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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 ASSFN convened a meeting of leaders in the field to discuss a path forward for psychiatric neurosurgery. • The participants were experts in the fields of neurology, neurosurgery, psychiatry, industry, government, ethics, and law. • We focused on interdisciplinary engagement, regulatory pathways, trial design, biomarkers, ethics, and resource allocation. • We present our strengths, weaknesses, opportunities, and threats analyses of the current state of psychiatric neurosurgery. [ABSTRACT FROM AUTHOR]

Electrical neuromodulation via direct electrical stimulation (DES) is an increasingly common therapy for a wide variety of neuropsychiatric diseases. Unfortunately, therapeutic efficacy is inconsistent, likely due to our limited understanding of the relationship between the massive stimulation parameter space and brain tissue responses. To better understand how different parameters induce varied neural responses, we systematically examined single pulse-induced cortico-cortico evoked potentials (CCEP) as a function of stimulation amplitude, duration, brain region, and whether grey or white matter was stimulated. We measured voltage peak amplitudes and area under the curve (AUC) of intracranially recorded stimulation responses as a function of distance from the stimulation site, pulse width, current injected, location relative to grey and white matter, and brain region stimulated (N = 52, n = 719 stimulation sites). Increasing stimulation pulse width increased responses near the stimulation location. Increasing stimulation amplitude (current) increased both evoked amplitudes and AUC nonlinearly. Locally (<15 mm), stimulation at the boundary between grey and white matter induced larger responses. In contrast, for distant sites (>15 mm), white matter stimulation consistently produced larger responses than stimulation in or near grey matter. The stimulation location-response curves followed different trends for cingulate, lateral frontal, and lateral temporal cortical stimulation. These results demonstrate that a stronger local response may require stimulation in the grey-white boundary while stimulation in the white matter could be needed for network activation. Thus, stimulation parameters tailored for a specific anatomical-functional outcome may be key to advancing neuromodulatory therapy. • Intracranial single pulse electrical stimulation (SPES) response increases with increased pulse duration near stimulation. • SPES response varies nonlinearly with injected current with an effect of distance from the stimulation site. • SPES near the grey-white boundary has larger local responses, but white matter stimulation induces larger distant responses. • The relationship between SPES location and responses depends on brain region stimulated. [ABSTRACT FROM AUTHOR]

The use of transcranial Direct Current Stimulation (tDCS) to study anatomical and physiological dynamics and circuits supporting cognition and executive functions in particular has dramatically increased in recent years. However, its mechanisms of action remain only partially understood. In this study we assess the cognitive and physiological effects of anodal tDCS to the DLPFC on executive function in order to understand (1) the role of DLPFC laterality, (2) the physiological dynamics sustaining the modulation of executive function by tDCS, and (3) the impact of state-dependent dynamics. In a randomized, placebo-controlled, cross-over study, we applied anodal tDCS targeting the left vs. right DLPFC vs. sham in 20 healthy individuals (10 males, 10 females). Immediately before and after tDCS, subjects performed the Flanker Task while we measured behavioral (reaction time and accuracy) and neurophysiological (ERP) responses. Specifically, the amplitude of N200, P300, ERN and Pe is compared before and after stimulation. Anodal tDCS to the left DLPFC lead to a significant improvement in reaction time, an increase in P300 amplitude and a decrease in N200 amplitude in a state-dependent manner: baseline ERP amplitudes conditioned the effects of tDCS. Given the role of these ERPs in conflict-related tasks, we speculate that tDCS is modulating the subconstructs of selective attention, conflict monitoring and response inhibition. These findings contribute to a further understanding of the role of left DLPFC in the modulation of executive function, and shed light into the mechanisms of action and the state dependent nature of tDCS. • Anodal tDCS to the left DLPFC leads to faster reaction times in the Flanker task. • Cognitive improvement is correlated with changes in N200 and P300 amplitudes. • Baseline physiology predicts cognitive and physiological effects of tDCS. • N200 and P300 amplitudes correlate with reaction time on a trial by trial basis. [ABSTRACT FROM AUTHOR]

Electrical neuromodulation via implanted electrodes is used in treating numerous neurological disorders, yet our knowledge of how different brain regions respond to varying stimulation parameters is sparse. We hypothesized that the neural response to electrical stimulation is both region-specific and non-linearly related to amplitude and frequency. We examined evoked neural responses following 400 ms trains of 10–400 Hz electrical stimulation ranging from 0.1 to 10 mA. We stimulated electrodes implanted in cingulate cortex (dorsal anterior cingulate and rostral anterior cingulate) and subcortical regions (nucleus accumbens, amygdala) of non-human primates (NHP, N = 4) and patients with intractable epilepsy (N = 15) being monitored via intracranial electrodes. Recordings were performed in prefrontal, subcortical, and temporal lobe locations. In subcortical regions as well as dorsal and rostral anterior cingulate cortex, response waveforms depended non-linearly on frequency (Pearson's linear correlation r < 0.39), but linearly on current (r > 0.58). These relationships between location, and input-output characteristics were similar in homologous brain regions with average Pearson's linear correlation values r > 0.75 between species and linear correlation values between participants r > 0.75 across frequency and current values per brain region. Evoked waveforms could be described by three main principal components (PCs) which allowed us to successfully predict response waveforms across individuals and across frequencies using PC strengths as functions of current and frequency using brain region specific regression models. These results provide a framework for creation of an atlas of input-output relationships which could be used in the principled selection of stimulation parameters per brain region. • Stimulation response varies nonlinearly with stimulation frequency. • Response properties are region specific, conserved across individuals and species. • An 'atlas' of response characteristics can aid design of neuromodulation systems. [ABSTRACT FROM AUTHOR]

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

Transcranial electrical stimulation (TES) is a proposed tool for noninvasively modulating human brain circuits, but its ability to affect cortical physiology remains unclear. A recent study merged TES with live animal and human cadaveric recordings to verify intracranial electrical effects, then used these findings to develop a novel neuromodulation protocol. [ABSTRACT FROM AUTHOR]

Abstract: Conductive polymers from the polythiophene (PT) family have attracted interest in numerous domains, including potential applications in biosensing. Despite this, atomistic simulations of PTs have tended to use general organic force fields without well-tuned PT parameters, and there exists no optimized and well-validated PT force field that is compatible and consistent with existing biomolecular simulation suites. We present here the development of a new PT forcefield following the AMBER approach, using the program ANTECHAMBER and ab initio calculations at the HF/6-31G* level of theory to assign partial charges and parameterize the critical backbone torsion potential. The optimized geometries and force field potentials match well with both empirical data and previous investigators’ calculations. Initial testing of these parameters through a series of replica exchange simulations of two PT derivatives in aqueous and organic implicit solvents demonstrates that the parameters can match empirical expectations within the limits of an implicit solvent model. This new force field forms a framework for modeling of proposed PT-based devices and sensors, and is expected to accelerate device design and eventual deployment. [Copyright &y& Elsevier]

Abstract: Objectives: This paper reports on a study of involuntarily childless Indian women/couples seeking in vitro fertilisation (IVF). The focus is on the social context of infertility and on women''s perceptions of and experiences with IVF. Methods: Twenty-two childless women/couples who sought IVF. The sample was drawn from consenting clients of clinics in two major Indian cities, viz. New Delhi and Mumbai. Result: In-depth interviews revealed that infertility is deeply feared, women''s status and security are affected, and they experience stigmatisation and isolation. IVF was pursued after less intrusive avenues had been exhausted. Inadequate information/counselling is provided, success rates are low, IVF is commercialised and the process is physiologically, emotionally and financially stressful. Conclusion: In Indian society fertility defines womanhood and motherhood, and infertility is stigmatised. Women faced a lot of pressures to produce a biological child, and go through all kinds of treatments, including the expensive ARTs, to have a child. Practice implications: Integration of infertility services into the state''s reproductive health programme and disseminate information on infertility and to offer other appropriate choices, such as adoption. Effective counselling on coping with psychosocial/sexual problems. Monitoring of the prevalence of sex preselection. [Copyright &y& Elsevier]

Abstract: There has been a surge of interest in biomarkers that can rapidly predict or assess response to psychiatric treatment, as the current standard practice of extended therapeutic trials is often dissatisfying to both clinicians and patients. Electroencephalographic (EEG) biomarkers in particular have been proposed as an inexpensive yet rapid way of determining whether a patient is responding to an intervention, usually before subjective mood improvement occurs. However, even the most well-reported EEG algorithms have not been subjected to independent replication, limiting their clinical generalizability. It is also unclear whether those biomarkers can generalize beyond their original study population, e.g. to patients undergoing somatic treatments for depression. We report here analysis of EEG data from the pivotal OPT-TMS study of transcranial magnetic stimulation (rTMS) for major depressive disorder. In this dataset, previously reported biomarkers of medication response showed no significant correlation with eventual response to rTMS treatment. Furthermore, EEG power in multiple bands measured at baseline and throughout the treatment course did not correlate with or predict either binary (response/nonresponse) or continuous (Hamilton Rating Scale for Depression) outcome measures. While somewhat limited by technical difficulties in data collection, these analyses are adequately powered to detect clinically relevant biomarkers. We believe this highlights a need for wider-scale independent replication of previous EEG biomarkers, both in pharmacotherapy and neuromodulation. [Copyright &y& Elsevier]

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. A systematic review was conducted to characterize the current use and efficacy of social media in recruiting participants for mental health research. 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. 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). 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. • Social media is increasingly employedin mental health research recruitment. • Compared to traditional methods, social media recruitment offers advantages in cost, speed, and efficiency. • Minimal federal guidance exists in using social media for recruitmentto avoid privacy violations. [ABSTRACT FROM AUTHOR]

Background: Western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs.Methods: The WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Eligible participants were healthy adults aged 18-50 years with no previous vaccination history with an investigational alphavirus vaccine. Participants were assigned to a dose group of 6 μg, 30 μg, or 60 μg vaccine product and were randomly assigned (1:1) to receive the WEVEE VLP vaccine with or without aluminium hydroxide suspension (alum) adjuvant by intramuscular injection at study day 0 and at week 8. The primary outcomes were the safety and tolerability of the vaccine (assessed in all participants who received at least one administration of study product) and the secondary outcome was immune response measured as neutralising titres by plaque reduction neutralisation test (PRNT) 4 weeks after the second vaccination. This trial is registered at ClinicalTrials.gov, NCT03879603.Findings: Between April 2, 2019, and June 13, 2019, 30 trial participants were enrolled (mean age 32 years, range 21-48; 16 [53%] female participants and 14 [47%] male participants). Six groups of five participants each received 6 μg, 30 μg, or 60 μg vaccine doses with or without adjuvant, and all 30 participants completed study follow-up. Vaccinations were safe and well tolerated. The most frequently reported symptoms were mild injection-site pain and tenderness (22 [73%] of 30) and malaise (15 [50%] of 30). Dose-dependent differences in the frequency of pain and tenderness were found between the 6 μg, 30 μg, and 60 μg groups (p=0·0217). No significant differences were observed between dosing groups for any other reactogenicity symptom. Two adverse events (mild elevated blood pressure and moderate asymptomatic neutropenia) were assessed as possibly related to the study product in one trial participant (60 μg dose with alum); both resolved without clinical sequelae. 4 weeks after second vaccine administration, neutralising antibodies were induced in all study groups with the highest response seen against all three vaccine antigens in the 30 μg plus alum group (PRNT80 geometric mean titre for EEEV 60·8, 95% CI 29·9-124·0; for VEEV 111·5, 49·8-249·8; and for WEEV 187·9, 90·0-392·2). Finally, 4 weeks after second vaccine administration, for all doses, the majority of trial participants developed an immune response to all three vaccine components (24 [83%] of 29 for EEEV; 26 [90%] of 29 for VEEV; 27 [93%] of 29 for WEEV; and 22 [76%] of 29 for EEEV, VEEV, and WEEV combined).Interpretation: The favourable safety profile and neutralising antibody responses, along with pressing public health need, support further evaluation of the WEVEE VLP vaccine in advanced-phase clinical trials.Funding: The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health funded the clinical trial. The US Department of Defense contributed funding for manufacturing of the study product. [ABSTRACT FROM AUTHOR]

Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction – primarily rodent extinction – have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction. • Impaired threat extinction may contribute to exposure-based treatment failure. • Efforts to strengthen exposure-based therapy response by boosting threat extinction have largely fallen short. • Preclinical studies that apply TMS and DBS during specific threat extinction/reconsolidation stages could inform the integration of circuit-based treatments with exposure-based therapy. [ABSTRACT FROM AUTHOR]

Closing the loop between brain activity and behavior is one of the most active areas of development in neuroscience. There is particular interest in developing closed-loop control of neural oscillations. Many studies report correlations between oscillations and functional processes. Oscillation-informed closed-loop experiments might determine whether these relationships are causal and would provide important mechanistic insights which may lead to new therapeutic tools. These closed-loop perturbations require accurate estimates of oscillatory phase and amplitude, which are challenging to compute in real time. We developed an easy to implement, fast and accurate Toolkit for Oscillatory Real-time Tracking and Estimation (TORTE). TORTE operates with the open-source Open Ephys GUI (OEGUI) system, making it immediately compatible with a wide range of acquisition systems and experimental preparations. TORTE efficiently extracts oscillatory phase and amplitude from a target signal and includes a variety of options to trigger closed-loop perturbations. Implementing these tools into existing experiments is easy and adds minimal latency to existing protocols. Most labs use in-house lab-specific approaches, limiting replication and extension of their experiments by other groups. Accuracy of the extracted analytic signal and accuracy of oscillation-informed perturbations with TORTE match presented results by these groups. However, TORTE provides access to these tools in a flexible, easy to use toolkit without requiring proprietary software. We hope that the availability of a high-quality, open-source, and broadly applicable toolkit will increase the number of labs able to perform oscillatory closed-loop experiments, and will improve the replicability of protocols and data across labs. [Display omitted] • TORTE provides a toolkit to investigate closed loop oscillation-informed experiments. • The toolkit is versatile and open-source promoting replicability across scientists. • The analytic signal algorithm within TORTE preforms equally to existing algorithms. [ABSTRACT FROM AUTHOR]