Neural Decoding and Feature Selection Techniques for Closed-Loop Control of Defensive Behavior.

Objective: Many psychiatric disorders involve excessive avoidant or defensive behavior, such as avoidance in anxiety and trauma disorders or defensive rituals in obsessive-compulsive disorders. Developing algorithms to predict these behaviors from local field potentials (LFPs) could serve as foundational technology for closed-loop control of such disorders. A significant challenge is identifying the LFP features that encode these defensive behaviors. Approach: We analyzed LFP signals from the infralimbic cortex and basolateral amygdala of rats undergoing tone-shock conditioning and extinction, standard for investigating defensive behaviors. We utilized a comprehensive set of neuro-markers across spectral, temporal, and connectivity domains, employing SHapley Additive exPlanations for feature importance evaluation within Light Gradient-Boosting Machine models. Our goal was to decode three commonly studied avoidance/defensive behaviors: freezing, bar-press suppression, and motion (accelerometry), examining the impact of different features on decoding performance. Main results: Band power and band power ratio between channels emerged as optimal features across sessions. High-gamma (80-150 Hz) power, power ratios, and inter-regional correlations were more informative than other bands that are more classically linked to defensive behaviors. Focusing on highly informative features enhanced performance. Across 4 recording sessions with 16 subjects, we achieved an average coefficient of determination of 0.5357 and 0.3476, and Pearson correlation coefficients of 0.7579 and 0.6092 for accelerometry jerk and bar press rate, respectively. Utilizing only the most informative features revealed differential encoding between accelerometry and bar press rate, with the former primarily through local spectral power and the latter via inter-regional connectivity. Our methodology demonstrated remarkably low time complexity, requiring <110 ms for training and <1 ms for inference. Significance: Our results demonstrate the feasibility of accurately decoding defensive behaviors with minimal latency, using LFP features from neural circuits strongly linked to these behaviors. This methodology holds promise for real-time decoding to identify physiological targets in closed-loop psychiatric neuromodulation.

Quantifying defensive behavior and threat response through integrated headstage accelerometry.

BACKGROUND: Defensive and threat-related behaviors are common models for aspects of human mental illness.These behaviors are typically quantified by potentially laborious and/or computationally intensive video recording and post hoc analysis. Depending on the analysis method, the resulting measurements can be noisy or inaccurate. Other defensive behaviors, such as suppression of operant reward seeking, require extensive animal pre-training. Inertial tracking and accelerometry can be computationally efficient, but require specialized hardware. NEW METHOD: We quantified rodent defensive behavior using a commercially available electrophysiology headstage with 3-axis accelerometry integration during a threat conditioning and extinction paradigm. We tested multiple pre-processing and smoothing methods and correlated them against video-derived freezing and suppression of operant bar pressing. RESULTS: The best approach to tracking defensive behavior from accelerometry was Gaussian filter smoothing of the first derivative. Behavior scores from this method reproduced canonical conditioning and extinction curves. Timepoint-to-timepoint correlations between accelerometry,video, and bar press metrics were statistically significant but modest (largest r = 0.53, between accelerometry and bar press). These increased when traditional thresholding-based analyses were used, at the cost of a loss of temporal resolution (r = 0.97 between thresholded accelerometry and percent time freezing). COMPARISON WITH EXISTING METHODS: Accelerometry's integration with standard electrophysiology systems and relatively light weight signal processing may make it particularly well suited to detect behavior in resource-constrainedor real-time applications. CONCLUSIONS: Accelerometry allows researchers already using electrophysiology to assess defensive behaviors without the need for additional behavioral measures or video. The modest correlations between metrics suggest that each measures a distinct aspect of defensive behavior. Accelerometry is a viable alternative to current defensive measurements, and its non-overlap with other metrics may allow for more sophisticated dissection of threat responses.

Paired Electrical Pulse Trains for Controlling Connectivity in Emotion-Related Brain Circuitry.

Neurostimulation therapies for psychiatric disorders often have limited clinical efficacy. The limited efficacy might arise from a mismatch between therapy and disease mechanisms. Mental disorders are believed to arise from communication breakdown in distributed brain circuits, and thus altering connectivity between brain regions might be an effective way to restore normal brain communication. Synchronized neural oscillations (coherence) and synaptic strength are two common measures of brain connectivity. In this work, we developed an electrical stimulation method for altering narrow-frequency-band (theta, 5-8 Hz) coherence and synaptic strength. We tested this method in a circuit between infralimbic cortex (IL) and basolateral amygdala (BLA), which is broadly implicated in fear regulation. 6 Hz pulse trains were delivered into IL and BLA with various inter-train lags. These paired trains induced long-lasting synaptic strength change and a brief coherence enhancement in the IL-BLA circuit. This enhancement was specific to the "top-down" (IL-to-BLA) direction, and only occurred when the IL and BLA pulse trains had a relative lag of 180° (83 ms). Since the IL-BLA connection is known to be highly relevant to fear regulation, this method provides a tool to study the relationship between brain connectivity and fear behaviors. Further, it may be a new approach to study the relative roles of synaptic strength and oscillatory synchrony in brain network communication.

Sex-specific attenuation of impulsive action by progesterone in a go/no-go task for cocaine in rats.

RATIONALE: Previous work indicated that progesterone (PRO) reduced impulsive choice for cocaine in female but not male rats (Smethells et al. Psychopharmacology 233:2999-3008, 2016). Impulsive action, typically measured by responding for a reinforcer during a signaled period of nonavailability of natural reinforcers, predicts initiation and escalation of drug use in animals and humans. The present study examined impulsive action for cocaine using PRO in male and female rats trained on a go/no-go task. OBJECTIVE: Rats were trained on a go/no-go task to respond for cocaine infusions (0.4 mg/kg/inf). During the "go" component, responding was reinforced on a VI 30-s schedule, whereas during the "no-go" component, withholding a response was reinforced on a differential reinforcement of other behavior (DRO) 30-s schedule. A response during the no-go component resets the DRO timer and served as a measure of impulsive action. After baseline responding was established, rats were pretreated with vehicle (VEH) or PRO (0.5 mg/kg), and DRO resets and responding during the go component for cocaine were compared in males vs. females. RESULTS: DRO resets were significantly lower following PRO treatment compared to VEH in female, but not male, rats. Response rates and overall infusions during the go component were not significantly altered by PRO in either females or males. CONCLUSION: Treatment with PRO resulted in a sex-specific reduction in impulsive action for cocaine, while not affecting cocaine self-administration.