Historical profile of perinatal brain research at UCL

Cranial ultrasound

UCL has been at the forefront of perinatal brain research for over 30 years. In the late 1970’s the team at UCH first reported outcomes following ultrasound examination of the brain in the preterm baby, pioneering a series of highly focused outcome studies based upon correlation with recognised patterns of ultrasound appearances, defining the risk of disability associated with specific findings (Stewart et al., 1983).

Phosphorus (31P) magnetic resonance spectroscopy (MRS) and secondary energy failure

This focus on the preterm widened to include the term-asphyxiated infant.  In 1982, UCL clinicians and physicists acquired 31P spectra from the brain of a newborn infant – the first ever spectra from a human brain (Cady, Lancet 1983; Hope, Lancet 1984). These landmark studies helped identify the great prognostic capability of MRS (Azzopardi et al., 1989), the concept of primary and secondary cerebral energy failure after perinatal cerebral hypoxia-ischaemia, a therapeutic window between these primary and secondary phases, and the development of hypothermic neuroprotection for the newborn. In 2009, therapeutic hypothermia is being introduced into clinical practice and is an excellent example of laboratory to cotside translational research.

Figure 1. Ern Cady (foreground), Dave Delpy (midground) and Prof Doug Wilkie FRS in 1982 when the first 31P spectrum was obtained from a living human brain. This was acquired from an infant suffering the consequences of birth asphyxia.

Figure 2. The original 1.9 Tesla MRS scanner sited in the UCL Rayne Institute in 1982 on whichthe early clinical work was performed

Figure 3. (above) Ern Cady (foreground) and Prof Os Reynolds holding up the first 31P spectrum from a living human brain; and Fig 4 (below) a spectrum as displayed by the scanner.

The significance of these 31P MRS data was realized when clinical studies following birth asphyxia demonstrated that early spectra often displayed apparently normal cerebral metabolism but a delayed "secondary" energy failure occurred several hours later (Hope  et al., 1984) and the severity of the secondary phase was strongly related to eventual outcome (Azzopardi et al., 1989). Secondary energy failure was later further characterized in a pre-clinical model (Lorek et al., 1994; Iwata et al., 2007) (Fig 5). Eventually therapeutic hypothermia was seen to ameliorate the delayed energy failure (Thoresen et al., 1995). This observation led to pilot studies of cooling in babies; RCTs followed in the 1990s.

Figure 5. Biphasic pattern of cerebral energy impairment following  transient hypoxia-ischaemia (Hope et al., 1984; O”Brien et al., 2006; Iwata et al., 2007)

Xenon

We have recently shown in pre-clinical studies that the addition of inhaled xenon may add neuroprotective benefit to therapeutic hypothermia. In collaboration with Imperial College London in 2010 we will be starting the first clinical RCT of cooling versus cooling plus xenon therapy.

Xenon was discovered by Sir William Ramsay in 1898, while he was Professor of Chemistry at UCL. He discovered neon, krypton and xenon within the space of 3 weeks by the fractional distillation of air. In 1904 he received the Nobel prize for Chemistry.