# Research Domain Criteria

The Research Domain Criteria (RDoC) project is an initiative of personalized medicine in psychiatry developed by US National Institute of Mental Health (NIMH). In contrast to the Diagnostic and Statistical Manual of Mental Disorders (DSM) maintained by the American Psychiatric Association (APA), RDoC aims to address the heterogeneity in the current nosology by providing a biologically-based, rather than symptom-based, framework for understanding mental disorders. "RDoC is an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioral science to the problem of mental illness."

## Call for creation

The 2008 NIMH Strategic Plan calls for NIMH to "Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures." The strategic plan continues:
   Currently, the diagnosis of mental disorders is based on clinical observation—identifying symptoms that tend to cluster together, determining when the symptoms appear, and determining whether the symptoms resolve, recur, or become chronic. However, the way that mental disorders are defined in the present diagnostic system does not incorporate current information from integrative neuroscience research, and thus is not optimal for making scientific gains through neuroscience approaches. It is difficult to deconstruct clusters of complex behaviors and attempt to link these to underlying neurobiological systems. Many mental disorders may be considered as falling along multiple dimensions (e.g., cognition, mood, social interactions), with traits that exist on a continuum ranging from normal to extreme. Co-occurrence of multiple mental disorders might reflect different patterns of symptoms that result from shared risk factors and perhaps the same underlying disease processes.
   To clarify the underlying causes of mental disorders, it will be necessary to define, measure, and link basic biological and behavioral components of normal and abnormal functioning. This effort will require integration of genetic, neuroscience, imaging, behavioral, and clinical studies. By linking basic biological and behavioral components, it will become possible to construct valid, reliable phenotypes (measurable traits or characteristics) for mental disorders. This will help us elucidate the causes of the disorder, while clarifying the boundaries and overlap between mental disorders. In order to understand mental disorders in terms of dimensions and/or components of neurobiology and behaviors, it will be important to:
   * Initiate a process for bringing together experts in clinical and basic sciences to jointly identify the fundamental behavioral components that may span multiple disorders (e.g., executive functioning, affect regulation, person perception) and that are more amenable to neuroscience approaches.
   * Develop reliable and valid measures of these fundamental components of mental disorders for use in basic studies and in more clinical settings.
   * Determine the full range of variation, from normal to abnormal, among the fundamental components to improve understanding of what is typical versus pathological.
   * Integrate the fundamental genetic, neurobiological, behavioral, environmental, and experiential components that comprise these mental disorders.

## Contrast with DSM

On April 29, 2013, a few weeks before the publication of the DSM-5, NIMH director Thomas Insel published a blog post critical of the DSM methodology and highlighting the improvement offered by the RDoC project.
Wrote Insel:
   While DSM has been described as a 'Bible' for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been "reliability" – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.
In that post, Insel wrote: "Patients with mental disorders deserve better." He would later elaborate on this point, saying "I look at the data and I'm concerned. ... I don't see a reduction in the rate of suicide or prevalence of mental illness or any measure of morbidity. I see it in other areas of medicine and I don't see it for mental illness. That was the basis for my comment that people with mental illness deserve better."
In their effort to resolve their issues with the new DSM, the NIMH launched the Research Domain Criteria Project (RDoC), based on four assumptions:
   * A diagnostic approach based on the biology as well as the symptoms must not be constrained by the current DSM categories,
   * Mental disorders are biological disorders involving brain circuits that implicate specific domains of cognition, emotion, or behavior,
   * Each level of analysis needs to be understood across a dimension of function,
   * Mapping the cognitive, circuit, and genetic aspects of mental disorders will yield new and better targets for treatment.
Insel stressed that the RDoC is not designed as diagnostic criteria to replace the DSM, but rather as a research framework, for future development. His argument centers around the claim that, "symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment." As a result of this position, the NIMH is no longer using the DSM as the criteria upon which they will evaluate funding of future clinic trials.
DSM researcher Eric Hollander was quoted as saying "I do think it does represent a lack of interest and faith on behalf of NIMH for the DSM process and an investment in alternative diagnostic systems."
A NIMH description of RDoC explained:
   Currently, diagnosis in mental disorders is based on clinical observation and patients' phenomenological symptom reports ... However, in antedating contemporary neuroscience research, the current diagnostic system is not informed by recent breakthroughs in genetics; and molecular, cellular and systems neuroscience.

## RDoC matrix

The RDoC matrix is one way of organizing the concepts involved, with domains as tables, constructs as rows, sub-constructs as subrows and units of analysis often presented as columns.
Negative Valence Systems, as of January 2022 :
| Construct | Construct | Genes | Molecules | Cells | Circuits | Physiology | Behavior | Self-reports | Paradigms |
| Acute Threat (Fear) | Acute Threat (Fear) | n/a | BDNFCCKCortisol / CorticosteroneCRF familyDopamineEndogenous cannabinoidFGF2GABAGlutamateNeuropeptide SNeurosteroidNMDARNPYOXOxytocinSerotoninVasopressin | GABAergic cellsGliaNeuronPyramidal cell | Amg basal aCeN lateral medial ACC dorsal rostral ANS Hi posterior anterior Hy ICMs Ins OFC PAG dorsal ventral Pons LC PFC vmPFC (il) dmPFC (pl) LPFC/Ins RPVM | BP EDA EMG facial Eye tracking Heart rate Pupillometry Breathing Response accuracy Startle context fear-potentiated | Analgesia (reduced pain perception)Early developmental approachAvoidanceFacial expressionFreezingOpen fieldInhibitory controlResponse timeRisk assessmentSocial approach | Fear survey scheduleSUDS | Behavioral approach testCO$_2$ challenge testCold pressor testFear conditioningStranger testsTrier social stress test |
| Potential Threat (Anxiety) | Potential Threat (Anxiety) | n/a | CortisolCRF family | Pituitary cells | BNST | ACTHAverage cortisol levelsPotentiated startle | n/a | Anxiety Sensitivity IndexBISFear of Negative Evaluation ScaleIntolerance of Uncertainty ScaleLEDS | NPU Threat Task |
| Sustained Threat | Sustained Threat | n/a | ACTHCRFHPA axis hormones | HiMicrogliaprefrontal | Attention network Dysregulation of Amg reactivity Dysregulation of cingulate reactivity Habit systems Striatum Caudate Accumbens Hy nuclei PVT Vigilance network | Dysregulated HPA axisError-related negativity | Anhedonia/decreased appetitive behaviorAnxious arousalAttentional bias to threatAvoidanceDecreased libidoHelplessness behaviorIncreased conflict detectionIncreased perseverative behaviorMemory retrieval deficitsPunishment sensitivity | Childhood Trauma QuestionnaireLEDSRisky FamiliesSTRAINTESIYouth Life Stress Interview | n/a |
| Loss | Loss | n/a | AndrogenCRHEstrogenGlucocorticoid receptorInflammatory moleculesOxtADH | n/a | Amg Default mode network DLPFC Habit systems Striatum Caudate Accumbens Hi Ins OFC Parietal cortex PCC PVN Reward circuitry vmPFC | ANSHPAneuroimmuneProlonged psychophysiological reactivity | AmotivationAnhedoniaAttentional bias to negative valenced informationCryingExecutive functionGuiltIncreased self-focusLoss of driveLoss-relevant recall biasMorbid thoughtsPsychomotor retardationRuminationSadnessShameWithdrawalWorry | LEDSSTRAIN | Sadness eliciting film clips |
| Frustrative Nonreward | Frustrative Nonreward | n/a | DopamineGABAGlutamateSerotoninSteroidsADH | n/a | AmgHyLCOFCPAGPNSSeptumStriatum | n/a | Relational and physical aggression | Frustrative Nonreward Responsiveness SubscaleQuestionnaire of Daily Frustrations | Lab-TABPSAP |
Positive Valence Systems, as of January 2022 :
| Construct / Subconstruct | Construct / Subconstruct | Genes | Molecules | Cells | Circuits | Physiology | Behavior | Self-reports | Paradigms |
| Reward Responsiveness | Reward Anticipation | n/a | n/a | n/a | n/a | n/a | n/a | n/a | Monetary incentive delay |
| Reward Responsiveness | Initial Response to Reward | n/a | CREBEndocannabinoidsFosBGlutamateMu and delta opioidOrexin | n/a | Anterior InsDorsal ACCLHMedial OFCNucleus accumbensVentral pallidumVentromedial PFCVTA | n/a | Taste reactivity | Consummatory subscale of TEPSPANAS (state version) | Simple guessing task |
| Reward Responsiveness | Reward Satiation | n/a | n/a | n/a | n/a | n/a | n/a | n/a | Fixed-ratio satiation schedule |
| Reward Learning | Probabilistic and Reinforcement Learning | n/a | n/a | n/a | n/a | n/a | n/a | n/a | Drifting double banditClassical conditioningProbabilistic reward taskProbabilistic stimulus selection task |
| Reward Learning | Reward Prediction Error | n/a | DopamineSerotonin | n/a | AmgBGDorsal ACCLateral habenulaOFCRostral medial tegmentumSubstantia nigra/VTAVentral striatum | Cortical slow wavesHeart rate changeSkin conductance | Goal trackingPavlovian approachReward-related speedingSign tracking | Affective forecastingASAM scaleEating Expectancy InventoryGeneralized reward and punishment expectancy scaleSelf-report of cravingTEPS anticipatory scale | Drifting Double BanditRutledge Passive Lottery Task |
| Reward Learning | Habit - PVS | n/a | AcetylcholineCo-released neuromodular glutamateCREBDopamine and dopamine-related moleculesFosB | Dopaminergic neuronsmedium spiny neuronsSubstantia Nigra | dorsal striatumMedial Prefrontal CortexSN/VTAVentral striatum | n/a | Compulsive behaviorsRepetitive behaviorsStereotypic behaviors | Aberrant behaviors checklistMeasures of repetitive behaviors | Devaluation taskHabit Learning TaskHabit Task |
| Reward Valuation | Reward (probability) | n/a | n/a | n/a | n/a | n/a | n/a | n/a | Probability Choice TaskWillingness to Pay Task |
| Reward Valuation | Delay | n/a | n/a | n/a | n/a | n/a | n/a | n/a | Delay discounting |
| Reward Valuation | Effort | n/a | AdenosineDopamineGABA | n/a | Basolateral amygdaladorsal ACCVentral pallidumVentral striatum (nACC)VTA | n/a | n/a | Drive subscale of the Behavioral Activation Scale | EEfRT task |
Cognitive Systems, as of January 2022 :
| Construct / Subconstruct | Construct / Subconstruct | Genes | Molecules | Cells | Circuits | Physiology | Behavior | Self-reports | Paradigms |
| Attention | Attention | n/a | Implementation GABA Glutamate Control ACh Dopamine Glutamate Histamine Serotonin | Parvalbumin-positive interneurons | Balance between TPN vs DMN Implementation local circuit interactions pulvinar TRN Control Amg Ascending / descending information pathways Attentional systems Basal forebrain limbic system Dorsal network Ventral network | fMRI Sensory areas from peripheral to central Auditory ERP N1 N2 Neural oscillations P1 P300 Processing negativity Visual ERP N2pc Negativity (SN) Neural oscillations P300 Selection modulations of sensory ERP components Slow waves Peripheral physiology Heart rate deceleration Pupil dilation | ANT task distractibilityAttentional lapses vs sustained attentionDistractibilityObject/feature attentionPsychophysicsSpatial attention | | Attentional blink and psychological refractory period paradigmBlocked channel-selection tasksDichotic listeningdistraction paradigms (capture)Dual-task paradigmsinter-modal selective attentionspatial and non-spatial cuing paradigmstime-series of response times to extract variability and frequency domain analysesvisual search |
| Perception | Visual | n/a | ACHCatecholaminesGABAGlutamateNMDAPeptidesSerotonin | Magnocellular (non-linear gain control)Parvalbumin-positive interneuronsParvoPyramidal cells | Subcortical Koniocellular Magnocellular Parvocellular Cortical Cortico-cortical connections into supra- and infra-granular layers Dorsal/ventral streams Non-retinogeniculate SC SCN Local circuitry Lateral interactions Top-down interactions Implicated in contextual and association fields (responsible for the influence of spatial context on target processing) | Adaptation/habituationBOLD activation of cortical regionsERP componentsNclOscillations (scalp EEG, LFP, and single/multi-unit recording)ssVEPtransient VEP | Discrimination, identification and localizationPerceptual learningPerceptual primingReadingStimulus detectionVisual acuity | Perceptual anomalies of schizophrenia and depression | Scheme 1: Stages of Vision Early Vision Local computations Retinotopic representations Intermediate Vision Nonlocal properties of images Transformations beyond retinotopic representations Late Vision Representations of external objects Scheme 2: Commonly Used Research Paradigms Backward masking Biological motion processing Bistability Coherent motion Contour integration/interpolation Contrast sensitivity Cross modality paradigms Emotion expression identification Face identification Figure ground Lateral facilitation Multistability Object perception Object recognition/perceptual closure/perceptual organization Parallel/serial search Reading Vernier discrimination Visual illusion susceptibility Other Schemes Action-Perception loops Re-entrant processing |
| Perception | Auditory | n/a | AcetylcholineGABAGlutamateNMDASerotonin | Cochlear hair cellsCortical and limbic inhibitory interneuronsRibbon synapses | Nodes in Circuit A1 Anterior insula Brainstem Cochlea Inferior colliculus MGN STG Circuits Corticofugal Dorsal/ventral streams | Adaptation/ habituationAuditory steady-state response (ASSR)fMRIIntracortical EEGMetabolic changesMismatch negativity (MMN)N1Neural oscillationsP3aP50startle and PPI | Perceptual identificationPerceptual learningPerceptual primingSpatial localizationStimulus detection | Auditory hallucinationsHyperacusis | Action-Perception loopsAuditory maskingauditory scene perception (e.g., streaming)BistabilityCategorizationCross-modal interactionsDetection of speech in noiseDeviance detectionGatinginhibitory controlManipulation of ISI and/or intensityMcGurk (multisensory)novelty/oddball detectionObject perceptionRegularity and change detectionsame-different tasksself-monitoringtone detection (e.g., JND tasks)Tone matching |
| Perception | Olfactory / Somatosensory / Multimodal | n/a | n/a | n/a | n/a | n/a | n/a | n/a | Manipulation of ISI and/or intensitySmell identification |
| Declarative Memory | Declarative Memory | n/a | CholinergicGlutamatergicNoradrenergicOpioid | GliaGranule cellsInhibitory and excitatory interneuronsPyramidal cells | Extrinsic hippocampal circuitryIntrinsic hippocampal circuitryPFC and PPC interactions with multiple association cortices | AMPA-related synaptic plasticityconjunction codesfrontal/temporal coordinated oscillationsLTP/LTDNMDA-related synaptic plasticityplace cell activitysubsequent memory effect (fMRI, ERP)up/down states | DiscriminationFamiliarityLearningRecallRecognition | Cognitive Assessment Interview | acquired equivalencedelayed recalllist and story learningPaired associate learningtransitive inference |
| Language | Language | n/a | n/a | n/a | Inferior frontal cortexInferior Parietal CortexInferior temporal cortexLateral superior and middle temporal corticesOverlap with memory, motor, sensory, and emotional circuits | anterior negativitiesN400P600/late positivities | Coherent discourseCoherent sentencesProduction and comprehension of words | Cognitive Assessment Interview | Language Production Linguistic corpus-based analyses of language output Naming Language Comprehension Ability to answer questions about the content of sentences and discourse Ability to distinguish between coherent and incoherent sentences and discourse Detection and classification of semantic relationships between words Listening and reading times to critical words and regions in linguistic input Patterns of eye movements (in eye tracking paradigms) or motor movements (in mouse tracking paradigms) to critical words and regions in linguistic input Patterns of eye movements to non-verbal visual stimuli during spoken language comprehension (the visual world paradigm) Experimental Manipulations Manipulations of different types of coherence and cohesion between clauses in discourse Manipulations of different types of relationships between individual words in priming paradigms Manipulations of predictability and acceptability, at different levels of representation, in a linguistic input Manipulations of relationships between language and non-verbal behaviors |
| Cognitive Control | 1 of 2: Goal Selection; Updating, Representation, and Maintenance | n/a | n/a | n/a | Frontopolar/Anterior LPFC (BA10)Inhibition of DMN | n/a | n/a | BRIEF (Gioa) | Badre tasksKoechlin paradigmTask switching |
| Cognitive Control | 2 of 2: Goal Selection; Updating, Representation, and Maintenance | n/a | ACHDopamineGABAGlutamateNorepinephrine | PVPyramidal cells | Dorsolateral Prefrontal CortexPosterior Parietal CortexThalamocortical | Gamma synchronyPupilometry | DistractibilityOff-task behaviors | BRIEF (Gioa)Cognitive Failures QuestionnaireSANS/SAPS/PANSS | AX paradigmsCued stimulus-response reversal tasksTask switchingTower tasks |
| Cognitive Control | 1 of 2: Response Selection; Inhibition / Suppression | n/a | ACHDopamineGABAGlutamateNorepinephrine | PVPyramidal cells | Dorsolateral Prefrontal CortexPosterior Parietal CortexVLPFC | GammaTheta | Impulsive behaviors | BRIEF (Gioa)SANS/SAPS/PANSS | FlankerSimonStroop |
| Cognitive Control | 2 of 2: Response Selection; Inhibition / Suppression | n/a | AcetylcholineDopamineGABAGlutamateNorepinephrine | Pyramidal cells | BA6/8 (FEF)Posterior Parietal CortexPre-Supplementary Motor AreaVentrofronto-striatal | AlphaPupilometryShort interval cortical inhibition (TMS) | DistractibilityImpulsive behaviorsOff-task behaviors | ADHD Rating Scale (Dupaul)ATQ/CBQ Effortful ControlBRIEF (Gioa)Conners impulsivity scale | AntisaccadeConflicting and contralateral motor response taskCountermandingGo/NogoMotor persistence paradigms (e.g. NEPSY statue task)Stimulus-Resp IncompatStop-Signal Reaction Time |
| Cognitive Control | Performance Monitoring | n/a | DopamineSerotonin | n/a | ACC / pre-SMA Insula | ERNN2N450 | Post-error or post-conflict adjustments in performance | YBOCS total score | FlankerSimonStroop |
| Working Memory | Active Maintenance | n/a | D1DopamineGABAGlutamateNMDA | Distinct types of inhibitory neuronsPyramidal cells | Inferior Parietal CortexPFC-parietal-cingulate-dorsal thalamus-dorsal striatumVLPFC | DeltaGamma wavesTheta waves | n/a | n/a | AX-CPT/DPXChange detection tasksComplex Span tasksdelayed match to non sampledelayed match to samplekeep track taskLetter memory/running memoryLetter Number SequencingN-backSelf-Ordered Pointingsequence encoding and reproductionSimple Span TasksSternberg Item Recognition |
| Working Memory | Flexible Updating | n/a | D2DopamineGABAGlutamate | Medium Spiny Neurons (basal ganglia) | dorsal striatumDorsolateral Prefrontal CortexMDPFC-parietal-cingulate-dorsal thalamus-dorsal striatumVA thalamus | DeltaGamma wavesTheta waves | n/a | n/a | AX-CPT/DPXComplex Span taskskeep track taskLetter memory/running memoryLetter Number SequencingN-backSelf-Ordered PointingSternberg Item Recognition |
| Working Memory | Limited Capacity | n/a | D1D2DopamineGABAGlutamate | n/a | Dorsal ParietalDorsolateral Prefrontal CortexInferior Parietal CortexMDPFC-parietal-cingulate-dorsal thalamus-dorsal striatumVA thalamusVLPFC | DeltaGamma wavesTheta waves | n/a | n/a | AX-CPT/DPXChange detection tasksComplex Span tasksdelayed match to non sampledelayed match to samplekeep track taskLetter memory/running memoryLetter Number SequencingN-backSelf-Ordered Pointingsequence encoding and reproductionSimple Span TasksSternberg Item Recognition |
| Working Memory | Interference Control | n/a | D1D2DopamineGABAGlutamate | CalbindinCalretininDistinct types of inhibitory neuronsParvalbumin | DLPFCPFC-parietal-cingulate-dorsal Th-dorsal striatum | Neural waves Delta Gamma Theta | n/a | n/a | Complex Span tasksDelayed match to non-sampleDelayed match to sampleKeep track taskLetter memory/running memoryLetter number sequencingn-backSelf-Ordered PointingSimple Span TasksSternberg Item Recognition |
Social Processes, as of January 2022 :
| Construct / Subconstruct | Construct / Subconstruct | Genes | Molecules | Cells | Circuits | Physiology | Behavior | Self-reports | Paradigms |
| Affiliation and Attachment | Affiliation and Attachment | n/a | 3CRFCRFR2D1DopamineKORMu opioid receptorOxytocinoxytocin receptorVasopressinvasopressin 1a receptor | Magnocellular OT | AmygdalaBNSTFF gyrusNAccOFCPVNVMPFCVTA- NAcc- VP-amygdala | activation of sympathetic activityHPA axis activationHPA down-regulationImmune markersimmune responses (“sickness”)Sex steroid changesVagal tonevagal withdrawal | Attachment Formation Maintaining proximity Preference for individual Attachment Maintenance Distress upon separation | Adult Attachment InterviewAttachment Questionnaire for Children ScaleAttachment Style interviewBartholomew and ShaverBereavement scalesExperience in Close Relationships ScaleInventory of Parent and Peer Attachment ScaleMultidimensional Scale of Perceived Social SupportParental Bonding InstrumentQSORT Parent Attachment interviewSocial Anhedonia scaleSocial subscales of depression | CyberballOne-armed Bandit Task |
| Social Communication | Reception of Facial Communication | n/a | DopamineFMRPGABAOxytocinSerotoninTestosteroneVasopressin | Face selective neuronsMirror neurons | amygdala-brainstemIFG-INS-amygdala/VSOFC-ACC-amygdala-striatumResting state networksV1-FFA-STS-amygdalaV1-FFA-STS-VS | ECoG frontal brain asymmetryFacial EMGHR/BP/respirationLocal cerebral blood flow changesN170N250Network dynamicsPupil dilationSCRStartle reflex | Behavioral observation/coding systemsEye gaze detectionIdentification of emotionImplicit mimicryScanning patterns | Arousal ratingsFace dimensional rating scales | Gaze CuingPenn Emotion Recognition (ER-40) |
| Social Communication | Production of Facial Communication | n/a | APContactin | n/a | Eye Movements PPC-SC-SNc-SEF-FEF-CB Facial Expression Regions including PAG, AC | Facial EMGHR variabilityNIRSPhotoplethysmography (skin color measure of capillary dilation; temperature)Pupil dilationSCTear production | Behavioral observation/coding systemsEye gaze aversion/contactFacial affect productionHead turningImitation of facial gesturesJoint attentionReciprocal emotional expressionReciprocal eye contact | Berkeley Expressivity Questionnaire | n/a |
| Social Communication | Reception of Non-Facial Communication | n/a | OxytocinVasopressin | n/a | A1-RSTGMPFCSuperior Temporal SulcusVLPFC | EEG features e.g., evoked gammaLocal cerebral blood flow changesNetwork dynamics | Comprehension of emotional prosodyComprehension of non-verbal gesturesHumor comprehensionIrony/sarcasm comprehensionMetaphor comprehension | Social Responsiveness Scale | Multimodal Social Paradigms |
| Social Communication | Production of Non-Facial Communication | n/a | n/a | n/a | R-IFG-RSTGSongbird circuits | n/a | Crying/laughingGestural/postural expressionsInteractive playResponse to distress/separation distressSpeech (affective) prosodyVocalizations | Social Responsiveness Scale | Multimodal Social Paradigms |
| Perception and Understanding of Self | Agency | n/a | n/a | n/a | Right insula-right inferior frontalRight parietalSMA-somatosensory-premotor | Scalp Motor Potentials | Delusions of controlEvidence that one understands ownership of one’s own body parts or action (thoughts/behaviors)HallucinationsStereotypic behaviors | Perceptual Aberration Scale | n/a |
| Perception and Understanding of Self | Self-Knowledge | n/a | n/a | Von Economo neurons | left inferior frontal cortexMPFCposterior cingulate/precuneusventral anterior cingulate (valence specific) | P300s to self-relevant stimuli | Developmentally appropriate perception of one’s competences, skills, abilities beliefs, intentions, desires, and/or emotional states | Levels of Emotional AwarenessPrivate Self-ConsciousnessSelf Components of Attributional Styles QuestionnaireSelf-monitoring scaleToronto Alexithymia scale | Self-Referential Memory Paradigm |
| Perception and Understanding of Others | Animacy Perception | n/a | n/a | n/a | extrastriate body areafusiform face areaoccipital face areaSuperior Temporal Sulcus | MU Suppression | Ability to appropriately attribute animacy to other agents | n/a | Point Light Displays of Biological Motion |
| Perception and Understanding of Others | Action Perception | n/a | n/a | Mirror neurons | Inferior Parietal CortexSuperior Temporal Sulcusventral/dorsal premotor | cortico-spinal facilitation (TMS)MU Suppression | Ability to identify what actions an agent is executingGaze followingImitationMimicry | Balanced Emotional Empathy ScaleEmpathy QuotientPerspective Taking and Empathic Concern subscales of the Interpersonal Reactivity Index | How/Why Task |
| Perception and Understanding of Others | Understanding Mental States | n/a | OxytocinVasopressin | n/a | MPFCprecuneusSuperior Temporal Sulcustemporal poleTPJ | n/a | Developmentally appropriate interpretations of other intentions, goals and beliefs | Balanced Emotional Empathy ScaleEmpathy QuotientOther components of Attributional Styles QuestionnairesPerspective Taking and Empathic Concern subscales of the Interpersonal Reactivity Index | Hinting TaskReading the Mind in the Eyes |
Arousal and Regulatory Systems, as of January 2022 :
| Construct | Construct | Genes | Molecules | Cells | Circuits | Physiology | Behavior | Self-reports | Paradigms |
| Arousal | Arousal | n/a | ACh CRF Cytokine Dopamine GABA Ghrelin Glutamate Histamine OX Leptin NPY NE/NA Opioid Oxt Serotonin ADH | Basal forebrain nuclei aCeN Dorsal raphe Hy LH perifornical dorsomedial LDT LC PPT TMN Ventral tegmental area | Basal nuclei to cortical circuits Cholinergic & monoaminergic nuclei / projections aCeN to monoaminergic and basal forebrain cholinergic nuclei brainstem projections to basal forebrain nuclei projections to Th and cortical projections to midbrain and Pn reciprocoal projection Circadian & sleep-related circuits modulate and are modulated by arousal Cortical circuits fronto-insular area 32 Hy to thalamic and cortical circuits Reciprocal Hy Reciprocal NTS-aCeN | EEG EMG ERP fMRI Neural activity Sex-specific differences in arousal Autonomic BP Breathing EDA Heart rate Pupil size HPA axis ACTH CRF Glucocorticoid | Affective state Agitation Cognition Emotional reactivity Blinking Motivated behavior Motor activity Sensory reactivity Startle Waking | ADACL POMS arousal subscale Self-assessment mannequin | Cardiac pre-ejection period EDA HRV Psychomotor vigilance task Pupillometry |
| Circadian Rhythms | Circadian Rhythms | n/a | Serotonin Input Dopamine GABA Glutamate Melanopsin NPY PACAP SP SCN synchronizing & modulating agents ADH Calbindin cAMP cGMP NO Steroids VIP Output ADH Cortisol GABA Melatonin VIP | Fibroblast ipRGC Medium spiny neuron Pars tuberalis cells Pinealocyte Rods and cones SCN "clock" cells | Input Raphe to SCN projection retinal cell RHT retinogeniculate tract Output BL / Hi central extended Amg (aCeN/BNST) HPA axis neuroendocrine cell groups Hy OX projections PVN, DMH, subparaventricular zone, PVT SCN / PVN / SCG / pineal SNS / PNS Intrinsic to SCN SCN core/shell Seasonal SCN / PVN / SCG / pineal | Gene expression Neural activity Neurotransmitter | Drive-regulated behavior Locomotor activity Masking Neurobehavioral function Sleep-rated and waking behavior Sleep-wake | Diary-based measures of daily regularity/rhythmicity (e.g., Social Rhythm Metric) Morningness–eveningness questionnaire Munich Chronotype Questionnaire Phase, diurnal preference, chronotype (e.g., Horne-Ostberg, CTQ) Sleepiness, alertness, well-being, mood | DLMO (phase estimate) Longitudinal Actigraphy Genetic approaches genome-wide association study candidate gene epigenomics circadian genomics (temporal gene expression) mutagenesis gene targeting quantitative trait locus |
| Sleep-Wakefulness | Sleep-Wakefulness | n/a | ACh Adenosine CRF Cytokine Dopamine GABA Galanin Glutamate Histamine OX NE/NA NPY Serotonin ADH | AH and basal forebrain Brainstem LC Raphe LDT/PPT VTA HACER Hy PHR (TMN) Th MD Rt | NREM sleep; forebrain basal forebrain and AH projections to arousal-promoting cell groups thalamocortical tract REM sleep; brainstem mesopontine nuclei Wakefulness Arousal and Circadian Rhythms circuits also subserve wakefulness | Brain metabolic activity Capacity for wakefulness under low stimulation EEG sleep spindle slow wave theta wave EMG EOG NREM sleep and REM sleep Physiologic measures of sleepiness, homeostatic sleep drive during waking Sex-specific sleep physiology Sleep hormones Sleep latency Temporal and topographic organization of... homeostatic sleep drive during sleep sleep dynamics Wakefulness | Intermediate/admixed sleep-wake states Rest-activity patterns Sensory arousal threshold Sleep co-sleeping deprivation and satiation inertia motor behaviors sex-specific behavior timing and variability Sleep-dependent neurobehavioral functions Wakefulness | Alertness Dream report Fatigue Insomnia severity index Sleep quality, restoration, quantity Sleep timing Sleep-modulated symptoms Sleepiness Specific sleep symptoms | Finger tapping motor sequence task Latency to persistent sleep Multiple sleep latency testing Non-REM sleep EEG slow wave activity Sleep spindle Total sleep time Wake time after sleep onset |
Sensorimotor Systems, as of January 2022 :
| Construct / Subconstruct | Construct / Subconstruct | Genes | Molecules | Cells | Circuits | Physiology | Behavior | Self-reports | Paradigms |
| Motor Action | Action Planning and Selection | n/a | n/a | n/a | Parietal cortex inferior posterior Premotor cortex STS SMA proper | n/a | Apraxia conceptual ideational ideomotor limb-kinetic | n/a | Go-before-you-know |
| Motor Action | Sensorimotor Dynamics | n/a | n/a | Granule cellsPurkinje cells | BGCerebello-olivary-pontine complexCerebellumParietal cortexSomatosensory cortexSubstantia nigraTh | Short afferent inhibition | DyspraxiaHyposensitivityWeakness | n/a | Sensory Motor Adaptation Tasks |
| Motor Action | Initiation | n/a | n/a | n/a | BGDorsal cingulateSMA proper | n/a | ApathyCatatonic stuporNegative symptomsPsychomotor retardationStuttering | Lille Apathy Rating Scale | Libet's Temporal Judgement |
| Motor Action | Execution | n/a | n/a | Alpha motor neuronsBetz cellsPyramidal cells | Efferent and afferent spinal and peripheral pathwaysMotor cortex | BereitschaftspotentialCorticospinal tract excitabilityHoffmann's reflexMovement-related cortical potentialsUse-dependent plasticity | Activity levelEhlers–Danlos syndromesPsychomotor retardation | n/a | Motor evoked potential latency |
| Motor Action | Inhibition and Termination | n/a | DopamineGABANE/NA | Intracortical inhibitory interneuronsStriatal interneurons | ACC BG Cerebellum DLPFC FEF IFG IPL Lateral premotor cortex Mid-CgG PCC SMA proper Pre-SMA SPL | Cortical inhibitionOscillatory rhythmsPrepulse inhibition | Activity level Automatic obedience Catatonia immobility rituals negativism Perseveration Stereotypy Tics Utilization behavior | n/a | Stop-signal reaction time |
| Agency and Ownership | Agency and Ownership | n/a | n/a | Mirror neuron | Cerebellum Corpus callosum IPL Sensorimotor Th S1 SMA proper Pre-SMA | Efference copyReadiness potential | Alien hand syndromeFunctional movement disorderNeglectPerception of external controlStereotypyTic | n/a | n/a |
| Habit - Sensorimotor | Habit - Sensorimotor | n/a | DopamineGABAGlutamateSerotonin | n/a | PtASensorimotor-BG | n/a | Compulsive behaviorStereotypy | Rush video-based tic rating scaleYale Global Tic Severity Scale | 2-step task |
| Innate Motor Patterns | Innate Motor Patterns | n/a | n/a | n/a | Brainstem Hy Motor cortex Occulomotor system | Corneal reflex | Disinhibition of early motor reflexes Incontinent affect Startle Stereotypy | n/a | n/a |
The domains are tentative: "It is important to emphasize that these particular domains and constructs are simply starting points that are not definitive or set in concrete." Also, subconstructs have been added to some constructs. For example, Visual Perception, Auditory Perception, and Olfactory/Somatosensory/Multimodal perception as subconstructs of the Perception construct.

## Methodology

The RDoC methodology distinguishes itself from traditional systems of diagnostic criteria.
Unlike conventional diagnostic systems (e.g. DSM) which use categorization, RDoC is a "dimensional system" — it relies on dimensions that "span the range from normal to abnormal."
Whereas conventional diagnostic systems incrementally revise and build upon their pre-existing paradigms, "RDoC is agnostic about current disorder categories." Official documents explain this feature, writing: "Rather than starting with an illness definition and seeking its neurobiological underpinnings, RDoC begins with current understandings of behavior-brain relationships and links them to clinical phenomena."
Unlike conventional diagnostic systems, which typically rely on self-report and behavioral measures alone, the RDoC framework has the "explicit goal" of allowing investigators access to a wider range of data. In addition to self-report measures or measure of behavior, RDoC also incorporates units of analysis beyond those found in the DSM — allowing RDoC to be informed by insights into genes, molecules, cells, circuits, physiology, and large-scale paradigms. Early data driven approaches to RDoC based continuous transdiagnostic psychiatric phenotypes predict clinical prognosis across diagnosis and have genetic correlates that in not only clinical populations.