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RDoC Constructs

  • Domain: Negative Valence Systems
    • Construct: Acute threat (“fear”)
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

BDNF, 5HT/5HTRs, CRF, FKB5, GABAARs, Glutamate system, NMDARs, Opioid system, COMT, Cannabinoid system, Dopamine, DAT, Cam kinase, MAP kinase, PI-3 kinase, PKA, PKC, Acetylcholine, Norepinephrine, Strathmin, Pkap, TRBC5

NMDAR, Glutamate, Dopamine, Serotonin, BDNF, GABA, Cortisol/
Corticosterone, Endogenous cannabinoids, orexin, NPY, CRF family, FGF2, Oxytocin, Vasopressin, CCK, Neuropeptide S, Neurosteroids

Neurons, Glia, Pyramidal cells, GABAergic cells

Central Nucleus, BasAmyg, LatAmyg, vPAG, dPAG, v-hippocampus (post), d-hippocampus (ant), latPFC/insula, vmPFC (il), dmPFC (pl), OFC, Hypothalamus, dorsal ACC, rostral/vent ACC, ICMs, Medial Amyg, PAG, RPVM, Pons, autonomic nervous system, insular cortex, LC

Fear Potentiated Startle, Context Startle, Skin Conductance, Heart Rate, EMG, BP, Eye Tracking, Response accuracy, facial EMG, Respiration, pupillometry

Freezing, Response time, Avoidance, Response inhibition, Open field, Social approach, Analgesia, approach (early development), Risk assessment, Facial expressions

Fear survey schedule, BAI, STAI, SUDS, Fear Questionnaire, Trait Fear Inventory, Eilam Ethogram, Structured Diagnostic and Assessment scales, Albany Panic & Phobia

Fear conditioning, viewing aversive pictures or films, emotional imagery


  • Domain: Negative Valence Systems
    • Construct: Potential Threat ("Anxiety")
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

CRF

CRF family, cortisol

Pituitary cells

Bed nucleus of stria terminalis

Average cortisol levels, ACTH, potentiated startle

 

 

Contextual threat, darkness (in humans), light (in rodents)


  • Domain: Negative Valence Systems
    • Construct: Sustained Threat
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

 

See reference: Heim JAMA article

Decreased prefrontal and hippocampal arborization;
Increased microglia

Dysregulation of amygdala reactivity;
Dysregulation of cingulate reactivity;
Attention network (per Corbetta and Schulman);
PVT (differentiates between acute and sustained);
Hypothalamic nuclei;
Habit systems (Striatum/
caudate/accumbens);
Increased activation of vigilance network including visual cortex

Dysregulated HPA axis;
Increased amplitude of error-related negativity;

Anxious arousal;
Increased conflict detection;
Attentional bias to threat;
Anhedonia/decreased appetitive behavior;
Helplessness behavior;
Decreased libido;
Punishment sensitivity;
Increased perseverative behavior;
Avoidance;
Memory retrieval deficits

 

 


  • Domain: Negative Valence Systems
    • Construct: Loss
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

MAOA, COMT, DAT1, 5HTTR, 5HTRs

Downregulation of glucocorticoid receptors; Upregulation of CRH; Estrogens; Androgens; Oxytocin; Vasopressin; Inflammatory molecules

 

Sustained amygdala reactivity; Decreased DLPFC recruitment; Decreased vmPFC (incl. rostral cingulate); Increased insula activation; Increased posterior cingulate activity; Decreased R parietal; PVN; Hippocampus; Orbitofrontal cortex; Habit systems (striatum/
caudate/accumbens); Increased default mode activity; Dysregulated reward circuitry

ANS & HPA & neuroimmune dysregulation; Prolonged psychophysiological reactivity

Rumination; Withdrawal; Worry; Crying; Sadness; Loss-relevant recall bias; shame; Attentional bias to negative valenced information; Guilt; Morbid Thoughts; Psychomotor retardation; Anhedonia; Increased self-focus; Deficits in executive function (e.g., impaired sustained attention); Loss of drive (sleep, appetite, libido); Amotivation

Change in attributional style; Hopelessness

 


  • Domain: Negative Valence Systems
    • Construct: Frustrative Nonreward
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

MAOA, COMT, DAT1, 5HTTR, 5HTRs

Glutamate, Dopamine, Serotonin, GABA, Vasopressin, steroids

 

Septum, PAG, amygdala, hypothalamus, OFC, striatum, parasympathetic system, LC

 

physical and relational aggression

Proactive/ reactive aggression questionnaire, Buss-Durkee and Buss Perry

Physical and relational aggression paradigms, resident/human intruder test, PSAP, social dominance test

  • Domain: Positive Valence Systems
    • Construct: Approach motivation
      • Subconstruct: Reward valuation
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
  Dopamine; Serotonin   Cortico-limbic circuit: Anterior medial OFC; Ventral limbic striatum (incl. ventral caudate); Ventral tegmental area/Substantia Nigra     BAS reward sensitivity subscale; Sensitivity to reward subscale of the Sensitivity to Punishment: Sensitivity to Reward questionnaire Kahneman-Spinner paradigm; Value-based decision making (e.g., preference test); can be explicit or implicit; Delay discounting; Counterfactual learning (“Armed bandit” task)
  • Domain: Positive Valence Systems
    • Construct: Approach motivation
      • Subconstruct: Effort valuation/Willingness to work
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
  Dopamine; GABA; Adenosine   Basolateral amygdala; Dorsal ACC; Ventral striatum (nACC), Ventral pallidum; VTA     Drive subscale of the Behavioral Activation Scale Progressive ratio task; Effort-related choice behavior (effort discounting); Scheduleless key press to view or avoid pictures (e.g., “beautiful faces”); “Effort” task (per Treadway)
  • Domain: Positive Valence Systems
    • Construct: Approach motivation
      • Subconstruct: Expectancy/Reward prediction error
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
  Dopamine; Serotonin   Lateral habenula; Rostral medial tegmentum; Ventral striatum; Basal ganglia; Dorsal ACC; Substantia nigra/VTA; Orbital Frontal Cortex; Amygdala Cortical slow waves; Heart rate change (e.g., HR deceleration in anticipatory period); Autonomic (e.g., skin conductance) Reward-related speeding; Goal tracking; Sign tracking; Pavlovian approach Affective forecasting; Self-report of craving; TEPS anticipatory scale; Generalized reward and punishment expectancy scale; Eating Expectancy Inventory; ASAM scale Monetary Incentive Delay; Non-learning/passive gambling/guessing tasks; Cue reactivity
  • Domain: Positive Valence Systems
    • Construct: Approach motivation
      • Subconstruct: Action selection/Preference-based decision making
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
      Amygdala       Modified Iowa Gambling Task; Card choice/gambling task per Sanfey (2003)
  • Domain: Positive Valence Systems
    • Construct: Initial responsiveness to reward attainment
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
DRD2; DAT; (TREK1) Mu and delta opioid; Endocannabinoids; Orexin; Glutamate; Plasticity-related genes (CREB; FosB)   Nucleus accumbens; Medial OFC; Ventromedial PFC; Dorsal ACC; VTA; Ventral pallidum; Anterior insula; Lateral hypothalamus   Taste reactivity PANAS (state version); Consummatory subscale of TEPS MID; Gambling/guessing tasks; Taste reactivity
  • Domain: Positive Valence Systems
    • Construct: Sustained/Longer-term responsiveness to reward attainment
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
  Serotonin; Opioids; Endocannabinoids; Orexin; Dopamine   Ventromedial hypothalamus; Medial preoptic area; Paraventricular hypothalamus; Arcuate nucleus; OFC; BA9/medial PFC Vagus nerve stimulation (CCK); Peripheral endocannabinoids; PYY; GLP1; Gonadal hormones Satiety sequence; Nipple refusal; Cessation of consumption/meal termination; Meal pattern analysis Visual analog scales of satiety; Reward responsiveness subscale of BIS/BAS; Loss of control scale; Drug effects questionnaire Devaluation task; Snaith Hamilton Pleasure Scale
  • Domain: Positive Valence Systems
    • Construct: Reward Learning
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
Various genes involved in dopamine synthesis, clearance, and receptor signaling; Plasticity-related genes (e.g., CREB, FosB); Synapse-related genes; Epigenetic factors (HDAC, methyl transferases, etc); DARP32; COMT; NMDA receptors on D1 neurons; Adenyl cyclase dopamine & dopamine-related molecules; acetylcholine; Co-released neuromodular glutamate medium spiny neurons; dopaminergic neurons dorsal striatum; Ventral striatum; Medial prefrontal; OFC; VTA/SN; Amygdala Error related negativity; Correct related negativity; Feedback related negativity; Midline theta Approach behaviors; Consummatory behaviors toward any goal object Ecological momentary assessment; Ambulatory assessment and monitoring probabilistic reinforcement learning; deterministic reinforcement learning; Pavlovian conditioning; Instrumental conditioning and all its variants; Prediction error tasks
  • Domain: Positive Valence Systems
    • Construct: Habit
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
Various genes involved in dopamine synthesis, clearance, and receptor signaling; Plasticity-related genes (e.g., CREB, FosB); Synapse-related genes; Epigenetic factors (HDAC, methyl transferases, etc); DARP32; DAT; NMDA receptor on D1 neurons; Adenyl cyclase dopamine & dopamine-related molecules; acetylcholine; Co-released neuromodular glutamate Medium spiny neurons; SN dopamine neurons dorsal striatum; Ventral striatum; Medial prefrontal cortex; SN/VTA   repetitive behaviors; stereotypic behaviors; compulsive behaviors Measures of repetitive behaviors; Aberrant behaviors checklist maze learning; knot tying; serial response task; devaluation; response time acceleration; attention blindness; dual task paradigm; long-term probabilistic response learning; Perseveration tasks
  • Domain: Cognitive Systems
    • Construct: Attention
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

Dopamine receptor genes (e.g., D4, D5); DAT1; Serotonin receptor gene

Implementation:
GABA, glut

Control:
Glut, Serotonin;
dopamine;
histamine;
Ach

Parvalbumin-positive interneurons

Implementation:
TRN; pulvinar; local circuit interactions
Control:
ascending/
descending information pathways; amygdala (vigilance);

Atentional systems:
dorsal attention network (superior parietal lobe, frontal eye fields, DLPFC); ventral attention network (temporal parietal junction (TPJ), VPFC, insula);
basal forebrain limbic system

Balance between task positive network (TPN) vs DMN

fMRI
Sensory areas from peripheral to central.
ERP--
Auditory: processing negativity; P1, N1, N2; P300; neural oscillations.
Visual:N2pc; Selection
modulations of sensory ERP components; negativity (SN); P300; slow waves; neural oscillations
Peripheral physiology both modalities:
Heart rate deceleration;
Pupil dilation;

Spatial attention;
Object/feature attention;
ANT task
Distractibility;
Attentional lapses (e.g., RT variability) vs sustained attn; Psychophysics

Yes (but often not attention that is impaired)

dichotic listening, visual search, spatial and non-spatial cuing paradigms, dual task paradigms (attentional blink and psychological refractory period paradigm); inter-modal selective attention; blocked channel-selection tasks; distraction paradigms (capture); time-series of response times to extract variability and frequency domain analyses
(target detection tasks in the absence of competition are considered measures of sustained attention and not selective or divided attention, which are subsumed under cog control)

1Many of these paradigms can be adapted for use in behavioral, ERP and fMRI protocols.

  • Domain: Cognitive Systems
    • Construct: Perception
      • Subconstruct: Visual Perception
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

Dysbindin/
NRG1/
Neuroligin/
Neurexin

Glutamate,GABA. NMDA, Serotonin,Ach, Catecholamines, peptides Magno (non-linear gain control). Parvo. “Frame and fill”. Pyramidal, parvalbumin positive interneurons.

Subcortical:
magnocellular, parvocellular, koniocellular.
Cortical: dorsal/ventral streams; cortico-cortical connections into supra- and infra-granular layers..
Non-retinogeniculate: Superior colliculus,
Suprachiasmatic nucleus. Local circuitry implicated in contextual fields and association fields (responsible for the influence of spatial context on target processing): lateral interactions; top-down interactions

Oscillations (scalp EEG, LFP, and single/multi-unit).

ERP components: All of the sensory evoked potentials (from stimulus onset through N1), Ncl, ssVEP, tVEP.

BOLD (activation) of cortical regions.

Adaptation/ habituation.

Stimulus detection. Discrimination, identification and localization. Perceptual priming. Visual acuity. Reading. Perceptual learning.

Perceptual anomalies of schizophrenia and depression.

Scheme I. Stages of Vision.
Early vision retinotopic representations, local computations.
Intermediate vision Nonlocal properties of images, transformations beyond retinotopic representations (e.g., surface properties of the object independent of light, head position).
Late vision Representations of external objects (e.g., object identification, classification, visually guided action).
Scheme 2. Commonly Used Research Paradigms
Vernier discrimination; Object recognition/perceptual closure/perceptual organization; object perception; contour integration/interpolation; face identification; emotion expression identification;
Parallel/serial search;
Reading; contrast sensitivity; lateral facilitation; biological motion processing; coherent motion; bistability; multistability; figure ground; backward masking; visual illusion susceptibility; cross modality paradigms.
Other schemes.
Re-entrant processing.
Action-Perception loops.

  • Domain: Cognitive Systems
    • Construct: Perception
      • Subconstruct: Auditory Perception
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

BDNF

Glutamate/
GABA/
NMDA/
serotonin/
ACh

Cochlear hair cells; Ribbon synapses; cortical and limbic inhibitory interneurons.

Nodes in circuits: Cochlea; brainstem; MGN; A1; STG; ant. Insula; Inferior Colliculus.
Circuits: Dorsal/ventral streams; Corticofugal.

Sensory ERPs (e.g, P50, N1), Auditory steady-state response (ASSR); Intracortical EEG, Mismatch negativity (MMN); P3a; metabolic changes (fMRI, PET); startle and PPI; neural oscillations (e.g., GBR); adaptation/habituation. fMRI:  regulation of hemodynamic components of sensory response and habituation.

Stimulus detection.
Spatial localization.

Perceptual identification.
Perceptual priming. Perceptual learning.

Auditory hallucinations; Hyperacusis

Tone matching; deviance detection, regularity and change detection; McGurk (multisensory); auditory scene perception (e.g., streaming); bistability; novelty/oddball detection; detection of speech in noise, cross-modal interactions; auditory masking; Manipulation of ISI; and intensity
Object perception; Categorization;
Gating; self-monitoring; inhibitory control; same-different tasks; tone detection (e.g., JND tasks)
Action-Perception loops.


  • Domain: Cognitive Systems
    • Construct: Perception
      • Subconstruct: Olfactory Somatosensory Multimodal Perception
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
             

Manipulation of ISI, intensity for somatosensory stimulation; smell identification;


  • Domain: Cognitive Systems
    • Construct: Declarative Memory
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
BDNF, KIBRA Cholinergic, Glutamatergic, Noradrenergic, and other neurotransmitters. Opioid and other neuromodulators Pyramidal cells, granule cells, many types of inhibitory and excitatory interneurons, glia, and other cell types. Intriinsic hippocampal circuitry (e.g., DG, CA1, CA3, subiculum); extrinsic hippocampal circuitry (bidirecitional connections between widespread higher order cortical areas and the parahippocampal region, and between the parahippocampal region and the hippocampus); PFC and PPC interactions with multiple association cortices. LTP/LTD, NMDA-related synaptic plasticity, AMPA-related synaptic plasticity, place cell activity, conjunction codes, up/down states, frontal/temporal coordinated oscillations, subsequent memory effect (fMRI, ERP) Learning, recall, discrimination, familiarity, recognition Cognitive Assessment Interview

Paired associate learning; delayed recall; transitive inference; acquired equivalence; list and story learning

FOXP2; songbird work; mouse knockout work     Lateral superior and middle temporal cortices, inferior temporal cortex, inferior frontal cortex, inferior parietal cortex.  Overlap with memory, motor, sensory, and emotional circuits ERPs N400 (lexico-semantic and contextual processing; P600/late positivities (continued analysis); anterior negativities (language-related working memory) Production and comprehension of words, coherent sentences, and coherent discourse (rating scales)    Thought, Language and Commuinication Scale, Thought Disorder Index,   See narrative

  • Domain: Cognitive Systems
    • Construct: Language
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
FOXP2; models based on songbirds; mouse knockout models     Language is mediated by networks distributed across lateral (including posterior superior and middle temporal), inferior temporal, anterior temporal, inferior frontal and inferior parietal (angular and supramarginal) cortices, which are often lateralized to the dominant hemisphere.
Language comprehension and production can also engage other regions, including dorsolateral prefrontal and superior frontal and subcortical regions (cerebellum, striatum, thalamus). It can also engage the non-dominant hemisphere.
These circuitries overlap with those mediating semantic, working, declarative and procedural memory processes.
Some of the meaning extracted through language may be situated or embodied within motor, sensory and emotional systems and their underlying circuitries.
N400 (indexing lexico-semantic processing in relation to preceding context and information stored within semantic memory), P600/late positivities (indexing continued analysis or reanalysis, often in response to conflict between levels of representation), anterior negativities (indexing working memory costs involved in holding and linking individual constituents within language).

The production and comprehension of words, coherent sentences, and coherent discourse.

Cognitive Assessment Interview

A) Language Production:
Naming
Verbal descriptions of visual depictions of events and states
Linguistic corpus-based analyses of language output.
B) Language Comprehension:
1) Offline measures
The detection and classification of semantic relationships between words.
The ability to distinguish between coherent and incoherent sentences and discourse.
The ability to answer questions about the content of sentences and discourse.
2) Online measures
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 relationships between individual words in priming paradigms.
Manipulations of predictability and acceptability, at different levels of representation, in a linguistic input.
Manipulations of different types of coherence and cohesion between clauses in discourse.
Manipulations of relationships between language and non-verbal behaviors.

  • Domain: Cognitive Systems
    • Construct: Cognitive Control
      • Subconstruct: Goal Selection, Updating, Representation and Maintenance
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
      Frontopolar/
Anterior LPFC (BA10)
Inhibition of DMN (?)
    BRIEF (Gioa) Badre tasks
Koechlin paradigm
Task Switching
COMT
BDNF
DISC1
5HT2A
DRD4
DRD2
5-HTTLPR
Glu
DA
GABA
NE
AcH
Pyramidal
PV
DLPFC
PPC
Thalamocortical
Gamma synchrony; pupilometry Off-task behaviors; distractibility Cognitive Failures Questionnaire
(Broadbent et al)
Disorganization Sx on SANS/SAPS/ PANSS
BRIEF (Gioa)

Task Switching
(inc. Switching Stroop);
AX paradigms;
Cued stimulus-response reversal tasks; Tower tasks

  • Domain: Cognitive Systems
    • Construct: Cognitive Control
      • Subconstruct: Response Selection, Inhibition or Suppression
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
COMT
CHRM4
BDNF
DRD4
Glu
DA
GABA
NE
AcH
Somatostatin
PV
Pyramidal
DLPFC
VLPFC
PPC
theta
gamma
Impulsive behaviors; Disorganization Sx on SANS/SAPS/ PANSS BRIEF (Gioa) Simon
Stroop
Flanker
DRD4
DAT1
MAO-A
5-HTT
Glu
DA
GABA
NE
AcH
Pyramidal Ventrofronto-striatal
BA6/8 (FEF)
Pre-SMA PPC
Alpha
Pupilometry Short interval cortical inhibition (TMS)
Impulsive behaviors; off-task behaviors; distractibility Conners impulsivity scale
ADHD Rating Scale (Dupaul)
BRIEF (Gioa)
ATQ/CBQ Effortful Control
Go/Nogo
Stimulus-Resp Incompat
Stop-Signal Reaction Time
Antisaccade
Countermanding
Conflicting and contralateral motor response task
              Motor persistence paradigms (e.g. NEPSY statue task)
  • Domain: Cognitive Systems
    • Construct: Cognitive Control
      • Subconstruct: Performance Monitoring
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms
5HTTLPR DA
5HT
  ACC / pre-SMA Insula (?) ERN
N2
N450
Post-error or post-conflict adjustments in performance YBOCS total score Simon
Stroop
Flanker

2 The Cognitive Control workgroup acknowledged that single gene findings are speculative, and may be misleading.

  • Domain: Social Processes
    • Construct: Affiliation and attachment
      • Subconstruct: Attachment formation and maintenance
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

OXTR, AVPR1A, MOR

3OXT, Tyrosine Hydroxylase, DRD2, MOR,
3CRF, KOR, CRFR2, DRD1

Oxytocin, vasopressin, oxytocin receptor, vasopressin 1a receptor, dopamine
Mu opioid receptor
3CRF, KOR, CRFR2, D1

3Magnocellular OT

VTA- NAcc- VP-amygdala, PVN, OFC, FF gyrus, VMPFC
3Amygdala, BNST, PVN, NAcc

 

 

Sex steroid changes; HPA down-regulation; Vagal tone; Immune markers
HPA axis activation; immune responses (“sickness”); activation of sympathetic activity; vagal withdrawal

Attachment Formation– maintaining proximity; preference for individual
Attachment maintenance --Distress upon separation

 

 

 

Inventory of Parent and Peer Attachment Scale; Attachment Questionnaire for Children Scale;
Adult Attachment Interview;
Bartholomew and Shaver
Examples (no comment on validity): Social Anhedonia scale; Experience in Close Relationships Scale, Parental Bonding Instrument, Attachment Style interview; QSORT Parent Attachment interview
Bereavement scales; social subscales of depression

Social Buffering of Stress
Strange Situation
Separation

 

3 Candidate molecules and circuits based on animal studies.


  • Domain: Social Processes
    • Construct: Social Communication
      • Subconstruct: Reception of Facial Communication
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

OXTR
CNTNAP2
5HTT
COMT
FMR1
BDFN
Other autism risk genes

Oxytocin
Vasopressin
Serotonin
GABA
FMRP
Testosterone
Dopamine

Face selective neurons- FFA, STS, amygdala

Neurons with mirror properties

 

V1-FFA-STS-amygdala
V1-FFA-STS-VS
IFG-INS-amygdala/VS
OFC-ACC-
amygdala-striatum
amygdala-brainstem
Resting state networks

SCR
HR/BP/respiration
Pupil dilation
Startle reflex
Facial EMG
ERP N170, N250; ECoG
Frontal brain asymmetry (decreased alpha to faces)
Local cerebral blood flow changes Network dynamics, including within and between network structure (e.g., coherence, functional connectivity)

Identification of emotion
Eye gaze detection
Scanning patterns
Behavioral observation/coding systems
Implicit mimicry

Face dimensional rating scales
Arousal ratings

Emotional face expression tests
Face feature manipulation (e.g. morphing)
Still Face paradigm
Distress paradigms
Social Reward paradigms
Emotional Stroop/emotional go/no-go
Social Flanker, other attention paradigms
Dynamic Social stimulus tasks
Conditioning paradigms
Joint attention tasks
Face priming tasks
Chimeric tasks
Masking paradigms
Implicit social perception tasks


  • Domain: Social Processes
    • Construct: Social Communication
      • Subconstruct: Production of Facial Communication
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

CNTNAP2
FOXP2
SHANK3
NRX1
OXTR
Other autism risk genes

Contactin AP

 

Eye movements: PPC-SC-SNc-SEF-FEF-CB
Facial Expression:
Regions including PAG, AC

Facial EMG
SC, HR variability, pupil dilation
Photoplethysmo-graphy (skin color measure of capillary dilation; temperature)
NIRS
Tear production

Eye gaze aversion/contact
Head turning
Reciprocal eye contact
Reciprocal emotional expression
Facial affect production
Joint attention
Behavioral observation/coding systems
Imitation of facial gestures

Berkeley Expressivity Questionnaire

 

Imitation of affect
Directed facial action tasks expression: FACS and FACES coding system; other automated facial analysis
“Thin slices” of non-verbal behavior test
Relived Memories paradigm
Human-Computer interaction
Social games e.g. cyberball
Provocative tasks/settings to elicit expressions
Still Face paradigm
Distress paradigms


 

  • Domain: Social Processes
    • Construct: Social Communication
      • Subconstruct: Reception of Non-Facial Communication
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

FOXP2
CNTNAP2
OXTR
? NGF

Oxytocin

 

 

A1-RSTG, STS, VLPFC, MPFC

EEG features, e.g., evoked gamma
Local cerebral blood flow changes
Network dynamics, including within and between network structure (e.g., coherence, functional connectivity)

Comprehension of emotional prosody
Irony/sarcasm comprehension?
Metaphor comprehension?
Comprehension of non-verbal gestures
Humor comprehension

Social Responsiveness Scale

Sentence Prosody tests
CELF Prosody
Language vs. non-language discrimination
Biological Motion discrimination (with and without emotion)
Olfactory hedonics measures
Profile of non-verbal sensitivity
“Thin slices” of non-verbal behavior test
Still Face paradigm


 

  • Domain: Social Processes
    • Construct: Social Communication
      • Subconstruct: Production of Non-Facial Communication
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

FOXP2
OXTR
? NGF

 

 

R-IFG-RSTG
(Songbird circuits?)

 

Response to distress/separation distress
Crying/laughing
Vocalizations
Speech (affective) prosody
Gestural/postural expressions
Interactive play

 

Computer interface tasks
Vocal production coding systems e.g., spectral analysis, computational linguistics
Still Face paradigm


 

  • Domain: Social Processes
    • Construct: Perception and Understanding of Self
      • Subconstruct: Agency
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

 

 

 

Right parietal; right insula, right inferior frontal; SMA, somatosensory, premotor

Scalp Motor Potentials

Evidence that one understands ownership of one's own body parts or action (thoughts/behaviors); Hallucinations; Delusions of Control

Perceptual Aberration Scale

Identification of one's own biological motion; Joy Stick manipulation (decoupling motor and sensory feedback); illusions of will; Ford Corollary Discharge Paradigm; Reality Monitoring


 

  • Domain: Social Processes
    • Construct: Perception and Understanding of Self
      • Subconstruct: Self-Knowledge
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

 

 

Von Economo neurons??

MPFC, posterior cingulate/precuneus, left inferior frontal cortex, ventral 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 Awareness; Toronto Alexithymia scale; Private Self-Consciousness; Self Components of Attributional Styles Questionnaire; Self-monitoring scale

Self Judgments; Self reference effect; Meta-cognition Tasks; Discrepancies in self and peer ratings [i.e., peer nomination]


 

  • Domain: Social Processes
    • Construct: Perception and Understanding of Others
      • Subconstruct: Animacy Perception
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

 

 

 

STS, extrastriate body area, occipital face area, fusiform face area

MU Suppression

The ability to appropriately attribute animacy to other agents

 

Point-light displays; Attributions of contingent behavior


 

  • Domain: Social Processes
    • Construct: Perception and Understanding of Others
      • Subconstruct: Action Perception
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

 

 

Mirror Neurons

Ventral/dorsal premotor, inferior parietal, STS

MU suppression, cortico-spinal facilitation (TMS)

Imitation; mimicry; Gaze following; Ability to identify what actions an agent is executing

Balanced Emotional Empathy Scale; Perspective Taking and Empathic Concern subscales of the Interpersonal Reactivity Index; Empathy Quotient

Action observation, Imitation, Self-Other Morphs; Non verbal decoding tasks; How component of Why/How Task; Profile of Non-Verbal Sensitivity; Empathic Accuracy Tasks


 

  • Domain: Social Processes
    • Construct: Perception and Understanding of Others
      • Subconstruct: Understanding Mental States
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

Genes that influence Vasopressin or oxytocin

Vasopressin; Oxytocin

 

MPFC, TPJ, temporal pole, precuneus; STS

 

Developmentally appropriate interpretations of other intentions, goals and beliefs

Other components of Attributional Styles Questionnaires; Balanced Emotional Empathy Scale; Perspective taking and empathic concern subscales of interpersonal reactivity index; Empathy Quotient

Other Trait or State Judgments; Strange Stores; Directors Task, Faux Pas; Reading the Mind in the Eye's; Why component of Why/How Task; Theory of Mind Tasks in children; Dunbar's Intentionality Questionnaire; Irony comprehension; Empathic Accuracy Tasks

  • Domain: Arousal and Regulatory Systems
    • Construct: Arousal
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

Musarinic receptors (mAChRs, M1-M5)

Nicotinic receptors (16 nAChR genes)

ACHE

CHAT

VAChT

Serotonin receptors (5HT1-7)

5HTTs

Tryptophan Hydroxylase

Adrenergic receptors (α1, α2; β1-3)

Histamine receptors (H1-4)

Dopamine receptors (D1-5)

OX1R, OX2R/HCRT1, HCRT2 GABA-A, GABA-B, GABA-C

Glutamate Receptors: AMPA, kainate, NMDA, delta; mGluRs

Aadenosine receptors (A1-3)

DBH

NET

DAT

Leptin
Ghrelin receptors
Cytokine recepors

Glutamate
Norepinephrine
Acetylcholine
Histamine
Dopamine
Hypocretin/Orexin
CRF
Serotonin
Leptin
Ghrelin
Opioids
Oxytocin
Vasopressin
Neuropeptide Y
GABA
Cytokines

Locus Coeruleus

Tuberomammillary Nucleus

LDT, PPT

Basal Forebrain Nuclei

Lateral, perifornical, and dorsomedial hypothalamus

Dorsal Raphe

Ventral Tegmental Area

Central Nucleus Amygdala

Cholinergic and monoaminergic Nuclei projections to thalamic and cortical (both neocortical and allocortical/hippocampus circuits)

Reciprocoal cholinergic and monoaminergic projection

Reciprocal hypothalamic (including hypocretin/orexin, tuberomammillary nucleus) projections to midbrain and pontine monoaminergic and cholinergic nuclei

Hypothalamic to thalamic and cortical circuits

Basal forebrain nuclei to cortical circuits

Corical circuits such as fronto-insular and dorsal anerior cingulate

Brainstem monoaminergic and cholinergic projections to basal forebrain

Central Amygdala to monoaminergic and basal forebrain cholinergic nuclei

Reciprocal NTS-Central N. Amygdala

Circadian and Sleep-related circuits modulate arousal and are modulated by arousal

EEG

EMG

ERPs

Autonomic: Heart Rate; Blood Pressure; Pupil Size; Galvanic skin Response; Breathing; etc.

HPA Axis: Glucocorticoids; ACTH; CRF

Sex-Specific Differences in Arousal

Brain activation as measured by fMRI

Neural activity

Waking

Startle

Eye Blink

Motor Activity (increases and decreases)

Cognition: learning & memory; attention; executive function; etc.

Affective states: anxiety; etc.

Agitation

Emotional Reactivity

Sensory Reactivity

Motivated Behavior

Arousal Self-Report Scales (e.g. ADACL, POMS arousal subscale, etc.); Self-assessment Mannequin

- EEG and EMG recording
- Indices of neural activity such as local field potentials and single neuron recordings; fMRI/PET
- Psycho-
motor vigilance and other continuous performance tasks
- Eye-blink
- Eyelid closure
- Startle
- Odd-ball tasks
- Auditory arousal threshold
- Maintenance of wakefulness test
- Actigraphy and other test of motor activity
- Cortisol awakening response


  • Domain: Arousal and Regulatory Systems
    • Construct: Circadian Rhythms
————— Units of Analysis —————
Genes1 Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

Canonical (Core) Clock Genes: Clock;
Npas2;
Bmal1; Bmal2
Per1,2;
Cry1,2;

Clock-Associated Genes: Rorα, β;
Rev-Erbα, β;
CK1 δ, ε;
CK2 α, β,
FBXL3,
FBXBL21,
DEC2, DEC2,
Dio2, Dio3,
Gsk 3β,
Per3

Potential additional clock associated genes1

Clock-controlled genes1

Receptor genes:
NMDAr;
AMPAr;
5HTr;
GABAr;
NPYr;
SPr; VPAC1,2;
MT1,2

Transcription/
translation factors/regulators:
(cFos;
JunB;
CREB;
MAPK;
mTOR;
PGC1a; miRNA (e.g. miR-206, miR-132)
Dbp)

Epigenetic factors (e.g. Sir2)

Input: melanopsin; PACAP; Glutamate; GABA; 5HT; NPY; Substance P; Dopamine

SCN-synchronizing and modulating agents: VIP; AVP; NO; cAMP; cGMP; Calbindin; steroid hormones (estrogen, testosterone, progesterone)

Output: melatonin; cortisol; AVP; VIP; GABA

ipRGC; rods and cones;

SCN “clock” cells;

Extra-SCN and peripheral tissue cells within the brain (e.g., medium spiny neurons, pars tuberalis cells, fibroblasts)

Pineal cells

Input:

Retinal cells; Retino-hypothalamic tract;

Retinogeniculate tract;

Raphe to SCN projection;

Intrinsic to SCN

Suprachiasmatic nucleus (SCN) core/shell

Output: SCN projections to:

- PVN, DMH, subparaventricular zone, PVT
- Central extended amygdala (central nucleus of the amygdala/ Bed nucleus of the stria terminalis)
- Hypothalamic neuroendocrine cell groups
- Hypothalamic orexin projections2
- Basolateral amygdala/ Hippo-campus
- SCN/PVN/SCG/pineal2
- HPA axis
- Sympathetic/ parasympathetic nervous system

Seasonal

- SCN/PVN/SCG/pineal2

Gene expression

Neural activity

Neural transmitters

Locomotor activity

Drive-regulated behaviors

Sleep-wake

Neurobehavioral functions (e.g., alertness, vigilance, affect, learning, memory)

Sleep-rated and waking behaviors

Masking (e.g., direct effect of environment on activity rhythms)

Phase, diurnal preference, chronotype (e.g., Horne-Ostberg, CTQ); Diary-based measures of daily regularity/ rhythmicity (e.g., Social Rhythm Metric); Sleepiness, alertness, well-being, mood

- Actigraphy of human circadian rest-activity rhythms in the real world
- Sleep measures (see Sleep-Wake paradigms)
- 24 hour LD light/dark (LD) cycle (test for entrainment of rhythms)
- T cycles (non-24 hour LD cycles)
- Phase response curve (PRC, phase dependent effects of single light [or other stimulus] pulses delivered at different circadian phases)
- Dim Light Melatonin Onset (DLMO, phase estimate)
- Acute melatonin suppression by light (relative index of the sensitivity of the circadian system to light, e.g. wavelength, intensity, duration curves)
- Pupillary light reflex (acute measure of rod, cone and melanopsin photosensitivity)
- Sensory threshold testing (ERG, ERP, etc.)
- Bioluminscent/
fluorescent real-time gene expression imaging
- Masking (e.g., sleep effect on cognitive behavioral therapy)
- Genetic Approaches – genome-wide association study, candidate gene, epigenomics, circadian genomics (temporal gene expression), mutagenesis, gene targeting, quantitative trait loci.


  • Domain: Arousal and Regulatory Systems
    • Construct: Sleep-Wakefulness
————— Units of Analysis —————
Genes Molecules Cells Circuits Physiology Behavior Self-Reports Paradigms

- Circadian Rhythms genes (see Circadian Rhythms table);
- Genes relevant to arousal (see Arousal table)
- Genes with sleep-specific effects: Per3, Clock, Sur2, Dec2

Neurotransmitters and neuromodulators, including:

- Acetylcholine
- Norepinephrine
- Serotonin
- Dopamine
- Histamine
- GABA
- Galanin
- Adenosine
- Hypocretin/Orexin
- Glutamate
- CRF
- Vasopressin
- NPY
- Cytokines

- Lateral and perifornical hypothalamus
- Anterior hypothalamus and basal forebrain
- Posterior hypothalamus (TMN)
- Brainstem (e.g., LC, Raphe, LDT/PPT, VTA)
- Thalamus (median thalamic nuclei, reticular nucleus)

Wakefulness

1 Arousal circuits also subserve wakefulness (see Arousal table)
- Circadian Rhythms circuits also subserve the organization of sleep and wakefulness (See Circadian Rhythms table)

Sleep

NREM sleep (forebrain):
- Basal forebrain and anterior hypothalamus projections to arousal promoting cell groups
- Thalamo-cortical circuits

REM sleep (brainstem):
- Mesopontine nuclei, especially regions ventral to locus coeruleus

- Brain electrical activity (EEG) (spindles, slow waves, theta)
- Brain metabolic activity
- Electromyographic activity (EMG)
- Electro-oculography (EOG)
- Things modulated by/ that happen during sleep (hormones [e.g., GH, prolactin, gonadotropins, etc.], other aspects of systemic physiology)
- NREM and REM sleep, wakefulness, and their transitions
- Temporal and topographic organization of sleep dynamics
- Temporal and topographic organization of homeostatic sleep drive during sleep
- Physiological sleep propensity (sleep latency)
- Capacity for wakefulness under low stimulation)
- Physiologic measures of sleepiness, homeostatic sleep drive during waking
- Sex-specific sleep physiology

- Sleep (duration, continuity/ fragmentation, architecture), wakefulness
- Sleep deprivation and satiation
- Sleep timing and variability
- Rest-activity patterns (actigraphy)
- Sleep inertia
- Sleep-dependent neurobehavioral functions (e.g., memory consolidation, affect, affect regulation, alertness, vigilance, impulsivity, risk-taking)
- Motor behaviors during sleep
- Intermediate/ admixed sleep-wake states
- Sensory arousal threshold
- Co-sleeping
- Sex-specific sleep behaviors

- Sleep quality, restoration, quantity (e.g., insomnia, hypersomnia)
- Sleep timing
- Alertness, sleepiness
- Fatigue
- Dream reports
- Specific sleep symptoms
- Sleep-modulated symptoms (e.g., mood, alertness)

- EEG (e.g., sleep staging, quantitative EEG, topographic mapping, source localization)
- MEG
- TMS
- Nocturnal polysomnography (may include measures of respiration, heart rate variability (HRV), other)
- Arousal threshold testing
- Multiple sleep latency testing
- Maintenance of wakefulness testing
- Measurement of slow eye movements during wakefulness (physiologic measures of sleepiness, homeostatic sleep drive)
- Locomotor activity (e.g., actigraphy)
- Total, partial, and stage-selective deprivation paradigms
- Non-24-hour sleep-wake schedules (e.g., forced desynchrony, ultrashort schedules)
- Neurobehavioral testing in relation to sleep
- Sleep-dependent memory consolidation, fear extinction
- Functional imaging techniques: e.g., fMRI, PET, MEG, high-density EEG
- Self-report methods include retrospective symptom and sleep reports, daily sleep diaries



Notes regarding the Units of Analysis

  • “Circuits” can refer to measurements of particular circuits as studied by neuroimaging techniques, and/or other measures validated by animal models or functional neuroimaging (e.g., emotion-modulated startle, event-related potentials).
  • “Physiology” refers to measures that are well-established indices of certain constructs, but that do necessarily not tap circuits directly (e.g., heart rate, event-related potentials).
  • “Behavior” can refer variously to behavioral tasks (e.g., a working memory task), or to behavioral observations.
  • “Self-reports” refer to interview scales, questionnaires, or other instruments that may encompass normal-range and/or abnormal aspects of the dimension of interest.