Treatment effects of N-acetyl cysteine on resting-state functional MRI and cognitive performance in patients with chronic mild traumatic brain injury: a longitudinal study.

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.

Characteristic dynamic functional connectivity during sevoflurane-induced general anesthesia.

General anesthesia (GA) during surgery is commonly maintained by inhalational sevoflurane. Previous resting state functional MRI (rs-fMRI) studies have demonstrated suppressed functional connectivity (FC) of the entire brain networks, especially the default mode networks, transitioning from the awake to GA condition. However, accuracy and reliability were limited by previous administration methods (e.g. face mask) and short rs-fMRI scans. Therefore, in this study, a clinical scenario of epilepsy patients undergoing laser interstitial thermal therapy was leveraged to acquire 15 min of rs-fMRI while under general endotracheal anesthesia to maximize the accuracy of sevoflurane level. Nine recruited patients had fMRI acquired during awake and under GA, of which seven were included in both static and dynamic FC analyses. Group independent component analysis and a sliding-window method followed by k-means clustering were applied to identify four dynamic brain states, which characterized subtypes of FC patterns. Our results showed that a low-FC brain state was characteristic of the GA condition as a single featuring state during the entire rs-fMRI session; In contrast, the awake condition exhibited frequent fluctuations between three distinct brain states, one of which was a highly synchronized brain state not seen in GA. In conclusion, our study revealed remarkable dynamic connectivity changes from awake to GA condition and demonstrated the advantages of dynamic FC analysis for future studies in the assessments of the effects of GA on brain functional activities.

Effect of Enlarged Perivascular Spaces in Reliable Distinction of Prospective Targeting During Deep Brain Stimulation in Patients With Advanced Parkinson's Disease: A Study of Deterministic and Probabilistic Tractography.

BACKGROUND: Precise electrode position is vital for effective deep brain stimulation in treating motor symptoms in Parkinson's disease (PD). Enlarged perivascular spaces (PVSs) are associated with pathophysiology of neurodegenerative diseases including PD and may affect the microstructure of surrounding brain tissue. OBJECTIVE: To quantify the clinical implications of enlarged PVS on tractography-based stereotactic targeting in patients with advanced PD selected to undergo deep brain stimulation. METHODS: Twenty patients with PD underwent MRI scanning. The PVS areas were visualized and segmented. Based on the size of the PVS areas, the patient group was split into 2 categories of large vs small PVSs. Probabilistic and deterministic tractography methods were applied to a diffusion-weighted data set. Fiber assignment was performed using motor cortex as an initiation seed and the globus pallidus interna and subthalamic nucleus, separately, as inclusion masks. Two exclusion masks used consisted of cerebral peduncles and the PVS mask. The center of gravity of the tract density map was measured and compared between the tracts generated with and without consideration of the PVS mask. RESULTS: The average differences between the center of gravity of the tracts made by excluding PVS and without excluding PVS using deterministic and probabilistic tractography methods were less than 1 mm. Statistical analysis showed nonsignificant differences between deterministic and probabilistic methods and differences between patients with large and small PVSs ( P > .05). CONCLUSION: This study demonstrated that the presence of enlarged PVS is unlikely to affect targeting of basal ganglia nuclei based on tractography.

Vascular and neuronal effects of general anesthesia on the brain: An fMRI study.

BACKGROUND AND PURPOSE: A number of functional magnetic resonance imaging (fMRI) studies rely on application of anesthetic agents during scanning that can modulate and complicate interpretation of the measured hemodynamic blood oxygenation level-dependent (BOLD) response. The purpose of the present study was to investigate the effect of general anesthesia on two main components of BOLD signal including neuronal activity and vascular response. METHODS: Breath-holding (BH) fMRI was conducted in wakefulness and under anesthesia states in 9 patients with drug-resistant epilepsy who needed to get scanned under anesthesia during laser interstitial thermal therapy. BOLD and BOLD cerebrovascular reactivity (BOLD-CVR) maps were compared using t-test between two states to assess the effect of anesthesia on neuronal activity and vascular factors (p < .05). RESULTS: Overall, our findings revealed an increase in BOLD-CVR and decrease in BOLD response under anesthesia in several brain regions. The results proposed that the modulatory mechanism of anesthetics on neuronal and vascular components of BOLD signal may work in different ways. CONCLUSION: This experiment for the first human study showed that anesthesia may play an important role in dissociation between neuronal and vascular responses contributed to hemodynamic BOLD signal using BH fMRI imaging that may assist the implication of general anesthesia and interpretation of outcomes in clinical setting.

Deep learning-based multimodality classification of chronic mild traumatic brain injury using resting-state functional MRI and PET imaging.

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.

The effect of general anesthesia on the test-retest reliability of resting-state fMRI metrics and optimization of scan length.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been known as a powerful tool in neuroscience. However, exploring the test-retest reliability of the metrics derived from the rs-fMRI BOLD signal is essential, particularly in the studies of patients with neurological disorders. Here, two factors, namely, the effect of anesthesia and scan length, have been estimated on the reliability of rs-fMRI measurements. A total of nine patients with drug-resistant epilepsy (DRE) requiring interstitial thermal therapy (LITT) were scanned in two states. The first scan was performed in an awake state before surgery on the same patient. The second scan was performed 2 weeks later under general anesthesia necessary for LITT surgery. At each state, two rs-fMRI sessions were obtained that each one lasted 15 min, and the effect of scan length was evaluated. Voxel-wise rs-fMRI metrics, including the amplitude of low-frequency fluctuation (ALFF), the fractional amplitude of low-frequency fluctuation (fALFF), functional connectivity (FC), and regional homogeneity (ReHo), were measured. Intraclass correlation coefficient (ICC) was calculated to estimate the reliability of the measurements in two states of awake and under anesthesia. Overall, it appeared that the reliability of rs-fMRI metrics improved under anesthesia. From the 15-min data, we found mean ICC values in awake state including 0.81, 0.51, 0.65, and 0.84 for ALFF, fALFF, FC, and ReHo, respectively, as well as 0.80, 0.59, 0.83, and 0.88 for ALFF, fALFF, FC, and ReHo, respectively, under anesthesia. Additionally, our findings revealed that reliability increases as the function of scan length. We showed that the optimized scan length to achieve less variability of rs-fMRI measurements was 3.1-7.5 min shorter in an anesthetized, compared to a wakeful state.

Cerebral Blood Flow and Brain Functional Connectivity Changes in Older Adults Participating in a Mindfulness-Based Stress Reduction Program.

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.

Identification of chronic mild traumatic brain injury using resting state functional MRI and machine learning techniques.

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].

Alterations in Functional Connectivity Measured by Functional Magnetic Resonance Imaging and the Relationship With Heart Rate Variability in Subjects After Performing Orgasmic Meditation: An Exploratory Study.

Background: We measured changes in resting brain functional connectivity, with blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), associated with a creative meditation practice that is augmented by clitoral stimulation and is designed to not only achieve a spiritual experience but to help individuals manage their most intimate personal relationships. Briefly, the meditative state is attained by both the male and female participants while the male stimulates the woman's clitoris. The goal of this practice, called orgasmic meditation (OM), according to the practitioners is not sexual, but to use the focus on clitoral stimulation to facilitate a meditative state of connectedness and calm alertness between the two participants. Methods: fMRI was acquired on 20 pairs of subjects shortly following one of two states that were randomized in their order - during the OM practice or during a neutral condition. The practice is performed while the female is lying down on pillows with the clitoris exposed. During the practice, the male performs digital stimulation of the clitoris for 15 min. Resting BOLD image acquisition was performed at completion of the practice to assess changes in functional connectivity associated with the performance of the practice. Results: The results demonstrated significant changes (p < 0.05) in functional connectivity associated with the OM compared to the neutral condition. For the entire group there was altered connectivity following the OM practice involving the left superior temporal lobe, the frontal lobe, anterior cingulate, and insula. In female subjects, there was altered connectivity involving the cerebellum, thalamus, inferior frontal lobe posterior parietal lobe, angular gyrus, amygdala and middle temporal gyrus, and prefrontal cortex. In males, functional connectivity changes involved the supramarginal gyrus, cerebellum, and orbitofrontal gyrus, cerebellum, parahippocampus, inferior temporal gyrus, and anterior cingulate. Conclusion: Overall, these findings suggest a complex pattern of functional connectivity changes occurring in both members of the couple pair that result from this unique meditation practice. The changes represent a hybrid of functional connectivity findings with some similarities to meditation based practices and some with sexual stimulation and orgasm. This study has broader implications for understanding the dynamic relationship between sexuality and spirituality.

N-acetyl cysteine administration affects cerebral blood flow as measured by arterial spin labeling MRI in patients with multiple sclerosis.

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.

Treatment-Specific Hippocampal Subfield Volume Changes With Antidepressant Medication or Cognitive-Behavior Therapy in Treatment-Naive Depression.

Background: Hippocampal atrophy has been consistently reported in major depressive disorder with more recent focus on subfields. However, literature on hippocampal volume changes after antidepressant treatment has been limited. The first-line treatments for depression include antidepressant medication (ADM) or cognitive-behavior therapy (CBT). To understand the differential effects of CBT and ADM on the hippocampus, we investigated the volume alterations of hippocampal subfields with treatment, outcome, and chronicity in treatment-naïve depression patients. Methods: Treatment-naïve depressed patients from the PReDICT study were included in this analysis. A total of 172 patients who completed 12 weeks of randomized treatment with CBT (n = 45) or ADM (n = 127) were included for hippocampal subfield volume analysis. Forty healthy controls were also included for the baseline comparison. Freesurfer 6.0 was used to segment 26 hippocampal substructures and bilateral whole hippocampus from baseline and week 12 structural MRI scans. A generalized linear model with covariates of age and gender was used for group statistical tests. A linear mixed model for the repeated measures with covariates of age and gender was used to examine volumetric changes over time and the contributing effects of treatment type, outcome, and illness chronicity. Results: Of the 172 patients, 85 achieved remission (63/127 ADM, 22/45 CBT). MDD patients showed smaller baseline volumes than healthy controls in CA1, CA3, CA4, parasubiculum, GC-ML-DG, Hippocampal Amygdala Transition Area (HATA), and fimbria. Over 12 weeks of treatment, further declines in the volumes of CA1, fimbria, subiculum, and HATA were observed regardless of treatment type or outcome. CBT remitters, but not ADM remitters, showed volume reduction in the right hippocampal tail. Unlike ADM remitters, ADM non-responders had a decline in volume in the bilateral hippocampal tails. Baseline volume of left presubiculum (regardless of treatment type) and right fimbria and HATA in CBT patients were correlated with a continuous measure of clinical improvement. Chronicity of depression had no effect on any measures of hippocampal subfield volumes. Conclusion: Two first-line antidepressant treatments, CBT and ADM, have different effects on hippocampal tail after 12 weeks. This finding suggests that remission achieved via ADM may protect against progressive hippocampal atrophy by altering neuronal plasticity or supporting neurogenesis. Studies with multimodal neuroimaging, including functional and structural analysis, are needed to assess further the impact of two different antidepressant treatments on hippocampal subfields.

Resting-State Functional MRI Metrics in Patients With Chronic Mild Traumatic Brain Injury and Their Association With Clinical Cognitive Performance.

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.

Methodological considerations in conducting an olfactory fMRI study.

The sense of smell is a complex chemosensory processing in human and animals that allows them to connect with the environment as one of their chief sensory systems. In the field of functional brain imaging, many studies have focused on locating brain regions that are involved during olfactory processing. Despite wealth of literature about brain network in different olfactory tasks, there is a paucity of data regarding task design. Moreover, considering importance of olfactory tasks for patients with variety of neurological diseases, special contemplations should be addressed for patients. In this article, we review current olfaction tasks for behavioral studies and functional neuroimaging assessments, as well as technical principles regarding utilization of these tasks in functional magnetic resonance imaging studies.