Evidence for Altered Electroencephalography Coherence in Depressed Adolescents with Suicidal Ideation and Behaviors.

Introduction: Major depressive disorder (MDD) is a primary risk factor for suicide, which is one of the leading causes of death among adolescents worldwide. Understanding the heterogeneity of suicidality in adolescents with MDD is critical for suicide prevention and intervention discovery. Quantitative electroencephalography (EEG) is a promising tool to address the knowledge gaps related to the neurophysiological characteristics of depression and suicidality. This study sought to examine resting-state EEG coherence differences in adolescents with MDD and suicidal ideation (SI)/behaviors (SB) and healthy controls (HC) to assess the utility of coherence as a biomarker of suicide. Methods: Twenty-six adolescents with MDD who were hospitalized for suicidality and 30 HC were recruited. The clinical sample was divided into SI (n = 9) and SB (n = 19) subgroups. Eyes closed resting-state EEG were recorded, and coherence was calculated. Depression severity and suicidality were assessed with the Children's Depression Rating Scale Revised and the Columbia Suicide Severity Rating Scale, respectively. Results: There were intrahemispheric differences in the right hemisphere across multiple electrode pairs. Delta, alpha, and beta coherence were higher in the SB group over the right prefrontofrontal and left parietooccipital electrode pairs, while alpha coherence was higher in the HC group over the right centroparietal electrode pair. There were no significant differences between HC and SI groups in any electrode pair. Conclusions: Patients with recent SB showed increased coherence in right frontal regions compared with patients with SI, suggesting altered cognitive states between those with SB and SI. These findings may have implications for suicide prevention in adolescents and could serve as useful biomarkers in clinical settings, but larger studies are needed to confirm the results.

Event-Related Potential Markers of Suicidality in Adolescents.

BACKGROUND: Implicit cognitive markers may assist with the prediction of suicidality beyond clinical risk factors. The aim of this study was to investigate neural correlates associated with the Death/Suicide Implicit Association Test (DS-IAT) via event-related potentials (ERP) in suicidal adolescents. METHODS: Thirty inpatient adolescents with suicidal ideations and behaviors (SIBS) and 30 healthy controls from the community were recruited. All participants underwent 64-channel electroencephalography, DS-IAT, and clinical assessments. Hierarchical generalized linear models with spatiotemporal clustering were used to identify significant ERPs associated with the behavioral outcome of DS-IAT (D scores) and group differences. RESULTS: Behavioral results (D scores) showed that the adolescents with SIBS had stronger implicit associations between "death" and "self" than the healthy group (P = .02). Within adolescents with SIBS, participants with stronger implicit associations between "death" and "self" reported more difficulty in controllability of suicidal ideation in the past 2 weeks based on the Columbia-Suicide Severity Rating Scale (P = .03). For the ERP data, the D scores and N100 component over the left parieto-occipital cortex had significant correlations. Significant group differences without behavioral correlation were observed for a second N100 cluster (P = .01), P200 (P = .02), and late positive potential (5 clusters, all P ≤ .02). Exploratory predictive models combining both neurophysiological and clinical measures distinguished adolescents with SIBS from healthy adolescents. CONCLUSIONS: Our results suggest that N100 may be a marker of attentional resources involved in the distinction of stimuli that are congruent or incongruent to associations between death and self. Combined clinical and ERP measures may have utility in future refinements of assessment and treatment approaches for adolescents with suicidality.

Noninvasive modulation of predictive coding in humans: causal evidence for frequency-specific temporal dynamics.

Increasing evidence indicates that the brain predicts sensory input based on past experiences, importantly constraining how we experience the world. Despite a growing interest on this framework, known as predictive coding, most of such approaches to multiple psychological domains continue to be theoretical or primarily provide correlational evidence. We here explored the neural basis of predictive processing using noninvasive brain stimulation and provide causal evidence of frequency-specific modulations in humans. Participants received 20 Hz (associated with top-down/predictions), 50 Hz (associated with bottom-up/prediction errors), or sham transcranial alternating current stimulation on the left dorsolateral prefrontal cortex while performing a social perception task in which facial expression predictions were induced and subsequently confirmed or violated. Left prefrontal 20 Hz stimulation reinforced stereotypical predictions. In contrast, 50 Hz and sham stimulation failed to yield any significant behavioral effects. Moreover, the frequency-specific effect observed was further supported by electroencephalography data, which showed a boost of brain activity at the stimulated frequency band. These observations provide causal evidence for how predictive processing may be enabled in the human brain, setting up a needed framework to understand how it may be disrupted across brain-related conditions and potentially restored through noninvasive methods.

A Systematic Review of Neuromodulation Treatment Effects on Suicidality.

Introduction: Neuromodulation is an important group of therapeutic modalities for neuropsychiatric disorders. Prior studies have focused on efficacy and adverse events associated with neuromodulation. Less is known regarding the influence of neuromodulation treatments on suicidality. This systematic review sought to examine the effects of various neuromodulation techniques on suicidality. Methods: A systematic review of the literature from 1940 to 2020 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was conducted. Any reported suicide-related outcome, including suicidal ideation, suicide intent, suicide attempt, completed suicide in reports were considered as a putative measure of treatment effect on suicidality. Results: The review identified 129 relevant studies. An exploratory analysis of a randomized controlled trial comparing the effects of sertraline and transcranial direct-current stimulation (tDCS) for treating depression reported a decrease in suicidal ideation favoring tDCS vs. placebo and tDCS combined with sertraline vs. placebo. Several studies reported an association between repetitive transcranial magnetic stimulation and improvements in suicidal ideation. In 12 of the studies, suicidality was the primary outcome, ten of which showed a significant improvement in suicidal ideation. Electroconvulsive therapy (ECT) and magnetic seizure therapy was also shown to be associated with lower suicidal ideation and completed suicide rates. There were 11 studies which suicidality was the primary outcome and seven of these showed an improvement in suicidal ideation or suicide intent and fewer suicide attempts or completed suicides in patients treated with ECT. There was limited literature focused on the potential protective effect of vagal nerve stimulation with respect to suicidal ideation. Data were mixed regarding the potential effects of deep brain stimulation on suicidality. Conclusions: Future prospective studies of neuromodulation that focus on the primary outcome of suicidality are urgently needed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=125599, identifier: CRD42019125599.

A Systematic Review of Long-Interval Intracortical Inhibition as a Biomarker in Neuropsychiatric Disorders.

Long-interval intracortical inhibition (LICI) is a paired-pulse transcranial magnetic stimulation (TMS) paradigm mediated in part by gamma-aminobutyric acid receptor B (GABAB) inhibition. Prior work has examined LICI as a putative biomarker in an array of neuropsychiatric disorders. This review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sought to examine existing literature focused on LICI as a biomarker in neuropsychiatric disorders. There were 113 articles that met the inclusion criteria. Existing literature suggests that LICI may have utility as a biomarker of GABAB functioning but more research with increased methodologic rigor is needed. The extant LICI literature has heterogenous methodology and inconsistencies in findings. Existing findings to date are also non-specific to disease. Future research should carefully consider existing methodological weaknesses and implement high-quality test-retest reliability studies.

Electroencephalography as a Biomarker for Functional Recovery in Spinal Cord Injury Patients.

BACKGROUND: Functional changes after spinal cord injury (SCI) are related to changes in cortical plasticity. These changes can be measured with electroencephalography (EEG) and has potential to be used as a clinical biomarker. METHOD: In this longitudinal study participants underwent a total of 30 sessions of robotic-assisted gait training (RAGT) over a course of 6 weeks. The duration of each session was 30 min. Resting state EEG was recorded before and after 30-session rehabilitation therapy. To measure gait, we used the Walking Index for Spinal Cord Injury Scale, 10-Meter- Walking Test, Timed-Up-and-Go, and 6-Min-Walking Test. Balance was measured using Berg Balance Scale. RESULTS: Fifteen participants with incomplete SCI who had AIS C or D injuries based on American Spinal Cord Injury Association Impairment Scale classification were included in this study. Mean age was 35.7 years (range 17-51) and the mean time since injury was 17.08 (range 4-37) months. All participants showed clinical improvement with the rehabilitation program. EEG data revealed that high beta EEG activity in the central area had a negative correlation with gait (p = 0.049; ß coefficient: -0.351; and adj-R 2: 0.23) and balance (p = 0.043; ß coefficient: -0.158; and adj-R 2:0.24) measured at baseline, in a way that greater high beta EEG power was related to worse clinical function at baseline. Moreover, improvement in gait and balance had negative correlations with the change in alpha/theta ratio in the parietal area (Gait: p = 0.049; ß coefficient: -0.351; adj-R 2: 0.23; Balance: p = 0.043; ß coefficient: -0.158; and adj-R 2: 0.24). CONCLUSION: In SCI, functional impairment and subsequent improvement following rehabilitation therapy with RAGT correlated with the change in cortical activity measured by EEG. Our results suggest that EEG alpha/theta ratio may be a potential surrogate marker of functional improvement during rehabilitation. Future studies are necessary to improve and validate these findings as a neurophysiological biomarker for SCI rehabilitation.

Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study.

STUDY OBJECTIVES: Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD. METHODS: Seventeen adolescents with treatment-resistant depression received 30 daily sessions of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology-Adolescent (17 Item)-Self Report (QIDS-A17-SR). Hypersomnia was measured with a single QIDS-A17-SR item. Depression severity was rated with the Children's Depression Rating Scale, Revised (CDRS-R). The effect of rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time (as a proxy of treatment), depression severity, age, and hypnotic medication use. RESULTS: No significant main effect of time was observed on the insomnia subscale (F4,43.442 = 1.078, p = 0 .379). However, there was a significant main effect of time on the QIDS-A17-SR hypersomnia score (F4,46.124 = 2.733, p = 0 .040), with significant improvement from baseline to treatment 10 (padj = 0.019) and from baseline to 6-month follow-up (padj = 0.044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes. CONCLUSIONS: rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed adolescents. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov identifiers are NCT00587639, NCT01502033, NCT01804270.

Transcranial Magnetic Stimulation Markers of Antidepressant Treatment in Adolescents With Major Depressive Disorder.

BACKGROUND: The goal of this study was to examine baseline transcranial magnetic stimulation measures of cortical inhibition and excitability in depressed patients and characterize their longitudinal posttreatment changes. METHODS: Fifteen adolescents (age 13-17 years) with moderate to severe major depressive disorder and 22 healthy controls (age 9-17) underwent single- and paired-pulse transcranial magnetic stimulation and clinical assessments. Transcranial magnetic stimulation measures included short-interval intracortical inhibition (2 and 4 milliseconds), long-interval intracortical inhibition (100, 150, and 200 milliseconds), cortical silent period, and intracortical facilitation (10, 15, and 20 milliseconds). Ten participants with major depressive disorder initiated antidepressant treatment or had dose adjustments. These participants were reassessed after treatment. Depression symptom severity was measured with the Children's Depression Rating Scale, Revised. Robust regression modeling compared healthy and depressed adolescents at baseline. Relationships between changes in cortical inhibition and changes in depressive symptom severity were assessed in the depressed adolescents receiving antidepressant treatment. RESULTS: Our results revealed that at baseline, short-interval intracortical inhibition-2 was significantly reduced (Padj = .01) in depressed participants, suggesting impaired cortical inhibition compared with healthy controls. At follow-up, improvement in Children's Depression Rating Scale, Revised scores correlated with improvement in short-interval intracortical inhibition-4 amplitude (greater inhibition) after antidepressant treatment (R2 = 0.63; P = .01). CONCLUSIONS: These results suggest that cortical inhibition measures may have promise as biomarkers in adolescents treated for depression.

Transcranial Direct Current Stimulation in Child and Adolescent Psychiatric Disorders.

Research involving transcranial direct current stimulation (tDCS) in child and adolescent psychiatry is limited. Early, short-term studies have found tDCS to be safe and well-tolerated in youth with neurodevelopmental disorders (attention-deficit hyperactivity disorder, autism, learning disorders). Preliminary data suggest potential utility in symptom reduction and improving cognitive function. Further careful research considering implications for the developing brain is necessary.

Therapeutic Applications of Noninvasive Neuromodulation in Children and Adolescents.

Recent advances and growing evidence supporting the safety and efficacy of noninvasive neuromodulatory techniques in adults have facilitated the study of neuromodulation applications in children and adolescents. Noninvasive brain stimulation methods such as transcranial direct current stimulation and transcranial magnetic stimulation have been considered in children with depression, autism spectrum disorder, attention-deficit hyperactivity disorder, and other neuropsychiatric disorders. However, current clinical applications of neuromodulation techniques in children and adolescents are nascent. There is a great need for developmentally informed, large, double-blinded, randomized, controlled clinical trials to demonstrate efficacy and safety of noninvasive brain stimulation in children and adolescents.

Therapeutic Applications of Invasive Neuromodulation in Children and Adolescents.

Although the application of noninvasive brain stimulation methods to children and adolescents has been frequently studied in depression, autism spectrum disorder, attention-deficit/hyperactivity disorder, and other neuropsychiatric disorders, invasive methods such as deep brain stimulation (DBS) and vagal nerve stimulation (VNS) have received less attention. DBS and VNS have demonstrated utility in young patients especially for dystonia and epilepsy. VNS has FDA clearance for intractable epilepsy in patients aged 4 years and older. Further measured work with invasive neuromodulation for children and adolescents with debilitating neuropsychiatric disorders could provide new treatment options and expand current knowledge base of neurocircuitry across development.