Transcranial Magnetic Stimulation for Developmental Neuropsychiatric Disorders with Inflammation.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that may potentially be helpful for neuropsychiatric symptoms of developmental disorders with inflammatory aspects. TMS utilizes a varying magnetic field to induce electrical changes in the brain. Repetitive use of TMS modulates plasticity at multiple levels, particularly at the synapse and network level. SUMMARY: As inflammation can affect synaptic plasticity negatively, TMS may theoretically be a tool to address this inflammation-induced dysfunction. There are also data to suggest that TMS can directly downregulate inflammation. Neuropsychiatric consequences of multiple disorders with inflammatory aspects, particularly neurodevelopmental disorders like autism, Tourette syndrome, and obsessive-compulsive disorder (OCD), maybe treated effectively with TMS. Treatment of OCD, treatment-resistant major depression, and nicotine cessation (all in adults) are currently FDA-cleared indications, while migraine is cleared for ages 12 and above. KEY MESSAGES: TMS will likely continue to grow in terms of indications as research continues to assess what brain networks are dysfunctional in various disorders and it becomes clearer how to modulate these networks. TMS may thus be best understood as a technology platform that can be utilized to modulate different brain networks affected in neuropsychiatric disorders. TMS is likely to become an increasingly important tool in targeting brain networks that could become dysfunctional in part due to inflammation in the developing brain and addressing consequent neuropsychiatric symptoms.

Transcranial Magnetic Stimulation and its Imaging Features in Patients With Depression, Post-traumatic Stress Disorder, and Traumatic Brain Injury.

Transcranial magnetic stimulation (TMS) is a type of noninvasive neurostimulation used increasingly often in clinical medicine. While most studies to date have focused on TMS's ability to treat major depressive disorder, it has shown promise in several other conditions including post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). As different treatment protocols are often used across studies, the ability to predict patient outcomes and evaluate immediate and long-term changes using imaging becomes increasingly important. Several imaging features, such as thickness, connectedness, and baseline activity of a variety of cortical and subcortical areas, have been found to be correlated with a greater response to TMS therapy. Intrastimulation imaging can reveal in real time how TMS applied to superficial areas activates or inhibits activity in deeper brain regions. Functional imaging performed weeks to months after treatment can offer an understanding of how long-term effects on brain activity relate to clinical improvement. Further work should be done to expand our knowledge of imaging features relevant to TMS therapy and how they vary across patients with different neurological and psychiatric conditions.

Efficacy of Transcendental Meditation to Reduce Stress Among Health Care Workers: A Randomized Clinical Trial.

Importance: Health care workers (HCWs) have been experiencing substantial stress and burnout, and evidence-based mitigation strategies are needed. Transcendental Meditation (TM) is a mantra meditation practice with potential efficacy in reducing stress. Objective: To assess the efficacy of TM practice in reducing stress among HCWs over a 3-month period. Design, Setting, and Participants: This single-center open-label randomized clinical trial was conducted among HCWs at an academic medical center from November 19, 2020, to August 31, 2021. Inclusion criteria comprised a score of 6 points or greater on the Subjective Units of Distress Scale and an increase of 5% or greater in baseline heart rate or an increase of 33% or greater in galvanic skin response after exposure to a stressful script. Exclusion criteria included the use of antipsychotic or ß blocker medications, current suicidal ideation, or previous TM training. Of 213 HCWs who participated in prescreening, 95 attended in-person visits, resulting in 80 eligible participants who were randomized to receive a TM intervention (TM group) or usual treatment (control group). Interventions: The TM group practiced TM for 20 minutes twice daily over a 3-month period. The control group received usual treatment, which consisted of access to wellness resources. Main Outcomes and Measures: The primary outcome was change in acute psychological distress measured by the Global Severity Index. Secondary outcomes included changes in burnout (measured by the Maslach Burnout Inventory), insomnia (measured by the Insomnia Severity Index), and anxiety (measured by the Generalized Anxiety Disorder-7 scale). Results: Among 80 participants, 66 (82.5%) were women, with a mean (SD) age of 40 (11) years. One participant (1.3%) was American Indian or Alaska Native, 5 (6.3%) were Asian, 12 (15.0%) were Black, 59 (73.8%) were White, and 3 (3.8%) were of unknown or unreported race; 4 participants (5.0%) were Hispanic, and 76 (95.0%) were non-Hispanic. A total of 41 participants were randomized to the TM group, and 39 were randomized to the control group. Participants in the TM group did not show a statistically significant decrease in psychological distress on the Global Severity Index compared with those in the control group (-5.6 points vs -3.8 points; between-group difference, -1.8 points; 95% CI, -4.2 to 0.6 points; P = .13). Compared with the control group, the TM group had significantly greater reductions in the secondary end points of emotional exhaustion (Maslach Burnout Inventory subscore: -8.0 points vs -2.6 points; between-group difference, -5.4 points; 95% CI, -9.2 to -1.6 points; P = .006), insomnia (Insomnia Severity Scale score: -4.1 points vs -1.9 points; between-group difference, -2.2 points; 95% CI, -4.4 to 0 points; P = .05), and anxiety (Generalized Anxiety Disorder-7 score: -3.1 points vs -0.9 points; between-group difference, -2.2 points; 95% CI, -3.8 to -0.5; P = .01) at 3 months. A total of 38 participants (92.7%) in the TM group adhered to home practice. Conclusions and Relevance: In this randomized clinical trial, TM practice among HCWs over a 3-month period did not result in a statistically significant reduction in the primary outcome of acute psychological distress compared with usual treatment but significantly improved the secondary outcomes of burnout, anxiety, and insomnia. These findings suggest that TM may be a safe and effective strategy to alleviate chronic stress among HCWs. Trial Registration: ClinicalTrials.gov identifier: NCT04632368.

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.

Low-Frequency Right Repetitive Transcranial Magnetic Stimulation for the Treatment of Depression After Traumatic Brain Injury: A Randomized Sham-Controlled Pilot Study.

OBJECTIVE: Major depression is the most common psychiatric sequela of traumatic brain injury (TBI), but effective treatment continues to be a challenge, with few studies providing guidance. METHODS: In a pilot study, the authors evaluated the effect size of low-frequency right-sided (LFR) repetitive transcranial magnetic stimulation (rTMS), compared with sham treatment, over the right dorsolateral prefrontal cortex (DLPFC) in patients (N=30) with TBI depression and co-occurring neuropsychiatric symptoms, including suicidal thoughts, anxiety, posttraumatic stress disorder, sleep disturbance, behavioral problems, and cognitive dysfunction. Exploratory analyses of diffusion tensor imaging pre- and postintervention were performed to determine the effect size of LFR rTMS on white matter integrity. RESULTS: Small (Hedge's g=0.19) and highly variable effects of LRF rTMS over right DLPFC in TBI depression were observed. Similarly, the effect of LFR rTMS for treatment of comorbid neuropsychiatric symptoms varied from small to moderate. CONCLUSIONS: These findings suggest that the observed effects of LFR rTMS over the right DLPFC in TBI depression and co-occurring neuropsychiatric symptoms are small, at best, and, preliminarily, that low-frequency right DLPFC stimulation has limited potential in this patient population. However, studies employing different rTMS parameters (e.g., type, location, frequency, duration) or other participant characteristics (e.g., TBI severity, chronicity, comorbidity, concurrent treatment) may potentially yield different responses.

Risk Factors for New-Onset Depression After First-Time Traumatic Brain Injury.

BACKGROUND: Major depression after traumatic brain injury (TBI) has devastating consequences as it increases the risk of suicide, impairs overall quality of life, and affects interpersonal, occupational, and social functioning. Although the literature has reported factors associated with depression after TBI, very few studies have examined the prevalence and correlates focused on the development of new-onset depression (NOD) after first-time TBI. Our study aimed to identify TBI- and non-TBI-related factors associated with the development of NOD in the first year after TBI. METHODS: A total of 103 subjects with first-time TBI were seen within 12 months postinjury and evaluated for the development of NOD at 3, 6, and 12 months. RESULTS: Frontal lobe functioning, frontal lesions, and pre-TBI/early post-TBI social impairment were not found to be predictors of development of NOD within the first year after injury. Decreased post-TBI social functioning as perceived by the subject at 3, 6, and 12 months was found to be associated with NOD at each of these time points, respectively. CONCLUSION: The study findings highlight the importance of psychotherapeutic interventions to address the individuals' overall perception of their social impairment in the early-TBI period. This may help decrease the progression of major depression within the first year after injury.

Correlates and Prevalence of Aggression at Six Months and One Year After First-Time Traumatic Brain Injury.

Few studies have examined clinical correlates of aggression after first-time traumatic brain injury (TBI) within the first year after injury. The authors aimed to identify the rates of aggression at 6 and 12 months post-TBI and establish clinical and demographic correlates. A total of 103 subjects with first-time TBI were seen within 12 months postinjury and evaluated for aggression. Post-TBI social functioning and new-onset depression (within 3 months of the TBI) may serve as particularly important predictors for aggression within the first year of TBI, as these factors may afford intervention and subsequent decreased risk of aggression.

Clinical Impact of Pharmacogenetic-Guided Treatment for Patients Exhibiting Neuropsychiatric Disorders: A Randomized Controlled Trial.

Objective: Pharmacogenetic testing holds promise as a personalized medicine tool by permitting individualization of pharmacotherapy in accordance with genes influencing therapeutic response, side effects, and adverse events. The authors evaluated the effect on outcomes for patients diagnosed with neuropsychiatric disorders of pharmacogenetics (PGx)-guided treatment compared to usual standard of care. Methods: This was a prospective, randomized study of 237 patients at an outpatient community-based psychiatric practice conducted between April 2015 and October 2015. Baseline patient assessments and a buccal swab were collected for pharmacogenetic testing at study initiation. For the experimental group, PGx results were provided to the clinicians as guides to treatment. Control subjects were treated according to the usual standard of care with no clinician reference to their PGx results. Neuropsychiatric Questionnaire (NPQ) and Symbol Digit Coding Test (SDC) scores and adverse drug events, hospitalizations, and medication information were collected at 30, 60, and 90 days. Results: More than half (53%) of patients in the control group reported at least 1 adverse drug event compared to 28% of patients with PGx-guided medication management (P = .001). NPQ and SDC scores improved for both groups, but no statistical difference in efficacy as measured by these assessments was observed within the 90-day observation period. Conclusions: Pharmacogenetic testing may facilitate psychiatric drug therapy with greater tolerability and similar efficacy compared to standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT02411123​​.

Neuropsychiatric aspects of concussion: acute and chronic sequelae.

Concussion - also known as mild traumatic brain injury - is a transient disturbance of neurological function resulting from traumatic forces imparted to the brain that often produce cognitive, behavioral and systemic symptoms. In this review of the literature, we discuss the pathophysiology of both acute and chronic neuropsychiatric sequelae of concussions, followed by a brief overview of evaluation and management of these sequelae.

Aggression after traumatic brain injury: prevalence and correlates.

Aggression after traumatic brain injury (TBI) is common but not well defined. Sixty-seven participants with first-time TBI were evaluated for aggression within 3 months of injury. The prevalence of aggression was found to be 28.4%, predominantly verbal aggression. Post-TBI aggression was associated with new-onset major depression (p=0.02), poorer social functioning (p=0.04), and increased dependency in activities of daily living (p=0.03), but not with a history of substance abuse or adult/childhood behavioral problems. Implications of the study include early screening for aggression, evaluation for depression, and consideration of psychosocial support in aggressive patients.

Behavioral neurology and neuropsychiatry fellowship training: the Johns Hopkins model.

Behavioral neurology and neuropsychiatry training has recently been codified as a unitary fellowship, under the supervision of the United Council for Neurologic Subspecialties (UCNS). The authors describe how the Johns Hopkins Behavioral Neurology & Neuropsychiatry Fellowship has approached the challenging job of providing training for an inherently multidisciplinary field.

Neuropsychiatric problems after traumatic brain injury: unraveling the silent epidemic.

BACKGROUND: Traumatic brain injury (TBI) is a significant public health concern. According to the Centers for Disease Control and Prevention, about 1.4 million people in the United States sustain a TBI annually. OBJECTIVE: This review places particular emphasis on the current knowledge of effective treatment of TBI symptoms, and proposes directions for future research. RESULTS: Neuropsychiatric problems are more prevalent and longer-lasting in TBI patients than in the general population. About 40% of TBI victims suffer from two or more psychiatric disorders, and a similar percentage experience at least one unmet need for cognitive, emotional, or job assistance 1 year after injury. The entire spectrum of TBI severity, from mild to severe, is associated with an increase in psychiatric conditions. CONCLUSION: Despite the high incidence of severe consequences of TBI, there are scarce empirical data to guide psychiatric treatment. Some approaches that have been helpful include cognitive and behavioral therapy and pharmacologic treatment. The authors list specific research recommendations that could further identify useful therapeutic interventions.

Case report of treatment of severe mood disorder in an inpatient setting: when less is more.

Inpatient treatment of severe and chronic mood disorders can be challenging as clinicians are often under pressure to stabilize mood symptoms in a short period of time with limited resources. However, a multipronged team approach can help in fairly rapid resolution of symptoms. The case presented illustrates that this is both practical and beneficial.

Prevalence and types of sleep disturbances acutely after traumatic brain injury.

PRIMARY OBJECTIVE: To assess the prevalence of and risk factors for sleep disturbances in the acute post-traumatic brain injury (TBI) period. RESEARCH DESIGN: Longitudinal, observational study. METHODS AND PROCEDURES: Fifty-four first time closed-head injury patients were recruited and evaluated within 3 months after injury. Pre-injury and post-injury sleep disturbances were compared on the Medical Outcome Scale for Sleep. The subjects were also assessed on anxiety, depression, medical comorbidity and severity of TBI. MAIN OUTCOMES AND RESULTS: Subjects were worse on most sleep measures after TBI compared to before TBI. Anxiety disorder secondary to TBI was the most consistent significant risk factor to be associated with worsening sleep status. CONCLUSIONS: Anxiety is associated with sleep disturbances after TBI. Further studies need to be done to evaluate if this is a causal relationship.

Quetiapine as monotherapy for social anxiety disorder: a placebo-controlled study.

Social anxiety disorder (SAD) is one of the most common anxiety disorders. Reports have suggested an effect of the atypical antipsychotic quetiapine in anxiety disorders. Given these considerations, we conducted a controlled trial of quetiapine monotherapy in SAD. Fifteen patients were randomized to quetiapine (up to 400 mg/day) or placebo for 8 weeks. The Brief Social Phobia Scale (BSPS) and the Clinical Global Impression of Improvement Scale (CGI-I) were the primary outcome measures, while the Social Phobia Inventory (SPIN) and the Sheehan Disability Inventory (SDI) were secondary measures. There was no significant difference on the BSPS score at endpoint between the quetiapine and placebo groups. There was a significant time effect but not a significant time x treatment group interaction, indicating that both the quetiapine and placebo patients did better over the course of the trial. 20% of the quetiapine patients had a 50% or greater drop in BSPS score at the end of the trial compared to baseline, while 0% had such a drop in the placebo group. There was no significant difference in responders (CGI-I score of 1 or 2) versus non-responder (CGI-I score of 3 or more) across the groups. However, 40% of quetiapine patients and 0% of the placebo patients showed much or very much improvement on the CGI-I. The Number Needed to Treat (NNT) to be a responder on the CGI-I was 3. Significant time effects were noted for the SPIN and SDI, as well as a significant time x treatment effect in favor of quetiapine on the SPIN. Additionally, quetiapine showed a large effect size on the SPIN.

An abbreviated version of the Connor-Davidson Resilience Scale (CD-RISC), the CD-RISC2: psychometric properties and applications in psychopharmacological trials.

Resilience may be an important component of the prevention of neuropsychiatric disease. Resilience has proved to be quantifiable by scales such as the Connor-Davidson Resilience Scale (CD-RISC). Here, we introduce a two-item version of this scale, the CD-RISC2. We hypothesize that this shortened version of the scale has internal consistency, test-retest reliability, convergent validity, and divergent validity as well as significant correlation with the full scale. Additionally, we hypothesize that the CD-RISC2 can be used to assess pharmacological modification of resilience. We test these hypotheses by utilizing data from treatment trials of post-traumatic stress disorder, major depression, and generalized anxiety disorder with setraline, mirtazapine, fluoxetine, paroxetine, venlafaxine XR, and kava as well as data from the general population, psychiatric outpatients, and family medicine clinic patients.

Perceived stress in anxiety disorders and the general population: a study of the Sheehan stress vulnerability scale.

The objectives of this study were to (1) validate and establish normative values for a single-item, self-rated measure of perceived stress, the Stress Vulnerability Scale (SVS); and (2) compare levels of perceived stress in patients with anxiety disorders with the general population. The sample was drawn from the general population (n=630) and from participants in pharmacotherapy trials of anxiety disorders (social phobia, n=127; posttraumatic stress disorder, n=116). The SVS was administered at baseline in all groups and following treatment in the placebo-controlled clinical trial samples. The SVS demonstrated good reliability and validity. Pretreatment scores in the anxiety disorders were significantly greater than in the general population. Perceptions of vulnerability to the effects of daily stress are considerably greater in anxiety disorders compared to the general population and also differ within the anxiety disorders.

Neuroimaging in late-life depression.

Late-life depression may be associated with vasculopathy. Neuroimaging has been a critical tool in exploring the relationship between this form of depression and vascular factors. Magnetic resonance imaging has been the most widely used tool, but there is potential to use other structural imaging techniques as well as functional neuroimaging methodologies. Neuroimaging may potentially be utilized at some point as a biomarker for late-life depression, thus helping with diagnosis and guiding treatment.

Modafinil for atypical depression: effects of open-label and double-blind discontinuation treatment.

Atypical depression, with features of hypersomnia, hyperphagia, anergia, and rejection sensitivity, is a common presentation of major depressive disorder. There are few available effective therapies for this disorder. We test modafinil, a novel wake-promoting agent, as monotherapy for atypical depression in a double-blind, placebo-controlled, relapse prevention trial after open-label treatment. We found that modafinil significantly improved atypical depression symptoms during 12 weeks of open-label treatment (mean +/- SD Hamilton Depression Scale (29-item version) score changed from 34 +/- 8.2 at baseline to 9.7 +/- 9.3, P < 0.0001), and that benefits were maintained alike in both the continuation and placebo arms during the double-blind treatment phase (P = 0.92). Modafinil was well tolerated and the drug was associated with significant weight loss compared with placebo (P = 0.01).