Steven R. Roys

Functional MRI determination of a dose-response relationship to lower extremity neuromuscular electrical stimulation in healthy subjects

Abstract.Although empirical evidence supports the use of neuromuscular electrical stimulation (NMES) to treat physical impairments associated with stroke, the mechanisms underlying the efficacy of this modality are poorly understood. Recent studies have employed functional imaging to investigations of brain responses to median nerve stimulation. These studies suggest a dose-response relationship may exist between selected stimulation parameters and hemodynamic responses in sensorimotor regions. However, substantial gaps exist in this literature. The present study was designed to address these deficiencies. Ten healthy subjects participated. In phase one, four stimulus intensity levels were established: (1) sensory threshold [Th], (2) (MM−Th)×0.333+Th [low-intermediate level, LI], (3) (MM−Th)×0.666+Th [high-intermediate level, HI], and (4) maximal motor (MM). In phase two, subjects were scanned using a spiral-echoplanar imaging technique at each stimulus level. Image sets were analyzed to determine hemodynamic responses at the highest Pearson correlation level (r) ascertained for each of five areas of interest (AOI): (1) primary sensory, (2) primary motor, (3) cingulate gyrus, (4) thalamus, and (5) cerebellum. ANOVA demonstrated significant main effects for BOLD signal amplitude (p<0.05) changes in all AOI. Similarly, ANOVA showed significant differences in the volume of activation (p<0.05) with increasing stimulus intensity in four AOI. Secondary analyses of pooled data showed increasing probabilities of activation at higher stimulus intensities within each AOI. Collectively, these data indicate a dose-response relationship exists between lower extremity NMES and brain activation in specific neural regions. The current results, while limited in their generalizability, are foundational for future studies of interventions using NMES.

Test-retest reliability estimation of functional MRI data.

Functional magnetic resonance imaging (fMRI) data are commonly used to construct activation maps for the human brain. It is important to quantify the reliability of such maps. We have developed statistical models to provide precise estimates for reliability from several runs of the same paradigm over time. Specifically, our method extends the premise of maximum likelihood (ML) developed by Genovese et al. (Magn Reson Med 1997;38:497–507) by incorporating spatial context into the estimation process. Experiments indicate that our methodology provides more conservative estimates of true positives compared to those obtained by Genovese et al. The reliability estimates can be used to obtain voxel‐specific reliability measures for activated as well as inactivated regions in future experiments. We derive statistical methodology to determine optimal thresholds for region‐ and context‐specific activations. Empirical guidelines are also provided on the number of repeat scans to acquire in order to arrive at accurate reliability estimates. We report the results from experiments involving a motor paradigm performed on a single subject several times over a period of 2 months. Magn Reson Med 48:62–70, 2002.

Early Microstructural and Metabolic Changes following Controlled Cortical Impact Injury in Rat: A Magnetic Resonance Imaging and Spectroscopy Study

Understanding tissue alterations at an early stage following traumatic brain injury (TBI) is critical for injury management and limiting severe consequences from secondary injury. We investigated the early microstructural and metabolic profiles using in vivo diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy ((1)H MRS) at 2 and 4 h following a controlled cortical impact injury in the rat brain using a 7.0 Tesla animal MRI system and compared profiles to baseline. Significant decrease in mean diffusivity (MD) and increased fractional anisotropy (FA) was found near the impact site (hippocampus and bilateral thalamus; p<0.05) immediately following TBI, suggesting cytotoxic edema. Although the DTI parameters largely normalized on the contralateral side by 4 h, a large inter-individual variation was observed with a trend towards recovery of MD and FA in the ipsilateral hippocampus and a sustained elevation of FA in the ipsilateral thalamus (p<0.05). Significant reduction in metabolite to total creatine ratios of N-acetylaspartate (NAA, p=0.0002), glutamate (p=0.0006), myo-inositol (Ins, p=0.04), phosphocholine and glycerophosphocholine (PCh+GPC, p=0.03), and taurine (Tau, p=0.009) were observed ipsilateral to the injury as early as 2 h, while glutamine concentration increased marginally (p=0.07). These metabolic alterations remained sustained over 4 h after TBI. Significant reductions of Ins (p=0.024) and Tau (p=0.013) and marginal reduction of NAA (p=0.06) were also observed on the contralateral side at 4 h after TBI. Overall our findings suggest significant microstructural and metabolic alterations as early as 2 h following injury. The tendency towards normalization at 4 h from the DTI data and no further metabolic changes at 4 h from MRS suggest an optimal temporal window of about 3 h for interventions that might limit secondary damage to the brain. Results indicate that early assessment of TBI patients using DTI and MRS may provide valuable information on the available treatment window to limit secondary brain damage.

Longitudinal and prognostic evaluation of mild traumatic brain injury: A 1H-magnetic resonance spectroscopy study.

In the majority of patients with mild traumatic brain injury (mTBI), brain tissue impairment is undetectable by computed tomography and/or structural magnetic resonance imaging. Even in confirmed cases of head injury, conventional neuroimaging methods lack sensitivity in predicting neuropsychological outcomes of patients. The objectives of this study were to (1) cross-sectionally determine deviations in the neurometabolic profile of patients with mTBI from healthy controls at different stages of mTBI using tightly controlled examination windows, and (2) determine associations between acute neurometabolic markers of mTBI and chronic neurocognitive performance. Patients were examined at the early subacute (n=43; 5.44 ± 3.15 days post-injury (DPI)), late subacute (n=33; 37.00 ± 12.26 DPI) and chronic (n=27; 195.30 ± 19.60 DPI) stages of mTBI. Twenty-one neurologically intact subjects were used as controls. Proton magnetic resonance spectroscopy imaging ((1)H-MRSI) was used to obtain metabolic measurements from different brain regions. The Automated Neuropsychological Assessment Metrics (ANAM) was used for cognitive evaluation of patients at the chronic stage of mTBI. Measurements in the thalamus and centrum semiovale (CSV) emerged as the most indicative of injury and were used to predict neurocognitive outcome. The major findings of this study are (1) decreases in Cho/Cre (choline-to-creatine ratio) measured in the thalamus (p=0.042) and CSV (p=0.017) at the late subacute stage of mTBI; (2) positive associations of early subacute Cre measurements in the CSV with chronic ANAM scores measuring performance in delayed (r=0.497, p=0.019) and immediate (r=0.391, p=0.072) code substitution. These findings show that metabolic measurements in the thalamus and CSV can potentially serve as diagnostic and prognostic markers of mTBI.

Design, development, and evaluation of a master-slave surgical system for breast biopsy under continuous MRI

Magnetic Resonance Imaging (MRI) provides superior soft-tissue contrast in cancer diagnosis compared to other imaging modalities. However, the strong magnetic field inside the MRI bore along with limited scanner bore size poses significant challenges. Since current approaches in breast biopsy using MR images are primarily blind targeting approaches, it is necessary to develop an MRI-compatible robot that can avoid multiple needle insertions into the breast tissue. This MRI-compatible robotic system could potentially lead to improvement in the targeting accuracy and reduce sampling errors. A master–slave surgical system has been developed comprising a MRI-compatible slave robot which consists of one piezo motor and five pneumatic cylinders connected by long pneumatic transmission lines. The slave robot follows the configuration of the master robot, which provides an intuitive manipulation interface for the physician and operates inside the MRI bore to adjust the needle position and orientation and perform needle insertion tasks. Based on the MRI experiments using the slave robot, there was no significant distortion in the images, and hence the slave robot can be safely operated inside the MRI with minimal loss in signal-to-noise ratio (SNR). Ex vivo and in vivo experiments have been conducted to evaluate the performance of the master–slave surgical system.

Disruptions in Resting State Functional Connectivity and Cerebral Blood Flow in Mild Traumatic Brain Injury Patients

Mild traumatic brain injury (mTBI) is often occult to conventional imaging techniques. However, there is growing evidence that mTBI patients who lack evidence of structural intracranial injury may develop post-concussive syndrome (PCS). We investigated longitudinal alterations in resting state functional connectivity (rs-FC) in brain networks in a population of 28 patients compared to 28 matched control participants. Rs-FC and cerebral blood flow (CBF) within the nodes of the Default Mode Network (DMN) and Task Positive Network (TPN) were assessed at three time points including acute, sub-acute, and chronic stages following mTBI. Participants received the Automated Neuropsychological Assessment Metrics (ANAM) to assess cognitive performance. Main findings indicate that despite normalized cognitive performance, chronic mTBI patients demonstrate increased rs-FC between the DMN and regions associated with the salience network (SN) and TPN compared to the control populations, as well as reduced strength of rs-FC within the DMN at the acute stage of injury. In addition, chronic mTBI patients demonstrate an imbalance in the ratio of CBF between nodes of the DMN and TPN. Furthermore, preliminary exploratory analysis suggests that compared to those without chronic PCS, patients with chronic PCS reveal an imbalance in the ratio of CBF between the DMN nodes and TPN nodes across multiple stages of recovery. Findings suggest that the altered network perfusion with the associated changes in rs-FC may be a possible predictor of which mTBI patients will develop chronic PCS.

Age-related changes in nociceptive processing in the human brain.

Abstract:  Functional magnetic resonance imaging (fMRI) was used to compare cortical nociceptive responses to painful contact heat in healthy young (ages 22–30, n= 7) and older (ages 56–75, n= 7) subjects. Compared to young subjects, older subjects had significantly smaller pain‐related fMRI responses in anterior insula (aINS) (P < 0.04), primary somatosensory cortex (S1) (P= 0.03), and supplementary motor area (P= 0.02). Gray matter volumes in S1 and aINS were significantly smaller for the older group (P= 0.02 and 0.0001, respectively), suggesting reduced processing capacity in these regions that might account for smaller pain‐related fMRI responses.

Phantom evaluation of angiographer performance using low frame rate acquisition fluoroscopy.

The authors have investigated the effect of 5 frames/s television fluoroscopy on the time required to selectively catheterize five test arteries in an angiographic phantom. Here, 5 frames/s acquisition was accomplished by sampling frames from a 30 frames/s video signal. Sampled frames were stored in a video memory which provided continuous display to the fluoroscopist between samples. The test phantom was a plastic model of an aorta with branching vessels immersed in an isodense suspension of barium in water. For four of the five vessels there was no significant difference in time required for catheter placement between 30 frames/s and 5 frames/s.

Investigation of Multiple Frequency Ranges Using Discrete Wavelet Decomposition of Resting-State Functional Connectivity in Mild Traumatic Brain Injury Patients

The aim of this study was to investigate if discrete wavelet decomposition provides additional insight into resting-state processes through the analysis of functional connectivity within specific frequency ranges within the default mode network (DMN) that may be affected by mild traumatic brain injury (mTBI). Participants included 32 mTBI patients (15 with postconcussive syndrome [PCS+] and 17 without [PCS-]). mTBI patients received resting-state functional magnetic resonance imaging (rs-fMRI) at acute (within 10 days of injury) and chronic (6 months postinjury) time points and were compared with 31 controls (healthy control [HC]). The wavelet decomposition divides the time series into multiple frequency ranges based on four scaling factors (SF1: 0.125-0.250 Hz, SF2: 0.060-0.125 Hz, SF3: 0.030-0.060 Hz, SF4: 0.015-0.030 Hz). Within each SF, wavelet connectivity matrices for nodes of the DMN were created for each group (HC, PCS+, PCS-), and bivariate measures of strength and diversity were calculated. The results demonstrate reduced strength of connectivity in PCS+ patients compared with PCS- patients within SF1 during both the acute and chronic stages of injury, as well as recovery of connectivity within SF1 across the two time points. Furthermore, the PCS- group demonstrated greater network strength compared with controls at both time points, suggesting a potential compensatory or protective mechanism in these patients. These findings stress the importance of investigating resting-state connectivity within multiple frequency ranges; however, many of our findings are within SF1, which may overlap with frequencies associated with cardiac and respiratory activities.

Longitudinal in vivo developmental changes of metabolites in the hippocampus of Fmr1 knockout mice

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied in the Fmr1 knockout (KO) mouse, which models both the anatomical and behavioral changes observed in FXS patients. In vitro studies have shown many alterations in synaptic plasticity and increased density of immature dendritic spines in the hippocampus, a region involved in learning and memory. In this study, magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopy (MRS) were used to determine in vivo longitudinal changes in volume and metabolites in the hippocampus during the critical period of early myelination and synaptogenesis at post‐natal days (PND) 18, 21, and 30 in Fmr1 KO mice compared with wild‐type (WT) controls. MRI demonstrated an increase in volume of the hippocampus in the Fmr1 KO mouse compared with controls. MRS revealed significant developmental changes in the ratios of hippocampal metabolites N‐acetylaspartate (NAA), myo‐inositol (Ins), and taurine to total creatine (tCr) in Fmr1 KO mice compared with WT controls. Ins was decreased at PND 30, and taurine was increased at all ages studied in Fmr1 KO mice compared with controls. An imbalance of brain metabolites in the hippocampus of Fmr1 KO mice during the critical developmental period of synaptogenesis and early myelination could have long‐lasting effects that adversely affect brain development and contribute to ongoing alterations in brain function.