If I had to choose one neurological disorder to be afflicted by...

In 1954, RCA released the first color television set, transforming shades of gray into rich, dazzling hues at dinner tables around the country. Imagine experiencing that tantalizing technicolor transformation when you hear a piece of music, or look at everyday objects like numbers, letters, and days of the week? There is a rare condition in which people do experience the world in this extraordinary way, such as Nobel prize-winning physicist Richard Feynman:

"When I see equations, I see the letters in colors – I don't know why. As I'm talking, I see vague pictures of Bessel functions from Jahnke and Emde's book, with light-tan j's, slightly violet-bluish n's, and dark brown x's flying around. And I wonder what the hell it must look like to the students."

This condition, in which certain sensory stimuli trigger unusual additional sensory experiences, is called "synesthesia." Grapheme-color synesthetes, like Feynman (as well as Vladmir Nabokov), look at printed black letters or numbers and see them in color, each a different hue. For example, 2 might appear dark green, 5 might be red, and 7 may be tinted orange, even though the synesthete is well aware that the numbers are black. Others see or "experience" colors when they hear certain musical tones ("sound-color synesthetes," most famous are Duke Ellington and Wassily Kandinsky); in others, individual words of spoken language evoke vivid taste sensations in the mouth.

This fascinating mingling of the senses was first brought to the attention of the scientific community in 1880, when Francis Galton (cousin of Charles Darwin) described the phenomenon in Nature. He described individuals with grapheme-color and sound-color synesthesia, and proposed that the condition was inheritable (a hypothesis recently supported by work from Simon Baron-Cohen, cousin of Sacha Baron-Cohen).

Galton's work was followed by a brief period of scientific interest in synesthesia, but because the condition could not be observed by anyone but the beholder, it was soon brushed aside as a curious anomaly, presumably the product of insanity, drugs, and/or an overactive imagination. In addition to the questionable neural basis, it was doubtful whether there were any significant implications beyond the phenomenon itself, thus offering little to tempt the scientific community. In the 1990's, however, internal states like consciousness became respectable areas of investigation, and attention returned to synesthesia.


In order to demonstrate that synesthesia was a real phenomenon, researchers designed clever cognitive tests that would reveal their abilities. V.S. Ramachandran, for example, showed that synesthetes could perceptually group graphemes according to their synesthetic colors. He designed a task in which a triangle composed of 2's was embedded in a background of 5's. As you can see in the top box, the numbers are similar enough (they are mirror images of vertical and horizontal lines) that they blend together. In order to discern the shape, one must actively search for the 2's in the sea of 5's. But imagine that the 2's are green and the 5's are red (as in the bottom box). It is now effortless (for most of us) to segregate the two numbers by color, and normal humans instantly perceive the shape. Similarly, a grapheme-color synesthete who perceives 2's and 5's as distinct colors can look at the top array of black digits and effortlessly discern the triangle of 2's.

Another intriguing clinical test for synesthesia, also designed by Ramachandran, takes advantage of the visual phenomenon known as the "crowding effect." If a person is staring straight ahead, and a number (e.g. 5) is presented off to one side, it is easy to discern. However, if the 5 is flanked by other numbers ("distractors," e.g. 3), the average person finds it difficult to recognize the middle number (an effect thought to result from limits in visual attention). Likewise, a synesthete will be unable to discern the middle number, but will still be able to identify it "because it looks red [or whichever color he or she associates with 5]"! Thus, even though the individual is not consciously aware of the number, it still evokes its respective color.

These studies, along with earlier research by Baron-Cohen, have established that syensthesia is clearly a very real sensory/perceptual phenomenon. Understanding the neural basis for this curious interweaving of the senses thus has enticing potential for linking the organization of the brain to perception and sensory experience.

So what is it that differs the brain of a synesthete from my brain, which perceives black numbers and letters as their dreary black selves? What happens to the visual information in the synesthetic brain such that it is transformed in an extraordinary way? In order to begin developing theories of how grapheme-color synesthesia might work, it's important to have an understanding of how the brain processes visual information. (There are, as I mentioned, many types of synesthesia: sound-color, sound-taste, grapheme-taste, texture-taste etc. Grapheme-color synesthetes, however, are the most common subset (representing 68% of all synesthetes), and are the easiest to study, hence this discussion, and most research, is limited to latter condition).

After light reflected from an object hits the cones in the back of the retina, the neural signal travels along several layers of neurons to the retinal ganglion cells. These cells send their axons out the back of the eye, through the optic nerve, to a small part of the thalamus called the lateral geniculate nucleus (LGN), which relays the stimulus directly to the primary visual cortex ("V1", aka "area 17" aka "striate cortex") in the back of the brain. If you locate that bump on the back of your head, V1 is right on the other side of the skull. (There is another major visual pathway--the retinotectal pathway--which bypasses the LGN and V1, but this pathway does not transmit information about color so I'll ignore it in this post). In V1, the visual information is partitioned into visual attributes such as color, form, and motion. Information from these categories is then communicated to the respective processing regions; for color, this is region V4, which is located in the fusiform gyrus of the inferior temporal cortex. After V4, the information is relayed to cognitively "higher" processing centers, including a region of the temporoparietal-occipital (TPO) junction, a structure on which multiple sensory pathways converge.

What about numbers and visual graphemes? Lo! Studies in humans and monkeys have shown that the shapes of numbers and letters are also processed in the fusiform gyrus, in a region adjacent to V4. Moreover, numerical concepts, such as sequence and quantity, are processed in the TPO.

The similarity and proximity of the color and grapheme processing routes has led to the hypothesis that there is some abnormal form of communication occurring between the two in the synesthetic brain. As a result, any time there is an activation of neurons representing numbers, there may be a corresponding activation of color neurons.

This insight has given rise to two neural models for synesthesia. According to one idea, synesthesia results from abnormal connections between the relevant brain areas. During development, the human fetus has dense interconnections between V4 and other inferior temporal regions (, most of which are removed through a process of pruning later in development. Synesthesia may result from a partial failure of this normal pruning process, resulting in excess connections between normally isolated sensory areas. Perceptually, this would lead to a blurring of the boundaries that normally exist between the senses.

The other neural model is called the "disinhibited feedback" theory, which posits that the connections in the brain of a synesthete are no different from those in the normal human adult. Remember that the TPO is a multisensory integration center, receiving information from multiple sensory pathways. This nexus also sends reciprocal feedback connections back to the contributing sensory areas (e.g. the TPO responds to input from V4 by sending output back to V4). This feedback is inhibited when its respective area is not activated (TPO will not send feedback to V4 if V4 has not provided it with input). In synesthetes, this theory proposes, one type of sensory information (e.g. a grapheme) may induce abnormal disinhibition of the feedback pathway of a different sensory pathway (e.g. color), thus propagating its information down the "wrong" pathway to a functionally distinct area. Thus, viewing a particular number may disinhibit the pathway that activates neurons representing a particular color in V4. This hypothesis is supported by accounts of synesthesia being induced by hallucinogenic drugs, implying that the experiences rely on normally existing circuitry, as opposed to the formation of new connections.

Although the cross-activation theory seems to have a bit more support in the scientific community, there was, until now, little evidence demonstrating that one theory was more accurate than the other. This week, however, Romke Rouw and H Steven Scholte of the Univeristy of Amsterdam made an important contribution to the field by examining the structural connectivity of the synesthetic brain. Their results, published online in Nature Neuroscience, demonstrated that the degree of structural connectivity was correlated with the existence and nature of the synesthetic experience.

One of the important methodological issues with this study is the acknowledgment of the heterogeneity of synesthetes (although the study was confined to grapheme-color synesthetes). Synesthetes with the most dramatic experiences of synesthesia actually see colors projected onto letters or numbers, and are referred to as "projectors." The majority of synesthetes, however, do not experience their colors in external space; instead, they use phrases like "in my mind's eye" or "in my head." The colors are just as specific and repeatable as those perceived by projectors, but are sensed internally. Such synesthetes are called "associators."

In line with the "cross-activation" theory explained above, the researchers explored whether there were, in fact, more connections in synesthetes than non-synesthetes, focusing their analysis on the fusiform gyrus. To examine the neural connectivity, the researchers used a technique called diffusion tensor imaging (DTI), which measures the direction of movement of water molecules. In most brain tissue, water molecules diffuse chaotically, at random. Along the myelin sheaths of axons, however, water movement is restricted, thus following the path of the axon. This technique allows the visualization of bundles of axons; more (or more densely bundled) connections will yield a higher signal. Thus, the strength of the DTI signal is related to the strength of the connection.

Their results confirmed that the brains of synesthetes have increased connectivity in the inferior parietal cortex (near the fusiform gyrus), as well as the frontal and parietal cortices (involved in controlling spatial attention) than in normal individuals. Morevover, subjects with the strongest connectivity at the fusiform gyrus were projectors, while associators had connections stronger than controls but weaker than the former. This hyperconnectivity is thus tightly correlated with the synesthetic experience, offering a neural basis for this sensory fusion.

The study also found significantly higher levels of connectivity in the frontal and parietal cortices of synesthetes, with no difference between associators and projectors. These areas had not been previously linked to synesthesia, but the authors mention that they may be involved in perceptual transitions, such as the fluctuations that occur when viewing bistable figures like Rubin's face-vase figure (on the right) or during binocular rivalry. This may be related to the synesthetic experience; many synesthetes see the color only transiently or as a flickering perception.

This study is the first to demonstrate that increased connectivity in specific areas of the brain is related to synesthesia. It is certainly possible that this structural phenomenon is supplemented by abnormal disinhibited feedback, or that it accounts for only a subset of synesthetic cases, and more studies are needed to support these theories. Moreover, it will be interesting to see whether similar structural abnormalities are present in cross-modal synesthesia, such as sound-color or sound-taste, which sensory centers are more isolated than the adjacent color and grapheme perceptual centers.

References:
Feynman, Richard (1988). What Do You Care What Other People Think? New York: Norton. P. 59.Rouw R and Scholte HS. Increased structural connectivity in grapheme-color synesthesia. Nature Neuroscience [Published online May 21, 2007]