High-resolution diffusion tensor imaging of the fornix predicts memory function in multiple sclerosis.

Background: Cognitive dysfunction is a known symptom of multiple sclerosis (MS), with memory recognized as a frequently impacted domain. Here, we used high-resolution MRI at 7 tesla to build on cross-sectional work by evaluating the longitudinal relationship of diffusion tensor imaging (DTI) measures of the fornix to episodic memory performance. Methods: A sample of 80 people with multiple sclerosis (mean age 51.9 ± 8.1 years; 24% male) underwent baseline clinical evaluation, neuropsychological assessment, and MRI. Sixty-four participants had follow-up neuropsychological testing after 1-2 years. Linear regression was used to assess the relationship of baseline imaging measures to follow-up episodic memory performance, measured using the Selective Reminding Test and Brief Visuospatial Memory Test. A reduced prediction model included cognitive function at baseline, age, sex, and disease course. Results: Radial (ß = -0.222, p < 0.026; likelihood ratio test (LRT) p < 0.018), axial (ß = -0.270, p < 0.005; LRT p < 0.003), and mean (ß = -0.242, p < 0.0139; LRT p < 0.009) diffusivity of the fornix significantly added to the model, with follow-up analysis indicating that a longer prediction interval may increase accuracy. Conclusion: These results suggest that fornix DTI has predictive value specific to memory function in MS and warrants additional investigation in the drive to develop predictors of disease progression.

Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

BACKGROUND AND PURPOSE: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. METHODS: Thirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). RESULTS: Statistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = -0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. CONCLUSION: This cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.

Magnetic resonance fingerprinting in multiple sclerosis.

BACKGROUND: In this cross sectional study, we used MRF to investigate tissue properties of normal-appearing white matter, gray matter, and lesions in relapsing remitting MS (n = 21), secondary progressive MS (n = 16) and healthy controls (n = 9). A FISP-based MRF sequence was used for acquisition, imaging time 5 min 15 s. MRF T1 and T2 relaxation times were measured from lesional tissue, normal-appearing frontal white matter, corpus callous, thalamus, and caudate. Differences between healthy controls and MS were examined using ANCOVA adjusted for age and sex. Spearman rank correlations were assessed between T1 and T2 relaxation times and clinical measures. OBJECTIVES: To examine brain T1 and T2 values using magnetic resonance fingerprinting (MRF) in healthy controls and MS. METHODS: The subjects included 21 relapsing-remitting (RR) MS, 16 secondary progressive (SP) MS, and 9 age- and sex-matched HC without manifest neurological disease participating in a longitudinal MRI study. A 3T/ FISP-based MRF sequence was acquired. Regions of interest were drawn for lesions and normal appearing white matter. ANCOVA adjusted for age and sex were used to compare the groups with significance set at 0.05. RESULTS: A step-wise increase in T1 and T2 relaxation times was found between healthy controls, relapsing remitting MS, and secondary progressive MS. Significant differences were found in T1 and T2 between MS and healthy controls in the frontal normal-appearing white matter, corpus callosum, and thalamus (p < 0.04 for all). Significant differences in T1 and T2 between RR and SPMS were found in the frontal normal-appearing white matter and T2 lesions (p < 0.02 for all). T1 relaxation from the frontal normal-appearing white matter correlated with the Expanded Disability Status Scale [ρ = 0.62, p < 0.001], timed 25 foot walk (ρ = 0.45, p = 0.01), 9 hole peg test (ρ = 0.62, p < 0.001), and paced auditory serial addition test (ρ = -0.4, p = 0.01). CONCLUSION: These results suggest that MRF may be a clinically feasible quantitative approach for characterizing tissue damage in MS.

Stimulation of the Premotor Cortex Enhances Interhemispheric Functional Connectivity in Association with Upper Limb Motor Recovery in Moderate-to-Severe Chronic Stroke.

Background: Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections. Objective: The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity. Methods: Participants with chronic stroke were randomly assigned to receive active-PMC or sham-tDCS with rehabilitation for 5 weeks. Resting-state functional magnetic resonance imaging was acquired to characterize change in FC across motor-cortical regions. Results: Our results indicated that moderate-to-severe participants who received active-tDCS had greater increases in PMC-to-PMC interhemispheric FC compared to those who received sham; this increase was correlated with reduction in proximal motor impairment. There was also an increase in intrahemispheric dorsal premotor cortex-primary motor cortex FC across participants regardless of severity or tDCS group assignment; this increase was correlated with a reduction in proximal motor impairment in only the mild participants. Conclusions: Our findings have significance for developing targeted brain stimulation approaches. While participants with milder impairments may inherently recruit viable substrates within the ipsilesional hemisphere, stimulation of PMC may enhance interhemispheric FC in association with recovery in more impaired participants. Trial Registration: ClinicalTrials.gov Identifier: NCT01539096; Registration date: February 21, 2012.

Gadolinium-based contrast agent exposures and physical and cognitive disability in multiple sclerosis.

BACKGROUND AND PURPOSE: The clinical correlation of gadolinium-based contrast agents (GBCAs) has not been well studied in multiple sclerosis (MS). We investigated the extent to which the number of GBCA administrations relates to self-reported disability and performance measures. METHODS: A cohort of MS patients was analyzed in this retrospective observational study. The main outcome was the association between the cumulative number of GBCA exposures (linear or macrocyclic GBCA), Patient-Determined Disease Steps (PDDS), and measures of physical and cognitive performance (walking speed test, manual dexterity test [MDT], and processing speed test [PST]). The analysis was performed first cross-sectionally and then longitudinally. RESULTS: The cross-sectional data included 1059 MS patients with a mean age of 44.0 years (standard deviation = 11.2). While the contrast ratio in globus pallidus weakly correlated with PDDS, MDT, and PST in a univariate correlational analysis (coefficients, 95% confidence interval [CI] = 0.11 [0.04, 0.18], 0.15 [0.08, 0.21], and -0.16 [-0.10, -0.23], respectively), the associations disappeared after covariate adjustment. A significant association was found between number of linear GBCA administrations and PDDS (coefficient [CI] = -0.131 [-0.196, -0.067]), and MDT associated with macrocyclic GBCA administrations (-0.385 [-0.616, -0.154]), but their signs indicated better outcomes in patients with greater GBCA exposures. The longitudinal data showed no significant detrimental effect of macrocyclic GBCA exposures. CONCLUSION: No detrimental effects were observed between GBCA exposure and self-reported disability and standardized objective measures of physical and cognitive performance. While several weak associations were found, they indicated benefit on these measures.

Cohesive parcellation of the human brain using resting-state fMRI.

BACKGROUND: The data burden for resting-state fMRI analysis rises with increasing resolutions available at ultrahigh fields. Therefore, a fundamental preprocessing step in brain network analysis is to reduce the data, usually by performing some kind of data parcellation. Most functional parcellations based on rsfMRI connectivity are synthesized from the dense connectome. In contrast, most network analyses begin by reducing each parcel to a single exemplar time series. This disconnect between parcel formation and usage assumes that parcel exemplars adequately represent their member voxels, which is not always the case for commonly used parcellations. NEW METHOD: We propose to parcellate the brain based on parcel cohesion, a measure of similarity between a parcel's exemplar and its member voxels. A spatially constrained agglomerative hierarchical framework is used to synthesize parcels based on a minimum cohesion threshold, rather than a predetermined number of parcels. RESULTS: Cohesive parcellation generally results in more parcels than existing approaches. The number of parcels scales with the amount of smoothing in preprocessing, yet retains adequate information to extract common intrinsic functional networks. COMPARISON WITH PREVIOUS METHODS: Cohesive parcellation performs better than several widely used anatomical, functional, and data-driven parcellations on the basis of parcel cohesion and comparably using several traditional measures of cluster validity. CONCLUSION: Cohesive parcellation ensures that the way parcels are synthesized directly corresponds to the way they are used in subsequent analyses. The resulting parcels are straightforward to interpret and optimal for downstream analysis.

Prediction of Naming Outcome With fMRI Language Lateralization in Left Temporal Epilepsy Surgery.

BACKGROUND AND OBJECTIVES: Naming decline after left temporal lobe epilepsy (TLE) surgery is common and difficult to predict. Preoperative language fMRI may predict naming decline, but this application is still lacking evidence. We performed a large multicenter cohort study of the effectiveness of fMRI in predicting naming deficits after left TLE surgery. METHODS: At 10 US epilepsy centers, 81 patients with left TLE were prospectively recruited and given the Boston Naming Test (BNT) before and ≈7 months after anterior temporal lobectomy. An fMRI language laterality index (LI) was measured with an auditory semantic decision-tone decision task contrast. Correlations and a multiple regression model were built with a priori chosen predictors. RESULTS: Naming decline occurred in 56% of patients and correlated with fMRI LI (r = -0.41, p < 0.001), age at epilepsy onset (r = -0.30, p = 0.006), age at surgery (r = -0.23, p = 0.039), and years of education (r = 0.24, p = 0.032). Preoperative BNT score and duration of epilepsy were not correlated with naming decline. The regression model explained 31% of the variance, with fMRI contributing 14%, with a 96% sensitivity and 44% specificity for predicting meaningful naming decline. Cross-validation resulted in an average prediction error of 6 points. DISCUSSION: An fMRI-based regression model predicted naming outcome after left TLE surgery in a large, prospective multicenter sample, with fMRI as the strongest predictor. These results provide evidence supporting the use of preoperative language fMRI to predict language outcome in patients undergoing left TLE surgery. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that fMRI language lateralization can help in predicting naming decline after left TLE surgery.

A comprehensive investigation of physiologic noise modeling in resting state fMRI; time shifted cardiac noise in EPI and its removal without external physiologic signal measures.

Hemodynamic cardiac and respiratory-cycle fluctuations are a source of unwanted non-neuronal signal components, often called physiologic noise, in resting state (rs-) fMRI studies. Here, we use image-based retrospective correction of physiological motion (RETROICOR) with externally measured physiologic signals to investigate cardiac and respiratory hemodynamic phase functions reflected in rs-fMRI data. We find that the cardiac phase function is time shifted locally, while the respiratory phase function is described as single, fixed phase form across the brain. In light of these findings, we propose an update to Physiologic EStimation by Temporal ICA (PESTICA), our publically available software package that estimates physiologic signals when external physiologic measures are not available. This update incorporates: 1) auto-selection of slicewise physiologic regressors and generation of physiologic fixed phase regressors with total slices/TR sampling rate, 2) Fourier series expansion of the cardiac fixed phase regressor to account for time delayed cardiac noise 3) removal of cardiac and respiratory noise in imaging data. We compare the efficacy of the updated method to RETROICOR.

Brain Injury and Mental Health Among the Victims of Intimate Partner Violence: A Case-Series Exploratory Study.

Intimate partner violence (IPV) survivors frequently report face, head, and neck as their injury site. Many mild traumatic brain injuries (TBIs) are undiagnosed or underreported among IPV survivors while these injuries may be linked to changes in brain function or pathology. TBI sustained due to IPV often occurs over time and ranges in severity. The aim of this case-series study was to explore risk factors, symptoms, and brain changes unique to survivors of intimate partner violence with suspicion of TBI. This case-series exploratory study examines the potential relationships among IPV, mental health issues, and TBI. Participants of this study included six women: 3 women with a history of IPV without any experience of concussive blunt force to the head, and 3 women with a history of IPV with concussive head trauma. Participants completed 7T MRI of the brain, self-report psychological questionnaires regarding their mental health, relationships, and IPV, and the Structured Clinical Interview. MRI scans were analyzed for cerebral hemorrhage, white matter disturbance, and cortical thinning. Results indicated significant differences in resting-state connectivity among survivors of partner violence as well as differences in relationship dynamics and mental health symptoms. White matter hyperintensities are also observed among the survivors. Developing guidelines and recommendations for TBI-risk screening, referrals, and appropriate service provision is crucial for the effective treatment of TBI-associated IPV. Early and accurate characterization of TBI in survivors of IPV may relieve certain neuropsychological consequences.

Seed-based test-retest reliability of resting state functional magnetic resonance imaging at 3T and 7T.

PURPOSE: Ultrahigh field (UHF) resting state functional magnetic resonance imaging (rsfMRI) has become increasingly available for clinical and basic research, bringing improvements in resolution and contrast over standard high field imaging. Despite these improvements, UHF connectivity studies present several challenges, including increased sensitivity to physiological confounds and a vastly increased data burden. We present a direct quantitative assessment of test-retest reliability of functional connectivity in several standard functional networks between subjects scanned at 3T and 7T. METHODS: Five healthy subjects were scanned over four sessions each in a scan-rescan design at both 3T and 7T field strengths. Resting state fMRI data were segmented into four major intrinsic connectivity networks, and seed-based peak correlations within and between these networks examined. The reliability of these correlations was assessed using intra-class correlation coefficients (ICC). RESULTS: Across all data, over 4000 peak correlations were extracted for assessment. The reliability over all intrinsic networks was greater at 7T than 3T (median ICC 0.40 vs. 0.33, p ≤ 0.0014), with each network individually showing improvement. Inter-network reliability was stronger than intra-network reliability, but intra-network reliability showed the greatest improvement between field strengths. CONCLUSION: We demonstrate significantly increased reliability of resting state connectivity at UHF strengths over conventional field strengths using a novel hybrid seed-based analysis. This result adds to the growing body of work supporting the migration of functional imaging studies to UHFs.

Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis.

Cognitive impairment is a common symptom in individuals with Multiple Sclerosis (MS), but meaningful, reliable biomarkers relating to cognitive decline have been elusive, making evaluation of the impact of therapeutics on cognitive function difficult. Here, we combine pathway-based MRI measures of structural and functional connectivity to construct a metric of functional decline in MS. The Structural and Functional Connectivity Index (SFCI) is proposed as a simple, z-scored metric of structural and functional connectivity, where changes in the metric have a simple statistical interpretation and may be suitable for use in clinical trials. Using data collected at six time points from a 2-year longitudinal study of 20 participants with MS and 9 age- and sex-matched healthy controls, we probe two common symptomatic domains, motor and cognitive function, by measuring structural and functional connectivity in the transcallosal motor pathway and posterior cingulum bundle. The SFCI is significantly lower in participants with MS compared to controls (p = 0.009) and shows a significant decrease over time in MS (p = 0.012). The change in SFCI over two years performed favorably compared to measures of brain parenchymal fraction and lesion volume, relating to follow-up measures of processing speed (r = 0.60, p = 0.005), verbal fluency (r = 0.57, p = 0.009), and score on the Multiple Sclerosis Functional Composite (r = 0.67, p = 0.003). These initial results show that the SFCI is a suitable metric for longitudinal evaluation of functional decline in MS.

Influence of equipment changes on MRI measures of brain atrophy and brain microstructure in a placebo-controlled trial of ibudilast in progressive multiple sclerosis.

BACKGROUND: Hardware changes can be an unavoidable confound in imaging trials. Understanding the impact of such changes may play an important role in the analysis of imaging data. OBJECTIVE: To characterize the effect of equipment changes in a longitudinal, multi-site multiple sclerosis trial. METHODS: Using data from a clinical trial in progressive multiple sclerosis, we explored how major changes in imaging hardware affected data. We analyzed the extent to which these changes affected imaging biomarkers and the estimated treatment effects by including such changes as a time-dependent covariate. RESULTS: Significant differences whole brain atrophy (brain parenchymal fraction, BPF) and microstructure (transverse diffusivity, TD) between scans with and without changes were found and depended on the type of hardware change. A switch from GE HDxt to Siemens Skyra led to significant shifts in BPF (p < 0.04) and TD (p < 0.0001). However, we could not detect the influence of hardware changes on overall trial outcomes- differences between placebo and treatment arms in change over time of BPF and TD (p > 0.5). CONCLUSIONS: The results suggest that differences among hardware types should be considered when planning and analyzing brain atrophy and diffusivity in a longitudinal clinical trial.

Functional Magnetic Resonance Imaging Correlates of Ventral Striatal Deep Brain Stimulation for Poststroke Pain.

OBJECTIVE: Deep brain stimulation (DBS) for pain has largely been implemented in an uncontrolled manner to target the somatosensory component of pain, with research leading to mixed results. We have previously shown that patients with poststroke pain syndrome who were treated with DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) demonstrated a significant improvement in measures related to the affective sphere of pain. In this study, we sought to determine how DBS targeting the VS/ALIC modifies brain activation in response to pain. MATERIALS AND METHODS: Five patients with poststroke pain syndrome who were blinded to DBS status (ON/OFF) and six age- and sex-matched healthy controls underwent functional magnetic resonance imaging (fMRI) measuring blood oxygen level-dependent activation in a block design. In this design, each participant received heat stimuli to the affected or unaffected wrist area. Statistical comparisons were performed using fMRI z-maps. RESULTS: In response to pain, patients in the DBS OFF state showed significant activation (p < 0.001) in the same regions as healthy controls (thalamus, insula, and operculum) and in additional regions (orbitofrontal and superior convexity cortical areas). DBS significantly reduced activation of these additional regions and introduced foci of significant inhibitory activation (p < 0.001) in the hippocampi when painful stimulation was applied to the affected side. CONCLUSIONS: These findings suggest that DBS of the VS/ALIC modulates affective neural networks.

Whole-brain, ultra-high spatial resolution ex vivo MRI with off-the-shelf components.

BACKGROUND: Ultra-high spatial resolution imaging of whole, ex vivo brains provides new opportunities to understand neurological disease. Recent work has demonstrated that 100 µm isotropic resolution can reveal anatomical details that are otherwise difficult to appreciate, but relied on fabrication facilities, fabrication expertise and programming expertise that is not available at clinical imaging sites that lack a dedicated research staff and resources. The purpose of this work is to describe a whole-brain, ultra-high spatial resolution imaging procedure for ex vivo specimens using equipment that can be purchased, assembled and implemented by most clinical sites. We provide enough detail so that other groups can readily reproduce the approach. METHODS: A container and hardware for holding the brain fixed for long scan times was developed, along with a procedure for removing bubbles, which can cause artifact. Imaging was performed on a standard knee coil on a whole-body 7 T MRI at 170 µm isotropic spatial resolution. Five specimens were examined in Fomblin or formalin to evaluate consistency of image quality. RESULTS: High quality images were acquired on all specimens. Anatomical features that are not readily observed at standard resolution, such as subthalamic nuclei, are readily observed. Disease-related features such as microscopic infarcts are also readily observed. CONCLUSIONS: Ultra-high spatial resolution, whole-brain images can be readily achieved without specialized hardware and software development. The approach is expected to be valuable as a complement to histology and to discover relationships among pathology located at different places throughout the brain.

Temporal lobe regions essential for preserved picture naming after left temporal epilepsy surgery.

OBJECTIVE: To define left temporal lobe regions where surgical resection produces a persistent postoperative decline in naming visual objects. METHODS: Pre- and postoperative brain magnetic resonance imaging data and picture naming (Boston Naming Test) scores were obtained prospectively from 59 people with drug-resistant left temporal lobe epilepsy. All patients had left hemisphere language dominance at baseline and underwent surgical resection or ablation in the left temporal lobe. Postoperative naming assessment occurred approximately 7 months after surgery. Surgical lesions were mapped to a standard template, and the relationship between presence or absence of a lesion and the degree of naming decline was tested at each template voxel while controlling for effects of overall lesion size. RESULTS: Patients declined by an average of 15% in their naming score, with wide variation across individuals. Decline was significantly related to damage in a cluster of voxels in the ventral temporal lobe, located mainly in the fusiform gyrus approximately 4-6 cm posterior to the temporal tip. Extent of damage to this region explained roughly 50% of the variance in outcome. Picture naming decline was not related to hippocampal or temporal pole damage. SIGNIFICANCE: The results provide the first statistical map relating lesion location in left temporal lobe epilepsy surgery to picture naming decline, and they support previous observations of transient naming deficits from electrical stimulation in the basal temporal cortex. The critical lesion is relatively posterior and could be avoided in many patients undergoing left temporal lobe surgery for intractable epilepsy.

Towards safe operation of an active retinal prosthesis during functional MRI and diffusion tensor imaging.

OBJECTIVE: To determine if the Argus II retinal prosthesis can operate during functional MRI (fMRI) and diffusion tensor imaging (DTI) acquisitions and if currents induced in the prosthesis by imaging are at safe levels. MATERIALS AND METHODS: One Argus II retinal prosthesis was modified to enable current measurements during imaging. Active electronics were modified to enable operation during scans. Induced current was measured during diagnostic scans, which were previously shown to be safe for implanted patients, and during fMRI and DTI scans. All measurements were performed using an ASTM phantom to ensure reproducible placement. RESULTS: The prosthesis was able to maintain communication with the external RF coil during the fMRI and DTI scans except briefly during pre-scans. Current levels induced during fMRI and DTI scans were consistently below those measured during diagnostic scans. CONCLUSIONS: fMRI and DTI may be safely performed while the Argus II retinal prosthesis is operating.

The role of the thalamus and hippocampus in episodic memory performance in patients with multiple sclerosis.

BACKGROUND: Episodic memory loss is one of the most common cognitive symptoms in patients with multiple sclerosis (MS), but the pathophysiology of this symptom remains unclear. Both the hippocampus and thalamus have been implicated in episodic memory and show regional atrophy in patients with MS. OBJECTIVE: In this work, we used functional magnetic resonance imaging (fMRI) during a verbal episodic memory task, lesion load, and volumetric measures of the hippocampus and thalamus to assess the relative contributions to verbal and visual-spatial episodic memory. METHODS: Functional activation, lesion load, and volumetric measures from 32 patients with MS and 16 healthy controls were used in a predictive analysis of episodic memory function. RESULTS: After adjusting for disease duration, immediate recall performance on a visual-spatial episodic memory task was significantly predicted by hippocampal volume ( p < 0.003). Delayed recall on the same task was significantly predicted by volume of the left thalamus ( p < 0.003). For both memory measures, functional activation of the thalamus during encoding was more predictive than that of volume measures ( p < 0.002). CONCLUSION: Our results suggest that functional activation may be useful as a predictive measure of episodic memory loss in patients with MS.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Scan-rescan repeatability and cross-scanner comparability of DTI metrics in healthy subjects in the SPRINT-MS multicenter trial.

PURPOSE: To assess intrascanner repeatability and cross-scanner comparability for diffusion tensor imaging (DTI) metrics in a multicenter clinical trial. METHODS: DTI metrics (including longitudinal diffusivity [LD], fractional anisotropy [FA], mean diffusivity [MD], and transverse diffusivity [TD]) from pyramidal tracts for healthy controls were calculated from images acquired on twenty-seven 3T MR scanners (Siemens and GE) with 6 different scanner models and 7 different software versions as part of the NN102/SPRINT-MS clinical trial. Each volunteer underwent two scanning sessions on the same scanner. Signal-to-noise ratio (SNR) and signal-to-noise floor ratio (SNFR) were also assessed. RESULTS: DTI metrics showed good scan-rescan repeatability. There were no significant differences between scans and rescans in LD, FA, MD, or TD values. Although the cross-scanner coefficient of variation (CV) values for all DTI metrics were <5.7%, significant differences were observed for LD (p < 3.3e-5) and FA (p < 0.0024) when GE scanners were compared with Siemens scanners. Significant differences were also observed for SNR when comparing GE scanners and Siemens Skyra scanners (p < 1.4e-7) and when comparing Siemens Skyra scanners and TIM Trio scanners (p < 1.0e-10). Analysis of background signal also demonstrated differences between GE and Siemens scanners in terms of signal statistics. The measured signal intensity from a background noise region of interest was significantly higher for GE scanners than for Siemens scanners (p < 1.2e-12). Significant differences were also observed for SNFR when comparing GE scanners and Siemens Skyra scanners (p < 2.5e-11), GE scanners and Siemens Trio scanners (p < 7.5e-11), and Siemens Skyra scanners and TIM Trio scanners (p < 2.5e-9). CONCLUSIONS: The good repeatability of the DTI metrics among the 27 scanners used in this study confirms the feasibility of combining DTI data from multiple centers using high angular resolution sequences. Our observations support the feasibility of longitudinal multicenter clinical trials using DTI outcome measures. The noise floor level and SNFR are important parameters that must be assessed when comparing studies that used different scanner models.

Spectral Dynamics of Resting State fMRI Within the Ventral Tegmental Area and Dorsal Raphe Nuclei in Medication-Free Major Depressive Disorder in Young Adults.

Background: Dorsal raphe nucleus (DRN) and ventral tegmental area (VTA) are major brainstem monamine nuclei consisting of serotonin and dopamine neurons respectively. Animal studies show that firing patterns in both nuclei are altered when animals exhibit depression like behaviors. Functional MRI studies in humans have shown reduced VTA activation and DRN connectivity in depression. This study for the first time aims at investigating the functional integrity of local neuronal firing concurrently in both the VTA and DRN in vivo in humans using spectral analysis of resting state low frequency fluctuation fMRI. Method: A total of 97 medication-free subjects-67 medication-free young patients (ages 18-30) with major depressive disorder and 30 closely matched healthy controls were included in the study to detect aberrant dynamics in DRN and VTA. For the investigation of altered localized dynamics we conducted power spectral analysis and above this spectral cross correlation between the two groups. Complementary to this, spectral dependence of permutation entropy, an information theoretical measure, was compared between groups. Results: Patients displayed significant spectral slowing in VTA vs. controls (p = 0.035, corrected). In DRN, spectral slowing was less pronounced, but the amount of slowing significantly correlated with 17-item Hamilton Depression Rating scores of depression severity (p = 0.038). Signal complexity as assessed via permutation entropy showed spectral alterations inline with the results on spectral slowing. Conclusion: Our results indicate that altered functional dynamics of VTA and DRN in depression can be detected from regional fMRI signal. On this basis, impact of antidepressant treatment and treatment response can be assessed using these markers in future studies.