Journal of the International Neuropsychological Society (2012), 18, 49–56. Copyright E INS. Published by Cambridge University Press, 2011. doi:10.1017/S1355617711001378 Visuospatial Associative Memory and Hippocampal Functioning in Congenital Hypothyroidism Sarah M. Wheeler, 1,2 Mary Pat McAndrews, 2,3 Erin D. Sheard, 1 AND Joanne Rovet 1,2,4 1 Neuroscience and Mental Health Research Program, The Hospital for Sick Children, Toronto, Ontario 2 Department of Psychology, University of Toronto, Toronto, Ontario 3 Krembil Neuroscience Centre, Toronto Western Hospital, Toronto, Ontario 4 Department of Pediatrics, University of Toronto, Toronto, Ontario (RECEIVED March 9, 2011; FINAL REVISION August 28, 2011; ACCEPTED August 29, 2011) Abstract Congenital hypothyroidism is a pediatric endocrine disorder caused by insufficient endogenous thyroid hormone production. Children with congenital hypothyroidism have difficulties with episodic memory and abnormalities in hippocampal structure, suggesting deficient hippocampal functioning. To assess hippocampal activation in adolescents with congenital hypothyroidism (N 5 14; age range, 11.5–14.7 years) compared with controls (N 5 15; age range, 11.2–15.5 years), a functional magnetic resonance imaging visuospatial memory task was used. In this task, participants had to decide if object pairings were novel or were previously studied or if object pairs were in the same location as they were at study or had switched locations. Despite no group differences in task performance, adolescents with congenital hypothyroidism showed both increased magnitude of hippocampal activation relative to controls and bilateral hippocampal activation when only the left was observed in controls. Furthermore, the increased activation in the congenital hypothyroidism group was correlated with the severity of the hypothyroidism experienced early in life. These results suggest that perinatal deprivation of thyroid hormone has longstanding effects on hippocampal function and may account for memory problems experienced by adolescents with congenital hypothyroidism. (JINS, 2012, 18, 49–56) Keywords: Hippocampal formation, Congenital hypothyroidism, Thyroid hormone, Episodic memory, fMRI, Adolescents INTRODUCTION Congenital hypothyroidism (CH) is a pediatric endocrine disorder of newborns caused primarily by a missing, ectopic, or dysfunctional thyroid gland. This leads to an early insuffi- ciency of thyroid hormone (TH) (LaFranchi, 1999), which is necessary for brain development. Although CH is readily treated with replacement TH, clinical diagnosis was pre- viously delayed due to the late appearance of outward symp- toms and as a result, CH was a leading cause of mental retardation. However, with the advent of newborn screening, diagnosis, and treatment of CH now take place shortly after birth thereby avoiding retardation (Dugbartey, 1998; Rovet, 1999). Nevertheless, affected children still exhibit a variety of subtle cognitive weaknesses (Rovet, 1999, 2002) that persist into adulthood (Oerbeck, Sundet, Kase, & Heyerdahl, 2005). One area of notable weakness among children with CH is their learning and memory abilities (Rovet, 2002), which typically fall below peers on standard neuropsychological tests, although still within the normal range of population norms (Oerbeck et al., 2005; Rovet, 1999; Rovet, Ehrlich, & Sorbara, 1992). Previous studies have shown that areas particularly affected are their verbal-associative recall and spatial learning abilities (Rovet, 1999, 2002), which are known to rely on the hippocampus. In contrast, their working memory, which involves primarily extra-hippocampal struc- tures (Eichenbaum, 2001; Mayes, Montaldi, & Migo, 2007; Milner, Corkin, & Teuber, 1968; Vargha-Khadem, Gadian, & Watkins, 1997) is preserved (Hepworth, Pang, & Rovet, 2006; Rovet, 1999). These findings are supported by basic research with rodents deprived perinatally of TH and showed significant learning and memory impairments as well as structural and functional abnormalities of the hippocampus (Gilbert, 2004; Gilbert & Sui, 2006; Rami, Rabie, & Patel, 1986; Rami, Patel, & Rabie ´, 1986). Consequently, these findings led us to speculate that the memory weaknesses in children with CH may also reflect altered hippocampal Correspondence and reprint requests to: Joanne Rovet, The Hospital for Sick Children, Psychology Research, 555 University Avenue, Toronto, Ontario, Canada M5G1X8. E-mail: joanne.rovet@sickkids.ca 49