Kim Annink

258 Chapter 12 was not treated with therapeutic hypothermia. In chapter six we assess which brain structures are most related to school-age outcome in this group. We included ten- year-old patients with a history of perinatal HIE who were born before therapeutic hypothermia became standard of care (non-HT group) and children who were treated with therapeutic hypothermia (HT-group). All children underwent a neuropsychological examination, motor tests and an MRI including 3D-T1-weighted imaging and diffusion tensor imaging (DTI). We found cognitive and episodic memory problems in both groups. In the group as a whole, smaller hippocampal volumes and atrophy of the mammillary bodies (MB) were associated with poorer cognition and episodic memory. Atrophic MB and smaller hippocampal volumes were also associated with lower FA values throughout the brain, especially in the fornix and corpus callosum. All these results implicate that the circuit of Papez (including the MB, hippocampus, anterior thalamus and fornix) is important for cognitive and memory problems in infants with HIE. Though therapeutic hypothermia reduces death, cerebral palsy and epilepsy, the circuit of Papez does not seem to be fully spared. When combining the findings in chapter five and six, it can be concluded that hippocampal and MB atrophy at ten years of age in children with a history of perinatal HIE are associated with neurocognitive and memory problems, irrespective of therapeutic hypothermia. Atrophy of these structures might be an early biomarker for memory and cognitive problems. It is known that MB atrophy is already visible at three months after birth (35). Currently, we are investigating whether hippocampal atrophy is also detectable at three months after birth, in collaboration with the Sick Kids Hospital in Toronto, Canada. In case atrophy of the MB and hippocampus are both visible at three months of age and are associated with long-term neurodevelopmental outcome, it might be useful to scan all infants with HIE three months after birth to identify the infants at risks for memory problems and start with early rehabilitation. Early memory training might improve memory, because of the plasticity of the hippocampus. For example, taxi drivers in London have larger hippocampal volumes than controls, because their (visuospatial) memory is very well trained (36). The effect of memory training on hippocampal and MB volumes and memory and cognitive functioning in infants with HIE will need further investigation. Chapter three and six have implications for the current MRI scoring systems (37,38). Based on chapter six, it can be advised to add the MB to these scoring systems . This also allows to investigate the association of neonatal MB injury and