View metadata, citation and similar ACPpapers at core.ac.uk 376 Dispatch: 3.6.04 Journal: ACP CE: Nagaraj brought to you by CORE Journal Name Manuscript No. B Author Received: No.provided of pages: 14by University PE: Vijay of Hertfordshire Research Archive Acta Psychiatr Scand 2004: 110: 1–14 Copyright Ó Blackwell Munksgaard 2004 Printed in UK. All rights reserved ACTA PSYCHIATRICA SCANDINAVICA Hypofrontality in schizophrenia: a meta- F analysis of functional imaging studies O Hill K, Mann L, Laws KR, Stephenson CME, Nimmo-Smith I, K. Hill1, L. Mann1, K. R. Laws2, McKenna PJ.Hypofrontality in schizophrenia: a meta-analysis of C. M. E. Stephenson3, I. Nimmo- functional imaging studies. Smith4, P. J. McKennaO1 Acta Psychiatr Scand 2004: 110: 1–14. Ó Blackwell Munksgaard 2004. 1 2 Fulbourn Hospital, Cambridge, Department of Psychology, Nottingham Trent University, Nottingham, Objective: Hypofrontality is not a well-replicated finding in 3Department of Psychiatry,R University of Cambridge, schizophrenia either at rest or under conditions of task activation. Brain Mapping Unit, Addenbrooke's NHS Trust, Method: Studies comparing whole brain and frontal blood flow/ Cambridge and 4MRC Cognition and Brain Sciences metabolism in schizophrenic patients and normal controls were Unit, Cambridge,P UK pooled.Voxel-based studies were also combined to examine the pattern of prefrontal activation in schizophrenia. Results: Whole brain flow/metabolism was reduced in schizophrenia to only a small extent.Resting and activation frontal flow/metabolism were both reduced with a medium effect size.Duration of illness D significantly moderated resting hypofrontality, but the moderating effects of neuroleptic treatment were consistent with an influence on global flow/metabolism only.Pooling of voxel-based studies did not Key words: schizophrenia; frontal lobe; functional E imaging suggest an abnormal pattern of activation in schizophrenia. Conclusion: Meta-analysis supports resting hypofrontality in Dr P. J. McKenna, Fulbourn Hospital, Cambridge CB1 schizophrenia.Task-activated hypofrontality is also supported,T but 5EF, UK. there is little from voxel-based studies to suggest that this is associated E-mail: [email protected] with an altered pattern of regional functional architecture.C Accepted for publication April 6, 2004 E patients with short and long durations of illness Introduction to a control group of abstinent alcoholics.The As it has become clear that structuralR brain finding was replicated in a number of subsequent pathology in schizophrenia is modest, and with studies, some of which used the newly developed neurochemical and other investigations remaining technique of photon emission tomography (PET) inconclusive (1, 2), functional imagingR has become (9–12).From the outset, however, there were the most promising candidate for identifying dys- negative reports (13–16), and conflicting findings functional brain systems in the disorder.The major have continued to dog the field to the present day finding to emerge from these studies has been (e.g. 17). In a recent review, Chua and McKenna hypofrontality, a loss of theO normal pattern of (18) found that hypofrontality was present in only higher resting cerebral blood flow or metabolism in a third of studies selected on the basis of simple anterior than posterior regions.Hypofrontality has methodological considerations, and in an editorial become one of the most widelyC cited and influential entitled ÔHypofrontality in schizophrenia: RIPÕ. findings in the literature on schizophrenia, which is Gur and Gur (19) argued that the finding was a referred to in the introduction or discussion of shibboleth, which had only meagre experimental many biological researchN papers and which has led support. most if not all contemporary theoretical approa- Partly in response to these inconsistencies, ches to invoke some form of executive dysfunction Weinberger et al.(20) proposed that hypofrontality (3–7). U in schizophrenia might be more easy to demon- Hypofrontality was first documented in 1974 by strate when cognitive demands were made on the Ingvar and Franzen (8) who used the 133Xenon prefrontal cortex.They found that a group of technique to compare groups of schizophrenic chronic schizophrenic patients showed only a trend 1 Hill et al. towards hypofrontality at rest, but markedly failed Ingvar and Franzen’s study (8) to July 2003. to activate the prefrontal cortex when they per- Studies were identified through MEDLINE, PSY- formed a prototypical executive task, the Wiscon- CHINFO and EMBASE using the key words sin Card Sorting Test.Like resting hypofrontality, ÔschizophreniaÕ, Ôtomography, emission-computedÕ, however, task-related or activation hypofrontality Ômagnetic resonance imagingÕ, Ôbrain mappingÕ, has not been consistently replicated.This applies Ôcerebral cortexÕ, Ôfrontal lobeÕ.The electronicF not only to studies using executive tasks (18, 21), search was supplemented by checking of review but also to those using memory and vigilance tasks articles on functional imaging in schizophrenia and (17, 18), which also activate the prefrontal cortex the reference lists of all research papersO obtained. (22). Hand searching of key journals was also carried The most recent development in the functional out from 1981, the year of the first replication of imaging of schizophrenia has been the use of voxel- Ingvar and Franzen’s (8) study.TheO journals based image analysis techniques such as statistical searched were Acta Psychiatrica Scandinavica, parametric mapping (SPM).Instead of measuring American Journal of Psychiatry, Archives of Gen- the average activity across an anatomically defined eral Psychiatry, British JournalR of Psychiatry, Ôregion of interestÕ, these studies make voxel-by- Biological Psychiatry, Psychiatry Research, Schizo- voxel comparisons across the entire brain, and phrenia Research and the Journal of Cerebral Blood identify clusters of significant activation in Flowand Metabolism .P response to a cognitive task.Voxel-based tech- When studies reported on overlapping groups of niques have now largely replaced studies using the patients or controls, the study with the largest region of interest approach.However, they have number of schizophrenic patients that provided brought their own problems, methodological, sta- usable data was used.Studies published as brief tistical (particularly how to correct for the large reports or lettersD were included, but findings in number of comparisons), and even philosophical. abstracts from conference proceedings were not. For example, a current area of controversy con- The small number of non-English-language papers cerns whether task-related hypofrontality in schi- locatedE in the search (approximately five) were zophrenia reflects an intrinsic functional brain found not to contain usable data. abnormality or whether it merely indexes schizo- ToT be included, studies had to use diagnostic phrenic patientsÕ poor performance on frontal criteria for schizophrenia, schizoaffective or schiz- tasks (21, 23). ophreniform disorder and compare adult patients Cwith normal controls.Studies reporting findings on adolescents or only on patients aged over 65 were Aims of the study excluded.Age and sex matching were not required As a finding which is not well supported by ÔvoteE as inclusion criteria, as virtually all studies matched countingÕ of positive and negative findings, hypo- patients and controls on these variables.Almost all frontality in schizophrenia is a suitable candidate the studies also used prospectively ascertained for meta-analysis.This systematic review addressesR volunteer controls. the questions of whether whole brain flow/meta- Data obtained from each study were converted bolism is reduced in the disorder, whether there is into an effect size d, the difference between the resting hypofrontality, and whether hypofrontalityR mean for the patient and control groups divided by appears under conditions of neuropsychological their pooled standard deviation.Hedges Õ correc- task activation.Not included in these analyses are tion was used (24); this corrects for the tendency of a considerable number of activation studies which small studies to overestimate the population effect have used voxel-based techniques,O which cannot be size.Where mean and standard deviations were not meta-analysed in the conventional way because it is available t-values, F-values or P-values were used. not possible to derive effect sizes from them.These, In several cases data were extracted from graphs or however, can be combinedC using a novel technique scatter plots using a digitizing program (ÔUngraphÕ, which allows the pattern as opposed to the degree http://www.biosoft.com). Authors were contacted of prefrontal activation to be examined in schizo- if effect sizes could not be extracted from any of the phrenia. N published data.All effect sizes were extracted a second time independently and differences resolved. Material and methods U Individual effect sizes were combined to produce Papers reporting functional imaging studies on an overall effect size, with each d-value weighted by schizophrenic patients were searched electronically the reciprocal of its variance.Analysis of moder- from January 1974, the year of publication of ator variables was based on the weighted effect size 2 Hypofrontality in schizophrenia for each study.The Q statistic was used for both absolute and relative values revealed that the categorical variables (24) and Rosenthal’s focused same study quite frequently produced widely