ANALYSIS & OPINION

Optical monitoring of neonatal brain injury: towards the development of compact clinical systems

A University College London research group describe their work on a miniature near-infrared spectrometer for neonatal brain imaging that’s small enough for use in intensive care units 

Our Multimodal-Spectroscopy (MMS) research team in the Biomedical Optics Research Laboratory at the Medical Physics and Biomedical Engineering department at University College London (UCL) has developed a compact broadband near-infrared spectrometer (NIRS) to monitor non-invasively brain tissue physiology in brain injury in infants. The portable instrument was modified from a high-performance laboratory CYtochrome Research Instrument and application system (or CYRIL), which was developed few years ago. The smaller version, called ‘Mini-CYRIL’, means it can be easily deployed in neonatal intensive care units (NICU) and accident and emergency (A&E) rooms. Mini-CYRIL is currently being used in preclinical studies and soon will be deployed in UCL-Hospital.

Although the larger instrument – CYRIL – was specifically built to enhance sensitivity, spatial and spectral resolution, it is very large and bulky and unsuitable for rapid deployment in a hospital clinic. Shrinking the system created numerous challenges, but was made possible thanks to off-the-shelf optical equipment and input from industry partners.

Baby brain injury such as hypoxic-ischaemic encephalopathy (HIE) or birth asphyxia can cause severe neurodevelopmental impairment. Due to their high metabolic rate, brain cells are very dependent on oxygen and nutrients; therefore, insufficient oxygen (hypoxia) and blood supply (ischaemia) can cause injury and even death. It is important for clinicians to be able to monitor infants with brain injuries at the cotside, in real-time, in order to assess patient outcome and redirect clinical care.

Broadband NIRS has been widely used in the study of adult and neonatal brains in the clinic to monitor brain tissue oxygen levels and metabolism. It is also a relatively cheap cerebral monitoring technique compared to other methods such as MRI.

However, there is an urgent need for a compact and more accessible broadband NIRS system to monitor infants at the bedside. There is also a clinical need for quick deployment of the system in accident and emergency rooms or during surgery.

In order to make a miniature version of our broadband NIRS system, Ocean Optics’ small white light source and spectrometers with integrated CCDs were investigated. Ocean Optics’ QE65-Pro and Ventana spectrometers use back-thinned CCD detectors with improved etaloning effects, enhancing their photosensitivity in the NIR.

In the Mini-CYRIL system, to obtain a one channel reflectance measurement of a baby’s frontal cortex, white light from a HL2000 light source from Ocean Optics is filtered and sent to the infant’s frontal cortex via an optical fibre. The reflected light is collected and focused onto Ventana’s slit through an identical detector fibre.

 

Image 1: Comparison between the sizes of the Action series LS-785 from CYRIL (a) and Ventana VIS-NIR miniature spectrometer from mini-CYRIL (b) with respect to the size of a term baby doll  

Broadband NIRS can distinguish between oxygenated and deoxygenated haemoglobin. Specific compounds (chromophores) in tissues such as haemoglobin express different colours when they are bound to oxygen, which is why oxygenated blood in arteries appears red while deoxygenated blood in veins appears purple blue.

Our group is interested in measuring another chromophore, cytochrome-c-oxidase (CCO), which has different absorption spectra in its oxidised and reduced states. CCO is a key enzyme in the mitochondria of cells and catalyses more than 95 per cent of oxygen to produce energy, providing information about oxygen consumption at cellular level.

Despite their favourable characteristics, using miniature off-the-shelf spectrometers for brain monitoring is not straightforward. There are challenges associated with an intrinsic contrast between the high numerical aperture (NA) of the optical fibres (that are attached to the head to deliver light and collect the attenuated reflected light) and the small throughput design of the spectrometers (large F-number).

The optical fibres are made with a high NA in order to enhance the signal collected from the brain, as it is a highly scattering medium. But, most miniaturised spectrometers are designed with small throughput to produce a flattened spectral field, minimise distortion and stray light, and produce high signal-to-noise ratio (SNR). So, when the detector fibre is in direct contact with the spectrometer’s slit, the irradiance at the slit is much lower and can result in some stray light. This results in poor SNR, because the large NA of the fibre drastically overfills the small acceptance cone of the spectrometer. This is problematic as detecting CCO in-vivo is a challenge due to its low concentration. Therefore, it is vital to have high intensity and SNR.

Modifications and practicality of the compact system in a clinical environment

Another challenge with using off-the-shelf instruments is that the design of the miniature spectrometers cannot be customised. The only modification that can be made to enhance the throughput is by f-matching. F-matching using miniature collimating packages is effective and can almost double the throughput, although this is still inefficient compared to larger spectrographs, such as the LS-785 from Princeton Instruments, which was used in the original CYRIL device.

The Ventana spectrometer is advantageous as it enhances the throughput by an order of magnitude. An external cooling device such as a fan could be useful, as the spectrometer is not thermoelectrically cooled, which increases the dark count significantly. However, the thermoelectric cooling of the QE65-Pro reduces the dark count which is ideal for low level light detection.

The larger CYRIL instrument system has already been used to monitor infants with HIE in the NICU at UCL-Hospital. Changes in cerebral tissue oxygenation and metabolism were successfully measured for continuous periods of up to five days, by estimating changes in oxygenated and deoxygenated-haemoglobin as well as the oxidation state of CCO.

 

Image 2:  (a) CYRIL doing a 2-channel reflectance measurement on baby’s frontal cortex (b)Mini-CYRIL doing a one channel reflectance measurement on baby’s frontal cortex   

The CYRIL system consists of two channels, each with a light source and four detectors. Optical fibres connect a thermally stable white light source (filtered for 650-1,000nm) to the tissue. The back-reflected light travelling through the head is collected from the tissue surface by detector fibres, which are connected to an Action Series LS-785 lens-based spectrograph from Princeton Instruments. The light throughput of lens-based spectrographs is superior (>99 per cent) to that of a mirror-based spectrograph. The light is focused onto a PIXIS:512F CCD with a resulting bandwidth of 136nm.

To reduce dark noise, the CCD is thermoelectrically cooled to -70°C. Princeton Instruments LightField acquisition software (with IntelliCal calibration package) was used for wavelength calibration.

Both CYRIL and the miniature version Mini-CYRIL were developed in the Multimodal Spectroscopy group by researchers from the Centre for Doctoral Training (CDT) in Integrated Photonic and Electronic Systems (IPES), a joint postgraduate teaching programme between UCL and the University of Cambridge. Dr Tachtsidis the team’s leader says that future work will focus on transforming these optical devices to clinical instruments that can be operated by medical doctors and nurses to provide real-time information of the brain function.

This project would not have been successful without the input from industry partners and their technical support.

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Authors: P. Kaynezhad, I. De Roever, G. Bale, I. Tachtsidis, Multimodal Spectroscopy Group, Biomedical Optics Research Laboratory, Medical Physics and Biomedical Engineering, UCL

References

  1. Bale, Gemma et al. “A New Broadband near-Infrared Spectroscopy System for in-Vivo Measurements of Cerebral Cytochrome-c-Oxidase Changes in Neonatal Brain Injury.” Biomedical Optics Express 5.10 (2014): 3450–3466

  2. British Research Group’s Near-Infrared Spectroscopy System Aids in Diagnosis of Neonatal Brain Injury by Using High-Throughput, Lens-Based Spectrograph and Cooled, Low-Noise CCD Camera from Princeton Instruments, press release,  princetoninstruments.com

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