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Executive functions after focal lesions to the lateral, orbital and medial subdivisions of the prefrontal cortex - neuropsychological, behavioral and electrophysiological findings Marianne Løvstad Sunnaas

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Executive functions after focal lesions to the lateral, orbital and medial subdivisions of the prefrontal cortex - neuropsychological, behavioral and electrophysiological findings Marianne Løvstad Sunnaas Rehabilitation Hospital Department of Research - Oslo University Hospital, Rikshospitalet Department of Neuropsychiatry and Psychosomatic Medicine Division of Surgery and Clinical Neuroscience - Department of Psychology Faculty of Social Sciences University of Oslo 2012 Marianne Løvstad, 2012 Series of dissertations submitted to the Faculty of Social Sciences, University of Oslo No. 366 ISSN All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Inger Sandved Anfinsen. Printed in Norway: AIT Oslo AS. Produced in co-operation with Akademika publishing, Oslo. The thesis is produced by Akademika publishing merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate. Table of contents Acknowledgements 3 Abbreviations 5 General Summary 6 List of papers 8 Introduction 9 Executive functions 10 The frontal lobes anatomical delineations and developmental features 11 Anatomical and functional networks in PFC 13 1) The dorsolateral prefrontal circuit cognitive executive control 14 2) The orbitofrontal circuit decision-making and self-regulation 15 3) The anterior cingulate circuit energizing and task monitoring 16 4) The frontal polar region - metacognition 17 Core cognitive domains in executive functioning attention and inhibition 18 The neuropsychology and assessment of EF 24 The electrophysiology of attentional control 30 Main research objectives 34 Methods 36 Participants 36 Procedures 38 EEG-recordings 40 MRI lesion reconstruction 40 Statistical analysis 41 Ethical considerations 41 Summary of papers 42 Paper I - Contribution of subregions of human frontal cortex to novelty processing. 42 Paper II - Executive functions after orbital or lateral prefrontal lesions: Neuropsychological profiles and self-reported executive functions in everyday living. 43 Paper III - Anterior cingulate cortex and cognitive control: Neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex. 44 Discussion 45 Fractionation and integration of cognitive control 45 Escaping the homunculus Reconciling the dispute 49 The usefulness of broad methodological approaches in assessment of EF 51 Methodological issues 53 Lesion etiology 53 Anatomical subgroups 56 Alternative strategies of analysis in lesion studies 57 Choice of neuropsychological assessment tools and questionnaires 58 The electrophysiology of lesioned brains 58 Clinical implications - treatment of executive functions 59 Conclusions and future directions 60 References 63 Papers I-III 2 Acknowledgements It has been said it s not a coincidence what topic you do research on. The last few years have challenged every bit of planning ability, strategic thinking, goal management and impulse control available. At times my frontal lobes ensured goal directed progress, while every now and then the fine tuned balance between inhibitory and excitatory control broke down at the cognitive and emotional level at once, leaving chaos and non-directionality. Executive functions define our humanity, also when they fail us. So many have contributed so much. To the patients who gave of their time and invested in telling their unique stories. Every single one argued that their participation was grounded in a wish to help others who have to go through what life had offered themselves. Being a clinician implies being awed again and again by the human capacity for survival, coping and empathy. Thank you. I went from clinical neuropsychology to neuroscience. I have learned more than I believed possible. Anne-Kristin Solbakk, my main supervisor, thank you. For your knowledge and experience, your devotion, your patience and loyalty, your everlasting capacity to persevere, and not the least, your friendship. Ingrid Funderud, my very smart colleague and fellow PhDstudent. The little sister I never had. Without each other, we would have died. To Robert T. Knight. It has been an honor and a huge privilege to work with you. You have shown me the very best of academic life on so many levels. To the FRONT research group, thank you Tor Endestad, co-supervisor, Magnus Lindgren, co-supervisor, Paulina Due-Tønnessen, Torstein Meling. Torstein, remember you are the only person allowed to cut in my brain. Bradley Voytek and Ulrike Krämer, great collaborators and saviors in MatLab scripting. Sunnaas rehabilitation hospital is my professional home. Some of my dearest colleagues and friends are there. Thank you to the psychologists for being such an awesome, dynamic and friendly collegiate. Anne-Kristine Schanke, my mentor in life and psychology. Jan Stubberud, for collaborations, friendship and tremendous emotional support. Solveig Lægreid Hauger, I cannot wait to embrace our common research, you are amazing. Jan-Egil Nordvik, for optimistically pointing towards the future. Solrun Sigurdardottir, for showing it was possible. Anette Johansen Quale, for sharing your positivism. You are deeply missed but always part of who we are. To the research department. Johan Stanghelle, the boss of my dreams, thank you 3 for calm, continuous and steady support. Frank Becker, friend and colleague, for good conversations about so many things. Sveinung Tornaas, for all you have done and will do for the brain injury population. Einar Magnus Strand, for not giving up on rehabilitation. To the brain injury department, for waiting, I am coming home. I am humbly grateful to belong at Sunnaas rehabilitation hospital, and to be part of it s proud neuropsychological tradition. Thank you to the department of Psychology at the University of Oslo for letting me follow their PhD program. Thank you to Helse Sør-Øst, the Norwegian Research Council and Sunnaas Rehabilitation Hospital for funding. Thank you to Oslo University Hospital, Rikshospitalet, Department of Neuropsychiatry and Psychosomatic Medicine for allowing me to conduct the research there. Thank you to Prof. Ivar Reinvang and Prof. Svein Magnussen, whom introduced me to ERP, experimental cognitive psychology and research. Thank you to the Norwegian Neuropsychological Association and all board members for being a great collegial group, and for tons of fun. To Erik Hessen, for believing in me when I didn t. Finally, but not least. Sigurd and Øystein, being your mother is the greatest gift of my life. No professional accomplishment can be compared with the proudness I feel over you. Remember, I love you simply because you exist, and that cannot change. Kyrre, you know what you have meant. Your knowledge, your experience, your ability to analyze with me and listen to my stories. As a biologist, you taught me that only humans are able to wait with the best food until the end of a meal. The essence of frontal lobe functioning. So many bottles of Italian red over science, statistics and the research process, but most of all my emotional well-being in it. Thank you for enduring. Lets have some fun now. Thank you to my mother and father and brother, you never stopped being proud. To my American family and second home in the Blue Ridge Mountains. I am blessed with many friends. Without them I would have been poor. No one mentioned no one left out. You know who you are, and you know I would suffocate without you. Finally, thank you Spot, the cutest and most loving dog. No frontal lobes, instant joy and affection. I am privileged. The journey into science has brought along a major professional and personal development. Thank you everyone for travelling with me. We ve only just begun. Marianne Løvstad, Nesodden, June 20 th Abbreviations ABI Acquired brain injury ACC anterior cingulate cortex ACcd anterior cingulate cognitive division ACad anterior cingulate affective division AD Alzheimers disease ADHD Attention Deficit Hyperactivity Disorder BA Brodmann area BOLD blood oxygen level dependent BVMT-R Brief Visuospatial Memory Test- Revised BRIEF-A Behavior Rating Inventory of Executive Function - Adult version CE central executive CT Computer Tomography CVA cerebrovascular accident CVLT-II the California Verbal Learning Test - Second Edition CWI Colour-Word Interference Test DAI diffuse axonal injury D-KEFS Delis-Kaplan Executive Function System DLPFC dorsolateral prefrontal cortex EF executive functions ERP event-related potentials fmri functional Magnetic Resonance Imaging GOS-E Glasgow Outcome Scale - Extended LGG low grade glioma LPFC lateral prefrontal cortex MD Major depression MRI Magnetic Resonance Imaging OCD Obsessive Compulsive Disorder OCI-R Obsessive-Compulsive Inventory Revised OFC orbitofrontal cortex PD Parkinsons disease PFC prefrontal cortex RT reaction time SAH subarachnoid haemorrhage SAS Supervisory Attention System SCL-90-R Symptom Checklist 90 Revised SMA supplementary motor area TBI traumatic brain injury TMT Trail Making Test ToM Theory of Mind VMPFC ventromedial prefrontal cortex WAIS-III Wechsler Adult Intelligence Scale - Third Edition WASI Wechsler Abbreviated Scale of Intelligence WCST Wisconsin Card Sorting Test 5 General Summary Executive functions (EF) ensure goal-directed behavior and flexible adaptation to changing environmental requirements. EF enable us to plan and anticipate future events, with the capacity to control and distribute attentional resources being an important part of normal EF. Executive deficit is common following acquired brain injury and results in problems with higher-order control over thoughts, emotions and behavior. Presence of executive problems complicates the rehabilitation process and has negative impact on long-term outcome. Executive control is mediated by distributed but anatomically dissociable neural networks where the prefrontal cortex (PFC) plays an important role. Three main frontal-subcortical circuits involving the lateral (LPFC), orbital (OFC), and medial (MPFC) subdivisions of PFC have been suggested. Each neurocircuitry is thought to subserve partly different functions. Whereas LPFC is primarily associated with cognitive aspects of EF, OFC is related to emotional self-regulation. The MPFC is involved in motivation and energization, and is suggested to play a role in detection and monitoring of cognitive conflict. Debate persists with regard to the level of regional specificity and functional fractionation within PFC. It has been argued that EF is subserved by distinct and dissociable functions with specific anatomical substrates, but also that the key feature distinguishing the PFC is the high level of flexibility and adaptability across sensory modalities and cognitive domains. Progress in revealing the neural underpinnings of EF requires a high level of conceptual and anatomical specificity. It has been suggested that future developments will be dependent upon research that combines knowledge and methodological approaches from clinical neuropsychology, neurology, cognitive neuroscience and modern imaging techniques. A main aim of the current study was to examine distinct cognitive control functions associated with the three main subdivisions of the PFC. To this end, a neurocognitive, electrophysiological and lesion study approach was adopted. Patients with focal lesions to one of the three subdivisions of PFC were included and assessed with neuropsychological behavioral tests as well as a questionnaire measure of executive functions in every-day living. Electrophysiological indices of attentional control following focal PFC lesions were also studied with event-related potentials (ERPs) in two experimental tasks. An auditory Novelty 6 Oddball task allowed investigation of novelty and target processing, while a Stop-Signal Task (SST) provided information about motor inhibition and error-monitoring. In Paper I, novelty and target processing was compared in patients with OFC and LPFC lesions and healthy controls. In paper II, neurocognitive functioning and self- and informant reported executive problems in everyday living were explored in patients with OFC and LPFC lesions. In paper III, the effect of unilateral MPFC damage including the anterior cingulate cortex (ACC) was investigated in two patients who were assessed with neuropsychological and questionnaire measures as well as ERPs in the Novelty Oddball and SST tasks. The findings reported in paper II largely confirmed our hypothesis that LPFC damage is particularly prone to cause cognitive executive deficit with reductions on tasks demanding sustained mental effort, working memory, response inhibition, and mental switching, while OFC injury is more strongly associated with self-reported dysexecutive symptoms in everyday living. The findings confirmed a functional dissociation between LPFC and OFC. Paper I and III on the other hand, showed that lesions to all three subdivisions of PFC resulted in altered processing of unexpected novel events, indexed by attenuation of the frontal Novelty P3 response. The findings extend current knowledge in suggesting that not only LPFC, as shown in previous studies, but OFC as swell as MPFC play a role in novelty processing. The studies therefore confirm a role of PFC in novelty processing, but do not lend strong support for a high degree of regional specificity within PFC. Target detection seems not to be critically dependent upon the PFC, as the target-related parietal P3b was normal after lesions to both OFC, LPFC and MPFC. The results in paper III did not confirm suggestions that the ACC is not involved in cognitive control, as the two patients displayed learning and memory deficit as well as an abolished Novelty P3. Interestingly, the error-related negativity (ERN) was however present in both patients, indicating that error detection can occur despite unilateral ACC lesion. In summary, the findings from the three studies lend support both to theories that highlight functional and anatomical specificity of distinct control functions within the PFC, as well as theories that emphasize adaptive, supramodal properties of the frontal lobes in complex tasks. 7 List of papers This thesis is based on the following papers which are referred to in the text by their Roman numbers I III. Paper I Løvstad, M., Funderud, I., Lindgren, M., Endestad, T., Due-Tønnessen, P., Meling, T.R., Voytek, B., Knight, R.T., & Solbakk, A.K. (2012). Contribution of subregions of human frontal cortex to novelty processing. Journal of Cognitive Neuroscience, 24(2), Paper II Løvstad, M., Funderud, I., Endestad, T., Due-Tønnessen, P., Meling, T.R., Lindgren, M., Knight, R.T., & Solbakk, A.K. (in press). Executive functions after orbital or lateral prefrontal lesions: Neuropsychological profiles and self-reported executive functions in everyday living. Brain Injury. Paper III Løvstad, M., Funderud, I., Meling, T., Krämer, U.M., Voytek B., Due-Tønnessen, P., Endestad, T, Lindgren, M., Knight, R.T., & Solbakk, A.K (2012). Anterior cingulate cortex and cognitive control: Neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex. Brain and Cognition, 80, Introduction In 1949, the Nobel price in medicine was awarded to Antonio Caetano de Abreu Freire Egas Moniz for his discovery of the therapeutic value of leucotomy in certain psychoses . In the award ceremony speech, professor Herbert Olivecrona from the Royal Caroline Institute in Sweden said: Frontal leucotomy, despite certain limitations of the operative method, must be considered one of the most important discoveries ever made in psychiatric therapy, because through its use a great number of suffering people and total invalids have recovered and have been socially rehabilitated. (http://www.nobelprize.org/nobel_prizes/medicine/laureates/1949/). Three years earlier, Wilder G. Penfield delivered the Ferrier lecture in London. He argued for highly specialized functional areas in the cerebral cortex. However, in relation to the frontal lobes, he drew the following conclusion: Complete removal of the frontal cortex on one side back to, but not including, the precentral gyrus and Broca s speech area, produces surprisingly little interference with the intellectual capacity and behavior of the individual (Penfield, 1947). In accord with this, the frontal lobes were often denoted as silent. Much has happened since these statements were made. To the notion that some parts of the brain should be considered to be largely without functional value, Devinsky (2005) commented: false view that many brain areas go unused and that certain cortical or subcortical regions and white matter tracts have little functional value. These myths reflected bias as well as the insensitivity of clinical and neuroscientific tools, not brain function (p. 385). It is no longer disputed whether the frontal lobes are dispensable, rather it is uniformly accepted that the PFC subserves complex mental capacities related to cognition, emotion and motivation, and extensive scientific effort has been invested in solving the riddle of the frontal lobes (Stuss & Alexander, 2007). A PubMed entry with the search term frontal lobe was performed in January 2012, giving hits. Of these, almost exactly half (27 388) were from the last 10 years. When entering the term executive functions, hits came up, whereof were from the last decade. Modern techniques for imaging of ongoing brain activation have contributed vastly to improved cognitive models of the brain, and helped disentangle the functional and anatomical 9 substructures of the PFC. One specific challenge regarding the PFC and EF lies in the seeming contrast between theories emphasizing that 1) elementary cognitive operations are strictly localized, while at the same time, 2) even simple tasks require orchestration of performance in distributed brain areas (Posner, Petersen, Fox, & Raichle, 1988). The work presented in this thesis forms part of the effort to enhance our understanding of frontal lobe functioning, its functional subdivisions, as well as the methodological challenges faced when trying to describe the effect of damage to this part of the brain. In this introduction, the current status of knowledge regarding development, functional anatomical distinctions, cognitive theories, as well as assessment issues related to the PFC and EF will be summarized. It will be argued that the human capacity to control attention is a core executive capacity, and that scientific progress will depend upon the degree to which we achieve clarity of concepts and understand their neural underpinnings (Stuss & Knight, 2002; Stuss, 2011). Executive functions The human capacity to maintain an overarching control over mental states and behavior relies on multiple, distributed and dynamically cooperating brain networks (Stuss & Alexander, 2000). When top-down control over mental processes breaks down, the information processing system is rendered inflexible and increasingly stimulus-bound (Fernandez-Duque, Baird, & Posner, 2000). There is not consensus on a single definition of this process, but the common denominator is top-down controlled processes, thereof terms such as executive functions, cognitive control, self-regulation, emotional regulation, and metacognition. In the following, the global term executive functions (EF) will be used when discussing this general capacity. In the International Neuropsychological Society dictionary of neuropsychology, EF is defined as the cognitive abilities necessary for complex goal-directed behavior and adaptation to a range of environmental changes and demands. Executive function includes the ability to plan and anticipate outcomes (cognitive flexibility) and to direct attentional resources to meet
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