Genetic Tests that Can Be Used for Synesthesia Patients

Background and Significance: Overview: Synesthesia is an intriguing neurological condition that is relatively rare and not well-researched. It comes in many different forms, but the common denominator in all the variations is “the automatic activation of unusual concurrent experiences in response to ordinary inducing stimuli.” In other words, the stimulation of one sensory system causes a response in a different, unrelated sensory system. Investigation into this phenomenon can allow for a deeper insight into the various sensory systems and their integration. Understanding synesthesia is important for learning more about the underlying brain structures and the development of our senses. Grapheme-color synesthesia is the most common form of synesthesia in which people visualize consistent colors associated with letters and numbers. As with all forms of synesthesia, the cause is unknown. A study by Simner et. al suggests that synesthetes (individuals with synesthesia) develop these associations during childhood as they learn alphabet and number sequences. Additionally, a study by Jäncke et. al suggests that synesthesia may be caused by increased structural connectivity and more cortical matter in the fusiform gyrus and areas by the V4 complex. A study from Rouw et. al also found a larger presence of white matter in the inferior temporal cortex for synesthetes, and more hyperconnectivity for those who could project color into the outside world versus those who could only visualize the colors in their mind. This distinction infers that synesthesia is likely caused by abnormalities in brain development, and the research done by Simner et. al suggests that a basic level of cognition is required before these associations can be formed. It is largely unknown whether this difference in brain matter is caused genetically or in some other manner.

Main Hypothesis: I hypothesize that grapheme-color synesthesia is a result of a genetic abnormal buildup of neural connections in the inferior temporal cortex and areas near the V4 complex. I will test this by monitoring brain activity during stimulation using MRI and EEG in the regions associated with visual cues, color processing, and perception (V4 complex, fusiform gyrus, inf. temp. cortex), and attempt to perform fractional anisotropy measurements in these regions to determine the neural connection volume and makeup. To determine whether grapheme-color synesthesia has a genetic basis, these tests will be done with the blood relatives of the affected who give consent as well.

Rationale: These experiments will be done under the assumption that the areas responsible for letter/number perception and color processing interact in individuals with grapheme-color synesthesia. The use of MRI procedures can determine whether there is heightened brain activity via blood flow changes when a synesthete perceives letters/numbers versus when an unaffected individual does the same. This will narrow down the affected areas in the brain, and possibly even pinpoint new ones. Invasive EEG monitoring will also be used for the same purpose by measuring currents indicating neuron activity in these regions when stimulated. Additionally, a statistically significant increase in cortical matter should affect the EEG readout if hyperconnectivity is indeed responsible for synesthesia. The MRI/EEG test will also be done by directly shocking the V4 complex and seeing whether that signal causes an excitatory reaction in an unrelated brain center associated with color processing. If this happens, that can suggest interconnectivity. Fractional anisotropy can be used to determine the density/makeup of matter in the regions targeted by the MRI and EEG tests. Performing these tests on relatives should indicate whether they have similar network buildups in the specified regions.

Methods: First, I would need to select a group of synesthetes with confirmed non drug-induced grapheme-color synesthesia along with a control group and blood relatives. A preliminary test would be done to ensure that the synesthetes all had color associations with the letters/numbers to be used. All participants will be flashed stimuli in a random order during the MRI procedure to determine activity localization. They will be shown the exact same letters/numbers while using invasive EEG, and the readings from both the MRI/EEG test will be combined to determine localized activity in synesthetes versus unaffected individuals. The MRI/EEG tests will be conducted again, but by directly exciting the V4 complex with electricity. Two separate fractional anisotropy experiments should be conducted on all participants. One will target diffusion in the regions specified in my hypothesis, and the second will target any outstanding high-activity regions determined by the previous MRI and EEG experiments.

Anticipated Results: If my hypothesis is on the right track, the combined MRI and EEG results should indicate heightened brain activity that exceeds normal readings in the areas near the V4 complex, fusiform gyrus, and inf. temp. cortex within the same period in synesthetes. If the centers are interconnected, exciting one center should cause activity in another. If the defined structures were unrelated, but hyperconnectivity still plays a role then there should be heightened activity between other regions. The anisotropic diffusion should be greater in the affected area for synesthetes over the control group in both experiments, suggesting a higher concentration of neurons or more cortical thickness. If synesthesia is genetically rooted, some of the relatives should exhibit higher activity and greater diffusion values provided they are not synesthetes and the offending gene is dominant. If a relative is a synesthete as well and has the same neural abnormalities in similar locations, the results can lend strength to a genetic basis for this phenomenon.

Problems and Pitfalls: A looming issue is that even if hyperconnectivity is consistent, it may not confirm that it is the cause of synesthesia as it is possible that it is a result. In order to narrow this down, a long-term study can be done on infants prone to synesthesia (if it is genetic) over 10 or so years to see if there is already an abnormal number of neurons in the affected areas. If it is a consequence, then the buildup should be gradual over time as associations are formed between characters and colors like Simner et al. suggest. Another obstacle is the accuracy of the MRI/EEG tests as the tested areas are relatively large, and the responsible hyperconnection could be anywhere in said areas. Unfortunately, there is no existing way to tag and follow an electrical signal down nerve cells. The intensity of associations in synesthetes also varies, and this can be problematic if certain stimuli do not have a large effect, causing holes in the activity tests. It is also unlikely but possible that different individuals with unique associations will have neural connectivity in different locations in the examined regions. Finally, it is possible that hyperconnectivity is caused by rogue proteins as opposed to a gene that directs or prunes neuron growth as suggested by previous studies.