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Brain Science Shintaro Funahashi Dorsolateral Prefrontal Cortex Working Memory and Executive Functions Brain Science SeriesEditors Hideyuki Okano, Department of Physiology, Keio University School of Medicine, Shinjuku-ku,Tokyo,Japan AtsushiIriki,LabforSymbolicCognitiveDevelopment,RIKENBrainScience Institute&RIKENCe,Wako-shi,Saitama,Japan The “BrainScience Series” providescritical and comprehensivediscussionsof the most significant areas of neuroscience research, written by scientific leaders and authorities. Each volume in the series presents the latest and most complete infor- mationonitsrespectivesubject,makingitanunrivalledreferencesource.Toanalyze brain functions that have been preserved through evolution, a reductive approach basedongenemanipulationusingmodelssuchasgeneticallymodifiedrodentswere mainly used. At the same time, to analyze high-order brain functions that are uniquely acquired only in non-human primates and humans, analyses of complex behaviorsusingapsychologicalapproachweremainlyadopted.TheBrainScience Seriesfocusesonclarifyingtheoperatingprinciplesoftheneuralcircuitrygoverning thehumanmind,aswellastheaccompanyingmolecularmechanisms. Shintaro Funahashi Dorsolateral Prefrontal Cortex Working Memory and Executive Functions ShintaroFunahashi KokoroResearchCenter KyotoUniversity Kyoto,Kyoto,Japan ISSN2570-0197 ISSN2570-0200 (electronic) BrainScience ISBN978-981-19-7267-6 ISBN978-981-19-7268-3 (eBook) https://doi.org/10.1007/978-981-19-7268-3 ©SpringerNatureSingaporePteLtd.2022 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthe materialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation, broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformation storageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodology nowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublication doesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevant protectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors, and the editorsare safeto assume that the adviceand informationin this bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsor theeditorsgiveawarranty,expressedorimplied,withrespecttothematerialcontainedhereinorforany errorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwithregardtojurisdictional claimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore This book is dedicated to my two great mentors, Profs. Kisou Kubota and Prof. Patricia S. Goldman-Rakic, and my wife, Mihoko Funahashi. Preface The prefrontal cortex is known to participate in a variety of higher cognitive functionsincludingappropriateplanning,thinking,reasoning,anddecision-making. The prefrontal cortex occupies a larger part in the cerebral cortex compared with other association cortices and consists of three main sectors (lateral, medial, and orbital sectors). Among these three sectors, the lateral sector, especially the dorso- lateralpartoftheprefrontalcortex,isverywellknowntoplaymostimportantroles inthosehighercognitivefunctions.Sinceneurophysiologicalstudiesusingmonkeys hadbeenstartedin1970sandsinceneuroimagingstudiesusinghumansubjectshad been started in 1990s, huge amount of information regarding prefrontal functions and their neural mechanisms has been accumulated. Based on accumulated information, several important books focused on prefrontal functions have been published. These include The Prefrontal Cortex (fifth edition) by Joaquin M. Fuster and The Neurobiology of the Prefrontal Cortex by Richard E.PassinghamandStevenP.Wise.Theformeristhemostcomprehensivetextbook oftheprefrontalcortexandthetopicsincludeanatomy,pharmacology,animaland human neuropsychology, neurophysiology, human neuroimaging, and a theory of prefrontal functions. I have used this book as the most important reference book from the first edition. In the latter, the authors described functions of each of five sectors (medial, orbital, caudal, dorsal, and ventral) of the prefrontal cortex and summarized the function of the prefrontal cortex as generating goals from current contextsandevents.ThethirdbookisPrinciplesofFrontallobeFunction(second edition) edited by Donald T. Stuss and Robert T. Knight, which is based on the secondsymposiumontheprefrontalcortexheldatTorontoin2010andconsistsofa varietyof topicsincluding models, social behavior, clinical neuropsychology, psy- chiatricdisorders,andrehabilitation. Thesebooksareimportantonestounderstandfunctionsoftheprefrontalcortex. Since1972,alargeamountofneurophysiologicalresultshasbeenaccumulatedfor the functions of the dorsolateral prefrontal cortex. It has been recognized that working memory is a useful concept to understand several important functions of the dorsolateral prefrontal cortex. However, there is no book which focuses on functionsofthedorsolateralprefrontalcortexandtheirrelationstoworkingmemory. vii viii Preface Therefore, this book focuses mainly on functions of the dorsolateral prefrontal cortex, especially how neural mechanisms related to working memory contribute to these functions. I have investigated dorsolateral prefrontal functions using mon- keys by neurophysiological techniques since 1977 at Kyoto University and Yale university. Therefore, I mainly focus on neurophysiological results obtained from monkeydorsolateralprefrontalcortexinthisbook.Becauseofthisreason,notmany studies regarding human neuroimaging studies,pharmacologicalstudies,and theo- retical studies are included in this book. However, I think that I can show and summarize important studies to understand dorsolateral prefrontal functions and their neural mechanisms in this book, which include working memory, executive control, cognitive control and memory management, decision-making, metacogni- tion,andtop-downcontrol. Kyoto,Japan ShintaroFunahashi April27,2022 Acknowledgments IwouldliketoexpressmysincerethankstoProf.KisouKubotaatKyotoUniversity for the long-time support and encouragement to my research. I would also like to express my sincere thanks to Late Prof. Patricia S. Goldman-Rakic and Charles J.BruceatYaleUniversityfortheirextremelyvaluablesupportandkindhelpduring my7-yearstayatYaleUniversityandthereafter.Andfinally,Iwouldliketoexpress my sincere thanks to the students of my group at Kyoto University, especially to MasatoInoue,KazuyoshiTakeda,YumikoWatanabe,SatoeIchihara-Takeda,Saori Igaki, Kei Watanabe, Jorge Mario Andreau, Kei Mochizuki, and Akio Tanaka. Without working with the students of my group at Kyoto University, this book would not be possible. I would like to thank for the funds (KAKENHI) from the JapaneseMinistryofEducation,Culture,Sports,ScienceandTechnology(MEXT) and from Japan Society for the Promotion of Science (JSPS) and the funds from JapanScienceandtechnologyAgency(JST)forsupportingmyresearchactivitiesat Kyoto University. I also express my thanks to Beijing Institute of Technology and Shenzhen Institute of Advanced Technology for supporting my continuation of prefrontalresearchesinChinaaftermyretirementfromKyotoUniversity. ix Contents 1 DorsolateralPrefrontalCortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 ThePrefrontalCortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.3 FeaturesofthePrefrontalCortex. . . . . . . . . . . . . . . . . . . . . . 5 1.4 AnatomicalFeaturesofthePrefrontalCortex. . . . . . . . . . . . . 9 1.4.1 CytoarchitectonicFeatures. . . . . . . . . . . . . . . . . . . 9 1.4.2 CytoarchitectonicFeaturesoftheLateralPrefrontal Cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.4.3 RelationstotheThalamicMediodorsalNucleus. . . . 13 1.4.4 GranularLayerIV. . . . . . . . . . . . . . . . . . . . . . . . . 15 1.4.5 Mesulam’sCorticalClassification. . . . . . . . . . . . . . 16 1.5 AnatomicalFeaturesoftheLateralPrefrontalCortex. . . . . . . . 18 1.5.1 CellularComponents. . . . . . . . . . . . . . . . . . . . . . . 18 1.5.2 AnatomicalHeterogeneityinArea46. . . .. . . . . . .. 23 1.5.3 Cortico-CorticalConnections. . . .. . . . . . . . . . . . .. 26 1.5.4 Cortico-SubcorticalConnections. . . . . . . . . . . . . . . 30 1.5.5 IntracorticalStructures:ColumnarOrganization. . .. 33 1.6 FunctionalFeaturesoftheLateralPrefrontalCortex. . . . . . . . 34 1.6.1 HumanPrefrontalFunctions. . . . . . . . . . . . . . . . . . 36 1.6.2 FunctionalHeterogeneityofthePrefrontalCortex. . . 37 1.6.3 FunctionalHeterogeneityinHumanPrefrontal Cortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 1.6.4 FunctionalDevelopmentofthePrefrontalCortex. . . 41 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 2 HistoricalPerspectiveofPrefrontalResearch. . . . . . . . . . . . . . . . . 53 2.1 FunctionalLocalizationoftheCerebralCortex. . . . . . . . . . . . 53 2.2 HistoricalPerspectiveofFrontalLobeFunctions. . . . . . . . . . . 55 2.2.1 DebateBetweenHolisticTheoryandLocalization Theory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 xi