Smartphone intervention to optimize medication assisted treatment outcomes for opioid use disorder: study protocol for a randomized controlled trial.

Background: Opioids accounted for 75% of drug overdoses in the United States in 2020, with rural states particularly impacted by the opioid crisis. While medication assisted treatment (MAT) with Suboxone remains one of the more efficacious treatments for opioid use disorder (OUD), approximately 40% of people receiving Suboxone for outpatient MAT for OUD (MOUD) relapse within the first 6 months of treatment. We developed the smartphone app-based intervention OptiMAT as an adjunctive intervention to improve MOUD outcomes. The aims of this study are to (1) evaluate the efficacy of adjunctive OptiMAT use in reducing opioid misuse among people receiving MOUD; and (2) evaluate the role of specific OpitMAT features in reducing opioid misuse, including the use of GPS-driven just-in-time intervention. Methods: We will conduct a two-arm, single-blind, randomized controlled trial of adults receiving outpatient MOUD in the greater Little Rock AR area. Participants are English-speaking adults ages 18 or older recently enrolled in outpatient MOUD at one of our participating study clinics. Participants will be allocated via 1:1 randomized block design to (1) MOUD with adjunctive use of OptiMAT (MOUD+OptiMAT) or (2) MOUD without OptiMAT (MOUD-only). Our blinded research statistician will evaluate differences between the two groups in opioid misuse (as determined by quantitative urinalysis conducted by clinical lab staff blinded to group membership) during the 6-months following study enrolment. Secondary analyses will evaluate if OptiMAT-usage patterns within the MOUD+OptiMAT group predict opioid misuse or continued abstinence. Discussion: This study will test if adjunctive use of OptiMAT improve MOUD outcomes. Study findings could lead to expansion of OptiMAT into rural clinical settings, and the identification of OptiMAT features which best predict positive clinical outcome could lead to refinement of this and similar smartphone appbased interventions. Trial registration: ClinicalTrials.gov identifier: NCT05336188, registered March 21, 2022, https://clinicaltrials.gov/ct2/show/NCT05336188.

Smartphone intervention to optimize medication-assisted treatment outcomes for opioid use disorder: study protocol for a randomized controlled trial.

BACKGROUND: Opioids accounted for 75% of drug overdoses in the USA in 2020, with rural states particularly impacted by the opioid crisis. While medication-assisted treatment (MAT) with Suboxone remains one of the more efficacious treatments for opioid use disorder (OUD), approximately 40% of people receiving Suboxone for outpatient MAT for OUD (MOUD) relapse within the first 6 months of treatment. We developed the smartphone app-based intervention OptiMAT as an adjunctive intervention to improve MOUD outcomes. The aims of this study are to (1) evaluate the efficacy of adjunctive OptiMAT use in reducing opioid misuse among people receiving MOUD and (2) evaluate the role of specific OptiMAT features in reducing opioid misuse, including the use of GPS-driven just-in-time intervention. METHODS: We will conduct a two-arm, single-blind, randomized controlled trial of adults receiving outpatient MOUD in the greater Little Rock AR area. Participants are English-speaking adults ages 18 or older recently enrolled in outpatient MOUD at one of our participating study clinics. Participants will be allocated via 1:1 randomized block design to (1) MOUD with adjunctive use of OptiMAT (MOUD+OptiMAT) or (2) MOUD without OptiMAT (MOUD-only). Our blinded research statistician will evaluate differences between the two groups in opioid misuse (as determined by quantitative urinalysis conducted by clinical lab staff blinded to group membership) during the 6-months following study enrolment. Secondary analyses will evaluate if OptiMAT-usage patterns within the MOUD+OptiMAT group predict opioid misuse or continued abstinence. DISCUSSION: This study will test if adjunctive use of OptiMAT improve MOUD outcomes. Study findings could lead to expansion of OptiMAT into rural clinical settings, and the identification of OptiMAT features which best predict positive clinical outcome could lead to refinement of this and similar smartphone app-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05336188 , registered March 21, 2022.

A test of affect processing bias in response to affect regulation.

In this study we merged methods from machine learning and human neuroimaging to test the role of self-induced affect processing states in biasing the affect processing of subsequent image stimuli. To test this relationship we developed a novel paradigm in which (n = 40) healthy adult participants observed affective neural decodings of their real-time functional magnetic resonance image (rtfMRI) responses as feedback to guide explicit regulation of their brain (and corollary affect processing) state towards a positive valence goal state. By this method individual differences in affect regulation ability were controlled. Attaining this brain-affect goal state triggered the presentation of pseudo-randomly selected affectively congruent (positive valence) or incongruent (negative valence) image stimuli drawn from the International Affective Picture Set. Separately, subjects passively viewed randomly triggered positively and negatively valent image stimuli during fMRI acquisition. Multivariate neural decodings of the affect processing induced by these stimuli were modeled using the task trial type (state- versus randomly-triggered) as the fixed-effect of a general linear mixed-effects model. Random effects were modeled subject-wise. We found that self-induction of a positive valence brain state significantly positively biased valence processing of subsequent stimuli. As a manipulation check, we validated affect processing state induction achieved by the image stimuli using independent psychophysiological response measures of hedonic valence and autonomic arousal. We also validated the predictive fidelity of the trained neural decoding models using brain states induced by an out-of-sample set of image stimuli. Beyond its contribution to our understanding of the neural mechanisms that bias affect processing, this work demonstrated the viability of novel experimental paradigms triggered by pre-defined cognitive states. This line of individual differences research potentially provides neuroimaging scientists with a valuable tool for exploring the roles and identities of intrinsic cognitive processing mechanisms that shape our perceptual processing of sensory stimuli.

Lessons learned: A neuroimaging research center's transition to open and reproducible science.

Human functional neuroimaging has evolved dramatically in recent years, driven by increased technical complexity and emerging evidence that functional neuroimaging findings are not generally reproducible. In response to these trends, neuroimaging scientists have developed principles, practices, and tools to both manage this complexity as well as to enhance the rigor and reproducibility of neuroimaging science. We group these best practices under four categories: experiment pre-registration, FAIR data principles, reproducible neuroimaging analyses, and open science. While there is growing recognition of the need to implement these best practices there exists little practical guidance of how to accomplish this goal. In this work, we describe lessons learned from efforts to adopt these best practices within the Brain Imaging Research Center at the University of Arkansas for Medical Sciences over 4 years (July 2018-May 2022). We provide a brief summary of the four categories of best practices. We then describe our center's scientific workflow (from hypothesis formulation to result reporting) and detail how each element of this workflow maps onto these four categories. We also provide specific examples of practices or tools that support this mapping process. Finally, we offer a roadmap for the stepwise adoption of these practices, providing recommendations of why and what to do as well as a summary of cost-benefit tradeoffs for each step of the transition.

Identifying the Neural Correlates of Resting State Affect Processing Dynamics.

There exists growing interest in understanding the dynamics of resting state functional magnetic resonance imaging (rs-fMRI) to establish mechanistic links between individual patterns of spontaneous neural activation and corresponding behavioral measures in both normative and clinical populations. Here we propose and validate a novel approach in which whole-brain rs-fMRI data are mapped to a specific low-dimensional representation-affective valence and arousal processing-prior to dynamic analysis. This mapping process constrains the state space such that both independent validation and visualization of the system's dynamics become tractable. To test this approach, we constructed neural decoding models of affective valence and arousal processing from brain states induced by International Affective Picture Set image stimuli during task-related fMRI in (n = 97) healthy control subjects. We applied these models to decode moment-to-moment affect processing in out-of-sample subjects' rs-fMRI data and computed first and second temporal derivatives of the resultant valence and arousal time-series. Finally, we fit a second set of neural decoding models to these derivatives, which function as neurally constrained ordinary differential equations (ODE) underlying affect processing dynamics. To validate these decodings, we simulated affect processing by numerical integration of the true temporal sequence of neurally decoded derivatives for each subject and demonstrated that these decodings generate significantly less (p < 0.05) group-level simulation error than integration based upon decoded derivatives sampled uniformly randomly from the true temporal sequence. Indeed, simulations of valence and arousal processing were significant for up to four steps of closed-loop simulation (Δt = 2.0 s) for both valence and arousal, respectively. Moreover, neural encoding representations of the ODE decodings include significant clusters of activation within brain regions associated with affective reactivity and regulation. Our work has methodological implications for efforts to identify unique and actionable biomarkers of possible future or current psychopathology, particularly those related to mood and emotional instability.

Action-value processing underlies the role of the dorsal anterior cingulate cortex in performance monitoring during self-regulation of affect.

In this study, we merged methods from engineering control theory, machine learning, and human neuroimaging to critically test the putative role of the dorsal anterior cingulate cortex (dACC) in goal-directed performance monitoring during an emotion regulation task. Healthy adult participants (n = 94) underwent cued-recall and re-experiencing of their responses to affective image stimuli with concurrent functional magnetic resonance imaging and psychophysiological response recording. During cued-recall/re-experiencing trials, participants engaged in explicit self-regulation of their momentary affective state to match a pre-defined affective goal state. Within these trials, neural decoding methods measured affect processing from fMRI BOLD signals across the orthogonal affective dimensions of valence and arousal. Participants' affective brain states were independently validated via facial electromyography (valence) and electrodermal activity (arousal) responses. The decoded affective states were then used to contrast four computational models of performance monitoring (i.e., error, predicted response outcome, action-value, and conflict) by their relative abilities to explain emotion regulation task-related dACC activation. We found that the dACC most plausibly encodes action-value for both valence and arousal processing. We also confirmed that dACC activation directly encodes affective arousal and also likely encodes recruitment of attention and regulation resources. Beyond its contribution to improving our understanding of the roles that the dACC plays in emotion regulation, this study introduced a novel analytical framework through which affect processing and regulation may be functionally dissociated, thereby permitting mechanistic analysis of real-world emotion regulation strategies, e.g., distraction and reappraisal, which are widely employed in cognitive behavioral therapy to address clinical deficits in emotion regulation.

Combining Physiological and Neuroimaging Measures to Predict Affect Processing Induced by Affectively Valent Image Stimuli.

The importance of affect processing to human behavior has long driven researchers to pursue its measurement. In this study, we compared the relative fidelity of measurements of neural activation and physiology (i.e., heart rate change) in detecting affective valence induction across a broad continuum of conveyed affective valence. We combined intra-subject neural activation based multivariate predictions of affective valence with measures of heart rate (HR) deceleration to predict predefined normative affect rating scores for stimuli drawn from the International Affective Picture System (IAPS) in a population (n = 50) of healthy adults. In sum, we found that patterns of neural activation and HR deceleration significantly, and uniquely, explain the variance in normative valent scores associated with IAPS stimuli; however, we also found that patterns of neural activation explain a significantly greater proportion of that variance. These traits persisted across a range of stimulus sets, differing by the polar-extremity of their positively and negatively valent subsets, which represent the positively and negatively valent polar-extremity of stimulus sets reported in the literature. Overall, these findings support the acquisition of heart rate deceleration concurrently with fMRI to provide convergent validation of induced affect processing in the dimension of affective valence.

Filtering and model-based analysis independently improve skin-conductance response measures in the fMRI environment: Validation in a sample of women with PTSD.

Numerous methods exist for the pre-processing and analysis of skin-conductance response (SCR) data, but there is incomplete consensus on suitability and implementation, particularly with regard to signal filtering in conventional peak score (PS) analysis. This is particularly relevant when SCRs are measured during fMRI, which introduces additional noise and signal variability. Using SCR-fMRI data (n = 65 women) from a fear conditioning experiment, we compare the impact of three nested data processing methods on analysis using conventional PS as well as psychophysiological modeling. To evaluate the different methods, we quantify effect size to recover a benchmark contrast of interest, namely, discriminating SCR magnitude to a conditioned stimulus (CS+) relative to a CS not followed by reinforcement (CS-). Findings suggest that low-pass filtering reduces PS sensitivity (Δd = -20%), while band-pass filtering improves PS sensitivity (Δd = +27%). We also replicate previous findings that a psychophysiological modeling approach yields superior sensitivity to detect contrasts of interest than even the most sensitive PS method (Δd = +110%). Furthermore, we present preliminary evidence that filtering differences may account for a portion of exclusions made on commonly applied metrics, such as below zero discrimination. Despite some limitations of our sample and experimental design, it appears that SCR processing pipelines that include band-pass filtering, ideally with model-based SCR quantification, may increase the validity of SCR response measures, maximize research productivity, and decrease sampling bias by reducing data exclusion.

Common Functional Brain States Encode both Perceived Emotion and the Psychophysiological Response to Affective Stimuli.

Multivariate pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) data has critically advanced the neuroanatomical understanding of affect processing in the human brain. Central to these advancements is the brain state, a temporally-succinct fMRI-derived pattern of neural activation, which serves as a processing unit. Establishing the brain state's central role in affect processing, however, requires that it predicts multiple independent measures of affect. We employed MVPA-based regression to predict the valence and arousal properties of visual stimuli sampled from the International Affective Picture System (IAPS) along with the corollary skin conductance response (SCR) for demographically diverse healthy human participants (n = 19). We found that brain states significantly predicted the normative valence and arousal scores of the stimuli as well as the attendant individual SCRs. In contrast, SCRs significantly predicted arousal only. The prediction effect size of the brain state was more than three times greater than that of SCR. Moreover, neuroanatomical analysis of the regression parameters found remarkable agreement with regions long-established by fMRI univariate analyses in the emotion processing literature. Finally, geometric analysis of these parameters also found that the neuroanatomical encodings of valence and arousal are orthogonal as originally posited by the circumplex model of dimensional emotion.

Individual differences in rate of acquiring stable neural representations of tasks in fMRI.

Task-related functional magnetic resonance imaging (fMRI) is a widely-used tool for studying the neural processing correlates of human behavior in both healthy and clinical populations. There is growing interest in mapping individual differences in fMRI task behavior and neural responses. By utilizing neuroadaptive task designs accounting for such individual differences, task durations can be personalized to potentially optimize neuroimaging study outcomes (e.g., classification of task-related brain states). To test this hypothesis, we first retrospectively tracked the volume-by-volume changes of beta weights generated from general linear models (GLM) for 67 adult subjects performing a stop-signal task (SST). We then modeled the convergence of the volume-by-volume changes of beta weights according to their exponential decay (ED) in units of half-life. Our results showed significant differences in beta weight convergence estimates of optimal stopping times (OSTs) between go following successful stop trials and failed stop trials for both cocaine dependent (CD) and control group (Con), and between go following successful stop trials and go following failed stop trials for Con group. Further, we implemented support vector machine (SVM) classification for 67 CD/Con labeled subjects and compared the classification accuracies of fMRI-based features derived from (1) the full fMRI task versus (2) the fMRI task truncated to multiples of the unit of half-life. Among the computed binary classification accuracies, two types of task durations based on 2 half-lives significantly outperformed the accuracies using fully acquired trials, supporting this length as the OST for the SST. In conclusion, we demonstrate the potential of a neuroadaptive task design that can be widely applied to personalizing other task-based fMRI experiments in either dynamic real-time fMRI applications or within fMRI preprocessing pipelines.

Brain States That Encode Perceived Emotion Are Reproducible but Their Classification Accuracy Is Stimulus-Dependent.

The brain state hypothesis of image-induced affect processing, which posits that a one-to-one mapping exists between each image stimulus and its induced functional magnetic resonance imaging (fMRI)-derived neural activation pattern (i.e., brain state), has recently received support from several multivariate pattern analysis (MVPA) studies. Critically, however, classification accuracy differences across these studies, which largely share experimental designs and analyses, suggest that there exist one or more unaccounted sources of variance within MVPA studies of affect processing. To explore this possibility, we directly demonstrated strong inter-study correlations between image-induced affective brain states acquired 4 years apart on the same MRI scanner using near-identical methodology with studies differing only by the specific image stimuli and subjects. We subsequently developed a plausible explanation for inter-study differences in affective valence and arousal classification accuracies based on the spatial distribution of the perceived affective properties of the stimuli. Controlling for this distribution improved valence classification accuracy from 56% to 85% and arousal classification accuracy from 61% to 78%, which mirrored the full range of classification accuracy across studies within the existing literature. Finally, we validated the predictive fidelity of our image-related brain states according to an independent measurement, autonomic arousal, captured via skin conductance response (SCR). Brain states significantly but weakly (r = 0.08) predicted the SCRs that accompanied individual image stimulations. More importantly, the effect size of brain state predictions of SCR increased more than threefold (r = 0.25) when the stimulus set was restricted to those images having group-level significantly classifiable arousal properties.

Robust reinforcement learning control using integral quadratic constraints for recurrent neural networks.

The applicability of machine learning techniques for feedback control systems is limited by a lack of stability guarantees. Robust control theory offers a framework for analyzing the stability of feedback control loops, but for the integral quadratic constraint (IQC) framework used here, all components are required to be represented as linear, time-invariant systems plus uncertainties with, for IQCs used here, bounded gain. In this paper, the stability of a control loop including a recurrent neural network (NN) is analyzed by replacing the nonlinear and time-varying components of the NN with IQCs on their gain. As a result, a range of the NN's weights is found within which stability is guaranteed. An algorithm is demonstrated for training the recurrent NN using reinforcement learning and guaranteeing stability while learning.

Distributed Neural Processing Predictors of Multi-dimensional Properties of Affect.

Recent evidence suggests that emotions have a distributed neural representation, which has significant implications for our understanding of the mechanisms underlying emotion regulation and dysregulation as well as the potential targets available for neuromodulation-based emotion therapeutics. This work adds to this evidence by testing the distribution of neural representations underlying the affective dimensions of valence and arousal using representational models that vary in both the degree and the nature of their distribution. We used multi-voxel pattern classification (MVPC) to identify whole-brain patterns of functional magnetic resonance imaging (fMRI)-derived neural activations that reliably predicted dimensional properties of affect (valence and arousal) for visual stimuli viewed by a normative sample (n = 32) of demographically diverse, healthy adults. Inter-subject leave-one-out cross-validation showed whole-brain MVPC significantly predicted (p < 0.001) binarized normative ratings of valence (positive vs. negative, 59% accuracy) and arousal (high vs. low, 56% accuracy). We also conducted group-level univariate general linear modeling (GLM) analyses to identify brain regions whose response significantly differed for the contrasts of positive versus negative valence or high versus low arousal. Multivoxel pattern classifiers using voxels drawn from all identified regions of interest (all-ROIs) exhibited mixed performance; arousal was predicted significantly better than chance but worse than the whole-brain classifier, whereas valence was not predicted significantly better than chance. Multivoxel classifiers derived using individual ROIs generally performed no better than chance. Although performance of the all-ROI classifier improved with larger ROIs (generated by relaxing the clustering threshold), performance was still poorer than the whole-brain classifier. These findings support a highly distributed model of neural processing for the affective dimensions of valence and arousal. Finally, joint error analyses of the MVPC hyperplanes encoding valence and arousal identified regions within the dimensional affect space where multivoxel classifiers exhibited the greatest difficulty encoding brain states - specifically, stimuli of moderate arousal and high or low valence. In conclusion, we highlight new directions for characterizing affective processing for mechanistic and therapeutic applications in affective neuroscience.

A human brain atlas derived via n-cut parcellation of resting-state and task-based fMRI data.

The growth of functional MRI has led to development of human brain atlases derived by parcellating resting-state connectivity patterns into functionally independent regions of interest (ROIs). All functional atlases to date have been derived from resting-state fMRI data. But given that functional connectivity between regions varies with task, we hypothesized that an atlas incorporating both resting-state and task-based fMRI data would produce an atlas with finer characterization of task-relevant regions than an atlas derived from resting-state alone. To test this hypothesis, we derived parcellation atlases from twenty-nine healthy adult participants enrolled in the Cognitive Connectome project, an initiative to improve functional MRI's translation into clinical decision-making by mapping normative variance in brain-behavior relationships. Participants underwent resting-state and task-based fMRI spanning nine cognitive domains: motor, visuospatial, attention, language, memory, affective processing, decision-making, working memory, and executive function. Spatially constrained n-cut parcellation derived brain atlases using (1) all participants' functional data (Task) or (2) a single resting-state scan (Rest). An atlas was also derived from random parcellation for comparison purposes (Random). Two methods were compared: (1) a parcellation applied to the group's mean edge weights (mean), and (2) a two-stage approach with parcellation of individual edge weights followed by parcellation of mean binarized edges (two-stage). The resulting Task and Rest atlases had significantly greater similarity with each other (mean Jaccard indices JI=0.72-0.85) than with the Random atlases (JI=0.59-0.63; all p<0.001 after Bonferroni correction). Task and Rest atlas similarity was greatest for the two-stage method (JI=0.85), which has been shown as more robust than the mean method; these atlases also better reproduced voxelwise seed maps of the left dorsolateral prefrontal cortex during rest and performing the n-back working memory task (r=0.75-0.80) than the Random atlases (r=0.64-0.72), further validating their utility. We expected regions governing higher-order cognition (such as frontal and anterior temporal lobes) to show greatest difference between Task and Rest atlases; contrary to expectations, these areas had greatest similarity between atlases. Our findings indicate that atlases derived from parcellation of task-based and resting-state fMRI data are highly comparable, and existing resting-state atlases are suitable for task-based analyses. We introduce an anatomically labeled fMRI-derived whole-brain human atlas for future Cognitive Connectome analyses.