Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Reciprocal and Indirect Effects Among Intervention, Perceived Social Support, and Anxiety Sensitivity Within a Randomized Controlled Trial for Anxiety Disorders.

Social support may facilitate adaptive reappraisal of stressors, including somatic symptoms. Anxiety sensitivity refers to negative beliefs about somatic symptoms of anxiety, which may influence one's perception of social support. Evidence-based treatment may impact these associations. The current longitudinal study evaluated reciprocal relationships between perceived social support and anxiety sensitivity, and explored indirect intervention effects, in a randomized controlled trial for anxiety disorders that compared cognitive behavioral therapy with or without medications (CALM) to usual care. Data collected over 18 months from 940 primary care patients were examined in random intercept cross-lagged panel models. There were significant reciprocal associations between perceived social support increases and anxiety sensitivity decreases over time. There were significant indirect effects from intervention to perceived social support increases through anxiety sensitivity decreases and from intervention to anxiety sensitivity decreases through perceived social support increases. These data suggest that, relative to usual care, CALM predicted changes in one construct, which predicted subsequent changes in the other. Secondary analyses revealed an influence of anxiety and depressive symptoms on reciprocal associations and indirect effects. Findings suggest that future treatments could specifically address perceived social support to enhance reappraisal of somatic symptoms, and vice versa.

Functional MRI Lateralization [M1] of dlPFC and Implications for Transcranial Magnetic Stimulation (TMS) Targeting.

The present study investigates a potential method of optimizing effective strategies for the functional lateralization of the dorsolateral prefrontal cortex (dlPFC) while in a scanner. Effective hemisphere lateralization of the dlPFC is crucial for lowering the functional risks connected to specific interventions (such as neurosurgery and transcranial magnetic stimulation (TMS), as well as increasing the effectiveness of a given intervention by figuring out the optimal location. This task combines elements of creative problem solving, executive decision making based on an internal rule set, and working memory. A retrospective analysis was performed on a total of 58 unique participants (34 males, 24 females, Mage = 42.93 years, SDage = 16.38). Of these participants, 47 were classified as right-handed, 7 were classified as left-handed, and 4 were classified as ambidextrous, according to the Edinburgh Handedness Inventory. The imaging data were qualitatively judged by two trained, blinded investigators (neurologist and neuropsychologist) for dominant handedness (primary motor cortex) and dominant dorsolateral prefrontal cortex (dlPFC). The results demonstrated that 21.4% of right-handed individuals showed a dominant dlPFC localized to the right hemisphere rather than the assumed left, and 16.7% of left-handers were dominant in their left hemisphere. The task completed in the scanner might be an efficient method for localizing a potential dlPFC target for the purpose of brain stimulation (e.g., TMS), though further study replications are needed to extend and validate these findings.

Mediators of Ethnic Differences in Dropout Rates From a Randomized Controlled Treatment Trial Among Latinx and Non-Latinx White Primary Care Patients With Anxiety Disorders.

ABSTRACT: Disparities in treatment engagement and adherence based on ethnicity have been widely recognized but are inadequately understood. Few studies have examined treatment dropout among Latinx and non-Latinx White (NLW) individuals. Using Andersen's Behavioral Model of Health Service Use (A behavioral model of families' use of health services. 1968; J Health Soc Behav. 1995; 36:1-10) as a framework, we examine whether pretreatment variables (categorized as predisposing, enabling, and need factors) mediate the relationship between ethnicity and premature dropout in a sample of Latinx and NLW primary care patients with anxiety disorders who participated in a randomized controlled trial (RCT) of cognitive behavioral therapy. Data from a total of 353 primary care patients were examined; 96 Latinx and 257 NLW patients participated. Results indicated that Latinx patients dropped out of treatment more often than NLW patients, resulting in roughly 58% of Latinx patients failing to complete treatment compared with 42% of NLW, and approximately 29% of Latinx patients dropping out before engaging in modules related to cognitive restructuring or exposure, relative to 11% of NLW patients. Mediation analyses suggest that social support and somatization partially explained the relationship between ethnicity and treatment dropout, highlighting the importance of these variables in understanding treatment disparities.

Pursuing personalized medicine for depression by targeting the lateral or medial prefrontal cortex with Deep TMS.

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Microbiome in Anxiety and Other Psychiatric Disorders.

Initial studies suggested that the fluctuations in the quantity, variety, and composition of the gut microbiota can significantly affect disease processes. This change in the gut microbiota causing negative health benefits was coined dysbiosis. Initial research focused on gastrointestinal illnesses. However, the gut microbiome was found to affect more than just gastrointestinal diseases. Numerous studies have proven that the gut microbiome can influence neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.

Noninvasive Delivery of Biologicals to the Brain.

In the past, psychotherapy and neuropharmacological approaches have been the most common treatments for disordered thoughts, moods, and behaviors. One new path of brain therapeutics is in the deployment of noninvasive approaches designed to reprogram brain function at the cellular level. Treatment at the cellular level may be considered for a wide array of disorders, ranging from mood disorders to neurodegenerative disorders. Brain-targeted biological therapy may provide minimally invasive and accurate delivery of treatment. The present article discusses the hurdles and advances that characterize the pathway to this goal.

Sonication of the Anterior Thalamus With MRI-Guided Transcranial Focused Ultrasound (tFUS) Alters Pain Thresholds in Healthy Adults: A Double-Blind, Sham-Controlled Study.

(Appeared originally in Brain Stimulation 2020; 13:1805-1812) Reprinted with permission from Elsevier.

Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.

(Appeared originally in American Journal of Psychiatry 2019; 176:931-938) Reprinted with permission from American Psychiatric Association Publishing.

Current State of Potential Mechanisms Supporting Low Intensity Focused Ultrasound for Neuromodulation.

Low intensity focused ultrasound (LIFU) has been gaining traction as a non-invasive neuromodulation technology due to its superior spatial specificity relative to transcranial electrical/magnetic stimulation. Despite a growing literature of LIFU-induced behavioral modifications, the mechanisms of action supporting LIFU's parameter-dependent excitatory and suppressive effects are not fully understood. This review provides a comprehensive introduction to the underlying mechanics of both acoustic energy and neuronal membranes, defining the primary variables for a subsequent review of the field's proposed mechanisms supporting LIFU's neuromodulatory effects. An exhaustive review of the empirical literature was also conducted and studies were grouped based on the sonication parameters used and behavioral effects observed, with the goal of linking empirical findings to the proposed theoretical mechanisms and evaluating which model best fits the existing data. A neuronal intramembrane cavitation excitation model, which accounts for differential effects as a function of cell-type, emerged as a possible explanation for the range of excitatory effects found in the literature. The suppressive and other findings need additional theoretical mechanisms and these theoretical mechanisms need to have established relationships to sonication parameters.

Translating state-of-the-art brain magnetic resonance imaging (MRI) techniques into clinical practice: multimodal MRI differentiates dementia subtypes in a traditional clinical setting.

BACKGROUND: This study sought to validate the clinical utility of multimodal magnetic resonance imaging (MRI) techniques in the assessment of neurodegenerative disorders. We intended to demonstrate that advanced neuroimaging techniques commonly used in research can effectively be employed in clinical practice to accurately differentiate heathy aging and dementia subtypes. METHODS: Twenty patients with dementia of the Alzheimer's type (DAT) and 18 patients with Parkinson's disease dementia (PDD) were identified using gold-standard techniques. Twenty-three healthy, age and sex matched control participants were also recruited. All participants underwent multimodal MRI including T1 structural, diffusion tensor imaging (DTI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). MRI modalities were evaluated by trained neuroimaging readers and were separately assessed using cross-validated, iterative discriminant function analyses with subsequent feature reduction techniques. In this way, each modality was evaluated for its ability to differentiate patients with dementia from healthy controls as well as to differentiate dementia subtypes. RESULTS: Following individual and group feature reduction, each of the multimodal MRI metrics except MRS successfully differentiated healthy aging from dementia and also demonstrated distinct dementia subtypes. Using the following ten metrics, excellent separation (95.5% accuracy, 92.3% sensitivity; 100.0% specificity) was achieved between healthy aging and neurodegenerative conditions: volume of the left frontal pole, left occipital pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, right planum temporale; perfusion of the left hippocampus and left occipital lobe; fractional anisotropy (FA) of the forceps major and bilateral anterior thalamic radiation. Using volume of the left frontal pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, perfusion of the left hippocampus and left occipital lobe; FA of the forceps major and bilateral anterior thalamic radiation, neurodegenerative subtypes were accurately differentiated as well (87.8% accuracy, 95.2% sensitivity; 85.0% specificity). CONCLUSIONS: Regional volumetrics, DTI metrics, and ASL successfully differentiated dementia patients from controls with sufficient sensitivity to differentiate dementia subtypes. Similarly, feature reduction results suggest that advanced analyses can meaningfully identify brain regions with the most positive predictive value and discriminant validity. Together, these advanced neuroimaging techniques can contribute significantly to diagnosis and treatment planning for individual patients.

Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.

OBJECTIVE: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib. METHODS: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline. RESULTS: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances. CONCLUSIONS: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. METHODS: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. RESULTS: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). CONCLUSIONS: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.

OBJECTIVE: Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. METHODS: Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. RESULTS: With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. SIGNIFICANCE: This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Brain circuitry underlying the ABC model of anxiety.

Anxiety Disorders are prevalent and often chronic, recurrent conditions that reduce quality of life. The first-line treatments, such as serotonin reuptake inhibitors and cognitive behavioral therapy, leave a significant proportion of patients symptomatic. As psychiatry moves toward targeted circuit-based treatments, there is a need for a theory that unites the phenomenology of anxiety with its underlying neural circuits. The Alarm, Belief, Coping (ABC) theory of anxiety describes how the neural circuits associated with anxiety interact with each other and domains of the anxiety symptoms, both temporally and spatially. The latest advancements in neuroimaging techniques offer the ability to assess these circuits in vivo. Using Neurosynth, a large open-access meta-analytic imaging database, the association between terms related to specific neural circuits was explored within the ABC theory framework. Alarm-related terms were associated with the amygdala, anterior cingulum, insula, and bed nucleus of stria terminalis. Belief-related terms were associated with medial prefrontal cortex, precuneus, bilateral temporal poles, and hippocampus. Coping-related terms were associated with the ventrolateral and dorsolateral prefrontal cortices, basal ganglia, and anterior cingulate. Neural connections underlying the functional neuroanatomy of the ABC model were observed. Additionally, there was considerable interaction and overlap between circuits associated with the symptom domains. Further neuroimaging research is needed to explore the dynamic interaction between the functional domains of the ABC theory. This will pave the way for probing the neuroanatomical underpinnings of anxiety disorders and provide an evidence-based foundation for the development of targeted treatments, such as neuromodulation.

Design, Development, and Operation of a Low-Intensity Focused Ultrasound Pulsation (LIFUP) System for Clinical Use.

Noninvasive low-intensity focused ultrasound pulsation (LIFUP) neuromodulation provides a unique approach to both investigating and treating the brain. This work describes a well-calibrated, simple-to-use ultrasound stimulation system for neuromodulation studies. It provides a single-element 650-kHz transducer design and a straightforward control mechanism, with extensive calibration and internal electronic monitoring to prevent unwanted over or under treatment. One goal of this approach is to relieve researchers of many of the details associated with developing their own exposure equipment. A unique transducer positioning system and distinctive MRI fiducial targets simplify alignment and targeting. The system design, control software, calibration, and alignment techniques are described in detail. Examples of transducer targeting and neurostimulation using the system are provided.