Background The purpose of this study was to explore if administration of N-acetylcysteine (NAC) in patients with multiple sclerosis (MS) resulted in altered neurophysiological function as determined by the combination of functional connectivity (FC) based on resting Blood Oxygen Level Dependent (BOLD) fMRI and cerebral glucose metabolism using Fluorodeoxyglucose Positron Emission Tomography (FDG PET) and whether those changes were associated with improvements in symptoms. Methods Thirty-six patients with mild to moderate MS were randomized to either NAC plus standard of care, or standard of care only. The experimental group received NAC intravenously (50mg/kg) once per week and orally (500mg 2x/day) the other six days. Patients in both groups were evaluated initially and after 4±2 months on an integrated PET-MRI platform with resting BOLD fMRI and FDG PET. Clinical symptom questionnaires were also completed at both time points. Results The FC data showed significant differences in several brain regions including the inferior frontal gyrus, inferior temporal gyrus, inferior parietal gyrus, insula, cerebellum, and brain stem in the MS group after treatment with NAC. FDG PET demonstrated increased cerebral glucose metabolism in several of these structures including the inferior frontal gyrus and inferior temporal gyrus. Self-reported scores related to cognition and attention significantly correlated with these neurophysiological changes in the NAC group compared to controls. Conclusions The results of this study suggest that NAC administration alters resting functional connectivity along with cerebral glucose metabolism in MS patients, and this is associated with qualitative improvements in cognition and attention.

BACKGROUND:Chronic pelvic pain is a substantial clinical challenge that profoundly impacts quality of life for many women. The Neuro Emotional Technique (NET) is a novel mind-body intervention designed to attenuate emotional arousal of distressing thoughts and pain. This study evaluated functional connectivity changes in key areas of the brain in patients with chronic pelvic pain receiving the NET intervention. The goal was to assess whether the NET intervention was associated with functional connectivity (FC) changes in the brain related to reductions in emotional distress and pain, particularly in the limbic areas, sensory/pain regions, and cerebellum. METHODS:This is a prospectively designed study that included twenty-six patients with a diagnosis of chronic pelvic pain who were randomised to either the NET intervention or a waitlist control. To evaluate the primary outcome of neurophysiological effects, all participants received resting state functional blood oxygen level dependent (BOLD) magnetic resonance imaging (rs-fMRI) before and after the NET intervention or waitlist control period. Pain, mood, anxiety, and quality of life also were assessed. RESULTS:Compared to the control group, the NET group demonstrated significant improvements in pain interference and pain intensity, and in emotional measures such anxiety and depression. Functional connectivity in the NET group compared to controls, was significantly decreased in the amygdala, cerebellum, and postcentral gyrus. There were also significant correlations between FC changes and changes in clinical measures. CONCLUSIONS:This study is an initial step towards describing a neurological signature of reducing emotional distress in women with chronic pelvic pain. Specifically, FC changes between the cerebellum and the amygdala and sensory areas appears to be associated with a reduction in pain and the effects of that pain. Future, larger clinical trials are warranted to further evaluate these mechanisms and NET as a potential therapeutic intervention in patients with chronic pelvic pain.

Objective: Concussion accounts for more than 80% of people experiencing traumatic brain injury. Acute concussion is associated with characteristic cognitive and functional deficits that may persist for weeks to months. A subgroup of these patients (from 10% to 50%) have persistent symptoms referred to as chronic post-concussion syndrome (PCS). There are limited treatment options for these patients and the pathophysiology is poorly understood, though oxidative stress is thought to be a contributing factor. The purpose of this study was to evaluate whether an antioxidant, N-acetylcysteine (NAC), might be beneficial in patients with PCS. Setting: Outpatient medicine center. Participants: Fifty patients with chronic PCS for at least 3 months post injury. Design: The patients with PCS were enrolled in this randomized unblinded clinical trial to receive the antioxidant NAC as a combination of daily oral and weekly intravenous infusions, or assigned to a waitlist control group where they would continue to receive standard of care. Main Measures: Resting-state functional connectivity (FC) magnetic resonance imaging (rsFC-MRI) was performed pre and post either NAC or the waitlist period along with cognitive, emotional, and sensory symptom assessments. Results: The results demonstrated significant (P < .05) improvements in symptoms as determined by the Rivermead Post-Concussion Symptoms Questionnaire, Spielberger State-Trait Anxiety Inventory, and Profile of Mood Scale in the PCS group receiving NAC as compared to patients receiving ongoing standard care. Importantly, there were significant (P< .01) changes in FC in the NAC group, particularly in networks such as the default mode network, salience network, and executive control network. These changes in FC also correlated with improvements in symptoms. Conclusions: In patients with chronic PCS, NAC treatment was associated with significant changes in resting state FC and improvement in a variety of symptoms, particularly cognitive and affective symptoms.

Purpose A growing number of research studies have explored the potential effects of vagus nerve stimulation (VNS) on brain physiology as well as clinical effects particularly related to stress and anxiety. However, there currently are limited studies showing functional changes during different frequencies of stimulation and laterality effects transcutaneous auricular VNS (TaVNS). In this study, we evaluated whether TaVNS alters functional connectivity in the brain of healthy controls. We hypothesized that TaVNS would significantly alter connectivity in areas involved with emotional processing and regulation including the limbic areas, insula, frontal lobe regions, and cerebellum.Methods We enrolled 50 healthy controls. Participants were placed in the MRI scanner with MRI compatible ear buds that provided TaVNS. Subjects underwent TaVNS in the left, right, and both ears in a randomized manner during the MRI session. Stimulation was provided for 5 min on and then there was a 5 min off period in between. To evaluate the primary outcome of neurophysiological effects, all participants received blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during the TaVNS on and off states.Results The results demonstrated significant changes in functional connectivity during TaVNS that differed depending on the frequency of stimulation and which ear was stimulated. In general, areas of the brain that had altered functional connectivity included the frontoparietal regions, limbic regions, insula, and cerebellum. Interestingly, cognitive areas were also involved including parts of the temporal lobe, salience network, and default mode network.Conclusion This study is an initial step toward understanding the functional connectivity changes associated with TaVNS. The findings indicate significant brain changes, particularly in areas that are involved with emotional processing and regulation, as well as cognition. Future studies can expand on this data and focus on specific patient populations to determine the effects of TaVNS.

Prior work suggests that differences in brain morphology and task-evoked neural activity may underlie extraordinary creative achievement. Here, we extend these findings by focusing on resting blood oxygen level-dependent (rsBOLD) functional connectivity differences between eminent creators from diverse fields of expertise and a "smart" comparison group of age- and education-matched non-eminent thinkers. Participants underwent rsBOLD imaging, along with a high-resolution structural brain scan, and completed a series of demographic and behavioral measures. The results revealed significant differences in rsBOLD connectivity between the eminent and noneminent thinkers. Eminent thinkers showed increased connectivity between (a) the right central operculum and the bilateral parietal operculum, right supramarginal gyrus, and left precentral gyrus; (b) the right precentral gyrus and the right postcentral gyrus; (c) the left parietal operculum and the right central operculum and the right sensorimotor cortex; and (d) the posterior cingulate gyrus and the right precentral gyrus. In contrast, they showed decreased connectivity between (a) the posterior cingulate gyrus and the left supracalcarine cortex and (b) between the left occipital fusiform gyrus and the left frontal operculum. These results suggest that extraordinary creativity may be associated with measurable differences in functional connectivity, particularly in areas that support creative functions.

BackgroundA growing number of advanced neuroimaging studies have compared brain structure and function in long term meditators to non-meditators. The goal is to determine if there may be long term effects on the brain from practicing meditation. In this paper, we present new data on the long term effects of a novel meditation practice in which the focus is on clitoral stimulation. The findings from such a study have implications for potential therapeutic uses with regard to various neurological or psychiatric conditions.MethodsWe evaluated the cerebral glucose metabolism in 40 subjects with an extended history (>1 year of practice, 2–3 times per week) performing the meditation practice called Orgasmic Meditation (OM) and compared their brains to a group of non-meditating healthy controls (N = 19). Both meditation and non-meditation subjects underwent brain PET after injection with 148 to 296 MBq of FDG using a standard imaging protocol. Resting FDG PET scans of the OM group were compared to the resting scans of healthy, non-meditating, controls using statistical parametric mapping.ResultsThe OM group showed significant differences in metabolic activity at rest compared to the controls. Specifically, there was significantly lower metabolism in select areas of the frontal, temporal, and parietal lobes, as well as the anterior cingulate, insula, and thalamus, in the OM group compared to the controls. In addition, there were notable distinctions between the males and females with the females demonstrating significantly lower metabolism in the thalamus and insula.ConclusionsOverall, these findings suggest that the long term meditation practitioners of OM have different patterns of resting brain metabolism. Since these areas of the brain in which OM practitioners differ from controls are involved in cognition, attention, and emotional regulation, such findings have implications for understanding how this meditation practice might affect practitioners over long periods of time.

Mild traumatic brain injury (mTBI) is a significant public health concern, specially characterized by a complex pattern of abnormal neural activity and functional connectivity. It is often associated with a broad spectrum of short-term and long-term cognitive and behavioral symptoms including memory dysfunction, headache, and balance difficulties. Furthermore, there is evidence that oxidative stress significantly contributes to these symptoms and neurophysiological changes. The purpose of this study was to assess the effect of N-acetylcysteine (NAC) on brain function and chronic symptoms in mTBI patients. Fifty patients diagnosed with chronic mTBI participated in this study. They were categorized into two groups including controls (CN, n = 25), and patients receiving treatment with N-acetyl cysteine (NAC, n = 25). NAC group received 50 mg/kg intravenous (IV) medication once a day per week. In the rest of the week, they took one 500 mg NAC tablet twice per day. Each patient underwent rs-fMRI scanning at two timepoints including the baseline and 3 months later at follow-up, while the NAC group received a combination of oral and IV NAC over that time. Three rs-fMRI metrics were measured including fractional amplitude of low frequency fluctuations (fALFF), degree centrality (DC), and functional connectivity strength (FCS). Neuropsychological tests were also assessed at the same day of scanning for each patient. The alteration of rs-fMRI metrics and cognitive scores were measured over 3 months treatment with NAC. Then, the correlation analysis was executed to estimate the association of rs-fMRI measurements and cognitive performance over 3 months (p < 0.05). Two significant group-by-time effects demonstrated the changes of rs-fMRI metrics particularly in the regions located in the default mode network (DMN), sensorimotor network, and emotional circuits that were significantly correlated with cognitive function recovery over 3 months treatment with NAC (p < 0.05). NAC appears to modulate neural activity and functional connectivity in specific brain networks, and these changes could account for clinical improvement. This study confirmed the short-term therapeutic efficacy of NAC in chronic mTBI patients that may contribute to understanding of neurophysiological effects of NAC in mTBI. These findings encourage further research on long-term neurobehavioral assessment of NAC assisting development of therapeutic plans in mTBI.

BACKGROUND AND PURPOSE:To determine the effect of mild chronic traumatic brain injury (cTBI) on cerebral blood flow and metabolism. METHODS:62 cTBI and 40 healthy controls (HCs) with no prior history of cTBI underwent both pulsed arterial spin labeling functional magnetic resonance imaging (PASL-fMRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) scanning via a Siemens mMR (simultaneous PET/MRI) scanner. 30 participants also took part in a series of neuropsychological clinical measures (NCMs). Images were processed using statistical parametric mapping software relevant to each modality to generate relative cerebral blood flow (rCBF) and glucose metabolic standardized uptake value ratio (gSUVR) grey matter maps. A voxel-wise two-sample T-test and two-tailed gaussian random field correction for multiple comparisons was performed. RESULTS:cTBI patients showed a significant increase in rCBF and gSUVR in the right thalamus as well as a decrease in bilateral occipital lobes and calcarine sulci. An inverse relationship between rCBF and gSUVR was found in the left frontal lobe, the left precuneus and regions in the right temporal lobe. Within those regions rCBF values correlated with 9 distinct NCMs and gSUVR with 3. CONCLUSION:Simultaneous PASL-fMRI and FDG-PET can identify functional changes in a mild cTBI population. Within this population FDG-PET identified more regions of functional disturbance than ASL fMRI and NCMs are shown to correlate with rCBF and glucose metabolism (gSUVR) in various brain regions. As a result, both imaging modalities contribute to understanding the underlying pathophysiology and clinical course of mild chronic traumatic brain injury.

Mild traumatic brain injury (mTBI) is a public health concern. The present study aimed to develop an automatic classifier to distinguish between patients with chronic mTBI (n = 83) and healthy controls (HCs) (n = 40). Resting-state functional MRI (rs-fMRI) and positron emission tomography (PET) imaging were acquired from the subjects. We proposed a novel deep-learning-based framework, including an autoencoder (AE), to extract high-level latent and rectified linear unit (ReLU) and sigmoid activation functions. Single and multimodality algorithms integrating multiple rs-fMRI metrics and PET data were developed. We hypothesized that combining different imaging modalities provides complementary information and improves classification performance. Additionally, a novel data interpretation approach was utilized to identify top-performing features learned by the AEs. Our method delivered a classification accuracy within the range of 79–91.67% for single neuroimaging modalities. However, the performance of classification improved to 95.83%, thereby employing the multimodality model. The models have identified several brain regions located in the default mode network, sensorimotor network, visual cortex, cerebellum, and limbic system as the most discriminative features. We suggest that this approach could be extended to the objective biomarkers predicting mTBI in clinical settings.

This study provides comprehensive evaluation of functional rs-fMRI biomarkers that are associated with chronic mTBI symptoms and predicting treatment outcome and patient recovery. We evaluate the effect of medication and nutrition treatments on brain function and cognitive performance in chronic mTBI patients using resting-state fMRI metrics and neuropsychological test. We propose that treatment strategies compensate mTBI disrupt communication between brain network nodes. Our results help understanding the implication of treatment strategies in chronic mTBI patients and prediction of outcomes in brain function and cognitive recovery.

Background and purposeTraumatic brain injury (TBI) can cause progressive neuropathology that leads to chronic impairments, creating a need for biomarkers to detect and monitor this condition to improve outcomes. This study aimed to analyze the ability of data-driven analysis of diffusion tensor imaging (DTI) and neurite orientation dispersion imaging (NODDI) to develop biomarkers to infer symptom severity and determine whether they outperform conventional T1-weighted imaging.Materials and methodsA machine learning-based model was developed using a dataset of hybrid diffusion imaging of patients with chronic traumatic brain injury. We first extracted the useful features from the hybrid diffusion imaging (HYDI) data and then used supervised learning algorithms to classify the outcome of TBI. We developed three models based on DTI, NODDI, and T1-weighted imaging, and we compared the accuracy results across different models.ResultsCompared with the conventional T1-weighted imaging-based classification with an accuracy of 51.7-56.8%, our machine learning-based models achieved significantly better results with DTI-based models at 58.7-73.0% accuracy and NODDI with an accuracy of 64.0-72.3%.ConclusionThe machine learning-based feature selection and classification algorithm based on hybrid diffusion features significantly outperform conventional T1-weighted imaging. The results suggest that advanced algorithms can be developed for inferring symptoms of chronic brain injury using feature selection and diffusion-weighted imaging.

Mild traumatic brain injury (mTBI) is a major public health concern that can result in a broad spectrum of short-term and long-term symptoms. Recently, machine learning (ML) algorithms have been used in neuroscience research for diagnostics and prognostic assessment of brain disorders. The present study aimed to develop an automatic classifier to distinguish patients suffering from chronic mTBI from healthy controls (HCs) utilizing multilevel metrics of resting-state functional magnetic resonance imaging (rs-fMRI). Sixty mTBI patients and forty HCs were enrolled and allocated to training and testing datasets with a ratio of 80:20. Several rs-fMRI metrics including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), degree centrality (DC), voxel-mirrored homotopic connectivity (VMHC), functional connectivity strength (FCS), and seed-based FC were generated from two main analytical categories: local measures and network measures. Statistical two-sample t -test was employed comparing between mTBI and HCs groups. Then, for each rs-fMRI metric the features were selected extracting the mean values from the clusters showing significant differences. Finally, the support vector machine (SVM) models based on separate and multilevel metrics were built and the performance of the classifiers were assessed using five-fold cross-validation and via the area under the receiver operating characteristic curve (AUC). Feature importance was estimated using Shapley additive explanation (SHAP) values. Among local measures, the range of AUC was 86.67–100% and the optimal SVM model was obtained based on combined multilevel rs-fMRI metrics and DC as a separate model with AUC of 100%. Among network measures, the range of AUC was 80.42–93.33% and the optimal SVM model was obtained based on the combined multilevel seed-based FC metrics. The SHAP analysis revealed the DC value in the left postcentral and seed-based FC value between the motor ventral network and right superior temporal as the most important local and network features with the greatest contribution to the classification models. Our findings demonstrated that different rs-fMRI metrics can provide complementary information for classifying patients suffering from chronic mTBI. Moreover, we showed that ML approach is a promising tool for detecting patients with mTBI and might serve as potential imaging biomarker to identify patients at individual level. Clinical trial registration [ clinicaltrials.gov ], identifier [NCT03241732].

Background: The relationship between sexuality, or the libido, and spirituality or religion has long been debated in psychiatry. Recent studies have explored the neurophysiology of both sexual experiences and spiritual practices such as meditation or prayer. In the present study, we report changes in cerebral glucose metabolism in a unique meditation practice augmented by clitoral stimulation called, Orgasmic Meditation, in which a spiritual state is described to be attained by both male and female participants engaged in the practice as a pair. Methods: Male (N=20) and female (N=20) subjects had an intravenous catheter connected to a bag of normal saline inserted prior to the practice. During the practice, men stimulated their partner’s clitoris for exactly 15 minutes (he received no sexual stimulation). Midway through the practice, researchers injected 18F-fluorodeoxyglucose so the scan would reflect cerebral metabolism during the practice. Positron emission tomography (PET) imaging was performed approximately 30 minutes later. Results: In the female participants, the meditation state showed significant decreases in the left inferior frontal, inferior parietal, insula, middle temporal, and orbitofrontal regions as well as in the right angular gyrus, anterior cingulate and parahippocampus compared to a neutral state (p<0.01). Male subjects had significant decreases in the left middle frontal, paracentral, precentral, and postcentral regions as well as the right middle frontal and paracentral regions during meditation (p<0.01). Men also had significantly increased metabolism in the cerebellum and right postcentral and superior temporal regions (p<0.01). Conclusions: These findings represent a distinct pattern of brain activity, for both men and women, that is a hybrid between that of other meditation practices and sexual stimulation. Such findings have potential psychotherapeutic implications and may deepen our understanding of the relationship between spiritual and sexual experience.

There is a growing interest in the potential beneficial effects of mindfulness meditation training in protecting against age-related physical, emotional, and cognitive decline. The current prospective, single-center, single-arm study investigated if functional magnetic resonance imaging-based changes in cerebral blood flow and brain functional connectivity could be observed in 11 elderly adults (mean age 79) after participation in a Mindfulness-Based Stress Reduction (MBSR) program. The results showed significantly (p < 0.05) altered cerebral blood flow and functional connectivity in the cingulate gyrus, limbic structures, and subregions of the temporal and frontal lobes, similar to findings of other meditation-related studies in younger populations. Furthermore, these changes were also associated with significant improvements in depression symptoms. This study suggests that the MBSR program can potentially modify cerebral blood flow and connectivity in this population.

Background Many patients who have traumatic brain injury experience a wide range of psychiatric and neurological symptoms (including impairment in functional status, cognition, and mood), and if persistent are referred to as persistent postconcussion syndrome (PCS). To our knowledge, this is the first study to broadly evaluate metabolic dysregulation in a heterogenous patient population meeting the criteria for PCS. Methods A total of 64 PCS patients and 37 healthy controls underwent 18F-fluorodeoxyglucose-PET (18F-FDG-PET) scanning, and 70 brain structures (including left and right structures where appropriate) were analyzed in each subject. Results Compared to the brains of healthy controls, those of PCS patients demonstrated 15 hypermetabolic and 23 hypometabolic regions. Metabolic changes in the brains of PCS patients were subsequently correlated with various indices of symptom severity, mood, and physical/cognitive function. Among PCS patients, increased metabolism in the right cingulate gyrus correlated with the severity of postconcussion symptoms. Conversely, increased metabolism in the left temporal lobe was associated with both improved mood and measures of adaptability/rehabilitation. Furthermore, increased metabolism in the bilateral orbitofrontal regions correlated with improved working memory. Conclusions Overall, these findings suggest a complex pattern of cerebral metabolism in PCS patients, with a mixture of hypometabolic and hypermetabolic regions that correlate with various symptoms, highlighting both potential pathological and compensatory mechanisms in PCS. The findings also suggest that FDG PET is useful for providing neurophysiological information in the evaluation of patients with PCS and may help guide future targeted therapies.

Mild traumatic brain injury (mTBI) accounts for more than 80% of people experiencing brain injuries. Symptoms of mTBI include short-term and long-term adverse clinical outcomes. In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was conducted to measure voxel-based indices including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and functional connectivity (FC) in patients suffering from chronic mTBI; 64 patients with chronic mTBI at least 3 months post injury and 40 healthy controls underwent rs-fMRI scanning. Partial correlation analysis controlling for age and gender was performed within mTBI cohort to explore the association between rs-fMRI metrics and neuropsychological scores. Compared with controls, chronic mTBI patients showed increased fALFF in the left middle occipital cortex (MOC), right middle temporal cortex (MTC), and right angular gyrus (AG), and increased ReHo in the left MOC and left posterior cingulate cortex (PCC). Enhanced FC was observed from left MOC to right precuneus; from right MTC to right superior temporal cortex (STC), right supramarginal, and left inferior parietal cortex (IPC); and from the seed located at right AG to left precuneus, left superior medial frontal cortex (SMFC), left MTC, left superior temporal cortex (STC), and left MOC. Furthermore, the correlation analysis revealed a significant correlation between neuropsychological scores and fALFF, ReHo, and seed-based FC measured from the regions with significant group differences. Our results demonstrated that alterations of low-frequency oscillations in chronic mTBI could be representative of disruption in emotional circuits, cognitive performance, and recovery in this cohort.

Background: Many individuals participate in spiritual retreats to enhance their sense of spirituality or to improve their overall mental and spiritual well-being. We are not aware of any studies specifically evaluating changes in functional connectivity using functional magnetic resonance imaging (fMRI) in individuals undergoing an intense spiritual retreat program. The goal of this study was to determine whether such changes occur as a result of participating in the Spiritual Exercises of St. Ignatius. Methods: We conducted psychological and spiritual measures in conjunction with functional connectivity analysis of fMRI in 14 individuals prior to and following shortly after their participation in a one-week spiritual retreat. Results: Significant changes in functional connectivity were observed after the retreat program, compared to baseline evaluation, particularly in the posterior cingulate cortex, pallidum, superior frontal lobe, superior parietal lobe, superior and inferior temporal lobe, and the cerebellum. Significant changes in a variety of psychological and spiritual measures were identified as result of participation in the retreat. Conclusion: Overall, these preliminary findings suggest that this intensive spiritual retreat resulted in significant changes in brain functional connectivity, and warrants further investigation to evaluate the physiological, psychological, and spiritual impact of these changes.

Background: The purpose of this study was to explore if administration of N-acetyl-cysteine (NAC) in patients with multiple sclerosis (MS) resulted in altered cerebral blood flow (CBF) based on Arterial Spin Labeling (ASL) magnetic resonance imaging (MRI). Methods: Twenty-three patients with mild to moderate MS, (17 relapsing remitting and 6 primary progressive) were randomized to either NAC plus standard of care (N = 11), or standard of care only (N = 12). The experimental group received NAC intravenously (50 mg/kg) once per week and orally (500mg 2x/day) the other six days. Patients in both groups were evaluated initially and after 2 months (of receiving the NAC or waitlist control) with ASL MRI to measure CBF. Clinical symptom questionnaires were also completed at both time points. Results: The CBF data showed significant differences in several brain regions including the pons, midbrain, left temporal and frontal lobe, left thalamus, right middle frontal lobe and right temporal/hippocampus (p < 0.001) in the MS group after treatment with NAC, when compared to the control group. Self-reported scores related to cognition and attention were also significantly improved in the NAC group as compared to the control group. Conclusions: The results of this study suggest that NAC administration alters resting CBF in MS patients, and this is associated with qualitative improvements in cognition and attention. Given these findings, large scale efficacy studies will be of value to determine the potential clinical impact of NAC over the course of illness in patients with MS, as well as the most effective dosages and differential effects across subpopulations.