Effect of scanning duration and sample size on reliability in resting state fMRI dynamic causal modeling analysis.

Despite its widespread use, resting-state functional magnetic resonance imaging (rsfMRI) has been criticized for low test-retest reliability. To improve reliability, researchers have recommended using extended scanning durations, increased sample size, and advanced brain connectivity techniques. However, longer scanning runs and larger sample sizes may come with practical challenges and burdens, especially in rare populations. Here we tested if an advanced brain connectivity technique, dynamic causal modeling (DCM), can improve reliability of fMRI effective connectivity (EC) metrics to acceptable levels without extremely long run durations or extremely large samples. Specifically, we employed DCM for EC analysis on rsfMRI data from the Human Connectome Project. To avoid bias, we assessed four distinct DCMs and gradually increased sample sizes in a randomized manner across ten permutations. We employed pseudo true positive and pseudo false positive rates to assess the efficacy of shorter run durations (3.6, 7.2, 10.8, 14.4 min) in replicating the outcomes of the longest scanning duration (28.8 min) when the sample size was fixed at the largest (n = 160 subjects). Similarly, we assessed the efficacy of smaller sample sizes (n = 10, 20, …, 150 subjects) in replicating the outcomes of the largest sample (n = 160 subjects) when the scanning duration was fixed at the longest (28.8 min). Our results revealed that the pseudo false positive rate was below 0.05 for all the analyses. After the scanning duration reached 10.8 min, which yielded a pseudo true positive rate of 92%, further extensions in run time showed no improvements in pseudo true positive rate. Expanding the sample size led to enhanced pseudo true positive rate outcomes, with a plateau at n = 70 subjects for the targeted top one-half of the largest ECs in the reference sample, regardless of whether the longest run duration (28.8 min) or the viable run duration (10.8 min) was employed. Encouragingly, smaller sample sizes exhibited pseudo true positive rates of approximately 80% for n = 20, and 90% for n = 40 subjects. These data suggest that advanced DCM analysis may be a viable option to attain reliable metrics of EC when larger sample sizes or run times are not feasible.

Subcortical functional connectivity and its association with walking performance following deployment related mild TBI.

Introduction: The relation between traumatic brain injury (TBI), its acute and chronic symptoms, and the potential for remote neurodegenerative disease is a priority for military research. Structural and functional connectivity (FC) of the basal ganglia, involved in motor tasks such as walking, are altered in some samples of Service Members and Veterans with TBI, but any behavioral implications are unclear and could further depend on the context in which the TBI occurred. Methods: In this study, FC from caudate and pallidum seeds was measured in Service Members and Veterans with a history of mild TBI that occurred during combat deployment, Service Members and Veterans whose mild TBI occurred outside of deployment, and Service Members and Veterans who had no lifetime history of TBI. Results: FC patterns differed for the two contextual types of mild TBI. Service Members and Veterans with deployment-related mild TBI demonstrated increased FC between the right caudate and lateral occipital regions relative to both the non-deployment mild TBI and TBI-negative groups. When evaluating the association between FC from the caudate and gait, the non-deployment mild TBI group showed a significant positive relationship between walking time and FC with the frontal pole, implicated in navigational planning, whereas the deployment-related mild TBI group trended towards a greater negative association between walking time and FC within the occipital lobes, associated with visuo-spatial processing during navigation. Discussion: These findings have implications for elucidating subtle motor disruption in Service Members and Veterans with deployment-related mild TBI. Possible implications for future walking performance are discussed.

Association of Cerebral Hemodynamics and Anemia on Processing Speed in Adults with Sickle Cell Disease.

Background and Purpose: Compared to healthy controls, adult patients with Sickle Cell Disease (SCD) are anemic, and therefore have higher cardiac output and Cerebral Blood Flow (CBF) to maintain brain oxygenation. They also demonstrate comparatively more cognitive deficits due to either overt strokes or silent cerebral ischemia. However, there are few correlative studies between CBF and cognitive deficits, specifically processing speed in SCD. Such studies are important to develop biomarkers of central brain processing and ischemia for diagnosis, prognosis, and evaluating the effectiveness of potential interventions. This pilot cross-sectional study tested the hypotheses that adults with SCD and elevated CBF demonstrate lower central brain processing speed than controls on average and that CBF is inversely correlated with processing speed. Methods: We conducted a pilot cross-sectional study to assess the relation-ships between CBF, central brain processing speed, and hemoglobin levels in asymptomatic adults with SCD and controls from an urban academic medical center. MRI acquisitions at 3T consisted of 2D phase-contrast quantitative arteriograms (Qflow) of the bilateral internal carotid and vertebral arteries and 3D pseudo-continuous arterial spin labeling (pCASL) of the brain. Participants were patients with SCD (hemoglobin [Hb]SS, [Hb] SBetaThal°, or [Hb]SC) aged 22-52 years of African American descent (N=7) or community controls (Hb AA) (n=3). Processing speed was assessed as an in-direct functional marker of ischemia using a recommended test from the NIH Toolbox for Assessment of Neurological and Behavioral Function, the Pattern Comparison Processing Speed Test. t-tests were used to compare means of CBF, hemoglobin, and cognition between SCD patients and healthy controls. Among SCD patients only multivariate correla-tions were used to evaluate relationships between brain perfusion in specific brain regions vs. processing speed and CBF. The significance level was set at p≤0.05. Results: Adults with SCD reported higher CBF compared to healthy con-trols (72.15±28.90 vs. 47.23±12.30 ml/min/100g, p=0.04), and lower hemoglobin concentration (8.64±2.33 vs. 13.33±0.58, p=0.001). Heart rate in SCD patients was higher than in controls (86.29±1.37 vs. 74.00±2.10, p=0.04). Patients with SCD demonstrated lower processing speed (96.14±21.04 vs.123±13.74, p=0.02) than controls. Among adult patients with SCD, perfusion in specific regions of the brain showed an inverse relationship with processing speed, as did whole-brain CBF (p=0.0325). Conclusion: These findings, although from a small sample, lend a degree of validity to the claim that processing speed is slower in people with SCD than in controls and that CBF is significantly higher in SCD patients com-pared to controls. The results also lend credence to the finding that the degree of processing speed deficiencies among adults with SCD is correlated with the degree of elevated CBF, which is known to correspond with the degree of anemia associated with SCD.

Executive control network resting state fMRI functional and effective connectivity and delay discounting in cocaine dependent subjects compared to healthy controls.

Resting state functional magnetic resonance imaging (fMRI) has been used to study functional connectivity of brain networks in addictions. However, most studies to-date have focused on the default mode network (DMN) with fewer studies assessing the executive control network (ECN) and salience network (SN), despite well-documented cognitive executive behavioral deficits in addictions. The present study assessed the functional and effective connectivity of the ECN, DMN, and SN in cocaine dependent subjects (CD) (n = 22) compared to healthy control subjects (HC) (n = 22) matched on age and education. This study also investigated the relationship between impulsivity measured by delay discounting and functional and effective connectivity of the ECN, DMN, and SN. The Left ECN (LECN), Right ECN (RECN), DMN, and SN functional networks were identified using FSL MELODIC independent component analysis. Functional connectivity differences between CD and HC were assessed using FSL Dual Regression analysis and FSLNets. Effective connectivity differences between CD and HC were measured using the Parametric Empirical Bayes module of Dynamic Causal Modeling. The relationship between delay discounting and functional and effective connectivity were examined using regression analyses. Dynamic causal modeling (DCM) analysis showed strong evidence (posterior probability > 0.95) for CD to have greater effective connectivity than HC in the RECN to LECN pathway when tobacco use was included as a factor in the model. DCM analysis showed strong evidence for a positive association between delay discounting and effective connectivity for the RECN to LECN pathway and for the DMN to DMN self-connection. There was strong evidence for a negative association between delay discounting and effective connectivity for the DMN to RECN pathway and for the SN to DMN pathway. Results also showed strong evidence for a negative association between delay discounting and effective connectivity for the RECN to SN pathway in CD but a positive association in HC. These novel findings provide preliminary support that RECN effective connectivity may differ between CD and HC after controlling for tobacco use. RECN effective connectivity may also relate to tobacco use and impulsivity as measured by delay discounting.

Chronic Cocaine Use and White Matter Coherence: A Diffusion Tensor Imaging Study.

OBJECTIVE: Chronic substance use and its effects on brain function and structure has long been of interest to clinicians and researchers. Prior cross-sectional comparisons of diffusion tensor imaging (DTI) metrics have suggested deleterious effects of chronic substance use (i.e., cocaine use) on white matter coherence. However, it is unclear how these effects may replicate across geographic regions when examined with similar technologies. In this study, we sought to conduct a replication of previous work in this area and determine whether there are any patterns of persistent differences in white matter microstructure between individuals with a history of cocaine use disorder (CocUD, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and healthy controls. METHOD: A total of 46 participants (21 healthy controls, 25 chronic cocaine users) were recruited from the Richmond, Virginia metropolitan area. Information regarding past and current substance use was collected from all participants. Participants also completed structural and DTI scans. RESULTS: Consistent with previous DTI studies, significant differences were found between fractional anisotropy (FA) and axial diffusivity (AD) CocUD and controls, with CocUD showing lower FA and AD in the right inferior and superior longitudinal fasciculus, the genu, body, and splenium of the corpus callosum, and the anterior, posterior, and superior corona radiata, among several other regions. These differences were not significant for other diffusivity metrics. Lifetime alcohol consumption was greater in the CocUD group, but lifetime alcohol consumption did not show a significant linear relationship with any of the DTI metrics in within-group regression analyses. CONCLUSIONS: These data align with previously reported declines in white matter coherence in chronic cocaine users. However, it is less clear whether comorbid alcohol consumption results in an additive deleterious effect on white matter microstructure.

Dynamic Causal Modeling Self-Connectivity Findings in the Functional Magnetic Resonance Imaging Neuropsychiatric Literature.

Dynamic causal modeling (DCM) is a method for analyzing functional magnetic resonance imaging (fMRI) and other functional neuroimaging data that provides information about directionality of connectivity between brain regions. A review of the neuropsychiatric fMRI DCM literature suggests that there may be a historical trend to under-report self-connectivity (within brain regions) compared to between brain region connectivity findings. These findings are an integral part of the neurologic model represented by DCM and serve an important neurobiological function in regulating excitatory and inhibitory activity between regions. We reviewed the literature on the topic as well as the past 13 years of available neuropsychiatric DCM literature to find an increasing (but still, perhaps, and inadequate) trend in reporting these results. The focus of this review is fMRI as the majority of published DCM studies utilized fMRI and the interpretation of the self-connectivity findings may vary across imaging methodologies. About 25% of articles published between 2007 and 2019 made any mention of self-connectivity findings. We recommend increased attention toward the inclusion and interpretation of self-connectivity findings in DCM analyses in the neuropsychiatric literature, particularly in forthcoming effective connectivity studies of substance use disorders.

Resting-State Directional Connectivity and Anxiety and Depression Symptoms in Adult Cannabis Users.

BACKGROUND: Anxiety and depression symptoms are common among cannabis users and could be a risk factor for cannabis use (CU) disorder. Thus, it is critical to understand the neuronal circuits underlying the associations between CU and these symptoms. Alterations in resting-state functional connectivity within and/or between the default mode network and salience network have been reported in CU, anxiety, and depressive disorders and thus could be a mechanism underlying the associations between CU disorder and anxiety/depression symptoms. METHODS: Using resting-state functional magnetic resonance imaging, effective connectivities (ECs) among 9 major nodes from the default mode network and salience network were measured using dynamic causal modeling in 2 datasets: the Human Connectome Project (28 CU participants and 28 matched non-drug-using control participants) and a local CU study (21 CU participants and 21 matched non-drug-using control participants) in separate and parallel analyses. RESULTS: Relative to the control participants, right amygdala to left amygdala, anterior cingulate cortex to left amygdala, and medial prefrontal cortex to right insula ECs were greater, and left insula to left amygdala EC was smaller in the CU group. Each of these ECs showed a reliable linear relationship with at least one of the anxiety/depression measures. Most findings on the right amygdala to left amygdala EC were common to both datasets. CONCLUSIONS: Right amygdala to left amygdala and anterior cingulate cortex to left amygdala ECs may be related to the close associations between CU and anxiety/depression symptoms. The findings on the medial prefrontal cortex to right insula and left insula to left amygdala ECs may reflect a compensatory mechanism.

Preliminary Findings of Weaker Executive Control Network Resting State fMRI Functional Connectivity in Opioid Use Disorder compared to Healthy Controls.

Objective: Resting state functional magnetic resonance imaging (fMRI) functional connectivity has been used as a tool to study brain mechanisms associated with addictions. Recent research in substance use disorders has focused on three brain networks termed the default mode network (DMN), salience network (SN), and executive control network (ECN). The purpose of this study was to examine the functional connectivity of those three networks in opioid use disorder (OUD) subjects compared to healthy control subjects (HC). Methods: The present study investigated functional connectivity differences between OUD subjects compared to HC using independent component analysis. This study also examined the relationship between functional connectivity and negative urgency scores, as well as compared the functional connectivity of severe OUD to mild or moderate OUD. Results: In OUD subjects (n=25) compared to HC (n=25), a cluster in the left dorsolateral prefrontal cortex within the left ECN had significantly weaker functional connectivity. No significant differences were found between groups for the functional connectivity of the DMN, SN, or right ECN. No significant associations were found between functional connectivity and negative urgency, and no differences were found between severe OUD and mild or moderate OUD. Conclusion: These novel preliminary results suggest that ECN functional connectivity may differ between OUD and HC. This finding is consistent with previous research showing altered executive function in OUD and supports further examination of ECN functional connectivity in association with treatment response in OUD. Given our relatively small sample size (50 subjects total; 25 subjects per group), our results should be treated as preliminary for hypothesis generation, and replication will be needed in future studies.

Altered Effective Connectivity of Central Autonomic Network in Response to Negative Facial Expression in Adults With Cannabis Use Disorder.

BACKGROUND: Cannabis use is associated with an increased risk of stress-related adverse cardiovascular events. Because brain regions of the central autonomic network largely overlap with brain regions related to the neural response to emotion and stress, the central autonomic network may mediate the autonomic response to negative emotional stimuli. We aimed to obtain evidence to determine whether neural connectivity of the central autonomic network is altered in individuals with cannabis use disorder (CUD) when they are exposed to negative emotional stimuli. METHODS: Effective (directional) connectivity (EC) analysis using dynamic causal modeling was applied to functional magnetic resonance imaging data acquired from 23 subjects with CUD and 23 control subjects of the Human Connectome Project while they performed an emotional face-matching task with interleaving periods of negative-face (fearful/angry) and neutral-shape stimuli. The EC difference (modulatory change) was measured during the negative-face trials relative to the neutral-shape trials. RESULTS: The CUD group was similar to the control group in nonimaging measures and brain activations but showed greater modulatory changes in left amygdala to hypothalamus EC (positively associated with Perceived Stress Scale score), right amygdala to bilateral fusiform gyri ECs (positively associated with Perceived Stress Scale score), and left ventrolateral prefrontal cortex to bilateral fusiform gyri ECs (negatively associated with Perceived Stress Scale score). CONCLUSIONS: Left amygdala to hypothalamus EC and right amygdala to bilateral fusiform gyri ECs are possibly part of circuits underlying the risk of individuals with CUD to stress-related disorders. Correspondingly, left ventrolateral prefrontal cortex to bilateral fusiform gyri ECs are possibly part of circuits reflecting a protective mechanism.

Cingulo-hippocampal effective connectivity positively correlates with drug-cue attentional bias in opioid use disorder.

Individuals with opioid use disorder (OUD) often relapse when exposed to opioid-related cues. Previous functional magnetic resonance imaging (fMRI) studies have identified neuronal corticolimbic changes related to drug cue reactivity in OUD. However, the corresponding manner in which brain regions interact is still unclear. Effective (directional) connectivity was analyzed using dynamic causal modeling of fMRI data acquired from 27 OUD participants (13 with OUD and 14 with OUD and cocaine use disorder [OUD+CUD]), while performing an opioid-word Stroop task. Participants were shown opioid and neutral words presented in different colors and were instructed to indicate word color but ignore word meaning. The effects of opioid words relative to neutral words on effective connectivity and on behavioral reaction time were defined as modulatory change and attentional bias, respectively. For all the 27 participants, left anterior cingulate cortex (ACC) to right hippocampus effective connectivity exhibited the largest modulatory change, which was positively correlated with attentional bias. The findings for the ACC to hippocampus EC were consistent across OUD and CUD found in a previous study.

Measures of possible allostatic load in comorbid cocaine and alcohol use disorder: Brain white matter integrity, telomere length, and anti-saccade performance.

Chronic cocaine and alcohol use impart significant stress on biological and cognitive systems, resulting in changes consistent with an allostatic load model of neurocognitive impairment. The present study measured potential markers of allostatic load in individuals with comorbid cocaine/alcohol use disorders (CUD/AUD) and control subjects. Measures of brain white matter (WM), telomere length, and impulsivity/attentional bias were obtained. WM (CUD/AUD only) was indexed by diffusion tensor imaging metrics, including radial diffusivity (RD) and fractional anisotropy (FA). Telomere length was indexed by the telomere to single copy gene (T/S) ratio. Impulsivity and attentional bias to drug cues were measured via eye-tracking, and were also modeled using the Hierarchical Diffusion Drift Model (HDDM). Average whole-brain RD and FA were associated with years of cocaine use (R2 = 0.56 and 0.51, both p < .005) but not years of alcohol use. CUD/AUD subjects showed more anti-saccade errors (p < .01), greater attentional bias scores (p < .001), and higher HDDM drift rates on cocaine-cue trials (Bayesian probability CUD/AUD > control = p > 0.99). Telomere length was shorter in CUD/AUD, but the difference was not statistically significant. Within the CUD/AUD group, exploratory regression using an elastic-net model determined that more years of cocaine use, older age, larger HDDM drift rate differences and shorter telomere length were all predictive of WM as measured by RD (model R2 = 0.79). Collectively, the results provide modest support linking CUD/AUD to putative markers of allostatic load.

Functional brain connectivity and cortical thickness in relation to chronic pain in post-911 veterans and service members with mTBI.

OBJECTIVES: Investigate the relation of chronic pain interference to functional connectivity (FC) of brain regions and to cortical thickness in post-911 Veterans and Service Members (SMs) who sustained a mild traumatic brain injury (mTBI). METHODS: This is an observational study with cross-sectional analyses. A sample of 65 enrollees completing initial evaluation at a single site of the Chronic Effects of Neurotrauma Consortium (CENC) reported pain interference ratings on the TBI QOL. Functional connectivity and cortical thickness were measured. RESULTS: Severity of pain interference was negatively related to FC of the default mode network (DMN), i.e., participants who reported more severe pain interference had less FC between mesial prefrontal cortex and posterior regions of the DMN including posterior cingulate cortex and precuneus. Cortical thickness of specific regions was positively related to severity of pain interference. CONCLUSION: The more that pain was perceived to interfere with daily life, the less the FC between regions in a network associated with self-referential thought and mind wandering. Although cortical thickness in specific brain regions was positively related to severity of pain interference, follow-up longitudinal data, control group data, and study of individual differences in this cohort will expand this initial report and replicate these findings.

Fronto-striatal effective connectivity of working memory in adults with cannabis use disorder.

Previous working memory (WM) studies found that relative to controls, subjects with cannabis use disorder (CUD) showed greater brain activation in some regions (e.g., left [L] and right [R] ventrolateral prefrontal cortex [VLPFC], and L dorsolateral prefrontal cortex [L-DLPFC]), and lower activation in other regions (e.g., R-DLPFC). In this study, effective connectivity (EC) analysis was applied to functional magnetic resonance imaging data acquired from 23 CUD subjects and 23 controls (two groups matched for sociodemographic factors and substance use history) while performing an n-back WM task with interleaved 2-back and 0-back periods. A 2-back minus 0-back modulator was defined to measure the modulatory changes of EC corresponding to the 2-back relative to 0-back conditions. Compared to the controls, the CUD group showed smaller modulatory change in the R-DLPFC to L-caudate pathway, and greater modulatory changes in L-DLPFC to L-caudate, R-DLPFC to R-caudate, and R-VLPFC to L-caudate pathways. Based on previous fMRI studies consistently suggesting that greater brain activations are related to a compensatory mechanism for cannabis neural effects (less regional brain activations), the smaller modulatory change in the R-DLPFC to L-caudate EC may be compensated by the larger modulatory changes in the other prefrontal-striatal ECs in the CUD individuals.

Altered anterior cingulate cortex to hippocampus effective connectivity in response to drug cues in men with cocaine use disorder.

Drug-related attentional bias may have significant implications for the treatment of cocaine use disorder (CocUD). However, the neurobiology of attentional bias is not completely understood. This study employed dynamic causal modeling (DCM) to conduct an analysis of effective (directional) connectivity involved in drug-related attentional bias in treatment-seeking CocUD subjects. The DCM analysis was conducted based on functional magnetic resonance imaging (fMRI) data acquired from fifteen CocUD subjects while performing a cocaine-word Stroop task, during which blocks of Cocaine Words (CW) and Neutral Words (NW) alternated. There was no significant attentional bias at group level. Although no significant brain activation was found, the DCM analysis found that, relative to the NW, the CW caused a significant increase in the strength of the right (R) anterior cingulate cortex (ACC) to R hippocampus effective connectivity. Greater increase of this connectivity was associated with greater CW reaction time (relative to NW reaction time). The increased strength of R ACC to R hippocampus connectivity may reflect ACC activation of hippocampal memories related to drug use, which was triggered by the drug cues. This circuit could be a potential target for therapeutics in CocUD patients. No significant change was found in the other modeled connectivities.

A preliminary longitudinal study of white matter alteration in cocaine use disorder subjects.

BACKGROUND: Previous diffusion tensor imaging (DTI) studies have consistently shown that subjects with cocaine use disorder (CocUD) had altered white matter microstructure in the corpus callosum. It is believed that these alterations are due to preexisting factors, chronic cocaine use, or both. However, there is no published longitudinal DTI study on human cocaine users yet which could shed light on the relationship between cocaine use and DTI findings. METHODS: This study used a longitudinal design and DTI to test if the white matter microstructure shows quicker alteration in CocUD subjects than controls. DTI data were acquired from eleven CocUD subjects who participated a treatment study and eleven non-drug-using controls at baseline (Scan 1) and after ten weeks (Scan 2). The baseline fractional anisotropy (FA), a general measure of white matter microstucture, and the change in FA (ΔFA, equals Scan 1 FA minus Scan 2 FA) were both compared between groups. RESULTS: The two groups did not show a difference in FA at baseline. The CocUD subjects had significantly greater ΔFA than the controls in the left splenium of the corpus callosum. In CocUD subjects, greater ΔFA in this region was associated with shorter lifetime cocaine use and greater number of positive cocaine urine samples collected during the treatment. CONCLUSION: The finding in the left splenium is consistent with previous animal studies and provide indirect evidence about the effects of chronic cocaine use on white matter alterations. The subject sample size is small, therefore the results should be treated as preliminary.

Novel fMRI working memory paradigm accurately detects cognitive impairment in multiple sclerosis.

BACKGROUND: Cognitive impairment (CI) cannot be diagnosed by magnetic resonance imaging (MRI). Functional magnetic resonance imaging (fMRI) paradigms, such as the immediate/delayed memory task (I/DMT), detect varying degrees of working memory (WM). Preliminary findings using I/DMT showed differences in blood oxygenation level dependent (BOLD) activation between impaired (MSCI, n = 12) and non-impaired (MSNI, n = 9) multiple sclerosis (MS) patients. OBJECTIVES: The aim of the study was to confirm CI detection based on I/DMT BOLD activation in a larger cohort of MS patients. The role of T2 lesion volume (LV) and Expanded Disability Status Scale (EDSS) in magnitude of BOLD signal was also sought. METHODS: A total of 50 patients (EDSS mean ( m) = 3.2, disease duration (DD) m = 12 years, and age m = 40 years) underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) and I/DMT. Working memory activation (WMa) represents BOLD signal during DMT minus signal during IMT. CI was based on MACFIMS. RESULTS: A total of 10 MSNI, 30 MSCI, and 4 borderline patients were included in the analyses. Analysis of variance (ANOVA) showed MSNI had significantly greater WMa than MSCI, in the left prefrontal cortex and left supplementary motor area ( p = 0.032). Regression analysis showed significant inverse correlations between WMa and T2 LV/EDSS in similar areas ( p = 0.005, 0.004, respectively). CONCLUSION: I/DMT-based BOLD activation detects CI in MS. Larger studies are needed to confirm these findings.

Limbic Pathway Correlates of Cognitive Impairment in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Distinct injuries to various limbic white matter pathways have been reported to be associated with different aspects of cognitive dysfunction in multiple sclerosis (MS). Diffusion tensor imaging (DTI) offers a noninvasive method to map tissue microstructural organization. We utilized quantitative magnetic resonance imaging methods to analyze the main limbic system-white matter structures in MS patients with cognitive impairment (CI). METHODS: Ten cognitively nonimpaired MS (MSNI) patients and 36 patients with diagnosed CI (MSCI) underwent the minimal assessment of Cognitive Function in MS (MACFIMS) battery. DTI measures of fornix, cingulum, uncinate fasciculus (UF) included tract volume and corresponding fractional anisotropy (FA), mean (MD), axial (AD), and radial (AD) diffusivities. These were statistically analyzed for associations with CI after adjusting for the confounders. RESULTS: Fornix FA and RD, left cingulum FA, MD, and RD, right cingulum FA, MD, and RD, and left UF FA showed significant differences between MSNI and MSCI (P < .001). Fornix FA (r = -.6) and RD (r = .52), and right cingulum FA (r = -.54) and RD (r = .5) correlated significantly with CI in regression analyses. CONCLUSIONS: The extent of disruption of microstructural disorganization in the main limbic pathways using DTI impacts the extent of CI seen in subjects with MS.

Elderly patients have an altered gut-brain axis regardless of the presence of cirrhosis.

Cognitive difficulties manifested by the growing elderly population with cirrhosis could be amnestic (memory-related) or non-amnestic (memory-unrelated). The underlying neuro-biological and gut-brain changes are unclear in this population. We aimed to define gut-brain axis alterations in elderly cirrhotics compared to non-cirrhotic individuals based on presence of cirrhosis and on neuropsychological performance. Age-matched outpatients with/without cirrhosis underwent cognitive testing (amnestic/non-amnestic domains), quality of life (HRQOL), multi-modal MRI (fMRI go/no-go task, volumetry and MR spectroscopy), blood (inflammatory cytokines) and stool collection (for microbiota). Groups were studied based on cirrhosis/not and also based on neuropsychological performance (amnestic-type, amnestic/non-amnestic-type and unimpaired). Cirrhotics were impaired on non-amnestic and selected amnestic tests, HRQOL and systemic inflammation compared to non-cirrhotics. Cirrhotics demonstrated significant changes on MR spectroscopy but not on fMRI or volumetry. Correlation networks showed that Lactobacillales members were positively while Enterobacteriaceae and Porphyromonadaceae were negatively linked with cognition. Using the neuropsychological classification amnestic/non-amnestic-type individuals were majority cirrhosis and had worse HRQOL, higher inflammation and decreased autochthonous taxa relative abundance compared to the rest. This classification also predicted fMRI, MR spectroscopy and volumetry changes between groups. We conclude that gut-brain axis alterations may be associated with the type of neurobehavioral decline or inflamm-aging in elderly cirrhotic subjects.

Reward vs. Retaliation-the Role of the Mesocorticolimbic Salience Network in Human Reactive Aggression.

The propensity for reactive aggression (RA) which occurs in response to provocation has been linked to hyperresponsivity of the mesocorticolimbic reward network in healthy adults. Here, we aim to elucidate the role of the mesocorticolimbic network in clinically significant RA for two competing motivated behaviors, reward-seeking vs. retaliation. 18 male participants performed a variant of the Point-Subtraction Aggression Paradigm (PSAP) during functional magnetic resonance imaging (fMRI). We examined whether RA participants compared with non-aggressive controls would choose to obtain a monetary reward over the opportunity to retaliate against a fictitious opponent, who provoked the participant by randomly stealing money from his earnings. Across all fMRI-PSAP runs, RA individuals vs. controls chose to work harder to earn money but not to retaliate. When engaging in such reward-seeking behavior vs. retaliation in a single fMRI-PSAP run, RA individuals exhibited increased activation in the insular-striatal part of the mesocorticolimbic salience network, and decreased precuneus and ventromedial prefrontal cortex activation compared to controls. Enhanced overall reward-seeking behavior along with an up-regulation of the mesocorticolimbic salience network and a down-regulation of the default-mode network in RA individuals indicate that RA individuals are willing to work more for monetary reward than for retaliation when presented with a choice. Our findings may suggest that the use of positive reinforcement might represent an efficacious intervention approach for the potential reduction of retaliatory behavior in clinically significant RA.

Effect of cocaine dependence on brain connections: clinical implications.

Cocaine dependence (CD) is associated with several cognitive deficits. Accumulating evidence, based on human and animal studies, has led to models for interpreting the neural basis of cognitive functions as interactions between functionally related brain regions. In this review, we focus on magnetic resonance imaging (MRI) studies using brain connectivity techniques as related to CD. The majority of these brain connectivity studies indicated that cocaine use is associated with altered brain connectivity between different structures, including cortical-striatal regions and default mode network. In cocaine users some of the altered brain connectivity measures are associated with behavioral performance, history of drug use, and treatment outcome. The implications of these brain connectivity findings to the treatment of CD and the pros and cons of the major brain connectivity techniques are discussed. Finally potential future directions in cocaine use disorder research using brain connectivity techniques are briefly described.