Functional magnetic resonance imaging (fMRI) is a noninvasive technique for observing brain activity. It is difficult to overestimate the role fMRI plays in the modern study of neuroscience. While fMRI is an indispensible tool for studying the neural system, the specific relationship between neural activity and the most commonly used fMRI signal, called the blood oxygenation level dependent (BOLD) signal, is not well understood. With funding from the National Science Foundation, Bosco Tjan, Ph.D., of the University of Southern California, is determining the precise linkage between neural activity and the BOLD signal by studying the visually-evoked BOLD signal in the brain of an achiasmatic person. Achiasma is a rare congenital condition; a person with achiasma is born without an optic chiasm, which is the part of the brain where half of the nerve fibers from each eye cross over to reach the opposite side of the brain. Achiasma's unusual development of the visual system has striking effects upon the mapping of the visual world onto the visual cortex. Normally, there is a one-to-one topological relationship between a point in the visual world and a location on an early visual cortical area. For example, when looking at the center of a clock face, each of the numbers on the clock face is projected to one distinct location on the primary visual cortex. In contrast, when an achiasmatic person looks at the same clock face, the symmetric locations about the vertical midline are projected to the same cortical locations in the early visual areas. For example, the numbers 4 and 8 on the clock face are both projected to the same location in the primary visual cortex, while the numbers 5 and 7 are both projected to a nearby location. Fortunately, an achiasmatic person does not confuse the left from the right half of a clock face, or the visual world for that matter. As it turns out, there are two comparable groups of neurons packed in the same cortical location in the visual cortex of an achiasmatic person, with one responsible for a left location of the visual world, and the other for the symmetric right location. These two groups of neurons appear to function independently of each other, but nevertheless share part of the same blood supply. By presenting identical stimuli to one or both sides of a pair of symmetric locations about the vertical midline, the investigator can effectively half or double the underlying neural activity that drives the blood supply at that location, without knowing the exact relationship between the stimulus and the absolute amount of the evoked neural activity. He can then measure the resulting fMRI BOLD signal, which is a signal related to the local blood flow, blood volume and blood oxygen concentration, and thereby characterize the mathematical relationship between neural activity and the BOLD signal.
Knowing the quantitative relationship between the BOLD signal and the underlying neural activity is of the utmost importance. It will allow researchers to use noninvasive fMRI measurement to quantify the underlying neural activity everywhere in the brain. In cognitive neuroscience, we may one day be able to use fMRI to quantitatively measure certain psychological constructs and provide deeper insight into the mechanics of the brain. For example, if the level of neural activity in a brain area is believed to be proportional to the subjective value of a reward a study participant has received, then observing noninvasively an x% change in the fMRI BOLD signal will allow a researcher to infer that the subjective value of the reward has changed by y%. The current investigation, although focused on the arguably aberrant visual system of an achiasmatic subject, can have a broad and sweeping impact on many subfields of cognitive neuroscience by providing a unique and decisive data set relating neural activity to the fMRI BOLD signal.
Intellectual Merit: 1) Quantifying the relationship between neural response and the fMRI BOLD signal had been difficult because neural response is multidimensional, and precisely measuring neural signals requires invasive techniques. Attempts to infer this relationship noninvasively from stimulus-evoked BOLD responses were frustrated by the complex nonlinearity between stimulus and neural response. In the low-level visual cortex of an individual who was born without optic chiasm, we found evidence for the intermixing of two nearly identical but independent populations of neurons with non-overlapping receptive fields. With this unique in-vivo system, it was possible to double the local neural response by stimulating both of the associated receptive fields relative to stimulating just one. Our results from a series of such "doubling" experiments show that BOLD response amplitude is proportional to the square root of the underlying neural response. Reanalyzing published data from a dozen studies shows that this inferred relationship is general. 2) In the absence of an optic chiasm, visual input to the right eye is represented in primary visual cortex (V1) in the right hemisphere, while visual input to the left eye activates only the left hemisphere. Retinotopic mapping reveals that left and right visual hemifield representations are overlaid in V1 in each hemisphere. To explain how overlapping hemifield representations in V1 do not impair vision, we tested the hypothesis that visual projections from nasal and temporal retina create interdigitated left and right visual hemifield representations in V1, similar to the ocular dominance columns observed in control subjects. We used high-resolution fMRI at 7T to measure the spatial distribution of responses to left- and right-hemifield stimulation in one achiasmic subject. T2-weighted 2D Spin Echo images were acquired at 0.8 mm isotropicresolution, covering parafoveal regions of V1 (24 slices per 2 sec TR). The left eye was occluded while flickering checkerboards were presented to the right eye. Twelve sec presentations alternated between the left and right visual hemifield, separated by 12 sec mean field presentations. The subject performed a demanding orientation-discrimination task at fixation. A general linear model was used to estimate the responses of voxels in V1 to left- versus right-hemifield stimulation. The spatial distribution of voxels with preference for one hemifield or the other showed interdigitated clusters which densely packed V1 in the right hemisphere. The spatial distribution of hemifield-preference voxels in the achiasmic subject was comparable to the distribution of ocular-dominance voxels in a control subject, measured using standard techniques. These results are consistent with the hypothesis that visual hemifield representations interdigitate in achiasmic V1 following a similar developmental course to that of ocular dominance columns in controls. Broader Impacts: It is difficult to overstate the role Functional magnetic resonance imaging (fMRI) plays in the modern study of neuroscience. fMRI is one of the most widespread neuroimaging techniques in the field, with thousands of studies published every month using BOLD response to measure neural activity. We feel that our finding, which provides evidence for a direct power-law fit relating changes in neural activity to changes in the BOLD response, offers unprecedented insight into fMRI, allows for more veridical assessment of neural activity from BOLD signal, and potentially strengthens and perhaps alters the conclusions of fMRI studies, past, present and future. Our finding of the interdigitated cortical representation of the left- and right-visual fields in achiasma further opens up the use of achiasma as a unique and powerful in vivo model for non-invasive investigations of the relationship between neural and fMRI responses in human. We have broadly disseminated our current results at scientific conferences, including presentations given by the lead graduate student (who has since completed his PhD training and took up a position of postdoctoral researcher at Cal Tech) and an undergraduate student (currently a graduate student at UC Berkeley). One manuscript has been submitted and one is in preparation.
