A device to detect and measure the progression of dementia by quantifying the interactions between neuronal and cardiovascular oscillations

Lead Research Organisation: Lancaster University
Department Name: Physics

Abstract

The social context of the research is the rapidly ageing population, and the fact that the number of people in the UK and the world experiencing dementia is increasing. It is predicted that 66 million individuals worldwide will have dementia in 2030. It was in recognition of this grim situation that the Prime Minister launched the Dementia Challenge in 2012.

The scientific context is that vast resources have been and are being expended on Alzheimer's disease by governments and the pharmaceutical industry. Almost all of these are based on the amyloid-cascade hypothesis. But this approach has not been notably successful to date, and is looking increasingly doubtful. There are now powerful arguments in favour of looking at alternatives and anticipating a paradigm shift in the understanding of Altzheimer's disease and, probably, of many or most other dementias. There are many indicators suggesting that dementia is often connected with nutritional failures at the neuronal level and that these may be reversed, or at least ameliorated, by changes in lifestyle and diet. It will be enormously advantageous if a simple means can be devised to monitor the severity of dementia, and to identify the at-risk population for whom early remedial action is likely to be helpful.

We therefore propose to develop a method of quantifying the degree of dementia, based on physics. It will apply new, sophisticated, analysis methods to brain signals measured from patients, including both electrical (EEG) signals and cardiovascular (blood flow/oxygenation) signals. The intention is to create a device that will be able to provide quantitative measurements of disease progression - or regression in cases where treatment and/or changes in diet or lifestyle are yielding beneficial results.

The device we propose is a system consisting of commercially-available state-of-the-art instruments plus novel data analysis algorithms. Its unique features are that it involves

1. Evaluation of both the cardiovascular and neuronal/cognitive oscillations simultaneously and noninvasively, leading to an assessment of the dysfunction in their mutual interactions.

2. Eventually, a standardised presentation of the results in terms of images and a single coefficient spanning from 0 to 100.

3. A relatively comfortable and inexpensive assessment method (especially when compared to MRI-related methods) that can easily be repeated either in the same day or as frequently as is needed or desired.

We will test the feasibility of the device, and develop the necessary data analysis algorithms, with the help of 10 clinically assessed dementia patients and 10 healthy controls, in Addenbrooke's Hospital (Cambridge). The data analysis will all be carried out in Lancaster using a range sophisticated methods, some of which are completely novel and highly promising. Assuming that the enterprise is successful, it may be expected to lead in turn to clinical trials, including longitudinal studies, but these are beyond the scope of the present proposal. Nonetheless we can expect to achieve proof-of-concept for the device, operating in a clinical environment.

In the longer term, we anticipate that the cost of the device can be substantially reduced, partly by making the near-infra-red-spectrometer (NIRS) purpose-designed, rather than relying on a flexible multi-purpose instrument, and partly by mass-production.

Planned Impact

1. Who will benefit from this research?
Anybody developing a form of dementia is a potential beneficiary, and so correspondingly are the family, social workers, and medical teams that are looking after her or him. The numbers are very large: there were 800,000 people with dementia in the UK in 2012, of whom 17,000 were under 65. It is estimated that by 2021 there will be a million dementia patients in the UK, with a projected growth to 1.7 million by 2051. Looking beyond the UK, to the world as a whole, the predicted number for 2030 is 66 million. There are also potential benefits for industry: for the medical instruments industry in manufacturing the proposed device; and for the pharmaceutical industry in providing an easy-to-use method to follow up and evaluate on a day-to-day basis the effect of treatment. It can of course be used to evaluate any treatment - including drugs, diet, or life style changes.


2. How will they benefit from this research?
The research offers a route to improved diagnosis together with a means of quantifying the severity of the disease. The research is expected to lead to eventually a device that will be easy and reasonably quick (minutes) to use, that is non-invasive, and which does not cause discomfort. It will therefore become feasible to carry out tests at frequent intervals where necessary, to evaluate not only the progression or remission of the disease, but to make explicit evaluations of the efficacy of treatment and the effects of diet, exercise, and lifestyle changes. Although the basic research proposed here requires some relatively expensive general-purpose equipment, it is anticipated that, once we have established exactly what is needed, and with large-scale production, the final device can realistically find a place in every GP's surgery. Manufacturers stand to gain from industrial production of the new device.

Publications

10 25 50
 
Description Combined near infrared spectroscopy (NIRS) and electroencephalography (EEG) measurements in healthy humans of different ages have revealed low frequency oscillations in the signals recorded via both techniques. Significant coherence was observed between these oscillations in some cases, and it was found that this coherence is altered with age. Analysis techniques for the extraction of more specific information about neurovascular coupling were developed. The reliable identification of dynamics in biomedical time series has been thoroughly investigated in a review paper on surrogate data testing, to ensure that conclusions arising from the project are robust. A software toolbox MODA (Multiscale Oscillatory Dynamics Analysis) has been developed and is very likely to be useful to a range of other scientists - both medical and non-medical. We investigated oscillations in signals recorded by NIRT - a similar technique to NIRS - and have demonstrated the dominance of low-frequency components related to vasomotion.
Exploitation Route The nature of low-frequency components in NIRS signals is of general importance for brain dynamics, not only for dementia. Further work is needed, but it is obvious that NIRS may eventually replace in many ways more expensive magnetic resonance imaging (MRI), especially because of its excellent time-resolution. NIRS in combination with the electroencephalography (EEG) seems highly promising for lay detection.
The knowledge arising from this project is also being used to inform collaborations in similar fields. A new proposal in collaboration with Psychology at Lancaster is in preparation, and a paper describing the low frequency oscillations in the similar technique of NIR-T/BSS, used for the measurement of subarachnoid space width, has been published in Scientific Reports in February 2018.
Sectors Communities and Social Services/Policy,Digital/Communication/Information Technologies (including Software),Education,Electronics,Healthcare,Government, Democracy and Justice,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Security and Diplomacy

 
Description Extensive outreach in terms of talks to schools, both students visiting Lancaster and staff visiting schools.
First Year Of Impact 2015
Sector Education
Impact Types Cultural

 
Description LU Impact Fund
Amount £6,980 (GBP)
Organisation Lancaster University 
Sector Academic/University
Country United Kingdom
Start 08/2016 
End 07/2017
 
Description The physiological significance of cardiorespiratory interactions: bridging between data analysis, mathematical theory and physiological models. Catalyst Seeding
Amount $80,000 (NZD)
Organisation Royal Society of New Zealand 
Sector Learned Society
Country New Zealand
Start 11/2018 
End 11/2020
 
Title System to assess neurovascular dynamics 
Description The system uniquely combines 16-channels EEG and 10-channels NIRS with high sampling frequencies. Simultaneously recorded data assessed for individual oscillatory dynamics and spatial and temporal couplings. The strength of oscillations and their couplings is used to asses the functional neurovascular state of the brain. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2016 
Provided To Others? No  
Impact Signatures of ageing in the neurovascular couplings observed. 
 
Title Healthy neurovascular ageing 
Description Twenty eight 30-min data sets, each containing 16 EEG channels and 10 NIRS channels were recorded in young and older subjects. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? No  
Impact The data is providing a control group for the data to be collected from dementia patients, who are likely to have a wide range of ages. At the same time they form a basis for study of healthy neurovascular ageing with the same methodology. 
 
Title SAS width/BP data 
Description The dataest contains recordings of subarachnoid space (SAS) width using near infrared transillumination backscattering sounding (NIRT) and blood pressure data used in the analysis in "Human subarachnoid space width oscillations in the resting state", Sci. Rep. 8, 3057, 2018. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact The data file is available on request only and was made available only in February 2018, after the publication of the Sci Rep paper, so it is too early to expect an impact. 
 
Description Collaboration on hypoxia 
Organisation University of Ljubljana
Department Medical Faculty
Country Slovenia 
Sector Academic/University 
PI Contribution Myself and my group contributed to the study design, the measurement set-up and the analysis of recorded data.
Collaborator Contribution The collaborators, Prof Damjan Osredkar and Prof Tadej Dobevec recruited the subjects, performed the measurements and contributed to the interpretation of results.
Impact A journal paper is drafted and is now being eddied between the co-authors.
Start Year 2017
 
Description Dementia collaboration in Lancaster 
Organisation Lancaster University
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution The collaboration includes Dr Trevor Crawford (Department of Psychology, Faculty of Science and Technology), Prof David Allsop (Division of Biomedical and Life Sciences, Faculty of Health and Medicine) and Prof Hedley Emsley (Lancaster Medical School, Faculty of Health and Medicine). Stefanovska and members of her group provided technical expertise in Physics of Dementia and conducted pilot studies for new proposals.
Collaborator Contribution Dr Trevor Crawford and his collaborators helped with recruitment of dementia patients. Each of the partners contributed different scientific aspects to the problem of detecting and treatment of dementia and in writing new proposals.
Impact Too early.
Start Year 2017
 
Description Dementia collaboration in Ljubljana 
Organisation University of Ljubljana
Department University Medical Centre Ljubljana
Country Slovenia 
Sector Hospitals 
PI Contribution Aneta Stefanovska established the connection with the Ljubljana dementia experts, including Dr Jan Kobal, who is in charge of Huntington's patients in Slovenia, Dr Bernard Meglic, who is an expert on autonomous systems, and Franci Benko, a research nurse in the Neurology Clinic. With her research team Stefanovska prepared the necessary signal analysis methods for data recorded from patients and healthy controls.
Collaborator Contribution Dr Jan Kobal, who is in charge of Huntington's patients in Slovenia, recruited around 50 patients for measurements, Dr Bernard Meglic recruited around 50 Alzheimer's patients and Franci Benko recruited 50 healthy control subjects and together with Dr Gemma Lancaster from the Lancaster group was in charge of measurement that were completed in June 2018.
Impact Measurements completed. Data analysis in progress. This is a highly multidisciplinary collaboration involving Physics, Biomedical Engineering, Neurology and Physiology.
Start Year 2017
 
Description Marcin 
Organisation Medical University of Gdansk
Department Department of Radiology Informatics and Statistics
Country Poland 
Sector Hospitals 
PI Contribution Helped the collaborator to investigate the relationship between blood pressure and pial artery pulsation oscillations in human.
Collaborator Contribution The collaboration comes from a group that has developed a new device for non-invasive measurements of intracranial flow (NIRT). They are contributing signals that when analysed by our methods promise great impact.
Impact Papers in preparation.
Start Year 2015
 
Description Tomislav Stankovski 
Organisation Saints Cyril and Methodius University of Skopje
Country Macedonia, the Former Yugoslav Republic of 
Sector Academic/University 
PI Contribution Aneta Stefanovska and Peter McClintock were PhD and PostDoc supervisors of Dr Tomislav Stankovski. During his stay in Lancaster (2008-2014) Tomislav mastered time series analysis methods and in particular Dynamical Bayesian inference.
Collaborator Contribution Dr Tomislav Stankovski expanded Dynamical Bayesian inference method to include multi-coupling analysis in collaboration with Valentina Ticcinelli, a PhD student funded by Physics Department to work on the project, who coded the algorithm. The method is very relevant for the data recorded during the study.
Impact Dr Tomislav Stankovski co-authored 5 journal papers relevant for our collaborative projects 1. G Nadzinski, M Dobrevski, C Anderson, PVE McClintock, A Stefanovska, M Stankovski, T Stankovski, Experimental Realization of the Coupling Function Secure Communications Protocol and Analysis of Its Noise Robustness, IEEE Transactions on Information Forensics and Security 13 (10), 2591-2601, 2018 2. T Stankovski, T Pereira, PVE McClintock, A Stefanovska, Coupling functions: universal insights into dynamical interaction mechanisms, Reviews of Modern Physics 89 (4), 045001, 2017 3. V Ticcinelli, T Stankovski, D Iatsenko, A Bernjak, AE Bradbury, AR Gallagher, P Clarkson, PVE McClintock, Aneta StefanovskaCoherence and coupling functions reveal microvascular impairment in treated hypertension, Frontiers in physiology 8, 749, 2017 4. T Stankovski, V Ticcinelli, PVE McClintock, A Stefanovska, Neural cross-frequency coupling functions, Frontiers in systems neuroscience 11, 33, 2017 5. T Stankovski, V Ticcinelli, PVE McClintock, A Stefanovska, Coupling functions in networks of oscillators, New Journal of Physics 17 (3), 035002, 2017 and a patent application T Stankovski, A Stefanovska, RJ Young, PVE McClintock, Encoding data using dynamic system coupling, US Patent App. 14/910,547, 2016.
Start Year 2014
 
Title MODA 
Description MODA is a toolbox that provides a set of methods to deal with signals affected by time variability. Currently, it contains 5 methods, including wavlet analysis, wavelet-based phase coherence analysis, wavelet-based bispectral analysis, ridge-extraction and coupling function analysis. It is intended to be very user friendly to be used by the wider scientific community. 
Type Of Technology Software 
Year Produced 2018 
Impact Too early. 
 
Title Toolbox with surrogate methods for testing dynamical hypotheses 
Description A toolbox that comprises most of the existing surrogate methods to test dynamical hypothesis, such as existence of oscillations, nonlinearities, coherence and coupling. 
Type Of Technology Software 
Year Produced 2017 
Impact The created library of surrogate techniques is used to test for significance of ageing effects. 
 
Description Biological Oscillations conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Stefanovska and her group organised the 9th conference of the European Study Group on Cardiovascular Oscillations which took place in Lancaster from 10th to 14th April 2016. This was also the first International Conference on Biological Oscillations.
The aim of the conference was to provide an interdisciplinary forum for discussions of biological oscillations between researchers drawn from areas such as physics, mathematics, engineering, computer science, cardiovascular regulation, neuroscience, time-series analysis, theory of nonlinear oscillatory dynamics, information processing, cardiovascular and microvascular physiology, cell biology and clinical sciences.
In addition to the signal processing view of cardiovascular oscillations this conference expanded to incorporate a more physics-based approach. It also generalized the topic to include all biological oscillations.
Year(s) Of Engagement Activity 2016
URL http://www.physics.lancs.ac.uk/ESGCO2016/
 
Description Contribution to Headstart Programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 30 Y12 Physics students from across the UK participated in the Headstart course. All students are studying A level Physics and another science in many cases and Mathematics and are high ability as indicated by their teachers. Our group organised a whole day event for the students and provided three workshop sessions: Physics of the Brain, Physics of the Cardiovascular System and Physics of the Cell. After a few introductory talks by members of the group students did either measurements or simulations, analysed their data and then presented the results to their audience.
Year(s) Of Engagement Activity 2017
URL http://www.etrust.org.uk/headstart/whatisheadstart
 
Description Data Science Institute workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Data Science Institute organized a Streaming Data workshop that was held in the Low Wood hotel 18-19 July 2016. I presented our work and participated in many activities of the workshop.The workshop was used to

• explore current Streaming Data research activities at Lancaster;
• identify challenges which can draw mutual interest;
• and develop ideas for future research and funding opportunities in this area.
Year(s) Of Engagement Activity 2016
 
Description Physics Department Colloquium, Royal Holloway, University of London, 18 May, 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Delivered a talk "Understanding systems operating far from equilibrium from the perspective of time-varying dynamics" and enjoyed vigorous discussion about differences in living and non-living systems dynamics.
Year(s) Of Engagement Activity 2018
 
Description Physics Master Class: Waves and Oscillations featuring Biomedical Physics Research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact 12 A-level students attended a whole day event which consisted of an introductory talk, two biomedical research taster projects and an oscillations and waves lab to complement their A-level studies. Students prepared group presentations and presented the results of their work. Several feedback - both from students and their A-level teachers indicate that students greatly enjoyed the day and developed an interest in the field.
Year(s) Of Engagement Activity 2017
 
Description Seminar (Reading) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Talk at the School of Biological Sciences Research Seminar Series, University of Reading, 16 October, 2018 to students of Biomedical Sciences and Biomedical Engineering and their lecturers interested in the filed of Biological Oscillators. Discussed examples related to ageing, dementia, ASD and the cell, cardiovascular system and brain oscillatory dynamics.
Year(s) Of Engagement Activity 2018
URL https://www.reading.ac.uk/biologicalsciences/SchoolofBiologicalSciences/Research/sbs-research-semina...