Hypoxia/ischaemia and patterns of neuropathology associated with memory impairment: From infancy through adolescence

Memory is a critical ability in the everyday lives of children, allowing them to establish a base of knowledge about the world and remember the events of everyday life and so learn from personal experiences. Certain medical conditions that affect the heart and/or the lungs can interfere with the supply of blood and oxygen to the brain, and result in injury to the hippocampus, a memory-related structure. Our past research showed that up to 30% of children who survived such conditions and were otherwise developing normally still had significant memory impairments. In our current research programme, we aim to study infants with these medical conditions, with the goal of providing information that will allow the early identification of those at risk for hippocampal injury and memory impairment so that treatments can be implemented as early as possible. We will enroll newly born babies into our study and follow their development at specific time points over a two year period, examining their behaviour and getting images of their brains to evaluate possible injury to the hippocampus. We will also determine whether other areas of the brain are damaged, and, in those cases where the injury is limited to the hippocampus, we will find out how this affects the pattern of communication between brain areas. We will also use specific memory tasks that are sensitive to the functions of the hippocampus so that we can determine when memory impairments, if they occur at all, first become evident, and assess the degree of the deficit. We will use medical information to see whether this provides any early clues to which children will be affected and to what degree. A second part of our research plan is to study older children who have had particular heart or breathing problems as babies. This part of our work builds on our previous studies which showed that children with medical conditions affecting the supply of blood and oxygen to their brains as infants had a high rate of memory difficulties. This work also indicated that whereas certain aspects of memory were affected, others remained relatively normal. We will investigate in more detail the pattern of affected and unaffected memory abilities and their brain basis. We hope that this work will give a better overall understanding of the brain basis of memory development and will also help health care professionals develop prevention and treatment strategies for memory impairment.

Memory is a fundamental aspect of cognitive development, allowing children to gain a knowledge base about the world and form a store of personal memories that are essential for establishing a sense of identity. Our prior research showed that selected aspects of memory development are at risk in children with medical conditions exposing them to hypoxic-ischaemic injury to the hippocampus. The research programme we now propose aims to investigate how such memory impairments evolve by studying young infants prospectively as well as investigate in more detail both the spared and impaired memory skills and their neural correlates in older children who had sustained hippocampal injury earlier in life, often neonatally. In the first part of our programme, infants with cardiorespiratory disease requiring extracorporeal membrane oxygenation, those with transposition of the great arteries requiring open heart surgery, and those with hypoplastic left heart, will be studied from the first weeks of life until two years of age using neuroimaging, neurophysiological methods, and cognitive behavioural testing to identify the presence of hippocampal atrophy, its effects on the development of brain connectivity patterns, and its impact on memory function. In the second part of our programme, we will build on our prior work using a retrospective design to study children who experienced cardiac arrest as infants. We will examine the incidence of memory impairment in this group, the degree and selectivity of any hippocampal injury, and the long-term impacts on brain connectivity. We will also assess the sensitivity of several tests of hippocampal-dependent memory, the relation of memory performance to degree of hippocampal injury, and the neural mechanisms that enable affected children to acquire a semantic knowledge base in spite of their severe learning deficits. This research programme will provide information relevant to theories of the neurocognitive organisation of memory as well as how the brain reorganises following early injury to this critical memory structure. An important goal is the earliest possible identification of hippocampal injury in infants who have suffered hypoxia/ischaemia, as these are the cases who will be at risk for memory impairment; this will allow the earliest possible remediation efforts, including how preserved memory skills can be exploited to improve overall level of function, as well as provide key information about the trajectory of memory impairments once they appear.