In this brief review I summarize some major findings demonstrating the specific anatomical and functional features of the brain of synaesthetes. There are several main findings of this research: (1) Brain areas, which are involved in controlling synaesthesia are anatomically different. (2) These brain areas are also differently activated during synaesthetic experiences. (3) There are not only anatomical and functional differences in those brain areas specifically involved. There are rather findings supporting the idea that the whole brain of synaesthetes is stronger interconnected compared to non-synaesthetes. (4) In terms of neurophysiological activations synaesthetes react different to the inducers quite early in the processing stream even when no conscious processing is taking place. Thus, the brain of synaesthetes is an extremely interesting example for a brain of specialists and is thus an interesting and precious research object.

Introduction

Synaesthesia is a rare perceptual phenomenon in which actual sensory impressions resulting from an inducing stimulus in one modality elicits concurrent perceptions in another sensory modality. The term synaesthesia was first used by the French neurophysiologist Vulpian (Vulpian, 1866). But the Swiss psychiatrists Bleuler and Lehmann (Bleuler & Lehmann, 1871) were the first to conduct sophisticated investigations of this particular phenomenon. Bleuler’s interest in synaesthesia was mainly driven by the goal of understanding hallucinatory experiences especially in schizophrenia. A better understanding of the psychological, neurophysiological, and neuroanatomical underpinnings of synaesthesia itself failed thereafter to attract research interest. But with the advent of modern brain imaging methods and techniques to measure the neurophysiological underpinnings of psychological phenomena, a growing community of neuroscientists is engaged in the studying of synaesthesia.

An important milestone was the first brain imaging study of Paulesu et al. (Paulesu et al., 1995) who used positron emission tomography to measure hemodynamic responses in synaesthetes during synaesthetic experiences. Several other studies followed using functional magnetic resonance imaging to explore the haemodynamic responses in synesthetes (Elias, Saucier, Hardie, & Sarty, 2003; Hubbard & Ramachandran, 2005; Nunn et al., 2002; van Leeuwen, Petersson, & Hagoort, 2010; Weiss, Shah, Toni, Zilles, & Fink, 2001; Weiss, Zilles, & Fink, 2005). In general, these studies show that the concurrent perception is associated with hemodynamic responses in brain areas that are normally involved in processing stimuli in the modality in which these are experienced. Thus, in coloured hearing synaesthetes a tone induces activations in the auditory cortex and in the fusiform colour area.

Alongside these first brain imaging studies, event-related potentials (ERP) were measured with electroencephalography (EEG) in synaesthetes, allowing the delineation of the time course of neurophysiological activations associated with synesthetic experiences (Barnett et al., 2008; Beeli, Esslen, & Jancke, 2008; Brang, Edwards, Ramachandran, & Coulson, 2008; Brang, Hubbard, Coulson, Huang, & Ramachandran, 2010a; Brang, Teuscher, Ramachandran, & Coulson, 2010; Cohen Kadosh, Cohen Kadosh, & Henik, 2007; Gebuis, Nijboer, & Van der Smagt, 2009; Goller, Otten, & Ward, 2009; Jäncke, Rogenmoser, Meyer, & Elmer, 2012; Schiltz et al., 1999). Based on these experiments, the neurophysiological underpinnings of synesthesia may be described and discussed in terms of three basically different neurophysiological models: (1) the two-stage cross-activation and hyper-binding model (Hubbard, 2007), (2) the disinhibited feedback model (Grossenbacher & Lovelace, 2001), and (3) the limbic-mediation model (Cytowic & Wood, 1982). I will briefly describe these models because they make different predictions about the time course of synaesthetic experiences and the underlying neurophysiological processes.

neurophysiological models

The cross-activation and hyper-binding model was proposed on the basis of fMRI studies in grapheme-colour synaesthetes (Hubbard, 2007). According to this model, the grapheme (posterior temporal grapheme area: PTGA) and colour processing brain areas (V4) are unusually connected. A key idea behind this is that cross-activation between these strongly connected brain areas occurs because of an abnormal excess of anatomical connections between the grapheme and colour processing brain areas. This aberrant connectivity should result in strong co-activation of these areas during grapheme processing. Both perceptions are then bound together by parietal mechanisms, resulting in hyper-binding. This model has received some support, specifically for experience of auditory-colour synaesthesia (Jancke & Langer, 2011).

The disinhibited feedback model is based on studies demonstrating specific forms of acquired and congenital synaesthesias rather than on data from brain imaging studies (Grossenbacher & Lovelace, 2001). The disinhibited feedback model diverges from the cross-activation and hyper-binding model in that it posits normal connectivity patterns in synaesthetes. It suggests also that synaesthesia results from disinhibited feedback from higher-level cortical areas in the visual processing hierarchy. A hybrid model, the so-called re-entrant processing model, shares with the cross-activation model the notion of hyper-connectivity between form and colour processing areas in the fusiform area, and suggests, like the disinhibited feedback model, that synesthetic colours require feedback of neural activity that originates in higher-level areas (e.g., anterior inferior temporal and posterior inferior temporal) to V4 (Smilek, Dixon, Cudahy, & Merikle, 2001).

The limbic mediation hypothesis, first proposed by Richard Cytowic and Frank Wood (1982), proposes that synaesthesia is mediated by the limbic system and especially the hippocampus, on which multiple sensory signals converge. According to this hypothesis, synaesthetes should have more connective fibres leading from the limbic system to the neocortex. Based on this limbic-neocortex hyper-connectivity, Cytowic and Wood propose that synaesthetes are more aware or conscious of functional cross-modal couplings. Thus, the notion of a kind of enhanced cross-modal coupling is pivotal to this theory. Interestingly, this model does not make any assumptions about the time course of synesthetic experiences and the associated neurophysiological activations.

Different predictions can be drawn from these models about the timing of neural activations. As explicitly formulated in Brang et al. (2010), but not considered in the paper of Grossenbacher and Lovelace (2001), there should be a particular time lag between the processing of the inducing stimulus (the inducer) and the concurrent perception. In terms of neurophysiological activation, it is thus hypothesized that the neurophysiological activation of the brain areas associated with processing of the concurrent perception follows with a significant delay the activation of the brain areas associated with the processing of the inducing stimulus. The cross-activation and hyper-binding model suggests increased local connectivity and predicts the activation of V4 during the initial sweep of activity in PTGA (Ramachandran & Hubbard, 2001). Activation of V4 and PTGA should therefore occur more or less simultaneously. The limbic mediation hypothesis does not make any assumptions about the timing of the neurophysiological processes. However, since the limbic system and the neocortex are strongly interconnected and the limbic system is involved in simple and complex cognitive and sensory processes fast and slow processes are possible. Thus, even when hyper-connectivity between limbic and neocortical systems would exist, activation time lags between the involved brain areas are possible but not necessary.

Neuroanatomy of synaesthete's brain

With the advent of modern brain imaging techniques several studies have ben conducted so far examining the specific features of the synaesthetes brain. Using functional magnetic resonance imaging (fMRI) techniques it has been shown that the sensory brain areas corresponding o the type of synaesthetic experience are activated.  Thus, synaesthetic colour experiences for example evoked by graphemes) can activate colour region in the occioito-temporal cortex, but this activation is not restricted to V4. However, the activations even go beyond that as it has been shown that a network of brain areas is involved the control of synaesthesia (Jancke & Langer, 2011; Rouw, Scholte, & Colizoli, 2011).

Several brain regions have been shown to be pivotal for synaesthetic experience among them are sensory and motor regions as well as so-called “higher level” regions in the parietal and frontal lobe. These “higher level” brain areas are most likely related to three different cognitive processes inherently part of synaesthesia: the sensory processes (with the sensory areas), the attentional processes especially controlling the binding process (within the parietal lobe), and the cognitive processes (controlled by frontal brain regions).  Most interestingly, these brain areas mostly demonstrate some kind of specific anatomical features as measured with structural MRI (sMRI). For example, the colour areas or the areas in the vicinity of V4 often demonstrate larger grey matter density. In addition, parietal brain areas (especially the intraparietal sulcus: IPS) have repeatedly been identified as a brain area with increased grey matter density in synaesthetes. Some papers have also identified specific anatomical features in frontal brain areas. Thus, those brain areas, which are strongly involved in generating and controlling the synaesthetic experiences, are anatomically different compared to non-synaesthetes. Only few studies have used diffusion tensor imaging (DTI) to measure and reconstruct the fibres connecting the different brain areas (Hanggi, Beeli, Oechslin, & Jancke, 2008; Jancke, Beeli, Eulig, & Hanggi, 2009). These few studies have shown that there are also some kinds of specific interconnections between he above-mentioned involved brain areas.

Of particular importance is a recent paper of our group in which we used graph-theoretical approaches on the basis of cortical thickness measures (Hanggi, Wotruba, & Jancke, 2011). Using cortical thickness measures obtained from sMRI measurements of the brain of synaesthetes we estimated to cortical connectivity on the basis of graph-theoretical techniques. As a result we identified that synaesthetes (here we studied grapheme-colour synaesthetes) showed increased whole-brain interconnectivity compared to non-synaesthetes. Thus no only the brain areas known to be involved in controlling synaesthetic experiences are strongly interconnected but also other brain which have not been identified as being specific for synesthetic experiences. Based on these findings we assume that the synaesthetic brain is characterized by a kind of over-connectivity.

In a previous paper we identified a kind of focal over-connectivity for our famous synaesthetes E.S. who is a tone-interval taste synaesthetes (Hanggi et al., 2008). She experiences particular tastes on he tongue when listening to particular tone intervals (Beeli, Esslen, & Jancke, 2005). This extraordinary synaesthesia is related to a kind of over-connectivity in the auditory cortex extending into the insula. This over-connectivity can possibly the reason why E.S. experiences tastes as a consequence of listening to tone-intervals because the auditory cortex is so strongly and tightly connected with the insula housing neural networks known to be involved in taste perception.

Taken together, the brain of synaesthetes demonstrates lots of anatomical and functional differences compared to non-synaesthetes. These differences support the idea of a highly individual brain where specific abilities are linked to specific anatomical and functional features.

time course of activation in SYNAESTHETEs

The analysis of the time course of neurophysiological activations during synesthetic experience enables the preceding neurophysiological models of synesthesia to be tested. The same time course data also provides a useful means with which to test whether synesthetic experiences are driven by early perceptual (bottom-up) or later more cognitive processing steps (top-down), or even by an interaction of these earlier and later processes. Recent papers have proposed that both bottom-up and top-down processes might be involved in synesthesia.

EEG and magnetencephalographic (MEG) methods have been used to delineate the time course of neurophysiological activation during synesthetic perceptions because they allow the measurement of cortical activation on a millisecond basis. Two types of studies have thus far used these techniques in synesthesia research: the first used measures of evoked potentials time-locked to the inducing stimuli (Beeli, Esslen, & Jäncke, 2007; Brang et al., 2008; Brang, Hubbard, Coulson, Huang, & Ramachandran, 2010b; Goller et al., 2009; Jäncke et al., 2012; Schiltz et al., 1999)which were either visual (e.g., graphemes for grapheme-colour synesthetes) or auditory stimuli (tones or words for auditory-colour graphemes), and the second type used priming techniques and measured higher-order cognitive processes in the context of synesthetic experience (Niccolai, Wascher, & Stoerig, 2012; Shalgi & Foxe, 2009)

Most of these studies have shown that synaesthetes demonstrate different neurophysiological reactions quite early in the processing stream happening around 80-150 ms after presentation of the inducer. The neurophysiological differences even extend into later processing stages up to 300 – 400 ms after stimulus presentation. Thus, synaesthetes obviously process inducers differently for a quite long time but the differences appear quite early at processing stages during which conscious processing is not likely (Jäncke et al., 2012).

summary and conclusion

Synaesthesia is a fascinating phenomenon meanwhile attracting many neuroscientists and psychologists. With the advent of modern brain imaging studies and the improvement of recording EEG and MEG data it is now possible to examine the brain of synaesthetes with high precision. Based on experiments exploiting the advantages of all methods it has been shown that synaesthetes demonstrate anatomical and functional differences in those brain areas, which are known to be involved in controlling (and probably generating) synaesthesia. Most interestingly is the fact that the whole brain of synaesthetes is anatomically differently organized with a higher interconnectivity in synaesthetes compared to non-synaesthetes. A further interesting finding is that early perceptual (bottom-up) as well as later occurring cognitive processes (top-down) are different in synaesthesia. Whether both processing steps are simultaneously altered in synesthetes or only one particular process, is however a question, which has to be answered in future studies.

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