Combining neuroimaging and brain stimulation to test alternative causal pathways for nicotine addiction in schizophrenia.

The smoking rate is high in patients with schizophrenia. Brain stimulation targeting conventional brain circuits associated with nicotine addiction has also yielded mixed results. We aimed to identify alternative circuitries associated with nicotine addiction in both the general population and schizophrenia, and then test whether modulation of such circuitries may alter nicotine addiction behaviors in schizophrenia. In Study I of 40 schizophrenia smokers and 51 non-psychiatric smokers, cross-sectional neuroimaging analysis identified resting state functional connectivity (rsFC) between the dorsomedial prefrontal cortex (dmPFC) and multiple extended amygdala regions to be most robustly associated with nicotine addiction severity in healthy controls and schizophrenia patients (p = 0.006 to 0.07). In Study II with another 30 patient smokers, a proof-of-concept, patient- and rater-blind, randomized, sham-controlled rTMS design was used to test whether targeting the newly identified dmPFC location may causally enhance the rsFC and reduce nicotine addiction in schizophrenia. Although significant interactions were not observed, exploratory analyses showed that this dmPFC-extended amygdala rsFC was enhanced by 4-week active 10Hz rTMS (p = 0.05) compared to baseline; the severity of nicotine addiction showed trends of reduction after 3 and 4 weeks (p ≤ 0.05) of active rTMS compared to sham; Increased rsFC by active rTMS predicted reduction of cigarettes/day (R = -0.56, p = 0.025 uncorrected) and morning smoking severity (R = -0.59, p = 0.016 uncorrected). These results suggest that the dmPFC-extended amygdala circuit may be linked to nicotine addiction in schizophrenia and healthy individuals, and future efforts targeting its underlying pathophysiological mechanisms may yield more effective treatment for nicotine addiction.

Electroconvulsive Therapy in the United States: A 2022 Survey of Practice.

OBJECTIVES: This study aimed to describe current US electroconvulsive therapy (ECT) practice, identify practice changes over time, and inform discussion of practice. METHOD: Our anonymous survey was open on SurveyMonkey.com from January to June 2022. We sent invitations to providers identified using a Medicare provider database, an advanced PubMed search function, and professional group listservs. Participants were instructed to submit 1 survey per ECT site. We examined frequency of responses, tabulated individual comments, and grouped data for comparison. RESULTS: We received responses from 74 US practice sites encompassing 283 providers. Forty-nine percent (n = 36) of respondents practiced at general academic medical centers, 23% (n = 17) at general medical centers, 16% (n = 12) at freestanding psychiatric hospitals, and 7% (n = 5) at Veterans Affairs medical centers. Proportions of female (29%) and Black or African American (AA) (1%) ECT providers were markedly lower than proportions of female (60%) and Black or African American ECT patients (10%). The median number of treatments for a major depressive episode was 10. The preferred electrode placement was right unilateral (66%, n = 45). The favored dosing strategy was seizure threshold titration. Quantitative outcome measures were used by 89% (n = 66) of sites for depressive symptoms and 84% (n = 62) for cognitive adverse effects. CONCLUSIONS: This survey is the first nationwide survey of ECT practice in nearly 40 years. Our results describe changes in practice over time and highlight the need to increase the number of female and Black or African American ECT providers. A comprehensive network of ECT sites could facilitate more frequent nationwide surveys.

Electroconvulsive Therapy Across Nations: A 2022 Survey of Practice.

OBJECTIVES: We aimed to characterize worldwide electroconvulsive therapy (ECT) practice and compare practice across nations and global regions. METHOD: Our anonymous survey was open on SurveyMonkey.com from January to June 2022. We sent invitations to providers identified using a Medicare provider database, an advanced PubMed search function, and professional group listservs. Participants were instructed to submit one survey per ECT site. Response frequencies were pooled by global region and compared using nonparametric methods. RESULTS: Responses came from 126 sites, mostly in the United States (59%, n = 74), Europe (18%, n = 23), Canada (10%, n = 12), and South/East Asia (6%, n = 8). With some exceptions, sites were broadly consistent in practice as indicated by: a likely shift internationally from bitemporal to right unilateral electrode placement; predominant use of pulse widths <1 ms; preference for seizure threshold titration over age-based dosing methods; widespread availability of continuation/maintenance ECT (97%); and frequent use of quantitative outcome measures for depressive symptoms (88%) and cognitive adverse effects (80%). CONCLUSIONS: This is the first, published survey that aimed to characterize worldwide ECT practice. With some exceptions, responses suggest a concordance in practice. However, responses were primarily from the Global North. To obtain a truly worldwide characterization of practice, future surveys should include more responses from the Global South.

Distinguishing Convulsive Syncope From Seizure Induced by Repetitive Transcranial Magnetic Stimulation: A Case Report.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is Food and Drug Administration cleared for clinical use in treatment-resistant depression and a growing list of other disorders. The clinical uptake of rTMS has been facilitated by its relatively benign adverse-effect profile compared with other treatment modalities. Seizure is a rare but serious adverse event that has been reported with rTMS, when dosage exceeds safety guidelines or in individuals at increased risk for seizure. Fortunately, most rTMS-induced seizures are typically transient, with no adverse sequelae, but they may lead to treatment discontinuation. Seizure is not the only cause of loss of conscious and abnormal movements induced by rTMS. Convulsive syncope, a more common adverse event that involves loss of consciousness associated with myoclonic movements, can be difficult to differentiate from an rTMS-induced seizure. We report the case of a 52-year-old man with no known seizure risk factors, enrolled in an institutional review board-approved research study who developed what appeared to be a convulsive syncopal episode lasting 10 to 15 seconds during day 2 of a 30-day rTMS protocol (10 Hz, 120% of motor threshold, 4-second pulse train, 26-second intertrain interval, 3000 pulses per session), with no adverse sequelae. The patient's history, screening, physical examination, pertinent laboratory, neurology consult, electroencephalogram, and imaging findings are discussed. This case demonstrates that distinguishing between convulsive syncope and rTMS-induced seizure can be a diagnostic challenge. Clinicians and researchers delivering rTMS should be familiar with the risk factors for rTMS-induced seizures and rTMS-induced convulsive syncope, to screen for predisposing factors and to manage these rare adverse events if they occur.

Noninvasive neuromodulation of the prefrontal cortex in mental health disorders.

More than any other brain region, the prefrontal cortex (PFC) gives rise to the singularity of human experience. It is therefore frequently implicated in the most distinctly human of all disorders, those of mental health. Noninvasive neuromodulation, including electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS) among others, can-unlike pharmacotherapy-directly target the PFC and its neural circuits. Direct targeting enables significantly greater on-target therapeutic effects compared with off-target adverse effects. In contrast to invasive neuromodulation approaches, such as deep-brain stimulation (DBS), noninvasive neuromodulation can reversibly modulate neural activity from outside the scalp. This combination of direct targeting and reversibility enables noninvasive neuromodulation to iteratively change activity in the PFC and its neural circuits to reveal causal mechanisms of both disease processes and healthy function. When coupled with neuronavigation and neurophysiological readouts, noninvasive neuromodulation holds promise for personalizing PFC neuromodulation to relieve symptoms of mental health disorders by optimizing the function of the PFC and its neural circuits. ClinicalTrials.gov Identifier: NCT03191058.

Glucose-6-phosphate dehydrogenase activity in bipolar disorder and schizophrenia: Relationship to mitochondrial impairment.

Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway that is essential to maintaining cellular redox balance. G6PD is especially plentiful in brain, and its deficiency has been linked to mood and psychotic disorders. We measured G6PD activity spectrophotometrically in four groups of 15 parietal somatosensory association cortex [Brodmann area (BA) 7] tissue samples (N = 60) from individuals with bipolar disorder (BPD); nonpsychotic unipolar major depression (UPD); schizophrenia (SCZ), and controls without psychiatric illness (CON). We report for the first time brain G6PD activity levels in these disorders. G6PD activity did not differ by brain group. In BPD and SCZ brains, however, it correlated significantly and inversely with percent of hexokinase 1 (HK1) in the tissue homogenate mitochondrial fraction as determined previously in another set of tissue samples obtained from the same brains and brain region. The correlation in SCZ brains lost statistical significance after controlling for brain pH. This finding indicates a positive relationship in BPD brains between G6PD activity and HK1 mitochondrial detachment, an indicator of mitochondrial impairment associated with increased mitochondrial generation of reactive oxygen species. We speculate that this relationship could be evidence that G6PD activity is proportionate to and may be a compensatory response to oxidative stress in the BA7 region of BPD brains. Future research should focus on clarifying the relationships among G6PD activity, markers of oxidative stress, brain pH, and evidence of mitochondrial impairment, particularly HK1 mitochondrial detachment, in brains of individuals with G6PD deficiency, BPD and SCZ.

Post-stroke fatigue as an indicator of underlying bioenergetics alterations.

Approximately half of stroke survivors suffer from clinically significant fatigue, contributing to poor quality of life, depression, dependency, and increased mortality. The etiology of post-stroke fatigue is not well understood and treatment is limited. This study tested the hypothesis that systemic aerobic energy metabolism, as reflected by platelet oxygen consumption, is negatively associated with fatigue and systemic inflammation is positively associated with fatigue in chronic ischemic stroke survivors. Data on self-reported level of fatigue, platelet oxygen consumption rates (OCR) and plasma inflammatory markers were analyzed from 20 ischemic stroke survivors. DNA copy number for two mitochondrial genes was measured as a marker of platelet mitochondrial content. Basal and protonophore-stimulated maximal platelet OCR showed a biphasic relationship to fatigue. Platelet OCR was negatively associated with low to moderate fatigue but was positively associated with moderate to high fatigue. DNA copy number was not associated with either fatigue or platelet OCR. Fatigue was negatively associated with C-reactive protein but not with other inflammatory markers. Post-stroke fatigue may be indicative of a systemic cellular energy dysfunction that is reflected in platelet energy metabolism. The biphasic relationship of fatigue to platelet OCR may indicate an ineffective bioenergetic compensatory response that has been observed in other pathological states.

The Safety of Electroconvulsive Therapy in Patients With Implanted Deep Brain Stimulators: A Review of the Literature and Case Report.

Currently there is no consensus statement about the safety of electroconvulsive therapy in patients who have implanted electrodes for deep brain stimulation. We present a summary of the existing literature on this topic, consisting of 21 cases, and then report a case performed at the University of Maryland Medical Center. Notably, with appropriate safety precautions and careful patient selection, there were no adverse events reported in the literature that were related to the presence of the deep brain stimulation device in any of the cases. Based on our review of the literature and the case we present, we have found no evidence so far to indicate that electroconvulsive therapy in patients with an implanted deep brain stimulator is unsafe.

Electroconvulsive Therapy in a Patient With a Recent Subarachnoid Hemorrhage.

The safety of electroconvulsive therapy (ECT) is improving with advances in anesthesia and ECT technique. There are published case reports of successful treatment of depression in patients who were once considered at high medical risk. Recent cerebral hemorrhage is one of the conditions considered to significantly increase the risk of ECT treatment. Literature search did not indicate any case reports of ECT treatment in patients with recent subarachnoid hemorrhage. We report the successful ECT treatment of depression in an older man who had developed a subarachnoid hemorrhage after a suicide attempt by ingestion of antifreeze.

Association of Electroconvulsive Therapy With Psychiatric Readmissions in US Hospitals.

Importance: Although electroconvulsive therapy (ECT) is considered the most efficacious treatment available for individuals with severe affective disorders, ECT's availability is limited and declining, suggesting that information about the population-level effects of ECT is needed. Objective: To examine whether inpatient treatment with ECT is associated with a reduction in 30-day psychiatric readmission risk in a large, multistate sample of inpatients with severe affective disorders. Design, Setting, and Participants: A quasi-experimental instrumental variables probit model of the association correlation of ECT administration with patient risk of 30-day readmission was estimated using observational, longitudinal data on hospital inpatient discharges from US general hospitals in 9 states. From a population-based sample of 490 252 psychiatric inpatients, a sample was drawn that consisted of 162 691 individuals with a principal diagnosis of major depressive disorder (MDD), bipolar disorder, or schizoaffective disorder. The key instrumental variable used in the analysis was ECT prevalence in the prior calendar year at the treating hospital. To examine whether ECT's association with readmissions was heterogeneous across population subgroups, analyses included interactions of ECT with age group, sex, race/ethnicity, and diagnosis group. The study was conducted from August 27, 2015, to March 7, 2017. Main Outcome and Measures: Readmission within 30 days of being discharged. Results: Overall, 2486 of the 162 691 inpatients (1.5%) underwent ECT during their index admission. Compared with other inpatients, those who received ECT were older (mean [SD], 56.8 [16.5] vs 45.9 [16.5] years; P < .001) and more likely to be female (65.0% vs 54.2%; P < .001) and white non-Hispanic (85.3% vs 62.1%; P < .001), have MDD diagnoses (63.8% vs 32.0%; P < .001) rather than bipolar disorder (29.0% vs 40.0%; P < .001) or schizoaffective disorder (7.1% vs 28.0%; P < .001), have a comorbid medical condition (31.3% vs 26.6%; P < .001), have private (39.4% vs 21.7%; P < .001) or Medicare (49.2% vs 39.4%; P < .001) insurance coverage, and be located in urban small hospitals (31.2% vs 22.3%; P < .001) or nonurban hospitals (9.0% vs 7.6%; P = .02). Administration of ECT was associated with a reduced 30-day readmission risk among psychiatric inpatients with severe affective disorders from an estimated 12.3% among individuals not administered ECT to 6.6% among individuals administered ECT (risk ratio [RR], 0.54; 95% CI, 0.28-0.81). Significantly larger associations with ECT on readmission risk were found for men compared with women (RR, 0.44; 95% CI, 0.20-0.69 vs 0.58; 95% CI, 0.30-0.88) and for individuals with bipolar disorder (RR, 0.42; 95% CI, 0.17-0.69) and schizoaffective disorder (RR, 0.44; 95% CI, 0.11-0.79) compared with those who had MDD (RR, 0.53; 95% CI, 0.26-0.81). Conclusions and Relevance: Electroconvulsive therapy may be associated with reduced short-term psychiatric inpatient readmissions among psychiatric inpatients with severe affective disorders. This potential population health effect may be overlooked in US hospitals' current decision making regarding the availability of ECT.

Elevated Plasma Aß42 in Cognitively Impaired Individuals Taking ACE Inhibitor Antihypertensives.

BACKGROUND/RATIONALE: Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-ß (Aß), possibly indicating improved Aß clearance from brain to blood. METHODS: We measured and compared plasma concentrations of Aß42, Aß40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer's disease (AD) dementia, and mixed probable AD/vascular dementia. RESULTS: Plasma Aß42 levels and Aß42/Aß40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10). CONCLUSIONS: This study is the first to show an association between ACE-I use and increased plasma Aß42 level and Aß42/Aß40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aß42 indicates improved Aß42 clearance from brain that contributes to protection from cognitive decline.

Nonconvulsive Electrotherapy for Treatment Resistant Unipolar and Bipolar Major Depressive Disorder: A Proof-of-concept Trial.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective therapy for treatment resistant major depressive disorder (TRD); however, some individuals with TRD refuse ECT over concern about adverse cognitive effects. Clinical observation of two patients with TRD who had a therapeutic response to intended ECT despite having only one or no seizure suggested that nonconvulsive electrical stimulation may be effective in some patients. OBJECTIVE/HYPOTHESIS: This study tested the hypothesis that electrical brain stimulation applied like standard ECT, but below seizure threshold, can have therapeutic effects on TRD with fewer adverse cognitive effects. METHODS: Thirteen outpatients with TRD (6 unipolar, 7 bipolar) who refused ECT participated in this open label adjunctive treatment study of nonconvulsive electrotherapy (NET) at the University of Maryland Medical Center. Brief pulse bifrontal electrical stimulation was given thrice weekly with a Thymatron System IV Integrated ECT Instrument. RESULTS: Seizure-free data were obtained from 11 of 13 subjects. Group mean Hamilton Depression Rating Scale 17-item version scores declined significantly (P = 0.001) from 20.3 to 8.6. Response and remission rates were 73% (8) and 55% (6), respectively. Cognitive testing using the Mini-Mental State Exam and the Autobiographical Memory Inventory-Short Form did not show declines typically observed with ECT. CONCLUSIONS: The therapeutic effect of NET on TRD was similar to that of ECT. Serious adverse effects and adverse cognitive effects were not observed. These results challenge the widespread belief that a seizure is necessary for the antidepressant effect of ECT and merit further investigation to determine whether NET is a viable alternative to ECT in some patients with TRD. Clinical trial posted on www.clinicaltrials.gov, identifier: NCT01065597.

A mitochondrial bioenergetic basis of depression.

Major depressive disorder (MDD) is an important public health problem affecting 350 million people worldwide. After decades of study, the pathophysiology of MDD remains elusive, resulting in treatments that are only 30-60% effective. This review summarizes the emerging evidence that implicates impaired mitochondrial bioenergetics as a basis for MDD. It is suggested that impaired mitochondrial bioenergetic function contributes to the pathophysiology of MDD via several potential pathways including: genetics/genomics, inflammation, oxidative stress, and alterations in neuroplasticity. A discussion of mitochondrial bioenergetic pathways that lead to MDD is provided. Evidence is reviewed regarding the mito-toxic or mito-protective impact of various antidepressant medications currently in use. Opportunities for further research on novel therapeutic approaches, including mitochondrial modulators, as stand-alone or adjunct therapy for reducing depression are suggested. In conclusion, while there is substantial evidence linking mitochondrial bioenergetics and MDD, there are currently no clear mitochondrial phenotypes or biomarkers to use as guides in targeting therapies beyond individuals with MDD and known mitochondrial disorders toward the general population of individuals with MDD. Further study is needed to develop these phenotypes and biomarkers, to identify therapeutic targets, and to test therapies aimed at improving mitochondrial function in individuals whose MDD is to some extent symptomatic of impaired mitochondrial bioenergetics.