Biology subjects

Milad, M. R.

Publications and source records attributed to Milad, M. R..

6 recordsLinked to original sources

bioRxiv2026

Sensory cortical disinhibition is required for long-term fear memory in humans

The transformation of transient threats into enduring memories is fundamental to survival, yet how the human brain constructs long-term fear memory remains elusive. Early sensory cortex, traditionally viewed as a passive feature analyzer, is increasingly recognized as an active participant in fear processing. Here, using a multimodal approach combining high-definition -frequency transcranial alternating current stimulation (HD -tACS) with simultaneous EEG-fMRI and transformer-based neural decoding, we tracked fear memory development across early formation, consolidation, and long-term retention stages (assessed at 15 min, 24 h, and 7 days post-conditioning). Spatiotemporal memory representations were evident at all three time points, beginning at an early sensory stage (40-60 ms post-stimulus). Conditioning potentiated occipital -oscillation desynchronization (a marker of visual cortical disinhibition), which predicted the strength of subsequent long-term memory traces. Critically, targeted -tACS over early visual cortex induced V1/V2 inhibition, abolished conditioning-potentiated desynchronization, and selectively disrupted fear-memory consolidation and retention while leaving initial acquisition intact. These findings establish sensory cortical disinhibition as a necessary mechanism for long-term fear memory in humans and identify early sensory cortex as a causal node for interventions targeting persistent maladaptive fear.

neuroscience↗

bioRxiv2026

Fear Learning Induced Brain Dynamics Predict Individual Extinction Memory Expression following Transcranial Magnetic Stimulation

Fear learning and extinction unfold as time-dependent processes. Herein, we examined how fear learning dynamically reorganizes brain activity immediately after learning, and whether such reorganization can be modulated with TMS application during extinction learning to prospectively predict extinction-memory expression. Eighty-seven healthy adults completed a three-day Pavlovian threat-learning protocol with resting-state fMRI acquired before and after conditioning (Day 1), dorsolateral prefrontal cortex (DLPFC) transcranial magnetic stimulation (TMS) applied during extinction learning (Day 2), and fMRI during extinction recall and renewal (Day 3). Using coactivation pattern analysis with a hidden Markov model within a 24-nodes threat-circuit parcellation, we identified a fear-learning-induced brain state characterized by global threat-circuit coactivation with heightened engagement and transition uncertainty post conditioning, and a progressive increase in engagement across post-conditioning. Critically, conditioning-induced functional connectivity reorganization within this state predicted individual differences in extinction recall- and renewal-related brain activation under TMS-modulated extinction (cross-validated; recall r = 0.47, p = 0.001; renewal r = 0.37, p = 0.01; permutation-tested), but not under natural extinction. Similar associations were observed between neural features and behavioral expression. These findings demonstrate that fear learning reshapes spontaneous brain-state dynamics and that such learning-induced reorganization serves as an interpretable biomarker for neuromodulation-linked extinction-memory expression.

neuroscience↗

bioRxiv2025

Local and network neural activations and their associations with sleep parameters during threat conditioning and extinction in persons with Generalized Anxiety Disorder with and without Insomnia Disorder

Deficient extinction learning and memory are hypothesized mechanisms for pathological anxiety that are associated with sleep disturbance. fMRI neural activations to threat conditioning, extinction learning, and extinction recall were measured. Activations were compared, in persons with Generalized Anxiety Disorder (GAD), between those with moderate to severe Insomnia Disorder (ID) and those with absent or sub-threshold ID. Relationships of activations with measures of sleep quality and physiology were examined. Between-group comparisons and whole-sample correlation with sleep parameters were examined in relation to large-scale brain networks using a liberal cluster-determining threshold. Localized activations were then identified using family-wise error correction. Activations to the reinforced stimulus (CS+) that increased from the beginning to end ("across") threat conditioning were more extensive within the GAD+ID group. Increased activations to the CS+ across extinction learning were greater within the GAD-ID than the GAD+ID group, and delayed 24h in the latter. Greater sleep efficiency was associated with decreased activations across threat conditioning, but with increased activations across extinction learning. Better sleep quality promoted greater engagement of neural substrates of extinction learning. The GAD+ID group failed to engage brain areas supporting extinction learning immediately following threat conditioning, but did so when stimuli were again presented following a delay. HighlightsGeneralized Anxiety Disorder subjects with moderate/severe vs absent/mild insomnia compared Neural responses to threat conditioning, extinction learning/memory analyzed and sleep recorded Low and high thresholds identified large-scale networks and localized activations respectively Threat and regulatory activations at extinction learning in mild insomnia delayed when more severe Better sleep quality predicted greater activation of regulatory areas during extinction learning

neuroscience↗

bioRxiv2025

Neural Representation of Associative Threat Learning in Pulvinar Divisions, Lateral Geniculate Nucleus, and Mediodorsal Thalamus in Humans

Understanding the neural mechanisms underlying associative threat learning is essential for advancing behavioral models of threat and adaptation. We investigated distinct activation patterns across thalamic pulvinar divisions, the lateral geniculate nucleus (LGN), and the mediodorsal thalamus (MD) during associative threat learning using fMRI. The anterior pulvinar and MD exhibited parallel activation patterns, that may reflect distinct contributions to automatic and more deliberative learning processes. Additionally, our findings suggest a hierarchical functional organization of pulvinar activation during fear conditioning, in which coordinated activation among inferior, lateral, medial, and anterior divisions may support the integration of threat-related information. Pulvinar divisions and the MD showed activation during extinction learning and exhibited activation patterns consistent with salience processing during extinction recall and threat renewal. LGN activation patterns were consistent with feedforward visual processing. These findings extend current models of threat learning and memory by suggesting distinct patterns of thalamic involvement across associative threat learning and memory and providing a functional framework for investigating thalamic contributions to these processes.

neuroscience↗

bioRxiv2025

Slow oscillation-sleep spindle coupling is associated with fear extinction retention in trauma-exposed individuals

Posttraumatic stress disorder (PTSD) can be characterized as a disorder of fear learning and memory, in which there is a failure to retain memory for the extinction of conditioned fear. Sleep has been implicated in successful extinction retention. The coupling of sleep spindles to slow oscillations (SOs) during non-rapid eye movement sleep has been shown to broadly underpin sleeps beneficial effect on memory consolidation. However, the role of this oscillatory coupling in the retention of extinction memories is unknown. In a large sample of 124 trauma-exposed individuals, we investigated SO-spindle coupling in relation to fear extinction memory. We found that participants with a PTSD diagnosis, relative to trauma-exposed controls, showed significantly altered SO-spindle timing, such that PTSD participants exhibited spindle coupling further away from the peak of the SO. Across participants, the amount of coupling significantly predicted extinction retention, with coupled spindles uniquely predicting successful extinction retention compared to uncoupled spindles. These results suggest that SO-spindle coupling is critical for successful retention of extinguished fear, and that SO-spindle coupling dynamics are altered in PTSD. These alterations in the mechanics of sleep may have substantial clinical implications, meriting further investigation.

neuroscience↗

bioRxiv2022

Parent-Child Autonomic Synchrony During Vicarious Extinction Learning in Pediatric PTSD

Children learn about threat and safety in their environment in part from their caregivers, a process which may be disrupted in child psychopathology. This transmission may be seen through biological measures like peripheral nervous system outputs such as skin conductance (SCR). Fear learning deficits have been observed in fear-related disorders like PTSD but have received little study in terms of parent-child learning transmission. We used a vicarious fear extinction paradigm to examine whether biological synchrony (SCR and heart rate variability [HRV]) is a potential mechanism by which children learn safety cues from their parents. In this pilot study, 16 dyads (PTSD n=11, typically developing [TD] n=5) underwent a vicarious fear extinction paradigm. We used cross-recurrence quantification analysis (CRQA) to assess SCR and HRV synchrony between parent-child dyads. We then used a linear model to examine group differences between PTSD dyads and TD dyads. For SCR, a significant group difference (p=.037) indicated that TD dyads had higher SCR synchrony compared to PTSD dyads. For HRV, there were no group differences between PTSD and TD dyads (p=.325). In exploratory analyses, increased synchrony was related to an overall decreased autonomic reactivity during recall of fear (p=0.032). These results suggest that SCR synchrony, but not HRV, may be a potential mechanism that allows for fear and safety learning in youth. While these data are preliminary, they provide novel insights on how disruptions in vicarious extinction learning may contribute to fear-related disorders in youth. Furthermore, this study suggests novel approaches to studying dyadic trauma-focused therapies which critically rely on parental coaching to model appropriate fear responses to help their child to recover from trauma. Significance StatementThis study provides evidence that biological synchrony is a potential mechanism through which youth learn threat and safety cues through their parents. We found that youth with PTSD have lower synchrony with their caregiver, and that synchrony was related to decreased overall autonomic reactivity, suggesting that synchrony may be indicative of overall safety learning. Further, decreased synchrony during fear extinction may potentially underlie the etiology of fear related disorders such as PTSD. These novel approaches may improve our understanding of dyadic trauma-focused therapies which critically rely on parental coaching to model appropriate fear responses to help their child to recover from trauma.

neuroscience↗