Closing the loop between brain activity and behavior is one of the most active areas of development in neuroscience. There is particular interest in developing closed-loop control of neural oscillations. Many studies report correlations between oscillations and functional processes. Oscillation-informed closed-loop experiments might determine whether these relationships are causal and would provide important mechanistic insights which may lead to new therapeutic tools. These closed-loop perturbations require accurate estimates of oscillatory phase and amplitude, which are challenging to compute in real time. We developed an easy to implement, fast and accurate Toolkit for Oscillatory Real-time Tracking and Estimation (TORTE). TORTE operates with the open-source Open Ephys GUI (OEGUI) system, making it immediately compatible with a wide range of acquisition systems and experimental preparations. TORTE efficiently extracts oscillatory phase and amplitude from a target signal and includes a variety of options to trigger closed-loop perturbations. Implementing these tools into existing experiments is easy and adds minimal latency to existing protocols. Most labs use in-house lab-specific approaches, limiting replication and extension of their experiments by other groups. Accuracy of the extracted analytic signal and accuracy of oscillation-informed perturbations with TORTE match presented results by these groups. However, TORTE provides access to these tools in a flexible, easy to use toolkit without requiring proprietary software. We hope that the availability of a high-quality, open-source, and broadly applicable toolkit will increase the number of labs able to perform oscillatory closed-loop experiments, and will improve the replicability of protocols and data across labs.
The orbitofrontal cortex–ventromedial striatum (OFC–VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. Male Long-Evans rats implanted with optical fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC–VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after, and 1 h after each stimulation, 1 and 2 weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC–VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional set-shifting. OFC–VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the stimulation protocol altered OFC–VMS synaptic weighting. In sum, although we induced physiological changes in the OFC–VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. This suggests possible limitations to translation of mouse findings to species higher on the phylogenetic chain.
Objective: Deep brain stimulation (DBS) of the ventral internal capsule/striatum (VCVS) is a potentially effective treatment for several mental health disorders when conventional therapeutics fail. Its effectiveness, however, depends on correct programming to engage VCVS sub-circuits. VCVS programming is currently an iterative, time-consuming process, with weeks between setting changes and reliance on noisy, subjective self-reports. An objective measure of circuit engagement might allow individual settings to be tested in seconds to minutes, reducing the time to response and increasing patient and clinician confidence in the chosen settings. Here, we present an approach to measuring and optimizing that circuit engagement. Approach: We leverage prior results showing that effective VCVS DBS engages circuits of cognitive control, that this engagement depends primarily on which contact(s) are activated, and that circuit engagement can be tracked through a state space modeling framework. We combine this framework with an adaptive optimizer to perform a principled exploration of electrode contacts and identify the contacts that maximally improve cognitive control. Main results: Using behavioral simulations directly derived from patient data, we show that an Upper Confidence Bound (UCB1) algorithm outperforms other optimizers (roughly 80% probability of convergence to a global optimum). Significance: We show that the optimization can converge even with lag between stimulation and effect, and that a complete optimization can be done in a clinically feasible timespan (a few hours). Further, the approach requires no specialized recording or imaging hardware, and thus could be a scalable path to expand the use of DBS in psychiatric and other non-motor applications.
Objective: Deep brain stimulation (DBS) of the ventral internal capsule/striatum (VCVS) is a potentially effective treatment for several mental health disorders when conventional therapeutics fail. Its effectiveness, however, depends on correct programming to engage VCVS sub-circuits. VCVS programming is currently an iterative, time-consuming process, with weeks between setting changes and reliance on noisy, subjective self-reports. An objective measure of circuit engagement might allow individual settings to be tested in seconds to minutes, reducing the time to response and increasing patient and clinician confidence in the chosen settings. Here, we present an approach to measuring and optimizing that circuit engagement. Approach: We leverage prior results showing that effective VCVS DBS engages cognitive control circuitry and improves performance on the Multi-Source Interference Task (MSIT), that this engagement depends primarily on which contact(s) are activated, and that circuit engagement can be tracked through a state space modeling framework. We develop a simulation framework based on those empirical results, then combine this framework with an adaptive optimizer to simulate a principled exploration of electrode contacts and identify the contacts that maximally improve cognitive control. We explore multiple optimization options (algorithms, number of inputs, speed of stimulation parameter changes) and compare them on problems of varying difficulty. Main results: We show that an Upper Confidence Bound (UCB1) algorithm outperforms other optimizers, with roughly 80% probability of convergence to a global optimum when used in a majority-vote ensemble. Significance: We show that the optimization can converge even with lag between stimulation and effect, and that a complete optimization can be done in a clinically feasible timespan (a few hours). Further, the approach requires no specialized recording or imaging hardware, and thus could be a scalable path to expand the use of DBS in psychiatric and other non-motor applications.
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