Frontoparietal beta event characteristics are associated with early life stress and psychiatric symptoms in adults.

Recent work has found that the presence of transient, oscillatory burst-like events, particularly within the beta band (15-29 Hz), is more closely tied to disease state and behavior across species than traditional electroencephalography (EEG) power metrics. This study sought to examine whether features of beta events over frontoparietal electrodes were associated with early life stress (ELS) and the related clinical presentation. Eighteen adults with documented ELS (n = 18; ELS + ) and eighteen adults without documented ELS (n = 18; ELS-) completed eyes-closed resting state EEG as part of their participation in a larger childhood stress study. The rate, power, duration, and frequency span of transient oscillatory events were calculated within the beta band at five frontoparietal electrodes. ELS variables were positively associated with beta event rate at Fp2 and beta event duration at Pz, in that greater ELS was associated with higher resting rates and longer durations. These beta event characteristics were used to successfully distinguish between ELS + and ELS- groups. In an independent clinical dataset (n = 25), beta event power at Pz was positively correlated with ELS. Beta events deserve ongoing investigation as a potential disease marker of ELS and subsequent psychiatric treatment outcomes.

Childhood stress, gender, and cognitive control: Midline theta power.

The emergence of psychiatric symptoms is a common consequence of childhood stress exposure. However, there are a dearth of reliable clinical hallmarks or physiological biomarkers to predict post-trauma symptom emergence. The objective of this study was to examine if childhood stressors and stress-related symptoms are associated with altered midline theta power (MTP) during cognitive control demands, and how these associations interact with gender and early adversity. N = 53 children (ages 9-13 years old) from a longitudinal study of children maltreated during early childhood and non-maltreated children participated in this study. EEG recorded neural activity during a Zoo-Themed Go/No-Go task. Stress-related symptoms, recent stressful events, and other adversity experiences were identified. MTP was analyzed with clinical variables in a series of follow-up analyses. The number of stressors in the past six months was negatively correlated with MTP in those with low preschool adversity, but not in those with high preschool adversity. MTP was higher in girls than in boys, and the associations of MTP with stressors and symptoms were moderated by gender. MTP was negatively associated with stressors in the past six months in girls, while in boys, MTP was associated with stress-related symptoms. Childhood stressful events were associated with reduced MTP during cognitive control demands, and this was finding was moderated by gender and early life adversity. These preliminary findings suggest that boys and girls may process stressful experiences in distinct ways, and preschool adversity may potentially blunt the interaction between current stress and neural dynamics. However, ongoing investigation is needed.

Pre-treatment frontal beta events are associated with executive dysfunction improvement after repetitive transcranial magnetic stimulation for depression: A preliminary report.

Repetitive transcranial magnetic stimulation (rTMS) is an established clinical treatment for major depressive disorder (MDD) that has also been found to improve aspects of executive functioning. The objective of this study was to examine whether oscillatory burst-like events within the beta band (15-29 Hz) prior to treatment could predict subsequent change in self-reported executive dysfunction (EDF) across a clinical course of rTMS for MDD. Twenty-eight adults (64% female) with MDD completed the self-report Frontal Systems Behavior Scale (FrSBe) and provided eyes-closed resting-state electroencephalography (EEG) before and after a clinical course of rTMS therapy for primary MDD. The rate, power, duration, and frequency span of transient EEG measured oscillatory beta events were calculated. Events within delta/theta and alpha bands were examined to assess for beta specificity. After controlling for improvement in primary depressive symptoms, a lower rate of beta events at F3, Fz, F4, and Cz prior to rTMS treatment was associated with a larger improvement in EDF after rTMS treatment. In addition, a decrease in beta event rate at Fz pre-to-post treatment was associated with a larger improvement in EDF after treatment. Results were largely specific to the beta band. In this study, the rate of frontrocentral beta events prior to treatment significantly predicted the likelihood of subsequent improvement in EDF symptoms following a clinical course of rTMS for MDD. These preliminary findings suggest the potential utility of EEG measured beta events and rTMS for targeting EDF across an array of neuropsychiatric disorders.

Corrigendum: Mechanical affective touch therapy for anxiety disorders: Feasibility, clinical outcomes, and electroencephalography biomarkers from an open-label trial.

[This corrects the article DOI: 10.3389/fpsyt.2022.877574.].

Combined Working Memory Training and Transcranial Magnetic Stimulation Demonstrates Low Feasibility and Potentially Worse Outcomes on Delay to Smoking and Cognitive Tasks: A Randomized 2 × 2 Factorial Design Pilot and Feasibility Study.

INTRODUCTION: Repetitive Transcranial Magnetic Stimulation (rTMS) has shown promising results in treating several Substance Use Disorders including Tobacco Use Disorder. However, questions remain regarding how to optimize treatment outcomes. Enhancement of working memory by rTMS is a potential therapeutic mechanism. The current pilot study examined whether rTMS plus a cognitive training program could enhance the effects of rTMS on smoking behaviors using a controlled, factorial design. AIMS AND METHODS: We hypothesized that cognitive training plus stimulation would improve control over smoking behaviors, resulting in enhanced cognitive performance and increased latency to smoke on a delay to smoking analog task. Using a 2 × 2 factorial design, nicotine dependent smokers (n = 43) were randomized to receive 10 sessions of active (10 Hz) or sham rTMS delivered to the left dorsolateral prefrontal cortex, plus active or sham working memory training (WMT) prior to and following stimulation. RESULTS: Contrary to hypotheses, we observed a significant interaction effect, indicating that combining the two active interventions (rTMS+WMT) resulted in worse performance on the smoking analog task (B = -33.0, 95% CI = -64.39, -1.61, p < .05), compared to delivering either intervention alone. Additionally, although active rTMS (compared to sham rTMS) improved letter-sequencing performance (B = 1.23, 95% CI = 0.08-2.38, p < .05), and active WMT (compared to sham WMT) improved back-digit task performance (B = 1.53, 95% CI = 0.02-3.05, p < .05), combining interventions worsened the effect of each on a back-digit task (B = -3.01, 95% CI = -5.96, -0.052, p < .05). CONCLUSIONS: These preliminary findings indicate potential iatrogenic effects of combining rTMS and this working memory training intervention and underscore the need for rigorous evaluation of substance specific conceptual frameworks when selecting future combination interventions. IMPLICATIONS: Counter to hypothesis, this study found no additional benefit of adding a working memory training program to a rTMS protocol in a sample of daily smokers. The combination condition (active rTMS + active training) resulted in worse performance on a delay to smoking analog task and a measure of working memory performance compared to delivering either intervention alone. These preliminary findings inform strategies for optimizing rTMS in smokers and highlight the need for future studies to consider several key components of candidate combination interventions, including effects on regulation of substance use. CLINICAL TRIAL REGISTRATION (IF ANY): The trial was registered at ClinicalTrials.gov (NCT03337113).

Mechanical Affective Touch Therapy for Anxiety Disorders: Feasibility, Clinical Outcomes, and Electroencephalography Biomarkers From an Open-Label Trial.

Background: Most external peripheral nerve stimulation devices designed to alter mood states use electrical energy, but mechanical stimulation for activation of somatosensory pathways may be harnessed for potential therapeutic neuromodulation. A novel investigational device for Mechanical Affective Touch Therapy (MATT) was created to stimulate C-tactile fibers through gentle vibrations delivered by piezoelectric actuators on the bilateral mastoid processes. Methods: 22 adults with anxiety disorders and at least moderate anxiety symptom severity enrolled in an open-label pilot trial that involved MATT self-administration using a simple headset at home at least twice per day for 4 weeks. Resting EEG data were acquired before and after a baseline MATT session and again before the final MATT session. Self-report measures of mood and anxiety were collected at baseline, week 2, and week 4, while interoception was assessed pre- and post-treatment. Results: Anxiety and depressive symptoms improved significantly from baseline to endpoint, and mindfulness was enhanced. EEG metrics confirmed an association between acute MATT stimulation and oscillatory power in alpha and theta bands; symptom changes correlated with changes in some metrics. Conclusion: Open-label data suggest MATT is a promising non-invasive therapeutic approach to anxiety disorders that warrants further development.

Mechanical Affective Touch Therapy for Anxiety Disorders: Effects on Resting State Functional Connectivity.

OBJECTIVES: Mechanical Affective Touch Therapy (MATT) is a safe, novel form of noninvasive peripheral nerve stimulation. Although mechanical stimulation activates nerves, we know little about its impact on psychiatric symptoms and their underlying cortical mechanisms. We examined the effects of open-label MATT on resting state functional connectivity (RSFC) and its relationship with anxiety and affective symptomatology (clinical results in separate report). MATERIALS AND METHODS: A total of 22 adults with an Axis I anxiety disorder were recruited from the community. After two initial sessions assisted by research staff, participants self-administered 20-minute sessions of MATT at home at least twice daily for four weeks. Self-report measures of mood and anxiety severity were collected at baseline, two weeks, and four weeks. Resting state functional magnetic resonance imaging was collected before the initial MATT session (n = 20), immediately after the first session (n = 18), and following four weeks of MATT (n = 14). Seed-based whole-brain functional connectivity analyses identified brain connectivity patterns correlated with responsiveness to MATT. Seeds were based on Neurosynth meta-analytic maps for "anxiety" and "pain" given MATT's hypothesized role in anxiety symptom amelioration and potential mechanism of action through C-tactile afferents, which play an important role in detecting pain and its affective components. Connectivity results were corrected for multiple comparisons (voxel p < 0.005, cluster p-FDR < 0.05). RESULTS: Baseline RSFC is predictive of symptom improvement with chronic MATT. Acute increases in insula connectivity were observed between mid-cingulate cortex and postcentral motor regions following the first MATT session. Chronic MATT was associated with increased connectivity between pain and anxiety regions of interest (ROIs) and posterior default mode network (DMN) regions involved in memory and self-reflection; the connectivity changes correlated with decreases in stress and depression symptoms. CONCLUSIONS: MATT is associated with alterations in RSFC in the DMN of anxiety disorder patients both acutely and after long-term administration, and baseline RSFC is predictive of post-treatment symptom improvement.

Large-scale EEG neural network changes in response to therapeutic TMS.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an effective therapy for patients with treatment-resistant depression. TMS likely induces functional connectivity changes in aberrant circuits implicated in depression. Electroencephalography (EEG) "microstates" are topographies hypothesized to represent large-scale resting networks. Canonical microstates have recently been proposed as markers for major depressive disorder (MDD), but it is not known if or how they change following TMS. METHODS: Resting EEG was obtained from 49 MDD patients at baseline and following six weeks of daily TMS. Polarity-insensitive modified k-means clustering was used to segment EEGs into constituent microstates. Microstates were localized via sLORETA. Repeated-measures mixed models tested for within-subject differences over time and t-tests compared microstate features between TMS responder and non-responder groups. RESULTS: Six microstates (MS-1 - MS-6) were identified from all available EEG data. Clinical response to TMS was associated with increases in features of MS-2, along with decreased metrics of MS-3. Nonresponders showed no significant changes in any microstate. Change in occurrence and coverage of both MS-2 (increased) and MS-3 (decreased) correlated with symptom change magnitude over the course of TMS treatment. CONCLUSIONS: We identified EEG microstates associated with clinical improvement following a course of TMS therapy. Results suggest selective modulation of resting networks observable by EEG, which is inexpensive and easily acquired in the clinic setting.

Audio-Guided Mindfulness Meditation During Transcranial Magnetic Stimulation Sessions for the Treatment of Major Depressive Disorder: A Pilot Feasibility Study.

Background: Mindfulness-Based Cognitive Therapy (MBCT) has been shown to enhance the long-term treatment outcomes for major depressive disorder (MDD), and engagement of specific brain activities during brain stimulation may produce synergistic effects. Audio-guided meditation exercises are a component of MBCT that might be combined with standard transcranial magnetic stimulation (TMS) therapy sessions. We developed and pilot-tested a modified MBCT protocol for patients undergoing a standard course of TMS for MDD. Methods: Four MBCT audiotracks with differing durations and types of mental focus were selected. Patients listened to the audiotapes through headphones during daily TMS sessions for 5 consecutive weeks. The primary goal was to evaluate the feasibility and acceptability of the meditation intervention with TMS. Changes in self-rated measures of symptom severity, stress, life satisfaction, and mindfulness were also assessed. Results: Seventeen depressed subjects completed the study and 12 terminated early. Reasons for discontinuation included an inability to meditate in the treatment setting and induction of negative mood states. TMS percussive sensations and clicking sounds hindered the ability of patients to fully concentrate on or hear the voice of the audiotape narrator. Some became overwhelmed or felt increased pressure, anxiety, or aggravation trying to do meditation exercises while receiving TMS. Conclusion: There is a growing interest in combining TMS with other concurrent psychotherapeutic interventions to optimize treatment outcomes. The results highlight numerous feasibility issues with MBCT via guided audiotapes during TMS treatment. Future work should draw on these shortcomings to evaluate the appropriateness of MBCT for depressed patients undergoing neuromodulation.

Effects of transcranial magnetic stimulation on anhedonia in treatment resistant major depressive disorder.

BACKGROUND: Anhedonia is one of the defining features of depression but it remains difficult to target and treat. Transcranial magnetic stimulation (TMS) is a proven treatment for depression, but its effects on anhedonia and whether anhedonia can be used as a predictive biomarker of response is not well known. METHODS: Snaith-Hamilton Pleasure Scale was administered to patients with depression before and after a standard course of TMS in a naturalistic outpatient setting. RESULTS: 144 patients were analyzed. There was an overall significant improvement in anhedonia from pre- to post-treatment (7.69 ± 3.88 vs. 2.96 ± 3.45; p < .001). Significant correlations between improvements in anhedonia and other depressive symptoms were present (r = 0.55, p < .001). Logistic regression revealed that baseline anhedonia severity was not a significant predictor of clinical outcome. CONCLUSION: This is the first large, naturalistic study examining the effects of standard, non-research TMS on anhedonia. Among depressed patients, TMS resulted in significant improvements in anhedonia. Patients with severe baseline anhedonia had an equal chance of achieving clinical response/remission. Patients with anhedonia should not be excluded from treatment if they are safe for outpatient care and otherwise appropriate candidates for treatment.

A preliminary investigation of childhood anxiety/depressive symptomatology and working memory across multiple units of analysis.

This exploratory study examined multiple units of working memory (WM) analysis in a transdiagnostic, treatment-seeking, pediatric sample. This included a) an electroencephalography marker of WM (coupling of theta and gamma oscillations [i.e., theta-gamma coupling] in frontal brain regions), b) WM test performance, and c) parent-reported WM symptoms. A composite score combining each of these units of analysis correlated with self-reported depressive and anxiety symptoms, with only theta-gamma coupling independently predicted anxiety/depressive symptoms. Results confirm prior findings on the association between WM and anxiety/depression, although the majority of this variance was explained by frontal theta-gamma coupling during WM demands.

Peripheral vascular endothelial growth factor changes after transcranial magnetic stimulation in treatment-resistant depression.

OBJECTIVES: To determine if vascular endothelial growth factor (VEGF) changes with transcranial magnetic stimulation (TMS) in treatment-resistant major depressive disorder (MDD). METHODS: Serum from a naturalistic population of 15 patients with MDD was collected at baseline and after standard TMS treatment. VEGF concentration was determined via ELISA. Inventory of Depressive Symptomatology Self Report and Patient Health Questionnaire were used as a measure of depression symptom severity, clinical response and remission. Mann-Whitney U and Kendall's Tau Correlation were used for continuous variables. RESULTS: VEGF increased from pre- to post-TMS (+30.3%) in remitters whereas VEGF decreased in non-remitters (-9.87%) (P < 0.05). This same pattern was observed when comparing mean %change in VEGF between responders (+14.7%) and non-responders (-14.9%) (P = 0.054). Correlation was present between change in VEGF concentration (baseline to post) and change in Inventory of Depressive Symptomatology-Self Report at Tx30 (r = -0.371, P < 0.054), reflecting greater increases in VEGF linked to greater improvement in depressive symptoms following the standard 6-week course of TMS. CONCLUSION: Patients with a successful treatment with TMS had significantly greater increase in VEGF from baseline to after treatment compared to non-responders/non-remitters and a larger increase in VEGF was associated with greater improvement in depressive symptoms after TMS. This is the first report examining VEGF levels in depressed patients receiving TMS. This study provides correlative data supporting further investigation into VEGF's role as an important mediator in the processes underpinning TMS' antidepressant effects and as a potential biomarker of clinical outcomes.

Effect of Previous Electroconvulsive Therapy on Subsequent Response to Transcranial Magnetic Stimulation for Major Depressive Disorder.

OBJECTIVES: Patients with major depressive disorder (MDD) who received electroconvulsive therapy (ECT) often seek transcranial magnetic stimulation (TMS) therapy as a less invasive treatment option. How prior history of ECT and its responsiveness may affect TMS treatment outcomes for MDD is unclear. We aim to contribute evidence to this important clinical question. MATERIALS AND METHODS: Retrospective naturalistic TMS treatment data from n = 257 MDD patients. Three sets of analyses were conducted: History of past exposure to ECT (n = 71, "+ECT" vs. n = 186 ECT-naïve, "-ECT") was examined as a potential predictor of TMS outcomes (measured by two self-report scales); A subset of n = 38 +ECT patients with adequate ECT trials in current depression episode were compared with -ECT patients blindly matched on clinical variables associated with TMS outcomes; for a subset with available data, TMS outcomes were explored in relation to positive/negative response to prior ECT. RESULTS: Compared to -ECT, +ECT patients more likely had past psychiatric hospitalizations (p < 0.01) and were more severely depressed at baseline (p = 0.07). Response (p = 0.07) and remission (p = 0.02) rates were higher in -ECT than +ECT groups on one scale. However, comparison between the subsets (n = 38 each) matched on confounding factors did not find history of ECT to be a significant independent predictor of TMS outcomes. Differential responsiveness to ECT and ECT treatment characteristics did not significantly impact TMS outcomes. CONCLUSIONS: Although limited by the retrospective nature of this analysis, the results suggest that history of the past ECT, regardless of responsiveness to ECT, may not independently portend differential TMS treatment outcomes.

Measurement of executive functioning with the National Institute of Health Toolbox and the association to anxiety/depressive symptomatology in childhood/adolescence.

INTRODUCTION: Despite preliminary research, there remain inconsistent findings with regard to the role of executive functioning (EF) deficits in childhood anxiety and depression. This report examined the association of The National Institute of Health (NIH) Toolbox to clinical neuropsychological measures and to childhood, anxiety/depressive symptomatology. Methods: One-hundred eight children and adolescents completed the three EF measures from the NIH Toolbox (List Sorting Working Memory Test [LSWMT], Dimensional Change Card Sorting Test [DCCST], and Flanker Test of Attention and Inhibition [Flanker]) in an outpatient neuropsychology program. These tests were compared to established measures of EF in terms of linear correlations and detection of impairment. Heaton's Global Deficit Score (GDS) was utilized to calculate impairment. The Toolbox-EF measures were paired with parent-reported EF symptoms (Behavior Rating Inventory of Executive Function [BRIEF2]) to identify the role of EF in childhood anxiety/depressive symptomatology. RESULTS: Toolbox-EF measures displayed medium sized correlations with their clinically comparable counterparts, and generally did not differ in their detection of impairment. Toolbox-GDS was associated with depression diagnosis and clinically significant child-reported anxiety and depressive symptoms. Together, Toolbox/BRIEF2 accounted for 26.8-30.9% of elevated depressive symptom variance, but only 13.2-14% of elevated anxiety symptom variance. Further, EF impairment was associated with depression across self report, parent report, and clinical diagnosis. DISCUSSION: The NIH Toolbox-EF measures display comparable psychometric properties to clinically available EF measures in a pediatric (primarily psychiatric) neuropsychology setting. The Toolbox appears to display an appropriate ability to detect EF deficits secondary to self-reported depression in childhood.

The relationship between individual alpha peak frequency and clinical outcome with repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD).

BACKGROUND: The individual α frequency (IAF) has been associated with the outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD), but the association has been inconsistent. HYPOTHESIS: Proximity of IAF to the stimulation frequency, rather than the value of IAF per se, is associated with outcome for patients receiving 10 Hz rTMS. METHODS: We examined the relationships between IAF, rTMS stimulation frequency, and treatment outcome in 147 patients. All patients initially received 10 Hz rTMS unilateral treatment delivered to left dorsolateral prefrontal cortex (DLPFC) (10UL), with subsets of patients changed to unilateral 5 Hz to left DLPFC (5UL) or sequential bilateral (SB) stimulation (10 Hz/1Hz) to left and right DLPFC based upon worsening symptoms with or intolerance of 10UL. Outcome was percent change in total score on the Inventory of Depressive Symptomatology - Self Report (IDS-SR) scale from pre-treatment baseline to the 30th treatment. IAF values and absolute difference between IAF and 10 Hz (|IAF-10Hz|) were examined in relation to outcome for the overall sample and for each stimulation group separately. RESULTS: There was no correlation between IAF value, or |IAF-10Hz| and outcome in the overall sample. ANCOVA showed a significant interaction between IAF measures and treatment type. Post-hoc analyses revealed that IAF and |IAF-10Hz| were both significantly associated with degree of improvement (IDS-SR % change) for patients who received 10UL (P < 0.01) but not 5UL or SB stimulation. There was a trend-level difference in IAF between responders and non-responders only within the 10 Hz group, but not within the other treatment groups (n.s.). For the 10UL group, membership in the highest IAF quartile was associated with significantly greater clinical improvement than membership in the lowest IAF quartile (p = 0.0034). CONCLUSIONS: IAF measures were associated with clinical outcome of patients treated with 10UL but not 5UL or SB rTMS treatment. This suggests that interactions between endogenous frequencies and treatment outcome may be related to the selected stimulation parameters and/or physiologic and clinical characteristics of patients who benefit from those parameters.

Behavioral activation therapy during transcranial magnetic stimulation for major depressive disorder.

BACKGROUND: Behavioral Activation (BA) Therapy and Transcranial Magnetic Stimulation (TMS) have each been shown to be effective in the treatment of adult outpatients with major depressive disorder (MDD). Combining both treatments may produce synergistic antidepressant outcomes. METHODS: We developed a new protocol for incorporating a simplified version of BA during a standard 6-week course of TMS and it was pilot tested in 11 consecutively treated outpatients with treatment resistant depression (TRD). BA was delivered in a 5-10 min interval daily prior to the start of TMS. Engagement in BA was measured by tracking the setting and attainment of between session "goals" during the course of TMS treatment. The Inventory of Depressive Symptoms (IDS-SR), the 9-item Patient Health Questionnaire (PHQ-9), and the Snaith-Hamilton Pleasure Scale (SHAPS) were used to measure overall symptom improvement. RESULTS: Patients who underwent a combined BA + TMS protocol demonstrated an average goal completion rate of 77% along with overall symptom improvement as demonstrated by an average decrease of 47%, 55%, and 39% in IDS-SR, PHQ-9, and SHAPS scores respectively. BA was easily incorporated into the daily routine of administering TMS procedures. LIMITATIONS: There is inadequate power in this current investigation to compare treatment efficacy of BA + TMS to TMS alone. CONCLUSION: Incorporation of a modified version of BA therapy into a standard acute course of TMS therapy is feasible, well tolerated, and holds potential for augmenting the efficacy of TMS treatment for patients with TRD.