Ken Sakaie

Resting state sensorimotor functional connectivity in multiple sclerosis inversely correlates with transcallosal motor pathway transverse diffusivity.

Recent studies indicate that functional connectivity using low‐frequency BOLD fluctuations (LFBFs) is reduced between the bilateral primary sensorimotor regions in multiple sclerosis. In addition, it has been shown that pathway‐dependent measures of the transverse diffusivity of water in white matter correlate with related clinical measures of functional deficit in multiple sclerosis. Taken together, these methods suggest that MRI methods can be used to probe both functional connectivity and anatomic connectivity in subjects with known white matter impairment. We report the results of a study comparing anatomic connectivity of the transcallosal motor pathway, as measured with diffusion tensor imaging (DTI) and functional connectivity of the bilateral primary sensorimotor cortices (SMC), as measured with LFBFs in the resting state. High angular resolution diffusion imaging was combined with functional MRI to define the transcallosal white matter pathway connecting the bilateral primary SMC. Maps were generated from the probabilistic tracking employed and these maps were used to calculate the mean pathway diffusion measures fractional anisotropy 〈FA〉, mean diffusivity 〈MD〉, longitudinal diffusivity 〈λ1〉, and transverse diffusivity 〈λ2〉. These were compared with LFBF‐based functional connectivity measures (Fc) obtained at rest in a cohort of 11 multiple sclerosis patients and ∼10 age‐ and gender‐matched control subjects. The correlation between 〈FA〉 and Fc for MS patients was r = −0.63, P < 0.04. The correlation between all subjects 〈λ2〉 and Fc was r = 0.42, P < 0.05. The correlation between all subjects 〈λ2〉 and Fc was r = −0.50, P < 0.02. None of the control subject correlations were significant, nor were 〈FA〉, 〈λ1〉, or 〈MD〉 significantly correlated with Fc for MS patients. This constitutes the first in vivo observation of a correlation between measures of anatomic connectivity and functional connectivity using spontaneous LFBFs. Hum Brain Mapp, 2008.

Experimental and theoretical characterization of the voltage distribution generated by deep brain stimulation

Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinsons disease and shows great promise for numerous other disorders. While the fundamental purpose of DBS is to modulate neural activity with electric fields, little is known about the actual voltage distribution generated in the brain by DBS electrodes and as a result it is difficult to accurately predict which brain areas are directly affected by the stimulation. The goal of this study was to characterize the spatial and temporal characteristics of the voltage distribution generated by DBS electrodes. We experimentally recorded voltages around active DBS electrodes in either a saline bath or implanted in the brain of a non-human primate. Recordings were made during voltage-controlled and current-controlled stimulation. The experimental findings were compared to volume conductor electric field models of DBS parameterized to match the different experiments. Three factors directly affected the experimental and theoretical voltage measurements: 1) DBS electrode impedance, primarily dictated by a voltage drop at the electrode-electrolyte interface and the conductivity of the tissue medium, 2) capacitive modulation of the stimulus waveform, and 3) inhomogeneity and anisotropy of the tissue medium. While the voltage distribution does not directly predict the neural response to DBS, the results of this study do provide foundational building blocks for understanding the electrical parameters of DBS and characterizing its effects on the nervous system.

A Validation Study of Multicenter Diffusion Tensor Imaging: Reliability of Fractional Anisotropy and Diffusivity Values

BACKGROUND AND PURPOSE: DTI is increasingly being used as a measure to study tissue damage in several neurologic diseases. Our aim was to investigate the comparability of DTI measures between different MR imaging magnets and platforms. MATERIALS AND METHODS: Two healthy volunteers underwent DTI on five 3T MR imaging scanners (3 Trios and 2 Signas) by using a matched 33 noncollinear diffusion-direction pulse sequence. Within each subject, a total of 16 white matter (corpus callosum, periventricular, and deep white matter) and gray matter (cortical and deep gray) ROIs were drawn on a single image set and then were coregistered to the other images. Mean FA, ADC, and longitudinal and transverse diffusivities were calculated within each ROI. Concordance correlations were derived by comparing ROI DTI values among each of the 5 magnets. RESULTS: Mean concordance for FA was 0.96; for both longitudinal and transverse diffusivities, it was 0.93; and for ADC, it was 0.88. Mean scan-rescan concordance was 0.96–0.97 for all DTI measures. Concordance correlations within platforms were, in general, better than those between platforms for all DTI measures (mean concordance of 0.96). CONCLUSIONS: We found that a 3T magnet and high-angular-resolution pulse sequence yielded comparable DTI measurements across different MR imaging magnets and platforms. Our results indicate that FA is the most comparable measure across magnets, followed by individual diffusivities. The comparability of DTI measures between different magnets supports the feasibility of multicentered clinical trials by using DTI as an outcome measure.

An objective method for regularization of fiber orientation distributions derived from diffusion-weighted MRI.

Spherical deconvolution is an elegant method by which the orientation of crossing fibers in the brain can be estimated from a diffusion-weighted MRI measurement. However, higher resolution of fiber directions comes at the cost of higher susceptibility to noise. In this study, we describe the use of linear regularization of the fiber orientation distribution function by Damped Singular Value Decomposition. Furthermore, the degree of regularization is optimized on a voxel-by-voxel basis with no user interaction using Generalized Cross Validation. We find, by simulations, that regularization can improve the reliability of fiber orientation determination when the signal-to-noise ratio is low. Simulations and in vivo measurements indicate that spurious peaks of the fiber orientation distribution function in regions with low anisotropy largely disappear when regularization is introduced. The methods examined are fast enough to be used on a routine basis with diffusion MRI data sets and may improve estimation of water diffusion properties in heterogeneous white matter and boost reliability of fiber tracking through regions of brain with complex fiber geometry.

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.

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.

A Preliminary Validation Study of Diffusion Tensor Imaging as a Measure of Functional Brain Injury

BACKGROUND Diffusion tensor imaging (DTI) characterizes multiple sclerosis (MS) tissue injury, although it has remained unproven whether DTI changes in disease have functional consequences. The medial longitudinal fasciculus (MLF) is a key brainstem pathway for ocular adduction and is commonly injured in patients with MS, typically resulting in internuclear ophthalmoparesis. OBJECTIVE To validate DTI as a physiologically relevant measure of brain tissue integrity. DESIGN A correlation study of ocular dysmotility and DTI conducted between January 2004 and September 2004. SETTING Multiple Sclerosis Center, University of Texas Southwestern Medical Center, Dallas. Patients Six patients with chronic, unilateral, or bilateral internuclear ophthalmoparesis and 10 healthy control subjects. Main Outcome Measure We used infrared oculography to correlate the velocity versional dysconjugacy index, defined as the ratio of the velocity of the abducting to adducting eye movements during horizontal saccades, and DTI measures within the MLF as measured through an anatomical overlay. Overall diffusion was measured by mean diffusivity, and anisotropy was measured by the lattice index. RESULTS Within the pontine MLF, the mean diffusivity was increased compared with healthy controls (P < .005), whereas the pontine lattice index was decreased (P < .03). Correlations were observed between the velocity versional dysconjugacy index and the mean diffusivity (left: r = 0.65, P < .01; right: r = 0.46, P = .07). Similar correlations were found between the versional dysconjugacy index and the lattice index (left: r = -0.43, P = .09; right: r = -0.65, P <.01). CONCLUSIONS We identified DTI evidence of pathologic disruption of a small brainstem fiber pathway, which is crucial for accurate horizontal eye movements. In this small study, we observed correlations between the DTI changes and oculomotor dysfunction. Our preliminary observations provide criterion validity of DTI as a surrogate marker of brain tissue integrity.

Diffusion Weighted Imaging of Prefrontal Cortex in Prodromal Huntington's Disease

Huntingtons disease (HD) is a devastating neurodegenerative disease with no effective disease‐modifying treatments. There is considerable interest in finding reliable indicators of disease progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion‐weighted imaging (DWI) may provide a reliable marker of disease progression by characterizing diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connections and documented role in executive function. This study uses DWI to characterize diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. Prodromal HD individuals were separated into three CAG‐Age Product (CAP) groups (16 low, 22 medium, 15 high) that indexed baseline progression. Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. For MD and RD, differences among controls and HD participants tracked with baseline disease progression. The smallest difference was for the low group and the largest for the high group. Significant correlations between Trail Making Test B (TMTB) and mean fractional anisotropy (FA) and/or RD paralleled group differences in mean MD and/or RD in several right hemisphere regions. The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression in future longitudinal studies as increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals. Hum Brain Mapp 35:1562–1573, 2014.

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.

Quantitative assessment of motion correction for high angular resolution diffusion imaging

Several methods have been proposed for motion correction of high angular resolution diffusion imaging (HARDI) data. There have been few comparisons of these methods, partly due to a lack of quantitative metrics of performance. We compare two motion correction strategies using two figures of merit: displacement introduced by the motion correction and the 95% confidence interval of the cone of uncertainty of voxels with prolate tensors. What follows is a general approach for assessing motion correction of HARDI data that may have broad application for quality assurance and optimization of postprocessing protocols. Our analysis demonstrates two important issues related to motion correction of HARDI data: (1) although neither method we tested was dramatically superior in performance, both were dramatically better than performing no motion correction, and (2) iteration of motion correction can improve the final results. Based on the results demonstrated here, iterative motion correction is strongly recommended for HARDI acquisitions.