We demonstrate the first use of Optically Pumped Magnetoencephalography (OP-MEG) in an epilepsy patient with unrestricted head movement. Current clinical MEG uses a traditional SQUID system, where sensors are cryogenically cooled and housed in a helmet in which the patient's head is fixed. Here, we use a different type of sensor (OPM), which operates at room temperature and can be placed directly on the patient's scalp, permitting free head movement. We performed OP-MEG recording in a patient with refractory focal epilepsy. OP-MEG-identified analogous interictal activity to scalp EEG, and source localized this activity to an appropriate brain region

Barnes, GR

Boto, E

Bowtell, R

Brookes, MJ

Hill, RM

Holmes, N

Leggett, J

Litvak, V

Mellor, S

Roberts, G

Tierney, TM

Vivekananda, U

Walker, MC

English

UCL Discovery

CASE STUDYOptically pumped magnetoencephalography in epilepsyUmesh Vivekananda1,2 , Stephanie Mellor1, Tim M. Tierney1, Niall Holmes3, Elena Boto3, JamesLeggett3, Gillian Roberts3, Ryan M. Hill3, Vladimir Litvak1, Matthew J. Brookes3, Richard Bowtell3,Gareth R. Barnes1 & Matthew C. Walker21Wellcome Centre for Human Neuroimaging, UCL, Queen Square, London, WC1N 3AR, United Kingdom2Department of Clinical and Experimental Epilepsy, UCL, Queen Square Institute of Neurology, London, WC1N 3BG, United Kingdom3Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, NG7 2RD, United KingdomCorrespondenceUmesh Vivekananda, Department of Clinicaland Experimental Epilepsy, Institute ofNeurology, Queen Square, London WC1N3BG, UK. Tel: 02078373611; Fax:02034488615; Email:u.vivekananda@ucl.ac.ukFunding InformationThis work was supported by the Departmentof Health’s National Institute for HealthResearch University College London/UniversityCollege London Biomedical Research Centreand Epilepsy Research UK. This work wasalso funded by a Wellcome collaborativeaward to Barnes, Brookes, and Bowtell,which involves a collaborative agreementwith the OPM manufacturer QuSpin. SM issupported by the EPSRC-funded UCL Centrefor Doctoral Training in Medical Imaging (EP/L016478/1). The Wellcome Centre forHuman Neuroimaging is supported by corefunding from the Wellcome (203147/Z/16/Z).Received: 23 December 2019; Revised: 27January 2020; Accepted: 30 January 2020doi: 10.1002/acn3.50995AbstractWe demonstrate the first use of Optically Pumped Magnetoencephalography(OP-MEG) in an epilepsy patient with unrestricted head movement. Currentclinical MEG uses a traditional SQUID system, where sensors are cryogenicallycooled and housed in a helmet in which the patient’s head is fixed. Here, weuse a different type of sensor (OPM), which operates at room temperature andcan be placed directly on the patient’s scalp, permitting free head movement.We performed OP-MEG recording in a patient with refractory focal epilepsy.OP-MEG-identified analogous interictal activity to scalp EEG, and source local-ized this activity to an appropriate brain region.IntroductionMagnetoencephalography (MEG) is a noninvasive brainimaging technique that gives a unique window intowhole brain function. In the field of epilepsy, MEG hasbeen the source of much interest due to significant tech-nical advantages it possesses over the ‘gold standard’noninvasive technique for functional recording; scalpelectroencephalography (EEG). Unlike EEG, the MEGsignal is not affected by the smearing effects of skull andscalp and has better immunity to muscle artifact, both ofwhich enable a greater ability to detect epileptic activity.1MEG has been shown to provide useful additionalinformation to EEG, which significantly contributes topatient selection, focus localization, and long-term sei-zure freedom after epilepsy surgery.2–4 However, use ofMEG in epilepsy thus far has been limited to the presur-gical evaluation of patients with drug-refractory epilep-sies. This is because current clinical MEG uses an arrayof cryogenically cooled sensors termed superconductingquantum interference devices or SQUIDs, placed aroundthe head,5,6 making MEG systems cumbersome andrestrictive as sensor positions are fixed in a limited selec-tion of helmet sizes. Consequently, any motion of thehead relative to the sensors, for example, during a sei-zure, affects MEG signal quality in spite of movementª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited.1compensation algorithms applied to it.7 This means thatMEG recording sessions are usually brief (1–2 h) whencompared with EEG telemetry that can last several days.Here, we describe the first use of an optically pumped(OP) MEG system8 in a case of medically refractory focalepilepsy. OP-MEG utilizes novel quantum sensors (opticallypumped magnetometers or OPMs) that do not rely onsuperconducting technology, but on the transmission oflaser light through a vapor of spin-polarized rubidiumatoms. The use of OPMs in epilepsy has already beendemonstrated in rodent models.9 Crucially, OPM sensorscan be worn directly on the head, allowing the subject tomove within a magnetically shielded environment whilebeing scanned. A recent OPM study showed sensory motorsignals robust to subject movement of 20 cm.8 In addition,as the magnetically sensitive volume within the OPM sitsjust 6 mm from the scalp surface by comparison to roughly3–4 cm in cryogenic MEG, the magnetic field strengths mea-sured due to cortical sources are typically four times greaterin adults10,11 as magnetic field strength decreases with dis-tance. The white noise floor of the most recent OPMs iscomparable to that SQUIDs (~10fT/sqrt(Hz)).8In this study, we demonstrate, for the first time inhumans, that interictal epileptiform activity can berecorded using OPMs. The localization of this activityagrees with that of other modalities. OP-MEG thereforepromises a combination of high spatiotemporal accuracyduring brain recording (with minimal effects of motionor muscle artifact) and, practicality, with subjects able tomove naturally during recordings.MethodOur test case was a 47-year-old woman who had Hemo-philus meningitis associated with status epilepticus aged18 months. After a period of seizure freedom, she devel-oped focal seizures with loss of awareness, refractory to anumber of antiepileptic drugs, and she is currently experi-encing up to 10 seizures a day. Repeated diagnostic EEGdemonstrated epileptic spikes, polyspikes, and spike andwave patterns indicative of a right posterior quadrantfocus for the epilepsy. MRI demonstrated right-sidedparieto-occipital damage of cortex and white matter,indicative of a previous ischemic insult.Prior ethical approval for this study was granted by TheMedicines and Healthcare products Regulatory Agency.Informed consent was obtained from the patient to partici-pate in the study. Band-pass filtering between 1 and 70Hzwas applied to the EEG and OP-MEG data. Prolonged EEGmonitoring (5 days) was performed with a MedTronic sys-tem with a 21-channel setup using the international 10-20electrode system and average reference montage. The patientsubsequently underwent two separate recording sessionsusing OP-MEG, each lasting 30 min. For both recordings,we used remote reference sensors placed near the patient torecord, and eventually regress out, environmental magneticnoise. The first session involved the patient lying on a bedwith her head resting on a bespoke plinth, which housedeight first-generation OPMs (Figure 1A2, left) for recordingbrain activity and six sensors were used for reference mea-surement. The second session was performed with the sub-ject wearing a bespoke 3D-printed scanner cast (Figure 1A1)to hold 15 second-generation OPMs (Figure 1A2, right).The scanner-cast design was informed by a previouslyacquired anatomical 3 T MRI scan.12 These casts provide arigid sensor mount with respect to the individual anatomyand ensure that any movement artifacts are common acrosssensors. The positions of the sensors in relation to the braincould be ascertained directly from the digital scanner castdesign (Figure 1B). Source reconstruction of an average ofinterictal spikes (manually identified by an experienced neu-rophysiologist, MW) was performed using dipole fittingwithin Fieldtrip software (http://fieldtriptoolbox.org) (Fig-ure 1D–F). We used the rising phase to maximal peak ofspike for reconstruction. Both recordings were performedwithin a magnetically shielded room and with the subject sit-ting between two biplanar coils separated by 1.5 meters,which were used to remove remnant static magnetic fields.13This allowed the patient to move her head naturally whilereclining in a chair.ResultsDuring EEG telemetry the patient exhibited frequent interic-tal activity including sharp waves, spikes and polyspikes, onaverage 30/hour (examples in Figure 1C). These were maxi-mal in channels T8 and Right Sphenoidal. She also had fourseizures heralded by right fronto-centro-temporal spikesand subsequent generalized attenuation of EEG activity. Wewere able to identify the same interictal patterns, on 23spikes/30 min during the first OP-MEG recording session(Figure S1), and 19 spikes/30 min during the second session(Figure 1C). The patient suffered no seizures during OP-MEG recording. Using spikes from the second session,where sensor position in relation to the brain could bedefined, we localized the epileptiform activity to the previ-ously EEG-identified abnormal right posterior quadrant,assumed to be the epileptogenic focus (Figure 1D). She sinceunderwent resective surgery (planned prior to the OPMrecordings) of this region with a reduction in her seizure fre-quency (Figure 1E).DiscussionWe have demonstrated the first use of OP-MEG in anepilepsy patient with unrestricted head movement. OP-2 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.Optically Pumped Magnetoencephalography in Epilepsy U. Vivekananda et al.ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 3U. Vivekananda et al. Optically Pumped Magnetoencephalography in EpilepsyMEG detected forms of abnormal interictal activity seenon clinical EEG (spikes, sharp and slow waves, polyspikes,and spike and waves) demonstrating similar morphology,and produced consistent localization of spike activity.One limitation of this study has been that EEG and OP-MEG were not acquired at the same time. However, thisstudy is an important proof-of-concept step in the use ofOP-MEG for epilepsy. Another limitation is that the OP-MEG sensors were concentrated around the region ofinterest when recording; that is, right posterior quadrant.This may introduce some bias as compared with whole-head coverage. An interesting comparison would havebeen to directly compare the OP-MEG recordings withthose made using cryogenic MEG. This was not possiblein this case due to the patient’s surgical schedule and eth-ical constraints. However, based on previous empiricalstudies,8,14 we would have expected a twofold to fivefoldreduction in signal magnitude using conventional MEG.The advantages of conventional MEG in this case wouldhave been increased channel number and whole-headcoverage. We are currently working toward a systemusing 50 OPM devices where we should expect to seecomparable whole-brain source-level discrimination15 to acryogenic system with approximately 250 sensors. Furtherdevelopment of the technique will include simultaneous30-channel OP-MEG and EEG recording, which hasalready been demonstrated in healthy subjects16 and pro-longed EEG/OP-MEG recording over several hours withvideo monitoring. Work is also underway in developingOP-MEG for children with refractory epilepsy wheremotion tolerance is of even more importance. In addi-tion, a new large OP-MEG recording suite (3 x 4 meters)has been completed at Wellcome Centre for Human Neu-roimaging, UCL, with improved low-frequency shieldingto allow a larger area for the patient to move in whilerecording. OP-MEG has the potential to improve thequality of functional imaging within epilepsy diagnosticsand finally translate MEG into a readily clinically availabletool.AcknowledgmentsWe would like to acknowledge the patient who partici-pated in this study. This work was supported by theDepartment of Health’s National Institute for HealthResearch University College London/University CollegeLondon Biomedical Research Centre and EpilepsyResearch UK. This work was also funded by a Wellcomecollaborative award to Barnes, Brookes, and Bowtell,which involves a collaborative agreement with the OPMmanufacturer QuSpin. SM is supported by the EPSRC-funded UCL Centre for Doctoral Training in MedicalImaging (EP/L016478/1). The Wellcome Centre forHuman Neuroimaging is supported by core funding fromthe Wellcome (203147/Z/16/Z). We confirm that we haveread the Journal’s position on issues involved in ethicalpublication and affirm that this report is consistent withthose guidelinesConflict of InterestThis work was in part funded by a Wellcome collabora-tive award, which involves a collaborative agreement withthe OPM manufacturer QuSpin. The design for biplanarmagnetic field compensation coils, as used in this study,has been patented by the University of Nottingham.References1. Baillet S. Magnetoencephalography for brainelectrophysiology and imaging. Nat Neurosci 2017;20:327–339.2. Blanco JA, Stead M, Krieger A, et al. Data miningneocortical high-frequency oscillations in epilepsy andcontrols. Brain 2011;134:2948–59.3. Plummer C, Vogrin SJ, Woods WP, et al. Interictal andictal source localization for epilepsy surgery using high-density EEG with MEG: a prospective long-term study.Brain 2019;142:932–951.4. Rampp S, Stefan H, Wu X, et al. Magnetoencephalographyfor epileptic focus localization in a series of 1000 cases.Brain 2019;142:3059–3071.5. Cohen D. Magnetoencephalography: detection of thebrain’s electrical activity with a superconductingmagnetometer. Science 1972;175:664–666.6. Hamalainen MS, Hari R, Ilmoniemi RJ, et al.Magnetoencephalography: theory, instrumentation, andapplications to non-invasive studies of the working humanbrain. Rev Mod Phys 1993;65:413–497.7. Nenonen J, Nurminen J, Kicic D, et al. Validation of headmovement correction and spatiotemporal signal spaceFigure 1. Use of OP-MEG in epilepsy. (A1) Rendered image of 3D scanner-cast. (A2) First-generation (left) and second-generation (right) OPMsensor. (B) Schematic of position of OPM sensors on the scalp for second recording session. (C) Example traces of typical epileptiform activityfrom scalp EEG and OP-MEG including spike and wave, sharp and slow wave, and sharp wave. Red denotes channels with highest-amplitudespikes. EEG labeled with average reference montage; Black bar = 1 second. (D) Source reconstruction of average interictal spike activity using OP-MEG; D1 coronal, D2 sagittal, and D3 axial using dipole fit. (E) Postoperative MRI demonstrating likely removal of same average MEG dipole. (F)Field map (measured left and modeled right) corresponding to the epileptic spike with sensor positions shown in relation to the inner skull mesh.Inset shows example average OP-MEG sharp wave used for reconstruction.4 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.Optically Pumped Magnetoencephalography in Epilepsy U. Vivekananda et al.separation in magnetoencephalography. Clin Neurophysiol2012;123:2180–2191.8. Boto E, Holmes N, Leggett J, et al. Moving brain imagingtowards real-world applications using a wearable MEGsystem. Nature 2018;17–19.9. Alem O, Benison AM, Barth DS, et al.Magnetoencephalography of epilepsy with amicrofabricated atomic magnetrode. J Neurosci2014;34:14324–14327.10. Iivanainen J, Stenroos M, Parkkonen L. Measuring MEGcloser to the brain: Performance of on-scalp sensor arrays.NeuroImage 2017;147:542–553.11. Boto E, Bowtell R, Kr€uger P, et al. On the potential of anew generation of magnetometers for MEG: a beamformersimulation study. PLoS ONE 2016;11:e0157655.12. Tierney TM, Homes N, Meyer SS, et al. Cognitiveneuroscience using wearable magnetometer arrays: Non-invasive assessment of language function. NeuroImage2018;181:513–520.13. Holmes N, Leggett J, Boto E, et al. A bi-planar coil systemfor nulling background magnetic fields in scalp mountedMagnetoencephalography. NeuroImage 2018;181:760–774.14. Boto E, Meyer SS, Shah V, et al. A new generation ofmagnetoencephalography: room temperaturemeasurements using optically-pumped magnetometers.NeuroImage 2017;1:404–414.15. Tierney TM, Mellor S, O’Neill GC, et al. Pragmatic spatialsampling for wearable MEG arrays. BioRxiv 2019;.https://doi.org/10.1101/2019.12.29.890426.16. Boto E, Seedat ZA, Holmes N, et al. Wearableneuroimaging: Combining and contrastingmagnetoencephalography and electroencephalography.NeuroImage 2019;116099.Supporting InformationAdditional supporting information may be found onlinein the Supporting Information section at the end of thearticle.Figure S1. A. Example traces of typical epileptiform activ-ity from scalp EEG and OP-MEG from first recordingsession; including spike and wave, polyspike and wave,and sharp wave.ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. 5U. Vivekananda et al. Optically Pumped Magnetoencephalography in Epilepsy

Optically pumped magnetoencephalography in epilepsy

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Optically pumped magnetoencephalography in epilepsy

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