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Current treatments for smoking yield suboptimal outcomes, partly because of an inability to reduce cue-induced smoking. Mindfulness training (MT) has shown preliminary efficacy for smoking cessation, yet its neurobiological target remains unknown. Our prior work with nonsmokers indicates that MT reduces posterior cingulate cortex (PCC) activity. In individuals who smoke, the PCC, consistently a main hub of the “default mode network,” activates in response to smoking cues. In this randomized controlled trial, we tested the effects of app-delivered MT on PCC reactivity to smoking cues and whether individual differences in MT-mediated PCC changes predicted smoking outcomes. Smoking cue-induced PCC reactivity was measured using functional magnetic resonance imaging at baseline and 1 month after receiving smartphone app-based MT (n = 33) vs. an active control (National Cancer Institute’s QuitGuide, n = 34). Whether individual differences in treatment-related changes in PCC activity predicted smoking behavior was assessed. The MT group demonstrated a significant correlation between a reduction in PCC reactivity to smoking cues and a decline in cigarette consumption (r = 0.39, p = 0.02). No association was found in the control group (r = 0.08, p = 0.65). No effects of group alone were found in PCC or cigarette reduction. Post hoc analysis revealed this association is sex specific (women, r = 0.49, p = 0.03; men: r = −0.08, p = 0.79). This initial report indicates that MT specifically reduces smoking cue-induced PCC activity in a subject-specific manner, and the reduction in PCC activity predicts a concurrent decline in smoking. These findings link the hypothesized behavioral effects of MT for smoking to neural mechanisms particularly in women. This lays the groundwork for identifying individuals who may benefit from targeted digital therapeutic treatments such as smartphone-based MT, yielding improved clinical outcomes.

Patients with chronic insomnia are characterized by alterations in default mode network and alpha oscillations, for which the medial parietal cortex (MPC) is a key node and thus a potential target for interventions. Fifty-six adults with chronic insomnia were randomly assigned to 2 mA, alpha-frequency (10 Hz), 30 min active or sham transcranial alternating current stimulation (tACS) applied over the MPC for 10 sessions completed within two weeks, followed by 4- and 6-week visits. The connectivity of the dorsal and ventral posterior cingulate cortex (vPCC) was calculated based on resting functional MRI. For the primary outcome, the active group showed a higher response rate (≥ 50% reduction in Pittsburgh Sleep Quality Index (PSQI)) at week 6 than that of the sham group (71.4% versus 3.6%) (risk ratio 20.0, 95% confidence interval 2.9 to 139.0, p = 0.0025). For the secondary outcomes, the active therapy induced greater and sustained improvements (versus sham) in the PSQI, depression (17-item Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale), and cognitive deficits (Perceived Deficits Questionnaire-Depression) scores. The response rates in the active group decreased at weeks 8-14 (42.9%-57.1%). Improvement in sleep was associated with connectivity between the vPCC and the superior frontal gyrus and the inferior parietal lobe, whereas vPCC-to-middle frontal gyrus connectivity was associated with cognitive benefits and vPCC-to-ventromedial prefrontal cortex connectivity was associated with alleviation in rumination. Targeting the MPC with alpha-tACS appears to be an effective treatment for chronic insomnia, and vPCC connectivity represents a prognostic marker of treatment outcome.

Fibromyalgia is a chronic pain condition contributing to significant disability worldwide. Neuroimaging studies identify abnormal effective connectivity between cortical areas responsible for descending pain modulation (pregenual anterior cingulate cortex, pgACC) and sensory components of pain experience (primary somatosensory cortex, S1). Neurofeedback, a brain-computer interface technique, can normalise dysfunctional brain activity, thereby improving pain and function. This study evaluates the safety, feasibility, and acceptability of a novel electroencephalography-based neurofeedback training, targeting effective alpha-band connectivity from the pgACC to S1 and exploring its effect on pain and function. Participants with fibromyalgia ( N  = 30; 15 = active, 15 = placebo) received 12 sessions of neurofeedback. Feasibility and outcome measures of pain (Brief Pain Inventory) and function (Revised Fibromyalgia Impact Questionnaire) were collected at baseline and immediately, ten-days, and one-month post-intervention. Descriptive statistics demonstrate effective connectivity neurofeedback training is feasible (recruitment rate: 6 participants per-month, mean adherence: 80.5%, dropout rate: 20%), safe (no adverse events) and highly acceptable (average 8.0/10) treatment approach for fibromyalgia. Active and placebo groups were comparable in their decrease in pain and functional impact. Future fully powered clinical trial is warranted to test the efficacy of the effective connectivity neurofeedback training in people with fibromyalgia with versus without chronic fatigue.

Default mode network (DMN) dysfunction (particularly within the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC)) has been implicated in major depressive disorder (MDD); however, its contribution to treatment outcome has not been clearly established. Here we tested the role of DMN functional connectivity as a general and differential biomarker for predicting treatment outcomes in a large, unmedicated adult sample with MDD. Seventy-five MDD outpatients completed fMRI scans before and 8 weeks after randomization to escitalopram, sertraline, or venlafaxine-XR. A whole-brain voxel-wise t-test identified profiles of pretreatment intrinsic functional connectivity that distinguished patients who were subsequently classified as remitters or non-remitters at follow-up. Connectivity was seeded in the PCC, an important node of the DMN. We further characterized differences between remitters, non-remitters, and 31 healthy controls and characterized changes pretreatment to posttreatment. Remitters were distinguished from non-remitters by relatively intact connectivity between the PCC and ACC/mPFC, not distinguishable from healthy controls, while non-remitters showed relative hypo-connectivity. In validation analyses, we demonstrate that PCC–ACC/mPFC connectivity predicts remission status with >80% cross-validated accuracy. In analyses testing whether intrinsic connectivity differentially relates to outcomes for a specific type of antidepressant, interaction models did not survive the corrected threshold. Our findings demonstrate that the overall capacity to remit on commonly used antidepressants may depend on intact organization of intrinsic functional connectivity between PCC and ACC/mPFC prior to treatment. The findings highlight the potential utility of functional scans for advancing a more precise approach to tailoring antidepressant treatment choices.

To assess the efficacy of horticultural therapy (HT) on anterior cingulate cortex (ACC) activity and the changes in rumination and catastrophizing scores in individuals with chronic low back pain (LBP). We conducted a randomized, controlled, cross-over, 3-week pilot study (ClinicalTrials.gov Identifier: NCT04656158). The departments of physical medicine and rehabilitation (hospital grounds and occupational therapy room) and imaging research were involved. The participants were adults with non-specific chronic LBP. All participants underwent two 90-min HT sessions and two 90-min handiwork sessions per week. The activity sequence order was randomized, and the activities were separated by a wash-out period of 1 week. Each participant underwent 3 brain MRIs: before, after the first, and after the second activity. The primary outcome was the change in ACC perfusion in ml/100g/min using arterial spin labeling MRI. The secondary outcomes were the changes in self-reported rumination and catastrophizing scores after each activity compared to baseline. Sixteen participants were included: 14 women (87.5%), LBP intensity (numeric rating scale) mean (SD) 45.1 (27.2)/100, specific activity limitation (Roland Morris disability questionnaire) 9.3 (4.1)/24. Change in ACC perfusion from baseline was -0.1 (10.7), 95% CI [-5.6, 5.8] ml (blood)/100g (tissue)/min after handiwork and -0.1 (8.7), [-4.7, 4.6] after HT and did not differ between the 2 activities (p = 0.91). Change in rumination [-0.5 (4.4) after handiwork and -0.3 (2.8) after HT] and catastrophizing scores [-2 (2.8) after handiwork and -1.4 (2.3) after HT] did not differ between activities (p = 0.99 and 0.22, respectively). Limited exposure to the interventions and the sample profile (moderate levels of pain) may explain our results. Our results highlight the need for future studies using the most appropriate outcomes to determine the exact effects of nature experiences in people with chronic musculoskeletal disease.

There is increasing evidence that redox dysregulation, which can lead to oxidative stress and eventually to impairment of oligodendrocytes and parvalbumin interneurons, may underlie brain connectivity alterations in schizophrenia. Accordingly, we previously reported that levels of brain antioxidant glutathione in the medial prefrontal cortex were positively correlated with increased functional connectivity along the cingulum bundle in healthy controls but not in early psychosis patients. In a recent randomized controlled trial, we observed that 6-month supplementation with a glutathione precursor, N-acetyl-cysteine, increased brain glutathione levels and improved symptomatic expression and processing speed. We investigated the effect of N-acetyl-cysteine supplementation on the functional connectivity between regions of the cingulate cortex, which have been linked to positive symptoms and processing speed decline. In this pilot study, we compared structural connectivity and resting-state functional connectivity between early psychosis patients treated with 6-month N-acetyl-cysteine (n = 9) or placebo (n = 11) supplementation with sex- and age-matched healthy control subjects (n = 74). We observed that 6-month N-acetyl-cysteine supplementation increases functional connectivity along the cingulum and more precisely between the caudal anterior part and the isthmus of the cingulate cortex. These functional changes can be partially explained by an increase of centrality of these regions in the functional brain network. N-acetyl-cysteine supplementation has a positive effect on functional connectivity within the cingulate cortex in early psychosis patients. To our knowledge, this is the first study suggesting that increased brain glutathione levels via N-acetyl-cysteine supplementation may improve brain functional connectivity.

Attention Deficit Hyperactivity Disorder (ADHD) is characterized by poor cognitive control/attention and hypofunctioning of the dorsal anterior cingulate cortex (dACC). In the current study, we investigated for the first time whether real-time fMRI neurofeedback (rt-fMRI) training targeted at increasing activation levels within dACC in adults with ADHD leads to a reduction of clinical symptoms and improved cognitive functioning. An exploratory randomized controlled treatment study with blinding of the participants was conducted. Participants with ADHD (n = 7 in the neurofeedback group, and n = 6 in the control group) attended four weekly MRI training sessions (60-min training time/session), during which they performed a mental calculation task at varying levels of difficulty, in order to learn how to up-regulate dACC activation. Only neurofeedback participants received continuous feedback information on actual brain activation levels within dACC. Before and after the training, ADHD symptoms and relevant cognitive functioning was assessed. Results showed that both groups achieved a significant increase in dACC activation levels over sessions. While there was no significant difference between the neurofeedback and control group in clinical outcome, neurofeedback participants showed stronger improvement on cognitive functioning. The current study demonstrates the general feasibility of the suggested rt-fMRI neurofeedback training approach as a potential novel treatment option for ADHD patients. Due to the study's small sample size, potential clinical benefits need to be further investigated in future studies. ISRCTN12390961.

One of the fundamental questions in real‐time functional magnetic resonance imaging neurofeedback (rt‐fMRI NF) investigations is the definition of a suitable neural target for training. Previously, we applied a meta‐analytical approach to define a network‐level target for connectivity‐based rt‐fMRI NF in substance use disorders. The analysis yielded consistent connectivity alterations between the insula and anterior cingulate cortex (ACC) as well as the dorsal striatum and the ACC. In the current investigation, we addressed the feasibility of regulating this network and its functional relevance using connectivity‐based neurofeedback. In a double‐blind, sham‐controlled design, 60 nicotine users were randomly assigned to the experimental or sham control group for one NF training session. The preregistered primary outcome was defined as improved inhibitory control performance after regulation of the target network compared to sham control. Secondary outcomes were (1) neurofeedback‐specific changes in functional connectivity of the target network; (2) changes in smoking behavior and impulsivity measures; and (3) changes in resting‐state connectivity profiles. Our results indicated no differences in behavioral measures after receiving feedback from the target network compared to the sham feedback. Target network connectivity was increased during regulation blocks compared to rest blocks, however, the experimental and sham groups could regulate to a similar degree. Accordingly, the observed activation patterns may be related to the mental strategies used during regulation attempts irrespective of the group assignment. We discuss several crucial factors regarding the efficacy of a single‐session connectivity‐based neurofeedback for the target network. This includes high fluctuation in the connectivity values of the target network that may impact controllability of the signal. To our knowledge, this investigation is the first randomized, double‐blind controlled real‐time fMRI study in nicotine users. This raises the question of whether previously observed effects in nicotine users are specific to the neurofeedback signal or reflect more general self‐regulation attempts. In a double‐blind, sham‐controlled design, we investigated the feasibility of targeting a meta‐analytically defined network (comprised of the anterior cingulated cortex, insula, and dorsal striatum) using connectivity‐based real‐time fMRI neurofeedback. Our findings indicate no superiority of receiving feedback from the target network over sham feedback.

Recent studies indicate that mindfulness meditation training interventions reduce stress and improve stress-related health outcomes, but the neural pathways for these effects are unknown. The present research evaluates whether mindfulness meditation training alters resting state functional connectivity (rsFC) of the amygdala, a region known to coordinate stress processing and physiological stress responses. We show in an initial discovery study that higher perceived stress over the past month is associated with greater bilateral amygdala-subgenual anterior cingulate cortex (sgACC) rsFC in a sample of community adults ( n  = 130). A follow-up, single-blind randomized controlled trial shows that a 3-day intensive mindfulness meditation training intervention (relative to a well-matched 3-day relaxation training intervention without a mindfulness component) reduced right amygdala-sgACC rsFC in a sample of stressed unemployed community adults ( n  = 35). Although stress may increase amygdala-sgACC rsFC, brief training in mindfulness meditation could reverse these effects. This work provides an initial indication that mindfulness meditation training promotes functional neuroplastic changes, suggesting an amygdala-sgACC pathway for stress reduction effects.

Abstract Mindfulness meditation training has been shown to increase resting-state functional connectivity between nodes of the frontoparietal executive control network (dorsolateral prefrontal cortex [DLPFC]) and the default mode network (posterior cingulate cortex [PCC]). We investigated whether these effects generalized to a Mindfulness-Based Stress Reduction (MBSR) course and tested for structural and behaviorally relevant consequences of change in connectivity. Healthy, meditation-naïve adults were randomized to either MBSR (N = 48), an active (N = 47) or waitlist (N = 45) control group. Participants completed behavioral testing, resting-state fMRI scans and diffusion tensor scans at pre-randomization (T1), post-intervention (T2) and ~5.5 months later (T3). We found increased T2–T1 PCC–DLPFC resting connectivity for MBSR relative to control groups. Although these effects did not persist through long-term follow-up (T3–T1), MBSR participants showed a significantly stronger relationship between days of practice (T1 to T3) and increased PCC–DLPFC resting connectivity than participants in the active control group. Increased PCC–DLPFC resting connectivity in MBSR participants was associated with increased microstructural connectivity of a white matter tract connecting these regions and increased self-reported attention. These data show that MBSR increases PCC–DLPFC resting connectivity, which is related to increased practice time, attention and structural connectivity.