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Ethical and Clinical Considerations at the Intersection of Functional Neuroimaging and Disorders of Consciousness: The Experts Weigh In
- ADRIAN C. BYRAM, GRACE LEE, ADRIAN M. OWEN, URS RIBARY, A. JON STOESSL, ANDREA TOWNSON, JUDY ILLES
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- Cambridge Quarterly of Healthcare Ethics / Volume 25 / Issue 4 / October 2016
- Published online by Cambridge University Press:
- 16 September 2016, pp. 613-622
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Recent neuroimaging research on disorders of consciousness provides direct evidence of covert consciousness otherwise not detected clinically in a subset of severely brain-injured patients. These findings have motivated strategic development of binary communication paradigms, from which researchers interpret voluntary modulations in brain activity to glean information about patients’ residual cognitive functions and emotions. The discovery of such responsiveness raises ethical and legal issues concerning the exercise of autonomy and capacity for decisionmaking on matters such as healthcare, involvement in research, and end of life. These advances have generated demands for access to the technology against a complex background of continued scientific advancement, questions about just allocation of healthcare resources, and unresolved legal issues. Interviews with professionals whose work is relevant to patients with disorders of consciousness reveal priorities concerning further basic research, legal and policy issues, and clinical considerations.
Progression from Vegetative to Minimally Conscious State Is Associated with Changes in Brain Neural Response to Passive Tasks: A Longitudinal Single-Case Functional MRI Study
- Francesco Tomaiuolo, Luca Cecchetti, Raechelle M. Gibson, Fiammetta Logi, Adrian M. Owen, Franco Malasoma, Sabino Cozza, Pietro Pietrini, Emiliano Ricciardi
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- Journal of the International Neuropsychological Society / Volume 22 / Issue 6 / July 2016
- Published online by Cambridge University Press:
- 06 June 2016, pp. 620-630
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Objectives: Functional magnetic resonance imaging (fMRI) may be adopted as a complementary tool for bedside observation in the disorders of consciousness (DOC). However, the diagnostic value of this technique is still debated because of the lack of accuracy in determining levels of consciousness within a single patient. Recently, Giacino and colleagues (2014) hypothesized that a longitudinal fMRI evaluation may provide a more informative assessment in the detection of residual awareness. The aim of this study was to measure the correspondence between clinically defined level of awareness and neural responses within a single DOC patient. Methods: We used a follow-up fMRI design in combination with a passive speech-processing task. Patient’s consciousness was measured through time by using the Coma Recovery Scale. Results: The patient progressed from a vegetative state (VS) to a minimally conscious state (MCS). Patient’s task-related neural responses mirrored the clinical change from a VS to an MCS. Specifically, while in an MCS, but not a VS, the patient showed a selective recruitment of the left angular gyrus when he listened to a native speech narrative, as compared to the reverse presentation of the same stimulus. Furthermore, the patient showed an increased response in the language-related brain network and a greater deactivation in the default mode network following his progression to an MCS. Conclusions: Our findings indicate that longitudinal assessment of brain responses to passive stimuli can contribute to the definition of the clinical status in individual patients with DOC and represents an adequate counterpart of the bedside assessment during the diagnostic decision-making process. (JINS, 2016, 22, 620–630)
Operationalizing Neuroimaging for Disorders of Consciousness: The Canadian Context
- Judy Illes, Adrian M. Owen, Adrian C. Byram, and the MCS Neuroimaging Workgroup
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- Canadian Journal of Neurological Sciences / Volume 43 / Issue 4 / July 2016
- Published online by Cambridge University Press:
- 04 February 2016, pp. 578-580
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Canadian Perspectives on the Clinical Actionability of Neuroimaging in Disorders of Consciousness
- Grace Lee, Adrian C. Byram, Adrian M. Owen, Urs Ribary, A. Jon Stoessl, Andrea Townson, Christine Stables, Judy Illes
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- Canadian Journal of Neurological Sciences / Volume 42 / Issue 2 / March 2015
- Published online by Cambridge University Press:
- 25 March 2015, pp. 96-105
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Background: Acquired brain injury is a critical public health and socioeconomic problem in Canada, leaving many patients in vegetative, minimally conscious, or locked-in states, unresponsive and unable to communicate. Recent advances in neuroimaging research have demonstrated residual consciousness in a few exemplary patients with acquired brain injury, suggesting potential misdiagnosis and changes in prognosis. Such progress, in parallel with research using multimodal brain imaging technologies in recent years, has promising implications for clinical translation, notwithstanding the many challenges that impact health care and policy development. This study explored the perspectives of Canadian professionals with expertise either in neuroimaging research, disorders of consciousness, or both, on the potential clinical applications and implications of imaging technology. Methods: Twenty-two professionals from designated communities of neuroimaging researchers, ethicists, lawyers, and practitioners participated in semistructured interviews. Data were analyzed for emergent themes. Results: The five most dominant themes were: (1) validation and calibration of the methods; (2) informed consent; (3) burdens on the health care system; (4) implications for the Canadian health care system; and (5) possibilities for improved prognosis. Conclusions: Movement of neuroimaging from research into clinical care for acquired brain injury will require careful consideration of legal and ethical issues alongside research reliability, responsible distribution of health care resources, and the interaction of technological capabilities with patient outcome.
Contributors
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- By Rose Teteki Abbey, K. C. Abraham, David Tuesday Adamo, LeRoy H. Aden, Efrain Agosto, Victor Aguilan, Gillian T. W. Ahlgren, Charanjit Kaur AjitSingh, Dorothy B E A Akoto, Giuseppe Alberigo, Daniel E. Albrecht, Ruth Albrecht, Daniel O. Aleshire, Urs Altermatt, Anand Amaladass, Michael Amaladoss, James N. Amanze, Lesley G. Anderson, Thomas C. Anderson, Victor Anderson, Hope S. Antone, María Pilar Aquino, Paula Arai, Victorio Araya Guillén, S. Wesley Ariarajah, Ellen T. Armour, Brett Gregory Armstrong, Atsuhiro Asano, Naim Stifan Ateek, Mahmoud Ayoub, John Alembillah Azumah, Mercedes L. García Bachmann, Irena Backus, J. Wayne Baker, Mieke Bal, Lewis V. Baldwin, William Barbieri, António Barbosa da Silva, David Basinger, Bolaji Olukemi Bateye, Oswald Bayer, Daniel H. Bays, Rosalie Beck, Nancy Elizabeth Bedford, Guy-Thomas Bedouelle, Chorbishop Seely Beggiani, Wolfgang Behringer, Christopher M. Bellitto, Byard Bennett, Harold V. Bennett, Teresa Berger, Miguel A. Bernad, Henley Bernard, Alan E. Bernstein, Jon L. Berquist, Johannes Beutler, Ana María Bidegain, Matthew P. Binkewicz, Jennifer Bird, Joseph Blenkinsopp, Dmytro Bondarenko, Paulo Bonfatti, Riet en Pim Bons-Storm, Jessica A. Boon, Marcus J. Borg, Mark Bosco, Peter C. Bouteneff, François Bovon, William D. Bowman, Paul S. Boyer, David Brakke, Richard E. Brantley, Marcus Braybrooke, Ian Breward, Ênio José da Costa Brito, Jewel Spears Brooker, Johannes Brosseder, Nicholas Canfield Read Brown, Robert F. Brown, Pamela K. Brubaker, Walter Brueggemann, Bishop Colin O. Buchanan, Stanley M. Burgess, Amy Nelson Burnett, J. Patout Burns, David B. Burrell, David Buttrick, James P. Byrd, Lavinia Byrne, Gerado Caetano, Marcos Caldas, Alkiviadis Calivas, William J. Callahan, Salvatore Calomino, Euan K. Cameron, William S. Campbell, Marcelo Ayres Camurça, Daniel F. Caner, Paul E. Capetz, Carlos F. Cardoza-Orlandi, Patrick W. Carey, Barbara Carvill, Hal Cauthron, Subhadra Mitra Channa, Mark D. Chapman, James H. Charlesworth, Kenneth R. Chase, Chen Zemin, Luciano Chianeque, Philip Chia Phin Yin, Francisca H. Chimhanda, Daniel Chiquete, John T. Chirban, Soobin Choi, Robert Choquette, Mita Choudhury, Gerald Christianson, John Chryssavgis, Sejong Chun, Esther Chung-Kim, Charles M. A. Clark, Elizabeth A. Clark, Sathianathan Clarke, Fred Cloud, John B. Cobb, W. Owen Cole, John A Coleman, John J. Collins, Sylvia Collins-Mayo, Paul K. Conkin, Beth A. Conklin, Sean Connolly, Demetrios J. Constantelos, Michael A. Conway, Paula M. Cooey, Austin Cooper, Michael L. Cooper-White, Pamela Cooper-White, L. William Countryman, Sérgio Coutinho, Pamela Couture, Shannon Craigo-Snell, James L. Crenshaw, David Crowner, Humberto Horacio Cucchetti, Lawrence S. Cunningham, Elizabeth Mason Currier, Emmanuel Cutrone, Mary L. Daniel, David D. Daniels, Robert Darden, Rolf Darge, Isaiah Dau, Jeffry C. Davis, Jane Dawson, Valentin Dedji, John W. de Gruchy, Paul DeHart, Wendy J. Deichmann Edwards, Miguel A. De La Torre, George E. Demacopoulos, Thomas de Mayo, Leah DeVun, Beatriz de Vasconcellos Dias, Dennis C. Dickerson, John M. Dillon, Luis Miguel Donatello, Igor Dorfmann-Lazarev, Susanna Drake, Jonathan A. Draper, N. Dreher Martin, Otto Dreydoppel, Angelyn Dries, A. J. Droge, Francis X. D'Sa, Marilyn Dunn, Nicole Wilkinson Duran, Rifaat Ebied, Mark J. Edwards, William H. Edwards, Leonard H. Ehrlich, Nancy L. Eiesland, Martin Elbel, J. Harold Ellens, Stephen Ellingson, Marvin M. Ellison, Robert Ellsberg, Jean Bethke Elshtain, Eldon Jay Epp, Peter C. Erb, Tassilo Erhardt, Maria Erling, Noel Leo Erskine, Gillian R. Evans, Virginia Fabella, Michael A. Fahey, Edward Farley, Margaret A. Farley, Wendy Farley, Robert Fastiggi, Seena Fazel, Duncan S. Ferguson, Helwar Figueroa, Paul Corby Finney, Kyriaki Karidoyanes FitzGerald, Thomas E. FitzGerald, John R. Fitzmier, Marie Therese Flanagan, Sabina Flanagan, Claude Flipo, Ronald B. Flowers, Carole Fontaine, David Ford, Mary Ford, Stephanie A. Ford, Jim Forest, William Franke, Robert M. Franklin, Ruth Franzén, Edward H. Friedman, Samuel Frouisou, Lorelei F. Fuchs, Jojo M. Fung, Inger Furseth, Richard R. Gaillardetz, Brandon Gallaher, China Galland, Mark Galli, Ismael García, Tharscisse Gatwa, Jean-Marie Gaudeul, Luis María Gavilanes del Castillo, Pavel L. Gavrilyuk, Volney P. Gay, Metropolitan Athanasios Geevargis, Kondothra M. George, Mary Gerhart, Simon Gikandi, Maurice Gilbert, Michael J. Gillgannon, Verónica Giménez Beliveau, Terryl Givens, Beth Glazier-McDonald, Philip Gleason, Menghun Goh, Brian Golding, Bishop Hilario M. Gomez, Michelle A. Gonzalez, Donald K. Gorrell, Roy Gottfried, Tamara Grdzelidze, Joel B. Green, Niels Henrik Gregersen, Cristina Grenholm, Herbert Griffiths, Eric W. Gritsch, Erich S. Gruen, Christoffer H. Grundmann, Paul H. Gundani, Jon P. Gunnemann, Petre Guran, Vidar L. Haanes, Jeremiah M. Hackett, Getatchew Haile, Douglas John Hall, Nicholas Hammond, Daphne Hampson, Jehu J. Hanciles, Barry Hankins, Jennifer Haraguchi, Stanley S. Harakas, Anthony John Harding, Conrad L. Harkins, J. William Harmless, Marjory Harper, Amir Harrak, Joel F. Harrington, Mark W. Harris, Susan Ashbrook Harvey, Van A. Harvey, R. Chris Hassel, Jione Havea, Daniel Hawk, Diana L. Hayes, Leslie Hayes, Priscilla Hayner, S. Mark Heim, Simo Heininen, Richard P. Heitzenrater, Eila Helander, David Hempton, Scott H. Hendrix, Jan-Olav Henriksen, Gina Hens-Piazza, Carter Heyward, Nicholas J. Higham, David Hilliard, Norman A. Hjelm, Peter C. Hodgson, Arthur Holder, M. Jan Holton, Dwight N. Hopkins, Ronnie Po-chia Hsia, Po-Ho Huang, James Hudnut-Beumler, Jennifer S. Hughes, Leonard M. Hummel, Mary E. Hunt, Laennec Hurbon, Mark Hutchinson, Susan E. Hylen, Mary Beth Ingham, H. Larry Ingle, Dale T. Irvin, Jon Isaak, Paul John Isaak, Ada María Isasi-Díaz, Hans Raun Iversen, Margaret C. Jacob, Arthur James, Maria Jansdotter-Samuelsson, David Jasper, Werner G. Jeanrond, Renée Jeffery, David Lyle Jeffrey, Theodore W. Jennings, David H. Jensen, Robin Margaret Jensen, David Jobling, Dale A. Johnson, Elizabeth A. Johnson, Maxwell E. Johnson, Sarah Johnson, Mark D. Johnston, F. Stanley Jones, James William Jones, John R. Jones, Alissa Jones Nelson, Inge Jonsson, Jan Joosten, Elizabeth Judd, Mulambya Peggy Kabonde, Robert Kaggwa, Sylvester Kahakwa, Isaac Kalimi, Ogbu U. Kalu, Eunice Kamaara, Wayne C. Kannaday, Musimbi Kanyoro, Veli-Matti Kärkkäinen, Frank Kaufmann, Léon Nguapitshi Kayongo, Richard Kearney, Alice A. Keefe, Ralph Keen, Catherine Keller, Anthony J. Kelly, Karen Kennelly, Kathi Lynn Kern, Fergus Kerr, Edward Kessler, George Kilcourse, Heup Young Kim, Kim Sung-Hae, Kim Yong-Bock, Kim Yung Suk, Richard King, Thomas M. King, Robert M. Kingdon, Ross Kinsler, Hans G. Kippenberg, Cheryl A. 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Rubenstein, Rosemary Radford Ruether, Markku Ruotsila, John E. Rybolt, Risto Saarinen, John Saillant, Juan Sanchez, Wagner Lopes Sanchez, Hugo N. Santos, Gerhard Sauter, Gloria L. Schaab, Sandra M. Schneiders, Quentin J. Schultze, Fernando F. Segovia, Turid Karlsen Seim, Carsten Selch Jensen, Alan P. F. Sell, Frank C. Senn, Kent Davis Sensenig, Damían Setton, Bal Krishna Sharma, Carolyn J. Sharp, Thomas Sheehan, N. Gerald Shenk, Christian Sheppard, Charles Sherlock, Tabona Shoko, Walter B. Shurden, Marguerite Shuster, B. Mark Sietsema, Batara Sihombing, Neil Silberman, Clodomiro Siller, Samuel Silva-Gotay, Heikki Silvet, John K. Simmons, Hagith Sivan, James C. Skedros, Abraham Smith, Ashley A. Smith, Ted A. Smith, Daud Soesilo, Pia Søltoft, Choan-Seng (C. S.) Song, Kathryn Spink, Bryan Spinks, Eric O. Springsted, Nicolas Standaert, Brian Stanley, Glen H. Stassen, Karel Steenbrink, Stephen J. Stein, Andrea Sterk, Gregory E. Sterling, Columba Stewart, Jacques Stewart, Robert B. Stewart, Cynthia Stokes Brown, Ken Stone, Anne Stott, Elizabeth Stuart, Monya Stubbs, Marjorie Hewitt Suchocki, David Kwang-sun Suh, Scott W. Sunquist, Keith Suter, Douglas Sweeney, Charles H. Talbert, Shawqi N. Talia, Elsa Tamez, Joseph B. Tamney, Jonathan Y. Tan, Yak-Hwee Tan, Kathryn Tanner, Feiya Tao, Elizabeth S. Tapia, Aquiline Tarimo, Claire Taylor, Mark Lewis Taylor, Bishop Abba Samuel Wolde Tekestebirhan, Eugene TeSelle, M. Thomas Thangaraj, David R. Thomas, Andrew Thornley, Scott Thumma, Marcelo Timotheo da Costa, George E. “Tink” Tinker, Ola Tjørhom, Karen Jo Torjesen, Iain R. Torrance, Fernando Torres-Londoño, Archbishop Demetrios [Trakatellis], Marit Trelstad, Christine Trevett, Phyllis Trible, Johannes Tromp, Paul Turner, Robert G. Tuttle, Archbishop Desmond Tutu, Peter Tyler, Anders Tyrberg, Justin Ukpong, Javier Ulloa, Camillus Umoh, Kristi Upson-Saia, Martina Urban, Monica Uribe, Elochukwu Eugene Uzukwu, Richard Vaggione, Gabriel Vahanian, Paul Valliere, T. J. Van Bavel, Steven Vanderputten, Peter Van der Veer, Huub Van de Sandt, Louis Van Tongeren, Luke A. Veronis, Noel Villalba, Ramón Vinke, Tim Vivian, David Voas, Elena Volkova, Katharina von Kellenbach, Elina Vuola, Timothy Wadkins, Elaine M. Wainwright, Randi Jones Walker, Dewey D. Wallace, Jerry Walls, Michael J. Walsh, Philip Walters, Janet Walton, Jonathan L. Walton, Wang Xiaochao, Patricia A. Ward, David Harrington Watt, Herold D. Weiss, Laurence L. Welborn, Sharon D. Welch, Timothy Wengert, Traci C. West, Merold Westphal, David Wetherell, Barbara Wheeler, Carolinne White, Jean-Paul Wiest, Frans Wijsen, Terry L. Wilder, Felix Wilfred, Rebecca Wilkin, Daniel H. Williams, D. Newell Williams, Michael A. Williams, Vincent L. Wimbush, Gabriele Winkler, Anders Winroth, Lauri Emílio Wirth, James A. Wiseman, Ebba Witt-Brattström, Teofil Wojciechowski, John Wolffe, Kenman L. Wong, Wong Wai Ching, Linda Woodhead, Wendy M. Wright, Rose Wu, Keith E. Yandell, Gale A. Yee, Viktor Yelensky, Yeo Khiok-Khng, Gustav K. K. Yeung, Angela Yiu, Amos Yong, Yong Ting Jin, You Bin, Youhanna Nessim Youssef, Eliana Yunes, Robert Michael Zaller, Valarie H. Ziegler, Barbara Brown Zikmund, Joyce Ann Zimmerman, Aurora Zlotnik, Zhuo Xinping
- Edited by Daniel Patte, Vanderbilt University, Tennessee
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- The Cambridge Dictionary of Christianity
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- 05 August 2012
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- 20 September 2010, pp xi-xliv
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Psychiatric, neurological and medical aspects of misidentification syndromes: a review of 260 cases
- Hans Förstl, Osvaldo P. Almeida, Adrian M. Owen, Alistair Burns, Robert Howard
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- Psychological Medicine / Volume 21 / Issue 4 / November 1991
- Published online by Cambridge University Press:
- 09 July 2009, pp. 905-910
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Two hundred and sixty case reports of misidentification syndromes were evaluated. One hundred and seventy-four patients had a Capgras syndrome misidentifying other persons, 18 a Fregoli syndrome, 11 intermetamorphosis, 17 reduplicative paramnesia and the rest had other forms or combinations of mistaken identification. Schizophrenia (127 cases), mostly of paranoid type, affective disorder (29), and organic mental syndromes including dementia (46) were the most common diagnoses in patients who misidentified others or themselves. The patients with reduplicative paramnesia more frequently suffered from head trauma or cerebral infarction and showed more features of right hemisphere lesions on neuropsychological testing or CT scan than the patients with other misidentification syndromes. Forty-one case-reports implicated underlying medical conditions. Forty-six of the patients were reported to show violent behavioaur.
The misidentification of persons can be a manifestation of any organic or functional psychosis, but the misidentification of place is frequently associated with neurological diseases, predominantly of the right hemisphere. Misidentification syndromes show a great degree of overlap and do not represent distinctive syndromes nor can they be regarded as an expression of a particular disorder. These patients deserve special diagnostic and therapeutic attention because of the possible underlying disorders and their potentially dangerous behavioura.
21 - Utility of CANTAB in functional neuroimaging
- from Part 5 - Future directions
- Edited by Monique Ernst, National Institutes of Health, Baltimore, Judith M. Rumsey, National Institute of Mental Health, Bethesda, Maryland
- Foreword by Joseph T. Coyle
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- Functional Neuroimaging in Child Psychiatry
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- 06 January 2010
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- 12 October 2000, pp 366-378
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Summary
This chapter describes the design, theoretical rationale, and validation of the Cambridge Neuropsychological Test Automated Battery (CANTAB). The utility of the battery for functional neuroimaging studies is examined, based on its links with animal neuropsychological research, its decomposition of complex tests of cognition into their constituent parts, and its validation in patient groups with defined brain lesions. The CANTAB has now been used quite extensively in the testing of patients with Alzheimer's disease and other forms of dementia. Two CANTAB tests specifically target spatial working memory functions, the spatial span and the self-ordered spatial working memory tasks. Both have been used in the context of positron emission tomography (PET) scanning to resolve a number of theoretical issues concerning the organization of working memory within the frontal lobe. In the CANTAB, short-term visual recognition memory is assessed using the delayed-matching-to-sample (DMTS) task.
8 - The role of executive deficits in memory disorders in neurodegenerative disease
- from PART II - Cognitive perspectives
- Edited by Alexander I. Tröster, Kansas University Medical Center
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- Memory in Neurodegenerative Disease
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- 23 November 2009
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- 29 October 1998, pp 157-171
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Summary
INTRODUCTION
There is now overwhelming evidence that patients with neurodegenerative disorders, including Parkinson's disease (PD), Huntington's disease (HD), progressive supranuclear palsy (also known as Steele-Richardson-Olszewski syndrome), multiple system atrophy, Alzheimer's disease (AD), Korsakoff's syndrome and fronto-striatal dementia exhibit diverse patterns of cognitive impairment that can include deficits of ‘executive function’. The term ‘executive function’ generally refers to those mechanisms by which performance is optimized in situations requiring the simultaneous operation of a number of different cognitive processes (Baddeley 1986). Executive functioning is required, therefore, when sequences of responses must be generated and scheduled and when novel plans of action must be formulated and carried out. The frontal lobes have long been known to play an important role in executive functioning, although the fact that the ‘dysexecutive syndrome’ may be observed in patients with damage to other brain regions (Morris et al. 1990), suggests that an equivalence between the prefrontal cortex and executive functioning cannot be assumed. In addition, much of the research on executive deficits in neurodegenerative groups has focused on broad descriptions of individual patient groups and how their behaviour might best be characterized using standard clinical neuropsychological tools. For example, impairments on the Wisconsin Card Sorting Test (Grant and Berg 1948), a classic test of executive function, have been described in many neurodegenerative groups including PD (Lees and Smith 1983), progressive supranuclear palsy (Pillon et al. 1986) and HD (Josiassen et al. 1983).
A study of performance on tests from the CANTAB battery sensitive to frontal lobe dysfunction in a large sample of normal volunteers: Implications for theories of executive functioning and cognitive aging
- TREVOR W. ROBBINS, MERLE JAMES, ADRIAN M. OWEN, BARBARA J. SAHAKIAN, ANDREW D. LAWRENCE, LYNN MCINNES, PATRICK M.A. RABBITT
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- Journal of the International Neuropsychological Society / Volume 4 / Issue 5 / September 1998
- Published online by Cambridge University Press:
- 01 September 1998, pp. 474-490
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Several tests from the CANTAB neuropsychological test battery previously shown to be sensitive to frontal lobe dysfunction were administered to a large group of normal volunteers (N = 341) ranging in age from 21 to 79 years. The main tests included a computerized form of the Tower of London test of planning, a self-ordered spatial working memory task, and a test of attentional set formation and shifting. A computerized form of the Corsi spatial span task was also given. Age-related graded declines in performance were seen, sometimes in a discontinuous manner, especially for the attentional set shifting task (at the extradimensional shift stage). Patterns of deficits reminiscent of frontal lobe or basal ganglia damage were observed in the oldest age group (74–79). However, overall the data were only partially consistent with the hypothesis that frontal lobe functions are the most sensitive to effects of aging. Factor analyses showed that performance in the executive tests was not simply related to a measure of fluid intelligence, and their performance had a factor loading structure distinct from that for the CANTAB tests of visual memory and learning previously administered to the same sample. Finally, only limited support was found for the hypothesis that cognitive aging depends on slowed information processing. (JINS, 1998, 4, 474–490.)