Document text
Principal Investigator: Mohammed R Milad
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2024
Award: $678,226
Funding agency: National Institute of Mental Health
Project Summary
Primary characteristics of posttraumatic stress disorder (PTSD) include persistent fears and excessive
maladaptive avoidance behaviors. Preclinical models of PTSD have heavily investigated the brain
mechanisms of fear inhibition and active avoidance learning. Significant progress has been made in
translating fear conditioning and extinction data into the human brain and their implications have helped
further our understanding of PTSD psychopathology. The mechanisms of active avoidance, however, have
scarcely been examined in the human brain, especially within the context of maladaptive responses as in
the case of PTSD. The studies proposed in this application are designed to begin to fill this scientific gap.
We will use a novel conditioning and active avoidance paradigm (CAAP) to examine the neural
correlates of active avoidance and fear extinction learning and explore how extinction modulates
active avoidance responses in participants with and without a PTSD diagnosis using functional
magnetic resonance imaging (fMRI). PTSD psychopathology involves dysfunctional limbic-frontal activity
including the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), and amygdala. Studies of
avoidance in rodents and a few fMRI studies in healthy humans suggest that the vmPFC and striatum
mediate threat response by toggling the expression of fear vs. avoidance responses. Participants (healthy
controls with trauma exposure, and patients diagnosed with PTSD) will undergo the novel (validated) two-
day CAAP. On day 1, participants will undergo Pavlovian fear conditioning, immediately followed by an active
avoidance conditioning phase. Avoidance is achieved by pressing a button to prevent a shock from occurring
but will not terminate the conditioned stimulus (CS). Pavlovian fear extinction learning (button removed; no
avoidance possible) will follow. On day 2, recall of extinction learning will be tested. Before the start of the
recall test, participants will receive a small monetary endowment and will be told that this money could be
used to pay for shock avoidance during the recall test. The first aim is to Identify neural correlates of active
avoidance. The second aim is to study activations after the CS+ terminates that index the relief from the
avoided shock. The third aim is to examine neural correlates of extinction-to-avoidance transfer. The
proposed studies are expected to provide a more integrated mechanistic understanding of the
psychopathology of PTSD and reduce the gap between the rodent literature and human neuroimaging in
avoidance research.
Terms: <Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Area><Avoidance Learning><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Characteristics><Circulatory Collapse><Color><Conditioned Stimulus><Control Groups><Cornu Ammonis><Corpus Striatum><Corpus striatum structure><Data><Data Reporting><Decision Making><Diagnosis><Dorsal><Encephalon><Endowment><Experimental Designs><Extinction><Fear><Financial cost><Fright><Functional MRI><Functional Magnetic Resonance Imaging><Future><Hippocampus><Human><Impairment><Intracellular Communication and Signaling><Learning><Light><Literature><Measures><Mediating><Methods><Modeling><Modern Man><Nucleus Accumbens><PTSD><Participant><Patients><Phase><Photoradiation><Play><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Pre-Clinical Model><Preclinical Models><Prefrontal Cortex><Price><Probability><Psychopathology><Research><Rewards><Rodent><Rodentia><Rodents Mammals><Role><Shock><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Striate Body><Striatum><Symptoms><Testing><Training><Translating><Translations><Ventral Tegmental Area><abnormal psychology><amygdaloid nuclear complex><avoidance behavior><biological signal transduction><circulatory shock><conditioned fear><conditioning><cost><data representation><data representations><design><designing><experience><experiment><experimental research><experimental study><experiments><exposure to trauma><fMRI><fear conditioning><hippocampal><indexing><learning extinction><monetary cost><neural><neural correlate><neural imaging><neural mechanism><neuro-imaging><neuroimaging><neurological imaging><neuromechanism><neuropathologic><neuropathological><neuropathology><novel><post-trauma stress disorder><posttrauma stress disorder><prevent><preventing><pricing><random forest><response><shocks><social role><striatal><success><translation><trauma exposure><traumatic neurosis><ventral tegmentum><willingness to pay>