"The World of Synesthesia" by Lindsey Jay
Imagine driving a car and tasting raspberries, seeing the number two only as blue with white polka dots, or feeling itchy every time you hear a doorbell ring. These experiences are examples of synesthesia, a hereditary condition in which stimulation of one sensory modality creates a simultaneous stimulation of another sensory modality, providing a unified perception of a multisensory experience [1,2]. Its estimated prevalence ranges from one in 200 to one in 20,000 people, and the most common form is grapheme-color synesthesia, in which subjects report seeing letters, digits, and words in unique colors . Scientists suspect that it is a neurological phenomenon, and they have been investigating where and how it arises in the brain.
Fig. 1. Hearing Color: Stepping into a Synesthete’s World. Due to cross-modalities in the brain, a synesthete may be able to hear a B sharp as “purple” or C flat as “green.” (Image Credit: http://www.sciencemag.org/news/2018/03/synesthesia-s-mysterious-mingling-senses-may-result-hyperconnected-neurons)
Locations in the Brain
Some studies have implicated the parietal lobe in grapheme-color synesthesia. Rouw and Scholte compared the gray matter structure (containing mainly neuronal cell bodies) and functioning in grapheme-color synesthetes and non-synesthetes, looking at potential mechanisms underlying associator synesthesia (synesthetic color experienced “in the mind”) versus projector synesthesia (synesthetic color experienced “in the outside world”). For example, associator synesthetes may view a black “A” but may feel that the “A” should be colored pink with brown stripes, though they can still see the “A” as black. Projector synesthetes will view every “A” as pink with brown stripes as if that letter is presented that way in the outside world, no matter what color the “A” is in reality.
Subjects’ gray matter structure was determined using voxel-based morphometry, in which the brain images of different participants are registered to a template to eliminate individual differences in brain anatomy and each voxel (pixel number in a grid) represents an average of itself and its neighbors. Gray matter functioning was determined using blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) during a grapheme perception task. Each subject was tested with tailored stimuli sets of eight graphemes (digits, letters, or symbols) that elicited a strong synesthetic color, eight graphemes that elicited a weak color, and eight graphemes that elicited no color. Subjects viewed each stimulus for 500 milliseconds (ms), followed by a 2500-9000 ms break of a gray isoluminant screen.
Both associator and projector synesthetes were found to have increased gray matter and increased activity in left superior parietal cortex (the part of the brain involved in processing sensory information) compared to controls, suggesting a role in grapheme-color synesthesia regardless of subtype . They proposed that this brain area may integrate multiple sensory processes with concurrent sensations, and its increased activity could contribute to the phenomenon of synesthesia. However, other overlapping brain regions of gray matter differed. Projector synesthetes had increased gray matter in the visual cortex, the auditory cortex, the somatosensory cortex, and the prefrontal cortex, suggesting that prefrontal and modality-specific areas may interact to create synesthetic experiences that mimic experiencing stimuli in the outside world. On the other hand, associator synesthetes had increased gray matter in the hippocampal area, which is implicated in memory, as well as the angular gyrus, which is involved in creating associations between different types of information and the use of metaphors. They also had increased activity in the parahippocampal gyrus, which is involved in memory encoding and retrieval. The associator synesthesia condition, therefore, may arise due to retrieving an “internal” experience mediated by hippocampus and supporting structures. Thus, the general phenomenon of grapheme synesthesia may involve the parietal lobe, but more specific forms may involve additional brain activity in other areas of the brain.
Fig. 2. Example Perception of a Sentence from a Synesthete’s Perspective. When we read black text (above), we usually perceive it as black. However, associator synesthetes may feel that the color is “off” and prefer the sentence to be written in the “correct” colors (below). Projector synesthetes would quite literally perceive the black text in specific colors only.
While the previous study had correlational data regarding synesthesia, Esterman et al. tested causality more directly by repetitive transcranial magnetic stimulation (rTMS) of the right parietal lobe. Two projector synesthetes participated in a color-naming task, in which a series of colored single letters were presented for 1000 ms in a color either congruent or incongruent with the synesthetic photism (perceptual color experience unique to one’s synesthesia), or presented a symbol that did not evoke synesthetic photism. Subjects pressed a button indicating the true color as fast as possible while trying to ignore the synesthetic photism, and their reaction time was recorded. Trials randomly switched between subjects receiving either sham or real stimulation to their right parietal lobe. During the sham rTMS trials, both participants experienced synesthetic interference for congruent, incongruent, and no synthetic photism trials . However, during real rTMS of the right parietal lobe, participants experienced significantly less interference, resulting in a disproportionate decrease in reaction times in incongruent trials during the first block of trials, when the effects of rTMS were strongest. This finding is in line with the evidence that the right parietal lobe is critical in normal color-form binding. It also suggests that rTMS of the right parietal lobe reduced the conflict experienced when viewing a letter incongruent with the subjects’ synesthetic photism. While the data strongly support a causal role, their results should also be taken with caution since the sample size of the study was so small. Further experimentation with additional subjects would strengthen their findings, and rTMS studies focusing on the brain areas implicated in associator versus projector synesthetes in Rouw and Scholte can further confirm their causal roles.
Neural Circuitry Theories
An additional aspect to consider in how synesthesia arises is the neural circuitry. Theories on the neurophysiological as well as the architectural levels have been proposed. On the neurophysiological level, synesthesia may develop as a result of a failure of neural form of pruning or disinhibition of neural feedback . The three architectural models, “local crossactivation,” “long-range disinhibited feedback,” and “re-entrant processing,” look more broadly at the cortical level of connectivity, incorporating neurophysiological aspects in their explanations.
Local crossactivation is the idea that adjacent brain areas may be active at the same time . For example, the visual word form area (VWFA) is adjacent to the color processing region hV4; therefore, grapheme synesthesia may occur due to this crossactivation left over from the failure of neural pruning during development. Evidence of cortical connections between these areas prenatally have been observed and support this hypothesis .
Long-range disinhibited feedback suggests that the lack of inhibitory feedback from a multi-sensory center in the brain, such as the temporo-parietal-occipital junction, could also lead to synesthesia . However, evidence supporting this theory has been shown in people who take psychedelic drugs, which have disinhibitory effects on the brain, and report complex synesthetic experiences, but it is suspected that congenital synesthesia may arise from a different mechanism.
Finally, re-entrant processing, a hybrid of the two previous theories, proposes that there is aberrant re-entry, which is ongoing bidirectional exchange of signals along axonal fibers between multiple brain areas . These theories are not necessarily exclusive, and it is possible that multiple mechanisms work together or that different mechanisms give rise to synesthesia in different people. Ongoing research is working to elucidate and expand upon these theories.
Future Directions and Conclusions
Future studies could look further into the neural circuitry in areas of the brain crucially associated with grapheme-color synesthesia, such as the parietal lobe. Other studies have also identified genes possibly linked to synesthesia . and studying the exact neural circuitry by inducing these mutations in primates may provide even further evidence of the cortical connectivity surrounding synesthesia.
When thinking about how synesthesia could affect everyday life, it does not have to be regarded as a “bad” thing to have. Famous artists, including Vincent Van Gogh and Pharrell Williams, have synesthesia, and some believe that having this experience improves their creativity . Many people with synesthesia do not treat it as an annoyance, but rather as a more colorful way of viewing the world. Rather than approaching synesthesia as something that needs to be “cured,” we can view it as a unique phenomenon showcasing the complex circuitry that underlies how the brain processes our senses.
 Carmichael, Duncan A, and Julia Simner. “The immune hypothesis of synesthesia.” Frontiers, Frontiers, 23 Aug. 2013, www.frontiersin.org/articles/10.3389/fnhum.2013.00563/full.
 Asher, J.E., et al. “A Whole-Genome Scan and Fine-Mapping Linkage Study of Auditory-Visual Synesthesia Reveals Evidence of Linkage to Chromosomes 2q24, 5q33, 6p12, and 12p12.” The American Journal of Human Genetics, Cell Press, 5 Feb. 2009, www.sciencedirect.com/science/article/pii/S0002929709000196.
 Palmeri, T.J., et al. “What is synesthesia?” Scientific American, Scientific American, www.scientificamerican.com/article/what-is-synesthesia/.
 Rouw, Romke, and H. Steven Scholte. “Neural Basis of Individual Differences in Synesthetic Experiences.” Journal of Neuroscience, Society for Neuroscience, 5 May 2010, www.jneurosci.org/content/30/18/6205.
 Esterman, M.E., et al. “Coming Unbound: Disrupting Automatic Integration of Synesthetic Color and Graphemes by Transcranial Magnetic Stimulation of the Right Parietal Lobe.” Journal of Cognitive Neuroscience, vol. 18, no. 9, Sept. 2006, pp. 1570–1576.
 Hubbard, E.M., and V.S. Ramachandran. “Neurocognitive Mechanisms of Synesthesia.” Neuron, Cell Press, 2 Nov. 2005, www.sciencedirect.com/science/article/pii/S0896627305008354.
 Elise, Kathleen. “12 Famous Artists With Synesthesia.” Mental Floss, 10 Nov. 2016, mentalfloss.com/article/88417/12-famous-artists-synesthesia.