Staff Profile

My primary research interest concerns how the brain regulates its activity levels.  Specifically, I have focused upon the neocortex and hippocampus, which are the parts of the brain concerned with higher cognitive function.  These are also the parts of the brain that are susceptible to epileptic activity, and a major part of my research involves trying to understand how and why epileptic seizures occur.  I am a clinically trained researcher, and worked briefly as a junior neurologist and neurosurgeon, although I no longer practice clinical medicine, choosing instead to do full-time neuroscientific research.

I am a current member of the Scientific Advisory Committee for Epilepsy Research UK.  I have held personal fellowships for my epilepsy work on both sides of the Atlantic, and was awarded a Schaefer Scholarship at Columbia University in 2016. I have published many papers on epileptic pathophysiology in Nature Communications, Brain, Journal of Neuroscience and Journal of Physiology among others.  I have also transcribed an electrophysiological recording of a seizure into a short piece of classical music.  A recording of this can be heard here (from ~9mins into video) together with a description of how it was achieved.  

Particular research highlights include the following:

• I was the first to use using network Ca² imaging to visualise a propagating ictal wave, leading to clinically important insights for surgical seizure localization.
• This work introduced the concepts of the “ictal core” and “ictal penumbra” (terminology that I coined) for the characterization of the spatial and temporal dynamics of seizure propagation.
• I have developed novel approaches for manipulating chloride levels in neurons, using optogenetics, in order to understand how chloride levels influence synaptic inhibitory function in physiology and disease.
• Latterly, we have addressed the role of dendritic excitability in creating a tipping point that defines the onset of a seizure.

We use many different experimental techniques in our research, including cellular and network electrophysiological recordings, optogenetics, microscopy, and computational simulations.

PhDs in Epilepsy at Newcastle University

We were recently awarded funds from ERUK (with matched funds from Newcastle University) to set up a Doctoral Training Programme in Epilepsy Research. More details can be found here.

Google Scholar: Click here.

Recent news (updated Jan 2022)

• The big news, just now is that we are advertising up to 6 PhD studentships for epilepsy research here at Newcastle University.  These will be funded by Epilepsy Research UK (with matched funds from the University), starting in autumn, 2022.  Click here for more details.

• Connie Mackenzie-Gray-Scott and Ryley Parrish have had a paper accepted in J.Neurophys.  In it, they describe the surprising finding that knocking down PGC1a (a gene involved in matching energy supplies to activity levels in cells) in an important subclass of cortical interneuron, reduces the susceptibilty to epileptic activation.  You can read the full paper here.

• Rob Graham defended his PhD last year (examined by Mike Hausser and Andy Jackson). The main finding was that optogenetic stimulation of cortical networks reveals a cryptic "tipping point" that heralds the imminent start of seizure activity in a wide range of experimental models of induced seizures.  The tipping point reflects a shift in dendritic excitability, with the stimulation starting to trigger dendritic plateau potentials.  We show how this shift relates to other factors that have been implicated in seizure initiation, to provide a coherent explanation of this critical moment in the pathophysiological process.  You can read a preprint of this work here - it has been submitted for full peer review.
• Rob has now taken up a postdoctoral position at UCL, with Vincent Magloire and Dimitri Kullmann.  Good luck with that!

• Laura Alberio was awarded a Newcastle University Faculty Fellowship, which has recently been extended.  Since joining the lab, she has helped established 2-photon imaging, and is progressing well with some exciting studies regarding Cl regulation in cortical neurons. 
  

• Darren Walsh and Elaine McDermott have both recently left the lab.  Darren has taken up a postdoc position in Edinburgh with Peter Kind, while Elaine is pursuing her hobbies, in retirement.  It was great having you in the lab.
  

• Mukilan Suresh has started his PhD studies in the lab, winning one of the BBSRC-DTP PhD studentships.  He will be co-supervised by my old colleague, Prof Jenny Read, and Drs Vivek Nityananda and Olena Riabinina (Durham), and will be trying to dissect out the stereopsis mechanism in praying mantids, using Ca² imaging.  This is a big change in research direction for me, but builds upon remarkable work that Jenny, Vivek and their team have done in recent years.  All very exciting and we are thrilled to have Mukilan join us.

• Welcome to Amy Marshall, who has joined the other lab members (Drs Laura Alberio, Faye McLeod, and Connie Mackenzie-Gray-Scott) for the next year, to help with the Cl-out project.
  

Videos of me talking about epilepsy and our research

We filmed a public presentation we made at the 2013 British Science Festival, and this has now been edited into a film that we have posted on-line (click here)

Feature about my work in Nature

Our studies about the nature of epileptic spread were the main focus of a recent review article in Nature.  (click here)

Some more information about my research

When the brain is working normally, very small numbers of brain cells are active at any given time.  Furthermore, the activity is kept tightly focussed as it flows through successive brain regions and is not allowed to spread out, in much the same way as water flowing in a river. 

The banks of the river determine where water can flow.  In the brain, the same job is done by a group of brain cells called inhibitory interneurons.  These brain cells allow activity to spread in one direction, but not to spread out sideways.  However, like a flood occurring when a bank is breached, these interneurons can fail too with similarly disastrous consequences.  Activity spreads out sideways, too many cells become active at once and an epileptic seizure is the result. 

A question I am trying to address in my research is what makes a brain seize.  Starting with tissue from a normal brain, one can increase the likelihood of “seizures” occurring, by changing the solution which bathes the neurons. After changing the solution, there is a very interesting transition period when the tissue behaves as if it were experiencing surges of activity, which are then overcome.  It is as if there are crises in the tissue, which are brought under control by the action of some powerful inhibition restraints.  I believe these restraints are rather like circuit breakers in electrical appliances, and my research has been directed at identifying which cells in the brain fulfil this role.

I am also interested in how these cells regulate activity in the brain.  This question is a fundamental one, addressing why cerebral cortex is built the way it is (see my review article in Trends in Neuroscience).  Furthermore, I want to understand the different ways in which these regulatory functions may break down.  We are also learning how to recognize when this pathology develops in humans.  For instance, we are using our insights from basic animal studies to learn how to interpret EEG recordings (electroencephalograms), one of the cornerstones of epilepsy diagnosis. 

A major effort in our lab is now invested in developing optogenetic strategies to investigate cortical function, and in particular to understand epilepsy and learn how we might manage it.  Last year, we developed a brand new optogenetic tool, designed to drive chloride out of neurons.  The build-up of chloride in neurons is thought to be involved in many epileptic conditions, and whilst there are drugs that try to limit this build up, once the chloride is inside the neurons there had been no way to extrude it.  This was the motivation for developing an optogenetic solution, which we called "Cl-out" (Alfonsa et al, (2016) Nature Communications).  We are continuing to develop this technology, funded through the grants from BBSRC. 

Part of this work is funded by a large grant, CANDO ("Controlling Abnormal Network Dynamics with Optogenetics", see http://www.cando.ac.uk/) involving 12 other Principal Investigators including clinical and non-clinical epilepsy researchers, bio-engineers manufacturing new LED / recording devices for implants into humans, experts in brain-machine interfaces, computational experts and molecular biologists developing new gene therapies.  

Particular research highlights include the following (links are provided to open access publications - please contact me for pdfs for any that you cannot access):

1. I was the first to use using network Ca² imaging to visualise a propagating ictal wave, leading to clinically important insights for surgical seizure localization.

The key papers are

Trevelyan et al., 2006

Trevelyan et al. 2007

Schevon et al., 2012

2. This work introduced the concepts of the “ictal core” and “ictal penumbra” (terminology that I coined) for the characterization of the spatial and temporal dynamics of seizure propagation.

See

Schevon et al., 2012

Trevelyan & Schevon, 2013 (review)

Weiss et al, 2014

3. I have developed novel approaches for manipulating chloride levels in neurons, using optogenetics, in order to understand how chloride levels influence synaptic inhibitory function in physiology and disease.

See

Alfonsa et al., 2015 and 2016

4. Latterly, we have addressed the role of dendritic excitability in creating a tipping point that defines the onset of a seizure.

See Graham et al., - preprint posted here; currently under peer review

• Firfilionis D, Hutchings F, Tamadoni R, Walsh D, Turnbull M, Escobedo-Cousin E, Bailey RG, Gausden J, Patel A, Haci D, Liu Y, LeBeau FEN, Trevelyan A, Constandinou TG, O'Neill A, Kaiser M, Degenaar P, Jackson A. A Closed-Loop Optogenetic Platform. Frontiers in Neuroscience 2021, 15, 718311.
• Mackenzie-Gray Scott CA, Parrish RR, Walsh DA, Racca C, Cowell RM, Trevelyan AJ. PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model. Journal of Neurophysiology 2022, 127(1), 86-98.
• Jones A, Barker-Haliski M, Ilie AS, Herd MB, Baxendale S, Holdsworth CJ, Ashton J-P, Placzek M, Jayasekera BAP, Cowie CJA, Lambert JJ, Trevelyan AJ, White HS, Marson AG, Cunliffe VT, Sills GJ, Morgan A. A multiorganism pipeline for antiseizure drug discovery: Identification of chlorothymol as a novel γ-aminobutyric acidergic anticonvulsant. Epilepsia 2020, 61(10), 2106-2118.
• Currin CB, Trevelyan AJ, Akerman CJ, Raimondo JV. Chloride dynamics alter the input-output properties of neurons. PLoS Computational Biology 2020, 16(5).
• Papasavvas CA, Trevelyan AJ, Kaiser M, Wang Y. Divisive gain modulation enables flexible and rapid entrainment in a neocortical microcircuit model. Journal of Neurophysiology 2020, 123(3), 1133-1143.
• Zhang J, Bhuiyan M, Zhang T, Karimy J, Wu Z, Fiesler VM, Zhang J, Huang H, Hasan MN, Skrzypiec AE, Mucha M, Duran D, Huang W, Pawlak R, Foley LM, Hitchens TK, Minnigh MB, Poloyac SM, Alper SL, Molyneaux BJ, Trevelyan AJ, Kahle KT, Sun D, Deng X. Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a. Nature Communications 2020, 11, 78.
• Papasavvas CA, Parrish RR, Trevelyan AJ. Propagating Activity in Neocortex, Mediated by Gap Junctions and Modulated by Extracellular Potassium. eNeuro 2020, 7(2).
• Schroeder GM, Diehl B, Chowdhury FA, Duncan JS, de Tisi J, Trevelyan A, Forsyth R, Jackson A, Taylor PN, Wang Y. Seizure pathways change on circadian and slower timescales in individual patients with focal epilepsy. Proceedings of the National Academy of Sciences of the United States of America 2020, 117(20), 11048-11058.
• Codadu NK, Graham RT, Burman RJ, Jackson-Taylor RT, Raimondo JV, Trevelyan AJ, Parrish RR. Divergent paths to seizure-like events. Physiological reports 2019, 7(19), e14226.
• Burman RJ, Selfe JS, Lee JH, van den Berg M, Calin A, Codadu NK, Wright R, Newey SE, Parrish RR, Katz AA, Wilmshurst JM, Akerman CJ, Trevelyan AJ, Raimondo JV. Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus. Brain 2019, 142(11), 3482-3501.
• Parrish RR, Codadu NK, Mackenzie-Gray Scott C, Trevelyan AJ. Feedforward inhibition ahead of ictal wavefronts is provided by both parvalbumin‐ and somatostatin‐expressing interneurons. Journal of Physiology 2019, 597(8), 2297-2314.
• Schevon CA, Tobochnik S, Eissa T, Merricks E, Gill B, Parrish RR, Bateman LM, McKhann GM, Emerson RG, Trevelyan AJ. Multiscale recordings reveal the dynamic spatial structure of human seizures. Neurobiology of Disease 2019, 127, 303-311.
• Codadu NK, Parrish RR, Trevelyan AJ. Region‐specific differences and areal interactions underlying transitions in epileptiform activity. The Journal of Physiology 2019, 597(7), 2079-2096.
• Parrish RR, Grady J, Codadu NK, Racca C, Trevelyan AJ. Graphical user interface for simultaneous profiling of activity patterns in multiple neuronal subclasses. Data in Brief 2018, 20, 226-233.
• Parrish RR, Codadu NK, Racca C, Trevelyan AJ. Pyramidal cell activity levels affect the polarity of gene transciption changes in interneurons. Journal of Neurophysiology 2018, 120(5), 2358-2367.
• Parrish RR, Grady J, Codadu NK, Trevelyan AJ, Racca C. Simultaneous profiling of activity patterns in multiple neuronal subclasses. Journal of Neuroscience Methods 2018, 303, 16-29.
• Parrish RR, Trevelyan AJ. Stress-testing the brain to understand its breaking points. Journal of Physiology 2018, 596(11), 2033-2034.
• Yazdani P, Read JCA, Whittaker RG, Trevelyan AJ. Assessment of epilepsy using noninvasive visual psychophysics tests of surround suppression. Physiological Reports 2017, 5(5), e13079.
• Wang Y, Trevelyan AJ, Valentin A, Alarcon G, Taylor PN, Kaiser M. Mechanisms underlying different onset patterns of focal seizures. PLoS Computational Biology 2017, 13(5), e1005475.
• Alfonsa H, Lakey JH, Lightowlers RN, Trevelyan AJ. Cl-out is a novel cooperative optogenetic tool for extruding chloride from neurons. Nature Communications 2016, 7, 13495.
• Trevelyan AJ. Do Cortical Circuits Need Protecting from Themselves?. Trends in Neuroscience 2016, 39(8), 502-511.
• Smith EH, Liou JY, Davis TS, Merricks EM, Kellis SS, Weiss SA, Greger B, House PA, McKhann GM, Goodman RR, Emerson RG, Bateman LM, Trevelyan AJ, Schevon CA. The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures. Nature Communications 2016, 7, 11098.
• Papasavvas CA, Wang Y, Trevelyan AJ, Kaiser M. Gain control through divisive inhibition prevents abrupt transition to chaos in a neural mass model. Physical Review E 2015, 92(3), 032723.
• Read JCA, Georgiou R, Brash C, Yazdani P, Whittaker R, Trevelyan A, Serrano-Pedraza I. Moderate acute alcohol intoxication has minimal effect on surround suppression measured with a motion direction discrimination task. Journal of Vision 2015, 15(1), 5.
• Stoll EA, Makin R, Sweet IR, Trevelyan AJ, Miwa S, Horner PJ, Turnbull DM. Neural stem cells in the adult subventricular zone oxidize fatty acids to produce energy and support neurogenic activity. Stem Cells 2015, 33(7), 2306-2319.
• Weiss SA, Lemesiou A, Connors R, Banks GP, McKhann GM, Goodman RR, Zhao BS, Filippi CG, Nowell M, Rodionov R, Diehl B, McEvoy AW, Walker MC, Trevelyan AJ, Bateman LM, Emerson RG, Schevon CA. Seizure localization using ictal phase-locked high gamma: A retrospective surgical outcome study. Neurology 2015, 84(23), 2320-2328.
• Merricks EM, Smith EH, McKhann GM, Goodman RR, Bateman LM, Emerson RG, Schevon CA, Trevelyan AJ. Single unit action potentials in humans and the effect of seizure activity. Brain 2015, 138(10), 2891-2906.
• Alfonsa H, Merricks EM, Codadu NK, Cunningham MO, Deisseroth K, Racca C, Trevelyan AJ. The Contribution of Raised Intraneuronal Chloride to Epileptic Network Activity. Journal of Neuroscience 2015, 35(20), 7715-7726.
• Trevelyan A, Muldoon SF, Merricks EM, Racca C, Staley K. The Role of Inhibition in Epileptic Networks. Journal of Clinical Neurophysiology 2015, 32(3), 227-234.
• Yazdani P, Serrano-Pedraza I, Whittaker RG, Trevelyan A, Read JC. Two common psychophysical measures of surround suppression reflect independent neuronal mechanisms. Journal of Vision 2015, 15(13).
• Allen JG, Coates G, Trevelyan J. Dynamically Controlled Variable-Fidelity Modelling for Aircraft Structural Design Optimisation. Proceedings of the Institution of Mechanical Engineers Part G: Journal of Aerospace Engineering 2014, 228(8), 1434-1449.
• Trevelyan AJ, Schevon CA. How inhibition influences seizure propagation. Neuropharmacology 2013, 69, 45-54.
• Weiss SA, Banks GP, McKhann GM, Goodman RR, Emerson RG, Trevelyan AJ, Schevon CA. Ictal high frequency oscillations distinguish two types of seizure territories in humans. Brain 2013, 136(12), 3796-3808.
• Pouille F, Watkinson O, Scanziani M, Trevelyan AJ. The contribution of synaptic location to inhibitory gain control in pyramidal cells. Physiological Reports 2013, 1(5), e00067.
• Trevelyan AJ, Bruns W, Mann EO, Crepel V, Scanziani M. The information content of physiological and epileptic brain activity. The Journal of Physiology 2013, 591(4), 799-805.
• Schevon CA, Weiss S, McKhann G, Goodman RR, Yuste R, Emerson RG, Trevelyan AJ. Evidence of an inhibitory restraint of seizure activity in humans. Nature Communications 2012, 3, 1060.
• Ali H, Forraz N, McGuckin C, Jurga M, Lindsay S, Ip BK, Trevelyan A, Basford C, Habibollah S, Ahmad S, Clowry GJ, Bayatti N. In vitro modelling of cortical neurogenesis by sequential induction of human umbilical cord blood stem cells. Stem Cell Reviews and Reports 2012, 8(1), 210-223.
• Jurga M, Forraz N, Basford C, Atzeni G, Trevelyan AJ, Habibollah S, Ali H, Zwolinski SA, McGuckin CP. Neurogenic Properties and a Clinical Relevance of Multipotent Stem Cells Derived from Cord Blood Samples Stored in the Biobanks. Stem Cells and Development 2012, 21(6), 923-936.
• Prida L, Trevelyan AJ. Cellular mechanisms of high frequency oscillations in epilepsy: on the diverse sources of pathological activities. Epilepsy Research 2011, 97(3), 308-317.
• Trevelyan AJ, Kirby DM, Smulders-Srinivasan TK, Nooteboom M, Acin-Perez R, Enriquez JA, Whittington MA, Lightowlers RN, Turnbull DM. Mitochondrial DNA mutations affect calcium handling in differentiated neurons. Brain 2010, 133(3), 787-796.
• Trevelyan A, Yuste R. Imaging seizure propagation in vitro. Neuromethods 2009, 40, 141-161.
• Schevon CA, Trevelyan AJ, Schroeder CE, Goodman RR, McKhann G, Emerson RG. Spatial characterization of interictal high frequency oscillations in epileptic neocortex. Brain 2009, 132(11), 3047-3059.
• Trevelyan AJ. The Direct Relationship between Inhibitory Currents and Local Field Potentials. Journal of Neuroscience 2009, 29(48), 15299-15307.
• Trevelyan AJ, Upton AL, Cordery PM, Thompson ID. An experimentally induced duplication of retinotopic mapping within the hamster primary visual cortex. European Journal of Neuroscience 2007, 26(11), 3277-3290.
• Trevelyan AJ, Sussillo D, Yuste R. Feedforward inhibition contributes to the control of epileptiform propagation speed. Journal of Neuroscience 2007, 27(13), 3383-3387.
• Trevelyan AJ, Baldeweg T, Van Drongelen W, Yuste R, Whittington M. The source of afterdischarge activity in neocortical tonic-clonic epilepsy. Journal of Neuroscience 2007, 27(49), 13513-13519.
• Trevelyan AJ, Sussillo D, Watson BO, Yuste R. Modular propagation of epileptiform activity: Evidence for an inhibitory veto in neocortex. Journal of Neuroscience 2006, 26(48), 12447-12455.