Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.

Frontal two-electrode transcranial direct current stimulation protocols may not affect performance on a combined flanker Go/No-Go task.

Transcranial direct current stimulation (tDCS) has been tested to modulate cognitive control or response inhibition using various electrode montages. However, electrode montages and current polarities have not been systematically compared when examining tDCS effects on cognitive control and response inhibition. In this randomized, sham-controlled study, 38 healthy volunteers were randomly grouped into receiving one session of sham, anodal, and cathodal each in an electrode montage that targeted either the dorsolateral prefrontal cortex (DLPFC) or the fronto-medial (FM) region. Participants performed a combined flanker Go/No-Go task during stimulation. No effect of tDCS was found in the DLPFC and FM groups neither using anodal nor cathodal stimulation. No major adverse effects of tDCS were identified using either montage or stimulation type and the two groups did not differ in terms of the reported sensations. The present study suggests that single-session tDCS delivered in two two-electrode montages might not affect cognitive control or response inhibition, despite using widely popular stimulation parameters. This is in line with the heterogeneous findings in the field and calls for further systematic research to exclude less reliable methods from those with more pronounced effects, identify the determinants of responsiveness, and develop optimal ways to utilize this technique.

Voxel-based asymmetry of the regional gray matter over the inferior temporal gyrus correlates with depressive symptoms in medicated patients with major depressive disorder.

The number of patients suffering from major depressive disorder (MDD) is increasing worldwide. Imbalanced hemispherical brain activity may be an underlying factor of MDD; however, whether structural asymmetry also contributes to the symptoms experienced in MDD has been scarcely investigated. In this study, we aimed to examine cortical asymmetry in association with the severity of depressive and cognitive symptoms observed in MDD during stable medication. The association between the affective and cognitive symptoms and gray matter asymmetry was evaluated in 17 MDD patients using voxel-wise gray matter asymmetry analysis on high-resolution T1-weighted MR images. Asymmetry index values in the inferior temporal gyrus (ITG) correlated with the scores of the 17-item Hamilton Depression Rating Scale (HDRS), but no association was found with the Beck Hopelessness Scale, and performance on the 1-, 2- and 3-back task. Our results indicate that the asymmetry of gray matter content in the ITG might be associated with higher depression severity. Our findings might help to better understand how structural changes contribute to depression severity in patients with MDD.

The Effects of Bilateral Theta-burst Stimulation on Executive Functions and Affective Symptoms in Major Depressive Disorder.

Major depressive disorder (MDD) is characterized by severe affective as well as cognitive symptoms. Moreover, cognitive impairment in MDD can persist after the remission of affective symptoms. Theta-burst stimulation (TBS) is a promising tool to manage the affective symptoms of major depressive disorder (MDD); however, its cognition-enhancing effects are sparsely investigated. Here, we aimed to examine whether the administration of bilateral TBS has pro-cognitive effects in MDD. Ten daily sessions of neuronavigated active or sham TBS were delivered bilaterally over the dorsolateral prefrontal cortex to patients with MDD. The n-back task and the attention network task were administered to assess working memory and attention, respectively. Affective symptoms were measured using the 21-item Hamilton Depression Rating Scale. We observed moderate evidence that the depressive symptoms of patients receiving active TBS improved compared to participants in the sham stimulation. No effects of TBS on attention and working memory were detected, supported by a moderate-to-strong level of evidence. The effects of TBS on psychomotor processing speed should be further investigated. Bilateral TBS has a substantial antidepressive effect with no immediate adverse effects on executive functions.

Non-invasive Brain Stimulation in Alzheimer's Disease and Mild Cognitive Impairment-A State-of-the-Art Review on Methodological Characteristics and Stimulation Parameters.

Background: Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) have been proposed as a new therapeutic way to enhance the cognition of patients with dementia. However, serious methodological limitations appear to affect the estimates of their efficacy. We reviewed the stimulation parameters and methods of studies that used TMS or tDCS to alleviate the cognitive symptoms of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Moreover, we evaluated the risk of bias in these studies. Our aim was to highlight the current vulnerabilities of the field and to formulate recommendations on how to manage these issues when designing studies. Methods: Electronic databases and citation searching were used to identify studies administering TMS or tDCS on patients with AD or MCI to enhance cognitive function. Data were extracted by one review author into summary tables with the supervision of the authors. The risk of bias analysis of randomized-controlled trials was conducted by two independent assessors with version 2 of the Cochrane risk-of-bias tool for randomized trials. Results: Overall, 36 trials were identified of which 23 randomized-controlled trials underwent a risk of bias assessment. More than 75% of randomized-controlled trials involved some levels of bias in at least one domain. Stimulation parameters were highly variable with some ranges of effectiveness emerging. Studies with low risk of bias indicated TMS to be potentially effective for patients with AD or MCI while questioned the efficacy of tDCS. Conclusions: The presence and extent of methodical issues affecting TMS and tDCS research involving patients with AD and MCI were examined for the first time. The risk of bias frequently affected the domains of the randomization process and selection of the reported data while missing outcome was rare. Unclear reporting was present involving randomization, allocation concealment, and blinding. Methodological awareness can potentially reduce the high variability of the estimates regarding the effectiveness of TMS and tDCS. Studies with low risk of bias delineate a range within TMS parameters seem to be effective but question the efficacy of tDCS.

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. OBJECTIVE: To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). METHODS: The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research - with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. RESULTS: A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. CONCLUSION: There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.

The effect of psychiatric comorbidities and stress-coping strategies on perceived quality of life in migraine.

BACKGROUND AND PURPOSE: Migraine is one of the most disabling primary headache conditions. We aimed to detect hidden symptoms of anxiety and depression and to survey stress-coping mechanisms and related quality of life in a large migraine population without any known psychiatric comorbidity. METHODS: 123 migraine patients (MG) and 66 healthy subjects (HC) completed the Beck Depression Inventory-II (BDI-II), the State and Trait Anxiety Inventory (S-STAI and T-STAI), the Stress and Coping Inventory (SCI) and the 36-Item Short Form Health Survey (SF-36). RESULTS: MG patients reached significantly higher scores on the BDI-II and the T-STAI yielding previously undetected anxiety and depression symptoms. Significant differences were present on the SCI: higher stress scores and lower coping levels suggested impaired stress-coping strategies in migraine. MG patients achieved significantly lower scores on most of SF-36 subscales indicating lower perceived quality of life. Significant correlations were found between BDI-II, T-STAI, SCI scores and subscales of the SF-36. CONCLUSION: Unrecognized symptoms of anxiety and depression, as well as less effective stress-coping strategies might be related to the lower perceived quality of life in migraine. The screening of these symptoms might lead to more focused and efficient therapeutic strategies. Addressing stress management techniques could improve quality of life on the long-term.

Continuous theta-burst stimulation over the dorsolateral prefrontal cortex inhibits improvement on a working memory task.

Theta-burst stimulation (TBS) over the dorsolateral prefrontal cortex (DLPFC) may be more effective for modulating cortical excitability compared to standard repetitive transcranial magnetic stimulation. However, the impact of intermittent (iTBS) and continuous TBS (cTBS) on working memory (WM) is poorly studied. The aim of our study was to compare the effects of iTBS and cTBS on WM over the left and right DLPFC. iTBS, cTBS or sham stimulation was administered over the right and left hemisphere of fifty-one healthy human subjects. WM was assessed before and after TBS using the 1-back, 2-back, and 3-back tasks. We found classical practice effects in the iTBS and the sham group: WM performance improved following stimulation as measured by the discriminability index. However, this effect could not be observed in the cTBS group. We did not find any hemisphere-dependent effects, suggesting that the practice effect is not lateralized, and TBS affects WM performance in a comparable manner if administered either over the left or the right hemisphere. We propose that our findings represent a useful addition to the literature of TBS-induced effects on WM. Moreover, these results indicate the possibility of clarifying processes underlying WM performance changes by using non-invasive brain stimulation.