001; Wallace et al., 1992; Wallace & Stein, 2000], and brain regions and circuits responsible for multisensory integration [Driver & Noesselt, 2008;…”

“…shown that the combination of information from multiple senses can result in behavioral enhancements, such as increased accuracies and reduced reaction times, when compared to behavioral performances under unisensory (i.e. visual, auditory, or tactile alone) conditions [Stevenson et al., 2014].”

“…behavioral measures, have determined that the development of multisensory integration might be delayed in these individuals [Beker et al., 2018; Brandwein et al., 2012; Foxe et al., 2015; Stevenson, Siemann, et al., 2013; Taylor et al., 2010], along with evidence of sex-dependent differences…”

“…individuals with ASD [Boyd et al., 2010; Boyd, McBee, Holtzclaw, Baranek, & Bodfish, 2009; Feldman et al., 2019; Foss-Feig, Heacock, & Cascio, 2012; Hilton et al., 2010; Kern et al., 2007; Schauder, Muller, Veenstra-VanderWeele, & Cascio, 2015; Stevenson et al., 2017; Stevenson et al., 2018;…”

“Founded on these differences in sensory function, a variety of sensory-based therapies and interventions including the Ayres Sensory Integration intervention [Parham et al., 2011] have been applied in ASD.”

“…found to rescue social or repetitive behaviors observed in genetic or behavioral mouse models of ASD [Gogolla et al., 2014; Silverman et al., 2012; Silverman et al., 2015]; however, those compounds that have been tested in translational clinical trials have not yet demonstrated comparable…”

“The use of animal models has been integral in determining the development [Stein, Stanford, & Rowland, 2014; Wallace & Stein, 1997, 2001; Wallace & Stein, 2007], neural mechanisms [Jiang, Wallace, Jiang, Vaughan, & Stein, 2001; Wallace et al., 1992; Wallace & Stein, 2000], and brain regions and…”

“…et al., 2015b; Brandwein et al., 2015; Collignon et al., 2013; Foss-Feig et al., 2010; Foxe et al., 2015; Irwin et al., 2011; Kwakye et al., 2011; Smith & Bennetto, 2007; Stevenson, Siemann, et al., 2013; Stevenson, Siemann, Schneider, et al., 2014; Stevenson, Siemann, Woynaroski, et al., 2014;…”

“Pharmacological [Wilkinson, Meredith, & Stein, 1996] and deactivation studies [Jiang et al., 2001; Jiang, Jiang, & Stein, 2002; Wallace & Stein, 1994] show that the AES is critical for this gating, in addition to being integral for the behavioral enhancements observed under multisensory conditions.”

“The importance of these studies is reinforced by the fact that serotonin has been consistently implicated in ASD [Cook & Leventhal, 1996; Mulder et al., 2004; Muller et al., 2016], has been shown to be important for sensory cortical development [Cases et al.”

“Collectively, this work has shown that multisensory inputs converge at many sites in the nervous system [Meredith, 2002; Wallace, Meredith, & Stein, 1992; Wallace, Ramachandran, & Stein, 2004] and that this convergence frequently results in dramatic changes in neuronal responses when stimuli from multiple modalities a…”

“, 2005] and the medial superior temporal area [Bruce et al., 1981; Ghazanfar et al., 2008; Gu et al., 2008].”

“…between multisensory processing and clinical domains such as social communication in ASD [Cascio, Woynaroski, Baranek, & Wallace, 2016; Feldman et al., 2018; Martínez et al., 2019; Patten, Labban, Casenhiser, & Cotton, 2016; Sartorato, Przybylowski, & Sarko, 2017; Wallace et al.,…”

“Importantly, similar findings to the rat have emerged in the mouse, where unisensory stimuli from other modalities can impact neuronal responses in primary sensory cortices [Cohen et al., 2011; Deneux et al., 2019; Knöpfel et al., 2019; McClure Jr & Polack, 2019; Meijer et al., 2017; Morrill & Hasenstaub, 2018; Zhang,…”

“However, it is important to note caveats such as the BTBR T+tf/J inbred mouse strain represents no known idiopathic form of ASD [Meyza & Blanchard, 2017], Rett syndrome itself is no longer considered within the autism diagnosis [APA, 2013], and the Shank3 mouse model is typically homozygous whereas…”

“Further, these multisensory deficits have been correlated with symptom severity [Brandwein et al., 2015; Yaguchi & Hidaka, 2018], and the development of multisensory function and its neural underpinnings may be atypical in ASD as well [Beker et al.”

“…processing in individuals with ASD [Baum et al., 2015a; Foss-Feig et al., 2010; Iarocci & McDonald, 2006; Kwakye, Foss-Feig, Cascio, Stone, & Wallace, 2011; Marco, Hinkley, Hill, & Nagarajan, 2011; Russo et al., 2010; Stevenson, Segers, Ferber, Barense, & Wallace, 2014; Wallace & Stevenson, 2014].”

“Overall, studies have demonstrated that individuals with ASD tend to perceive the McGurk effect less frequently in comparison to TD individuals [Irwin, Tornatore, Brancazio, & Whalen, 2011; Mongillo et al., 2008; Stevenson, Siemann, et al., 2013; Stevenson, Siemann, Schneider, et al., 2014; Taylor et al., 2010], with…”

“, 2015]; however, those compounds that have been tested in translational clinical trials have not yet demonstrated comparable benefits in humans with autism spectrum disorder [Ooi, Weng, Kossowsky, Gerger, & Sung, 2017; Silverman & Crawley, 2014; Veenstra-VanderWeele et al., 2017].”

“…unisensory cortices and their overlapping border regions, studies have identified the cerebellum [Ishikawa, Shimuta, & Häusser, 2015], insula [Rodgers et al., 2008], parietal cortex [Brett-Green et al., 2003; Lippert et al., 2013; Menzel & Barth, 2005], prefrontal cortex [Lipton et al.,…”

“Indeed, if multisensory integration is a key building block in the construction of higher-order cognitive representations, it may serve as a tractable target for intervention that would have benefits that have cascading impact across both the processing hierarchy as well as in development [Baum et al., 2015a; Robertso…”

“A number of studies have utilized lesions, pharmacology, and/or cooling blockades to disrupt and evaluate multisensory circuits and function in animal models [Burnett et al., 2002; Burnett, Stein, Perrault, & Wallace, 2007; Jiang et al., 2001; Jiang, Jiang, & Stein, 2006; Wilkinson et al., 1996].”

“From these studies, many of the connections and neural structures critical for multisensory processing have been determined [Meredith & Stein, 1986b; Olcese, Iurilli, & Medini, 2013; Stein, Wallace, Stanford, & Jiang, 2002; Wallace & Stein, 1994].”

“…shown that the combination of information from multiple senses can result in behavioral enhancements, such as increased accuracies and reduced reaction times, when compared to behavioral performances under unisensory (i.e. visual, auditory, or tactile alone) conditions [Stevenson et al., 2014].”

“, 2013], and if this ultimately leads to lasting and positive changes in higher order domains for both typically developed and clinical populations [Wallace et al., 2020].”

“…work identifying subcortical (i.e. inferior colliculus - [Dillingham, Gay, Behrooz, & Gabriele, 2017], superior colliculus - [Doykos et al., 2020; Drager & Hubel, 1975a; Drager & Hubel, 1975b] to cortical connections [Lesicko, Hristova, Maigler, & Llano, 2016], cortical–cortical connections…”

“In sum, numerous findings, using a variety of approaches, have demonstrated the presence of multisensory and temporal processing deficits in individuals with autism spectrum disorder [Baum et al., 2015b; Brandwein et al., 2015; Collignon et al., 2013; Foss-Feig et al., 2010; Foxe et al., 2015; Irwin et al., 2011; Kwak…”

“Most relevant to our work, there is evidence that serotonin may play a role in cross-modal plasticity [Jitsuki et al., 2011].”

“Further, primary unisensory cortices such as visual and auditory cortex have been shown to be modulated by multisensory stimulation, expanding greatly the view of what constitutes a “multisensory” brain region [Foxe & Schroeder, 2005; Ghazanfar et al., 2005; Lakatos et al., 2007; Wang et al., 2008].”

“Beyond behavioral studies, work has identified neural structures important for multisensory processing in rats [Barth et al., 1995; Brett-Green et al., 2003; Hirokawa et al., 2008; Menzel & Barth, 2005; Sieben et al., 2013; Tees, 1999], including specific border regions between primary sensory cortices (visual, audito…”

“Collectively, the body of evidence points to altered multisensory temporal function in ASD, and these temporal alterations are likely to have cascading effects on higher-order social communicative skills that necessitate the rapid and accurate integration of multisensory information [Stevenson et al., 2016, 2018; Yagu…”

“Striking similarities have been shown in both the development [Wallace, 2004], and neural response properties [Wallace & Stein, 2001] of multisensory integration in the cat and monkey [Wallace & Stein, 1996].”

“…studies have evaluated these sensory-based therapies with mixed results, largely concluding there is little efficacy of these treatments or at least more evidence is still needed [Case-Smith et al., 2015; Lang et al., 2012; Schaaf, Dumont, Arbesman, & May-Benson, 2018; Watling & Hauer, 2015].”

“Over the past decade, increasing interest has focused on multisensory research in the mouse [Borges-Merjane & INSARSiemann et al./Multisensory function in ASD1436 Trussell, 2015; Hornix, Havekes, & Kas, 2018; Olcese et al., 2013; Radvansky & Dombeck, 2018; Reig & Silberberg, 2014].”

“…[Brandwein et al., 2015; Yaguchi & Hidaka, 2018], and the development of multisensory function and its neural underpinnings may be atypical in ASD as well [Beker et al., 2018; Brandwein et al., 2012; Cuppini et al., 2017; Foxe et al., 2015; Stevenson et al., 2013; Taylor, Isaac, & Milne, 2010].”

“…various psychophysical behavioral measures, have determined that the development of multisensory integration might be delayed in these individuals [Beker et al., 2018; Brandwein et al., 2012; Foxe et al., 2015; Stevenson, Siemann, et al., 2013; Taylor et al., 2010], along with evidence of…”

“…with autism spectrum disorder [Baum et al., 2015b; Brandwein et al., 2015; Collignon et al., 2013; Foss-Feig et al., 2010; Foxe et al., 2015; Irwin et al., 2011; Kwakye et al., 2011; Smith & Bennetto, 2007; Stevenson, Siemann, et al., 2013; Stevenson, Siemann, Schneider, et al., 2014;…”

“As observed in the rat (Table 1), studies have also shown that the parietal cortex [Kuroki et al., 2018; Lyamzin & Benucci, 2019; Najafi et al., 2019; Song et al., 2017], orbitofrontal cortex [Sharma & Bandyopadhyay, 2019], cerebellum [Chabrol, Arenz, Wiechert, Margrie, & DiGregorio, 2015] are…”

“While most studies in humans have focused on treating the core symptoms of ASD, this approach has had relatively limited success [Dove et al., 2012; Warren et al., 2011].”

“Evidence of decreased multisensory gain or benefit has been reported utilizing both simple and complex stimuli [Collignon et al., 2013; Mongillo et al., 2008; Stevenson et al., 2014; Stevenson et al., 2014].”

“…shown that the combination of information from multiple senses can result in behavioral enhancements, such as increased accuracies and reduced reaction times, when compared to behavioral performances under unisensory (i.e. visual, auditory, or tactile alone) conditions [Stevenson et al., 2014].”

“…2015], insula [Rodgers et al., 2008], parietal cortex [Brett-Green et al., 2003; Lippert et al., 2013; Menzel & Barth, 2005], prefrontal cortex [Lipton et al., 1999; Reid et al., 2014], perirhinal cortex [Jacklin, Cloke, Potvin, Garrett, & Winters, 2016], and the lateral entorhinal cortex…”

“…integration might be delayed in these individuals [Beker et al., 2018; Brandwein et al., 2012; Foxe et al., 2015; Stevenson, Siemann, et al., 2013; Taylor et al., 2010], along with evidence of sex-dependent differences in audiovisual speech development in both typically developed and ASD…”

“, 2011; Nath & Beauchamp, 2012], is also a key hub for the processing of social communicative stimuli [Pelphrey, Morris, & Mccarthy, 2004; Stevenson et al., 2011; Zilbovicius et al., 2006], and has been found to be both structurally and functionally atypical in ASD [Boddaert et al.”

“…emerged in the mouse, where unisensory stimuli from other modalities can impact neuronal responses in primary sensory cortices [Cohen et al., 2011; Deneux et al., 2019; Knöpfel et al., 2019; McClure Jr & Polack, 2019; Meijer et al., 2017; Morrill & Hasenstaub, 2018; Zhang, Kwon, Ben-Johny,…”

“…border regions, studies have identified the cerebellum [Ishikawa, Shimuta, & Häusser, 2015], insula [Rodgers et al., 2008], parietal cortex [Brett-Green et al., 2003; Lippert et al., 2013; Menzel & Barth, 2005], prefrontal cortex [Lipton et al., 1999; Reid et al., 2014], perirhinal cortex…”

“, 2001], and can modulate responses to a variety of sensory stimuli [Esaki et al., 2005; Hurley, Thompson, & Pollak, 2002; Waterhouse, Azizi, Burne, & Woodward, 1990].”

“…structures important for multisensory processing in rats [Barth et al., 1995; Brett-Green et al., 2003; Hirokawa et al., 2008; Menzel & Barth, 2005; Sieben et al., 2013; Tees, 1999], including specific border regions between primary sensory cortices (visual, auditory, somatosensory) that contain a…”

“In addition, studies have found that sensory disturbances correlate with greater deficits in social communication, along with the presence of more repetitive behaviors in individuals with ASD [Boyd et al., 2010; Boyd, McBee, Holtzclaw, Baranek, & Bodfish, 2009; Feldman et al., 2019; Foss-Feig, Heacock, & Cascio, 2012;…”

“Importantly, similar findings to the rat have emerged in the mouse, where unisensory stimuli from other modalities can impact neuronal responses in primary sensory cortices [Cohen et al., 2011; Deneux et al., 2019; Knöpfel et al., 2019; McClure Jr & Polack, 2019; Meijer et al., 2017; Morrill & Hasenstaub, 2018; Zhang,…”

“…conditions in humans, nonhuman primates, cats, rats, and mice using comparable behavioral tasks (Table 1) [Carandini & Churchland, 2013; Raposo et al., 2012; Raposo et al., 2014; Schormans, Scott, et al., 2017; Sheppard et al., 2013; Siemann et al., 2015; Stevenson, Ghose, Fister, et al., 2014].”

“…& Rowland, 2014; Wallace & Stein, 1997, 2001; Wallace & Stein, 2007], neural mechanisms [Jiang, Wallace, Jiang, Vaughan, & Stein, 2001; Wallace et al., 1992; Wallace & Stein, 2000], and brain regions and circuits responsible for multisensory integration [Driver & Noesselt, 2008; Stein, 2012].”

“…Meijer et al., 2017; Morrill & Hasenstaub, 2018; Zhang, Kwon, Ben-Johny, O’Connor, & Issa, 2020]; results that may be supported by growing evidence that primary sensory cortices may share underlying connections with one another [Massé, Ross, Bronchti, & Boire, 2017; Morrill & Hasenstaub, 2018].”

“Importantly, many of these subcortical and cortical findings are similar to those that have been observed in larger animal models (Table 1) [May, 2006; Wallace & Stein, 1996].”

“, 2004], despite the fact that rodents tend to have fairly poor vision and more specialized somatosensory and olfactory systems [Ihara, Yoshikawa, & Touhara, 2013; Petersen, 2014].”

“In addition, non-human primate work has identified both subcortical and cortical connections and circuits needed for multisensory processing [Clavagnier, Falchier, & Kennedy, 2004; Falchier et al., 2010; Rockland & Ojima, 2003; Smiley & Falchier, 2009].”

“Striking similarities have been shown in both the development [Wallace, 2004], and neural response properties [Wallace & Stein, 2001] of multisensory integration in the cat and monkey [Wallace & Stein, 1996].”

“In addition, the brain region (STS) shown to be critical in the perception of this illusion [McGurk effect) (Beauchamp et al., 2010; Nath et al., 2011; Nath & Beauchamp, 2012], is also a key hub for the processing of social communicative stimuli [Pelphrey, Morris, & Mccarthy, 2004; Stevenson et…”

“…studies, work has identified neural structures important for multisensory processing in rats [Barth et al., 1995; Brett-Green et al., 2003; Hirokawa et al., 2008; Menzel & Barth, 2005; Sieben et al., 2013; Tees, 1999], including specific border regions between primary sensory cortices…”

“…where unisensory stimuli from other modalities can impact neuronal responses in primary sensory cortices [Cohen et al., 2011; Deneux et al., 2019; Knöpfel et al., 2019; McClure Jr & Polack, 2019; Meijer et al., 2017; Morrill & Hasenstaub, 2018; Zhang, Kwon, Ben-Johny, O’Connor, & Issa, 2020];…”

“These behavioral findings provide the foundation for beginning to investigate the underlying cellular components and circuits that may lead to altered multisensory processing related to genetic risk factors [Hornix et al., 2018].”

“Studies have demonstrated altered sensory processing in individuals with ASD [17].”

“Recent research suggests the need for sensory integration, but stronger evidence is needed (Siemann et al., 2020).”

“Electrophysiological and neuroimaging studies have established that neural circuits and brain structure play a crucial role in multisensory integration, which provides a basis for exploring the biological links between sensation and social interaction (60).”

“Furthermore, we assessed behavioral responsivity for low-level stimuli in a controlled environment, but in ASD, overresponsivity might be modulated by unpredictable versus predictable, or multimodal versus unimodal stimuli (Green et al., 2015; Siemann et al., 2020).”

“Historically, proximal senses such as smell, taste, and touch were considered to be particularly affected and to be a sign of developmental immaturity [34,35], and, more recently, the research has shown a growing interest in multisensory integration (MSI) in ASD [36].”

“In this sense, it has been suggested that multisensory integration is impacted in ASD [7,8].”

“Through our study, we aimed to further characterize sensory processing divergences in autism spectrum and improve our ability to explore their potential underlying neurobiological mechanisms (Siemann et al., 2020).”

“While a definitive diagnosis from 18 to 24 months is rare, these early observations contribute to a better understanding of sensory development and its relevance for early ASD detection and interventions (Siemann et al., 2020).”

“Moreover, genetic analyses have identified candidate genes (e.g., SHANK3 , SCN2A , CNTNAP2 , MECP2 ) implicated in multisensory processing differences, suggesting shared heritability with core ASD traits [17,39–41].”

“…temporal binding has been extensively studied in autistic and non-autistic individuals using both complex speech stimuli (e.g., /ga/; both sensory and semantic processing required) and simple flash-beep stimuli (de Boer-Schellekens et al., 2013; Siemann et al., 2020; Stevenson & Wallace, 2013).”

“More recent studies have offered novel, more encompassing explanations of these de fi cits in multisensory processing, especially their sociocultural behavioural manifestations of ASD (11).”

“Recent conceptualizations of autism have proposed that altered multisensory processing may help explain many core features of autism, including social and communication difficulties and sensory sensitivities (Siemann et al. 2020).”

“Conversely, those with sensory hyposensitivity may not perceive discomfort or recognize the need to clean their teeth, leading them to neglect daily hygiene [4].”

“, 2022), as is our understanding of the way deficits in sensory processing and MSI play a role in human disorders of social behavior (Tseng et al., 2015; Siemann et al., 2020).”

“Additionally, some studies reported multisensory dysfunctions in individuals with ASD [13].”

“Senses can be affected individually, or processing differences can occur in multiple modalities [54].”

“Patients with ASD also exhibit sensory dysfunction, characterized by hypersensibility to sound and tactile or visual stimuli (DSM-V; Green et al., 2015; Mikkelsen et al., 2018; Siemann et al., 2020).”

“Moreover, a signi fi cant number of children with ASD experience sensory integration disorders, which can hinder the effective processing of external sensory information in the brain, leading to uncoordinated body functions (38).”

“Multiple studies have indicated that individuals with ASD might also display a different sensory pro fi le, with hyper or hypo-sensitivity to certain stimuli, such as loud noises, temperature, and touch (Siemann et al., 2020).”

“Sensory processing differences distinguish Autism from other developmental disorders [11].”

“In recent years, several studies have shown that behavioral alterations described in ASD patients can be closely recapitulated in animal models (Pasciuto et al., 2015; Schroeder et al., 2017; Zhou Y. et al., 2019; Siemann et al., 2020; Castro and Monteiro, 2022; Ivashko-Pachima et al., 2022).”

“This theory is supported by observed sensory dysfunction in ASD and accounts from autistic adults who use motor stereotypy to block overwhelming stimulation (Joyce et al., 2017; Kapp et al., 2019; Siemann et al., 2020).”

“This, in turn, signifies dysfunction in the GABAergic and serotonergic systems, implying a disruption of the hormonal system, specifically the one responsible for melatonin regulation [55–57].”

“66,67 Beyond the diagnostic differences, the findings supported that MSN organization strongly aligns with sensory processing difficulties across all participants.”

“Sensory issues in ASD include difficulties adapting to temperature changes, discomfort with specific sounds, textures, or smells, attachment to moving objects, and aversion to light, and these symptoms often manifest simultaneously [4–9].”

“However, there is increasing recognition of abnormal sensory responses in ASD [5–10] which relate to quantitative autism traits [7] such that they constitute one of the four sub-criteria under the restricted, repetitive behaviors domain in the Diagnostic and Statistical Manual of Mental Disorders,…”

“Research has also shown that individuals with ASD may experience both hypersensitivity and hyposensi-tivity to various sensory stimuli, even both within one individual [17].”

“In the context of ASD, deficits in visual processing—particularly in integrating social cues such as facial expressions and eye gaze—are core characteristics (Siemann et al. 2020).”

“Atypical multisensory integration in autism has also been demonstrated, and a cascading effect thereof on the development of atypical social communication has been suggested [13–19].”

“For biological analysis, monoamines were measured by high ‐ performance liquid chromatography (HPLC) in the hippocampus, prefrontal cortex, 18 amygdala, 19 hypothalamus, 20 and visual cortex, 21 which are important for multisensory processing and related to anxiety and characteristics of ASD.”

“…functions, including social interactions and communicative functions (Foss-Feig et al., 2012; Robertson & Baron-Cohen, 2017; Ross et al., 2015, 2024; Siemann et al., 2020; Stevenson, Segers, et al., 2014), which are the core symptoms associated to autism (American Psychiatric Association, 2022).”

“Moreover, the core symptoms of ASD are closely related to abnormal sensory processing, with auditory processing abnormalities being a primary concern [19].”

“Several studies have shown that this effect is less pronounced in autistic people (36, 39 – 42).”

“Further, there are few interventions directly targeting the sensory symptoms of ASD (Yuan et al. 2022), and studies evaluating available treatments have had mixed results (Siemann et al. 2020).”

“Emerging evidence suggests that differences in altered responses across visual, auditory, and somatosensory pathways and multisensory processing may contribute to the social communicative differences observed in autistic individuals (109 – 113).”