The immune hypothesis of synesthesia

Synesthesia is a hereditary, neurological condition in which a wide range of common stimuli (e.g., letters, sounds, flavors) trigger unexpected secondary sensations, for example, synesthetes listening to music might see colors in addition to hearing sounds (Ward et al., 2006; see Simner and Hubbard, 2013, for review). Current explanations of synesthesia posit structural and/or functional differences in the synesthete brains, and frame their models in terms of excess cortical connectivity or altered cortical feedback. Here, we propose an immune hypothesis of synesthesia, which supplements existing models by suggesting how such altered connectivity may arise and how associations between synesthesia and other conditions might be explained. Two categories of model seek to explain the generation of synesthetic experiences, and more recent models are a hybrid of both (Brang et al., 2010). The crossactivation model (Ramachandran and Hubbard, 2001) suggests that excess connectivity between functional areas of the cortex allows activation in one cortical area (e.g., auditory cortex) to directly trigger activation in another (e.g., visual cortex). Evidence in support of this model comes for example from diffusion tensor imaging (DTI) and shows that excessive connectivity is indeed a feature of the synesthetic brain (Rouw and Scholte, 2007). Re-entrant and disinhibited feedback models propose that synesthetic sensations are caused by disinhibited feedback from higher cortical areas (e.g., in parietal lobe) failing to suppress non-relevant activation from lower cortical areas (Grossenbacher and Lovelace, 2001). This type of disinhibited feedback may result from excessive activity of excitatory neurons within the delicate balance between both excitatory and inhibitory neurons in the brain (Hubbard et al., 2011). Despite appearing superficially different, connectivity and feedback models need not be mutually exclusive. It is unlikely that altered feedback happens entirely in the absence of changes in cortical connectivity, given the Hebbian principle that simultaneous activity strengthens interconnectivity between neurons. Therefore, these two approaches might be considered somewhat unified in that connectivity models propose aberrant connectivity as the primary causal mechanism underlying synesthesia whereas feedback models might allow altered connectivity as an indirect consequence of disinhibited feedback. While these models are now more than a decade old, explanations of how these cortical characteristics might arise have proven elusive thus far (but see Brang and Ramachandran, 2008; Mitchell, 2013) and we explore this here. Synesthesia is thought to be primarily neurodevelopmental in nature (Spector and Maurer, 2009). Consequentially, known processes of brain development are likely to be implicated in its emergence. We propose that insight might be gained from examining the functionality of genes that regulate the types of altered synesthetic cortical connectivity assumed in these models above (i.e., genes for axon guidance, synapse density). This is the approach we follow here.