Neural correlates of learning accommodation and consolidation in generalised anxiety disorder.

OBJECTIVE.: Anxiety can interfere with attention and working memory, which are components that affect learning. Statistical models have been designed to study learning, such as the Bayesian Learning Model, which takes into account prior possibilities and behaviours to determine how much of a new behaviour is determined by learning instead of chance. However, the neurobiological basis underlying how anxiety interferes with learning is not yet known. Accordingly, we aimed to use neuroimaging techniques and apply a Bayesian Learning Model to study learning in individuals with generalised anxiety disorder (GAD). METHODS.: Participants were 25 controls and 14 individuals with GAD and comorbid disorders. During fMRI, participants completed a shape-button association learning and reversal task. Using a flexible factorial analysis in SPM, activation in the dorsolateral prefrontal cortex, basal ganglia, and hippocampus was compared between groups during first reversal. Beta values from the peak of these regions were extracted for all learning conditions and submitted to repeated measures analyses in SPSS. RESULTS.: Individuals with GAD showed less activation in the basal ganglia and the hippocampus only in the first reversal compared with controls. This difference was not present in the initial learning and second reversal. CONCLUSION.: Given that the basal ganglia is associated with initial learning, and the hippocampus with transfer of knowledge from short- to long-term memory, our results suggest that GAD may engage these regions to a lesser extent during early accommodation or consolidation of learning, but have no longer term effects in brain activation patterns during subsequent learning.

Beyond Description and Deficits: How Computational Psychiatry Can Enhance an Understanding of Decision-Making in Anorexia Nervosa.

PURPOSE OF REVIEW: Despite decades of research, knowledge of the mechanisms maintaining anorexia nervosa (AN) remains incomplete and clearly effective treatments elusive. Novel theoretical frameworks are needed to advance mechanistic and treatment research for this disorder. Here, we argue the utility of engaging a novel lens that differs from existing perspectives in psychiatry. Specifically, we argue the necessity of expanding beyond two historically common perspectives: (1) the descriptive perspective: the tendency to define mechanisms on the basis of surface characteristics and (2) the deficit perspective: the tendency to search for mechanisms associated with under-functioning of decision-making abilities and related circuity, rather than problems of over-functioning, in psychiatric disorders. RECENT FINDINGS: Computational psychiatry can provide a novel framework for understanding AN because this approach emphasizes the role of computational misalignments (rather than absolute deficits or excesses) between decision-making strategies and environmental demands as the key factors promoting psychiatric illnesses. Informed by this approach, we argue that AN can be understood as a disorder of excess goal pursuit, maintained by over-engagement, rather than disengagement, of executive functioning strategies and circuits. Emerging evidence suggests that this same computational imbalance may constitute an under-investigated phenotype presenting transdiagnostically across psychiatric disorders. A variety of computational models can be used to further elucidate excess goal pursuit in AN. Most traditional psychiatric treatments do not target excess goal pursuit or associated neurocognitive mechanisms. Thus, targeting at the level of computational dysfunction may provide a new avenue for enhancing treatment for AN and related disorders.

Deep brain stimulation for psychiatric disorders: From focal brain targets to cognitive networks.

Deep brain stimulation (DBS) is a promising intervention for treatment-resistant psychiatric disorders, particularly major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Up to 90% of patients who have not recovered with therapy or medication have reported benefit from DBS in open-label studies. Response rates in randomized controlled trials (RCTs), however, have been much lower. This has been argued to arise from surgical variability between sites, and recent psychiatric DBS research has focused on refining targeting through personalized imaging. Much less attention has been given to the fact that psychiatric disorders arise from dysfunction in distributed brain networks, and that DBS likely acts by altering communication within those networks. This is in part because psychiatric DBS research relies on subjective rating scales that make it difficult to identify network biomarkers. Here, we overview recent DBS RCT results in OCD and MDD, as well as the follow-on imaging studies. We present evidence for a new approach to studying DBS' mechanisms of action, focused on measuring objective cognitive/emotional deficits that underpin these and many other mental disorders. Further, we suggest that a focus on cognition could lead to reliable network biomarkers at an electrophysiologic level, especially those related to inter-regional synchrony of the local field potential (LFP). Developing the network neuroscience of DBS has the potential to finally unlock the potential of this highly specific therapy.

Local and distant responses to single pulse electrical stimulation reflect different forms of connectivity.

Measuring connectivity in the human brain involves innumerable approaches using both noninvasive (fMRI, EEG) and invasive (intracranial EEG or iEEG) recording modalities, including the use of external probing stimuli, such as direct electrical stimulation. To examine how different measures of connectivity correlate with one another, we compared 'passive' measures of connectivity during resting state conditions to the more 'active' probing measures of connectivity with single pulse electrical stimulation (SPES). We measured the network engagement and spread of the cortico-cortico evoked potential (CCEP) induced by SPES at 53 out of 104 total sites across the brain, including cortical and subcortical regions, in patients with intractable epilepsy (N=11) who were undergoing intracranial recordings as a part of their clinical care for identifying seizure onset zones. We compared the CCEP network to functional, effective, and structural measures of connectivity during a resting state in each patient. Functional and effective connectivity measures included correlation or Granger causality measures applied to stereoEEG (sEEGs) recordings. Structural connectivity was derived from diffusion tensor imaging (DTI) acquired before intracranial electrode implant and monitoring (N=8). The CCEP network was most similar to the resting state voltage correlation network in channels near to the stimulation location. In contrast, the distant CCEP network was most similar to the DTI network. Other connectivity measures were not as similar to the CCEP network. These results demonstrate that different connectivity measures, including those derived from active stimulation-based probing, measure different, complementary aspects of regional interrelationships in the brain.

CLoSES: A platform for closed-loop intracranial stimulation in humans.

Targeted interrogation of brain networks through invasive brain stimulation has become an increasingly important research tool as well as therapeutic modality. The majority of work with this emerging capability has been focused on open-loop approaches. Closed-loop techniques, however, could improve neuromodulatory therapies and research investigations by optimizing stimulation approaches using neurally informed, personalized targets. Implementing closed-loop systems is challenging particularly with regard to applying consistent strategies considering inter-individual variability. In particular, during intracranial epilepsy monitoring, where much of this research is currently progressing, electrodes are implanted exclusively for clinical reasons. Thus, detection and stimulation sites must be participant- and task-specific. The system must run in parallel with clinical systems, integrate seamlessly with existing setups, and ensure safety features are in place. In other words, a robust, yet flexible platform is required to perform different tests with a single participant and to comply with clinical requirements. In order to investigate closed-loop stimulation for research and therapeutic use, we developed a Closed-Loop System for Electrical Stimulation (CLoSES) that computes neural features which are then used in a decision algorithm to trigger stimulation in near real-time. To summarize CLoSES, intracranial electroencephalography (iEEG) signals are acquired, band-pass filtered, and local and network features are continuously computed. If target features are detected (e.g. above a preset threshold for a certain duration), stimulation is triggered. Not only could the system trigger stimulation while detecting real-time neural features, but we incorporated a pipeline wherein we used an encoder/decoder model to estimate a hidden cognitive state from the neural features. CLoSES provides a flexible platform to implement a variety of closed-loop experimental paradigms in humans. CLoSES has been successfully used with twelve patients implanted with depth electrodes in the epilepsy monitoring unit. During cognitive tasks (N=5), stimulation in closed loop modified a cognitive hidden state on a trial by trial basis. Sleep spindle oscillations (N=6) and sharp transient epileptic activity (N=9) were detected in near real-time, and stimulation was applied during the event or at specified delays (N=3). In addition, we measured the capabilities of the CLoSES system. Total latency was related to the characteristics of the event being detected, with tens of milliseconds for epileptic activity and hundreds of milliseconds for spindle detection. Stepwise latency, the actual duration of each continuous step, was within the specified fixed-step duration and increased linearly with the number of channels and features. We anticipate that probing neural dynamics and interaction between brain states and stimulation responses with CLoSES will lead to novel insights into the mechanism of normal and pathological brain activity, the discovery and evaluation of potential electrographic biomarkers of neurological and psychiatric disorders, and the development and testing of patient-specific stimulation targets and control signals before implanting a therapeutic device.

Social media recruitment for mental health research: A systematic review.

BACKGROUND: Social media holds exciting promise for advancing mental health research recruitment, however, the extent and efficacy to which these platforms are currently in use are underexplored. OBJECTIVE: A systematic review was conducted to characterize the current use and efficacy of social media in recruiting participants for mental health research. METHOD: A literature review was performed using MEDLINE, EMBASE, and PsychINFO. Only non-duplicative manuscripts written in the English language and published between 1/1/2004-3/31/2019 were selected for further screening. Data extracted included study type and design, participant inclusion criteria, social media platform, advertising strategy, final recruited sample size, recruitment location, year, monetary incentives, comparison to other recruitment methods if performed, and final cost per participant. RESULTS: A total of 176 unique studies that used social media for mental health research recruitment were reviewed. The majority of studies were cross-sectional (62.5%) in design and recruited adults. Facebook was overwhelmingly the recruitment platform of choice (92.6%), with the use of paid advertisements being the predominant strategy (60.8%). Of the reviewed studies, substance abuse (43.8%) and mood disorders (15.3%) were the primary subjects of investigation. In 68.3% of studies, social media recruitment performed as well as or better than traditional recruitment methods in the number and cost of final enrolled participants. The majority of studies used Facebook for recruitment at a median cost per final recruited study participant of $19.47. In 55.6% of the studies, social media recruitment was the more cost-effective recruitment method when compared to traditional methods (e.g., referrals, mailing). CONCLUSION: Social media appears to be an effective and economical recruitment tool for mental health research. The platform raises methodological and privacy concerns not covered in current research regulations that warrant additional consideration.

Multimodal Encoding of Novelty, Reward, and Learning in the Primate Nucleus Basalis of Meynert.

Associative learning is crucial for daily function, involving a complex network of brain regions. One region, the nucleus basalis of Meynert (NBM), is a highly interconnected, largely cholinergic structure implicated in multiple aspects of learning. We show that single neurons in the NBM of nonhuman primates (NHPs; n = 2 males; Macaca mulatta) encode learning a new association through spike rate modulation. However, the power of low-frequency local field potential (LFP) oscillations decreases in response to novel, not-yet-learned stimuli but then increase as learning progresses. Both NBM and the dorsolateral prefrontal cortex encode confidence in novel associations by increasing low- and high-frequency LFP power in anticipation of expected rewards. Finally, NBM high-frequency power dynamics are anticorrelated with spike rate modulations. Therefore, novelty, learning, and reward anticipation are separately encoded through differentiable NBM signals. By signaling both the need to learn and confidence in newly acquired associations, NBM may play a key role in coordinating cortical activity throughout the learning process.SIGNIFICANCE STATEMENT Degradation of cells in a key brain region, the nucleus basalis of Meynert (NBM), correlates with Alzheimer's disease and Parkinson's disease progression. To better understand the role of this brain structure in learning and memory, we examined neural activity in the NBM in behaving nonhuman primates while they performed a learning and memory task. We found that single neurons in NBM encoded both salience and an early learning, or cognitive state, whereas populations of neurons in the NBM and prefrontal cortex encode learned state and reward anticipation. The NBM may thus encode multiple stages of learning. These multimodal signals might be leveraged in future studies to develop neural stimulation to facilitate different stages of learning and memory.

A Shared Vision for Machine Learning in Neuroscience.

With ever-increasing advancements in technology, neuroscientists are able to collect data in greater volumes and with finer resolution. The bottleneck in understanding how the brain works is consequently shifting away from the amount and type of data we can collect and toward what we actually do with the data. There has been a growing interest in leveraging this vast volume of data across levels of analysis, measurement techniques, and experimental paradigms to gain more insight into brain function. Such efforts are visible at an international scale, with the emergence of big data neuroscience initiatives, such as the BRAIN initiative (Bargmann et al., 2014), the Human Brain Project, the Human Connectome Project, and the National Institute of Mental Health's Research Domain Criteria initiative. With these large-scale projects, much thought has been given to data-sharing across groups (Poldrack and Gorgolewski, 2014; Sejnowski et al., 2014); however, even with such data-sharing initiatives, funding mechanisms, and infrastructure, there still exists the challenge of how to cohesively integrate all the data. At multiple stages and levels of neuroscience investigation, machine learning holds great promise as an addition to the arsenal of analysis tools for discovering how the brain works.

Decoding Hidden Cognitive States From Behavior and Physiology Using a Bayesian Approach.

Cognitive processes, such as learning and cognitive flexibility, are both difficult to measure and to sample continuously using objective tools because cognitive processes arise from distributed, high-dimensional neural activity. For both research and clinical applications, that dimensionality must be reduced. To reduce dimensionality and measure underlying cognitive processes, we propose a modeling framework in which a cognitive process is defined as a low-dimensional dynamical latent variable-called a cognitive state, which links high-dimensional neural recordings and multidimensional behavioral readouts. This framework allows us to decompose the hard problem of modeling the relationship between neural and behavioral data into separable encoding-decoding approaches. We first use a state-space modeling framework, the behavioral decoder, to articulate the relationship between an objective behavioral readout (e.g., response times) and cognitive state. The second step, the neural encoder, involves using a generalized linear model (GLM) to identify the relationship between the cognitive state and neural signals, such as local field potential (LFP). We then use the neural encoder model and a Bayesian filter to estimate cognitive state using neural data (LFP power) to generate the neural decoder. We provide goodness-of-fit analysis and model selection criteria in support of the encoding-decoding result. We apply this framework to estimate an underlying cognitive state from neural data in human participants (N=8) performing a cognitive conflict task. We successfully estimated the cognitive state within the 95% confidence intervals of that estimated using behavior readout for an average of 90% of task trials across participants. In contrast to previous encoder-decoder models, our proposed modeling framework incorporates LFP spectral power to encode and decode a cognitive state. The framework allowed us to capture the temporal evolution of the underlying cognitive processes, which could be key to the development of closed-loop experiments and treatments.

Deficits in frontoparietal activation and anterior insula functional connectivity during regulation of cognitive-affective interference in bipolar disorder.

OBJECTIVES: Bipolar disorders (BD) are characterized by emotion and cognitive dysregulation. Mapping deficits in the neurocircuitry of cognitive-affective regulation allows for potential identification of intervention targets. This study used functional MRI data in BD patients and healthy controls during performance on a task requiring cognitive and inhibitory control superimposed on affective images, assessing cognitive and affective interference. METHODS: Functional MRI data were collected from 39 BD patients and 36 healthy controls during performance on the Multi-Source Interference Task overlaid on images from the International Affective Picture System (MSIT-IAPS). Analyses examined patterns of activation in a priori regions implicated in cognitive and emotional processing. Functional connectivity to the anterior insula during task performance was also examined, given this region's role in emotion-cognition integration. RESULTS: BD patients showed significantly less activation during cognitive interference trials in inferior parietal lobule, dorsomedial prefrontal cortex, anterior insula, mid-cingulate, and ventrolateral prefrontal cortex regardless of affective valence. BD patients showed deviations in functional connectivity with anterior insula in regions of the default mode and frontoparietal control networks during negatively valenced cognitive interference trials. CONCLUSIONS: Our findings show disruptions in cognitive regulation and inhibitory control in BD patients in the presence of irrelevant affective distractors. Results of this study suggest one pathway to dysregulation in BD is through inefficient integration of affective and cognitive information, and highlight the importance of developing interventions that target emotion-cognition integration in BD.

Closed-loop neuromodulation systems: next-generation treatments for psychiatric illness.

Despite deep brain stimulation's positive early results in psychiatric disorders, well-designed clinical trials have yielded inconsistent clinical outcomes. One path to more reliable benefit is closed-loop therapy: stimulation that is automatically adjusted by a device or algorithm in response to changes in the patient's electrical brain activity. These interventions may provide more precise and patient-specific treatments. This article first introduces the available closed-loop neuromodulation platforms, which have shown clinical efficacy in epilepsy and strong early results in movement disorders. It discusses the strengths and limitations of these devices in the context of psychiatric illness. It then describes emerging technologies to address these limitations, including pre-clinical developments such as wireless deep neurostimulation and genetically targeted neuromodulation. Finally, ongoing challenges and limitations for closed-loop psychiatric brain stimulation development, most notably the difficulty of identifying meaningful biomarkers for titration, are discussed. This is considered in the recently-released Research Domain Criteria (RDoC) framework, and how neuromodulation and RDoC are jointly very well suited to address the problem of treatment-resistant illness is described.

Predictors of Hypomania During Ventral Capsule/Ventral Striatum Deep Brain Stimulation.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is a novel therapy for neuropsychiatric disorders. Hypomania is a known complication of VC/VS DBS, but who is at risk is less understood. Factors such as family history, combined with details of DBS programming, might quantify that risk. The authors performed an iterative modeling procedure on a VC/VS DBS patient registry to identify key predictors. Hypomania was less common for men and for patients stimulated on the ventral right contact. It was more common with right monopolar stimulation. These findings may help to establish decision rules to reduce complications of VC/VS DBS.

Closing the loop in psychiatric deep brain stimulation: physiology, psychometrics, and plasticity.

Deep brain stimulation (DBS) is an invasive approach to precise modulation of psychiatrically relevant circuits. Although it has impressive results in open-label psychiatric trials, DBS has also struggled to scale to and pass through multi-center randomized trials. This contrasts with Parkinson disease, where DBS is an established therapy treating thousands of patients annually. The core difference between these clinical applications is the difficulty of proving target engagement, and of leveraging the wide range of possible settings (parameters) that can be programmed in a given patient's DBS. In Parkinson's, patients' symptoms change rapidly and visibly when the stimulator is tuned to the correct parameters. In psychiatry, those same changes take days to weeks, limiting a clinician's ability to explore parameter space and identify patient-specific optimal settings. I review new approaches to psychiatric target engagement, with an emphasis on major depressive disorder (MDD). Specifically, I argue that better engagement may come by focusing on the root causes of psychiatric illness: dysfunction in specific, measurable cognitive functions and in the connectivity and synchrony of distributed brain circuits. I overview recent progress in both those domains, and how it may relate to other technologies discussed in companion articles in this issue.

Electronic health records and stratified psychiatry: bridge to precision treatment?

The use of a stratified psychiatry approach that combines electronic health records (EHR) data with machine learning (ML) is one potentially fruitful path toward rapidly improving precision treatment in clinical practice. This strategy, however, requires confronting pervasive methodological flaws as well as deficiencies in transparency and reporting in the current conduct of ML-based studies for treatment prediction. EHR data shares many of the same data quality issues as other types of data used in ML prediction, plus some unique challenges. To fully leverage EHR data's power for patient stratification, increased attention to data quality and collection of patient-reported outcome data is needed.

EEG complexity in emotion conflict task in individuals with psychiatric disorders.

Analyzing EEG complexity may help to elucidate complex brain dynamics in individuals with psychiatric disorders and provide insight into neural connectivity and its relationship with deficits such as emotion-related impulsivity. EEG complexity was calculated through multiscale entropy and compared between a heterogeneous psychiatric patient group and a healthy control group during the emotion conflict resolution task. Twenty-eight healthy adults and ten psychiatric patients were recruited and compared on the multiscale entropy of EEG acquired in the task. Our results revealed a lower multiscale entropy in the psychiatric patient group compared to the healthy group during the task. This decrease in multiscale entropy suggests reduced long-range interaction between the left frontal region and other brain regions during the emotion conflict resolution task among psychiatric patients. Notably, a positive correlation was observed between multiscale entropy and impulsivity measures in the psychiatric patient group, where the higher the EEG complexity during the emotion regulation task, the higher the level of self-reported impulsivity in the psychiatric patients. Such impulsivity was evident in both healthy individuals and psychiatric patients, with healthy individuals showing shorter reaction times on incongruent conditions compared to congruent conditions and psychiatric patients displaying similar reaction times in both conditions, This study highlights the significance of investigating EEG complexity and its potential applications in the transdiagnostic exploration of impulsivity in psychiatric disorders.

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.

Neural decoding and feature selection methods for closed-loop control of avoidance 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 the 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 training/inference time and memory usage, requiring <310 ms for training, <0.051 ms for inference, and 16.6 kB of memory, using a single core of AMD Ryzen Threadripper PRO 5995WX CPU. 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. .

Pharmacogenomic Clinical Support Tools for the Treatment of Depression.

OBJECTIVE: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression. METHODS: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized. RESULTS: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results. CONCLUSIONS: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.

Chronic, Reusable, Multiday Neuropixels Recordings during Free-Moving Operant Behavior.

Electrophysiological recording is a powerful technique to examine neuronal substrates underlying cognition and behavior. Neuropixels probes provide a unique capacity to capture neuronal activity across many brain areas with high spatiotemporal resolution. Neuropixels are also expensive and optimized for acute, head-fixed use, both of which limit the types of behaviors and manipulations that can be studied. Recent advances have addressed the cost issue by showing chronic implant, explant, and reuse of Neuropixels probes, but the methods were not optimized for use in free-moving behavior. There were specific needs for improvement in cabling/connection stability. Here, we extend that work to demonstrate chronic Neuropixels recording, explant, and reuse in a rat model during fully free-moving operant behavior. Similar to prior approaches, we house the probe and headstage within a 3D-printed housing that avoids direct fixation of the probe to the skull, enabling eventual explant. We demonstrate innovations to allow chronic headstage connection with protection against environmental factors and a more stable cabling setup to reduce the tension that can interrupt recording. We demonstrate this approach with rats performing two different behavioral tasks, in each case showing: (1) chronic single- or dual-probe recordings in free-moving rats in operant chambers and (2) reusability of Neuropixels 1.0 probes with continued good single-unit yield after retrieval and reimplant. We thus demonstrate the potential for Neuropixels recordings in a wider range of species and preparations.