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Fitzpatrick, A.

Publications and source records attributed to Fitzpatrick, A..

2 recordsLinked to original sources

The neural basis of hand choice: An fMRI investigation of the Posterior Parietal Interhemispheric Competition model.

The current study investigates a new neurobiological model of human hand choice: The Posterior Parietal Interhemispheric Competition (PPIC) model. The model specifies that neural populations in bilateral posterior intraparietal and superior parietal cortex (pIP-SPC) encode actions in hand-specific terms, and compete for selection across and within hemispheres. Actions with both hands are encoded bilaterally, but the contralateral hand is overrepresented. We use a novel fMRI paradigm to test the PPIC model. Participants reach to visible targets while in the scanner, and conditions involving free choice of which hand to use (Choice) are compared with when hand-use is instructed. Consistent with the PPIC model, bilateral pIP-SPC is preferentially responsive for the Choice condition, and for actions made with the contralateral hand. In the right pIP-SPC, these effects include anterior intraparietal and superior parieto-occipital cortex. Left dorsal premotor cortex, and an area in the right lateral occipitotemporal cortex show the same response pattern, while the left inferior parietal lobule is preferentially responsive for the Choice condition and when using the ipsilateral hand. Behaviourally, hand choice is biased by target location - for targets near the left/right edges of the display, the hand in ipsilateral hemispace is favoured. Moreover, consistent with a competitive process, response times are prolonged for choices to more ambiguous targets, where hand choice is relatively unbiased, and fMRI responses in bilateral pIP-SPC parallel this pattern. Our data provide support for the PPIC model, and reveal a selective network of brain areas involved in free hand choice, including bilateral posterior parietal cortex, left-lateralized inferior parietal and dorsal premotor cortices, and the right lateral occipitotemporal cortex.

neuroscience

A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease

In this study we used age at onset of Alzheimers disease (AD), cerebrospinal fluid (CSF) biomarkers, and cis-expression quantitative trait loci (cis-eQTL) datasets to identify candidate causal genes and mechanisms underlying AD GWAS loci. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (P < 5x10-8) or suggestively (P < 1x10-5) associated with age at onset-defined survival (AAOS) and a further fourteen novel loci reached suggestive significance. Using stratified LD score regression we demonstrated a significant enrichment of AD heritability in hematopoietic cells of the myeloid and B-lymphoid lineage. We then investigated the impact of these 22 AAOS-associated variants on CSF biomarkers and gene expression in cells of the myeloid lineage. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (P=8.40x10-6), higher CSF levels of A{beta}42 (P=1.2x10-4), and lower expression of SPI1 in monocytes (P=1.50x10-105) and macrophages (P=6.41x10-87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD-associated genes, APOE, CLU/APOJ, CD33, MS4A4A/MS4A6A, and TYROBP. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.

neuroscience