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.

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.

Iron deposition in pain-regulatory nuclei in episodic migraine and chronic daily headache by MRI.

BACKGROUND: Progression of migraine toward a more disabling chronic form of at least 15 days/month is linked with frequency of attacks. Magnetic resonance imaging (MRI) findings of iron accumulation in the brain, especially in periaqueductal gray and red nucleus, have been correlated with both duration of illness and frequency of attacks. METHODS: This study therefore evaluated iron deposition as measured with MRI in basal ganglia and pain regulatory nuclei in neurologically healthy control volunteers and in patients with various migraine subtypes: episodic migraine (n = 10) with (n = 4) or without aura (n = 6), and chronic daily headache (n = 11), including medication overuse headache (MOH, n = 8), chronic tension-type headache (n = 1), and primary chronic migraine (n = 2). The goal was to assess differences in iron deposition among migraine subtypes and controls in the hopes of linking the by-products of frequent attacks or long duration of illness with these changes. RESULTS: The study sought to evaluate the tradeoff between sensitivity and specificity in T2 imaging of patients with migraine, and found that only T2 imaging in the globus pallidus was able to distinguish between episodic and chronic migraine, suggesting that this technique may be the most appropriate to assess migraine frequency. Patients with MOH did not demonstrate T2' shortening. CONCLUSIONS: Because iron accumulation should cause shortening of both T2 and T2', although the lack of significance in observed T2' difference could be due to increased variance in T2' the measurement, these results suggest that a mechanism other than increased iron deposition may play a role in the genesis or pathophysiology of MOH.

A practical clinical method to quantify language lateralization in fMRI using whole-brain analysis.

Surgery is often the only effective treatment for intractable epilepsy, but its benefits must be balanced by potential disruption of eloquent cortical functions. Wada test is the standard technique to lateralize language before surgery; however, it is invasive and associated with complications. fMRI provides an attractive noninvasive alternative, which has been previously shown to correlate with Wada results. However this correlation is imperfect since standard fMRI laterality indices are dependent on a particular arbitrary statistical threshold used in the data processing. We report a novel automated, threshold-independent fMRI methodology to assess language lateralization, which we hypothesize provides a robust and unbiased pre-operative assessment. This hemispheric histogram analysis method can accurately interrogate language lateralization, as validated against the Wada test. Fifty-nine subjects with intractable epilepsy received preoperative evaluation for language lateralization using fMRI. fMRI data then were analyzed using a novel automated threshold-independent method for determining language lateralization. The methodology generated a lateralization score based on hemispheric activation of language areas and a quality index based on multiple factors, including patient motion and signal-to-noise characteristics. Lateralization scores were compared to Wada test results (51 patients), direct cortical stimulation (3 patients), and subdural grid stimulation (5 patients). Data sets were used to generate a probability score for language lateralization for each subject. The lateralization scores correlated well with the objective measures of language lateralization (r(2)=0.46). Cumulative historical data were utilized to prospectively determine probabilities of language lateralization for individual patients. In conclusion, hemispheric language lateralization can be accurately determined using a novel objective and automated methodology that calculates language lateralization in a threshold-independent manner and can be used to determine the probability of language dominance in individual patients.

Comparison of unilateral and bilateral complex finger tapping-related activation in premotor and primary motor cortex.

Sixteen healthy right-handed subjects performed a complex finger-tapping task that broadly activates the motor and premotor regions, including primary motor (M1), ventral premotor (PMv), and dorsal premotor (PMd) cortex. This task was performed with the right hand only, left hand only and both hands simultaneously. Behavioral performance and the possibility of mirror movements were controlled through the use of MRI-compatible gloves to monitor finger movements. Using spatially normalized ROIs from the Human Motor Area Template (HMAT), comparisons were made of the spatial extent and location of activation in the left and right motor regions between all three tasks. During unilateral right and left hand tapping, ipsilateral precentral gyrus activation occurred in all subjects, mainly in the PMv and PMd. Ipsilateral M1 activation was less consistent and shifted anteriorly within M1, towards the border of M1 and premotor cortex. Regions of ipsilateral activation were also activated during contralateral and bilateral tasks. Overall, 83%/70%/58% of the ipsilaterally activated voxels in M1/PMd/PMv were also activated during contralateral and bilateral tapping. The mean percent signal change of spatially overlapping activated voxels was similar in PMv and PMd between all three tasks. However, the mean percent signal change of spatially overlapping M1 activation was significantly less during ipsilateral tapping compared with contra- or bilateral tapping. Results suggest that the ipsilateral fMRI activation in unilateral motor tasks may not be inhibitory in nature, but rather may reflect part of a bilateral network involved in the planning and/or execution of tapping in the ipsilateral hand.

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 lambda(1), and transverse diffusivity lambda(2). These were compared with LFBF-based functional connectivity measures (F(c)) obtained at rest in a cohort of 11 multiple sclerosis patients and approximately 10 age- and gender-matched control subjects. The correlation between FA and F(c) for MS patients was r = -0.63, P < 0.04. The correlation between all subjects lambda(2) and F(c) was r = 0.42, P < 0.05. The correlation between all subjects lambda(2) and F(c) was r = -0.50, P < 0.02. None of the control subject correlations were significant, nor were FA, lambda(1), or MD significantly correlated with F(c) for MS patients. This constitutes the first in vivo observation of a correlation between measures of anatomic connectivity and functional connectivity using spontaneous LFBFs.

Activation volume vs BOLD signal change as measures of fMRI activation - Its impact on GABA - fMRI activation correlation.

PURPOSE: To explore the relative robustness of functional MRI (fMRI) activation volume and blood oxygen level-dependent (BOLD) signal change as fMRI metric, and to study the effect of relative robustness on the correlation between fMRI activation and cortical gamma amino butyric acid (GABA) in healthy controls and patients with multiple sclerosis (MS). METHODS: fMRI data were acquired from healthy controls and patients with MS, with the subjects peforming self paced bilateral finger tapping in block design. GABA spectroscopy was performed with voxel placed on the area of maximum activation during fMRI. Activation volume and BOLD signal changes at primary motor cortex (M1), as well as GABA concentration were calculated for each patient. RESULTS: Activation volume correlated with BOLD signal change in healthy controls, but no such correlation was observed in patients with MS. This difference was likely the result of higher intersubject noise variance in the patient population. GABA concentration correlated with M1 activation volume in patients but not in controls, and did not correlate with any fMRI metric in patients or controls. CONCLUSION: Our data suggest that activation volume is a more robust measure than BOLD signal change in a group with high intersubject noise variance as in patients with MS. Additionally, this study demonstrated difference in correlation behavior between GABA concentration and the 2 fMRI metrics in patients with MS, suggesting that GABA - activation volume correlation is more appropriate measure in the patient group.

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.

High spatial and angular resolution diffusion-weighted imaging reveals forniceal damage related to memory impairment.

INTRODUCTION: Diffusion tensor imaging (DTI) measures in patients with multiple sclerosis (MS), particularly those measures associated with a specific white matter pathway, have consistently shown correlations with function. This study sought to investigate correlations between DTI measures in the fornix and common cognitive deficits in MS patients, including episodic memory, working memory and attention. MATERIALS AND METHODS: Patients with MS and group age- and sex-matched controls underwent high-resolution diffusion scanning (1-mm isotropic voxels) and cognitive testing. Manually drawn forniceal regions of interest were applied to individual maps of tensor-derived measures, and mean values of transverse diffusivity (TD), mean diffusivity (MD), longitudinal diffusivity (LD) and fractional anisotropy (FA) were calculated. RESULTS: In 40 patients with MS [mean age ± S.D.=42.55 ± 9.1 years; Expanded Disability Status Scale (EDSS)=2.0 ± 1.2; Multiple Sclerosis Functional Composite (MSFC) score=0.38 ± 0.46] and 20 healthy controls (mean age ± S.D.=41.35 ± 9.7 years; EDSS=0.0 ± 0; MSFC score=0.74 ± 0.24), we found that FA, MD and TD values in the fornix were significantly different between groups (P<.03), and patient performance on the Brief Visuospatial Memory Test-Revised (BVMT-R) was correlated with DTI measures (P<.03). DISCUSSION: These results are consistent with findings of axonal degeneration in MS and support the use of DTI as an indicator of disease progression.

In vivo magnetic resonance spectroscopy measurement of gray-matter and white-matter gamma-aminobutyric acid concentration in sensorimotor cortex using a motion-controlled MEGA point-resolved spectroscopy sequence.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the brain. Understanding the GABA concentration, in vivo, is important to understand normal brain function. Using MEGA point-resolved spectroscopy sequence with interleaved water scans to detect subject motion, GABA level of sensorimotor cortex was measured using a voxel identified from a functional magnetic resonance imaging scan. The GABA level in a 20×20×20-mm(3) voxel consisting of 37%±7% gray matter, 52%±12% white matter and 11%±8% cerebrospinal fluid in the sensorimotor region was measured to be 1.43±0.48 mM. In addition, using linear regression analysis, GABA concentrations within gray and white matter were calculated to be 2.87±0.61 and 0.33±0.11 mM, respectively.

Deep brain stimulation for obsessive-compulsive disorder: using functional magnetic resonance imaging and electrophysiological techniques: technical case report.

OBJECTIVE AND IMPORTANCE: To demonstrate the pattern of activation associated with electrical stimulation through bilateral deep brain stimulation electrodes placed within the anterior limb of the internal capsule to the level of the ventral striatum for treatment of obsessive-compulsive disorder. CLINICAL PRESENTATION: A 44-year-old man with a 26-year history of obsessive-compulsive disorder underwent functional magnetic resonance imaging (fMRI) and deep brain stimulation-evoked cortical potential testing after bilateral implantation of deep brain stimulation leads. Stimulation was delivered independently through the distal two contacts of each percutaneously extended lead using an external pulse generator. On postoperative Day 2, we used a 3-Tesla magnetic resonance system to measure changes in the fMRI blood oxygen level-dependent signal using stimulation parameters that were predetermined to demonstrate behavioral effects. INTERVENTION: All studies were well tolerated. Trial stimulations performed intraoperatively as well as on postsurgical Day 1 were associated with acutely elevated mood and reduced anxiety. Although the benefit achieved acutely was relatively symmetric between the bilaterally placed leads, follow-up programming showed a clear advantage to right-sided stimulation. Three of the four fMRI trials demonstrated good activation, with the fourth being moderately corrupted by motion artifact. The beneficial effects observed with right-sided stimulation were associated with activation of the ipsilateral head of the caudate, medial thalamus, and anterior cingulate cortex as well as the contralateral cerebellum. The distribution of the cortical evoked potentials was consistent with the locus of cortical activation observed with fMRI. CONCLUSION: High-frequency stimulation via a lead placed in the anterior limb of the internal capsule induced widespread hemodynamic changes at both the cortical and subcortical levels including areas typically associated with the pathogenesis of obsessive-compulsive disorder.

Variability in RF-induced heating of a deep brain stimulation implant across MR systems.

PURPOSE: To compare the MRI-related heating per unit of specific absorption rate (SAR) profile of a conductive implant between two 1.5-Tesla/64 MHz MR systems using a transmit/receive (t/r) head coil configuration. MATERIALS AND METHODS: Deep brain stimulation (DBS) leads were configured within a gel-filled phantom of the human head and torso. Temperature variation at each of four contacts of the bilaterally-placed leads was monitored using fluoroptic thermometry. MRI was performed using the t/r head coils of two different-generation 1.5-Tesla MR systems from the same manufacturer. Temperature changes were normalized to SAR values for the head (DeltaT/SAR-H), and the slope of this DeltaT/SAR-H by time relationship was compared between the two scanners. RESULTS: The DeltaT/SAR-H for the implant ranged from 3.5 to 5.5 times higher on one MR system as compared to the other (P < 0.01) depending on the measurement site. CONCLUSION: The findings support previous observations that console-reported SAR does not constitute a reliable index of heating for elongated, conductive implants, such as the DBS hardware system tested. In contrast to our previous findings using a t/r body coil, the data presented here reveal marked differences between two MR systems using t/r head coils (the coil configuration was consistent with the implant manufacturer's imaging guidelines). J. Magn. Reson. Imaging 2006. (c) 2006 Wiley-Liss, Inc.

Parkinson disease: pattern of functional MR imaging activation during deep brain stimulation of subthalamic nucleus--initial experience.

PURPOSE: To prospectively determine the pattern of functional magnetic resonance (MR) imaging activation at 3 T produced by deep brain stimulation (DBS) of subthalamic nucleus (STN) for treatment of Parkinson disease and to determine the safety of DBS electrode stimulation during functional MR imaging at 3 T. MATERIALS AND METHODS: Informed consent was obtained from all subjects participating in the study, and the study protocol was approved by the institutional review board at the Cleveland Clinic Foundation and was HIPAA compliant. After extensive phantom safety testing of DBS lead systems, five patients (three men, two women; mean age, 49.4 years +/- 14.5 [standard deviation]; range, 31-74 years) with percutaneously extended bilateral DBS electrodes placed in the STN for treatment of Parkinson disease were examined at 3 T on the 1st or 2nd postoperative day. Imaging consisted of a three-dimensional anatomic data set with leads disconnected and a blood oxygen level-dependent functional MR image with a single lead connected to the external pulse generator in the MR imaging control room by using stimulation parameters previously determined to produce optimal stimulation for alleviation of symptoms. A total of nine leads were tested with the functional MR imaging protocol. Subjects underwent neurologic examination immediately before and after MR imaging. RESULTS: All five patients completed the study without change in their neurologic examination and with activation seen in eight of nine electrodes stimulated. Activation was seen in the ipsilateral basal ganglia in all subjects and ipsilateral thalamus in six of the electrodes tested. Two of the electrode stimulations demonstrated additional activation in the STN and/or substantia nigra region adjacent to the electrode tip. For three electrode stimulations, activation was seen in the contralateral superior cerebellum. CONCLUSION: Therapeutically effective DBS of STN can be performed safely during functional MR imaging at 3 T and produces a consistent pattern of ipsilateral activation of deep brain motor structures.

Functional pathway-defined MRI diffusion measures reveal increased transverse diffusivity of water in multiple sclerosis.

The diffusion properties of water are sensitive to microscopic changes in the white matter of multiple sclerosis (MS) patients. Typical MRI measures of disease burden in MS demonstrate modest to poor correlation with disability. Functional MRI and DTI-based fiber tracking were used to define the interhemispheric white matter pathway connecting bilateral supplementary motor areas (SMA) in 16 MS patients sand 16 control subjects. Fractional anisotropy (FA), mean diffusivity (MD), longitudinal (lambda(1)) and transverse diffusivity (lambda(2)) were measured along this pathway in all subjects. Mean FA was 0.587 +/- 0.032 for patients and 0.608 +/- 0.020 for controls (P < 0.02). Mean MD was (0.821 +/- 0.055) x 10(-3) mm(2) s(-1) for patients and (0.770 +/- 0.020) x 10(-3) mm(2) s(-1) for controls (P < 0.004). Mean lambda(1) values were (1.462 +/- 0.099) x 10(-3) mm(2) s(-1) for patients and (1.400 +/- 0.034) x 10(-3) mm(2) s(-1) for controls (P < 0.02). Mean lambda(2) values were (0.500 +/- 0.047) x 10(-3) mm(2) s(-1) for patients and (0.454 +/- 0.027) x 10(-3) mm(2) s(-1) for controls (P < 0.001). In addition, the correlation between the Multiple Sclerosis Functional Composite (MSFC) and transverse diffusivity was -0.341 (P < 0.05). The component test of the MSFC most related to the SMA pathway studied with our MRI method (Nine-hole Peg Test) showed significant correlation with transverse diffusivity (r = 0.392, P < 0.02), indicating that probing functional pathways with MRI measures can lead to a better reflection of disease status.

Multiple sclerosis: low-frequency temporal blood oxygen level-dependent fluctuations indicate reduced functional connectivity initial results.

PURPOSE: To study the correlation of low-frequency blood oxygenation level-dependent (BOLD) fluctuations on magnetic resonance (MR) images obtained of the left- and right-hemisphere primary motor regions in healthy control subjects and patients with multiple sclerosis (MS). MATERIALS AND METHODS: Sixteen healthy volunteers and 20 patients with MS underwent MR imaging with a 1.5-T imager by using a protocol designed to monitor low-frequency BOLD fluctuations. Data for low-frequency BOLD fluctuations were acquired with subjects at rest and during continuous performance of a bilateral finger-tapping task. These data were low-pass filtered (<0.08 Hz), and cross correlations of all acquired pixels to a region of interest in the left precentral gyrus were calculated. Confidence levels were calculated from the cross correlations. The fraction of pixels in the right precentral gyrus above a confidence level of 95% for correlation with the left precentral gyrus was calculated for each subject. RESULTS: A plot of the fraction of the right precentral gyrus with high correlation with the left precentral gyrus for the finger-tapping state versus the resting state showed a clear discrimination between patients with MS and control subjects. Compared with control subjects, patients with MS generally had a smaller fraction of the pixels in the right precentral gyrus above the confidence level. This finding indicates that our method results in greater than 60% sensitivity and 100% specificity for discriminating patients with MS from control subjects. No significant correlation was found between clinical measures of MS disease and correlations of low-frequency BOLD fluctuations between left and right precentral gyri. CONCLUSION: On the basis of the connectivity measure of low-frequency BOLD fluctuations, patients with MS exhibited lower functional connectivity between right- and left-hemisphere primary motor cortices when compared with that in control subjects.