patient registries in cognitive neuroscience research: advantages

Patient Registries in Cognitive NeuroscienceResearch: Advantages, Challenges,

and Practical Advice

Lesley K. Fellows1, Marianna Stark2, Arlene Berg1,and Anjan Chatterjee2

Abstract

& Neuropsychological work is the historical foundation of cog-nitive neuroscience and continues to be an important method inthe study of the neural basis of human behavior, complementingnewer techniques for investigating brain structure–function rela-tionships in human subjects. Recent advances in neuroimag-ing, statistics and information management provide powerfultools to support neuropsychological research. At the same time,changing ethical requirements and privacy concerns impose in-creasingly high standards on the procedures used to recruit

research participants, and on subsequent data management.Shared, centrally managed research registries provide a frame-work for facilitating access to this method for nonclinicians, ad-dressing ethical concerns, streamlining recruitment and screeningprocedures, and coordinating subsequent research contacts anddata storage. We report the experience of two such registries: thepatient database of the Center for Cognitive Neuroscience at theUniversity of Pennsylvania, and the Cognitive Neuroscience Re-search Registry at McGill University. &

INTRODUCTION

The scientific study of human brain–behavior relation-ships began in the clinic. The initial insights into theneural underpinnings of the major areas of human cog-nition came first from observation, and then from exper-imental investigation of the effects of brain injury onbehavior. Such work has provided a framework both forparsing complex behaviors and for understanding howthey relate to the brain (Chatterjee, 2005). Although thismethodology can be traced back to the mid 19th cen-tury, it remains a foundation for cognitive neurosciencein the new millenium.

The advent of other methods, particularly functionalneuroimaging, has changed the landscape of cognitiveneuroscience dramatically (Fellows et al., 2005), leadingsome to muse in print about the continued relevance ofexperimental neuropsychology (Rorden & Karnath,2004). As we and others have pointed out, lesion studieshave particular inferential strengths that make them avital complement to correlational methods such asfunctional neuroimaging (Fellows et al., 2005; Rorden& Karnath, 2004). As a loss-of-function method, lesionwork can test whether a given region of the brain isnecessary for a particular process. The dissociability ofdeficits after brain injury can also shed light on thecomponent processes that make up a complex behavior.

Finally, although the type of patient-based work de-scribed here aims to address basic science questions, itis also a naturally ‘‘translational’’ method: The results ofsuch studies often have immediate applicability in clin-ical settings.

Human lesion studies have certain strengths, but theyalso have important limitations. Some of these limita-tions are of a theoretical and inferential nature, and areintrinsic to the method (Farah, 1994; Shallice, 1988).Many others are practical, and so potentially address-able. Perhaps the major practical limitation is havingaccess to appropriate patients with damage involvingbrain areas of interest, and relatedly, recruiting anadequate number of patients to provide the necessarystatistical power for group studies.

Increasingly strict ethical and privacy regulations haveadded a new set of practical challenges to the back-ground difficulties inherent in the study of patients withbrain injury. Changing societal views have, on the onehand, led to increasingly tight restrictions on who mayview an individual’s medical record, or otherwise haveaccess to medical information. On the other hand, medi-cal paternalism has been replaced by patient-centeredmedicine, which emphasizes the patient’s central, au-tonomous role as decision-maker in clinical and, byextension, medical research settings. Related changesin human research ethics place restrictions on howpersonal information collected for research purposesmay be used. Typically, for example, explicit consent is1McGill University, 2University of Pennsylvania

D 2008 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 20:6, pp. 1107–1113

needed for so-called secondary use of data that wereoriginally collected for a different purpose.

As these societal, legal, and ethical changes haveoccurred, medical practice has also changed. Hospitalstays are brief, patient care is more fragmented, and thepatient populations being cared for in tertiary academicmedical centers are increasingly complex, often withcomorbidities or atypical features that make these pa-tients less suitable for basic research.

Over about the same time frame, there have beenmajor advances in anatomical neuroimaging, image anal-ysis, statistical methods, and databasing, which have thepotential to dramatically enhance what can be learnedfrom traditional lesion studies. Hand-drawn sketches ofbrain injuries are being replaced by digital image pro-cessing techniques that facilitate increasingly sophisti-cated analyses of brain structure–function relationships(Rorden, Karnath, & Bonilha, 2007; Rorden & Karnath,2004; Bates, Appelbaum, Salcedo, Saygin, & Pizzamiglio,2003; Bates, Wilson, et al., 2003; Rorden & Brett, 2000).Magnetic resonance imaging techniques can provide notonly very detailed delineation of chronic brain injury butalso information about acute, and even transient, path-ological changes in brain function that can be linked tochanges in behavior (Hillis, 2007; Ashburner & Friston,2000). These data can be readily stored and manipulatedin digital form, and easily linked to behavioral, clinical,and demographic measures in database form.

In summary, human lesion studies remain a vital pillarof cognitive neuroscience in the 21st century, and mod-ern imaging, statistical, and data management methodscan address some of the practical challenges of thiswork. However, the fundamental challenge of partici-pant recruitment and access remains, and modern ethicsand privacy considerations add further constraints.Here, we describe a research registry system designedto efficiently address this challenge; similar responses tothese constraints have been reported in support ofclinical neuropsychological research (Schwartz, Brecher,Whyte, & Klein, 2005). The registry system provides anorganizational structure; a set of recruitment, access,and retention procedures; and a data managementframework to support cognitive neuroscience researchin brain-injured participants. We describe the implemen-tation of this system at the University of Pennsylvania(UPenn) and McGill University, and discuss the advan-tages and drawbacks of this approach (Table 1).

REGISTRY ORGANIZATION

The structure of both registries is similar because theMcGill registry was modeled on the one developed atthe UPenn’s Center for Cognitive Neuroscience. Bothare conceived of as a shared research resource. Thelinchpin of the organizational framework is a dedicatedcoordinator who plays a variety of roles. The coordinatoris, in turn, supervised by a clinician–researcher, who, in

both cases, happens to be a neurologist. There areadvantages to the person in the supervisory role beinga clinician, preferably in the clinical neurosciences: Sucha position facilitates communication with other referringphysicians (most often neurologists, neurosurgeons andphysiatrists). Residents are also more likely to alert thedatabase coordinator about relevant cases when theyhave an already-established relationship with the super-vising clinician.

The coordinator’s duties include identifying and sub-sequently recruiting potential research participants, ob-taining informed consent for their participation in theregistry, and then gathering the relevant backgroundinformation about these participants, including per-forming a screening neuropsychological evaluation andaccessing available clinical neuroimaging. These data aremaintained in a computerized database. Only the coor-dinator has access to identifying and contact informa-tion. Individual investigators can view a more limited setof information within the database (e.g., lesion location,basic demographic and clinical information, results ofscreening tests) in order to select potential candidatesfor a specific research project. The coordinator serves asthe contact point between investigators and registryparticipants. She or he informs the registry participantof the opportunity to participate in a particular study. Ifthe patient is interested, the coordinator then arranges

Table 1. Current Challenges for Human Lesion Studies

Accessibility

Making patient-based research methods available tononclinicians

Autonomy

Putting participants at the center of research participationdecisions

Information management

Respecting modern privacy policies

Ethics

Recruiting while respecting confidentiality rules, specifyinguses of collected data

Efficiency

Harnessing information technologies to optimize datamanagement

Scale

Achieving an adequate sample size to support modern imageanalysis techniques, and to study behaviors with largeindividual differences in the normal population

Sustainability

Investing in infrastructure and personnel, and establishingrecruitment and retention procedures that can be sustainedover the long time frame required for such work

1108 Journal of Cognitive Neuroscience Volume 20, Number 6

the study visit with the investigator and maintains recordsabout the frequency and duration of study visits, and, ingeneral terms, the nature of the study.

The coordinator’s ‘‘go-between’’ role serves severalcrucial functions. First, it protects the privacy of registryparticipants to the fullest extent possible. Investigatorshave access only to anonymized clinical informationuntil the point the patient agrees to participate in theirstudy. Second, it improves the informed consent pro-cess by reducing the likelihood of coercion: The personobtaining initial consent for participation in a givenstudy is the coordinator, a (relatively) neutral party,rather than the investigator or the patient’s personalphysician. Third, it puts a human face on what mightotherwise be a rather soulless bureaucratic mechanismfor tracking research subjects. Patients get to know thecoordinator, and vice versa. Among other benefits, thisrelationship allows the coordinator to gauge the appro-priate intensity of a given participant’s involvement inresearch. This is done explicitly by asking how often apatient is willing to be contacted, and implicitly, by beingsensitive to changes in their life circumstances and tothe kinds of demands that might be placed on individualparticipants if they meet inclusion criteria for severalongoing investigations.

ETHICAL CONSIDERATIONS

The registry is not a research project, but rather, a toolto support research projects. Consequently, the consentdocument describes in very general terms the kinds ofresearch that registry participants may become involvedin, and focuses instead on what kind of information willbe collected in the registry, who will have access to thatinformation, and how that information will be used. Inestablishing such a registry, it may be important toconsider how wide a range future projects may cover,particularly in terms of the demands placed on partic-ipants. Will future projects be limited to noninvasivebehavioral studies, or are functional imaging, event-related potential, transcranial magnetic stimulation, orgenetic studies also possibilities? What about treatmentstudies? Local institutional review boards may requirethat this full range be specified in detail during theconsent process, or that participants be asked to indi-cate their willingness to be contacted for different kindsof studies. It is important to be clear (both to partic-ipants and to ethics oversight committees) that registryparticipants are consenting only to be informed aboutfuture research opportunities, and are completely freeto accept or decline participation in any particular study.

Participants with brain damage may have difficultyproviding fully informed consent due to the very cogni-tive deficits that make them eligible for participation,and these issues need to be addressed in compliancewith the standards of the local institutional reviewboard. Although neither of the registries described here

currently enrolls children younger than 18 years, thispopulation also requires particular attention to ethicaland consent issues.

The possibility of using such registries as recruitmentsources for treatment studies raises an interesting issue:If the treatment has a measurable effect on performance,then the participants would be different from other,untreated registry members, presumably making themineligible for participation in future basic research stud-ies. Treatment studies may also place greater demandson patients in terms of time and effort, and potentiallyexpose them to greater risk, all of which might influencetheir ability or willingness to participate in basic re-search. On the other hand, patients may be more willingto be listed in the registry if it means they will have theopportunity to participate in treatment trials. Given thelimited state of current treatments for cognitive impair-ments after brain injury, these are relatively minor con-cerns at the moment, but they may well become moreimportant considerations in the medium term.

A further question to consider when planning a registryis how wide a range of investigators will have access to it.Is it open to a specific list of researchers, to those affiliatedwith a specific institution or center, or to any researcheranywhere in the world? Currently, both registries de-scribed here limit access to those affiliated with the centeror institution at which they are based. Access by nonaffil-iated researchers can be undertaken in collaboration.This has the advantage of more-or-less capping the in-tensity of database use, and means that the same institu-tional review board will approve individual studies.

Although the registry is primarily a research supporttool, as the database associated with it grows, it maybecome a resource for research in its own right. That is,research questions could be answered by analysis of thedata routinely collected about registry participants. Twosteps need to be taken to permit this to occur: First,consent documents must make clear that the datacollected may be used for this purpose in the future,the so-called ‘‘secondary use.’’ Second, it may be worththinking about potential secondary-use applicationswhen deciding which clinical, demographic, and neuro-psychological information to acquire.

A final consideration for the consent process is ger-mane both to the registry consent, and the consentdocuments for the individual research studies that willdraw participants from the registry. This relates to thedirection of information flow between the registry data-base and individual research projects. Various modelsare possible: At one extreme, researchers draw informa-tion from the registry, and return only the minimuminformation needed for smooth functioning of the reg-istry service, such as the frequency and duration of anindividual’s participation in a particular study. At theother, all data collected in the course of all experimentscompleted by a given participant are eventually linkedback to the registry database. The latter model would

Fellows et al. 1109

provide a particularly rich dataset for secondary-usepurposes. Currently, both registries function somewherebetween these extremes. Individual investigators returninformation to the database about the experimentaltasks they have administered. If these included standardmeasures that might be useful to other researchers inthe future, these results are added to the database. Ofcourse, this requires that the researcher obtain consentfor this type of data sharing. Finally, addition of informalobservations made by individual investigators to theprimary database can be extremely useful. For example,noting that a particular participant fatigues quickly ishelpful in planning subsequent studies.

RECRUITMENT

Potential participants can be identified in a variety ofways, limited primarily by privacy considerations. Clini-cian referral is the main mechanism of recruitment atboth sites. Clinicians who care for patient populations ofpotential interest (such as stroke, tumor, surgicallytreated epilepsy) are asked to mention the registry toappropriate patients, and if the patients are interested inhearing more about the program, to pass their contactinformation to the registry coordinator. Where confiden-tiality policies permit, this process is facilitated by havingthe coordinator screen charts, generate a list of patientswho might be candidates, and then provide that list tothe relevant clinicians to aid in the recruitment process.A brochure explaining the registry can also be a helpfulrecruitment aid; this is often sent to patients after theinitial telephone contact.

The focus of recruitment will vary across registries,and over time, depending on the needs of the inves-tigators making use of the registry. This situation canbecome a counterproductive vicious circle if a potentialuser queries the database, finds few subjects appropriatefor their planned study, and so abandons the study. Thisprevents a specific study from being carried out, but alsomakes it unlikely that future work in that area will beattempted. Both registries encourage a more construc-tive approach, in which the recruitment mechanisms areadjusted to support the specific project. This works bestwhen it is interactive: when the researcher specifies thepatient population of interest, but also works with thecoordinator (often in conjunction with the neurologistsupervising the registry) to determine how that popula-tion can be accessed. Clearly, this process is morecumbersome than when appropriate patients are alreadylisted in the registry, but it still has advantages over thead hoc recruitment methods that would have been usedto solve this problem in the past. First, the registryprovides an experienced person as well as establishedprocedures to undertake the recruitment, and second,the process will result in a new population being addedto the registry, facilitating future research in this area. In-deed, where multiple investigators make use of the reg-

istry, this form of investigator-initiated recruitment willresult in a particularly rich and relevant resource over time.

This flexibility means that patient recruitment in bothdatabases does not follow rigid inclusion and exclusionrules: Recruitment can be syndrome-based in one area(e.g., McGill’s registry recruits patients with acquiredaphasia, regardless of lesion site or sites), and neuro-anatomically driven in another (e.g., identifying patientswith damage to a specific region within the frontal lobe,regardless of clinical symptoms). Similarly, patients aregenerally included in the registries even if they meetwhat might be considered ‘‘relative’’ exclusion criteria(e.g., a past history of drug or alcohol abuse, or ofdepression). This information is flagged in the database,and investigators can then decide for themselves if agiven patient is eligible for a particular study. Thisheterogeneity of inclusion and exclusion criteria is thepractical result of meeting the needs of many investi-gators. It is worth noting that this lack of consistencymay have implications for secondary-use studies, de-pending on their specific designs.

Recruitment is the rate-limiting step in the develop-ment and use of such registries. It requires sustainedeffort and takes time. A sense of the expected time coursecan be gained from Figure 1, which shows accrual to bothregistries since their inceptions. This figure shows onlythose subjects actually enrolled in the database, com-prising the 10–20% of potential participants who arefound to be eligible, interested, and available to partici-pate. Thus, for every patient enrolled in each registry, 5 to10 more were identified as possible candidates, but ex-cluded at various stages of the screening process.

RETENTION

Given the ‘‘front end’’ investment of time and resourcesin recruiting patients, once they are enrolled in theregistry, minimizing dropout becomes crucial. We haveidentified a number of factors that seem to be important

Figure 1. Cumulative recruitment into the UPenn (solid line) andMcGill (dashed line) registries since inception, by year.


in this regard. As mentioned, the relationship betweenthe patients and the database coordinator puts a humanface to the process, which we suspect is a critical factor.This connection is strengthened through intermittentcontact with all registry participants, including thosewho may not have recently participated in any specificstudy, such as through holiday cards.

Continuity of the coordinator position is importanthere; this is not a position to fill with a series of tem-porary employees, or part-time student help. In addi-tion, clearly explaining the purpose of this kind ofresearch breeds loyalty to the enterprise. When patientsunderstand the contribution they are making, they areoften remarkably generous with their time and effort.(This is perhaps particularly the case when patients areno longer able to carry out their usual occupational orsocial roles because of their brain injury.) The purposeof the research can be made concrete by providingintermittent summaries of the research being donethrough the registry. At UPenn, a biannual newsletteris sent to all registry participants. The newsletter pro-vides an update on recent findings, publications andpresentations, profiles of the investigators involved, andinformation about ongoing projects. Feedback aboutthis newsletter from registry participants has been over-whelmingly positive.

It is also important to ensure that investigator–users,and their research staff, conform to a standard set ofpractices so that the experience of registry participants isuniform across all studies. One bad experience can lead toa participant withdrawing from the registry entirely,having an obviously negative impact on the resource asa whole. Both sites have documents outlining policy inthis regard. These includes standard approaches to com-pensating participants for their time and effort. They alsostipulate commonsense recommendations regardingprofessional behavior, dress, and what to do if a medicalemergency occurs. The UPenn database makes this ma-terial available on their Website, and has an annual,mandatory training session for research assistants, stu-dents, and others wishing to recruit through their regis-try. Such a session is particularly useful for students andresearch assistants, whose only relevant experience maybe participating in or conducting behavioral experimentsin healthy undergraduate students.

These measures seem to be effective: Although regis-try attrition due to illness, death, or patients movingaway is inevitable, withdrawal at the patient’s request isuncommon (1–2 patients/year at both sites).

SCREENING

Once participants are recruited and consent, some formof screening assessment is carried out. The optimalextent of this screening is a matter of debate, and variesacross the two sites. On the one hand, more detailedscreening provides better service to end-users of the

registry, allowing investigators to select their studypopulation precisely, cutting down on the backgroundevaluations that need to be done as part of a particularstudy, and enhancing the registry database’s secondaryuse capabilities. On the other hand, longer screeningtakes additional time, effort, and money, and with thebest of intentions, may still not meet the requirementsof particular studies. Furthermore, all registry partici-pants undergo screening, but only a subset will actuallyparticipate in further research, making intensive screen-ing assessments potentially inefficient.

Both registries described here compromise with a rel-atively brief intake session, which includes consent, col-lection of demographic and medical information, detailsof the neurological history, and a screening neurological/neuropsychological assessment. At UPenn, the main in-strument has been the Mattis dementia rating scale,which provides a brief (and standardized) assessment ofmajor cognitive domains, although one that is not partic-ularly specific for the deficits commonly seen after focalbrain injury. A new battery, the Philadelphia Brief Assess-ment of Cognition (PBAC), is under development and willbe used as the screening instrument. At McGill, a com-puterized screening battery is being piloted, intended toscreen for focal deficits while minimizing the expertiserequired of the person administering the battery. At bothsites, the coordinator carries out the screening. In gen-eral, these screening batteries have the dual aims ofidentifying cognitive deficits that may be of researchinterest, and documenting the presence or absence ofother, potentially confounding deficits.

DATA MANAGEMENT

The information collected in the screening assessment isentered into secure, computerized databases. Thesedatabases have two levels of accessibility: the coordina-tor has full access, including identifying and contactinformation, whereas investigators are limited to viewingdeidentified information only. The main practical issuessurrounding the database are to ensure appropriatesecurity and to use consistent terminology particularlyfor fields which are very likely to be searched by inves-tigators (e.g., site of damage, symptoms, signs).

Neuroimaging data are also stored in digital formwherever possible, although at the moment neitherregistry has integrated these data, in full, directly inthe database. Improved handling of lesion data is a goalof both sites. Ideally, lesion data could be directlysearched and visualized as images, rather than filteredthrough cumbersome labeling. Efforts to develop thesetools are ongoing.

FUNDING

These registries are conceived of as shared, cooperativeresearch tools. As such, they present particular funding

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challenges. Unlike some shared research resources,where costs can be recovered through a per-use charge,registries require sustained support regardless of inten-sity of use. This is particularly true when the registry isfirst being established; even with energetic recruitmentefforts, it may be 2 or 3 years before the registry is ofsufficient size to viably support multiple users. Althoughthe costs associated with such a project are relativelylow, they are continuous. Beyond basic computer re-sources, there are few equipment costs; the bulk ofthe financial requirement is for salary. Such ‘‘human-powered,’’ long-term research resources are often ill-served by traditional grant structures.

In principle, individual users should be able to even-tually cover the costs of patient registries through grantsupport: If anything, the registry is a more efficientmechanism for recruitment than traditional, ad hocmethods that would be funded through investigator-initiated grants. An established registry also strengthensgrant applications by ensuring the feasibility of recruit-ing brain-damaged subjects. Institutional support to startthe database is extremely helpful as the entire programrequires steady funding over time to be useful, regard-less of short-term intensity of use or short-term grantsuccess. Per-use charges can recoup some of the costs,particularly those associated with screening, and per-haps neuroimaging. At UPenn, the first investigator tosee a new patient bears the cost of the screening visit.In addition, those making use of the resource contributeto other costs as possible, depending on their expecteduse, and their level of grant support. Every new grantthat proposes to use the database is required to budgetfor personnel salary costs. At McGill, the consortium ofresearchers supporting this resource makes a more-or-less fixed annual contribution to its upkeep, includingcosts associated with the initial screening visit. TheMontreal Neurological Institute also provides support.

HEALTHY CONTROL PARTICIPANTS

Although recruitment of brain-injured participants oughtto be the major challenge in carrying out lesion studies,it sometimes seems that recruiting healthy, age-matchedcontrol participants is even harder. The procedures andtools that support the patient registries are readily adapt-able to healthy controls, and both McGill and UPennhave companion registries for this purpose. This resultsin efficiencies for both participants and investigators.Participants have already been recruited and screened,and do not need to scan the classifieds for researchopportunities, or submit to repeated assessments withstandard instruments. For investigators, a quick searchin the database can identify potential participants ac-cording to demographic or neuropsychological varia-bles, allowing rapid recruitment of a matched controlsample.

OUTCOMES

The purpose of a database registry is to facilitate re-search. Effective facilitation should be reflected in its useby investigators, presentations, publications, and grantsupport. At UPenn, eight faculty make use of the regis-try; at McGill, six faculty are actively using this newresource, and a further eight have committed to sup-porting the project with the intent of future use. Inves-tigators using the UPenn registry have generated 35presentations at meetings and 22 peer-reviewed publi-cations over the 8 years of its existence, and that workhas been supported by more than 20 externally fundedgrants. Although these measures are not ‘‘outcomes’’ inany controlled sense, they support the view that suchdatabases can be a rich resource in facilitating research.

DISCUSSION

It is unfortunate that the colorful phrase ‘‘experimentof nature’’ is often applied to human lesion studies, withthe attendant implication of an effortless, if haphazard,enterprise. Although the lesions themselves ‘‘just hap-pen,’’ the experiments do not. As with any experimentalmethod, this kind of enquiry rests on a set of proceduresand techniques. We argue that the evidence that can begleaned from lesion studies is important in understand-ing human brain–behavior relationships, and that im-proving the procedures and techniques in support ofthis method will enhance the quality and applicability ofthis work to cognitive neuroscience as a whole. Theexperience reviewed here indicates that research regis-tries are a useful mechanism for supporting this kind ofresearch, and for making it accessible to a wider com-munity of investigators. We have tried to identify theimportant elements of success, and to point out pitfallsand potential difficulties. The framework we describe iscertainly not the only means of achieving this goal, butwe hope that it will provide a starting point for othersinterested in establishing this kind of registry, andencourage those who have taken different approachesto solving these problems to share their expertise.

The registries described here are cooperative re-sources at the level of single institutions; extending thiscooperation across multiple sites would have advan-tages. In theory, this could further shorten recruitmenttimes, permit group studies of patients with lesions inrarely injured locations, and increase sample sizes acrossthe board (with the latter particularly important forsupporting newer voxel-based analysis methods). Onthe other hand, it also would add further complexityto issues of consent, accessibility, and funding, andmight reduce the likelihood of independent labs repli-cating crucial results. Nonetheless, multi-site collabora-tion is increasingly commonplace in clinical studies ofrare conditions, for example, in pediatric oncology(Reaman, 2004). The organizational procedures found


to be effective in such collaborative clinical researchsettings could be adapted to support multisite cognitiveneuroscience research.

Although full multi-site collaboration may take time toestablish, other levels of collaboration might be worthconsidering in the shorter term. At a minimum, thesecould include sharing tools, data management methods,and recruitment approaches. The collaborative use ofparticular screening instruments across sites could sup-port interesting secondary-use studies in larger sampleswith a minimum of coordination.

Research registries or other mechanisms to identifyresearch subjects are a necessary step in lesion work, butthere are other challenges. Recent and ongoing workaddresses appropriate experimental design and statisti-cal analysis (Kimberg, Coslett, & Schwartz, 2007; Rordenet al., 2007; Crawford, Garthwaite, Azzalini, Howell, &Laws, 2006; Stuss et al., 2005; Bates, Appelbaum, et al.,2003; Bates, Wilson, et al., 2003). The statistical ap-proaches and image analysis tools developed for func-tional imaging are potentially applicable, or adaptable,to address these challenges, particularly as sample sizesincrease. Creative experiments that take advantage ofthe strengths of the lesion method, bolstered by thesetools and resources, will continue to shape our under-standing of human brain–behavior relationships. Thedevelopment of such registries would provide accessto lesion methods for cognitive neuroscientists, manyof whom tacitly regard ‘‘cognitive neuroscience’’ assynonymous with functional neuroimaging. Our hopeis that wider familiarity with and use of data from lesionstudies will continue to advance our understanding ofbrain–behavior relationships and impose important con-straints on inferences made in functional neuroimagingstudies.

Acknowledgments

UPenn’s Center for Cognitive Neuroscience patient databasehas been supported by the University of Pennsylvania and byindividual grants to Anjan Chatterjee, Branch Coslett, MarthaFarah, Lesley Fellows, Daniel Kimberg, Myrna Schwartz, andSharon Thompson-Schill. The McGill Cognitive NeuroscienceResearch Registry is supported by the Montreal NeurologicalInstitute, and by many individual investigators at McGill. Bothsites are grateful to the many hundreds of patients and theirfamilies who have so generously participated in these researchprograms. L. K. F. acknowledges the support of a CIHRClinician–Scientist award.

Reprint requests should be sent to Lesley K. Fellows, MontrealNeurological Institute, Rm. 276, 3801 University Street, Montreal,QC, Canada H3A 2B4, or via e-mail: [email protected].

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