Theodore P. Trouard

The neural substrates of writing: A functional magnetic resonance imaging study

Background: Hypotheses regarding the neural substrates of writing have been derived from the study of individuals with acquired agraphia. Functional neuroimaging offers another methodology to test these hypotheses in neurologically intact individuals. Aims: This study was designed to identify possible neural substrates for the linguistic and motor components of writing in normal English-speaking individuals. Methods & Procedures: Functional magnetic resonance imaging was used with 12 adults to examine activation associated with generative writing of words from semantic categories contrasted with writing letters of the alphabet and drawing circles. In addition, the generative writing condition was contrasted with a subvocal generative naming condition. Outcomes & Results: Semantically guided retrieval of orthographic word forms for the generative writing condition revealed activation in the left inferior and dorsolateral prefrontal cortex, as well as the left posterior inferior temporal lobe (BA 37). However, no activation was detected in the left angular gyrus (BA 39). The motor components of writing were associated with activation in left fronto-parietal cortex including the region of the intraparietal sulcus, superior parietal lobule, dorsolateral and medial premotor cortex, and sensorimotor areas for the hand. Conclusions: These observations suggest an important role of the left posterior inferior temporal cortex in lexical-orthographic processing and fail to support the long-held notion that the dominant angular gyrus is the storage site for orthographic representations of familiar words. Our findings also demonstrate the involvement of left superior parietal and frontal premotor regions in translating orthographic information into appropriate hand movements.

Predicting Functional Gains in a Stroke Trial

Background and Purpose— A number of therapies in development for patients with central nervous system injury aim to reduce disability by improving function of surviving brain elements rather than by salvaging tissue. The current study tested the hypothesis that, after adjusting for a number of clinical assessments, a measure of brain function at baseline would improve prediction of behavioral gains after treatment. Methods— Twenty-four patients with chronic stroke underwent baseline clinical and functional MRI assessments, received 6 weeks of rehabilitation therapy with or without investigational motor cortex stimulation, and then had repeat assessments. Thirteen baseline clinical/radiological measures were evaluated for ability to predict subsequent trial-related gains. Results— Across all patients, bivariate analyses found that greater trial-related functional gains were predicted by (1) smaller infarct volume, (2) greater baseline clinical status, and (3) lower degree of activation in stroke-affected motor cortex on baseline functional MRI. When these 3 variables were further assessed using multivariate linear regression modeling, only lower motor cortex activation and greater clinical status at baseline remained significant predictors. Note that lower baseline motor cortex activation was also associated with larger increases in motor cortex activation after treatment. Conclusions— Lower motor cortex activity at baseline predicted greater behavioral gains after therapy, even after controlling for a number of clinical assessments. The boosts in cortical activity that paralleled behavioral gains suggest that in some patients, low baseline cortical activity represents underuse of surviving cortical resources. A measure of brain function might be important for optimal clinical decision-making in the context of a restorative intervention.

Influence of cholesterol on dynamics of dimyristoylphosphatidylcholine bilayers as studied by deuterium NMR relaxation

Investigation of the deuterium (2H) nuclear magnetic resonance (NMR) relaxation rates of lipid bilayers containing cholesterol can yield new insights regarding its role in membrane function and dynamics. Spin-lattice (R1Z) and quadrupolar order (R1Q) 2H NMR relaxation rates were measured at 46.1 and 76.8 MHz for macroscopically oriented bilayers of 1,2-diperdeuteriomyristoyl-sn-glycero-3-phosphocholine (DMPC-d54) containing cholesterol (1/1 molar ratio) in the liquid-ordered phase at 40 °C. The data for various segmental positions along the DMPC-d54 acyl chain were simultaneously fitted to a composite membrane deformation model, including fast segmental motions which preaverage the coupling tensor along the lipid acyl chain, slow molecular reorientations, and small-amplitude collective fluctuations. In contrast to pure DMPC-d54 in the liquid-crystalline (Lα) phase, for the DMPC-d54:cholesterol (1/1) system a linear square-law functional dependence of the relaxation rates on the order parameter (quadrupola...

High‐resolution diffusion imaging with DIFRAD‐FSE (Diffusion‐Weighted Radial Acquisition of Data With Fast Spin‐Echo) MRI

A novel MRI method, DIFRAD‐FSE (diffusion‐weighted radial acquisition of data with fast spin‐echo), is demonstrated that enables rapid, high‐resolution multi‐shot diffusion‐weighted MRI without significant artifacts due to motion. Following a diffusion‐weighting spin‐echo preparation period, multiple radial lines of Fourier data are acquired using spin‐echo refocusing. Images can be reconstructed from the radial data set using a magnitude‐only filtered back‐projection reconstruction algorithm that removes phase errors due to motion. Results from human brain imaging demonstrate the ability of DIFRAD‐FSE to acquire multiple radial lines of Fourier data each TR period without significant artifacts due to relaxation and to produce high‐resolution diffusion‐weighted MR images without significant artifacts from motion. Magn Reson Med 42:11–18, 1999.

Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice.

Niemann‐Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1–/– mice). We confirmed previous results showing that a single injection of 250 μg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1–/– mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota‐Rod performance. T2‐weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild‐type mice than those of untreated Npc1–/– mice. Neuropathology showed that day‐7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1–/– mice. Similar effects of allopregnanolone treatment were observed in Npc1–/–, mdr1a–/– double‐mutant mice, which have a deficient blood–brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1–/– mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1–/– mice, presumably by effects on myelination or neuronal connectivity.

Radial fast spin-echo method for T2-weighted imaging and T2 mapping of the liver

To evaluate a multishot radial fast‐spin echo (RAD‐FSE) method developed to improve the quality of abdominal T2‐weighted imaging as well as the characterization of focal liver lesions.

fMRI variability and the localization of languages in the bilingual brain.

The cerebral localization of multiple languages is a topic of active research. This study presents a method for assessing whether partial overlap of active voxels reflects differential language localization, or simply the variability known to occur with multiple runs of the same task in fMRI studies. Two groups of bilingual subjects (early and later learners of L2) performed word fluency and sentence generation tasks in both languages. The degree of separation for regions of activation did not exceed that associated with run-to-run variability for either task or either group. Early bilinguals, however, showed greater total numbers of active voxels than Late bilinguals for both tasks. This effect occurred despite a lack of a behavioral performance differences by the two groups.

A novel mouse model of Niemann–Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations

We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1(nmf164)) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1(spm) allele and identifying a truncating mutation, confirm that the mutation in Npc1(nmf164) mice is distinct from those in other existing mouse models of NPC disease (Npc1(nih), Npc1(spm)). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1(nmf164) mutant mice than in mice with the null mutations (Npc1(nih), Npc1(spm)). Although Npc1 mRNA levels appear relatively normal, Npc1(nmf164) brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1(nih) mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1(nmf164) mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases.

A general method for the preparation of mixed micelles of hydrophobic peptides and sodium dodecyl sulphate

A new method is reported for the incorporation of hydrophobic peptides into sodium dodecyl sulphate (SDS) micelles. First, a homogeneous solution of peptide and detergent is obtained by adding the peptide in trifluoroethanol to an equal volume of an aqueous solution of SDS. Upon subsequent addition of excess water, mixed peptide‐SDS micelles are formed. Next, all solvent is removed by lyophilization and an appropriate amount of water is added to the dry powder. For various hydrophobic peptides this was shown to yield clear and stable solutions that are highly concentrated and suitable for characterization by spectroscopic techniques.

Angular dependence of deuterium spin‐lattice relaxation rates of macroscopically oriented dilauroylphosphatidylcholine in the liquid‐crystalline state

Deuterium (2H) NMR relaxation plays a major role in the study of lipid reorientational dynamics, with the angular dependence of the relaxation rates providing a novel and critical test of proposed motional models. Spin‐lattice relaxation rates (R1Z) were measured for macroscopically oriented bilayers of 1,2‐diperdeuteriolauroyl‐sn‐glycero‐3‐phosphocholine (DLPC‐d46) in the liquid‐crystalline (Lα) phase. The results for different positions along the chain (index i) were dependent on the angle θ between the macroscopic bilayer normal and the static external magnetic field, and allowed the anisotropy of R(i)1Z to be determined for nine resolved quadrupolar resonances. Angular‐dependent relaxation data were evaluated using simple models of anisotropic rotational diffusion within an odd or even potential of mean torque as a framework for describing (i) segmental reorientations of the chains, or alternatively (ii) noncollective molecular motions within the bilayer. Moreover, (iii) a simple quasi‐hydrodynamic fo...