Aguirre, Geoffrey K
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PublicationFunctional Neuroimaging: Technical, Logical, and Social Perspectives(2014-03-14) Aguirre, Geoffrey K; Aguirre, Geoffrey KNeuroscientists have long sought to study the dynamic activity of the human brain—what's happening in the brain, that is, while people are thinking, feeling, and acting. Ideally, an inside look at brain function would simultaneously and continuously measure the biochemical state of every cell in the central nervous system. While such a miraculous method is science fiction, a century of progress in neuroimaging technologies has made such simultaneous and continuous measurement a plausible fiction. Despite this progress, practitioners of modern neuroimaging struggle with two kinds of limitations: those that attend the particular neuroimaging methods we have today and those that would limit any method of imaging neural activity, no matter how powerful. In this essay, I consider the liabilities and potential of techniques that measure human brain activity. I am concerned here only with methods that measure relevant physiologic states of the central nervous system and relate those measures to particular mental states. I will consider in particular the preeminent method of functional neuroimaging: BOLD fMRI. While there are several practical limits on the biological information that current technologies can measure, these limits—as important as they are—are minor in comparison to the fundamental logical restraints on the conclusions that can be drawn from brain imaging studies. PublicationCanine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation(2007-06-26) Aguirre, Geoffrey K; Komáromy, András M; Cideciyan, Artur V; Brainard, David H; Aleman, Tomas S; Avants, Brian B; Gee, James C; Aguirre, Geoffrey K; Komáromy, András M; Aguirre, Gustavo D; Cideciyan, Artur V; Jacobson, Samuel G; Brainard, David H; Aleman, Tomas S; Roman, Alejandro J; Avants, Brian B; Gee, James C; Korczykowski, Marc; Hauswirth, William W; Acland, Gregory M; Jacobson, Samuel GBackground RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA). Methods and Findings RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation. Conclusions Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease. PublicationA Digital Atlas of the Dog Brain(2012-12-20) Datta, Ritobrato; Lee, Jongho; Avants, Brian B; Vite, Charles H; Datta, Ritobrato; Gee, Jim C; Lee, Jongho; Aguirre, Geoffrey K; Aguirre, Gustavo D; Duda, Jeffrey; Avants, Brian B; Vite, Charles H; Tseng, Ben; Gee, Jim C; Aguirre, Geoffrey KThere is a long history and a growing interest in the canine as a subject of study in neuroscience research and in translational neurology. In the last few years, anatomical and functional magnetic resonance imaging (MRI) studies of awake and anesthetized dogs have been reported. Such efforts can be enhanced by a population atlas of canine brain anatomy to implement group analyses. Here we present a canine brain atlas derived as the diffeomorphic average of a population of fifteen mesaticephalic dogs. The atlas includes: 1) A brain template derived from in-vivo, T1-weighted imaging at 1 mm isotropic resolution at 3 Tesla (with and without the soft tissues of the head); 2) A co-registered, high-resolution (0.33 mm isotropic) template created from imaging of ex-vivo brains at 7 Tesla; 3) A surface representation of the gray matter/white matter boundary of the high-resolution atlas (including labeling of gyral and sulcal features). The properties of the atlas are considered in relation to historical nomenclature and the evolutionary taxonomy of the Canini tribe. The atlas is available for download (https://cfn.upenn.edu/aguirre/wiki/public:data_plosone_2012_datta). PublicationThe Representation of Parts and Wholes in Face-selective Cortex(2008-05-01) Harris, Alison; Aguirre, Geoffrey Karl; Aguirre, Geoffrey KarlAlthough face perception is often characterized as depending on holistic, rather than part-based, processing, there is behavioral evidence for independent representations of face parts. Recent work has linked ‘‘face-selective’’ regions defined with functional magnetic resonance imaging (fMRI) to holistic processing, but the response of these areas to face parts remains unclear. Here we examine part-based versus holistic processing in ‘‘face-selective’’ visual areas using face stimuli manipulated in binocular disparity to appear either behind or in front of a set of stripes [Nakayama, K., Shimojo, S., & Silverman, G. H. Stereoscopic depth: Its relation to image segmentation, grouping, and the recognition of occluded objects. Perception, 18, 55–68, 1989]. While the first case will be ‘‘filled in’’ by the visual system and perceived holistically, we demonstrate behaviorally that the latter cannot be completed amodally, and thus is perceived as parts. Using these stimuli in fMRI, we found significant responses to both depth manipulations in inferior occipital gyrus and middle fusiform gyrus (MFG) ‘‘faceselective’’ regions, suggesting that neural populations in these areas encode both parts and wholes. In comparison, applying these depth manipulations to control stimuli (alphanumeric characters) elicited much smaller signal changes within faceselective regions, indicating that the part-based representation for faces is separate from that for objects. The combined adaptation data also showed an interaction of depth and familiarity within the right MFG, with greater adaptation in the back (holistic) condition relative to parts for familiar but not unfamiliar faces. Together, these data indicate that face-selective regions of occipito-temporal cortex engage in both part-based and holistic processing. The relative recruitment of such representations may be additionally influenced by external factors such as familiarity.