Alpha oscillatory activity is causally linked to working memory retention.

Although previous studies have reported correlations between alpha oscillations and the "retention" subprocess of working memory (WM), causal evidence has been limited in human neuroscience due to the lack of delicate modulation of human brain oscillations. Conventional transcranial alternating current stimulation (tACS) is not suitable for demonstrating the causal evidence for parietal alpha oscillations in WM retention because of its inability to modulate brain oscillations within a short period (i.e., the retention subprocess). Here, we developed an online phase-corrected tACS system capable of precisely correcting for the phase differences between tACS and concurrent endogenous oscillations. This system permits the modulation of brain oscillations at the target stimulation frequency within a short stimulation period and is here applied to empirically demonstrate that parietal alpha oscillations causally relate to WM retention. Our experimental design included both in-phase and anti-phase alpha-tACS applied to participants during the retention subprocess of a modified Sternberg paradigm. Compared to in-phase alpha-tACS, anti-phase alpha-tACS decreased both WM performance and alpha activity. These findings strongly support a causal link between alpha oscillations and WM retention and illustrate the broad application prospects of phase-corrected tACS.

Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

The impact of body mass index on the clinical features of bipolar disorder: A STEP-BD study.

INTRODUCTION: The effects of body mass index (BMI) on the core symptoms of bipolar disorder (BD) and its implications for disease trajectory are largely unexplored. OBJECTIVE: To examine whether BMI impacted hospitalization rate, medical and psychiatric comorbidities, and core symptom domains such as depression and suicidality in BD. METHODS: Participants (15 years and older) were 2790 BD outpatients enrolled in the longitudinal STEP-BD study; all met DSM-IV criteria for BD-I, BD-II, cyclothymia, BD NOS, or schizoaffective disorder, bipolar subtype. BMI, demographic information, psychiatric and medical comorbidities, and other clinical variables such as bipolarity index, history of electroconvulsive therapy (ECT), and history of suicide attempts were collected at baseline. Longitudinal changes in Montgomery-Åsberg Depression Rating Scale (MADRS) score, Young Mania Rating Scale (YMRS) score, and hospitalizations during the study were also assessed. Depending on the variable of interest, odds-ratios, regression analyses, factor analyses, and graph analyses were applied. RESULTS: A robust increase in psychiatric and medical comorbidities was observed, particularly for baseline BMIs >35. A significant relationship was noted between higher BMI and history of suicide attempts, and individuals with BMIs >40 had the highest prevalence of suicide attempts. Obese and overweight individuals had a higher bipolarity index (a questionnaire measuring disease severity) and were more likely to have received ECT. Higher BMIs correlated with worsening trajectory of core depression symptoms and with worsening lassitude and inability to feel. CONCLUSIONS: In BD participants, elevated BMI was associated with worsening clinical features, including higher rates of suicidality, comorbidities, and core depression symptoms.

The Efficacy of Transcranial Magnetic Stimulation in the Treatment of Obsessive-Compulsive Disorder: An Umbrella Review of Meta-Analyses.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been increasingly used for treating obsessive-compulsive disorder (OCD). Although several meta-analyses have explored its effectiveness and safety, there is no umbrella review specifically focused on rTMS for OCD. This umbrella review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and analyzed relevant meta-analyses on rTMS for OCD. METHODS: Twenty-three articles were identified from PubMed, and after screening, 12 meta-analyses were included in the review. The studies analyzed in the meta-analyses ranged from 10 to 27, with total participants ranging from 282 to 791. The most commonly studied regions were the dorsolateral prefrontal cortex (DLPFC), supplementary motor area (SMA), and orbito-frontal cortex (OFC). RESULT: The majority of the meta-analyses consistently supported the effectiveness of rTMS in reducing OCD symptoms when applied to the DLPFC and SMA. Encouraging results were also observed when targeting the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) through deep transcranial magnetic stimulation (dTMS). However, there was a high level of heterogeneity in the findings of nine out of 12 meta-analyses. CONCLUSION: In conclusion, existing evidence suggests that rTMS targeting the DLPFC and SMA consistently reduces OCD symptoms, but targeting the mPFC and ACC through dTMS shows variable results. However, the high heterogeneity in the study findings indicates a need for further research and standardization in the field.

Device-Based Modulation of Neurocircuits as a Therapeutic for Psychiatric Disorders.

Device-based neuromodulation of brain circuits is emerging as a promising new approach in the study and treatment of psychiatric disorders. This work presents recent advances in the development of tools for identifying neurocircuits as therapeutic targets and in tools for modulating neurocircuits. We review clinical evidence for the therapeutic efficacy of circuit modulation with a range of brain stimulation approaches, including subthreshold, subconvulsive, convulsive, and neurosurgical techniques. We further discuss strategies for enhancing the precision and efficacy of neuromodulatory techniques. Finally, we survey cutting-edge research in therapeutic circuit modulation using novel paradigms and next-generation devices.

Electroconvulsive therapy, electric field, neuroplasticity, and clinical outcomes.

Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes, but the underlying mechanisms for antidepressant response and procedure-induced cognitive side effects have yet to be elucidated. Such mechanisms may be complex and involve certain ECT parameters and brain regions. Regarding parameters, the electrode placement (right unilateral or bitemporal) determines the geometric shape of the electric field (E-field), and amplitude determines the E-field magnitude in select brain regions (e.g., hippocampus). Here, we aim to determine the relationships between hippocampal E-field strength, hippocampal neuroplasticity, and antidepressant and cognitive outcomes. We used hippocampal E-fields and volumes generated from a randomized clinical trial that compared right unilateral electrode placement with different pulse amplitudes (600, 700, and 800 mA). Hippocampal E-field strength was variable but increased with each amplitude arm. We demonstrated a linear relationship between right hippocampal E-field and right hippocampal neuroplasticity. Right hippocampal neuroplasticity mediated right hippocampal E-field and antidepressant outcomes. In contrast, right hippocampal E-field was directly related to cognitive outcomes as measured by phonemic fluency. We used receiver operating characteristic curves to determine that the maximal right hippocampal E-field associated with cognitive safety was 112.5 V/m. Right hippocampal E-field strength was related to the whole-brain ratio of E-field strength per unit of stimulation current, but this whole-brain ratio was unrelated to antidepressant or cognitive outcomes. We discuss the implications of optimal hippocampal E-field dosing to maximize antidepressant outcomes and cognitive safety with individualized amplitudes.

Computation of transcranial magnetic stimulation electric fields using self-supervised deep learning.

Electric fields (E-fields) induced by transcranial magnetic stimulation (TMS) can be modeled using partial differential equations (PDEs). Using state-of-the-art finite-element methods (FEM), it often takes tens of seconds to solve the PDEs for computing a high-resolution E-field, hampering the wide application of the E-field modeling in practice and research. To improve the E-field modeling's computational efficiency, we developed a self-supervised deep learning (DL) method to compute precise TMS E-fields. Given a head model and the primary E-field generated by TMS coils, a DL model was built to generate a E-field by minimizing a loss function that measures how well the generated E-field fits the governing PDE. The DL model was trained in a self-supervised manner, which does not require any external supervision. We evaluated the DL model using both a simulated sphere head model and realistic head models of 125 individuals and compared the accuracy and computational speed of the DL model with a state-of-the-art FEM. In realistic head models, the DL model obtained accurate E-fields that were significantly correlated with the FEM solutions. The DL model could obtain precise E-fields within seconds for whole head models at a high spatial resolution, faster than the FEM. The DL model built for the simulated sphere head model also obtained an accurate E-field whose average difference from the analytical E-fields was 0.0054, comparable to the FEM solution. These results demonstrated that the self-supervised DL method could obtain precise E-fields comparable to the FEM solutions with improved computational speed.

Using diffusion tensor imaging to effectively target TMS to deep brain structures.

TMS has become a powerful tool to explore cortical function, and in parallel has proven promising in the development of therapies for various psychiatric and neurological disorders. Unfortunately, much of the inference of the direct effects of TMS has been assumed to be limited to the area a few centimeters beneath the scalp, though clearly more distant regions are likely to be influenced by structurally connected stimulation sites. In this study, we sought to develop a novel paradigm to individualize TMS coil placement to non-invasively achieve activation of specific deep brain targets of relevance to the treatment of psychiatric disorders. In ten subjects, structural diffusion imaging tractography data were used to identify an accessible cortical target in the right frontal pole that demonstrated both anatomic and functional connectivity to right Brodmann area 25 (BA25). Concurrent TMS-fMRI interleaving was used with a series of single, interleaved TMS pulses applied to the right frontal pole at four intensity levels ranging from 80% to 140% of motor threshold. In nine of ten subjects, TMS to the individualized frontal pole sites resulted in significant linear increase in BOLD activation of BA25 with increasing TMS intensity. The reliable activation of BA25 in a dosage-dependent manner suggests the possibility that the careful combination of imaging with TMS can make use of network properties to help overcome depth limitations and allow noninvasive brain stimulation to influence deep brain structures.

Links between electroconvulsive therapy responsive and cognitive impairment multimodal brain networks in late-life major depressive disorder.

BACKGROUND: Although electroconvulsive therapy (ECT) is an effective treatment for depression, ECT cognitive impairment remains a major concern. The neurobiological underpinnings and mechanisms underlying ECT antidepressant and cognitive impairment effects remain unknown. This investigation aims to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks and assesses whether they are associated with the ECT-induced electric field (E-field) with an optimal pulse amplitude estimation. METHODS: A single site clinical trial focused on amplitude (600, 700, and 800 mA) included longitudinal multimodal imaging and clinical and cognitive assessments completed before and immediately after the ECT series (n = 54) for late-life depression. Another two independent validation cohorts (n = 84, n = 260) were included. Symptom and cognition were used as references to supervise fMRI and sMRI fusion to identify ECT antidepressant-response and cognitive-impairment multimodal brain networks. Correlations between ECT-induced E-field within these two networks and clinical and cognitive outcomes were calculated. An optimal pulse amplitude was estimated based on E-field within antidepressant-response and cognitive-impairment networks. RESULTS: Decreased function in the superior orbitofrontal cortex and caudate accompanied with increased volume in medial temporal cortex showed covarying functional and structural alterations in both antidepressant-response and cognitive-impairment networks. Volume increases in the hippocampal complex and thalamus were antidepressant-response specific, and functional decreases in the amygdala and hippocampal complex were cognitive-impairment specific, which were validated in two independent datasets. The E-field within these two networks showed an inverse relationship with HDRS reduction and cognitive impairment. The optimal E-filed range as [92.7-113.9] V/m was estimated to maximize antidepressant outcomes without compromising cognitive safety. CONCLUSIONS: The large degree of overlap between antidepressant-response and cognitive-impairment networks challenges parameter development focused on precise E-field dosing with new electrode placements. The determination of the optimal individualized ECT amplitude within the antidepressant and cognitive networks may improve the treatment benefit-risk ratio. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02999269.

The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response.

Dysfunction in a wide array of systems-including the immune, monoaminergic, and glutamatergic systems-is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18-65) received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes-including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)-were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Ictal Theta Power as an Electroconvulsive Therapy Safety Biomarker: A Pilot Study.

OBJECTIVE: Electroconvulsive therapy (ECT) remains the benchmark for treatment resistant depression, yet its cognitive adverse effects have a negative impact on treatment. A predictive safety biomarker early in ECT treatment is needed to identify patients at cognitive risk to maximize therapeutic outcomes and minimize adverse effects. We used ictal electroencephalography frequency analysis from suprathreshold treatments to assess the relationships between ECT dose, ictal power across different frequency domains, and cognitive outcomes. METHODS: Seventeen subjects with treatment resistant depression received right unilateral ECT. Structural magnetic resonance imaging was obtained pre-ECT for electric field modeling to assess ECT dose. Serial assessments with 24-lead electroencephalography captured ictal activity. Clinical and cognitive assessments were performed before and after ECT. The primary cognitive outcome was the change in Delis Kaplan Executive Function Verbal Fluency Letter Fluency. RESULTS: Ictal theta (4-8 Hz) power in the Fp1/Fp2 channels was associated with both whole-brain electric field strength (t(2,12) = 19.5, P = 0.007)/(t(2,10) = 21.85, P = 0.02) and Delis Kaplan Executive Function Verbal Fluency Letter Fluency scores (t(2,12) = -2.05, P = 0.05)/(t(2,10) = -2.20, P = 0.01). Other frequency bands (beta, alpha, delta, and gamma) did not demonstrate this relationship. CONCLUSIONS: This pilot data identify ictal theta power as a potential safety biomarker in ECT and is related to the strength of the ECT dose. Ictal theta power could prove to be a convenient and powerful tool for clinicians to identify those patients most susceptible to cognitive impairment early in the treatment series. Additional studies are needed to assess the role of longitudinal changes in ictal theta power throughout the ECT series.

Electroconvulsive Therapy Pulse Amplitude and Clinical Outcomes.

INTRODUCTION: Electroconvulsive therapy (ECT) pulse amplitude, which determines the induced electric field magnitude in the brain, is currently set at 800-900 milliamperes (mA) on modern ECT devices without any clinical or scientific rationale. The present study assessed differences in depression and cognitive outcomes for three different pulse amplitudes during an acute ECT series. We hypothesized that the lower amplitudes would maintain the antidepressant efficacy of the standard treatment and reduce the risk of neurocognitive impairment. METHODS: This double-blind investigation randomized subjects to three treatment arms: 600, 700, and 800 mA (active comparator). Clinical, cognitive, and imaging assessments were conducted pre-, mid- and post-ECT. Subjects had a diagnosis of major depressive disorder, age range between 50 and 80 years, and met clinical indication for ECT. RESULTS: The 700 and 800 mA arms had improvement in depression outcomes relative to the 600 mA arm. The amplitude groups showed no differences in the primary cognitive outcome variable, the Hopkins Verbal Learning Test-Revised (HVLT-R) retention raw score. However, secondary cognitive outcomes such as the Delis Kaplan Executive Function System Letter and Category Fluency measures demonstrated cognitive impairment in the 800 mA arm. DISCUSSION: The results demonstrated a dissociation of depression (higher amplitudes better) and cognitive (lower amplitudes better) related outcomes. Future work is warranted to elucidate the relationship between amplitude, electric field, neuroplasticity, and clinical outcomes.

Association between tDCS computational modeling and clinical outcomes in depression: data from the ELECT-TDCS trial.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention investigated for the treatment of depression. Clinical results have been heterogeneous, partly due to the variability of electric field (EF) strength in the brain owing to interindividual differences in head anatomy. Therefore, we investigated whether EF strength was correlated with behavioral changes in 16 depressed patients using simulated electric fields in real patient data from a controlled clinical trial. We hypothesized that EF strength in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), brain regions implicated in depression pathophysiology, would be associated with changes in depression, mood and anxiety scores. SimNIBS were used to simulate individual electric fields based on the MRI structural T1-weighted brain scans of depressed subjects. Linear regression models showed, at the end of the acute treatment phase, that simulated EF strength was inversely associated with negative affect in the bilateral ACC (left: ß = - 160.463, CI [- 291.541, - 29.385], p = 0.021; right: ß = - 189.194, CI [- 289.479, - 88.910], p = 0.001) and DLPFC (left: ß = - 93.210, CI [- 154.960, - 31.461], p = 0.006; right: ß = - 82.564, CI [- 142.867, - 22.262], p = 0.011) and with depression scores in the left ACC (ß = - 156.91, CI [- 298.51, - 15.30], p = 0.033). No association between positive affect or anxiety scores, and simulated EF strength in the investigated brain regions was found. To conclude, our findings show preliminary evidence that EF strength simulations might be associated with further behavioral changes in depressed patients, unveiling a potential mechanism of action for tDCS. Further studies should investigate whether individualization of EF strength in key brain regions impact clinical response.

Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study.

OBJECTIVE: There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHODS: Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05. RESULTS: A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest. CONCLUSION: This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

The development and modelling of devices and paradigms for transcranial magnetic stimulation.

Magnetic stimulation is a non-invasive neurostimulation technique that can evoke action potentials and modulate neural circuits through induced electric fields. Biophysical models of magnetic stimulation have become a major driver for technological developments and the understanding of the mechanisms of magnetic neurostimulation and neuromodulation. Major technological developments involve stimulation coils with different spatial characteristics and pulse sources to control the pulse waveform. While early technological developments were the result of manual design and invention processes, there is a trend in both stimulation coil and pulse source design to mathematically optimize parameters with the help of computational models. To date, macroscopically highly realistic spatial models of the brain, as well as peripheral targets, and user-friendly software packages enable researchers and practitioners to simulate the treatment-specific and induced electric field distribution in the brains of individual subjects and patients. Neuron models further introduce the microscopic level of neural activation to understand the influence of activation dynamics in response to different pulse shapes. A number of models that were designed for online calibration to extract otherwise covert information and biomarkers from the neural system recently form a third branch of modelling.

Multifactorial determinants of the neurocognitive effects of electroconvulsive therapy.

For many patients with neuropsychiatric illnesses, standard psychiatric treatments with mono or combination pharmacotherapy, psychotherapy, and transcranial magnetic stimulation are ineffective. For these patients with treatment-resistant neuropsychiatric illnesses, a main therapeutic option is electroconvulsive therapy (ECT). Decades of research have found ECT to be highly effective; however, it can also result in adverse neurocognitive effects. Specifically, ECT results in disorientation after each session, anterograde amnesia for recently learned information, and retrograde amnesia for previously learned information. Unfortunately, the neurocognitive effects and underlying mechanisms of action of ECT remain poorly understood. The purpose of this paper was to synthesize the multiple moderating and mediating factors that are thought to underlie the neurocognitive effects of ECT into a coherent model. Such factors include demographic and neuropsychological characteristics, neuropsychiatric symptoms, ECT technical parameters, and ECT-associated neurophysiological changes. Future research is warranted to evaluate and test this model, so that these findings may support the development of more refined clinical seizure therapy delivery approaches and efficacious cognitive remediation strategies to improve the use of this important and widely used intervention tool for neuropsychiatric diseases.