The Role of the Superior Temporal Cortex in Ordinal-Color Synaesthesia.

By Noah David Fishel

Submitted to Pomona College in Partial Fulfillment of the Degree of Bachelor of Arts

Professor Weekes December 12th 2007

BACKGROUND AND SIGNIFICANCE

IntroductionSynaesthesia is a relatively rare neurological condition in which a stimulus causes an unrelated conceptual association or perceptual experience. These extra experiences are often sensory and can occur across sensory modalities. Illustrative examples include a man who sees colors when listening to music, or a woman who experiences tastes in response to tactile stimulation (Barnett et al., 2007). Forms of synaesthesia are named with the inducing stimulus followed by the resulting concurrent stimulus. The previously mentioned forms of synaesthesia are respectively referred to as auditory-color synaesthesia and tactile-gustatory synaesthesia. The most common form is grapheme-color synaesthesia; this type of sensory abnormality causes those afflicted to experience colors in response to numbers and letters. Because of its more frequent occurrence compared to other forms, grapheme-color synaesthesia has become the focus of synaesthetic research. Interestingly, these synaesthetes also commonly experience colors in response to months or days of the week: including numbers and letters, all these stimuli share the distinction of being ordinal sequences. Other reported forms of synaesthesia include gustatory-color, auditory-color, gustatory-shape, olfactory-color, musical-shape, lexical-gustatory, and color-pain (Barnett et al., 2007). Synaesthesia is a genetically inherited trait (Barnett et al., 2007). The prevalence of the condition in the general population has been estimated

anywhere from 1 in 20 (Galton, 1880) to 1 in 25,000 (Cytowic, 1989) and is six times more likely to occur in females (Barnett et al., 2007). This information, coupled with analysis of family trees strongly suggests that the gene coding for synaesthesia is an X-linked dominant gene (Barnett et al., 2007). However, inheritance of the gene does not ensure expression of the trait, and forms of synaesthesia are not passed down in families, only the broader symptom of anomalous associations (Barnett et al., 2007). Persons with one form of synaesthesia are more likely to possess a second or multiple forms of synaesthesia (Barnett et al., 2007). This information suggests that synaesthesia is caused by fundamental differences in brain connectivity. Each synaesthete experiences the world in his or her own unique way, but with several shared characteristics. Synaesthesia has been demonstrated to be a genuine, unidirectional, involuntary, and reproducible experience (Ramachandran and Hubbard, 2001). With regard to reproducibility, synaesthetes who report color as their concurrent stimuli are asked to report the specific hues they experience in response to various inducing stimuli. The same synaesthetes, when tested months or years later, show a remarkable consistency in their reports. Asher et al. (2006) found that synaesthetes have a retest accuracy of 73% while control subjects score an average of 33%. When greater leniencies for small changes in hue are permitted, synaesthetes average upwards of 96% accuracy a year later (Ward et al., 2006). While these grapheme-color associations are consistent for an individual synaesthete, colors are not consistent across synaesthetes (Beeli et al., 2007).

Synaesthetic associations are known to be unidirectional. This means that while the letter B induces a concurrent experience of the color yellow, the color yellow will not cause an association with the letter B in the same individual. Synaesthetes may develop associations in the other direction, but these associations are learned and never have the genuine sensory property that is evoked by a true synaesthetic inducer (Ramachandran and Hubbard, 2001). Synaesthetic associations are involuntary and cannot be suppressed by the individual. This is demonstrated using a modified Stroop task created specifically for synaesthetes. In the normal Stroop test, names of colors are written in incongruent colors, and participants are asked to name the color of the word. Involuntary reading of the word interferences with color naming (Stroop, 1935)

RED YELLOW GREEN BROWN BLUE PURPLE YELLOW GREEN RED BLUE
Figure 1: An example of stimuli used in a Stroop test for non-synaesthetic individuals.

The modified Stroop test for synaesthetes takes advantage of those synaesthetes with inherent color associations. Synaesthetes are presented with letters that evoke their synaesthetic colors, called photisms, and asked to name the color depicted on the monitor (the video color). Video colors of these letters are either congruent or incongruent with the synaesthetes photism colors. If the synaesthetic color experience is involuntary, photism colors should interfere with the naming of video colors on incongruent trials. Multiple studies have found

significant differences in response times for congruent and incongruent trials in synaesthetes (Dixon et al., 2004; Ward et al., 2006). In addition, synaesthetes respond faster than control subjects on congruent trials, which shows that their photisms facilitate quick responses (Dixon et al., 2004; Ward et al., 2006). Synaesthetes performance relative to controls on the reproducibility test and congruent Stroop test trials demonstrates the genuine nature of their associations.

Significance of the FieldIt is not immediately obvious how research on the subject of synaesthesia can increase our knowledge of normal brain functioning. However, synaesthesia provides a unique window into sensory processing in the human brain. The interaction of sensory modalities is common in normal cognition; the condition of synaesthesia simply brings an explicit nature to these interactions. The famous bouba and kiki study by Kohler (1929) provides a good example of implicit interactions between modalities. When asked to arbitrarily assign the names bouba and kiki to two shapes (shown below, Fig. 2), 95% of participants will give the shape on the left the name kiki (Kohler, 1929). Figure 2: Adapted from Ramachandran and Hubbard (2001). Shows two forms used in the famous kiki bouba study,

This shows the pervasiveness of inherent spatial-linguistic associations in human perception. These underlying associations may be responsible for the human ability to create and understand metaphor. Synaesthetes are known to be creative and gifted in the art of metaphor (Ramachandran and Hubbard, 2001). Research on synaesthetes could progress the understanding of creativity and metaphor by taking advantage of the fact that synaesthetes experience tangible metaphors in their daily lives. In addition to creativity, studies of synaesthetes have addressed a wide variety of subjects including attention, feature binding, object representation, and pre-conscious processing. While the phenomenal quality of synaesthesia may limit the applicability to normal brain functioning, the explicit nature of these sensory associations can be used to constrain neuroanatomical theories. Before the full potential of synaesthetic research can be realized, a greater understanding of what causes synaesthesia must be attained. This requires an elucidation of the relevant subtypes of synaesthesia, the brains areas involved, and the neural basis for modality crossing associations. The focus of this paper is on the role of the Superior Temporal Cortex (STC) in synaesthesia. For this purpose, what follows is a background of the cognitive phenomena that constrain the anatomical theories of synaesthesia.

Cognitive VariantsIn addition to the different forms of synaesthesia, there are quite a few cognitive variants that occur within all forms of synaesthesia. These manifest

themselves in the representational level of inducers and in the spatial reference frame of the concurrent experience. These variations were first shown in grapheme-color synaesthetes, but the distinctions have since been extended to other forms of synaesthesia (Smilek et al., 2007; Stevenson et al., 2007; Ward et al., 2005). It is important to study the differences in synaesthetic experience because these cognitive differences likely translate to physical differences in the brains of these synaesthetes. Based on the quality of their concurrent experiences, grapheme-color synaesthetes can be placed into two groups: projectors and associators. The difference between these two groups pertains to the spatial reference frame in which they experience colors (Ward et al., 2006). Projectors experience colors in their visual field, often directly on top of the inducing stimuli (Dixon et al., 2004). Associators experience their colors in their minds eye in the same frame of reference that normally supports visual imagery (Ward et al., 2006). Synaesthetes are also categorized as higher or lower based on the representational level of the inducing stimuli that cause synaesthetic associations. Higher grapheme-color synaesthesia is characterized by consistent color associations with conceptual representations of a grapheme or other ordinal concepts. If that grapheme is a letter, then all fonts, cases and even thoughts of the letter can induce photisms. If the grapheme is a number, then roman numerals, dice, mathematical equations, or the word for the number can evoke color. Lower synaesthetes perceive concurrent stimuli in response to only the simplest form of the grapheme. Being a higher synaesthete does not imply

that one experiences photisms in response to all conceptual stimuli. One can be a higher synaesthete with respect to some inducing stimuli, and a lower synaesthete with respect to others (Ward et al., 2006).

Neural Basis of SynaesthesiaWhile the goal of this proposal is to investigate which parts of the brain participate in synaesthesia, it is important to have a neuroanatomical context in which to place these brain areas. There are two leading theories as to the neural basis of synaesthesia. The first is called the disinhibited cortical feedback model and was presented by Grossenbacher and Lovelace (2001). This theory posits that synaesthesia occurs because of disinhibited feedback at areas of sensory convergence. Grossenbacher hypothesizes that the inducing pathway and concurrent pathway feed forward to the same cortical junction. When the inducing signal reaches this junction, it propagates along pathways that support feedback to the concurrent pathway (Grossenbacher and Lovelace, 2001). In the normal human brain these feedback signals are inhibited at the sensory nexus. Grossenbacher goes on to suggest the STC as a possible multi-sensory nexus as it receives input from nearly every sensory modality (Blakemore et al., 2005; Bruce et al, 1981; Hikosaka et al, 1988; Karnath, 2001). The theory of disinhibited feedback is appealing because it requires no extra neural connections and could easily explain cases of acquired and drug-induced synaesthesia.

The second theory is based on the presence of additional connections between normally unconnected brain areas and is referred to as the crossactivation hypothesis. Ramachandran and Hubbard (2001) proposed that these connections exist due to deficient neuronal pruning during development. It is suggested that these connections are akin to those that arise in the somatosensory cortex leading to the phenomenon of phantom limbs (Ramachandran and Hubbard, 2001). This theory is convenient because the cognitive variations in synaesthesia can be easily explained by cross connections between different areas of the brain. For example, Ramachandran and Hubbard (2001) propose that lower grapheme-synaesthesia is caused by connections between the color area V4 and the grapheme recognition areas of the inferior temporal lobe. Higher synaesthesia can be explained by connections between the Superior Temporal Cortex (STC) and the angular gyrus (Ramachandran and Hubbard, 2001). Although brain areas may play variable roles, it is unlikely that there are multiple underlying neuronal mechanisms for synaesthetic associations. While the condition of synaesthesia itself is heritable, there are no trends in the form, spatial reference frame or processing level found in related synaesthetes (Rich at al., 2005). Synaesthetes can, and often do, experience multiple forms of synaesthesia (Barnett et al., 2007). Additionally, one synaesthete can be a higher projector with respect to some stimuli and a lower associator with respect to others (Ward et al, 2006). For these reasons, all forms and variations of synaesthesia are likely caused by the same underlying neuronal properties.

While in the disinhibited feedback model the STC plays a role in all variants of synaesthesia, it is only theorized to be involved in higher synaesthesia under the cross-activation hypothesis. For this reason, studies of the role of the STC in synaesthetes may lead to one model being favored over the other.

Neuroanatomical ConsiderationsThe abundance of behavioral and cognitive studies provides necessary information for guiding conjectures about the neuronal properties responsible for synaesthesia. However, these theories must be tested with rigorous neuroscientific methods. Many studies have assessed the neuroanatomical properties of synaesthetes using methods such as Transcranial Magnetic Stimulation (TMS), functional Magnetic Resonance Imaging (fMRI) and Diffusion Tensor Imaging (DTI). The applicability of results obtained from these studies has been compromised by the experimenters failure to accurately phenotype their synaesthetes. Since cognitive distinctions such as projector/associator and higher/lower may translate to physical differences in the brains of these synaesthetes, negative results obtained without these distinctions are difficult to interpret. Compelling evidence has been presented for the roles of V4 (Nikolic et al., 2007, Hubbard et al., 2005, Nunn et al., 2002, Sperling et al., 2006), the Inferior Temporal Cortex (ITC) (Gray et al, 2006; Rouw and Scholte, 2007) and the area comprised of the posterior parietal lobe and angular gyrus (Aleman et al., 2001; Esterman et al., 2006; Muggleton et al., 2006, Nunn et al., 2002) in synaesthesia.

10

Despite the fact that the STC has connections with each of these brains areas (Karnath, 2001; Kellenbacher et al., 2005; Saleem et al., 2001; Zeki, 1977), little attention has been paid to this surprisingly relevant brain area with respect to its role in synaesthesia. Studies of the STC may be the key to connecting all of these brain areas into one cohesive model.

Superior Temporal CortexThe Superior Temporal Cortex (STC) is a logical candidate site for synaesthetic action for many reasons. The STC receives inputs from almost every sensory modality including somatosensory (Blakemore et al., 2005), auditory (Karnath, 2001), and olfactory (Gottfried and Dolan, 2003; Kettenmann, 1996; Kettenmann et al., 2003; Mohedano-Moriano et al., 2005). The STC also receives variety of visual information from both the ventral and dorsal stream including information concerning motion (Howard et al., 1996), color (Zeki and Marini, 1998), spatial orientation (Karnath, 2001), word meaning (Simos, 2000) and form (Beauchamp et al., 2004). Furthermore, in animal models superior temporal cells have been shown to respond to multiple sensory modalities (Hikosaka et al., 1988; Bruce et al., 1981). The STC projects to areas of olfactory processing (Mohedano-Moriano et al., 2005) and early color processing (Zeki, 1977) which are both commonly experienced concurrents in synaesthesia (Barnett et al., 2007). Almost every form of synaesthesia can be explained by connections within or disinhibition from the STC. Cells in the human STC have been shown to respond preferentially to multiple features of an object, which

11

suggests that the STC is likely necessary for learning arbitrary associations between objects and their sensory properties (Beauchamp et al., 2004). The STC has been identified as an area of activation in brain-imaging studies of synaesthetes (Aleman et al., 2001; Blakemore et al, 2003; Nunn et al., 2002; Paulesu et al., 1995; Sperling et al., 2006), but no researchers have taken the time to test critical predictions about the role of the STC in any form of synaesthesia. In the interest of elucidating an appropriate line of experimentation, it is necessary to review the literature concerning the STC. Two different studies have measured single cell recordings from areas of the Superior Temporal Sulcus (STS) in Macaque monkeys. Of 383 neurons tested in the anterior portion of the STS, 41% responded exclusively to visual stimuli, 21% responded to auditory and visual stimuli, 17% responded to somatosensory and visual stimuli, and 17% responded to all three modalities (Bruce et al., 1981). The remaining 2% were unresponsive. Hikosaka et al. (1988) made similar findings in the posterior portion of the STS. Of 200 neurons, 51% responded only to one modality (59 visual, 33 auditory and 10 somatosensory), 36% responded bimodally, (21 visual-auditory, 7 visualsomatosensory and 8 somatosensory-auditory) and 2% were trimodal (Hikosaka et al., 1988). In both studies, these cells had large receptive fields and were not topographically organized (Bruce et al., 1981; Hikosaka et al., 1988). Both populations of cells were found to receive inputs from the inferior temporal region, the IntraParietal Sulcus (IPS) and areas of the Superior Temporal Gyrus (STG) (Bruce at al., 1981; Hikosaka et al., 1988).

12

Of all the visual stimuli processed in the STC, the color information may be the most relevant to synaesthesia. The STC receives input from areas of the ventral stream integral to color processing such as V4 and the ITC. Lesions to the V4 of Macaque monkeys lead to degeneration of cells in the posterior bank of the STS (Zeki, 1977). Neurons in this same area of the STS in non-lesioned Macaques responded selectively to certain colors (Zeki, 1977). Some cells responded preferentially to colors on one end of the spectrum, while others were more specific, and maximum activation was observed only with a certain wavelength (Zeki, 1977). In animal models, it has been shown that not only does the posterior STC receive color input from V4, but the STC also has projections back to V4 (Zeki, 1977). In humans, the STS is involved in processing of object related color information (Chao and Martin, 1999). The STS is activated when human subjects make judgments about object color, but not when making object judgments dissociated with color (Kellenbach et al., 2005). Additionally, activation is significantly different when the object is dressed in congruent or incongruent colors (Taylor et al., 1997; Chao and Martin, 1999). In synaesthesia, this color information must be integrated with the representation of the inducing stimuli. Accordingly, the STC plays a significant role in the integration of object properties from separate modalities. Beauchamp et al. (2004) used fMRI to show that the human STS responds to both visual and auditory stimuli. Further, some parts of the STS respond preferentially to simultaneous presentation of auditory and visual stimuli or two distinct visual features relating to the same object (Beauchamp et al.,

13

2004). This implies that areas of the STS are primed for integration of sensory information pertaining to an individual object within and across sensory modalities. For example, a certain area of the STS may respond preferentially to the visual presentation of a cat along with the sound of a meow localized to the same spatial location. This is an example of an arbitrary relationship that must be learned. Beauchamp and colleagues (2004) go on to suggest that the STS may be a region critical for learning arbitrary associations such as that between the shape of a letter and its sound. All this evidence implies that the STS has a large role in relating correct semantic information about objects from multiple sensory modalities. Abnormal connections to this area could lead to integration of incorrect object properties that manifest as unusual cross-modal associations. While the STC may have a pivotal role in all forms of synaesthesia, the goal of this proposal will be to demonstrate that the STC has a critical role in the most common form of synaesthesia: grapheme-color. If cells in the posterior STC that integrate color properties of objects were to establish connections with cells representing conceptual aspects of graphemes, it is feasible that these connections would results in the assignment of color properties to graphemes. Feedback from the STC to lower visual areas could then cause the perceptual experience of color. Before moving on to the specific hypothesis and critical predictions of this proposal, it is necessary to discuss the role of other brains areas such as V4 and the angular gyrus, as they provide context for this proposed role of the STC. Studies of these areas will also help understand which forms and variants of synaesthesia might rely on the STC.

14

Spatial and Semantic Processing Areas (Angular Gyrus, Intraparietal Sulcus)The area near the junction of the parietal and occipital corti, containing the IPS and angular gyrus, is necessary for the binding of synaesthetic colors to a spatial frame of reference (Esterman et al., 2006; Muggelton et al., 2007). Lesions to the left angular gyrus in particular show a host of relevant effects including spatial neglect, agraphia (inability to form graphemes), acalculia (inability to manipulate conceptual aspects of numbers), loss of ability to understand ordinal concepts and the loss of the ability to interpret metaphor (Carota et al., 2003; Hubbard et al., 2005b; Ramachandran and Hubbard, 2001). It was on the basis of these observations that Ramachandran and Hubbard (2001) hypothesized that the left angular gyrus may be involved in conceptually driven associations between numbers, letters, months, and days of the week. Four independent studies have found activation in the angular gyrus of lexical-color synaesthetes (Aleman et al., 2001; Elias et al, 2003; Nunn et al., 2002; Steven et al., 2006). It is notable that all of these studies used conceptual stimuli to induce color. Using Diffusion Tensor Imaging (DTI), Rouw and Sholte (2007) found greater connectivity in the left posterior parietal cortex in synaesthetes than in controls. Recent TMS studies have shown that areas of the parietal occipital junction are necessary for the binding of synaesthetic color to the inducing stimulus. Esterman et al. (2006) and Muggleton et al. (2007) both performed Transcranial Magnetic Stimulation (TMS) on an area encompassing

15

the IPS and angular gyrus while synaesthetes participated in a modified Stroop task. Esterman et al. (2006) originally performed this experiment on two projectors and Muggleton et al. (2007) extended the study by performing a very similar procedure on one projector and four associators. TMS of the Right Parieto-Occipital (RPO) site decreased response times on incongruent trials in all synaesthetes (Esterman et al, 2007; Muggleton et al., 2007). These results show that the RPO is necessary for synaesthetic binding of colors to graphemes (Esterman et al., 2007). Muggleton and colleagues (2007) also found attenuation of interference after TMS of the LPO, but only in four out of five synaesthetes tested. The findings of increased connectivity near the LPO (Rouw and Scholte, 2007) and its necessity in the majority of synaesthetic experiences (Esterman et al., 2006; Muggleton et al., 2007) support the hypothesis that connections originating in this area are responsible for color associations with conceptual stimuli. Specifically, these findings suggest that connections may exist between cells of the left angular gyrus activated by ordinal concepts and cells in the left posterior STC responsible for integrating colors properties of objects. Before stating a hypothesis, information presented about areas of conceptual representation must be reconciled with the large quantity of research done on the role of early visual areas in grapheme-color synaesthesia.

Early Visual Processing Areas (V4, Inferior Temporal Cortex)-

16

V4 is a part of the visual cortex contained within the fusiform gyrus and is the first stage of color processing (Zeki and Marini, 1998). Eight fMRI studies found V4 activation in synaesthetes who experience color as their concurrent stimuli (Elias et al., 2003; Gray et al., 2006; Hubbard et al., 2005; Nunn et al., 2002; Rich et al., 2006; Sperling et al., 2006; Steven et al. 2006; Weiss et al., 2000). The level of activation in V4 varies significantly across synaesthetes (Hubbard et al., 2005, Sperling et al., 2006) and likely corresponds to the perceptual strength of their color experience. For example, of four associator synaesthetes in Sperling et al. (2006), two reported the experience of a fully colored screen in their minds eye, and two reported the perception of a small colored version of the inducing grapheme. The first two subjects showed significant activation while the second two showed a modest activation of V4 that did not reach significance (Sperling et al., 2006). In addition to subjective reports of color strength, V4 activation is correlated with improved performance on an embedded figure task (Hubbard et al., 2005): a task facilitated by synaesthetic colors (Ramachandran and Hubbard, 2001). While V4 mediates the perceptual experience of synaesthetic colors, the question remains as to whether V4 is the location where synaesthetic colors are integrated. It is possible that higher-level color processing areas such as the STC are the first to be activated on the concurrent pathway, and that this activation feeds back to V4. With this possibility in mind, Nikolic et al. (2007) took advantage of the fact that V4 processes color in opponent channels (Zeki, 1980). Cells in V4 that are activated by red are deactivated by green, and cells that are excited by blue are

17

inhibited by yellow (Zeki, 1980). Nikolic et al (2007) employed a modified Stroop task similar to that of Smilek et al. (2004) with two incongruent trials: one in which the incongruent color was opponent to the photism color (i.e. blue vs. yellow), and one in which it was not (i.e. blue vs. red). They found that opponent incongruent colors cause more interference in color-naming tasks. To ensure that opponent colors are not causing this interference at a semantic level, subjects were asked to name the natural color of incongruently dressed objects such as a lemon or a heart (Nikolic et al., 2007). In this case, opponent colors did not produce greater interference, and this was consistent across synaesthetes and non-synaesthetic controls (Nikolic et al., 2007). These results show that processing of synaesthetic colors is occurring concurrently with processing of real colors in V4. However, Nikolic and colleagues (2007) failed to phenotype their synaesthetes as higher or lower, and thus it is unclear whether these findings can be applied to all grapheme-color synaesthetes. Adjacent to V4 and the fusiform gyrus is the Inferior Temporal Cortex (ITC). The left ITC is thought to be involved in the retrieval of object color knowledge (Chao and Martin, 1998) and contains the Visual Word Form Area (VWFA), which preferentially responds to letters and letter strings (Cohen and Dehaene, 2004; Joseph et al., 2006). Ramachandran and Hubbard (2001) proposed that connections between V4 and areas of the ITC concerned with letter and word processing account for cases of lower synaesthesia. The proximity of these areas may not be the necessary component in the formation of connections, but may account for the relative abundance of grapheme-color

18

synaesthetes (Ramachandran and Hubbard, 2001). In support of this hypothesis, Diffusion Tensor Imaging (DTI) showed greater structural connectivity in grapheme-color synaesthetes brains in areas of the ITC adjacent to V4 (Rouw and Sholte, 2007). Interestingly, this was found only in the right ITC whereas the areas thought to be involved in letter and word processing are lateralized to the left (Cohen and Dehaene, 2004). However, lateralization in synaesthetes must be approached carefully because synaesthetes sometimes exhibit novel patterns of lateralization (Nunn et al., 2002; Gray et al., 2006). Rouw and Sholte (2007) conducted an fMRI study on the same synaesthetes and found that activation in one portion of the ITC when synaesthetes viewed color inducing graphemes was correlated with structural connectivity in that same area. The main shortcoming of this study is that the authors chose to analyze synaesthetes as a group instead of on an individual basis. They established that synaesthesia can be identified by greater structural connectivity, but some of the synaesthetes showed less connectivity than controls in the area of interest. Perhaps these synaesthetes experiences are mediated by increased connectivity in a different brain location. One interpretation l is that the synaesthetes who showed greater connectivity in this study were lower synaesthetes and their experience is mediated by connections between early color areas (V4) and areas that process representations of grapheme form (ITC, VWFA). The synaesthetes who did not show greater structural connectivity in the ITC are higher synaesthetes, and their colors experiences are mediated by connections between areas of higher color

19

processing in the STC and conceptual grapheme representation in the angular gyrus.

HypothesisThe main hypothesis of this proposal is that synaesthesia characterized by colored associations with conceptual representations of ordinal sequences (letters, numbers, months and days of the week) is mediated by connections between areas of the Left Posterior Superior Temporal Cortex (LPSTC) related to color and the areas of the left angular gyrus that process concepts of ordinality. This is likely not the only role of the STC in synaesthesia. However, this hypothesis leads to easily testable predictions with a sufficient base of synaesthetic subjects.

Predictions1. Synaesthetes viewing months that induce synaesthetic colors will show significant activation in the LPSTC as compared to controls. Connections between cells activated by ordinal concepts in the angular gyrus will lead to subsequent activation of the color processing areas in the LPSTC. Controls will not show similar activation of the LPSTC because they do not perceive colors. 2. These color associations are conceptual, and will not show different interference effects in a photism naming Stroop test with opponent and nonopponent colors. Increased opponent interference would be seen only if color

20

integration was occurring in V4, which contains opponent color channels (Zeki, 1980). 3. Inhibition of the LPSTC with TMS will cause an attenuation of Stroop interference effects in ordinal-color synaesthetes. Attenuation of interference will not be seen in lower synaesthetes whose colors are induced by the perceptual correlates of ordinal concepts. The connections in these lower synaesthetes occur independent of the STC, likely between early visual areas in the ITC (Rouw and Scholte, 2007).

Methods

SubjectsThree groups will be recruited. The first is a group of synaesthetes who experience colored photisms in response to visual presentation of words corresponding to months. It is important that these synaesthetes not respond to words in general, but rather only words corresponding to ordinal sequences. This may seem like a highly specific phenotype, but it is quite common. Six of the fourteen synaesthetes used in Ward et al. (2006) would qualify. This group of synaesthetes will be referred to as Group 1. Group 2 will be made up of lower grapheme-color synaesthetes that have colored experiences only in response to the visual presentation of basic letterforms. The synaesthetic subjects will be recruited based on their participation in previous studies as well as through advertisements in regional synaesthesia newsletters. The control group will be

21

non-synaesthetes matched to Group 1 for age, sex, handedness, and ethnicity. The larger the groups the better, but a reasonable minimum would be twelve. The genuineness of the synaesthetes will be assessed using the test-retest paradigm established in Asher et al. (2006). Synaesthetes will be asked to assign their specific photism colors to the months. Without prior knowledge, they will be asked to perform this task again up to a year later and tested for accuracy.

Experiment 1In this first experiment Group 1 synaesthetes and controls will both be presented with achromatic visual stimuli while undergoing fMRI. fMRI settings on all trials will be in line with those of Sperling et al. (2006). The data for each subject will be transformed into Talairach space by specifying the location of the anterior and posterior commissure manually. fMRI will be centered around Talairach coordinates (-50, -45, 11) as shown to be active in Nunn et al. (2002) and Sperling et al. (2006). Trial 1 stimuli will consist of words corresponding to the months of the year (January, February, March, April, May, June, July, August, October, November, December). Synaesthetes will be asked to name their concurrent colors in order to ensure they are consciously experiencing those colors. Trial 2 will consist of viewing words that are unrelated to ordinal concepts. These words will be matched to the words of Trial 1 for prevalence in the English language (Steven et al., 2006). Thus there are four trials to analyze. 1. Synaesthetes viewing Ordinal Words (SOW) 2. Controls viewing Ordinal Words (COW)

22

3. Synaesthetes viewing Neutral Words (SNW) 4. Controls viewing Neutral Words (CNW)

Experiment 2Experiment 2 will take advantage of the fact that perceptual processing of color happens in opponent channels of V4 while semantic processing is independent of these opponent color relationships (Nikolic et al., 2007; Zeki, 1980). Group 1 synaesthetes will be shown three sets of stimuli, a Congruent Set (CS), an Incongruent Set (IS) and an Incongruent Opponent Set (IOS). All three sets will consist of the same set of month words but the coloration will vary. The CS will be colored consistently with the synaesthetes photism colors. In the IOS the months will have colors opponent to those of the synaesthetes photisms (on the opposite side of the color wheel). In the IS the months will be colored incongruently, but this time avoiding opponent colors (90 degrees away on the color wheel). Stimuli will be presented on a standard monitor with a 750ms gap between presentations. Group 1 will be asked to respond by naming the photism color they experience in response to the word. Reaction times will be measured based on the onset of a verbal response.

Experiment 3Group 1 synaesthetes will participate in a modified color-naming Stroop task similar to that used in Experiment 2. Unlike Experiment 2, there will only be a Congruent Set (CS) and Incongruent Set (IS) of colored months. TMS of the

23

LPSTC will occur before the administration of the Stroop test. Participants will receive TMS of the LPSTC as outlined in Esterman et al. (2006) using an ironcored figure-8 coil centered around Talairach coordinates (-50, -45, 11). Each stimulation will consist of 480 pulses at a frequency of 1Hz (Esterman et al., 2006). As a control, participants will also be subjected to sham-TMS trials in which the coil is pointed away from the participant, and thus has no effect on their brain tissue. Participants will be ignorant of whether they are receiving genuine or sham-TMS. Group 2 synaesthetes will undergo the same procedure with the only difference being that their stimuli sets will consist of letters congruent (CS) and incongruent (IS) with their reported photisms. Four Stroop tests will be conducted: 1. Ordinal-Color synaesthetes with Genuine TMS (OCG) 2. Ordinal-Color synaesthetes with Sham TMS (OCS) 3. Grapheme-color synaesthetes with Genuine TMS (GCG) 4. Grapheme-color synaesthetes with Sham TMS (GCS)

DISCUSSION

Subject DiscussionSynaesthetes who experience months as their inducing stimuli were chosen because months are an inherently conceptual ordinal sequence. Had letters or numbers been selected, more distinctions would have had to be made about the types of stimuli presented. In the case of months, the word for the

24

month triggers the conceptual representation and is the only stimulus that can accomplish this. It is important that Group 2 synaesthetes have no conceptually induced color. Otherwise it is possible that presentation of perceptual stimuli might facilitate synaesthesia through feed forward activation of conceptual representations. In this case we could not be sure that Group 2 is truly distinct from Group 1.

Experiment 1 DiscussionExperiment 1 aims to confirm the prediction that the LPSTC is involved in ordinal-color synaesthesia. This will be established by subtracting the activation in the COW trial from the SOW trial. Additionally, COW CNW can be used to confirm the observation that the angular gyrus is activated in response to ordinal concepts. It is predicted that SOW will be the trial with the greatest activation of the LPSTC because this is the only trial in which colors are experienced. SOW trials may also show activation of lower visual areas involved in color processing. The confirmation that the LPSTC is activated selectively in ordinal-color synaesthetic experiences would be considered a positive result and confirms the involvement but not the necessity of the LPSTC in the binding of colors to ordinal concepts. The inducing stimulus is represented at the conceptual level in the left angular gyrus. Where the signal travels from here is still unclear. There are two models of how the LPSTC becomes activated in this situation. One possibility is that, as proposed, the angular gyrus has anomalous connections with the

25

LPSTC. Activation of earlier visual pathways can be explained by feedback connections from the STC as demonstrated by Zeki (1977). Figure 3: Model 1 of ordinal-color synaesthesia. The red arrows depict propagation of activation from the angular gyrus.

The second possibility is that activation in the angular gyrus causes activation in early visual areas such as V4. The inevitable cascade of information up the color-processing pathway causes the subsequent activation of the STC.

26

Figure 4: Model 2 of ordinal-color synaesthesia. Propagation of activation from angular gyrus is depicted in red.

It is possible that ordinal-color synaesthesia could be mediated by either of these models in different synaesthetes. For this reason, it will be important to analyze each synaesthete on an individual basis. Even if some of the synaesthetes show patterns suggesting model 2 (fig. 4), it is predicted that more will show patterns suggesting model 1 (fig. 3) because of the relative proximity of the posterior STC and angular gyrus. Experiment 1 alone cannot distinguish between the two models. Before moving on to experiments that can distinguish between the two models, it is important to consider the implications of null findings. There are three possible forms of negative results that are contradictory to the predictions of this proposal. 27

1. SOW activation in the LPSTC is similar to SNW activation. This implies that the color experience is not causing activation of the LPSTC. However, this does not rule out the involvement of the STC. The STC could be acting as a multisensory nexus, and disinhibited feedback down the ventral color-processing pathway could mediate the color experience as proposed by Grossenbacher and Lovelace (2001). In this situation one would not necessarily expect greater activation in the STC.

Figure 5: Model 3 of ordinal-color synaesthesia facilitated by disinhibited feedback from the STC. Path of activation shown in red.

2. Both SOW and COW show LPSTC activation. This implies that the activation in the STC is not due to the color processing. Instead, activation of the STC is attributable to the processing of ordinal concepts. As in the previous example, if early color processing areas of the ventral stream are

28

activated in the SOW trial, this can be explained by disinhibited feedback from the LPSTC. If the LPSTC is the site from which disinhibited feedback originates then it is expected that these synaesthetes will show attenuation of interference effects after TMS of the LPSTC in Experiment 3. 3. All four trials show similar activation in the LPSTC. In this case, it is unlikely that the STC has any role in ordinal-color synaesthesia. All that can be inferred is that the STC is activated when subjects view words. Future studies of the STCs role in synaesthesia might be justified in investigating its role in other forms of synaesthesia, notably those that experience olfactory sensations as their concurrent. The STC is unique in that it projects forward to the olfactory processing areas (MohedanoMoriano, 2005) but also has many connections to more posterior sensory processing (Karnath, 2001)

Experiment 2 DiscussionExperiment 2 can provide insight into any of the results from Experiment 1 except for the third null result. Experiment 2 will show whether the colors of Group 1 synaesthetes are being processed in V4 or in areas processing semantic properties of colors. If the Group 1 synaesthetes show greater interference on the IOS than the IS (negative results), this implies that synaesthetic colors are being processed in the opponent channels of V4. As was discussed in the background, Nikolic et al., (2007) established that these same

29

interference patterns are not seen with more semantic and object related aspects of color. For this reason, if color activation is occurring in the LPSTC as predicted, IOS and IS trials will show similar interference (positive results). Positive results demonstrate that colors in ordinal-color synaesthetes are processed above V4. Any activation of V4 is then due to feedback from higher processing areas as suggested in model 1 (fig. 3). This establishes that the synaesthetic colors are being induced at the level of semantic interpretation and object binding, which occurs in the STC (Beauchamp et al., 2001; Zeki and Marini, 1998). However, there may be other places in the brain that process semantic properties of color. It still must be shown that the STC is necessary for binding of synaesthetic colors to ordinal concepts. If inhibition of the LPSTC by TMS causes disruption of synaesthetic color binding, then the LPSTC is necessary for this binding to occur. Positive results in Experiment 2 combined with null results from Experiment 1 would pose a conundrum. These results imply that the color processing is not occurring in V4 or in the LPSTC. Future research would need to look to other areas known to be involved in semantic properties of color processing such as the anterior portions of the inferior temporal cortex (Baylis, 1987; Chao and Martin 1999) or the frontal cortex (Zeki and Marini, 1998). Regardless of results from Experiment 1, negative results in Experiment 2 lead to the conclusion that synaesthetic colors are being processed in V4. However, it still begs the question of how this activation propagates to V4. Is it coming straight from the angular gyrus (model 2, fig. 4) or passing through the

30

STC, which serves as a site of multi-sensory convergence (model 3, fig. 5)? Experiment 3 can distinguish between these two possibilities by disrupting activity in the LPSTC.

Discussion of Experiment 3The third experiment has the power to establish conclusively that the LPSTC is necessary for the binding of synaesthetic color to objects. Results from this experiment can also help constrain interpretations of negative results from the previous two experiments. TMS of areas pivotal to the binding process has been shown to cause attenuation of the Stroop effect (Esterman et al., 2006; Muggleton et al., 2007). This attenuation manifests itself only in the form of faster responses on incongruent trials which implies that normal colors are binding as usual. If TMS of the LPSTC interferes with binding of both real and synaesthetic colors, we would expect to see slower response times on both congruent and incongruent trials. For this reason, interference will be calculated as the difference in response times between the congruent and incongruent trials. Interference will be compared between sham and genuine TMS trials across each group of synaesthetes. If attenuation of interference is seen on the OCG trial, this shows that the LPSTC is necessary for the binding of synaesthetic colors to ordinal concepts. If the GCG trial does not show attenuation of interference on incongruent trials, there must be something unique about the processing of ordinal-color synaesthetes that involves the LPSTC. The predicted mechanism fits these results. In ordinal-color synaesthetes connections between

31

ordinal concepts in the angular gyrus and areas of the LPSTC binding color properties to objects facilitate a color experience. In perceptually driven experiences of lower grapheme-color synaesthetes the connections between the inducing and concurrent pathways occur independent of the STC. As can be seen in the figure below, without TMS, both types of synaesthetes show interference on incongruent trials in model 1 (fig, 3). When TMS is applied to the LPSTC, the signals passing through are inhibited.

Figure 6: Model 1. Activation in ordinal-color synaesthetes shown in red. Lower synaesthetes shown in blue. Path of real video colors shown in green.

32

Figure 7: Model 1 with TMS applied to STC. Path of activation in ordinal-color synaesthetes (shown in red) is inhibited in STC. Processing of video colors and photisms of lower synaesthetes is unaffected.

If both groups of synaesthetes show similar attenuation of interference, then it can be inferred that the LPSTC is necessary for both forms of synaesthesia. These results would suggest that the LPSTC is acting as a convergence point of the inducing and concurrent pathways. In this situation, both the viewing of ordinal concepts and letters causes activation in the LPSTC through the inducing pathway. Disinhibition of feedback from the STC then causes activation of lower visual areas leading to a color experience. The figure below displays how both types of synaesthetes would show attenuation of interference in model 3 (fig 5).

33

Figure 8: Model 3 with TMS applied to STC. Both lower (blue) and higher (red) synaesthetes will show disruption in color binding.

If no synaesthetes in either group show attenuation of interference, it will have to be noted if response times in general were slower on TMS trials. If this is true, then the TMS may have interfered with binding of both real and synaesthetic color. If response times are similar across sham and genuine TMS trails, this suggests that the LPSTC has no role in color binding in either form of synaesthesia. Future studies of the STC could investigate its involvement in other forms of synaesthesia involving olfactory (Mohedano-Moriano et al., 2005) or tactile concurrents (Blakemore et al., 2005). These null results combined with negative results on the first two experiments might suggest that direct connections between the angular gyrus and V4, as shown in model 2 (fig. 4), are responsible for the color associations of ordinal-color synaesthetes. A future study could use a combination of TMS and fMRI to establish causation or

34

correlation. If inhibition of the angular gyrus by TMS causes a change in activation of V4 as compared to sham TMS trials, it can be concluded that activation of the angular gyrus is leading to the activation in V4. Negative results would indicate that activation in both areas is propagating from a third source.

ConclusionsThe main weakness of my predictions is that the models they are based upon are very simplified. The true functioning of the brain cannot be displayed in an aesthetic flow chart. However, in much of the literature, this is the way models of synaesthesia are constructed because it allows for accessible theories that lead to testable predictions. Many studies in the field have conducted experiments and made conclusions based on these sorts of models. A calculated strength of the proposed line of experimentation is that the nulls results can provide useful information to the study of synaesthesia and the role of the STC. For example, if the LPSTC is found to be necessary for synaesthesia in the TMS experiment, but not found to be activated in response to synaesthetic colors, this presents conflicting results. These two findings can be reconciled if the LPSTC is acting as an area of sensory convergence as proposed by Grossenbacher and Lovelace (2001). The strength of this model is that it requires no additional connectivity in the human brain, only abnormal activity of already existing feedback pathways. This provides a simple explanation for drug-induced synaesthesia that is experienced by some users of drugs like LSD and mescaline (Grossenbacher and Lovelace, 2001). While this

35

is an interesting phenomenon, it is debatable whether this is caused by the same mechanisms as congenital synaesthesia. Drug-induced synaesthesia manifests itself in a fundamentally different way. The associations are not consistent across even small time periods and can be suppressed or accentuated by top-down processes of the individual (Ramachandran and Hubbard, 2001). A weakness of this model is that it has trouble reconciling the existence of higher and lower synaesthetes. Higher and lower synaesthetes differ in the level of representation on the inducing pathway. The question is: how does the multi-sensory nexus distinguish between signals that originate in lower processing areas and those that originate in higher processing areas? One explanation is that direct connections to the multi-sensory pathway occur from both lower and higher sensory processing areas. This condition is met in the case of the STC, which receives input from different levels of representation in the left ventral and dorsal stream (Karnath, 2001; Saleem et al., 2000). If all three predictions of this proposal are confirmed with positive results, sufficient evidence has been provided to show that the LPSTC is active in binding colors to ordinal concepts in certain synaesthetes. Activation of the angular gyrus causes concurrent activation in the LPSTC. Any subsequent activity in lower visual areas is likely mediated by feedback connections from the STC. Future studies should investigate the role of the STC in other forms of higher synaesthesia such as those with inducing stimuli like roman numerals or words. It will also be important to determine whether the connections between the angular gyrus and the LPSTC exist in all human brains, or if they are unique

36

to synaesthetes. DTI imaging could be used to show that ordinal-color synaesthetes have more connectivity in the area at the junction of the occipital, parietal and temporal lobe than do controls and lower synaesthetes. There is already a good deal of evidence to support synaesthetes having extra connections in their brains. Rouw and Scholte (2007) found direct evidence that synaesthetes have greater connectivity in the right inferior temporal, frontal and left parietal lobe. These connections may arise due to deficient pruning during development. This pattern of pruning in areas of sensory processing has been shown in Macaque monkeys. In fetal Macaque monkeys 70-90% of the connections to V4 are from higher areas in the temporal cortex, notably the Macaques version of the human inferior temporal cortex, where the VWFA is located (Kennedy et al., 1997). In adult Macaques, these connections from higher areas dwindle to only 20-30% (Kennedy et al., 1997). It remains to be seen whether those same pre-natal connections exist in higher pathways such as the angular gyrus and STC. Future studies could test synaesthetic qualities of infant sensory processing. Studies have avoided working with infants because they cannot explicitly express their experiences. However, a recent study has shown that synaesthetic experiences can be reliably assessed using pupil dilations (Paulsen and Laeng, 2006). Cross-activation has also been observed in humans who experience the phenomenon of phantom limbs. A time after losing a limb, the amputee may experience tactile stimulation of the missing limb in response to tactile stimulation of the face or chest (Ramachandran, 1992). This is an example of cortical reorganization. The neurons in the now unused section of

37

the somatosensory cortex corresponding to the missing limb have established connections to adjacent cells activated by facial stimulation (Ramachandran, 1992). This cross-activation occurs within one sensory modality, but is similar to synaesthesia because these aberrant tactile sensations are genuine, involuntary, and reproducible. The STC has a hypothesized role in almost every form of synaesthesia. If it is found that the STC mediates one synaesthetic experience, a possible explosion of research into other forms could follow. Not only does the STC probably have variable roles in perceptually and conceptually driven synaesthetic experiences, but also, investigations into its activity could lead to a resolution of the debate between cortical disinhibition and cross-activation. Future studies should attempt to extend to the role of the STC to other forms and phenotypes of synaesthesia. Additionally, sensitive fMRI and quick pulse TMS could be used to establish a temporal sequence of activation in the brains of synaesthetes. TMS can also be used to establish causation of activation between different brain areas. Future research needs to be cognizant of the vast differences in synaesthetes, as well as the fact that these differences translate to physical differences in brain function. Synaesthetes need to be analyzed on an individual basis, as cognitive variants and brain mechanisms likely fall on a continuum. The STC may be at the center of this exciting field with old roots and modern appeal.

38

References
1. Aleman, A., Rutten, G.J., Sitskoorn, M.M., Dautzenberg, G., Ramsey, N.F. (2001) Activation of striate cortex in the absence of visual stimulation: an fMRI studt of synesthesia. NeuroReport Vol. 12, No. 13 2001. 2. Asher, J.E., Aitken, M.R.F., Farooqi, N., Kurmani, S., Baron-Cohen, S. (2006) Diagnosing and phenotyping visual synaesthesia: A preliminary evaluation of the revised test of genuiness. Cortex. (2006) 42, 137-146. 3. Barnett, K.J., Newell, F.N, (2007) Synaesthesia is associated with enhanced, self-rated visual imagery. Consciousness and Cognition (2007) 4. Barnett K.J., et Al., (2007) Familial patterns and the origins of individual differences in synaesthesia. Cognition (2007) 5. Basser, P.J., and Jones, D.K. (2002) Diffusion-tensor MRI: theory, experimental design and data analysis a technical review. NMR Biomed 2002; 15: 456-467 6. Baylis, G.C., Rolls, E.T, Leonard, C.M. (1987) Functional subdivisions of the Temporal Lobe Neocortex. The Journal of Neuroscience 7(2) 330-342 1987 7. Beauchamp, M.S., Lee, K.E., Argail, B.D., Martin, A. (2004) Integration of auditory and visual information about objects in Superior Temporal Sulcus. Neuron Vol. 41, 809-823 March 2004. 8. Beeli, G., Esslen, M., Jancke, L (2005) When coloured sounds taste sweet. Nature Vol. 434 p. 38 9. Beeli, G., Esslen, M., Jancke, L. (2007) Frequency correlates in grapheme-color synaesthesia. Association for Psychological Science 2007 Vol. 18, Number 9. 10. Blakemore, S.J., Bristow, D., Bird, G., Frith, C, Ward, J. (2005) Somatosensory activations during the observation of touch and a case of vision-touch synaesthesia. Brain (2005), 128, 1571-1583 11. Bruce, C., Desimone, R., Gross, C.G. (1981) Visual properties of neurons in polysensory area in the superior temporal sulcus of the macaque. Journal of Neuropsychology Vol. 46, No. 2, August 1981. 12. Bullmore, E.T., and Suckling, J. (2001) Functional magnetic resonance imaging. International Review of Psychiatry (2001), 13, 24-33 13. Carota, A., Pietro, M.D., Ptak, R., Poglia, D., Schnider, A. (2004) Defective spatial imagery with pure Gerstmanns syndrome. European Neurology 2004; 52: 1-6. 14. Cerf-Ducastel, B., Moortele, P.F., MacLeod, P., Bihan, D.L., Faurion, A. (2001) Interaction of gustatory and lingual perceptions at the cortical level in the human: a functional magnetic resosnance imaging study. Chemical Senses 26: 371-383, 2001 15. Chao, L.L., Martin, A., Cortical regions associated with perceiving, naming and knowing about colors. Journal of Cognitive Neuroscience. 11:1, pp. 25-35

39

16. Claeys, K.G., Dupont, P., Cornette, L., Sunaert, S., Hecke, P.V., Schutter, E.D, Orban, G.A. (2004) Color Discrimination Involves Ventral and Dorsal Stream visual areas. Cerebral Cortex. Vol. 14. N. 7. 2004 17. Clark, RC., Egan, G.F., McFarlane, A.C., Morris, P., Weber, D., Sonkkilla, C., Marcina, J., Tochon-Danguy, H.J. (2000) Human Brain Mapping 9:4254 (2000) 18. Cohen, L. and Dehaene, S. (2004) Specialization within the ventral stream: the case for the visual word form area. Neuroimage 22 (2004) 466-476 19. Cytowic, R.E. (1989) Synaesthesia: A union of senses (2nd ed. New York: Springer-Verlag) 20. Dixon, M.J, Smilek, D., Merikle, P.M., (2004) Not all synaesthetes are created equal: Projector versus associator synaesthetes. Cognitive, Affective and Behavioural Neuroscience 2004 4 (3) 335-343 21. Elias, Lorin J., Saucier, Deborah M., Hardie, Coleen, Sarty, Gordon E.,(2002) Dissociating semantic and perceptual components of synaesthesia: behavioural and functional neuroanatomical investigations. Cognitive Brain Research 16 (2003) 232-237 22. Esterman, M. et al., Coming unbound: disrupting automatic intergration of synesthetic color and graphemes by transcranial magnetic stimulation of the right parietal lobe. Journal of Cognitive Neuroscience 18:9, pp. 15701576 23. Galton, F. (1880) Visualized numerals, Nature, 22, pp. 494-5. 24. Gottfried, J.A., Dolan, R.J., (2003)The nose smells what the eye sees: crossmodal visual facilitation of human olfactory perception. Neuron Vol. 39, 375-386. 25. Gray, J.A., Parslow, D.M., Brammer, M.J., Chopping, S. Vythelingum, G.N, Ffytche, D.H. (2006) Evidence against functionalism from neuroimaging of the alien color effect in synaesthesia. Cortex (2006) 42, 309-318 26. Grossenbacher, P.G., Lovelace, C.T., (2001) Mechanisms of synaesthesia: cognitive and physiological constraints. Trends in Cognitive Science Vol. 5, No. 1. Jan. 2001. 27. Hallett, M. (2007) Transcranial Magnetic Stimulation: A Primer Neuron 55 2007 28. Hikosaka, K., Iwai, E., Saito, H., Tanaka, K. (1988) Polysensory properties of neurons in the anterior bank of the caudal superior temporal sulcus of the macaque monkey. Journal of Neuropsychology Vol. 60, No. 5 Nov. 1988. 29. Howard, R.J., Brammer, M., Wright, I., Woodruff, P.W., Bullmore, E.T., Zeki, S. (1996) A direct demonstration of functional specialization within motion-related visual and auditory cortex of the human brain. Current Biology 1996, Vol. 6 No. 8: 1015-1019. 30. Howard, R.J., Ffytche, D.H., Barnes, J., McKeefry, D., Ha, Y., Woodruff, P.W., et al. (1998). The functional anatomy of imagining and perceiving colour. Neuroreport, 9, 1019-1023.

40

31. Hubbard, E.M., Ramachandran V.S.,(2003) Refining the Experimental Lever. Journal of Consciousness Studies, 10, No. 3, 2003, pp. 77-84. 32. Hubbard, Edward M., Arman Cyrus A., Ramachandran, V.S., Boynton, Geoffrey M., (2005a) Individual differences among grapheme-color synesthetes: brain-behavior correlations. Neuron, Vol. 45, 975-985, March 2005. 33. Hubbard, E.M., Ramachandran V.S., (2005) Neurocognitive Mechanisms of Synesthesia Neuron, Vol. 48, 509-520 Nov. 3 2005. 34. Hubbard, E.M., Piazza, M., Pinel, P., Dehaene S.(2005b) Interactions between number and space in parietal cortex. Nature Reviews Vol. 6, June 2005. 35. Hubbard, E.M., (2007) A real red letter day Nature Neuroscience Vol. 10, Num. 6 June 2007 36. Jansari, A.S., Spiller, M.J., Redfern, S. (2006) Number synaesthesia: when hearing four plus five looks like gold. Cortex (2006) 42, 253-258 37. Johnson, A., Jepma, M., De Jong, R., (2007) Colours sometimes count: Awareness and bidirectionality in grapheme-colour synaesthesia. The Quarterly Journal of Experimental Psychology 2007, 60(10) 1406-1422 38. Joseph, Jane E. et al., (2005) fMRI correlates of cortical specialization and generalization for letter processing. Neuroimage 32 (2006) 806-820. 39. Kadosh, R.C., Walsh, V. Cognitive Neuroscience: Rewired or Crosswired Brains. Current Biology Vol. 16 No. 22. 40. Kadosh, R.C., Henik, A., (2006) Color congruity effect: where do colors and numbers interact in synaesthesia? Cortex. (2006) 42, 259-263 41. Kadosh, R.C., Henik, A., Can synaesthesia research inform cognitive science? Trends in Cognitive Sciences. Vol. 11. No. 4. 42. Karneth, H, (2001) New insights into the functions of the superior temporal cortex. Vol. 2, 568, August 2001. 43. Kellenbach, M.L., Hovius, Marjolijn, H., Patterson, K. (2005) A PET study of visual and semantic knowledge about objects. Cortex 41, 121-132. 44. Kettenmann, B. Jousmaki, V., Portin, K., Salmelin, R., Kobal, G., Hari, R. (1996) Odorants activate the human superior temporal sulcus. Neuroscience Letters203 143-145 45. Kettenmann, B., Hummel, C., Stefan, H., Kobal, G. (1997) Chemical Senses 22: 493-502 1997. 46. Kohler, W. (1929), Gestalt Psychology. (New York: Liveright) 47. Macleod, C.M. (1991) Half a century of research on the Stroop effect: an integrative review. Psychol. Bull., 109, 163-203 (1991) 48. Mohedano-Moriano, A., Martinez-Marcos, A., Munoz, M., Arroyo-Jimenez, M., Marcos, P., Artacho-Perula, E., Blaizot, X., Insausti, R. (2005) Reciprocal connections between olfactory structures are the cortex of the rostral surperior temporal sulcus in the Macaca fascicularis monkey. European Journal of Neuroscience, Vol. 22, pp. 2503-2518, 2005. 49. Muggleton, M et. Al., (2007) Disruption of synaesthesia following TMS of the right posterior parietal cortex. Neuropsychologia 45 (2007) 1582-1585

41

50. Nikolic, D., Lichti, P., Singer, W., (2007) Color Oppoonency in Synaesthetic Experiences. Psychological Science Vol. 18, Num. 6. 51. Nunn et Al., (2002) Functional magnetic resonance imaging of synaesthesia: activation of V4/V8 by spoken words. Nature neuroscience Vol. 5 Num. 4 April 2002 52. Ochai, T., Grimault, S., Scarvada, D., Roch, G., Hori, T., Riviere, D., Mangin, J.F., Regis, J. (2004) Sulcal pattern and morphology of the superior temporal sulcus. Neuroimage 22 (2004) 706-719 53. Plameri, T.J., Blake, R., Marios, R., Flanery, M.A., Whetsell, W.. (2002) The perceptual reality of synesthetic colors. PNAS, vol. 99, no. 6. 54. Paulsen, H.G. and Laeng, B. (2006) Pupillometry of Grapheme-Color Synaesthesia. Cortex (2006) 42, 290-294 55. Paulesu, E., Harrison, J., Baron-Cohen, S., Watson, J.D., Goldstein, L., Heather, J., Frackowiak, R.S., Frtih, C.D. (1995) The physiology of colored hearing: a PET activation study of colour-word synaesthesia. Brain. 118: 661-676, 1995. 56. Pearce, J.M.S. (2007) Synaesthesia. European Neurology 2007; 57; 120124 57. Pesenti et Al., (2000) Neuroanatomical substrates of arabic number processing, numerical comparison and simple addition: A PET study. Journal of Cognitive Neuroscience 12:3, pp 461-479 58. Pribram, K., (2003) Commentary on Synaesthesia by Ramachandran and Hubbard. Journal of Consciouness Studies, 10, No. 3, 2003, pp 75-76 59. Ramachandran V.S. at Al., (1992) Perceptual Correlates of Massive Cortical Reorganization Science Vol. 258, No. 5085 pp. 1159-1160 60. Ramachandran, V.S., and Hubbard, E.M., (2000) Psychophysical investigations into the neural basis of synaesthesia. Proc. R. Soc. Lond. B (2001) 268 979-983 61. Ramachandran, V.S. and Hubbard, E.M., (2003) The Phenomenology of Synaesthesia. Journal of Consciousness Studies, 10, No. 8, 2003, pp. 4957 62. Ramachandran, V.S. and Hubbard, E.M., (2001) Synaesthesia A window into perception, thought and language. Journal of Consciousness Studies, 8, No. 12, 2001, p. 3-34 63. Rich, A. and Mattingley J., (2002) Anomalous perception in synaesthesia: A cognitive neuroscience perspective. Nature Reviews: Neuroscience Volume 3, January 2002, 43. 64. Rich, A.N., Bradshaw, J.L, Mattingley, J.B. (2005) A systematic, large scale study of synaesthesia: implications for the role of early experience in lexical-colour associations. Cognition 98 (2005) 53-84 65. Rich A.N., Williams, M.A., Puce, A, Syngeniotis, A., Howard, M.A., McGlone, F., Mattingley, J.B. (2006) Neural correlates of imagined and synaesthetic colours. 66. Rickard T.C. et Al., (2000) The calculating brain: an fMRI study. Neuropsychologica 38 (2000) 325-335

42

67. Rouw, R., Scholte, H. S., (2007) Increased structural connectivity in grapheme-color synaesthesia. Nature Neuroscience. Vol. 10. Number 6. June 2007. 68. Sagiv, N., Heer, J., Robertson, L., (2006) Does binding of synaesthetic color to the evoking grapheme require attention? Cortex, (2006) 42, 232242 69. Saleem, K.S., Suzuki, W., Tanaka, K., Hashikawa T. (2000) Connections between anterior inferotemporal cortex and superior temporal sulcus regions in the macaque monkey. The Journal of Neuroscience. July 1, 2000 20 (13) 5038-5101. 70. Schiller, P.H., Lee, K. (1991) The Role of the Primate Extrastriate Area V4 in Vision Science Vol. 251, No. 4998 pp. 1251-1253 71. Schiltz, K., Trocha, K., Wieringa, B.M., EMrich, H.M., Johannes, S., Munte, T.F. (1999) Neuropsysiological Aspects of Synesthetic Experience Journal of Neuropsychiatry Clinical Psychiatric Press 11:1, 1999. 72. Simos, P.G. (2000) Brain mechanisms for reading: the role of the superior temporal gyrus in word and pseudoword naming. Neuroreport. (2000) Vol.11., Iss.11, p. 2443. 73. Smilek, D., Callejas, A., Dixon, M.J., Merikle, P.M. (2007) Ovals of time: Time-space associations in synaesthesia. Consciousness and Cognition 16 (2007) 507-516 74. Shanon, Benny. Three stories concerning synaesthesia. Journal of Consciousness Studies, 10, No. 3, 2003, pp. 69-74 75. Simner, J., Ward, J., (2006) The taste of words on the tip of the tongue. Nature, Vol. 444, Nov. 2006. 76. Simner, J., Hubbard, E.M., (2006) Variants of synaesthesia interact in cognitive tasks: evidence for implicit associations and late connectivity in cross-talk theories. Neuroscience 143 (2006) 805-814 77. Sperling, J.M. et Al. (2006) Neuronal correlates of colour-graphemic synaesthesia a fMRI study. Cortex (2006) 42, 295-303. 78. Steven, M.S., Hansen, P.C., Blakemore, C. (2006) Activation of colorselective areas of the visual cortex in a blind synaesthete. Cortex (2006) 42, 304-308. 79. Stevenson, R.J., Tomiczek, C. (2007) Olfactory-induced synesthesia: A review and Model. Psychological Bulletin 2007, Vol. 133, No. 2, 294-309 80. Stroop, J.R. (1935) Studies of interference in serial verbal reactions. Journal of Experimental Psychology, 18. 643-662. 81. Taylor, S.F., Kornblum, S., Lauber, E.J., Minoshima, S., Koeppe, R.A. (1997( Isolation of specific interference progressing in the stroop task: PET activation studies. Neuroimage 6, 81-92 (1997) 82. Ward, J., Simner, J., Auyeung, V. (2005) A comparison of lexical-gustatory and grapheme-colour synaesthesia. Cognitive Neuropsychology 2005, 22 (1), 28-41 83. Ward, Jamie, Li, Ryan, Salih, Shireen, Sagiv, Noam. (2006) Varieties of grapheme-colour synaethesia: A new theory of phenomenological and behavioural differences. Consciousness and Cognition (2007)

43

84. Ward, J., Mattingley J.B., (2006) Synaesthesia: An overview of contemporary findings and controversies. Cortex (2006) 42, 129-136 85. Ward, J. (2007) Acquired Auditory-Tactile Synesthesia. Animals of Neuroloy Vol. 62, No. 5, 2007. 86. Weiss, P.H., Toni, I., Shah, N.J., Fink, G., Zilles, K. (2000) Color perception in synaesthesia: an fMRI study. NeuroImage 11, Number 5, 2000. 87. Zeki, S.M. (1977) Colour coding in the superior temporal sulcus of rhesus monkey visual cortex. Vol. 197, No. 1127. Pp.195-223 88. Zeki, S. (1980) The representation of colours in the cerebral cortex. Nature, 284, 412-418. 89. Zeki, S., Marini, L., (1998) Three cortical stages of colour processing in the human brain. Brain (1998), 121, 1669-1685

44