Neuron Advancing Translational Research Using NIMH Research Domain Criteria and Computational Methods Charles A. Sanisiow,'.” Michele Ferrante," Jennifer Pacheco,”° Matthew V. Rudorfer,” and Sarah E. Morris?" “Department of Psychology, Program in Neuroscience and Braver, Wesleyan University, Middletown, CT 06469, USA "Department of Psychiatry, Yale Unversity, New Haven, CT, USA Division of Translational Research, Natonal Insitute of Mental Health, Bethesda, MD 20892, USA ‘Division of Neurosc'ence and Basic Behavioral Research, National Insitute of Mental Health, Bethesda, MD 20892, USA 5RDOC Unit, Nationa Insitute of Mental Health, Bethesda, MD 20892, USA SDivsion of Services and inervention Research, National insttute of Mental Heath, Gethesca, MD 20892, USA “Correspondence: sarah.moris@rih.gov hitps1/doiore/t0.1016/,neuron.2018.02.024 The NIMH Research Domain Criteria (RDOC) can aid in the translation of integrative neuroscience. We argue that the RDOC framework, with its emphasis on integration across units of analysis, leveraged with compu- tational approaches, can organize intermediary treatment targets and clinical outcomes, augmenting the translational stream. Background and Development fled, and falures in these systems were ADOC will enhance the. translational of ADOC markers forelnical problems (e.g.,\aher, stream, Improvements in the dlagnasis and treat- 1966). In contrast, today’s transitional ment of mental disorders have not kept research relies heavily on broad, hetero- The RDC Framework pace with advances in integrative neuro- geneous clinical syndromes as defined The crux of the RDOC initiative is a matrix, science, and one limiting factor is that by diagnostic manuals. Characterizing consisting of domains that group func~ treatment targels—clnical syndromes clinical problems diferently and more tional constructs (e.g., reward leaming, and disorders—have beon defined by pa- precisely would better allow translational cognitive contol) across the rows and tientreports and clinical observations and researchers to incorporate increasing units of analysis (e.g. circult measures, rot by neural and psychological mecha- knowledge ‘tom integrative neufosci- behavioral task data) down the columns risms (ryan, 2010). For these reasons, ence. Specifically, classifying mental (Figure 1). The resultant cells of the matrix the National Institute of Mental Health illness with more proximate intermeciary are thus occupied by elements that have (NIMH) launched the Research Domain linkages that connect clinical symptoms demonstrated utlily in assessing a given Criteria (DOC) iniative n2009. The stra- and neural substrates would better construct at a given unt of analysis tegic purpose was to faciitate novel advance research efforts, This requires (e.,, orbitofrontal cortex and dorsal stria- research approaches to understanding re-thinking of research design as well as tum activity and reward-relates behavior the disturbances of nervous system struc- changes to regulations for the outcome for measuring reward learning) across ture and function and their behavioral variables employed in the final stages of the full range from normal to abnormal ‘manifestations that constitute psychiatric clinical transation. functioning. The matrix ‘san evohing symptoms. RDOCTiled agapbyprovicing DOC allows a way to do this by structure to specity fundamental mental a conceptual structure to organize providing researchers an altemative to processes that can be measured across and communicate our understanding of tradtional dagnostic categories. It is biological and behavioral unts (the latter fundamental behavioralneural systems explicit agnostic with respect to syndro- comprising both overt behavior and (e.g. fear or working memory). RDOC al- mal definitions of aisorders provided by phenomenological self-reports). It pro- lows researchers to specify independent clinical diagnostic manuals. RDOG is pre- vides a framework to organize research ‘and dependent variabies to investigate mised on clartying how cisruptions in efforts that frees researchers from con- the mechanisms of mental iiness. Uli normative intemal mechanisms relate to straints imposed by categorical clinica ‘mately, hi will low a transformation of the expression of clinical symptoms in or- syndromes, the latter of which are prob- the translational process so that treat- der to pinpoint more precisely treatment _lematic because they are over-specitied ment targets are more precisely linked to targets than approaches that begin with heterogeneous, and overlapping (Cut~ dysfunctional internal mechanisms rele- observed clinical syndromes. A central bert and Inse', 2013). The domains and vant to clinical mantestations. goal is to develop a scientiic basis for subsidiary constructs in the matrix were ‘The RDOC approach has rootsinexper- future neuroscience-informed diagnostic chosen to best capture te current know!- imental psychopathology, where neural, systems that will facilitate more precise edgebase and are amended as scientific psychological, and behavioral mecha- treatment targets by integrating relevant evidence accumulates, Because RDOC risms for normal processes were identi- neural circuits. Through this process, was developed at NIMH as a resource 2 Nouron 101, March 6, 2018 @ 2018 Publishod by Elsovior Inc. 779 ey Pres:CelPress Figure 1. The NIMH Res for researchers, the National Advisory ‘Mental Heath Council (NAMHC) provides foversight for changes. The NAMHC has convened a workgroup to address the fongoing “Changes to the RDoC Matrix” (CMAT). The CMAT workgroup is encour- aged—and provided resources—to seek consultation from leading experts in areas whore questions about change arise. Like the summaries of the process and ratio- nale for the development ofthe ADOC do- ‘mains, documents detaling each major ‘change to the matrix are available on the DOC website, and older versions of the matrix are archived on the matrix website The CMAT workgroup handles changes both large (e.g. considering addition a ‘new domain) and small (.g., hanging el- ‘ements inthe ind vidual cells) An example ‘of matrix revision based on the accumu- lation of scientific knowledge is a series of refinements that were made to the Posi- tive Valence Systems (PVS) domain. The {goals of the reorganization of this domain were to make the constructs more straightforward and less redundant and to align more closely with recent data stemming from such areas as reinforce- ‘ment learning, reward prediction errors, and response to reward. Originally, the PVS domain included five constructs, 780 Neuron 101, March 6, 2018 a eon ENVIRONMEWy Ww ch Domain Criteria Matrix ‘one of which (approach motivation) had four subconstructs. The revised domain has three constructs, which span reward responsiveness, reward leaming, and reward valuation, and each includes three sub-constructs. Revisions may also be based on the need for better specification, An example ofthis kind of change involved the evalu- ation of tasks and measures for quanti- fying ADOC constructs and explicating standards and ideals for reliabiity and valicty of tasks and measures used in DOC research studies. The rationale for changes can also be based on the realization that there is a gap where relevant mechanisms are not adequately captured. An example here isthe Sensori- ‘motor Domain, which was recently added ‘because of observations made by investi- gators that motor system disruptions are present ina number of cnical syndromes (e.g,, newrodevelopmental and psychosis spectrum disorders), Deploying Principles of RDOC Rosoarch to Advance Translation Organizing Algorithms for New Treatment Targets and Timing Computational neuroscience offers promising ways for advances using Neuron data-driven, integrative approaches. Ex- isting psychlatic research typeally fo- ‘cuses on a single mode of action, often with a linear causal model. However, in lignt of the abundance of biological mech- ‘anisms involved in mental liness and the heterogeneous nature of the phenome- nology characterizing psychiatric. syn- ‘rome, itis not surrising that unimodal studies have yet to provide a clear under- ‘standing of connections among biological mechanisms and clinical presentation. ‘Several factors have hampered the devel- ‘opment of valid psychiatric biomarkers, including that relevant mechanisms (1) are dietrbuted across distinct bio-behav- ioral continua: (2) unfold across diferent ‘spatiotemporal dimensions of neural cir- ‘cuts and development; and (3) involve ‘causal dynamics where muftiple causes ‘can lead to a similar outcome or similar ‘causal pathways can lead to different ‘outcomes. cent studies that are almed at inte- ‘grating pathophysiological dimensions ‘among patients with varied presentation atthe clinical syndrome level but charac- terized by one or more biological mecha- nisms provide complementary informa- tion to elaborate the complex pathways (of promising biomarkers. This approach has been described as “deep pheno- typing.” where pathological processes are comprehensively detailed (Robinson, 2012). The units of analysis in the RDoC ramework provide astructureto explicate land organize these details. At the same time, computational strategies offerapos- sibilty to seamlessly specify multimodal ata streams in order to improve valiity ‘of psychiatric diagnosis and enrich the translational stream. In other words, ‘computational strategies otter a way to speci the relations of RDOC elements. Using computational models to inte- ‘grate pathological processes that span muttiple units of analysis in the RDOC matrix has the potential to improve the accuracy, sensitity, and specificity of diagnostic tools. Computational mode's ‘can also incorporate different stages of iliness, including early asymptomatic at- Yisk periods, prodromal phases where symptoms may be attenuated, full fledged symptomatic periods, and end stages. These models can also incorpo- rate dimensions such as, for example, hormal to severe cognitive impairmentNeuron Developmental processes and dimen- sional approaches are fundamental prin ciples of ADOC, and the comprehensive nature of combining these approaches could identity pathognomonic markers of ‘mental ness that occur during neurode- velopment well before the manifestation of frank disorder. This, in tum, would allow for the discovery of more optimal timing for interventions as well as new tar- {gots for treatment based on such neuro developmental markers, Combining muttiple imaging and behavioral measures could provide missing links to understand compiex mental illnesses leading to improved diagnostic or treatment assignment per formance compared to using unimodal biomarkers. For instance, batteries of ‘mental-neatth-relevant behavioral tasks that evaluate specific domains of function could be parametrically detailed into components that could then be linked to measures of neural processes to specity the relation of brain and behavioral pa- rameters. Or, diagnostic scales could be {developed based on brain changes using structural imaging or alterations in con- rectivity using resting-state or task- based functional imaging. These parame- ters would serve network analyses to develop models of aberrant mechanisms in patent populations. Neuropnysiolog- ical imaging could be used to quantity variations in metabolism and integrated polygenie risk scores as wel as temporal dynamics of peripheral measures such as molecular markers. Analysis. tech: niques such as matrix and tensor decom- postions hold promise to better account for the heterogeneity of mechanisms that vary within and across patients. over time. NIMH has recognized the potential for computational psychiatry approaches to develop novel data-driven solutions (Ferrante eta, 2018). Precision Medicine Research informed by ROC principles can advance explanations of istur- Dances in effect and behavior by facil- tating the study of dtferent granular com- ponents that have not been incorporated into syndromal specications of mental iliness. This offers the prospect of utilizing Do concepts to ‘further treatment development efforts by offering a wider range of treatment targets and outcomes. In regard to outcomes, the present models for efficacy studies emioraced by regulatory bodies base indicatons for psychotropic medications or neurostimu: lation techniques on standard categorical iagnoses. That is, a given medication ‘would be evalusted for approval for use in the treatment of one of more mental disorders as defined by the relevant diag- nostic manual, Mechanisms revealed with RDoC-ramed research introduce a wider range of potential targets and outcomes. For instance, by allowing the study o ‘components that may apply to one or more clinical syndromes, RDOC research might reveal a target that more directly ‘connects to an aberrant mechanism, Even if intervening on that mechanism ‘would not remit a syndromal diagnosis, this precision medicine approach could ameliorate a specific patnological mecha- nism and bring clinically significant rele. RDCC specification of disturbances in brain circuity in the context of other DOC units of analysis that are associated vwitn mental illnesses offers the prospect of addressing specific symptoms that have been demonstrated to cut across siagnostic lines. ‘Overcoming Pseudospeciticity with Improved Treatment Targets Progress inthis area has been hampered not only because of reliance on diagnostic ‘categories as indications for prescription drugs (Pankevich et l., 2014) but to an understandable concem about pseudo- specificity, whereby improvement in one aspect of a disorder might not reflect a precisely delineated treatment response by one particular component of a disor- der. Rather, if the clinical syndrome is believed to be a unitary entity, then there follows @ potentially errant assumption that all signs and symptoms would benefit ‘commensurately from successful treat ment. For example, a depressive episode Is composed of a number of symptoms, feach of which may be imperfect for the diagnosis. Consider among the ‘symptoms of poor sleep, increased or decreased appetite, decreased Ibid, land impaired concentration, all of which ‘could be part-and-parcel of the clinical ‘syndrome. The neurological mechanisms for these problems are not unitary and involve complex biological and psycho- logical intermediary processes. Thus, it is reasonable to expect that the symp- toms of the diagnostic category would Improve at varying rates and in different \ways in the remission process, ‘There are examples of research that hhas moved beyond the pseudospeciicty fof the schizophrenia diagnosis. For Instance, the International Suicide Pre- vention Trial (InterSePT) found that indi- Viduals dagnosed wth schizophrenia or schizoatfective disorder and at elevated tisk for sulcide who were teated with the atypical antipsychotic clozapine had 24% lower risk of suicide attempt ‘or hospitalization to prevent suicide compared with olanzapine-reated pa- tionts during a 2-year folow-up (Weltzor tai, 2003). This result was strkng, given that [psychosis symptom severty was equivalent across. the two treatment ‘groups, indicating that the reduction in suicidality was independent of changes in psychosis. Although it remains Unclear whether clozapine targets a distinct mechanisin specifically related to ‘suicide risk, subsequent FDA approval of labeling of the drug as indl- cated for “reducing the risk of recurrent suicidal behavior in patients with schizo- phrenia or schizoaffective disorder who are judged to be at chronic risk for re- ‘experiencing suicidal behavior" set areg- latory precedent for approving the use of 2 drug to treat a specific component of a isorder rather than remission trom the lumped symptoms of a syncrome that is ‘assumed to be unitary, Cognitive dysfunction, evident across the schizophrenia spectrum and affective spectrum disorders, nas a'so been invest gated as an entity apart from a specific Clinical syndrome (Buchanan et a, 201") |Athough some differences in the features fof cognitive disturbances in psychotic versus afectve conditions have been ‘observed, research on cognitive dysfunc tion across diagnostic categories tlus- trates a transdiagnostic approach consis- tent with RDOC by suggesting outcome variables other than remission for efficacy studies. This opens the door for develop ment and evaluation of pro-cognitive drugs as well as for behavioral interven tions forcognitveremediation. psychotic symptoms and cognitive imoairments are mediated by independent brain circuits, then different targets would be incicated for two comorbid. mechanisms. ADOC provides the research framework to sys tematically study this possibilty. NNowron 407, March 6, 2018. 781 ey Pres:CelPress Inthe area ot atfective disorders, one of the newest antidepressant medications, Vortioxetine, a selective serotonin reup- take inhibitor (SSRI with mutiple actions at several serotonin receptors, demon- strates. a multiciomain beneficial eftect ‘on cognitive performance, evidenced by Improvements in measures of executive function, attention and speed of process- Ing, and memory (Harrison et al, 2016) These cognitive effects have surpassed those evidenced by other antidepressant ‘medications and have been shown in short-term controlled trials to result pri- marly from a direct treatment effect on Cognitive function rather than attbutable to a secondary effect of the alleviation of depressed mood {Vahableshwvarkar et al, 2015). In response, regulatory agencies, first in Europe and then in the United States, have approved adai- tional labeling language describing the two major industy- sponsored cognitive function studies but have proceeded cautiously without expanded ingications for prescribers, Conolusion ‘The ADOC intiatve was introduced to Lunbridle researchers trom constraints Imposed by using clinical syndromes for translational research and invites. novel 782 Neuron 101, March 6, 2018 approaches to research conceptualiza- tions and elassifeations of peyehopathol- ogy to build new translational pathways. This approach, as well asthe transdiag- nostic and intermediate phenotype ap- proaches, offers potential to enhance the translational steam. The RDOC matrix offers the additional advantage of a common schematic to organize, commu Ficate, and relate research findings. Bio physically informed theory-driven models ‘that encompass muttiple biological and behavioral dimensions to test mecha- ristic hypotheses can draw on findings from RDOC research by incorporating ele- ments from the RDOC matrix, and the r= lations among the elements in the RDO ‘matrix could be expiicated with computa tional approaches. Progress thus far has set the stage for RDOC to be implemented In intervention development. REFERENCES ‘Buchanan, AW. Keats, A'S, Ube . Gree, Me, caugiver. Tan Maser SF 204") Tho FOR'NIH-MATRICS gudeines fer cincal ta {design of cogntne-anhanengsruge: wnat do we ietow'® yeas eter? Schizophr Bul 97, 1200" uth. BN, and ies, TR. (2019) Toward the taupe of sayciave aagness: he sven pars oF ADoe, BNC Med. 17,528, Neuron Frame, My Rear, AD, Cauendo, MA, ‘eeoeck, BA, Kimara, ME. and Cordon, LA (20t8), Camouistion! psychi: @ repo ‘ron {he 2017 NIH workshop on appertunies and halogen Mol" Payhany” estos. 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