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Cell - Circuit- and Systems-level mechanisms underlying
perceptual decision making in synesthesia and autism.
Hari Srinivasan
Neuroscience Graduate Program, Vanderbilt University
Nuro 8340: Fundamentals of Neuroscience II
Prof. Thilo Womelsdorf
Oct 27, 2022
Abstract
Synesthesia is an interesting perceptual experience, often described as a melding of the senses or when the stimulation of one modality stimulates additional modalities. 20% of the autistic population (Baron-Cohen et al., 2013) is reported to have synesthesia, compared to just 2-4% in the general population (Brang & Ramachandran, 2011). The high prevalence of synesthesia in autism suggests common mechanisms and this paper looked at what is known about neural mechanisms underlying perceptual decision making in synesthetes, more specifically findings (where available) with respect to autism, at the cell, circuit and systems level. Original research as well as review papers were looked at, with multiple findings and observations. These findings add to our knowledge and understanding on neural processes behind synesthesia and more specifically synesthesia in autism. However a fundamental limitation remains in all studies relating to autism, which is the heterogeneity in autism, common only in behavioral phenotypes rather than physiological biomarkers. So results of any study may apply only to a portion of the autistic population.
Keywords: autism, synesthesia, perception, neural correlates
Introduction and Background
My grapheme-color synesthesia has been consistent ever since I realized I had it, which was in late middle school. When I look at black and white text there’s almost like an overlay - all the letters have a different color associated with them. With music it’s stronger – the example I give to folks is, if I ask them to close their eyes and imagine running their hand over a wooden table, most can do it - you can feel the wood grain, maybe your finger went over a little bump or knurl, and you have an internal mental representation of that texture. That kind of happens spontaneously when I’m listening to music. It’s almost like a conveyor belt of different textures evoked by different components of the arrangement, and then different textures can have different colors or visual characteristics. It’s kind of like a more sensory version of those dynamic backgrounds that used to be in Windows Media Player or like Windows XP that would have the colorful ribbons or patterns as you listened to music. Except those ones are totally wrong. (Synthesia experience narrated by Syamantak Payra, Ph.D student, Stanford University).
Synesthesia is an interesting perpetual experience, when the stimulation of one modality stimulates additional modalities like in the experiences described above. Curiously, synesthesia is reported in 20% of the autistic population (Baron-Cohen et al., 2013) compared to just 2-4 percent in the general population (Brang & Ramachandran, 2011), with the above narrated experience from the latter group. An example of visual-tactile synesthesia experienced by this autistic author is the visual sight of a canvas tent (that covers the booths at college fairs) also produces concurrent sensations of feeling the texture of that canvas material on my skin.
A key feature of synesthesia is that these experiences are automatic, where the synesthete cannot consciously influence the ‘inducer’ (trigger) and its associative ‘concurrent’ synesthetic experience. The concurrent sensation itself can be a projection (in the visual field away from the body like seeing a colored letter) or associative (internal as in the mind’s eye). Another important feature is that synesthesia is not a simple conceptual/semantic association found in the general population such as the, ‘sky is blue;’ rather the “synesthetic association is with a modality-specific or sensory feature” (Rouw et al., 2011).
The high prevalence of synesthesia in autism suggests common circuitry, and this paper will focus on a few findings on neural mechanisms underlying perceptual decision making in synesthetes, especially (where available) with respect to autism.
The most common form of synesthesia in the general population has been linguistic-color (where an inducer in the form of a meaningful letter or word, evokes a concurrent color) which could be either grapheme-color (tested with visual presentation of words) or colored-hearing (tested with auditory presentation of words). The presence of most forms of synesthesia for stability, consistency and systematicity over time and within-subject is verifiable using tests like Eagleman Synesthesia Battery (Eagleman et al., 2007).
Synesthesia is thought to be developmental, drug-induced or acquired in nature, with autism falling in the developmental category. However I would argue that the latter two categories also relate to autism. For instance, drug induced synesthesia is most frequently associated with the use of hallucinogens like LSD that selectively activate serotonin 5-HT2A in the general population. Brang & Ramachandran (2007) even suggested that hyperactive serotonin receptors are causal factors in all three forms of synesthesia. Autism is a highly medicated population with 30 - 40% of autistic children and youth prescribed medication for managing aggression, irritability, self-injurious behaviors and other challenging behaviors (Logan et al., 2012). Drugs used to target behaviors like bupropion (Wellbutrin) and fluoxetine (Prozac) both inhibit 5-HT2A, while melatonin supplements, commonly used to address sleep issues in autism, disinhibits 5-HT2A (Brang & Ramachandran, 2007).
Similarly, acquired synesthesia, often defined as some sort of “neuropathologic insult to the brain,” (Afra et al., 2009) could relate to autism as anywhere from as 20% (Besag, 2017) to 39% (Bolton et al., 2011) of autistics are believed to have epilepsy. Synesthesia is shown to be common in temporal lobe epilepsy (Neckar & Bob, 2016) and a personal experience has been vivid synesthetic experiences at the onset of a grand-mal seizure.
Synesthesia has long been of interest to researchers, leading to speculations and theories around its cause. Some of the more interesting explanations follow:
Preserved Neural Connectivity: Babies are born synesthetes, with the ability to mix senses, but lose that ability at around 3 months of age (Baron-Cohen, 1997). In neonates, somatosensory potentials were evoked with white noise (auditory stimulation) rather than just the expected tactile stimulation alone (Neville et al., 1993). Similarly human language (auditory stimulation) evoked potentials in the occipital cortex rather than just the expected auditory cortex (Neville et al., 1993) in neonates. Thus synesthesia could be due to disruptions in neuronal pruning during development (Bargary & Mitchell, 2008).
Anatomically adjacent cortical regions are more predisposed to form synesthesia pairs, explaining the predominance of grapheme-color synesthesia in developmental synesthesia (Ramachandran & Hubbard, 2011).
Genetic Basis. 4 percent of the population has inherited synesthesia (Brang & Ramachandran, 2011)
Limbic System as “seat of synesthesia” (Cytowic, 1989): He suggested that “parts of the brain were disconnected … causing normal processes of the limbic system to be released... and experienced as synesthesia". Neckar & Bob (2016) do suggest links between limbic irritability and synesthesia in temporal lobe epilepsy.
Some findings around synesthesia at cell level, circuit level and system level and their neural correlates follow, though there may be overlaps in between individual sections due to the nature of the findings.
Cell-specific decision correlates/ mechanisms
Though autism is the fastest growing and most common neurodevelopmental disability today, a challenge has been studying what seems like a seemingly heterogeneous population with no biological diagnosis, no clear etiology and just observable behavioral commonalities. One of the commonly used models in autism research is the BTBR T+Itpr3tf/J strain, considered a good model of “idiopathic autism;” that is, they exhibit behavioral phenotypes seen in autism - such as impairments in social skills, in play, atypical vocalizations, repetitive behaviors and high levels of anxiety (Meyza & Blanchard, 2017). Other autistic rodent strains include Neuroligin-3 (NL3) R451C knock-in mice (as this gene is found to be associated with human autism), and Scn1a R1407X knock-in mice (which links autism and epilepsy) (Hattori et al., 2017). The non-autistic C57/BL6/J strain is a popular strain used in behavioral studies (Bryant, 2011).
At the cellular level animal study, I looked at original research by Hattori et al., (2017) which made use of the BTBR strain which has weak GABAergic inhibitions. The study started with the assumption based on earlier research that there are impairments in GABA-mediated inhibitions in both autistics and in synesthesia. And given the prevalence of synesthesia in autism, they explored common neural mechanisms when there is co-occurrence of both conditions. Some of the interesting findings from this study follow.
Flavoprotein imaging was used to look at auditory response in the primary visual cortex (V1) of autistic BTBR mice (n = 5). They found that in the superficial layer, there was “sound driven response as well as audio-visual interaction” in both VI and V2 areas, with the effect more robust with combined audio-visual stimulus.
The study also recorded auditory-driven field potentials in V1 in autistic BTBR mice versus the non-autistic C57/BL6/J strain and found “negative peak amplitude (N1) of cross-modal auditory-evoked potential (cAEP) was larger at both L2/3 (C57: 16 mice, BTBR: 8 mice) and L4 (C57: 5 mice, BTBR: 4 mice),” for autistic BTBR mice. Spectral analysis of cAEP further revealed a “notable difference at γ frequency range where sound mostly suppressed power” in the non-autistic strain but enhanced power in the autistic strain.
Cross-modal spiking activity in VI was recorded to look to the audio-visual interactions at a cellular level. There were “significant sound-driven spiking responses and multisensory spike enhancement in the V1 of BTBR strain with its mean onset latency faster than visual response.”
Comparisons between the non-autistic C57 strain and three autistic strains (BTBR, NL3 R451C knock-in mice, and Scn1a R1407X knock-in mice) showed “sound-driven spike suppression was abolished,” in all three autism models. That is to say, “the ratio of sound-driven spike enhancement/ suppression was commonly increased in mouse models of autism.”
In summary, the study had looked at rodent autism models to suggest sensory blending. It found that in rodent V1, visual input and inhibition regulated cross-modal auditory response. Given there was also impaired sound-driven spike suppression across autism mouse models, they concluded that Excitatory/Inhibitory “(E/I) imbalance may be the common circuit dysfunction for both autism and synesthesia.”
Circuit-level decision correlates/mechanisms.
The Asher et al. (2009) study made use of whole genome scan for auditory-visual synesthesia (n=43). They identified candidate chromosomes - 2q24, 5q33, 6p12, and 12p12. Interestingly there was no x-chromosome linkage and there were male-male transmission in families. What it implies is multiple loci of inheritance of synesthesia. Within the four identified regions there were interesting candidate genes with respect to autism. For instance, ‘the marker obtaining the highest LOD score (D2S142, with HLOD = 3.025) has been linked to autism.” Chromosome 12 contains NMDA receptors which play a role in learning and memory; overexpression resulted in savantism in mice, savantism is again linked to autism. TBR1, SCN2A, SCN3A in the region are also linked to familial autism.
The close association between synesthesia with autism was explored in Neufeld et al., (2013) study (n = 29, 8 women) examining grapheme-color synesthesia through the use of questionnaires and consistency tests. They did establish a higher prevalence of grapheme-color synesthesia in autism (31%) and discussed their findings in relation to altered sensory processing in autism; as “sensory-hypersensitivity” is common in autism across modalities (visual, tactile, auditory) with prior studies also pointing to “activation of visual processing areas for a variety of cognitive tasks.” They simultaneously pointed to other studies that show altered sensory processing of the concurrent along with increased visual evoked potentials as a feature of synesthesia. They concluded this could be related to “altered low-level perception” or activation of “low level areas (e.g., more posterior visual areas) during higher order perceptual tasks” in both autism and synesthesia.
Neufeld et al., (2013) also pointed out that synesthesia has been linked to hyper connectivity and autism studies have suggested a “developmental bias in autism toward forming more short range connections, leading to hyper connectivity of local networks,” which lead them to think of gene mutations or pruning as underlying causes, as there has been a genetic marker (Asher et al, 2009) associated with auditory-visual synesthesia in autism.
Systems-level decision correlates/mechanisms.
The Rouw & Scholte (2010) original study looked at gray matter structure (using voxel-based morphometry) and functioning (using fMRI) differences in grapheme-color synesthetes (N=42 females, 16 projectors, 26 associators) and non synesthetes (42 female controls). Three different stimuli were used - strong, weak and no color. They also highlight the fact that there are different neural mechanisms in the experiences of internal associator type of synesthesia (which would involve hippocampus, parahippocampal gyrus) versus the external projection type of synesthesia (which would involve visual cortex, auditory cortex, motor cortex, frontal brain areas). However irrespective of the method used, both associators and projectors showed activation in the posterior superior parietal lobe, a region important for integration of sensory information.
Other whole brain areas implicated for grapheme-color synesthesia in numerous fMRI studies are inferior parietal lobule, ventral occipito-temporal cortex, bilateral insula, precentral gyrus and right dorsolateral prefrontal cortex (Rouw & Scholte, 2011).
Neufeld et al. (2013), in the study discussed in the previous section, also speculated on the associative brain regions for autism and synesthesia. Autism fMRI studies had shown increased activation in, “associative cortex regions in higher order sensory in the visual domain,” along with “increased functional connectivity between frontal areas and between posterior cingulate and medial temporal cortex.” In different types of synesthesia, the parietal cortex was activated, more so in the sensory areas, suggesting a top down modulation of sensory areas. Essentially for Neufeld et al., (2013) this combination of low level and top down pointed to both genetic and developmental basis for autistic synesthesia.
Summary and Conclusion
Synesthesia is the phenomenon where there is an automatic concurrent sensory experience of a modality that is other than the inducer trigger modality. 20% of autistics also experience synesthesia (Baron-Cohen et al. 2013). The prevalence of synesthesia in autism suggests common mechanisms and this paper looked at what is known about neural mechanisms underlying perceptual decision making in synesthetes, more specifically on findings (where available) with respect to autism.
The most common form of synesthesia and the most studied is grapheme-color synesthesia. Synesthesia is also thought to be developmental, drug-induced or acquired, with autism falling in the developmental category, though I argue that the latter two categories also apply to autism due to almost 30-40% of autistics being on medications (Logan et al., 2012) with commonly used drugs like Prozac, Wellbutrin and Melatonin selectively acting on 5-HT2A (Brang and Ramachandran, 2007). Similarly the 20% prevalence of seizures in autistics (Besag, 2017) firmly also places autism in the acquired synesthesia category.
At the cellular level, the Hattori et al., (2017) original research compared an autism rodent model (BTBR) with a non-autistic rodent (C57 strain) as well as comparisons between three different autism mouse models (BTBR, NL3 R451C knock-in mice, and Scn1a R1407X knock-in mice). It found that in rodent V1, visual input and inhibition regulate cross-modal auditory response. Given there was also impaired sound-driven spike suppression across autism mouse models, they concluded that Excitatory/Inhibitory “(E/I) imbalance may be the common circuit dysfunction for both autism and synesthesia.”
At the circuit level, the Asher et al. (2009) study made use of whole genome scan for auditory-visual synesthesia (n=43) and identified four areas of chromosomes - 2q24, 5q33, 6p12, and 12p12. Within the four identified regions they identified interesting candidate genes that had links to autism. The Neufeld et al., (2013) study established a higher prevalence of grapheme-color synesthesia in autism (31%) and discussed their findings in relation to altered sensory processing in autism. Commonalities were activation of “low level areas (e.g., more posterior visual areas) during higher order perceptual tasks” and hyper-connectivity at local levels, leading them to gene-pruning or a genetic basis as underlying cause.
At the systems level, the parietal cortex was activated in both synesthesia and autism (Neufeld et al., 2013), more so in the sensory areas, suggesting a top down modulation of sensory areas.
Such findings add to our knowledge on neural processes behind synesthesia and more specifically synesthesia in autism. However a fundamental issue remains in all studies relating to autism, which is heterogeneity of the autism population, common only in catch-all, behavioral phenotypes rather than physiological biomarkers. So results of any study may apply to only a portion of the autistic population.
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