A phase I trial of accelerated intermittent theta burst rTMS for amnestic MCI.

BACKGROUND: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) enhances cognition in mild cognitive impairment (MCI). Accelerated intermittent theta burst stimulation (iTBS) rTMS protocols are promising as they substantially reduce burden by shortening the treatment course, but the safety, feasibility, and acceptability of iTBS have not been established in MCI. METHODS: 24 older adults with amnestic MCI (aMCI) due to possible Alzheimer's disease enrolled in a phase I trial of open-label accelerated iTBS to the left dorsolateral prefrontal cortex (8 stimulation sessions of 600 pulses of iTBS/day for 3 days). Participants rated common side effects during and after each session and retrospectively (at post-treatment and 4-week follow-up). They completed brain MRI (for safety assessments and electric field modeling), neuropsychiatric evaluations, and neuropsychological testing before and after treatment; a subset of measures was administered at follow-up. RESULTS: Retention was high (95%) and there were no adverse neuroradiological, neuropsychiatric, or neurocognitive effects of treatment. Participants reported high acceptability, minimal side effects, and low desire to quit despite some rating the treatment as tiring. Electric field modeling data suggest that all participants received safe and therapeutic cortical stimulation intensities. We observed a significant, large effect size (d=0.98) improvement in fluid cognition using the NIH Toolbox Cognition Battery from pre-treatment to post-treatment. CONCLUSIONS: Our findings support the safety, feasibility, and acceptability of accelerated iTBS in aMCI. In addition, we provide evidence of target engagement in the form of improved cognition following treatment. These promising results directly inform future trials aimed at optimizing treatment parameters. TRIAL REGISTRATION NUMBER: NCT04503096.

Who tests for lead and why? A 10-year analysis of blood lead screening, follow-up and CNS outcomes in a statewide US healthcare system.

OBJECTIVES: This study aims to determine (1) which providers in US healthcare systems order lead tests, why and at what frequency and (2) whether current patient population lead levels are predictive of clinical outcomes. METHODS: Retrospective medical record study of all blood lead tests in the Medical University of South Carolina healthcare system 2012-2016 and consequent evidence of central nervous system (CNS)-related disease across a potential 10-year window (2012-2022). RESULTS: Across 4 years, 9726 lead tests resulted for 7181 patients (49.0% female; 0-94 years), representing 0.2% of the hospital population. Most tests were for young (76.6%≤age 3) and non-Hispanic black (47.2%) and Hispanic (26.7%) patients. A wide variety of providers ordered tests; however, most were ordered by paediatrics, psychiatry, internal medicine and neurology. Lead levels ranged from ≤2.0 µg/dL (80.8%) to ≥10 µg/dL (0.8%; max 36 µg/dL). 201 children (3.1%) had initial lead levels over the reference value for case management at the time (5.0 µg/dL). Many high level children did not receive follow-up testing in the system (36.3%) and those that did often failed to see levels fall below 5.0 µg/dL (80.1%). Non-Hispanic black and Hispanic patients were more likely to see lead levels stay high or go up over time. Over follow-up, children with high lead levels were more likely to receive new attention-deficit/hyperactivity disorder and conduct disorder diagnoses and new psychiatric medications. No significant associations were found between lead test results and new CNS diagnoses or medications among adults. CONCLUSIONS: Hospital lead testing covers a small portion of patients but includes a wide range of ages, presentations and provider specialities. Lack of lead decline among many paediatric patients suggests there is room to improve provider guidance around when to test and follow-up.

Neurophysiology of predictable unpleasant event processing in pre-adolescents and early adolescents, part II: Reflex and event-related potential markers of defensive reactivity and peripheral attention modulation.

The ability to anticipate and process predictable unpleasant events, while also regulating emotional reactivity, is an adaptive skill. The current article and a companion in this issue test for potential changes in predictable event processing across the childhood-to-adolescence transition, a key developmental period for biological systems that support cognitive/ emotional abilities. While the companion article focuses on neurophysiology of predictable event processing itself, the present article examines peripheral emotional response regulation and attention modulation that coincides with event processing. A total of 315 third-, sixth-, or ninth-grade individuals saw 5-s cues predicting "scary," "every day," or uncertain pictures, and here, blink reflexes and brain event-related potentials (ERPs) elicited by peripheral noise probes are analyzed. During the cue, blink reflexes and probe ERP (P200) amplitudes were increased when the cue predicted scary, compared to everyday, content. After picture onset, reflex enhancement by scary content then disappeared for predictable images, whereas ERP modulation was similar regardless of predictability. Patterns are similar to those in adults and suggest (1) sustained defensive response priming and enhancement of peripheral attention during aversive anticipation, and (2) an ability, even in pre-adolescents, to downregulate defensive priming while maintaining attentional modulation once an awaited predictable aversive event occurs.

Neurophysiology of predictable unpleasant event processing in preadolescents and early adolescents, part I: Event-related potential markers of unpleasant image anticipation and processing.

The ability to anticipate and process predictable unpleasant events, while also regulating emotional reactivity, is an adaptive skill. The current article and a companion in this issue test for potential changes in predictable event processing across the childhood-to-adolescence transition, a key developmental period for biological systems that support cognitive/emotional abilities. While the companion article focuses on emotion regulation and peripheral attention modulation in predictable unpleasant contexts, the current paper presents neurophysiological markers of predictable event processing itself. 315 third-, sixth-, or ninth-grade individuals saw 5-s cues predicting "scary," "every day," or uncertain image content; in this paper, cue- and picture-locked event-related potentials (ERPs) are analyzed. During the cue, early ERP positivities were increased and later slow-wave negativities were reduced when predicted content was scary as compared with mundane. After picture onset, a picture processing-related positivity was then increased for scary compared with everyday images regardless of predictability. Cue-interval data suggest enhanced processing of scary cues and reduced anticipatory processing of scary images-opposite to adults. After event onset, meanwhile, emotional ERP enhancement regardless of predictability is similar to adults and suggests that even preadolescent individuals maintain preferential engagement with unpleasant events when they are predictable.

Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

Anxiety-related shifts in smell function in children and adolescents.

Anxious adults show changes in smell function that are consistent with a durable shift in sensitivity toward particular odorants and away from others. Little is known regarding the development of these changes, including whether they exist in youth, are stable during the transition from childhood to adolescence, and whether odorant properties (e.g. trigeminal features, hedonic valence) affect anxiety-related differences in detection. To address this, we measured smell detection thresholds to phenyl ethyl alanine (PEA), a rose-like odorant with little trigeminal properties, and guaiacol (GUA), a smoke-like odorant with high trigeminal properties. These thresholds were measured at baseline and after an acute stress challenge, the Trier Social Stress Tests, in 131 healthy youth (in 4th, 7th, and 10th grades, age 9-16 years) that reported normal to elevated levels of anxiety. At baseline, high anxious youth exhibited heightened sensitivity to GUA coupled with reduced sensitivity to PEA, as well as a further exaggeration of this bias with acute stress. Importantly, sex, age, and hedonic valence moderated the relationship between trait anxiety and sensitivity to both odorants. Smell function and its aberrations are often overlooked in the literature on biomarkers of stress and anxiety. Taken together with the extant literature, these findings suggest that greater attention is warranted to characterize potential novel olfactory therapeutic targets-across the lifespan.

Transcranial magnetic stimulation of the dorsal lateral prefrontal cortex inhibits medial orbitofrontal activity in smokers.

BACKGROUND AND OBJECTIVE: Several studies have shown that repetitive transcranial magnetic stimulation (rTMS), applied to the dorsolateral prefrontal cortex (DLPFC), can reduce cue-elicited craving in smokers. Currently, the mechanism of this effect is unknown. We used functional magnetic resonance imaging (fMRI) to explore the effect of a single treatment of rTMS on cortical and sub-cortical neural activity in non-treatment seeking nicotine-dependent participants. METHODS: We conducted a randomized, counterbalanced, crossover trial in which participants attended two experimental visits separated by at least 1 week. On the first visit, participants received either active, or sham rTMS (10 Hz, 5 s-on, 10 s-off, 100% motor threshold, 3,000 pulses) over the left DLPFC, and on the second visit they received the opposite condition (active or sham). Cue craving fMRI scans were completed before and after each rTMS session. RESULTS: A total of 11 non-treatment seeking nicotine-dependent cigarette smokers were enrolled in the study [six female, average age 39.7 ± 13.2, average cigarettes per day 17.3 ± 5.9]. Active rTMS decreased activity in the contralateral medial orbitofrontal cortex (mOFC) and ipsilateral nucleus accumbens (NAc) compared to sham rTMS. CONCLUSIONS: This preliminary data suggests that one session of rTMS applied to the DLPFC decreases brain activity in the NAc and mOFC in smokers. SCIENTIFIC SIGNIFICANCE: rTMS may exert its anti-craving effect by decreasing activity in the NAc and mOFC in smokers. Despite a small sample size, these findings warrant future rTMS/fMRI studies in addictions. (Am J Addict 2017;26:788-794).

COGNITION-CHILDHOOD MALTREATMENT INTERACTIONS IN THE PREDICTION OF ANTIDEPRESSANT OUTCOMES IN MAJOR DEPRESSIVE DISORDER PATIENTS: RESULTS FROM THE iSPOT-D TRIAL.

BACKGROUND: Childhood maltreatment (CM) history has been associated with poor treatment response in major depressive disorder (MDD), but the mechanisms underlying this relationship remain opaque. Dysfunction in the neural circuits for executive cognition is a putative neurobiological consequence of CM that may contribute importantly to adverse clinical outcomes. We used behavioral and neuroimaging measures of executive functioning to assess their contribution to the relationship between CM and antidepressant response in MDD patients. METHODS: Ninety eight medication-free MDD outpatients participating in the International Study to Predict Optimized Treatment in Depression were assessed at baseline on behavioral neurocognitive measures and functional magnetic resonance imaging during tasks probing working memory (continuous performance task, CPT) and inhibition (Go/No-go). Seventy seven patients completed 8 weeks of antidepressant treatment. Baseline behavioral and neuroimaging measures were assessed in relation to CM (history of childhood physical, sexual, and/or emotional abuse) and posttreatment depression outcomes. RESULTS: Patients with maltreatment exhibited decreased modulation of right dorsolateral prefrontal cortex (DLPFC) activity during working memory updating on the CPT, and a corresponding impairment in CPT behavioral performance outside the scanner. No between-group differences were found for imaging or behavior on the Go/No-go test of inhibition. Greater DLPFC activity during CPT significantly predicted posttreatment symptom improvement in patients without maltreatment, whereas the relationship between DLPFC activity and symptom change was nonsignificant, and in the opposite direction, in patients with maltreatment. CONCLUSIONS: The effect of CM on prefrontal circuitry involved in executive function is a potential predictor of antidepressant outcomes.

Systematic Evaluation of the Effects of Voluntary Activation on Lower Extremity Motor Thresholds.

The purpose of this investigation was to elucidate the relationship between the resting motor threshold (rMT) and active motor threshold (aMT). A cross-sectional comparison of MTs measured at four states of lower extremity muscle activation was conducted: resting, 5% maximal voluntary contraction (MVC), 10%MVC, and standing. MTs were measured at the tibialis anterior in the ipsilesional and contralesional limbs in participants in the chronic phase (>6 months) of stroke (n = 11) and in the dominant limb of healthy controls (n = 11). To compare across activation levels, the responses were standardized using averaged peak-to-peak background electromyography (EMG) activity measured at 10%MVC + 2SD for each participant, in addition to the traditional 0.05 mV criterion for rMT (rMT50). In all participants, as muscle activation increased, the least square mean estimates of MTs decreased (contralesional: p = 0.008; ipsilesional: p = 0.0015, healthy dominant: p < 0.0001). In healthy controls, rMT50 was significantly different from all other MTs (p < 0.0344), while in stroke, there were no differences in either limb (p > 0.10). This investigation highlights the relationship between rMT and aMTs, which is important as many stroke survivors do not present with an rMT, necessitating the use of an aMT. Future works may consider the use of the standardized criterion that accounted for background EMG activity across activation levels.

Coping in the Clinic: Effects of Clinically Elevated Anxiety on Dynamic Neurophysiological Mechanisms of Escape/Avoidance Preparation.

BACKGROUND: Treatments for anxiety and related disorders target exaggerated escape/avoidance as a core feature, but current methods fail to improve escape/avoidance habits for many treatment-seeking individuals. To support developing tools that increase treatment efficacy by targeting mechanisms more directly, the current work examined potential distinctions in the neurophysiologies of escape and avoidance and tested how clinical anxiety affects these neurophysiologies. METHODS: Twenty-five treatment-seeking individuals with varied principal diagnoses (e.g., generalized anxiety disorder, posttraumatic stress disorder) and 20 non-treatment-seeking control subjects participated. In the study task, approximately 5.25-second cues predicted aversive images that could be avoided (blocked by a button press before image onset), escaped (ended by a button press after image onset), or not controlled. To examine neural processing and defensive response modulation, anticipatory event-related potentials were derived, and startle reflexes were probed throughout each cue. RESULTS: Multidimensional profiles were observed such that 1) anticipatory event-related potential enhancement was only reliable during avoidance preparation, and event-related potentials potentially reflected perceived/instrumental control; and 2) startle reflexes were inhibited during avoidance preparation, relatively enhanced during escape preparation, and further enhanced during uncontrollable anticipation, thus potentially reflecting fear-related activation. Treatment-seeking status, then, did not affect cortical processing, but it did moderate context-dependent fear (if individuals with severe depression were excluded) such that treatment-seeking individuals without depression showed exaggerated startle during escape, but not avoidance, preparation. CONCLUSIONS: Data suggest a specific effect of anxiety on fear system activation during preparation to escape aversion. This effect warrants further investigation as a precision target for interventions that directly modulate the specific underlying neural circuitry.

Template MRI scans reliably approximate individual and group-level tES and TMS electric fields induced in motor and prefrontal circuits.

Background: Electric field (E-field) modeling is a valuable method of elucidating the cortical target engagement from transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), but it is typically dependent on individual MRI scans. In this study, we systematically tested whether E-field models in template MNI-152 and Ernie scans can reliably approximate group-level E-fields induced in N = 195 individuals across 5 diagnoses (healthy, alcohol use disorder, tobacco use disorder, anxiety, depression). Methods: We computed 788 E-field models using the CHARM-SimNIBS 4.0.0 pipeline with 4 E-field models per participant (motor and prefrontal targets for TMS and tES). We additionally calculated permutation analyses to determine the point of stability of E-fields to assess whether the 152 brains represented in the MNI-152 template is sufficient. Results: Group-level E-fields did not significantly differ between the individual vs. MNI-152 template and Ernie scans for any stimulation modality or location (p > 0.05). However, TMS-induced E-field magnitudes significantly varied by diagnosis; individuals with generalized anxiety had significantly higher prefrontal and motor E-field magnitudes than healthy controls and those with alcohol use disorder and depression (p < 0.001). The point of stability for group-level E-field magnitudes ranged from 42 (motor tES) to 52 participants (prefrontal TMS). Conclusion: MNI-152 and Ernie models reliably estimate group-average TMS and tES-induced E-fields transdiagnostically. The MNI-152 template includes sufficient scans to control for interindividual anatomical differences (i.e., above the point of stability). Taken together, using the MNI-152 and Ernie brains to approximate group-level E-fields is a valid and reliable approach.

The anxiety spectrum and the reflex physiology of defense: from circumscribed fear to broad distress.

Guided by the diagnostic nosology, anxiety patients are expected to show defensive hyperarousal during affective challenge, irrespective of the principal phenotype. In the current study, patients representing the whole spectrum of anxiety disorders (i.e., specific phobia, social phobia, panic disorder with or without agoraphobia, obsessive-compulsive disorder, generalized anxiety disorder (GAD), posttraumatic stress disorder(PTSD)), and healthy community control participants, completed an imagery-based fear elicitation paradigm paralleling conventional intervention techniques. Participants imagined threatening and neutral narratives as physiological responses were recorded. Clear evidence emerged for exaggerated reactivity to clinically relevant imagery--most pronounced in startle reflex responding. However, defensive propensity varied across principal anxiety disorders. Disorders characterized by focal fear and impairment (e.g., specific phobia) showed robust fear potentiation. Conversely, for disorders of long-enduring, pervasive apprehension and avoidance with broad anxiety and depression comorbidity (e.g., PTSD secondary to cumulative trauma, GAD), startle responses were paradoxically diminished to all aversive contents. Patients whose expressed symptom profiles were intermediate between focal fearfulness and broad anxious-misery in both severity and chronicity exhibited a still heightened but more generalized physiological propensity to respond defensively. Importantly, this defensive physiological gradient--the inverse of self-reported distress--was evident not only between but also within disorders. These results highlight that fear circuitry could be dysregulated in chronic, pervasive anxiety, and preliminary functional neuroimaging findings suggest that deficient amygdala recruitment could underlie attenuated reflex responding. In summary, adaptive defensive engagement during imagery may be compromised by long-term dysphoria and stress-a phenomenon with implications for prognosis and treatment planning.

A transdiagnostic review of safety, efficacy, and parameter space in accelerated transcranial magnetic stimulation.

BACKGROUND: Accelerated transcranial magnetic stimulation (aTMS) is an emerging delivery schedule of repetitive TMS (rTMS). TMS is "accelerated" by applying two or more stimulation sessions within a day. This three-part review comprehensively reports the safety/tolerability, efficacy, and stimulation parameters affecting response across disorders. METHODS: We used the PubMed database to identify studies administering aTMS, which we defined as applying at least two rTMS sessions within one day. RESULTS: Our targeted literature search identified 85 aTMS studies across 18 diagnostic and healthy control groups published from July 2001 to June 2022. Excluding overlapping populations, 63 studies delivered 43,873 aTMS sessions using low frequency, high frequency, and theta burst stimulation in 1543 participants. Regarding safety, aTMS studies had similar seizure and side effect incidence rates to those reported for once daily rTMS. One seizure was reported from aTMS (0.0023% of aTMS sessions, compared with 0.0075% in once daily rTMS). The most common side effects were acute headache (28.4%), fatigue (8.6%), and scalp discomfort (8.3%), with all others under 5%. We evaluated aTMS efficacy in 23 depression studies (the condition with the most studies), finding an average response rate of 42.4% and remission rate of 28.4% (range = 0-90.5% for both). Regarding parameters, aTMS studies ranged from 2 to 10 sessions per day over 2-30 treatment days, 10-640 min between sessions, and a total of 9-104 total accelerated TMS sessions per participant (including tapering sessions). Qualitatively, response rate tends to be higher with an increasing number of sessions per day, total sessions, and total pulses. DISCUSSION: The literature to date suggests that aTMS is safe and well-tolerated across conditions. Taken together, these early studies suggest potential effectiveness even in highly treatment refractory conditions with the added potential to reduce patient burden while also expediting response time. Future studies are warranted to systematically investigate how key aTMS parameters affect treatment outcome and durability.

Neuronavigation maximizes accuracy and precision in TMS positioning: Evidence from 11,230 distance, angle, and electric field modeling measurements.

BACKGROUND: Researchers and clinicians have traditionally relied on elastic caps with markings to reposition the transcranial magnetic stimulation (TMS) coil between trains and sessions. Newer neuronavigation technology co-registers the patient's head and structural magnetic resonance imaging (MRI) scan, providing the researcher with real-time feedback about how to adjust the coil to be on-target. However, there has been no head to head comparison of accuracy and precision across treatment sessions. OBJECTIVE: /Hypothesis: In this two-part study, we compared elastic cap and neuronavigation targeting methodologies on distance, angle, and electric field (E-field) magnitude values. METHODS: In 42 participants receiving up to 50 total accelerated rTMS sessions in 5 days, we compared cap and neuronavigation targeting approaches in 3408 distance and 6816 angle measurements. In Experiment 1, TMS administrators saved an on-target neuronavigation location at Beam F3, which served as the landmark for all other measurements. Next, the operators placed the TMS coil based on cap markings or neuronavigation software to measure the distance and angle differences from the on-target sample. In Experiment 2, we saved each XYZ coordinate of the TMS coil from cap and neuronavigation targeting in 12 participants to compare the E-field magnitude differences at the cortical prefrontal target in 1106 cap and neuronavigation models. RESULTS: Cap targeting was significantly off-target for distance, placing the coil an average of 10.66 mm off-target (Standard error of the mean; SEM = 0.19 mm) compared to 0.3 mm (SEM = 0.03 mm) for neuronavigation (p < 0.0001). Cap targeting also significantly deviated for angles off-target, averaging 7.79 roll/pitch degrees (SEM = 1.07°) off-target and 5.99 yaw degrees (SEM = 0.12°) off-target; in comparison, neuronavigation targeting positioned the coil 0.34 roll/pitch degrees (SEM = 0.01°) and 0.22 yaw (SEM = 0.004°) off-target (both p < 0.0001). Further analyses revealed that there were significant inter-operator differences on distance and angle positioning for F3 (all p < 0.05), but not neuronavigation. Lastly, cap targeting resulted in significantly lower E-fields at the intended prefrontal cortical target, with equivalent E-fields as 110.7% motor threshold (MT; range = 58.3-127.4%) stimulation vs. 119.9% MT (range = 115-123.3%) from neuronavigated targeting with 120% MT stimulation applied (p < 0.001). CONCLUSIONS: Cap-based targeting is an inherent source of target variability compared to neuronavigation. Additionally, cap-based coil placement is more prone to differences across operators. Off-target coil placement secondary to cap-based measurements results in significantly lower amounts of stimulation reaching the cortical target, with some individuals receiving only 48.6% of the intended on-target E-field. Neuronavigation technology enables more precise and accurate TMS positioning, resulting in the intended stimulation intensities at the targeted cortical level.

DLPFC stimulation alters working memory related activations and performance: An interleaved TMS-fMRI study.

BACKGROUND: Findings from correlative neuroimaging studies link increased frontoparietal network (FPN) activation and default mode network (DMN) deactivation to enhanced high cognitive demand processing. To causally investigate FPN-DMN contributions to high cognitive demand processing, the current interleaved TMS-fMRI study simultaneously manipulated and indexed neural activity while tracking cognitive performance during high and low cognitive load conditions. METHODS: Twenty participants completed an n-back task consisting of four conditions (0-back, 0-backTMS, 2-back, 2-backTMS) while undergoing interleaved TMS-fMRI. During TMS concurrent with n-back blocks, TMS single pulses were delivered to the left DLPFC at 100% motor-threshold every 2.4s. RESULTS: TMS delivered during high cognitive load strengthened cognitive processing. FPN node activations and DMN node deactivations were increased in the high versus low cognitive load TMS condition. Contrary to our hypothesis, TMS did not increase high load related activation in FPN nodes. However, as hypothesized, increased DMN node deactivations emerged as a function of TMS during high load (right angular gyrus) and from interactions between cognitive load and TMS (right middle temporal gyrus). Load and TMS combined to dampen activation within the DMN at trend level (p = .058). Deactivation in a dorsomedial DMN node was associated with TMS driven improvements in high load cognitive processing. CONCLUSIONS: Exogenous perturbation of the DLPFC via single pulse TMS amplified DMN node deactivations and enhanced high cognitive demand processing. Neurobehavioral findings linking these effects hint at a promising, albeit preliminary, cognitive control substrate requiring replication in higher-powered studies that use control stimulation.

Electrical stimulation of the trigeminal nerve improves olfaction in healthy individuals: A randomized, double-blind, sham-controlled trial.

BACKGROUND: Both activated by environmental odorants, there is a clear role for the intranasal trigeminal and olfactory nerves in smell function. Unfortunately, our ability to perceive odorants decreases with age or with injury, and limited interventions are available to treat smell loss. OBJECTIVE: We investigated whether electrical stimulation of the trigeminal nerve via trigeminal nerve stimulation (TNS) or transcranial direct current stimulation (tDCS) modulates odor sensitivity in healthy individuals. METHODS: We recruited 20 healthy adults (12 Female, mean age = 27) to participate in this three-visit, randomized, double-blind, sham-controlled trial. Participants were randomized to receive one of three stimulation modalities (TNS, tDCS, or sham) during each of their visits. Odor detection thresholds were obtained at baseline, immediately post-intervention, and 30-min post-intervention. Furthermore, participants were asked to complete a sustained attention task and mood assessments before odor detection testing. RESULTS: Findings reveal a timeXcondition interaction for guaiacol (GUA) odorant detection thresholds (F (3.188, 60.57) = 3.833, P = 0.0125), but not phenyl ethyl alcohol (PEA) odorant thresholds. At 30-min post-stimulation, both active TNS and active tDCS showed significantly increased sensitivity to GUA compared to sham TNS (Sham TNS = -8.30% vs. Active TNS = 9.11%, mean difference 17.43%, 95% CI 5.674 to 29.18, p = 0.0044; Sham TNS = -8.30% vs. Active tDCS = 13.58%, mean difference 21.89%, 95% CI 10.47 to 33.32, p = 0.0004). CONCLUSION: TNS is a safe, simple, noninvasive method for boosting olfaction. Future studies should investigate the use of TNS on smell function across different stimulation parameters, odorants, and patient populations.

Enhancing Prolonged Exposure therapy for PTSD using physiological biomarker-driven technology.

Prolonged Exposure (PE) therapy is one of the most efficacious, evidence-based treatments for posttraumatic stress disorder (PTSD). A key component of PE involves in vivo exposures (IVEs) during which patients approach situations or activities in "real life" that are safe but avoided because they elicit a fear response. Despite their critical role in treatment, little research has focused on IVEs. This gap in knowledge is primarily due to the fact that IVEs are typically conducted by patients in between therapy sessions, leaving clinicians reliant upon patient self-report. This approach has numerous shortcomings, which the current study addresses by leveraging technology to develop an innovative device that allows for physiological, biomarker-driven, therapist-guided IVEs. The new system enables clinicians to virtually accompany patients during IVEs and provides real-time physiological (heart rate, skin conductance) and self-report (subjective units of distress) data that clinicians can use to modify the exposure and optimize therapeutic value. This Small Business Innovation Research (SBIR) Phase I project aims to: (1) integrate physiological sensors and live audio/visual streaming into a system for clinicians to guide patients during IVEs; (2) determine feasibility and acceptability of the system; and (3) conduct a pilot randomized clinical trial among veterans with PTSD (N = 40) to evaluate the preliminary efficacy of the system in reducing PTSD symptoms during PE. This paper describes the rationale, design, and methodology of the Phase I project. The findings from this study have the potential to innovate clinical practice, advance the science of exposure therapy, and improve clinical outcomes.

Neurophysiologic Effects of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) via Electrical Stimulation of the Tragus: A Concurrent taVNS/fMRI Study and Review.

(Appeared originally in Brain Stimulation 2018; 11:492-500) Reprinted with permission from Elsevier.

Technology-enhanced in vivo exposures in Prolonged Exposure for PTSD: A pilot randomized controlled trial.

In vivo exposures (IVEs) are a key component of exposure-based treatments, during which patients approach fear-provoking, yet safe, situations in "real life." This pilot study assessed the use of a wearable technology (Bio Ware) during IVEs to enhance Prolonged Exposure (PE) therapy for PTSD. Bio Ware provides a clinician dashboard with real-time physiological and subjective data for clinicians to use for virtually guided IVEs. Participants (N = 40) were randomized to a Guided group that received standard PE and virtual, clinician-guided IVEs with the Bio Ware device, or a Non-Guided group that received standard PE and used the Bio Ware device on their own for IVEs. Multilevel linear models with bootstrapping were completed on the intent-to-treat (ITT; N = 39) and per-protocol samples (PP; n = 23), defined as completing at least eight sessions of PE and using the Bio Ware system during ≥ 1 IVEs. In the PP sample, there were significant effects of treatment condition (b = -14.55, SE = 1.47, 95% CI [-17.58, -11.78], p < .001) and time (b = -1.98, SE = 0.25, 95% CI [-2.47, -1.48], p < .001). While both groups showed reductions in PTSD symptoms, the Guided group evidenced significantly greater reductions than the Non-Guided group. These findings demonstrate the feasibility and safety of leveraging Bio Ware for virtual, clinician-guided IVEs during PE therapy for PTSD and suggest that virtual, clinician-guided exposures may enhance treatment outcomes. CLINICAL TRIAL REGISTRATION: NCT04471207.

Neighborhood Disadvantage Associated With Blunted Amygdala Reactivity to Predictable and Unpredictable Threat in a Community Sample of Youth.

BACKGROUND: Childhood socioeconomic disadvantage is a form of adversity associated with alterations in critical frontolimbic circuits involved in the pathophysiology of psychiatric disorders. Most work has focused on individual-level socioeconomic position, yet individuals living in deprived communities typically encounter additional environmental stressors that have unique effects on the brain and health outcomes. Notably, chronic and unpredictable stressors experienced in the everyday lives of youth living in disadvantaged neighborhoods may impact neural responsivity to uncertain threat. METHODS: A community sample of children (N = 254) ages 8 to 15 years (mean = 12.15) completed a picture anticipation task during a functional magnetic resonance imaging scan, during which neutral and negatively valenced photos were presented in a temporally predictable or unpredictable manner. Area Deprivation Index (ADI) scores were derived from participants' home addresses as an index of relative neighborhood disadvantage. Voxelwise analyses examined interactions of ADI, valence, and predictability on neural response to picture presentation. RESULTS: There was a significant ADI × valence interaction in the middle temporal gyrus, anterior cingulate cortex, hippocampus, and amygdala. Higher ADI was associated with less amygdala activation to negatively valenced images. ADI also interacted with predictability. Higher ADI was associated with greater activation of lingual and calcarine gyri for unpredictably presented stimuli. There was no three-way interaction of ADI, valence, and predictability. CONCLUSIONS: Neighborhood disadvantage may impact how the brain perceives and responds to potential threats. Future longitudinal work is critical for delineating how such effects may persist across the life span and how health outcomes may be modifiable with community-based interventions and policies.