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.

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.

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.

Transcranial Direct Current Stimulation Targeting Primary Motor Versus Dorsolateral Prefrontal Cortices: Proof-of-Concept Study Investigating Functional Connectivity of Thalamocortical Networks Specific to Sensory-Affective Information Processing.

The pain matrix is comprised of an extensive network of brain structures involved in sensory and/or affective information processing. The thalamus is a key structure constituting the pain matrix. The thalamus serves as a relay center receiving information from multiple ascending pathways and relating information to and from multiple cortical areas. However, it is unknown how thalamocortical networks specific to sensory-affective information processing are functionally integrated. Here, in a proof-of-concept study in healthy humans, we aimed to understand this connectivity using transcranial direct current stimulation (tDCS) targeting primary motor (M1) or dorsolateral prefrontal cortices (DLPFC). We compared changes in functional connectivity (FC) with DLPFC tDCS to changes in FC with M1 tDCS. FC changes were also compared to further investigate its relation with individual's baseline experience of pain. We hypothesized that resting-state FC would change based on tDCS location and would represent known thalamocortical networks. Ten right-handed individuals received a single application of anodal tDCS (1 mA, 20 min) to right M1 and DLPFC in a single-blind, sham-controlled crossover study. FC changes were studied between ventroposterolateral (VPL), the sensory nucleus of thalamus, and cortical areas involved in sensory information processing and between medial dorsal (MD), the affective nucleus, and cortical areas involved in affective information processing. Individual's perception of pain at baseline was assessed using cutaneous heat pain stimuli. We found that anodal M1 tDCS and anodal DLPFC tDCS both increased FC between VPL and sensorimotor cortices, although FC effects were greater with M1 tDCS. Similarly, anodal M1 tDCS and anodal DLPFC tDCS both increased FC between MD and motor cortices, but only DLPFC tDCS modulated FC between MD and affective cortices, like DLPFC. Our findings suggest that M1 stimulation primarily modulates FC of sensory networks, whereas DLPFC stimulation modulates FC of both sensory and affective networks. Our findings when replicated in a larger group of individuals could provide useful evidence that may inform future studies on pain to differentiate between effects of M1 and DLPFC stimulation. Notably, our finding that individuals with high baseline pain thresholds experience greater FC changes with DLPFC tDCS implies the role of DLPFC in pain modulation, particularly pain tolerance.

Assessment of Vascular Stent Heating with Repetitive Transcranial Magnetic Stimulation.

OBJECTIVE: A high proportion of patients with stroke do not qualify for repetitive transcranial magnetic stimulation (rTMS) clinical studies due to the presence of metallic stents. The ultimate concern is that any metal could become heated due to eddy currents. However, to date, no clinical safety data are available regarding the risk of metallic stents heating with rTMS. METHODS: We tested the safety of common rTMS protocols (1 Hz and 10 Hz) with stents used commonly in stroke, nitinol and elgiloy. In our method, stents were tested in gelled saline at 2 different locations: at the center and at the lobe of the coil. In addition, at each location, stent heating was evaluated in 3 different orientations: parallel to the long axis of coil, parallel to the short axis of the coil, and perpendicular to the plane of the coil. RESULTS: We found that stents did not heat to more than 1°C with either 1 Hz rTMS or 10 Hz rTMS in any configuration or orientation. Heating in general was greater at the lobe when the stent was oriented perpendicularly. CONCLUSIONS: Our study represents a new method for ex vivo quantification of stent heating. We have found that heating of stents was well below the Food and Drug Administration standards of 2°C. Thus, our study paves the way for in vivo testing of rTMS (≤10 Hz) in the presence of implanted magnetic resonance imaging-compatible stents in animal studies. When planning human safety studies though, geometry, orientation, and location relative to the coil would be important to consider as well.

Quetiapine Extended Release Open-Label Treatment Associated Changes in Amygdala Activation and Connectivity in Anxious Depression: An fMRI Study.

BACKGROUND: This study investigated extended release quetiapine (quetiapine XR) associated changes in functional MRI (fMRI) measures of task-induced amygdalar activation and resting state connectivity in anxious unipolar major depressive disorder (AMDD). METHODS: Anxious unipolar major depressive disorder patients (n = 15) (17-item Hamilton Depression Rating Scale (HAM-D) >18 and Hamilton Anxiety Scale (HAM-A) >18) and closely matched healthy control (HC) subjects were compared at baseline for task induced amygdala activation and resting state connectivity on fMRI. Subsequently, AMDD patients were treated for 8 weeks with open-label quetiapine XR. Weekly HAM-D and HAM-A ratings were obtained, and the fMRI scan was repeated at weeks 2 and 8. Changes in fMRI measures were calculated using repeated-measures analysis of variance and correlation with decrease in HAM-D and HAM-A scores was examined. RESULTS: At baseline, AMDD compared with HC exhibited increased task-induced left amygdalar activation (P = 0.05 clusterwise corrected) and decreased resting state amygdala-cortical and amygdala-pons connectivity (P < 0.05 clusterwise corrected). Quetiapine XR treatment was associated with significant decrease in HAM-D (df = 1,28; female [F] = 39; P = 0.001) and HAM-A scores (df = 1,28; F = 55; P = 0.001). The AMDD group showed increased amygdala-cortical connectivity (P < 0.05 [clusterwise corrected]) at week 2, which was maintained at week 8. At week 8, additional areas showed increased connectivity including insula and putamen. At 8 weeks, decrease in HAM-D scores correlated with increase in amygdala-mid cingulate and amygdala-cuneus connectivity (P = 0.05 [clusterwise corrected]). Decrease in HAM-A scores correlated with increase in amygdala-cuneus and parietal cortex connectivity (P = 0.05 [clusterwise corrected]). LIMITATIONS: Small sample-size, open-label single-arm design, HC only tested at baseline, focused only on amygdala. CONCLUSIONS: Quetiapine XR effects in the treatment of AMDD are associated with modulation of amygdala connectivity.

Structural and Functional MRI Differences in Master Sommeliers: A Pilot Study on Expertise in the Brain.

Our experiences, even as adults, shape our brains. Regional differences have been found in experts, with the regions associated with their particular skill-set. Functional differences have also been noted in brain activation patterns in some experts. This study uses multimodal techniques to assess structural and functional patterns that differ between experts and non-experts. Sommeliers are experts in wine and thus in olfaction. We assessed differences in Master Sommeliers' brains, compared with controls, in structure and also in functional response to olfactory and visual judgment tasks. MRI data were analyzed using voxel-based morphometry as well as automated parcellation to assess structural properties, and group differences between tasks were calculated. Results indicate enhanced volume in the right insula and entorhinal cortex, with the cortical thickness of the entorhinal correlating with experience. There were regional activation differences in a large area involving the right olfactory and memory regions, with heightened activation specifically for sommeliers during an olfactory task. Our results indicate that sommeliers' brains show specialization in the expected regions of the olfactory and memory networks, and also in regions important in integration of internal sensory stimuli and external cues. Overall, these differences suggest that specialized expertise and training might result in enhancements in the brain well into adulthood. This is particularly important given the regions involved, which are the first to be impacted by many neurodegenerative diseases.

Resting State Brain Network Disturbances Related to Hypomania and Depression in Medication-Free Bipolar Disorder.

Research on resting functional brain networks in bipolar disorder (BP) has been unable to differentiate between disturbances related to mania or depression, which is necessary to understand the mechanisms leading to each state. Past research has also been unable to elucidate the impact of BP-related network disturbances on the organizational properties of the brain (eg, communication efficiency). Thus, the present work sought to isolate network disturbances related to BP, fractionate these into components associated with manic and depressive symptoms, and characterize the impact of disturbances on network function. Graph theory was used to analyze resting functional magnetic resonance imaging data from 60 medication-free patients meeting the criteria for BP and either a current hypomanic (n=30) or depressed (n=30) episode and 30 closely age/sex-matched healthy controls. Correction for multiple comparisons was carried out. Compared with controls, BP patients evidenced hyperconnectivity in a network involving right amygdala. Fractionation revealed that (hypo)manic symptoms were associated with hyperconnectivity in an overlapping network and disruptions in the brain's 'small-world' network organization. Depressive symptoms predicted hyperconnectivity in a network involving orbitofrontal cortex along with a less resilient global network organization. Findings provide deeper insight into the differential pathophysiological processes associated with hypomania and depression, along with the particular impact these differential processes have on network function.

Cortical and motor responses to acute forced exercise in Parkinson's disease.

INTRODUCTION: Studies in animal models of Parkinson's disease (PD) have suggested that the rate of exercise performance is important in treatment efficacy and neuroprotection. In humans with PD, lower-extremity forced-exercise (FE) produced global improvements in motor symptoms based on clinical ratings and biomechanical measures of upper extremity function. METHODS: fMRI was used to compare the underlying changes in brain activity in PD patients following the administration of anti-parkinsonian medication and following a session of FE. RESULTS: Nine individuals with PD completed fMRI scans under each condition: off anti-PD medication, on anti-PD medication, and off medication + FE. Unified Parkinson's Disease Rating Motor Scale scores improved by 50% in the FE condition compared to the off-medication condition. The pattern of fMRI activation after FE was similar to that seen with anti-PD medication. Direct comparison of the fMRI activation patterns showed high correlation between FE and anti-PD medication. CONCLUSION: These findings suggest that medication and FE likely utilize the same pathways to produce symptomatic relief in individuals with PD.

Modern Methods for Interrogating the Human Connectome.

OBJECTIVES: Connectionist theories of brain function took hold with the seminal contributions of Norman Geschwind a half century ago. Modern neuroimaging techniques have expanded the scientific interest in the study of brain connectivity to include the intact as well as disordered brain. METHODS: In this review, we describe the most common techniques used to measure functional and structural connectivity, including resting state functional MRI, diffusion MRI, and electroencephalography and magnetoencephalography coherence. We also review the most common analytical approaches used for examining brain interconnectivity associated with these various imaging methods. RESULTS: This review presents a critical analysis of the assumptions, as well as methodological limitations, of each imaging and analysis approach. CONCLUSIONS: The overall goal of this review is to provide the reader with an introduction to evaluating the scientific methods underlying investigations that probe the human connectome.

Differential Resting-State Functional Connectivity of Striatal Subregions in Bipolar Depression and Hypomania.

Bipolar disorder (BP) is characterized by periods of depression (BPD) and (hypo)mania (BPM), but the underlying state-related brain circuit abnormalities are not fully understood. Striatal functional activation and connectivity abnormalities have been noted in BP, but consistent findings have not been reported. To further elucidate striatal abnormalities in different BP states, this study investigated differences in resting-state functional connectivity of six striatal subregions in BPD, BPM, and healthy control (HC) subjects. Ninety medication-free subjects (30 BPD, 30 BPM, and 30 HC), closely matched for age and gender, were scanned using 3T functional magnetic resonance imaging (fMRI) acquired at resting state. Correlations of low-frequency blood oxygen level dependent signal fluctuations for six previously described striatal subregions were used to obtain connectivity maps of each subregion. Using a factorial design, main effects for differences between groups were obtained and post hoc pairwise group comparisons performed. BPD showed increased connectivity of the dorsal caudal putamen with somatosensory areas such as the insula and temporal gyrus. BPM group showed unique increased connectivity between left dorsal caudate and midbrain regions, as well as increased connectivity between ventral striatum inferior and thalamus. In addition, both BPD and BPM exhibited widespread functional connectivity abnormalities between striatal subregions and frontal cortices, limbic regions, and midbrain structures. In summary, BPD exhibited connectivity abnormalities of associative and somatosensory subregions of the putamen, while BPM exhibited connectivity abnormalities of associative and limbic caudate. Most other striatal subregion connectivity abnormalities were common to both groups and may be trait related.

Exercise Therapy for Parkinson's Disease: Pedaling Rate Is Related to Changes in Motor Connectivity.

Forced-rate lower-extremity exercise has recently emerged as a potential safe and low-cost therapy for Parkinson's disease (PD). The efficacy is believed to be dependent on pedaling rate, with rates above the subjects' voluntary exercise rates being most beneficial. In this study, we use functional connectivity magnetic resonance imaging (MRI) to further elucidate the mechanism underlying this effect. Twenty-seven PD patients were randomized to complete 8 weeks of forced-rate exercise (FE) or voluntary-rate exercise (VE). Exercise was delivered using a specialized stationary bicycle, which can augment patients' voluntary exercise rates. The FE group received assistance from the cycle. Imaging was conducted at baseline, end of therapy, and after 4 weeks of follow-up. Functional connectivity (FC) was determined via seed-based correlation analysis, using activation-based seeds in the primary motor cortex (M1). The change in FC after exercise was compared using linear correlation with pedaling rate. Results of the correlation analysis showed a strong positive correlation between pedaling rate and change in FC from the most affected M1 to the ipsilateral thalamus. This effect persisted after 4 weeks of follow-up. These results indicate that a plausible mechanism for the therapeutic efficacy of high-rate exercise in PD is that it improves thalamo-cortical connectivity.

The relationship between cognitive function and high-resolution diffusion tensor MRI of the cingulum bundle in multiple sclerosis.

BACKGROUND: Imaging can provide noninvasive neural markers of disease progression in multiple sclerosis (MS) that are related to behavioral and cognitive symptoms. Past work suggests that diffusion tensor imaging (DTI) provides a measure of white matter pathology, including demyelination and axonal counts. OBJECTIVES: In the current study, the authors investigate the relationship of DTI measures in the cingulum bundle to common deficits in MS, including episodic memory, working memory, and information processing speed. METHODS: Fifty-seven patients with MS and 17 age- and education-matched controls underwent high-spatial resolution diffusion scans and cognitive testing. Probabilistic tracking was used to generate tracks from the posterior cingulate cortex to the entorhinal cortex. RESULTS: Radial and axial diffusivity values were significantly different between patients and controls (p < 0.031), and in patients bilateral diffusion measures were significantly related to measures of episodic memory and speed of processing (p < 0.033). CONCLUSIONS: The tractography-based measures of posterior cingulum integrity reported here support further development of DTI as a viable measure of axonal integrity and cognitive function in patients with MS.

Disruption of caudate working memory activation in chronic blast-related traumatic brain injury.

Mild to moderate traumatic brain injury (TBI) due to blast exposure is frequently diagnosed in veterans returning from the wars in Iraq and Afghanistan. However, it is unclear whether neural damage resulting from blast TBI differs from that found in TBI due to blunt-force trauma (e.g., falls and motor vehicle crashes). Little is also known about the effects of blast TBI on neural networks, particularly over the long term. Because impairment in working memory has been linked to blunt-force TBI, the present functional magnetic resonance imaging (fMRI) study sought to investigate whether brain activation in response to a working memory task would discriminate blunt-force from blast TBI. Twenty-five veterans (mean age = 29.8 years, standard deviation = 6.01 years, 1 female) who incurred TBI due to blast an average of 4.2 years prior to enrollment and 25 civilians (mean age = 27.4 years, standard deviation = 6.68 years, 4 females) with TBI due to blunt-force trauma performed the Sternberg Item Recognition Task while undergoing fMRI. The task involved encoding 1, 3, or 5 items in working memory. A group of 25 veterans (mean age = 29.9 years, standard deviation = 5.53 years, 0 females) and a group of 25 civilians (mean age = 27.3 years, standard deviation = 5.81 years, 0 females) without history of TBI underwent identical imaging procedures and served as controls. Results indicated that the civilian TBI group and both control groups demonstrated a monotonic relationship between working memory set size and activation in the right caudate during encoding, whereas the blast TBI group did not (p < 0.05, corrected for multiple comparisons using False Discovery Rate). Blast TBI was also associated with worse performance on the Sternberg Item Recognition Task relative to the other groups, although no other group differences were found on neuropsychological measures of episodic memory, inhibition, and general processing speed. These results could not be attributed to caudate atrophy or the presence of PTSD symptoms. Our results point to a specific vulnerability of the caudate to blast injury. Changes in activation during the Sternberg Item Recognition Task, and potentially other tasks that recruit the caudate, may serve as biomarkers for blast TBI.

The cyclical lower extremity exercise for Parkinson's trial (CYCLE): methodology for a randomized controlled trial.

BACKGROUND: Motor and non-motor impairments affect quality of life in individuals with Parkinson's disease. Our preliminary research indicates that forced exercise cycling, a mode of exercise in which a participant's voluntary rate of exercise is augmented on a stationary cycle, results in global improvements in the cardinal symptoms of Parkinson's disease. The objective of the Cyclical Lower Extremity Exercise (CYCLE) trial for Parkinson's disease is to determine the effects of forced exercise cycling on motor and non-motor performance when compared to voluntary rate cycling and a non-exercise control group. Additionally, we plan to identify any associated changes in neural activity determined by functional magnetic resonance imaging. METHODS/DESIGN: A total of 100 individuals with mild to moderate idiopathic Parkinson's disease will participate in a single-center, parallel-group, rater-blind study. Participants will be randomized 2:2:1 into a forced exercise, voluntary exercise, or no-exercise control group, respectively. Both exercise groups will cycle 3 times per week for 8 weeks at identical aerobic intensities for 40 minutes, but participants in the forced exercise group will cycle 30% faster than their voluntary rate by means of an augmented motorized bicycle. Neuroimaging, clinical, and biomechanical assessments of motor and non-motor performance will be made at baseline both 'on' and 'off' medication, after four weeks of exercise (midpoint), end of treatment, 4 weeks after end of treatment, and 8 weeks after end of treatment. DISCUSSION: CYCLE trial will play a critical role in determining the effectiveness of two different types of aerobic exercise, forced and voluntary, on motor and non-motor performance in individuals with Parkinson's disease. Additionally, the coupling of clinical, biomechanical, and neuroimaging outcomes has the potential to provide insight into mechanisms underlying change in function as a result of exercise. TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT01636297.

Distortion correction in EPI using an extended PSF method with a reversed phase gradient approach.

In echo-planar imaging (EPI), such as commonly used for functional MRI (fMRI) and diffusion-tensor imaging (DTI), compressed distortion is a more difficult challenge than local stretching as spatial information can be lost in strongly compressed areas. In addition, the effects are more severe at ultra-high field (UHF) such as 7T due to increased field inhomogeneity. To resolve this problem, two EPIs with opposite phase-encoding (PE) polarity were acquired and combined after distortion correction. For distortion correction, a point spread function (PSF) mapping method was chosen due to its high correction accuracy and extended to perform distortion correction of both EPIs with opposite PE polarity thus reducing the PSF reference scan time. Because the amount of spatial information differs between the opposite PE datasets, the method was further extended to incorporate a weighted combination of the two distortion-corrected images to maximize the spatial information content of a final corrected image. The correction accuracy of the proposed method was evaluated in distortion-corrected data using both forward and reverse phase-encoded PSF reference data and compared with the reversed gradient approaches suggested previously. Further we demonstrate that the extended PSF method with an improved weighted combination can recover local distortions and spatial information loss and be applied successfully not only to spin-echo EPI, but also to gradient-echo EPIs acquired with both PE directions to perform geometrically accurate image reconstruction.

Assessment of inter-hemispheric imbalance using imaging and noninvasive brain stimulation in patients with chronic stroke.

OBJECTIVE: To determine how interhemispheric balance in stroke, measured using transcranial magnetic stimulation (TMS), relates to balance defined using neuroimaging (functional magnetic resonance [fMRI], diffusion-tensor imaging [DTI]) and how these metrics of balance are associated with clinical measures of upper-limb function and disability. DESIGN: Cross sectional. SETTING: Laboratory. PARTICIPANTS: Patients with chronic stroke (N = 10; age, 63 ± 9 y) in a population-based sample with unilateral upper-limb paresis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Interhemispheric balance was measured with TMS, fMRI, and DTI. TMS defined interhemispheric differences in the recruitment of corticospinal output, size of the corticomotor output maps, and degree of mutual transcallosal inhibition that they exerted on one another. fMRI studied whether cortical activation during the movement of the paretic hand was lateralized to the ipsilesional or to the contralesional primary motor cortex (M1), premotor cortex (PMC), and supplementary motor cortex (SMA). DTI was used to define interhemispheric differences in the integrity of the corticospinal tracts projecting from the M1. Clinical outcomes tested function (upper extremity Fugl-Meyer [UEFM]) and perceived disability in the use of the paretic hand (Motor Activity Log [MAL] amount score). RESULTS: Interhemispheric balance assessed with TMS relates differently to fMRI and DTI. Patients with high fMRI lateralization to the ipsilesional hemisphere possessed stronger ipsilesional corticomotor output maps (M1: r = .831, P = .006; PMC: r = .797, P = .01) and better balance of mutual transcallosal inhibition (r = .810, P = .015). Conversely, we found that patients with less integrity of the corticospinal tracts in the ipsilesional hemisphere show greater corticospinal output of homologous tracts in the contralesional hemisphere (r = .850, P = .004). However, an imbalance in integrity and output do not relate to transcallosal inhibition. Clinically, although patients with less integrity of corticospinal tracts from the ipsilesional hemisphere showed worse impairments (UEFM) (r = -.768, P = .016), those with low fMRI lateralization to the ipsilesional hemisphere had greater perception of disability (MAL amount score) (M1: r = .883, P = .006; PMC: r = .817, P = .007; SMA: r = .633, P = .062). CONCLUSIONS: In patients with chronic motor deficits of the upper limb, fMRI may serve to mark perceived disability and transcallosal influence between hemispheres. DTI-based integrity of the corticospinal tracts, however, may be useful in categorizing the range of functional impairments of the upper limb. Further, in patients with extensive corticospinal damage, DTI may help infer the role of the contralesional hemisphere in recovery.

Anatomic connectivity assessed using pathway radial diffusivity is related to functional connectivity in monosynaptic pathways.

This work presents a pathway-dependent anatomic and functional connectivity analysis in 19 patients with relapse-remitting multiple sclerosis (MS) and 16 age-, education-, and gender-matched controls. An MS population is used in this study as a model for anatomic connectivity, permitting us to observe relationships between anatomic and functional connectivity more easily. A combined resting-state functional magnetic resonance imaging (fMRI) and whole-brain, high angular resolution diffusion imaging analysis is performed in three independent, monosynaptic pathways. The pathways chosen were transcallosal pathway connecting the bilateral primary sensorimotor regions, right and left posterior portion of the Papez circuit, connecting the posterior cingulate cortex and hippocampus. The Papez circuit is known to be involved in memory function, one of the most frequently impacted cognitive domains in patients with MS. We show that anatomic connectivity, as measured with diffusion-weighted imaging, and functional connectivity, as measured with resting-state fMRI, are significantly reduced in patients as compared with controls for at least some of the pathways considered. In addition when all pathway measures are combined, anatomic and functional connectivity are significantly correlated in patients with MS as well as healthy controls. We suggest that anatomic and functional connectivity are related for monosynaptic pathways and that radial diffusivity, as a diffusion-tensor-based measure of white matter integrity, is a robust measure of anatomic connectivity in the general population.

SimPACE: generating simulated motion corrupted BOLD data with synthetic-navigated acquisition for the development and evaluation of SLOMOCO: a new, highly effective slicewise motion correction.

Head motion in functional MRI and resting-state MRI is a major problem. Existing methods do not robustly reflect the true level of motion artifact for in vivo fMRI data. The primary issue is that current methods assume that motion is synchronized to the volume acquisition and thus ignore intra-volume motion. This manuscript covers three sections in the use of gold-standard motion-corrupted data to pursue an intra-volume motion correction. First, we present a way to get motion corrupted data with accurately known motion at the slice acquisition level. This technique simulates important data acquisition-related motion artifacts while acquiring real BOLD MRI data. It is based on a novel motion-injection pulse sequence that introduces known motion independently for every slice: Simulated Prospective Acquisition CorrEction (SimPACE). Secondly, with data acquired using SimPACE, we evaluate several motion correction and characterization techniques, including several commonly used BOLD signal- and motion parameter-based metrics. Finally, we introduce and evaluate a novel, slice-based motion correction technique. Our novel method, SLice-Oriented MOtion COrrection (SLOMOCO) performs better than the volumetric methods and, moreover, accurately detects the motion of independent slices, in this case equivalent to the known injected motion. We demonstrate that SLOMOCO can model and correct for nearly all effects of motion in BOLD data. Also, none of the commonly used motion metrics was observed to robustly identify motion corrupted events, especially in the most realistic scenario of sudden head movement. For some popular metrics, performance was poor even when using the ideal known slice motion instead of volumetric parameters. This has negative implications for methods relying on these metrics, such as recently proposed motion correction methods such as data censoring and global signal regression.

Hippocampal volume is related to cognitive decline and fornicial diffusion measures in multiple sclerosis.

PURPOSE: To assess for associations between hippocampal atrophy and measures of cognitive function, hippocampal magnetization transfer ratio (MTR), and diffusion measures of the fornix, the largest efferent white matter tract from the hippocampus, in patients with multiple sclerosis (MS) and controls. MATERIALS AND METHODS: A total of 53 patients with MS and 20 age- and sex-matched healthy controls participated in cognitive testing and scanning including high spatial-resolution diffusion imaging and a T1-MPRAGE scan. Hippocampal volume and fornicial thickness measures were calculated and compared to mean values of fornicial transverse diffusivity, mean diffusivity, longitudinal diffusivity, fractional anisotropy, mean hippocampal MTR, and scores on measures of episodic memory, processing speed, and working memory tasks. RESULTS: In patients with MS, hippocampal volume was significantly related to fornicial diffusion measures (P<7×10(-4)) and to measures of verbal (P=0.030) and visual spatial (P=0.004) episodic memory and a measure of information processing speed (P<0.037). DISCUSSION: These results highlight the role of the hippocampus in cognitive dysfunction in patients with MS and suggest that measures of hippocampal atrophy could be used to capture aspects of disease progression.