Distinct cognitive and functional connectivity features from healthy cohorts can identify clinical obsessive-compulsive disorder.

Improving diagnostic accuracy of obsessive-compulsive disorder (OCD) using models of brain imaging data is a key goal of the field, but this objective is challenging due to the limited size and phenotypic depth of clinical datasets. Leveraging the phenotypic diversity in large non-clinical datasets such as the UK Biobank (UKBB), offers a potential solution to this problem. Nevertheless, it remains unclear whether classification models trained on non-clinical populations will generalise to individuals with clinical OCD. This question is also relevant for the conceptualisation of OCD; specifically, whether the symptomology of OCD exists on a continuum from normal to pathological. Here, we examined a recently published "meta-matching" model trained on functional connectivity data from five large normative datasets (N=45,507) to predict cognitive, health and demographic variables. Specifically, we tested whether this model could classify OCD status in three independent clinical datasets (N=345). We found that the model could identify out-of-sample OCD individuals. Notably, the most predictive functional connectivity features mapped onto known cortico-striatal abnormalities in OCD and correlated with genetic brain expression maps previously implicated in the disorder. Further, the meta-matching model relied upon estimates of cognitive functions, such as cognitive flexibility and inhibition, to successfully predict OCD. These findings suggest that variability in non-clinical brain and behavioural features can discriminate clinical OCD status. These results support a dimensional and transdiagnostic conceptualisation of the brain and behavioural basis of OCD, with implications for research approaches and treatment targets.

Exploring functional connectivity in large-scale brain networks in obsessive-compulsive disorder: a systematic review of EEG and fMRI studies.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric condition that is difficult to treat due to our limited understanding of its pathophysiology. Functional connectivity in brain networks, as evaluated through neuroimaging studies, plays a pivotal role in understanding OCD. While both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have been extensively employed in OCD research, few have fully synthesized their findings. To bridge this gap, we reviewed 166 studies (10 EEG, 156 fMRI) published up to December 2023. In EEG studies, OCD exhibited lower connectivity in delta and alpha bands, with inconsistent findings in other frequency bands. Resting-state fMRI studies reported conflicting connectivity patterns within the default mode network (DMN) and sensorimotor cortico-striato-thalamo-cortical (CSTC) circuitry. Many studies observed decreased resting-state connectivity between the DMN and salience network (SN), implicating the 'triple network model' in OCD. Task-related hyperconnectivity within the DMN-SN and hypoconnectivity between the SN and frontoparietal network suggest OCD-related cognitive inflexibility, potentially due to triple network dysfunction. In conclusion, our review highlights diverse connectivity differences in OCD, revealing complex brain network interplay that contributes to symptom manifestation. However, the presence of conflicting findings underscores the necessity for targeted research to achieve a comprehensive understanding of the pathophysiology of OCD.

Quantitative Analysis of Factors of Attrition in a Double-blind rTMS Study for Alzheimer Treatment.

Attrition is a particular concern in studies examining the efficacy of a treatment for Alzheimer disease. Analyzing reasons for withdrawal in Alzheimer studies is crucial to ruling out attrition bias, which can undermine a study's validity. In contrast, attrition in studies using repetitive transcranial magnetic stimulation (rTMS) has received much less attention. Our goal was to identify any commonalities between participants who withdrew for the same reasons. Three independent coders rated each response concerning the reasons for withdrawal, and frequency tables were generated to characterize the participants within each category. This study was conducted on the 28 withdrawn cases from a 7-month study investigating the short-term and long-term therapeutic effects of rTMS for Alzheimer disease among 156 participants across 3 sites of the study. Seven reasons for withdrawal were identified, with health and medical changes being the most commonly reported reason (7 participants). Personal issues involving family or caregivers were the next most common (5 participants), and the remaining 5 categories consisted of 3 participants each. Although the limited sample size prevented the use of inferential statistics, our findings highlight the need for more transparent reporting of attrition rates and withdrawal reasons by rTMS researchers.

Revisiting the effects of rTMS over the dorsolateral prefrontal cortex on pain: An updated systematic review and meta-analysis.

BACKGROUND: Our previous study synthesized the analgesic effects of repetitive Transcranial Magnetic Stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) trials up to 2019. There has been a significant increase in pain trials in the past few years, along with methodological variabilities such as sample size, stimulation intensity, and rTMS paradigms. OBJECTIVES/METHODS: This study therefore updated the effects of DLPFC-rTMS on chronic pain and quantified the impact of methodological differences across studies. RESULTS: A total of 36 studies were included. Among them, 26 studies were clinical trials (update = 9, 307/711 patients), and 10 (update = 1, 34/249 participants) were provoked pain studies. The updated meta-analysis does not support an effect on neuropathic pain after including the additional trials (pshort-term = 0.20, pmid-term = 0.50). However, there is medium-to-large analgesic effect in migraine trials extending up to six weeks follow-up (SMDmid-term = -0.80, SMDlong-term = -0.51), that was not previously reported. Methodological differences wthine the studies were considered. DLPFC-rTMS also induces potential improvement in the emotional aspects of pain (SMDshort-term = -0.28). CONCLUSIONS: The updated systematic meta-analysis continues to support analgesic effects for chronic pain overall. However, the updated results no longer support DLPFC-rTMS for pain relief in neuropathic pain, and do supports DLPFC-rTMS in the management of migraine. There is also evidence for DLPFC-rTMS to improve emotional aspects of pain.

Pilot study with randomised control of dual site theta burst transcranial magnetic stimulation (TMS) for methamphetamine use disorder: a protocol for the TARTAN study.

BACKGROUND: Transcranial magnetic stimulation (TMS) (including the theta burst stimulation (TBS) form of TMS used in this study) is a non-invasive means to stimulate nerve cells in superficial areas of the brain. In recent years, there has been a growth in the application of TMS to investigate the modulation of neural networks involved in substance use disorders. This study examines the feasibility of novel TMS protocols for the treatment of methamphetamine (MA) use disorder in an ambulatory drug and alcohol treatment setting. METHODS: Thirty participants meeting the criteria for moderate to severe MA use disorder will be recruited in community drug and alcohol treatment settings and randomised to receive active TMS or sham (control) intervention. The treatment is intermittent TBS (iTBS) applied to the left dorsolateral prefrontal cortex (DLPFC), then continuous TBS (cTBS) to the left orbitofrontal cortex (OFC). Twelve sessions are administered over 4 weeks with opt-in weekly standardized cognitive behaviour therapy (CBT) counselling and a neuroimaging sub-study offered to participants. Primary outcomes are feasibility measures including recruitment, retention and acceptability of the intervention. Secondary outcomes include monitoring of safety and preliminary efficacy data including changes in substance use, cravings (cue reactivity) and cognition (response inhibition). DISCUSSION: This study examines shorter TBS protocols of TMS for MA use disorder in real-world drug and alcohol outpatient settings where withdrawal and abstinence from MA, or other substances, are not eligibility requirements. TMS is a relatively affordable treatment and staff of ambulatory health settings can be trained to administer TMS. It is a potentially scalable and translatable treatment for existing drug and alcohol clinical settings. TMS has the potential to provide a much-needed adjuvant treatment to existing psychosocial interventions for MA use disorder. A limitation of this protocol is that the feasibility of follow-up is only examined at the end of treatment (4 weeks). TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry ACTRN12622000762752. Registered on May 27, 2022, and retrospectively registered (first participant enrolled) on May 23, 2022, with protocol version 7 on February 24, 2023.

No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

BACKGROUND: Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. OBJECTIVE: The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. METHOD: Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. RESULTS: During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. CONCLUSIONS: The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

Site Dependency of Anodal Transcranial Direct-Current Stimulation on Reaction Time and Transfer of Learning during a Sequential Visual Isometric Pinch Task.

Considering the advantages of brain stimulation techniques in detecting the role of different areas of the brain in human sensorimotor behaviors, we used anodal transcranial direct-current stimulation (a-tDCS) over three different brain sites of the frontoparietal cortex (FPC) in healthy participants to elucidate the role of these three brain areas of the FPC on reaction time (RT) during a sequential visual isometric pinch task (SVIPT). We also aimed to assess if the stimulation of these cortical sites affects the transfer of learning during SVIPT. A total of 48 right-handed healthy participants were randomly assigned to one of the four a-tDCS groups: (1) left primary motor cortex (M1), (2) left dorsolateral prefrontal cortex (DLPFC), (3) left posterior parietal cortex (PPC), and (4) sham. A-tDCS (0.3 mA, 20 min) was applied concurrently with the SVIPT, in which the participants precisely controlled their forces to reach seven different target forces from 10 to 40% of the maximum voluntary contraction (MVC) presented on a computer screen with the right dominant hand. Four test blocks were randomly performed at the baseline and 15 min after the intervention, including sequence and random blocks with either hand. Our results showed significant elongations in the ratio of RTs between the M1 and sham groups in the sequence blocks of both the right-trained and left-untrained hands. No significant differences were found between the DLPFC and sham groups and the PPC and sham groups in RT measurements within the SVIPT. Our findings suggest that RT improvement within implicit learning of an SVIPT is not mediated by single-session a-tDCS over M1, DLPFC, or PPC. Further research is needed to understand the optimal characteristics of tDCS and stimulation sites to modulate reaction time in a precision control task such as an SVIPT.

Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of ß-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

Can Brain Volume-Driven Characteristic Features Predict the Response of Alzheimer's Patients to Repetitive Transcranial Magnetic Stimulation? A Pilot Study.

This study is a post-hoc examination of baseline MRI data from a clinical trial investigating the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for patients with mild-moderate Alzheimer's disease (AD). Herein, we investigated whether the analysis of baseline MRI data could predict the response of patients to rTMS treatment. Whole-brain T1-weighted MRI scans of 75 participants collected at baseline were analyzed. The analyses were run on the gray matter (GM) and white matter (WM) of the left and right dorsolateral prefrontal cortex (DLPFC), as that was the rTMS application site. The primary outcome measure was the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog). The response to treatment was determined based on ADAS-Cog scores and secondary outcome measures. The analysis of covariance showed that responders to active treatment had a significantly lower baseline GM volume in the right DLPFC and a higher GM asymmetry index in the DLPFC region compared to those in non-responders. Logistic regression with a repeated five-fold cross-validated analysis using the MRI-driven features of the initial 75 participants provided a mean accuracy of 0.69 and an area under the receiver operating characteristic curve of 0.74 for separating responders and non-responders. The results suggest that GM volume or asymmetry in the target area of active rTMS treatment (DLPFC region in this study) may be a weak predictor of rTMS treatment efficacy. These results need more data to draw more robust conclusions.

Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial.

We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer's disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham rTMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. The rTMS pulses (20 â€‹Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied serially to the left and right dorsolateral prefrontal cortex using neuro-navigation. We compared the primary outcome measure's (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment up to two months post-treatment with either sham or active coils. The results show both short and long-term benefits of active rTMS treatment but also show similar benefits for sham coil treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil's potential to induce a low-level current in the brain. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02908815.

Electroconvulsive Therapy Credentialing for Psychiatrists-Review of Required Standards Across States and Territories in Australia.

ABSTRACT: Electroconvulsive therapy (ECT) is a complex medical procedure, the delivery of which requires specialist knowledge and skills. We reviewed the standards required for ECT credentialing in different jurisdictions in Australia. We reviewed the Chief Psychiatrist guidelines and statewide policy standards on ECT and focused on standards required for initial credentialing and ongoing privileging in ECT. We compared the credentialing requirements within these documents with the standards specified in the Royal Australian and New Zealand College of Psychiatrists professional practice guideline for ECT. Most of the jurisdictions had specific standards for initial credentialing and maintenance of this credentialing; however, there was significant variance in the credentialing process and standards required. It would be useful to have a minimum standard for credentialing for ECT psychiatrists and prescribers. This standard would be relevant for practice of ECT internationally. States and territories would have the responsibility for implementation of these standards. Appropriate training and establishing good clinical governance processes are essential to the provision of high quality ECT.

Uncovering a stability signature of brain dynamics associated with meditation experience using massive time-series feature extraction.

Previous research has examined resting electroencephalographic (EEG) data to explore brain activity related to meditation. However, previous research has mostly examined power in different frequency bands. The practical objective of this study was to comprehensively test whether other types of time-series analysis methods are better suited to characterize brain activity related to meditation. To achieve this, we compared >7000 time-series features of the EEG signal to comprehensively characterize brain activity differences in meditators, using many measures that are novel in meditation research. Eyes-closed resting-state EEG data from 49 meditators and 46 non-meditators was decomposed into the top eight principal components (PCs). We extracted 7381 time-series features from each PC and each participant and used them to train classification algorithms to identify meditators. Highly differentiating individual features from successful classifiers were analysed in detail. Only the third PC (which had a central-parietal maximum) showed above-chance classification accuracy (67 %, pFDR = 0.007), for which 405 features significantly distinguished meditators (all pFDR < 0.05). Top-performing features indicated that meditators exhibited more consistent statistical properties across shorter subsegments of their EEG time-series (higher stationarity) and displayed an altered distributional shape of values about the mean. By contrast, classifiers trained with traditional band-power measures did not distinguish the groups (pFDR > 0.05). Our novel analysis approach suggests the key signatures of meditators' brain activity are higher temporal stability and a distribution of time-series values suggestive of longer, larger, or more frequent non-outlying voltage deviations from the mean within the third PC of their EEG data. The higher temporal stability observed in this EEG component might underpin the higher attentional stability associated with meditation. The novel time-series properties identified here have considerable potential for future exploration in meditation research and the analysis of neural dynamics more broadly.

Comparisons of Accelerated Continuous and Intermittent Theta Burst Stimulation for Treatment-Resistant Depression and Suicidal Ideation.

BACKGROUND: Suicidal ideation is a substantial clinical challenge in treatment-resistant depression (TRD). Recent work demonstrated promising antidepressant effects in TRD patients with no or mild suicidal ideation using a specific protocol termed intermittent theta burst stimulation (iTBS). Here, we examined the clinical effects of accelerated schedules of iTBS and continuous TBS (cTBS) in patients with moderate to severe suicidal ideation. METHODS: Patients with TRD and moderate to severe suicidal ideation (n = 44) were randomly assigned to receive accelerated iTBS or cTBS treatment. Treatments were delivered in 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days (total of 90,000 pulses). Neuronavigation was employed to target accelerated iTBS and cTBS to the left and right dorsolateral prefrontal cortex (DLPFC), respectively. Clinical outcomes were evaluated in a 4-week follow-up period. RESULTS: Accelerated cTBS was superior to iTBS in the management of suicidal ideation (pweek 1 = .027) and anxiety symptoms (pweek 1 = .01). Accelerated iTBS and cTBS were comparable in antidepressant effects (p < .001; accelerated cTBS: mean change at weeks 1, 3, 5 = 49.55%, 54.99%, 53.11%; accelerated iTBS: mean change at weeks 1, 3, 5 = 44.52%, 48.04%, 51.74%). No serious adverse events occurred during the trial. One patient withdrew due to hypomania. The most common adverse event was discomfort at the treatment site (22.73% in both groups). CONCLUSIONS: These findings provide the first evidence that accelerated schedules of left DLPFC iTBS and right DLPFC cTBS are comparably effective in managing antidepressant symptoms and indicate that right DLPFC cTBS is potentially superior in reducing suicidal ideation and anxiety symptoms.

Gamma connectivity predicts response to intermittent theta burst stimulation in Alzheimer's disease: a randomized controlled trial.

There is growing evidence that neural network dysfunction is a likely proximate cause of cognitive impairment in Alzheimer's disease and may represent a promising therapeutic target. Here, we investigated whether a course of intermittent theta burst stimulation (iTBS) could modulate functional connectivity and cognition in mild to moderate Alzheimer's. In a double-blind parallel randomized sham-controlled trial, 58 participants were randomized to either active or sham iTBS. Stimulation was applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, left posterior parietal cortex, and right posterior parietal cortex in every treatment session. Neurobiological (electroencephalography), cognitive, and behavioral functional assessments were undertaken at baseline and end of treatment. Cognitive and functional assessments were also conducted at 3 (blinded) and 6 month (active group only) follow-ups. Active iTBS increased resting-state gamma connectivity and improved delayed recall on an episodic memory task. Both baseline gamma connectivity and change in gamma connectivity predicted improved delayed recall following active treatment. These findings support future research into iTBS for Alzheimer's focusing on protocol optimization.

Neurophysiological correlates of non-motor symptoms in late premanifest and early-stage manifest huntington's disease.

OBJECTIVE: To find sensitive neurophysiological correlates of non-motor symptoms in Huntington's disease (HD), which are essential for the development and assessment of novel treatments. METHODS: We used resting state EEG to examine differences in oscillatory activity (analysing the isolated periodic as well as the complete EEG signal) and functional connectivity in 22 late premanifest and early stage people with HD and 20 neurotypical controls. We then assessed the correlations between these neurophysiological markers and clinical measures of apathy and processing speed. RESULTS: Significantly lower theta and greater delta resting state power was seen in the HD group, as well as significantly greater delta connectivity. There was a significant positive correlation between theta power and processing speed, however there were no associations between the neurophysiological and apathy measures. CONCLUSIONS: We speculate that these changes in oscillatory power and connectivity reflect ongoing, frontally concentrated degenerative and compensatory processes associated with HD. SIGNIFICANCE: Our findings support the potential utility of quantitative EEG as a proximate marker of processing speed, but not apathy in HD.

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study.

BACKGROUND: Prolonged intermittent theta-burst stimulation (iTBS) is effective for major depressive disorder (MDD). However, whether longer piTBS treatment in a single session could have antidepressant efficacy remains elusive. Therefore, this double-blind, randomized, sham-controlled study aimed to investigate the antidepressant efficacy of 2 daily piTBS sessions for treating MDD patients with a history of poor responses to at least 1 adequate antidepressant trial in the current episode. METHODS: All patients received 2 uninterrupted sessions per day for 10 weekdays (i.e., 2 weeks; a total of 20 sessions). Seventy-two patients were recruited and 1:1:1 randomly assigned to one of three groups: piTBS (piTBSx2), 10-Hz rTMS (rTMSx2), or sham treatment (shamx2, randomly assigned to piTBS or rTMS). 10-Hz rTMS group was included as an active comparison group to enhance assay sensitivity. RESULTS: piTBSx2 group had significantly more responders at week 2 than shamx2 group, but it did not yield better antidepressant effects regarding the %depression changes. The changes of antidepressant scores were not different among the three groups at week 1 (-26.2% vs. -23.3% vs. -22.%) or at week 2 (-34.1% vs. -37.1% vs. -30.1%). Longer treatment duration did not result in stronger placebo effects [sham(piTBS)x2: - 31.7% vs. sham(rTMS)x2: - 26.7%]. CONCLUSION: The present sham-controlled study confirmed that piTBS is an effective antidepressant option, but found no evidence to support that longer piTBS treatment duration resulted in more rapid or better antidepressant effects. A high placebo effect was observed, but longer treatment duration of brain stimulation was not linearly associated with stronger placebo effects.

Prescribing electroconvulsive therapy for depression: Not as simple as it used to be.

In the last century, prescribing electroconvulsive therapy usually involved considering the relative merits of unilateral versus bilateral electroconvulsive therapy, with most other parameters fixed. However, research over the last 30 years has discovered that several parameters of the electroconvulsive therapy stimulus can have a significant impact on efficacy and cognitive side effects. The stimulus dose relative to seizure threshold was shown to significantly affect efficacy, especially for right unilateral electroconvulsive therapy, where suprathreshold doses in the vicinity of 5-6 times seizure threshold were far more efficacious than doses closer to threshold. However, this did not hold for bitemporal electroconvulsive therapy, where near-threshold stimuli were equally effective as suprathreshold stimuli. Then, changes in stimulus pulse width were found to also have a significant impact on both efficacy and side effects, with ultrabrief pulse widths of 0.3 ms having significantly fewer cognitive side effects in unilateral electroconvulsive therapy than standard brief pulse widths of 1.0 ms, with only slightly reduced efficacy. Therefore, choosing the optimum electroconvulsive therapy prescription for an individual patient now requires consideration of placement, pulse width and stimulus dose relative to seizure threshold, and how these three interact with each other. This viewpoint aims to raise awareness of these issues for psychiatrists involved in electroconvulsive therapy practice.