OPINION ARTICLEpublished: 11 September 2013

doi: 10.3389/fnhum.2013.00563

The immune hypothesis of synesthesiaDuncan A. Carmichael1,2,3* and Julia Simner1

1 Department of Psychology, University of Edinburgh, Edinburgh, UK2 Institute for Adaptive and Neural Computation, University of Edinburgh, Edinburgh, UK3 Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK*Correspondence: d.a.carmichael@ed.ac.uk

Edited by:

Nicolas Rothen, University of Sussex, UK

Reviewed by:

Berit Brogaard, University of Missouri, USA

Keywords: synesthesia, genetics, immunity, neurological basis, genes, cortical connectivity, immune system

Synesthesia is a hereditary, neurologicalcondition in which a wide range of com-mon stimuli (e.g., letters, sounds, flavors)trigger unexpected secondary sensations,for example, synesthetes listening to musicmight see colors in addition to hearingsounds (Ward et al., 2006; see Simnerand Hubbard, 2013, for review). Currentexplanations of synesthesia posit struc-tural and/or functional differences in thesynesthete brains, and frame their mod-els in terms of excess cortical connectivityor altered cortical feedback. Here, we pro-pose an immune hypothesis of synesthe-sia, which supplements existing models bysuggesting how such altered connectivitymay arise and how associations betweensynesthesia and other conditions might beexplained.

Two categories of model seek to explainthe generation of synesthetic experiences,and more recent models are a hybridof both (Brang et al., 2010). The cross-activation model (Ramachandran andHubbard, 2001) suggests that excess con-nectivity between functional areas of thecortex allows activation in one corticalarea (e.g., auditory cortex) to directlytrigger activation in another (e.g., visualcortex). Evidence in support of this modelcomes for example from diffusion tensorimaging (DTI) and shows that exces-sive connectivity is indeed a feature ofthe synesthetic brain (Rouw and Scholte,2007). Re-entrant and disinhibited feedbackmodels propose that synesthetic sensationsare caused by disinhibited feedback fromhigher cortical areas (e.g., in parietal lobe)failing to suppress non-relevant activationfrom lower cortical areas (Grossenbacherand Lovelace, 2001). This type of disinhib-ited feedback may result from excessiveactivity of excitatory neurons within

the delicate balance between both exci-tatory and inhibitory neurons in thebrain (Hubbard et al., 2011). Despiteappearing superficially different, con-nectivity and feedback models need notbe mutually exclusive. It is unlikely thataltered feedback happens entirely in theabsence of changes in cortical connec-tivity, given the Hebbian principle thatsimultaneous activity strengthens inter-connectivity between neurons. Therefore,these two approaches might be consideredsomewhat unified in that connectivitymodels propose aberrant connectiv-ity as the primary causal mechanismunderlying synesthesia whereas feedbackmodels might allow altered connectivityas an indirect consequence of disinhibitedfeedback.

While these models are now more thana decade old, explanations of how thesecortical characteristics might arise haveproven elusive thus far (but see Brangand Ramachandran, 2008; Mitchell, 2013)and we explore this here. Synesthesia isthought to be primarily neurodevelop-mental in nature (Spector and Maurer,2009). Consequentially, known processesof brain development are likely to beimplicated in its emergence. We proposethat insight might be gained from examin-ing the functionality of genes that regulatethe types of altered synesthetic corti-cal connectivity assumed in these mod-els above (i.e., genes for axon guidance,synapse density). This is the approach wefollow here.

DUAL GENE FUNCTIONALITY:CONNECTIVITY AND IMMUNITYAbove, we saw that current models linksynesthesia to altered structural connec-tivity, misregulated feedback mechanisms,

or a combination thereof. Explaining howsynesthesia develops might therefore comefrom considering the developmental pro-cesses responsible for cortical connectivity.The immune system is known to play a sig-nificant role in these processes (for review,see Boulanger, 2009) and we ask herewhether a propensity to develop synes-thesia may be linked to the expression ofimmune proteins in the CNS, since thisexpression can be conferred by genes withfunctions of both immunity and corti-cal development. Indeed, many genes havebeen shown to have precisely this dualfunctionality (Boulanger, 2009). As well astheir immunity function, such genes actin cortical development, altering structuraland/or functional connectivity by influ-encing the development of axonal guid-ance, synaptic connectivity, and synapticpruning. One outcome of these changesmay therefore be the anomalous patternof connectivity proposed by the cross-activation theory in the development ofsynesthesia. Alternatively, the immune sys-tem could have a direct influence onexcitatory neuronal activity, leading to theoutcomes proposed by disinhibited feed-back models. This is because the immunesystem plays an important role in theinitial development and subsequent plas-ticity of glutamatergic synapses, the pri-mary excitatory transmission pathway inthe mammalian cortex (Fourgeaud andBoulanger, 2010).

CAN THE IMMUNE SYSTEMINFLUENCE THE DEVELOPMENT OFTHE BRAIN?Is it plausible to make a link betweenthe immune system and regulationof the central nervous system (CNS)?Isolated from the rest of the body by

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Carmichael and Simner The immune hypothesis of synesthesia

the blood-brain-barrier, the CNS wasonce thought to barely interact with theimmune system, leading to the long heldview that the CNS was “immune priv-ileged” (McAllister and van de Water,2009). However, research now showsa complex communication betweenthe CNS and immune system, withwide-reaching consequences for brainregulation and development, both inhealth and disease (Elmer and McAllister,2012). Immune proteins are known toplay a role at many stages in the devel-opmental pathway. They are integralcomponents of phases critical to braindevelopment and plasticity, such as neu-ronal guidance, synapse development, andsynaptic remodeling (Boulanger, 2009).We therefore hypothesize that CNS andimmune system interaction may be thebiological mechanism which confers thepredisposition to develop synesthesia.

Which aspects of the immune sys-tem are known to exhibit the type ofdual functionality under discussion in thisarticle (i.e., functionality in both immu-nity and cortical development)? Severalareas of this extraordinarily complicatedsystem are worth highlighting. The com-plement system is one possible candidate—a complex cascade of protein interactionsinvolved in immunity which has alsobeen shown to play an important rolein tagging of synapses to be eliminatedby pruning during development (Stephanet al., 2012). Another candidate relates tocytokines, which are immune proteins thathave also been shown to play significantroles in neurogenesis and synaptic plas-ticity (Bauer et al., 2007). A third can-didate relates to major histocompatibilitycomplex (MHC) proteins, which are anintegral part of the adaptive immune sys-tem found on the surface of the majorityof nucleated cells and widely expressed inneurons of the CNS (Boulanger, 2004).In addition to fulfilling a crucial func-tion in immune response, MHC class Imolecules and related components arethought to be involved in a range ofdevelopmental processes, such as activity-dependent plasticity and synaptic refine-ment (Boulanger, 2009). The MHC locuscontains several hundred genes, and hasalso been widely implicated in a range ofautoimmune conditions, such as multiplesclerosis (MS), irritable bowel syndrome

(IBS), and rheumatoid arthritis (Fernandoet al., 2008). We point out, however thatthe immune system consists of manyhundreds of individual factors and pro-cesses. Given this, our suggestions aboveshould be considered speculative and byno means exhaustive. Nevertheless, weconsider them to each be plausible candi-dates for future investigation.

We end this section by asking whetherexisting studies into the genetics of synes-thesia would support our immunityhypothesis. In other words, have theyidentified areas of the genome contain-ing immune system genes? Research intosynesthesia genetics is in its infancy andas yet, there are insufficient data to drawfirm conclusions. No synesthesia geneshave yet been identified and no firmmode of inheritance has yet been eluci-dated. However, evidence from the twoexisting studies on the genetics of synes-thesia (Asher et al., 2009; Tomson et al.,2011) have identified several chromoso-mal regions of interest, and these regionsdo contain immune function genes. Asheret al. (2009) found significant linkage tochromosome 2q24 and possible linkageto areas on other chromosomes (5q33,6p12, and 12p12), while Tomson et al.(2011) identified a candidate region onchromosome 16q12.2-23.1. The authorsof both studies draw the conclusion thatsynesthesia is likely to be a condition influ-enced by a variety of genes in multiple loci.Nonetheless, the chromosomal regions ofinterest highlighted in these two investiga-tions do contain immune function genes(e.g., interleukin-17, a cytokine proteinfound on chromosome 6p12), althoughwe wish to be clear that many other viablecandidates also lie outwith these regions.

THE IMMUNE HYPOTHESIS AS AFRAMEWORK FOR THE STUDY OFCO-MORBIDITIESAn immune hypothesis of synesthesiamight additionally explain recent co-morbidity data which suggests that hav-ing synesthesia may be associated withincreased risk of other clinical conditions.Carruthers et al. (2012) report an associ-ation between synesthesia and IBS, havingfound an elevated prevalence of synesthe-sia in a population of people with IBS.Other researchers have raised the possi-bility that synesthesia may also be found

at elevated rates within populations withautism (Baron-Cohen et al., 2007) ormigraine (Alstadhaug and Benjaminsen,2010). The immune system plays a promi-nent role in all of these conditions (Collins,2002; Bruno et al., 2007; Enstrom et al.,2009), suggesting that altered immune sys-tem function may be a common causallink. If so, the immune model proposesa plausible framework by which to inves-tigate co-morbidity between synesthesiaand other conditions. If this hypothesis iscorrect, we might ask whether the preva-lence of synaesthesia is also higher in pop-ulations with other autoimmune condi-tions. Indeed, recent data from our lab hasled us to explore whether developmentalsynaesthesia might occur more prevalentlyin people with the radiological profile ofmultiple sclerosis (MS), for example, ademyelinating disease of the human CNS(Simner et al., submitted). A maladaptiveimmune system is an undisputed factorin the pathogenesis of MS (Trapp andNave, 2008), and the majority of genesimplicated in MS have an immune func-tion (Gourraud et al., 2012). The immunehypothesis of synaesthesia might thereforelead us to investigate whether synaesthesiaand autoimmune conditions such as MScould share overlapping genetic origins incontributing to cortical development andimmune function.

CONCLUSION AND FUTUREDIRECTIONSWe have proposed that CNS/immune sys-tem interactions during early life may playa role in the development of synesthe-sia. We have asked whether genes withdual functionality in brain developmentand immunity may be at the origin ofexisting models of synesthesia, and thismechanism would provide a framework toinvestigate associations between synesthe-sia and other immune-related conditions.We make our proposal here as a modelfor developmental synesthesia, althoughnot all cases of synesthesia are develop-mental in nature. Synesthesia may alsobe acquired, for example as a result ofbrain injury (Schweizer et al., 2013) orinduced by consumption of psychoactivedrugs such as Lysergic acid diethylamide(LSD; e.g., Cytowic, 1989). Our hypothesisdoes not speak directly to such cases, andit is not yet known whether these different

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Carmichael and Simner The immune hypothesis of synesthesia

forms of synesthesia have the same neuralorigins or mechanisms. It is interesting tonote however that immune system activityis elevated after brain injury, and processessuch as apoptosis do become activated(Griffiths et al., 2010). It is therefore atleast plausible to ask whether the immunesystem might also play a role in the appear-ance of non-developmental synesthesias.Identification of genes that contribute tothe development of synesthesia will makea significant contribution to the validityof this hypothesis, and whether synesthesiahas one cause or many.

ACKNOWLEDGMENTSWe are grateful to Richard Shillcock foruseful discussions, Lisa Boulanger forinsightful suggestions and feedback andthe anonymous reviewers for helpfulcomments on the manuscript. DuncanA. Carmichael was supported in part bygrants EP/F500385/1 and BB/F529254/1for the University of Edinburgh, Schoolof Informatics Doctoral Training Centrein Neuroinformatics and ComputationalNeuroscience (www.anc.ac.uk/dtc) fromthe UK Engineering and PhysicalSciences Research Council (EPSRC), UKBiotechnology and Biological SciencesResearch Council (BBSRC), and the UKMedical Research Council (MRC).

REFERENCESAlstadhaug, K., and Benjaminsen, E. (2010).

Synesthesia and migraine: case report. BMCNeurol. 10:121. doi: 10.1186/1471-2377-10-121

Asher, J. E., Lamb, J. A., Brocklebank, D., Cazier, J.-B.,Maestrini, E., Addis, L., et al. (2009). A whole-genome scan and fine-mapping linkage study ofauditory-visual synaesthesia reveals evidence oflinkage to chromosomes 2q24, 5q33, 6p12, and12p12. Am. J. Hum. Genet. 84, 279–285. doi:10.1016/j.ajhg.2009.01.012

Baron-Cohen, S., Bor, D., Billington, J., Asher, J.,Wheelwright, S., and Ashwin, C. (2007). Savantmemory in a man with colour form-numbersynaesthesia and asperger. J. Conscious. Stud. 14,9–10.

Bauer, S., Kerr, B. J., and Patterson, P. H. (2007).The neuropoietic cytokine family in development,plasticity, disease and injury. Nat. Rev. Neurosci. 8,221–232. doi: 10.1038/nrn2054

Boulanger, L. M. (2004). MHC class I in activity-dependent structural and functional plasticity.Neuron Glia Biol. 1, 283. doi: 10.1017/S1740925X05000128

Boulanger, L. M. (2009). Immune proteins in braindevelopment and synaptic plasticity. Neuron 64,93–109. doi: 10.1016/j.neuron.2009.09.001

Brang, D., Hubbard, E. M., Coulson, S., Huang,M., and Ramachandran, V. S. (2010).Magnetoencephalography reveals early activationof V4 in grapheme-color synesthesia. Neuroimage53, 268–274. doi: 10.1016/j.neuroimage.2010.06.008

Brang, D., and Ramachandran, V. S. (2008).Psychopharmacology of synesthesia; the roleof serotonin S2a receptor activation. Med.Hypotheses 70, 903–904. doi: 10.1016/j.mehy.2007.09.007

Bruno, P. P., Carpino, F., Carpino, G., and Zicari,A. (2007). An overview on immune system andmigraine. Eur. Rev. Med. Pharmacol. Sci. 11, 245.

Carruthers, H. R., Miller, V., Tarrier, N., andWhorwell, P. J. (2012). Synesthesia, pseudo-synesthesia, and irritable bowel syndrome. Dig.Dis. Sci. 57, 1629–1635. doi: 10.1007/s10620-012-2054-2

Collins, S. M. (2002). A case for an immuno-logical basis for irritable bowel syndrome.Gastroenterology 122, 2078–2080. doi: 10.1053/gast.2002.34097

Cytowic, R. E. (1989). Synesthesia: A Union of theSenses. New York, NY: Springer.

Elmer, B. M., and McAllister, A. K. (2012). Major his-tocompatibility complex class I proteins in braindevelopment and plasticity. Trends Neurosci. 35,660–670. doi: 10.1016/j.tins.2012.08.001

Enstrom, A. M., Van de Water, J. A., and Ashwood,P. (2009). Autoimmunity in autism. Curr. Opin.Investig. Drugs 10, 463–473.

Fernando, M. M., Stevens, C. R., Walsh, E. C., DeJager, P. L., Goyette, P., Plenge, R. M., et al.(2008). Defining the role of the MHC in autoim-munity: a review, and pooled analysis. PLoSGenet. 4:e1000024. doi: 10.1371/journal.pgen.1000024

Fourgeaud, L., and Boulanger, L. M. (2010). Role ofimmune molecules in the establishment and plas-ticity of glutamatergic synapses. Eur. J. Neurosci.32, 207–217. doi: 10.1111/j.1460-9568.2010.07342.x

Gourraud, P. A., Harbo, H. F., Hauser, S. L., andBaranzini, S. E. (2012). The genetics of multi-ple sclerosis: an up−to−date review. Immunol.Rev. 248, 87–103. doi: 10.1111/j.1600-065X.2012.01134.x

Griffiths, M. R., Gasque, P., and Neal, J. W. (2010). Theregulation of the CNS innate immune responseis vital for the restoration of tissue homeostasis(repair) after acute brain injury: a brief review. Int.J. Inflam. doi: 10.4061/2010/151097

Grossenbacher, P. G., and Lovelace, C. T. (2001).Mechanisms of synesthesia: cognitive and physio-logical constraints. Trends Cogn. Sci. 5, 36–41. doi:10.1016/S1364-6613(00)01571-0

Hubbard, E. M., Brang, D., and Ramachandran, V.S. (2011). The cross−activation theory at 10.J. Neuropsychol. 5, 152–177. doi: 10.1111/j.1748-6653.2011.02014.x

McAllister, A. K., and van de Water, J. (2009).Breaking boundaries in neural-immune interac-tions. Neuron 64, 9–12. doi: 10.1016/j.neuron.2009.09.038

Mitchell, K. J. (2013). “Synesthesia and cortical con-nectivity - a neurodevelopmental perspective,” inOxford Handbook of Synesthesia, eds J. Simner andE. Hubbard (Oxford: Oxford University Press),530–557.

Ramachandran, V. S., and Hubbard, E. M. (2001).Psychophysical investigations into the neural basisof synaesthesia. Proc. Biol. Sci. 268, 979–983. doi:10.1098/rspb.2000.1576

Rouw, R., and Scholte, H. S. (2007). Increased struc-tural connectivity in grapheme-color synesthesia.Nat. Neurosci. 10, 792–797. doi: 10.1038/nn1906

Schweizer, T. A., Li, Z., Fischer, C. E., Alexander, M. P.,Smith, S. D., Graham, S. J., et al. (2013). From thethalamus with love: a rare window into the locus ofemotional synesthesia. Neurology 81, 509–510. doi:10.1212/WNL.0b013e31829d86cc

Simner, J., and Hubbard, E. M. (2013). OxfordHandbook of Synesthesia. Oxford: OxfordUniversity Press.

Spector, F., and Maurer, D. (2009). Synesthesia: anew approach to understanding the developmentof perception. Dev. Psychol 45, 175. doi: 10.1037/a0014171

Stephan, A. H., Barres, B. A., and Stevens, B. (2012).The complement system: an unexpected role insynaptic pruning during development and disease.Annu. Rev. Neurosci. 35, 369–389. doi: 10.1146/annurev-neuro-061010-113810

Tomson, S. N., Avidan, N., Lee, K., Sarma, A. K.,Tushe, R., Milewicz, D. M., et al. (2011). The genet-ics of colored sequence synesthesia: suggestive evi-dence of linkage to 16q and genetic heterogeneityfor the condition. Behav. Brain Res. 223, 48–52.doi: 10.1016/j.bbr.2011.03.071

Trapp, B. D., and Nave, K. A. (2008). Multiple scle-rosis: an immune or neurodegenerative disorder?Annu. Rev. Neurosci. 31, 247–269. doi: 10.1146/annurev.neuro.30.051606.094313

Ward, J., Huckstep, B., and Tsakanikos, E. (2006).Sound-colour synaesthesia: to what extent does ituse crossmodal mechanisms common to us all?Cortex 42, 264–280.

Received: 31 July 2013; accepted: 23 August 2013;published online: 11 September 2013.Citation: Carmichael DA and Simner J (2013)The immune hypothesis of synesthesia. Front. Hum.Neurosci. 7:563. doi: 10.3389/fnhum.2013.00563This article was submitted to the journal Frontiers inHuman Neuroscience.Copyright © 2013 Carmichael and Simner. This is anopen-access article distributed under the terms of theCreative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is per-mitted, provided the original author(s) or licensor arecredited and that the original publication in this journalis cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted whichdoes not comply with these terms.

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