Synesthesia

Description

Synesthesia is broadly defined as the experience of involuntary sensory crossactivation in which the presentation of a particular stimulus elicits a secondary sensory-perceptual experience (Barnett et al., 2008). Although this phenomenon can be acquired or transient due to trauma or drugs, there is a congenital or developmental form that shows familial patterns. Synesthesia can occur between any 2 sensory modalities, but the most common and best-studied forms of synesthesia involve the association of color with linguistic stimuli such as letters, numbers, or words, or with music ('colored hearing,' 'colored music'; Baron-Cohen et al., 1996). Other less common forms include the induction of tastes by words, the induction of touch by vision, the induction of shapes by tastes, and the personification of numbers (Barnett et al., 2008).

Clinical Features

Barnett et al. (2008) evaluated 64 individuals from 22 families with synesthesia recruited from a population-based survey. Most of the study participants were from Ireland. The female-to-male ratio was 6:1, and synesthetic parents were more likely to pass the trait to their daughters (61%) than to their sons (17%). The majority, 95%, of individuals reported synesthesia throughout their lifetimes, with the remaining 5% noting it from early childhood. Most synesthetes experienced linguistic-color synesthesia only (45%) or experienced linguistic-color synesthesia plus another form, such as colored music or spatial numbers or numbers with personalities (47%). The remaining 8% had other forms of synesthesia such as colored, textured, or shaped taste and smell. Seventy-two percent reported the sensation in the 'mind's eye.'

Mattingley et al. (2001) studied 15 individuals with color-graphemic synesthesia, each of whom experienced highly consistent colors for letters, digits, and words. Use of a color-form interference paradigm, in which, for example, letters incongruent to the associated color were shown to a synesthete, resulted in delayed naming of colors, similar to controls. Synesthetes shown congruent color-forms could name colors faster than controls. These findings suggested that synesthetic experiences could not be consciously suppressed. However, in a second experiment, if letters or digits were briefly presented and masked, synesthesia was eliminated. The findings showed that synesthetic experiences can be prevented despite substantial processing of the sensory stimuli that trigger them. Mattingley et al. (2001) concluded that automatic binding of color and alphanumeric form in synesthesia arises after initial processing of visual form, and that overt recognition of inducing stimuli is critical for the phenomenon to occur.

Beeli et al. (2005) reported an unusual synesthetic connection in a 27-year-old female professional musician. She reported specific tastes in response to specific tone intervals. For example, a major third was sweet, a minor third was salty, and a major second was bitter. She also reported the more common tone-to-color synesthesia, for example, F sharp and violet, C and red.

Asher et al. (2009) noted that in some cases, synesthesia can result in perceptual and cognitive dysfunction due to sensory overload, whereas in others, it can result in improved recall or elevated performance. It has also been anecdotally associated with absolute pitch (AP; 159300).

Gregersen et al. (2013) found that 151 (20.1%) of 768 individuals with AP reported synesthesia. Associations between pitch and color were most common (84%), with fewer numbers of individuals having synesthesia involving smell, shapes, or other more complex sensory experiences. There was no difference in the prevalence of synesthesia between Caucasian and Asian AP individuals. The analysis yielded an OR of about 6.0 for synesthesia in AP individuals, suggesting that these 2 cognitive traits are phenotypically and genetically related. In addition, 8 (22%) of 36 families with synesthesia reported a family member with AP. Gregersen et al. (2013) suggested that the association likely reflects a common neurodevelopmental mechanism of brain connectivity.

Neuroradiology

Paulesu et al. (1995) used PET scan to study 6 women with color-word synesthesia and 6 controls, all of whom were blindfolded and presented with spoken words or pure tones. Auditory word, but not tone, stimulation triggered synesthesia in synesthetes. In both groups, word stimulation activated the classic language areas of the perisylvian regions. In synesthetes, a number of additional visual associative areas were activated, including the posterior inferior temporal cortex and the parietooccipital junctions. The former has been implicated in the integration of color with shape and in verbal tasks that require attention to visual features of objects. Synesthetes also showed activations in the right prefrontal cortex, insula, and superior temporal gyrus. By contrast, no significant activity was detected in relatively lower visual areas, including areas V1, V2, and V4. The results suggested that color-word synesthesia results from integrative activity of brain areas concerned with language and higher visual functions. In the case of color-word synesthesia, conscious visual experience appeared to occur without activation of the primary visual cortex, suggesting unusual anatomic connectivity.

Inheritance

Baron-Cohen et al. (1996) reported 6 families with synesthesia. The prevalence of synesthesia among first-degree relatives was 48.6%.

Barnett et al. (2008) found that 22 (42%) of 53 probands with synesthesia had at least 1 other family member with the trait. There was evidence that different types of synesthesia can occur within the same family, suggesting a single genetic mechanism conferring an underlying predisposition to the trait, regardless of type.

Mapping

By genomewide linkage analysis using 410 microsatellite markers at 9.05-cM density in 43 multiplex families with auditory-visual synesthesia, Asher et al. (2009) found significant linkage to chromosome 2q24.1 at D2S142 (hlod score of 3.025, empirical genomewide p = 0.047). Suggestive linkage was found to chromosomes 5q33, 6p12, and 12p12. No support was found for linkage to the X chromosome. The results suggested that auditory-visual synesthesia is likely to be an oligogenic disorder subject to multiple modes of inheritance and locus heterogeneity.

By genomewide linkage analysis of 53 families with AP and 36 families with synesthesia, Gregersen et al. (2013) found evidence for a common locus on chromosome 6q14.1-q16.1 when combining the data for both disorders (nonparametric lod score of 4.68). There was also evidence for a more complex pattern of linkage on chromosome 2 (heterogeneity lod score of 4.7 at rs1482308) in the combined AP and synesthesia families. These findings provided genetic evidence that the 2 cognitive traits may be related.

Molecular Genetics

Tilot et al. (2018) reported 3 unrelated multigenerational families in which 5 members in each family had sound-color synesthesia. Whole-exome sequencing identified rare coding variants that segregated with the phenotype in each family, although the genes in each family were different and no single gene contained a perfectly segregating variant in all 3 families, consistent with genetic heterogeneity. Using gene ontology, 6 genes found among the families were highlighted as candidates: COL4A1 (120130), ITGA2 (192974), MYO10 (601481), ROBO3 (608630), SLC9A6 (300231), and SLIT2 (603746). Gene ontology analysis showed that these genes were primarily involved in neural development, including axonogenesis and cell migration. Each of the 6 genes was demonstrated to be expressed in the auditory, visual, and parietal cortices during human fetal development and early childhood, when synesthetic associations are formed. Tilot et al. (2018) hypothesized that synesthesia may result from neuronal hyperconnectivity between brain regions.

Population Genetics

In the U.K population, Baron-Cohen et al. (1996) found the female-to-male ratio of synesthesia to be about 6:1, and the general prevalence of the trait to be 1 in 2,000.