Table Of ContentZhe Chen · Sridevi V. Sarma Editors
Dynamic
Neuroscience
Statistics, Modeling, and Control
Dynamic Neuroscience
Zhe Chen • Sridevi V. Sarma
Editors
Dynamic Neuroscience
Statistics, Modeling, and Control
123
Editors
ZheChen SrideviV.Sarma
SchoolofMedicine InstituteforComputationalMedicine
NewYorkUniversity JohnsHopkinsUniversity
NewYork,NY,USA Baltimore,MD,USA
ISBN978-3-319-71975-7 ISBN978-3-319-71976-4 (eBook)
https://doi.org/10.1007/978-3-319-71976-4
LibraryofCongressControlNumber:2017962864
©SpringerInternationalPublishingAG2018
Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartof
thematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,
broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation
storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology
nowknownorhereafterdeveloped.
Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication
doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant
protectivelawsandregulationsandthereforefreeforgeneraluse.
Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthisbook
arebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor
theeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinorforany
errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional
claimsinpublishedmapsandinstitutionalaffiliations.
Printedonacid-freepaper
ThisSpringerimprintispublishedbySpringerNature
TheregisteredcompanyisSpringerInternationalPublishingAG
Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland
Dedicatedtothe60thbirthdayof
ProfessorEmeryNeal Brown
Preface
Apre-prefacenote:ThisbookisdedicatedtoProfessorEmeryN.Browninhonorof
hisgreatscientificcontributionsandhis60thbirthday(inparallelwithasymposium
held in MIT on September 14–15, 2017). Noticing diverse scientific themes of
Emery’s work, the editors have invited Professor Rob Kass and Professor Ralph
Lydic to write their personalreflections on Emery’s scientific contributionsin the
fieldsofneurostatisticsandanesthesiology,respectively.
Reflections from RobKass
ItisagreatpleasuretobeginthisvolumebyofferingashortperspectiveonEmery
N. Brown. There is much to admire in Emery’s research, and also much to learn
from his unique path to scientific leadership. As Emery’s students and colleagues
know,butsomereadersofthisbookmaynot,EmerycombinedhisM.D.,including
a fellowship and board certification in anesthesiology, with a Ph.D. in statistics,
and his professionallife reflects this unusualtraining:he is in the operatingroom
onedayeveryweek,andrunshis humananesthesiologystudies, atMassachusetts
GeneralHospital(MGH),yetheteachesclassesinstatisticsandhashismainoffice
intheDepartmentofBrainandCognitiveSciencesatMIT.Togetherwithhismany
collaborators, Emery has produced important new methods for analysis of neural
data, advancingknowledge in a variety of scientific subdisciplines in the process,
whilehisresearchonthe mechanismsbywhichanesthesiaproducesalteredstates
ofarousalis puttingthe subjectona firm foundation.Emeryisthe onlypersonto
holdchairedprofessorshipsatbothHarvardMedicalSchoolandMIT.
One clue in trying to understand Emery’s trajectory comes from his under-
graduatemajorinappliedmathematics,whichgavehimtwothings:knowledgeof
elementarymethodsin dynamicalsystems and an appreciationfor the importance
of statistics. Emery brought these strands together in his PhD thesis work on
time series analysis for circadian rhythms data. In addition, Emery recognized
vii
viii Preface
the potential for exploiting the connection between dynamical system models
represented by differential equations, in continuous time, and certain time series
models—including,especially,state-spacemodels—thatcanbeconsidereddiscrete
analogues, where differential equations are replaced by difference equations. It
is hard to overstate the importance of Emery’s fundamental contribution, even
though it will someday seem obvious: dynamic neural phenomena should be
describedusingdynamicmethods,whichincludesbothmathematicalmodelstoaid
understanding and statistical models to guide data analysis. Emery has made this
big picturecontribution,which I see as his enduringtechnicallegacy,notthrough
asinglediscovery,butthroughasteadystreamofcasesthat,takentogether,forma
compellingwhole.Inretrospect,itisnothardtoseethearcfromEmery’sscientific
startingpointincircadianrhythms,whichheidentifiedasafertilesubjectinwhich
differential equations and statistical inference could be brought together to move
thescienceforward,tohisnumerouscreativeapplicationsofstate-spacemodeling
intheanalysisofneuraldata,tohisrecentdiscoveries,enabledbybiophysicaland
statisticalmodeling,thatareestablishingamechanisticneuroscienceofanesthesia.
Beyond the seemingly prescient choices he made in his education, Emery has
hadarareabilitytoadoptgoodstrategiesforachievingworthygoals.Atmanykey
pointsinhiscareer,hehashadthepatienceandconfidencetoturnawayfromshort-
termgainandhas,instead,investedhistimeandenergyinlearningwhatheneeded
to know, and creating the environmentnecessary to achieve results he recognized
as truly important. This has required not only foresight and dogged persistence
but also a kind of dexterity in sidestepping the inevitable pitfalls. Emery himself
emphasizedthisduringaninformaltalkhegavemanyyearsagoatCarnegieMellon
University, to a group of underrepresented minority students: he spoke of some
unpleasant childhood experiences, which began while public schools in his home
stateofFloridaweresegregated,andthencontinuedwhen,afterdesegregation,he
facedinstancesofblatantracialdiscrimination.DuringhisremarksEmerystressed
that while it is natural to be angered at such injustices, it is more productive to
findwaysaroundtheobstaclestheycreated;headdedthateveryonefacesobstacles
of variouskinds, butthe mostsuccessfulamongusare those who stay mindfulof
their goals and stay focused on finding paths to achievement. Those words have
stayed with me as I have witnessed Emery’s uncanny mastery of circumventing
obstructions,whichcomeinsomanydifferentforms.Thereisalimittowhicheach
of us can be like our heroes, but we would all be wise to take the advice Emery
offered to those students, and, at least in this respect, try to emulate his success.
Finally, I’d like to add that, from many, many conversations, I know how deeply
Emerycaresabouttrainingatalllevels.Ontheonehand,hehasputgreatenergyinto
hiscoursesatMIT,andintospecializedshortcoursesaroundtheworld.Ontheother
hand,hedemonstratessincereconcernforallhismanystudentsandpostdocs.This
bookis a greattestimonyto what Emeryhasdone for histrainees, as they review
some of their recentscientific advances,thereby givingback to him somethingof
lastingvalue,inthebestintellectualspirit,andwithcontinuingaffection.
Preface ix
Reflections from RalphLydic
It is my great pleasure to highlight selected aspects of Emery Brown’s many
contributions to anesthesia research. The editorial directives were to provide a
brief, personal perspective. Of primary importance is the fact that the future of
every discipline depends on the acquisition of new knowledge via recruitment
andretentionofinvestigators.ThisFestschrift,organizedbyEmery’scollaborators
and former students, effectively conveys the admiration and affection with which
Emeryis regarded.Emeryisuniquelysuccessfulatprovidingnovelandclinically
relevant scientific discoveries while promoting his colleagues. Emery’s ability to
create an extended scientific family powerfully supplants the dehumanizing view
of faculty and staff as a “human resource.” Emery became an Assistant Professor
of anesthesiology in 1993 and during the ensuing 24 years he has mentored
morethan200undergraduates,graduatestudents,andfellows.Menteesinclude28
anesthesiology residents and faculty, some of whom remain actively engaged in
research.Emery’sroleasamentorhasgeneratedanincalculablypositive“returnon
investment”foracademicanesthesiology.
IviewEmery’sanesthesia-relatedresearchasalinesegmentoriginatingdecades
ago from his successful mathematical modeling of sleep and circadian rhythms.
Several of Emery’s early papers are regarded as classics today. I first met Emery
in the mid-1980s when he and I were associated with different Harvard training
programs. It was kindness of Robert (Bob) McCarley that Emery and I had
our first scientific exchange. A decade earlier Bob, using Lotka-Volterra type
equations, had developed the first cellularly based, mathematical model of the
mammaliansleepcycle.Aboutthesametime,Emerywasindependentlydeveloping
dynamical systems models and nonlinear filtering techniques to characterize the
oscillatory properties of biological rhythms. I was recording the discharge of
dorsal raphe neurons across the sleep/wake cycle. We were keen to combine our
respectiveapproaches.Inwhatmaybeanexampleofexcessivesynapticdelay,our
collaborativeplansfinallymaturedin2010whenEmeryinvitedNicholasSchiffand
metocoauthorareviewfortheNewEnglandJournalofMedicine.Relativetothe
present volume, that review presents a structurally based story model concerning
theneuralnetworksthatgeneratestatesofanesthesia,sleep,andcoma.
Anesthesiaandsleeparedistinctlydifferentstatesofconsciousnessidentifiedby
constellations of physiological and behavioral traits. Emery’s early mathematical
modeling of sleep is thematically related to his current anesthesiology research.
The present prologue was written 117 years after the first demonstration of ether
anesthesia.Incontrast,modernhumanshaveexistedforabout160,000years.The
ratio of these two numbers illustrates the small percentage of time that humans
have been able to reliably manage surgical pain. At the beginning of the current
millennium,the 6June 2000issue oftheNew EnglandJournalofMedicinelisted
anesthesiaas“oneofthemostimportantmedicaldevelopmentsofthepastthousand
x Preface
years.” At present, there are approximately 60,000 cases of general anesthesia
each day in the United States. When delivered by expert caregivers, anesthesia is
remarkably safe. In no case, however, is it understood how anesthetics eliminate
wakingconsciousness.Understandingthemechanismsofanestheticactionwillbe
asignificantscientificadvance.Atthelevelofclinicalcare,suchanunderstanding
willhelpdevelopcountermeasuresthatdiminishoreliminateunwantedanesthetic
sideeffectssuchasnauseaandvomiting,aswellasinadequatepainreliefcurrently
experienced by about half of postsurgical patients. All of the desired effects
producedbygeneralanesthetics,sedatives,andopiatesareproductsofthenervous
system. Thus, anesthesiology can be viewed as a branch of clinical neuroscience.
In addition, Emery’s anesthesia research has the potential to advance neurology,
sleep disorders medicine, pain medicine, and biological psychiatry. An enhanced
understandingoftheneuronalmechanismsofanesthesiaalsoislikelytocontribute
toconsciousnessstudies.
Directly relevant to the present volume is Emery’s creative application of
computationalbiology to problemsrelevantfor anesthesiology.One challenge for
sucharesearchprogramiscomplexity.Anestheticeffectsonanydependentmeasure
varybytraitandbyscale.Sourcesofvariabilityincludetheclassandamountofdrug
administered,brainregionsactedupon,sex,age,species,andtime,tonameafew.
All of these features also are subject to individualallelic variability. Obviously, a
furthercomplexityisthattraitsandscalesvaryasafunctionofdiseasestates.
Rapidlyadvancingtechnologieswillhelpaddressmanyoftheforgoingcomplex-
ities. Forexample,the2014Intelmicroprocessorcontainingmorethan35million
transistors per square mm will soon be surpassed by a smaller chip that triples
the number of transistors per square mm. Computational neuroscience can build
largedatamatricesthatareidealfornovelanalyticapproaches,suchasJimGrey’s
“fourthscienceparadigm”using“bigdata.”Supercomputerdevelopmentalsoholds
excitingpromiseforadvancingcomputationalneuroscience.The26June2016issue
of Science reported that 167 of the World’s top 500 supercomputersare in China
and have a total capacity of 211Pflop/s compared to 165 supercomputers in the
UnitedStateswithacumulativecapacityof173Pflop/s.IamconfidentthatEmery’s
research,discoveriesbyhistraineesandcolleagues,andbookssuchasthisonewill
continuetoadvancecomputationalneurosciencethatenhancesanesthesia.
Pittsburgh,PA,USA RobertE.Kass
Knoxville,TN,USA RalphLydic
July2017
Acknowledgements
We are deeply indebted to Professor Emery Brown, without whom this book
would be impossible. Most chapter contributors are former graduate students or
postdoctoralfellowswithstrongacademiccareersandhavegreatlybenefitedfrom
theirtrainingwith Emery.Itgoeswithoutsayingthatallofusareforevergrateful
forEmery’smentorship.
WearealsogratefultotheeditorsandstaffmembersofSpringerforsupporting
thisbookproject.Inparticular,MartaMoldvaihasbeenaconstantcontactwithus
duringthedevelopmentofthisproject,fromthemomentwesubmittedourproposal
forthisbook.Fromthestartoftheproject,ZoeKennedyandMurugesanTamilsevan
havealsobeenhelpinguskeepeverythinginorderandtodeliverontime.
We are indebted to Professor Rob Kass and Professor Ralph Lydic, who have
kindly accepted our invitation to write the preface of this book. Their personal
reflectionsontheirownrelationshipswithEmeryreflectEmery’sbroadknowledge
and impact in multiple fields. In preparing the book proposal, Professor Kass has
alsoofferedsomeadvice,includingthetitleofthisbook.Thisbookalsobenefited
intellectuallyfromaspecialsymposiumheldatMassachusettsInstituteofTechnol-
ogy(MIT)onSeptember14–15,2017,forwhichwealsothankMs.SheriLeoneand
Ms. Kara Pavone who offered tremendous help in logistics and communications.
We would like to express our deep gratitude to the generous financial support
on the symposium from the Burroughs Wellcome Fund, Massachusetts General
Hospital(MGH),andMIT.Finally,wealso liketothankourdedicatedcolleagues
forvaluablecommentsandproofreadingeffort.
NewYork,NY,USA ZheChen
Baltimore,MD,USA SrideviV.Sarma
xi
