Figure 2.
Mediodorsal lateral nucleus shows significant atrophy in C9orf72 HRE carriers, independent of global thalamic atrophy. Five thalamic nuclei were significantly different in C9orf72 HRE carriers versus controls at pFDR < 0.05. Covariates in the multiple regression included total thalamic volume, age, sex, education, and MRI scanner type. The most significant association was observed in the R MDl nucleus (p = 1.48 × 10−5). To illustrate the extent of volumetric differences observed in HRE carriers compared with controls, representative coronal and axial images (radiologic orientation) from a normal healthy control (Control) and an FTD case (C9orf72 FTD). The R MDl nucleus is shown in turquoise and indicated by white arrows (insets). Of note, several nuclei that were significantly different in carriers versus controls, including the R MDl and left paratenial nuclei, are notable for connectivity to cortical regions frequently implicated in FTD (Vertes and Hoover, 2008; Mitchell and Chakraborty, 2013; Vertes et al., 2015; Ouhaz et al., 2018). Further, these nuclei are implicated in behavioral changes prominently affected in C9-FTD, including executive function and affect (Mitchell and Chakraborty, 2013; Vertes et al., 2015; Ouhaz et al., 2018). Additional nuclei significantly associated with HRE carrier status include the left ventral posterolateral nucleus, which projects to the spinothalamic tract and sensory cortex and is involved in nociception (Al-Chaer et al., 1996; Darian-Smith et al., 1999; Krause et al., 2012); the left centromedian nucleus, which projects to motor cortex and is involved in motor regulation, pain perception, and arousal (Mai and Forutan, 2012; Ilyas et al., 2019); and the right pulvinar anterior nucleus, which projects to the somatosensory cortex and is involved in somatosensory function (Mai and Forutan, 2012). Extended Data Figure 2-1 shows full results from the regression analyses.