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Research ReportOccasional PaperFunctional MagneticResonance Imaging (fMRI):An Invaluable Tool inTranslational NeuroscienceLori A. WhittenDecember 2012RTI Press

About the AuthorLori A. Whitten, PhD, is a sciencewriter in the Knowledge Translationand Strategic Communicationgroup in RTI International’s Social,Statistical, and EnvironmentalSciences unit.RTI Press publication OP-0010-1212This PDF document was made available from www.rti.org as a public serviceof RTI International. More information about RTI Press can be found athttp://www.rti.org/rtipress.RTI International is an independent, nonprofit research organization dedicatedto improving the human condition by turning knowledge into practice. TheRTI Press mission is to disseminate information about RTI research, analytictools, and technical expertise to a national and international audience. RTI Presspublications are peer-reviewed by at least two independent substantive expertsand one or more Press editors.Suggested CitationWhitten, L. A. (2012). Functional magnetic resonance imaging (fMRI):An invaluable tool in translational neuroscience. RTI Press publicationNo. OP-0010-1212. Research Triangle Park, NC: RTI Press. Retrieved fromhttp://www.rti.org/rtipress.This publication is part of theRTI Research Report series.Occasional Papers are scholarlyessays on policy, methods, or othertopics relevant to RTI areas ofresearch or technical focus.RTI International3040 Cornwallis RoadPO Box 12194Research Triangle Park, NC27709-2194 USATel:Fax:E-mail:Web site: 1.919.541.6000 1.919.541.5985rtipress@rti.orgwww.rti.org 2012 Research Triangle Institute. RTI International is a trade name of Research TriangleInstitute.All rights reserved. This report is protected by copyright. Credit must be provided to the authorand source of the document when the content is quoted. Neither the document nor partial orentire reproductions may be sold without prior written permission from the op.0010.1212www.rti.org/rtipress

Functional Magnetic ResonanceImaging (fMRI): An Invaluable Tool inTranslational NeuroscienceLori A. WhittenContentsNeuroimaging: A Major Driverof Neuroscience ResearchIntroduction22A Brain With a View: FunctionalNeuroimaging3Neuroimaging: A New Driver ofTranslational Neuroscience 4fMRI as a Tool in the Diagnosisand Treatment ofNeurobehavioral Problems 4Importance of Integrating fMRIWith Other Approaches8AbstractThe sophisticated methods of neuroscience—including molecular genetics,structural and functional neuroimaging, animal models, and experimentaltasks that approximate real-world behaviors in human research—have yieldedimportant insights about typical functioning and neurobehavioral disorders.Translational neuroscience endeavors to use this knowledge to improvethe human condition by developing and improving interventions for thesedisorders. This paper reviews the literature on the contribution of functionalmagnetic resonance imaging (fMRI) and two related techniques, resting-statefMRI (rs-fMRI) and real-time fMRI (rt-fMRI), to the diagnosis and treatment ofbehavioral problems and psychiatric disorders. It also explains how incorporatingneuroscience principles and techniques into research on the prevention ofsubstance misuse and antisocial behavior may spur advances and innovationsin this important area. This article argues that fMRI’s potential contribution tothese prevention efforts has yet to be fully realized, explores new ways in whichthe technique could be adapted to that end, highlights some of the work byresearchers in the vanguard of this effort, and notes limitations of fMRI andethical concerns the technique raises.Translational Neuroscience andPrevention: Substance Misuse9and Antisocial BehaviorThe Complex Etiology ofSubstance Misuse andAntisocial Behavior10Neurobehavioral CharacteristicsAssociated With LaterSubstance Misuse andAntisocial Behavior11fMRI Research on SubstanceMisuse and AntisocialBehavior, and Implications12for PreventionIntegrating fMRI intoPrevention Research15RTI International’sTransdisciplinary Scienceand TranslationalPrevention Program16fMRI Limitations andNeuroethics17Future Applications andConclusions19References21Acknowledgments Inside back cover

2Whitten, 2012Neuroimaging: A Major Driver ofNeuroscience ResearchIntroductionWhat is the final frontier of human exploration?Some, particularly neuroscientists, might answerthat it is the human brain—“inner space” rather thanouter space. During the 40 years since men walked onthe moon, scientists have accumulated a tremendouswealth of knowledge about the brain, its functions,its relationship with behavior, and its underlyingrole in neurological and psychiatric diseases.Researchers trained in many different disciplines—including physiology, psychology, pharmacology,molecular biology, psychiatry, and neurology—workin neuroscience through a common passion todetermine how the brain and nervous system work.No function or behavior appears too complex forneuroscience to tackle—from how children learnlanguage (Kuhl, 2010) to the memory systems thatpreserve our experiences and knowledge (Squire,2009)—and advances continue at a breathtaking pace.As in all areas of biomedical research, a crucialchallenge for neuroscientists is to translate theknowledge derived from scientific inquiry intopractical tools or programs that improve people’slives. Translational neuroscientists strive to developinterventions for neurological and psychiatricdisorders based on the latest brain and behaviorresearch. By understanding how brain structure andfunction are influenced by genes, environmentalfactors, and their interactions, translationalneuroscientists strive to alleviate the individual andsocietal impact of neurobehavioral disorders.A great deal of translational neuroscience resourcesand efforts are dedicated to developing newpharmacotherapies to treat debilitating neurologicaland psychiatric disorders (e.g., dementia,neurodegenerative diseases, autism, schizophrenia,and depression). Other neuroscientists aim totranslate research on brain and behavior intonon-pharmacological treatments for psychiatricand neurobehavioral disorders (e.g., behavioralor cognitive therapies). Increasingly, biologicalfactors and their reciprocal interaction withRTI Pressthe environment are incorporated into work onprevention and intervention for a wide range ofbehavioral problems (Beauchaine, Neuhaus, Brenner,& Gatzke-Kopp, 2008; Cicchetti & Gunnar, 2008;van Goozen & Fairchild, 2008; Blair & Diamond,2008; Fishbein & Tarter, 2009). Such work is basedon the well-established neuroscience principle ofbrain plasticity—that is, the brain can change withexperience and environmental influences.Functional neuroimaging techniques—varioustypes of scans that visualize brain activity—offer apowerful set of tools for observing experience-relatedchanges. With functional neuroimaging, researcherscan look at the brain’s response to a particular input,such as a cognitive stimulus, a contextual settingor, in the clinical realm, a change in response to anintervention. For example, functional neuroimaginghas examined the neural impact of peer observationon teens’ risky decisions and accidents duringsimulated driving (Chein, Albert, O’Brien, Uckert,& Steinberg, 2011) and of a regimen of cognitivebehavioral therapy for depression (Fu et al., 2008).Findings from functional neuroimaging studieshave great potential to contribute to the diagnosis,treatment, and prevention of behavioral problems andpsychiatric disorders. The prevention field, however,has underutilized this knowledge. Researcherscan help overcome this research-to-practice gapby translating knowledge from neuroscience tothe science and practice of prevention. Brainscience can help generate solutions and providea foundation for a non-political, non-rhetoricbased dialog on these problems. To illustrate this,a brief description is provided on widely usedtechniques in functional magnetic resonanceimaging (fMRI)—including resting-state fMRI(rs-fMRI) and real-time fMRI (rt-fMRI)—andhow they are contributing to translational effortsin the treatment of neurobehavioral problems. Thepotential contributions of fMRI to prevention ofneurobehavioral problems are then summarized.To highlight the potential of this technology inprevention research, the use of fMRI by RTI’sTransdisciplinary Science and TranslationalPrevention Program, which focuses on substancemisuse and related problems (e.g., aggression,

fMRI in Translational Neuroscienceviolence), is reviewed in this paper. Finally, fMRI’slimitations and ethical issues regarding its use arediscussed in the context of neuroimaging in researchon neurobehavioral disorders.A Brain With a View: FunctionalNeuroimagingFunctional neuroimaging includes a variety oftechniques that examine how the brain is working—typically, to relate a change in activity in a particularregion with specific task performances, experiences,or behaviors. Some methods record electrical currentsor magnetic fields as a measure of activity in the brainareas just underneath the skull. Other techniques,such as positron emission tomography (PET) andfunctional magnetic resonance imaging (fMRI),examine changes in glucose utilization or blood flow,from which researchers infer neural activity (Raichle& Mintun, 2006).The fMRI technique, which emerged in the early1990s, offered significant advances over othermethods of studying brain function. For example, thewidely available scanning technique visualizes activityin all areas of the brain, not just those close to thesurface. Unlike PET, it does not rely on radiation or aradiolabeled tracer. Without requiring any injection,it measures altered oxygenation and deoxygenationof hemoglobin as brain blood flow shifts to activatedregions, a process that takes from 1 to 5 seconds.An increased local ratio of oxyhemoglobin todeoxyhemoglobin is a marker of activity, calledblood-oxygen-level-dependent (BOLD), and fMRIscanners record images of this signal over time(Logothetis, Pauls, Augath, Trinath, & Oeltermann,2001; Heeger & Ress, 2002). By applying highpowered computing and statistical analyses,researchers use the BOLD signal to infer changes inneuronal activity with high spatial resolution in aparticular brain region (Glover, 2011).What accounts for the dominance of the fMRItechnique in research to understand the relationshipbetween mind and body? Both the technicaladvantages mentioned above and the successfulblending of brain scanning with relevant behavioralparadigms play important roles (Raichle, 2009a).The development of stereotaxic brain atlases for3standardization, the capability to average multiplebrain scans, and the development of powerfulstatistical analyses have helped enable fMRI toproduce physiological measures relevant to behaviorand mental processes.Early in its development, fMRI research wasstrengthened by the involvement of behavioralscientists—particularly cognitive psychologistsfamiliar with tasks that tapped into mental states(e.g., discriminating stimuli, recognition memory,and verbal processing). The field was thus founded onestablished experimental paradigms. These behavioralscientists were also familiar with techniques tocontrol for practice, fluctuating attention, and otherimportant factors. The technical advantages offMRI and well-established behavioral tasks provideresearchers with a unique tool to visualize what ishappening in the brain as participants experience andrespond to a wide range of stimuli or tasks.Event-Related (Task-Based) fMRIScans taken while subjects are engaged in a taskcan enable researchers to link the activity of neuralstructures with a particular function, experience,or behavior. Building on behavioral studies,psychometrics, and other fields—and often workingin interdisciplinary teams—researchers have beencreative in designing fMRI tasks and protocols thatbear on real-world thoughts and behaviors (Spiers &Maguire, 2007). The imaging technique has providednew information about uniquely human emotions(Takahashi et al., 2009) and has had practicalimplications regarding typical cognitive function(Houdé, Rossi, Lubin, & Joliot, 2010; Arsalidou &Taylor, 2011; Kim, 2011) and responses to peopleand social experiences (Dosch, Loenneker, Bucher,Martin, & Klaver, 2010; Swain, 2008; Chein et al.,2011; Sebastian et al., 2011).Resting-State (rs-fMRI)More recently, the neuroimaging field has recognizedthat the brain not only responds to events but isconstantly active—consuming most of its energy atrest rather than during goal-directed tasks (Raichle,2010). Communication between interconnectedstructures is continuous, although individual circuits

4RTI PressWhitten, 2012may be more or less active at various times. MarcusRaichle laid the evidentiary groundwork for rsfMRI. He showed that when individuals appear tobe doing nothing—as in, for example, the controlcondition of a task-based fMRI experiment in whichparticipants stare at a mark in the center of a screen—interconnected brain circuits remain active insynchronized patterns, which he named the defaultmode network (Raichle et al., 2001; Raichle & Snyder,2007). This constant communication reflects manyhighly coherent functional networks and reveals thebrain’s functional organization (Raichle, 2009b; Deco,Jirsa, & McIntosh, 2011).Research on the default-mode network has yieldedinsights on brain development. For example, de Bieand colleagues (2012) found that children aged 5to 8 have sensory and motor networks with robust,adult-like functional organization but demonstrateimmature characteristics in circuits related tohigher-order cognitive functions. Similarly, Powerand colleagues (2010) noted that the organizationalcharacteristics of brain networks are present duringchildhood but undergo significant refinement withmaturation. Results from rs-fMRI are complementaryto those from structural neuroimaging—techniquesthat visualize the brain’s structures and the fiber tractconnections between them (Damoiseaux & Greicius,2009)—and critical in advancing the understandingof neural network development (Supekar et al., 2010).Studies that apply rs-fMRI to healthy adultvolunteers are helping researchers test hypothesesabout particular functional networks (Taylor,Seminowicz, & Davis, 2009), sub-networks (Vogel,Power, Petersen, & Schlaggar, 2010), and the impactof specific activities (e.g., mindfulness meditation)on the brain’s intrinsic connectivity (Kilpatrick etal., 2011). Collaborative efforts to pool rs-fMRIbrain scans into publicly accessible databases helpovercome the problem of small-sample studies. Twoongoing efforts—the grassroots 1,000 FunctionalConnectomes Project (Biswal et al., 2010; m) and agovernment-initiated effort, the Human ConnectomeProject, which also includes genetic, behavioral,and structural imaging data, will further increaseknowledge about the brain’s intrinsic ).Real-Time (rt-fMRI)Instantaneous analyses of fMRI data yield a realtime view of neural responses. Combining suchtechnology with well-established neurofeedbacktechniques offers a powerful tool, called real-timefMRI, to teach people to control their brain activity(deCharms, 2007). Proponents of rt-fMRI argue thatit can increase a person’s awareness of brain function,permitting him or her to change their thoughts oremotions (deCharms, 2008). (Preliminary evidencefrom rt-fMRI studies among healthy volunteers isdescribed in the next section). This tool for teachingpeople to control activity in a specific brain region hastherapeutic potential for pain modulation (deCharmset al., 2005) and perhaps as a component of treatmentfor behavioral and emotional problems (deCharms,2008; Linden & Fallgatter, 2009).Neuroimaging: A New Driver ofTranslational NeuroscienceSince the 1970s, when structural neuroimagingdemonstrated that people with schizophrenia haveenlarged cerebral ventricles, some psychiatristshave encouraged incorporation of such techniquesinto their field (Linden, 2012). With the adventof biological psychiatry, functional neuroimagingresearch on behavioral problems exploded. Althoughfunctional neuroimaging has not yielded clinicallyrelevant biomarkers for mental disorders, currentstudies lay the groundwork for its eventual use in thediagnosis, treatment, and prevention of behavioralproblems and psychiatric disorders (Linden, 2012;Bigos & Weinberger, 2010; Loth, Carvalho, &Schumann 2011; Hasler & Northoff, 2011). Powerfulfunctional neuroimaging tools are helping researchersunderstand the origins of mental disorders andthe mechanisms of effective treatments—bothpharmacological and behavioral (Linden, 2012;Carter et al., 2011).fMRI as a Tool in the Diagnosis andTreatment of Neurobehavioral ProblemsOf all the neuroimaging techniques, fMRI is thoughtto have the greatest potential to change psychiatricpractice. When combined with other techniques,particularly structural neuroimaging, fMRI can help

fMRI in Translational Neuroscienceidentify the pathophysiology underlying psychiatricdisorders (Linden & Fallgatter, 2009). Much of thisresearch compared brain activity patterns of patientpopulations with those of healthy controls.Highly prevalent disorders, including depression,anxiety, and attention-deficit hyperactivity (Rigucci,Serafini, Pompili, Kotzalidis, & Tatarelli, 2010;Robinson & Shergill, 2011; Casey, Ruberry, et al.,2011; Wilens & Spencer, 2010) are being studiedin this manner. Pediatric psychiatry increasinglyuses fMRI to uncover the development of disorders(Pavuluri & Sweeney, 2008; Hulvershorn, Cullen, &Anand, 2011).Descriptions of the pathology underlyingneurobehavioral disorders based on structural andfunctional neuroimaging provide vital, objectivedata to improve psychiatric diagnoses. fMRI has thepotential to provide biological indicators of disease,or biomarkers—critical for diagnosis in other fieldsof medicine—to psychiatry, although a great deal ofwork remains for this potential to be fully realized(Malhi & Lagopoulos, 2008; Linden & Fallgatter,2009). Such neural markers would not replacesymptom-based diagnosis and behavioral assessmentsin psychiatry, but they would augment clinicaldecision making (Linden & Fallgatter, 2009).Task-Based fMRIUsing task-based fMRI, researchers have identifiedspecific differences in brain response between healthyand psychiatric populations. These differences mayserve as neural markers to identify underlyingpathology and, ultimately, aid diagnosis. The processof identifying the emotion represented on others’faces, for example, not only guides how individualsinteract with others but also may serve to gauge thepresence of a mood disorder. To map areas of thebrain involved in this important function, researchershave applied meta-analysis to many functionalneuroimaging studies investigating how healthyvolunteers process the emotions faces display—forexample, identifying responses to happy, fearful, andsad faces (Fusar-Poli et al., 2009; Sabatinelli et al.,2011). Such mapping of the typical neural responseis critical for interpreting aberrant brain activityobserved among patient populations.5For example, depressed people who have notundergone treatment show heightened responsesin the amygdala (a brain structure involved infear and anxiety) in response to emotional facialexpressions (Peluso et al., 2009; Fu et al., 2008;Victor, Furey, Fromm, Ohman, & Drevets, 2010),although results are not always consistent (Townsendet al., 2010). With confirmatory research, suchneural responses may ultimately comprise an fMRIdiagnostic for depression. Current diagnosticmethods are characterized by a great deal of overlapwithin disorders, and fMRI may contribute to betterspecification of disease subtypes (Linden, 2012).It may be the case that subtypes of disorders arecharacterized by different patterns of brain activitydespite simil

magnetic resonance imaging (fMRI) and two related techniques, resting-state fMRI (rs-fMRI) and real-time fMRI (rt-fMRI), to the diagnosis and treatment of behavioral problems and psychiatric disorders. It also explains how incorporating neuroscience

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