Translational neurophysiology in sheep:Measuring sleep and neurological dysfunction in CLN5 affected Batten disease sheep

This is the final published version of a paper originally published in BRAIN 2015: 138; 862?874, DOI: http://dx.doi.org/10.1093/brain/awv026Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders.This work was funded by CHDI Inc. (AJM). Founding the\ud sheep flock, and costs in NZ relating to the rearing and\ud genotyping of the animals were funded by a series of grants\ud from the Neurological Foundation of NZ and the Batten\ud Disease Support and Research Association (DNP, NLM)

Characterization of pulsed ELF magnetic fields generated by GSM mobile phone handsets

Human provocation studies that investigate the effects of Global System for Mobiles (GSM) communication systems on the brain have focused on RF exposure. We wish to further extend such study by investigating the effect of both RF and ELF magnetic field exposure, the latter being emitted by the GSM handset’s battery switching. The use of a commercial handset as an exposure source for such investigations is problematic and therefore a simulated exposure source, capable of producing both RF and ELF components of exposure, is desirable. As a first step in developing such a source, we have quantified and characterized the ELF radiation from several commercial handsets (the RF characteristics being already well understood). Here we present experimental results where, field distribution, and pulse waveform characteristics at ELF frequencies are measured. Finally, an equivalent source suitable for reproducing the ELF component of human exposure to GSM handset radiation is proposed

Automated detection and characterisation of rumination in sheep using in vivo electrophysiology.

Rumination is a precisely timed process that occupies a large part of a sheep's day. The complex motor coordination required to chew and swallow means that quantification of rumination may provide a surrogate marker for effective motor function. Here, data from 24h in vivo electrophysiological recordings, collected as part of an earlier study, were reanalysed for chewing- and swallowing-related activity. The electroencephalographic (EEG) and electromyographic (EMG) data were collected from sheep with surgically-implanted electrodes. An algorithm was designed to detect coordinated, rhythmic muscle activity. This could distinguish episodes of eating from those of rumination. Normal sheep spent ~29% of their time ruminating. Rumination comprised ~40s bouts of regular (~1.7s(-1)) chewing interspersed by ~6.5s intervals during which time no chewing took place. Eating was significantly less regular than rumination, with quicker chewing (~2.7s(-1)). Biomarkers for measuring progression of disease would be invaluable for studying neurodegenerative disease such as Huntington's disease (HD). To test the feasibility of using rumination as such a biomarker, we also made recordings from two neurologically impaired sheep. These showed deviations from the pattern of rumination and eating seen in normal sheep. This validates not only our use of rumination as a measure of normal motor function, but also as a surrogate biomarker for measuring motor dysfunction in impaired sheep.This work was funded by CHDI Inc. (AJM). Costs in New Zealand relating to the rearing and genotyping of the CLN5 animal from which one of the data sets used here were derived were provided by grants from the Neurological Foundation of NZ and the Batten Disease Support and Research Association (Nadia Mitchell and David Palmer, Dept. of Molecular Biosciences, Faculty of Agricultural and Life Sciences, Lincoln University, Christchurch, New Zealand) and CHDI Inc. (AJM).This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.physbeh.2016.05.02

Exposure compliance methodologies for multiple input multiple output (mimo) enabled networks and terminals

Multiple input multiple output (MIMO) enabled handsets and base-stations feature antenna systems that generate electromagnetic fields for which relevant exposure standards and guidelines do not explicitly define compliance testing methodologies. Here, through computational modeling, we explore several field summation schemes for evaluating such exposures and propose compliance testing methodologies that limit the degree of exposure under/over-estimation for both base stations and handsets. The methodologies rely on scalar field probe measurements thus avoiding significant equipment upgrades and are applicable to cases where access to signals from eachMIMO antenna element can be arranged

An EEG Investigation of Sleep Homeostasis in Healthy and CLN5 Batten Disease Affected Sheep.

UNLABELLED: Sheep have large brains with human-like anatomy, making them a useful species for studying brain function. Sleep homeostasis has not been studied in sheep. Here, we establish correlates of sleep homeostasis in sheep through a sleep deprivation experiment. We then use these correlates to elucidate the nature of sleep deficits in a naturally occurring ovine model of neuronal ceroid lipofuscinosis (NCL, Batten disease) caused by a mutation in CLN5 In humans, mutations in this gene lead to cortical atrophy and blindness, as well as sleep abnormalities. We recorded electroencephalograms (EEGs) from unaffected and early stage CLN5(-/-) (homozygous, affected) sheep over 3 consecutive days, the second day being the sleep deprivation day. In unaffected sheep, sleep deprivation led to increased EEG delta (0.5-4 Hz) power during non-rapid eye movement (NREM) sleep, increased time spent in the NREM sleep state, and increased NREM sleep bout length. CLN5(-/-) sheep showed comparable increases in time spent in NREM sleep and NREM sleep bout duration, verifying the presence of increased sleep pressure in both groups. Importantly, CLN5(-/-) sheep did not show the increase in NREM sleep delta power seen in unaffected sheep. This divergent delta power response is consistent with the known cortical degeneration in CLN5(-/-) sheep. We conclude that, whereas sleep homeostasis is present in CLN5(-/-) sheep, underlying CLN5(-/-) disease processes prevent its full expression, even at early stages. Such deficits may contribute to early abnormalities seen in sheep and patients and warrant further study. SIGNIFICANCE STATEMENT: Sleep abnormalities pervade most neurological diseases, including the neuronal ceroid lipofuscinoses (NCLs). Here, we show that, in an ovine model of a variant late-infantile NCL, there is abnormal expression of sleep homeostasis. Whereas some sleep pressure correlates respond to sleep deprivation, the strongest electroencephalogram (EEG) correlate of sleep pressure, non-REM delta power, failed to increase. This highlights the relevance of sleep deficits in this disease, in which the drive for sleep exists but the underlying disease prevents its full expression. Sleep abnormalities could contribute to early disease symptoms such as behavioral disorder and cognitive decline. Our study also shows sleep homeostatic EEG correlates in sheep, opening up new opportunities for studying sleep in a large social mammal with complex human-like brain neuroanatomy.This work was funded by CHDI, Inc.. Founding the sheep flock and costs in New Zealand relating to the rearing and genotyping of the animals were funded by a series of grants from the Neurological Foundation of New Zealand and the Batten Disease Support and Research Association by a grant from CHDI, Inc..This is the final version of the article. It first appeared from the Society for Neuroscience via http://dx.doi.org/10.1523/JNEUROSCI.4295-15.201