Trajectory Modeling and Response Prediction in Transcranial Magnetic Stimulation for Depression.

Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by better and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modelling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models can predict clinical outcomes. We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression (TRD), across multiple coils and protocols. We then compared the predictive power of those models. LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52-0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 - 0.94], but likewise, not before. In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.

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.

Post-Roe v Wade psychiatry: legal, clinical, and ethical challenges in psychiatry under abortion bans.

In recent history, the world has witnessed a trend towards liberalization of abortion laws driven by an increasing understanding of the negative personal and public health consequences of criminalizing abortion. By contrast, several countries have recently implemented restrictive reproductive laws, joining the 112 countries where access to abortion care is banned completely or with narrow exceptions. On June 24, 2022, the US Supreme Court ruling in Dobbs v Jackson Women's Health Organization overturned its landmark decisions in Roe v Wade that established abortion until the point of viability of the fetus as a constitutional right. After Roe v Wade having been overturned, it is projected that many women in the USA will be prevented from accessing safe abortion care. Importantly, abortion bans not only impose constraints on patient autonomy, they also restrict physicians' ability to practice evidence-based medicine, which will negatively impact psychiatric care. It is therefore crucial for the practicing psychiatrist to be familiar with this new legal landscape. In this Personal View, we aim to provide a topical overview to help clinicians gain a clear understanding of legal, clinical, and ethical responsibilities, focusing on the USA. We also discuss the reality that psychiatrists might be called upon to determine medical necessity for an abortion on psychiatric grounds, which is new for most US psychiatrists. We predict that psychiatrists will be confronted with very difficult situations in which lawful and ethical conduct might be incongruent, and that abortion bans will result in greater numbers of patients needing psychiatric care from a system that is ill-prepared for additional demands.

Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

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.

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.

Deep transcranial magnetic stimulation for adolescents with treatment-resistant depression: A preliminary dose-finding study exploring safety and clinical effectiveness.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD. OBJECTIVE/HYPOTHESIS: This pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD. METHODS: 15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R). RESULTS: 14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response. LIMITATIONS: Main limitations include a small sample size and open-label design. CONCLUSIONS: These findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.

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.

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.

Deep Brain Stimulation for Substance Use Disorders? An Exploratory Qualitative Study of Perspectives of People Currently in Treatment.

OBJECTIVE: Although previous studies have discussed the promise of deep brain stimulation (DBS) as a possible treatment for substance use disorders (SUDs) and collected researcher perspectives on possible ethical issues surrounding it, none have consulted people with SUDs themselves. We addressed this gap by interviewing people with SUDs. METHODS: Participants viewed a short video introducing DBS, followed by a 1.5-hour semistructured interview on their experiences with SUDs and their perspective on DBS as a possible treatment option. Interviews were analyzed by multiple coders who iteratively identified salient themes. RESULTS: We interviewed 20 people in 12-step-based, inpatient treatment programs (10 [50%] White/Caucasian, 7 Black/African American [35%], 2 Asian [10%], 1 Hispanic/Latino [5%], and 1 [5%] Alaska Native/American Indian; 9 women [45%], 11 men [55%]). Interviewees described a variety of barriers they currently faced through the course of their disease that mirrored barriers often associated with DBS (stigma, invasiveness, maintenance burdens, privacy risks) and thus made them more open to the possibility of DBS as a future treatment option. CONCLUSIONS: Individuals with SUDs gave relatively less weight to surgical risks and clinical burdens associated with DBS than previous surveys of provider attitudes anticipated. These differences derived largely from their experiences living with an often-fatal disease and encountering limitations of current treatment options. These findings support the study of DBS as a treatment option for SUDs, with extensive input from people with SUDs and advocates.

Future directions in psychiatric neurosurgery: Proceedings of the 2022 American Society for Stereotactic and Functional Neurosurgery meeting on surgical neuromodulation for psychiatric disorders.

OBJECTIVE: Despite advances in the treatment of psychiatric diseases, currently available therapies do not provide sufficient and durable relief for as many as 30-40% of patients. Neuromodulation, including deep brain stimulation (DBS), has emerged as a potential therapy for persistent disabling disease, however it has not yet gained widespread adoption. In 2016, the American Society for Stereotactic and Functional Neurosurgery (ASSFN) convened a meeting with leaders in the field to discuss a roadmap for the path forward. A follow-up meeting in 2022 aimed to review the current state of the field and to identify critical barriers and milestones for progress. DESIGN: The ASSFN convened a meeting on June 3, 2022 in Atlanta, Georgia and included leaders from the fields of neurology, neurosurgery, and psychiatry along with colleagues from industry, government, ethics, and law. The goal was to review the current state of the field, assess for advances or setbacks in the interim six years, and suggest a future path forward. The participants focused on five areas of interest: interdisciplinary engagement, regulatory pathways and trial design, disease biomarkers, ethics of psychiatric surgery, and resource allocation/prioritization. The proceedings are summarized here. CONCLUSION: The field of surgical psychiatry has made significant progress since our last expert meeting. Although weakness and threats to the development of novel surgical therapies exist, the identified strengths and opportunities promise to move the field through methodically rigorous and biologically-based approaches. The experts agree that ethics, law, patient engagement, and multidisciplinary teams will be critical to any potential growth in this area.

The Role of Family Members in Psychiatric Deep Brain Stimulation Trials: More Than Psychosocial Support.

Family members can provide crucial support to individuals participating in clinical trials. In research on the "newest frontier" of Deep Brain Stimulation (DBS)-the use of DBS for psychiatric conditions-family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and their family members as interview participants. Using dyadic thematic analysis-an approach that takes both the individuals and the relationship as units of analyses-this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions. Supplementary Information: The online version contains supplementary material available at 10.1007/s12152-023-09520-7.

Closed-Loop Deep Brain Stimulation for Psychiatric Disorders.

ABSTRACT: Deep brain stimulation (DBS) is a well-established approach to treating medication-refractory neurological disorders and holds promise for treating psychiatric disorders. Despite strong open-label results in extremely refractory patients, DBS has struggled to meet endpoints in randomized controlled trials. A major challenge is stimulation "dosing"-DBS systems have many adjustable parameters, and clinicians receive little feedback on whether they have chosen the correct parameters for an individual patient. Multiple groups have proposed closed loop technologies as a solution. These systems sense electrical activity, identify markers of an (un)desired state, then automatically deliver or adjust stimulation to alter that electrical state. Closed loop DBS has been successfully deployed in movement disorders and epilepsy. The availability of that technology, as well as advances in opportunities for invasive research with neurosurgical patients, has yielded multiple pilot demonstrations in psychiatric illness. Those demonstrations split into two schools of thought, one rooted in well-established diagnoses and symptom scales, the other in the more experimental Research Domain Criteria (RDoC) framework. Both are promising, and both are limited by the boundaries of current stimulation technology. They are in turn driving advances in implantable recording hardware, signal processing, and stimulation paradigms. The combination of these advances is likely to change both our understanding of psychiatric neurobiology and our treatment toolbox, though the timeframe may be limited by the realities of implantable device development.

In silicodevelopment and validation of Bayesian methods for optimizing deep brain stimulation to enhance cognitive control.

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, 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 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.

Structural Racism in Psychiatric Research Careers: Eradicating Barriers to a More Diverse Workforce.

Investigators from minoritized backgrounds are underrepresented in psychiatric research. That underrepresentation contributes to disparities in outcomes of access to mental health care. Drawing on lived experience, scholarly qualitative reports, and empirical data, the authors review how the underrepresentation of minoritized researchers arises from interlocking, self-reinforcing effects of structural biases in our research training and funding institutions. Minoritized researchers experience diminished early access to advanced training and opportunities, stereotype threats and microaggressions, isolation due to lack of peers and senior mentors, decreased access to early funding, and unique community and personal financial pressures. These represent structural racism-a system of institutional assumptions and practices that perpetuates race-based disparities, in spite of those institutions' efforts to increase diversity and in contradiction to the values that academic leaders outwardly espouse. The authors further review potential approaches to reversing these structural biases, including undergraduate-focused research experiences, financial support for faculty who lead training/mentoring programs, targeted mentoring through scholarly societies, better use of federal diversity supplement funding, support for scientific reentry, cohort building, diversity efforts targeting senior leadership, and rigorous examination of hiring, compensation, and promotion practices. Several of these approaches have empirically proven best practices and models for dissemination. If implemented alongside outcome measurement, they have the potential to reverse decades of structural bias in psychiatry and psychiatric research.

A 16-Channel Low-Power Neural Connectivity Extraction and Phase-Locked Deep Brain Stimulation SoC.

Growing evidence suggests that phase-locked deep brain stimulation (DBS) can effectively regulate abnormal brain connectivity in neurological and psychiatric disorders. This letter therefore presents a low-power SoC with both neural connectivity extraction and phase-locked DBS capabilities. A 16-channel low-noise analog front-end (AFE) records local field potentials (LFPs) from multiple brain regions with precise gain matching. A novel low-complexity phase estimator and neural connectivity processor subsequently enable energy-efficient, yet accurate measurement of the instantaneous phase and cross-regional synchrony measures. Through flexible combination of neural biomarkers such as phase synchrony and spectral energy, a four-channel charge-balanced neurostimulator is triggered to treat various pathological brain conditions. Fabricated in 65-nm CMOS, the SoC occupies a silicon area of 2.24 mm2 and consumes 60 µW, achieving over 60% power saving in neural connectivity extraction compared to the state-of-the-art. Extensive in-vivo measurements demonstrate multi-channel LFP recording, real-time extraction of phase and neural connectivity measures, and phase-locked stimulation in rats.

Closed-loop enhancement and neural decoding of cognitive control in humans.

Deficits in cognitive control-that is, in the ability to withhold a default pre-potent response in favour of a more adaptive choice-are common in depression, anxiety, addiction and other mental disorders. Here we report proof-of-concept evidence that, in participants undergoing intracranial epilepsy monitoring, closed-loop direct stimulation of the internal capsule or striatum, especially the dorsal sites, enhances the participants' cognitive control during a conflict task. We also show that closed-loop stimulation upon the detection of lapses in cognitive control produced larger behavioural changes than open-loop stimulation, and that task performance for single trials can be directly decoded from the activity of a small number of electrodes via neural features that are compatible with existing closed-loop brain implants. Closed-loop enhancement of cognitive control might remediate underlying cognitive deficits and aid the treatment of severe mental disorders.

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.

Hybrid Decoders for Marked Point Process Observations and External Influences.

OBJECTIVE: Internal physiological processes govern multiple state variables within the human body. Estimating these from point process-type bioelectric and biochemical observations is a challenge. Here we seek to estimate cortisol-related energy production and sympathetic arousal based on point process and continuous-valued data while permitting an external influence to affect the state estimates. METHODS: Traditional point process state-space methods, such as those used for estimating the aforementioned quantities from cortisol and skin conductance measurements respectively, suffer from the inability to permit the state estimates to also fit to an external influence (e.g. labels) or be guided by it. Here we modify an existing recurrent neural network (RNN) approach for state-space estimation through a weighted cost-function to enable a hybrid estimator that has this capability. RESULTS: Results on cortisol data based on a hypothetical sleep-wake influence term show how energy production can be estimated by permitting the estimates to fit to the external influence as much as desired. We further show how overfitting may be reduced by using circadian rhythm-based influence terms. Results on skin conductance data also indicate how the method can be used to estimate sympathetic arousal in an experiment containing stressors and relaxation, and permit an external influence as well. CONCLUSION: The RNN-based hybrid method is thus able to recover internal physiological states from point process and continuous-valued observations while permitting an external influence to guide the estimates. SIGNIFICANCE: The hybrid estimator could be embedded within wearable monitors that can be tailored based on domain expertise or individual feedback.