Peter S. Allen

Decreased Prefrontal Myo-Inositol in Major Depressive Disorder

BACKGROUND Postmortem studies have shown robust prefrontal cortex glial losses and more subtle neuronal changes in major depressive disorder (MDD). Earlier proton magnetic resonance spectroscopy (1H-MRS) studies of the glial marker myo-inositol in MDD were subject to potential confounds. The primary hypothesis of this study was that MDD patients would show reduced prefrontal/anterior cingulate cortex levels of myo-inositol. METHODS Thirteen nonmedicated moderate-severe MDD patients and 13 matched control subjects were studied (six male, seven female per group). Proton magnetic resonance spectroscopy stimulated echo acquisition mode spectra (3.0 T; echo time=168 msec; mixing time=28 msec; repetition time=3000 msec) were obtained from prefrontal/anterior cingulate cortex. Metabolite data were adjusted for tissue composition. RESULTS Patients with MDD showed significantly lower myo-inositol/creatine ratios (.94+/-.23) than control subjects (1.32+/-.37) [F(1,23)=6.9; p=.016]. CONCLUSIONS These data suggest a reduction of myo-inositol in prefrontal/anterior cingulate cortex in MDD, which could be a consequence of glial loss or altered glial metabolism. Additional in vivo studies of glial markers could add to the understanding of the pathophysiology of MDD.

Multicomponent water proton transverse relaxation and T2-discriminated water diffusion in myelinated and nonmyelinated nerve

The influence of compartmental boundaries on water proton transverse relaxation and diffusion measurements was investigated in three distinct excised nerves, namely, the non-myelinated olfactory nerve, the Schwann cell myelinated trigeminal nerve, and the oligodendrocyte myelinated optic nerve of the garfish. The transverse relaxation decay curves were multiexponential and their decomposition yielded three primary components with T2 values approximately 30-50, 150, and 500 ms, which were subsequently assigned to water protons in the myelin, axoplasm, and interaxonal compartments. The short T2 component was absent in the non-myelinated olfactory nerve, but present in both myelinated nerves and thus provides supporting evidence for the use of quantitative T2 measurements to measure the degree of myelination. The signal contribution of each T2 component to the apparent diffusion coefficient measurements was varied by incrementing the spin-echo time with a preparatory CPMG train of radiofrequency pulses. The apparent diffusion coefficient and its anisotropy were shown to be independent of the spin-echo time over the range of 70 to 450 ms.

The Brain at High Altitude: Hypometabolism as a Defense against Chronic Hypoxia?:

The brain of hypoxia-tolerant vertebrates is known to survive extreme limitations of oxygen in part because of very low rates of energy production and utilization. To assess if similar adaptations may be involved in humans during hypoxia adaptation over generational time, volunteer Quechua natives, indigenous to the high Andes between about 3,700 and 4,900 m altitude, served as subjects in positron emission tomographic measurements of brain regional glucose metabolic rates. Two metabolic states were analyzed: (a) the presumed normal (high altitude-adapted) state monitored as soon as possible after leaving the Andes and (b) the deacclimated state monitored after 3 weeks at low altitudes. Proton nuclear magnetic resonance spectroscopy studies of the Quechua brain found normal spectra, with no indication of any unusual lactate accumulation; in contrast, in hypoxia-tolerant species, a relatively large fraction of the glucose taken up by the brain is released as lactate. Positron emission tomographic measurements of [18F]2-deoxy-2-fluoro-d-glucose (FDG) uptake rates, quantified in 26 regions of the brain, indicated systematically lower region-by-region glucose metabolic rates in Quechuas than in lowlanders. The metabolic reductions were least pronounced in primitive brain structures (e.g., cerebellum) and most pronounced in regions classically associated with higher cortical functions (e.g., frontal cortex). These differences between Quechuas with lifetime exposure to hypobaric hypoxia and lowlanders, which seem to be expressed to some degree in most brain regions examined, may be the result of a defense adaptation against chronic hypoxia.

Estimation of brainstem neuronal loss in amyotrophic lateral sclerosis with in vivo proton magnetic resonance spectroscopy

In vivo proton magnetic resonance spectroscopy (MRS) may be used to quantify brainstem neuronal degeneration in ALS because of the neuronal localization of N-acetylaspartate and N-acetylaspartylglutamate, together termed NA, which are estimated with this technique. We measured the ratio of NA to creatine/phosphocreatine(NA/Cr) with proton MRS at 3.0 tesla (T) in a 4.3-cm3 volume in the pons and upper medulla of 12 ALS patients and 17 age-matched control subjects. Brainstem NA/Cr was reduced in ALS versus control subjects (mean± SD: 1.57 ± 0.20 versus 1.95 ± 0.14; p< 0.0001). Patients with severe spasticity or prominent bulbar weakness had the lowest NA/Cr ratios; those with predominantly lower motor neuron limb weakness had near-normal ratios. We conclude that proton MRS may quantify region-specific neuronal dysfunction in ALS.

Sources of variability in the response of coupled spins to the PRESS sequence and their potential impact on metabolite quantification

Using a numerical method of solving the equation of motion of the density matrix, an evaluation is presented of the sources of the marked variability in the response to the point resolved spectroscopy (PRESS) pulse sequence of coupled proton spin systems. The consequences of an inappropriate 180° pulse design and of the limitations on radiofrequency power are demonstrated for a weakly coupled example, lactate. The dominating role of strong coupling, which is present in most brain metabolites, is demonstrated for glutamate, in which 160 terms in the density operator were tracked to monitor the gross changes in lineshape and signal intensity as a function of the two echo times. The predictions of the numerical solutions were confirmed by experiments on phantoms of aqueous metabolite solutions. Magn Reson Med 41:1162–1169, 1999.

Generalized mitochondrial dysfunction in Parkinson's disease detected by magnetic resonance spectroscopy of muscle

Objective To explore mitochondrial dysfunction in Parkinsons disease (PD) using 31P magnetic resonance spectroscopy of resting muscle. Design Case-ccntrol study (28 PD patients and 28 normal controls) determining resting forearm inorganic phosphate/phosphocreatine (Pi/PCr) ratio. Results Significant difference (p = 0.004, one-tailed test) in Pi/PCr ratio between PD patients (0.122) and controls (0.104). No correlation of Pi/PCr ratio with duration, severity, or speed of onset of disease. Positive correlation of Pi/PCr ratio with age in control group; reversed in PD group. Conclusions Suggests small generalized mitochondrial defect in PD. The possibility that earlier onset of disease is associated with more severe mitochondrial dysfunction needs further study.

T2 measurement and quantification of glutamate in human brain in vivo

The proton NMR transverse relaxation time T2 of glutamate (Glu) in human brain was measured by means of spectrally selective refocusing at 3.0 T in vivo. An 81.4‐ms‐long dual‐band Gaussian 180° RF pulse, designed for refocusing at 2.35 and 3.03 ppm, was employed within point‐resolved spectroscopy (PRESS) to generate the Glu C4‐proton target multiplet and the total creatine (tCr) singlet. Six optimal echo times (TEs) between 128 and 380 ms were selected from numerical analysis of the filtering performance for effective detection of the Glu signal with minimal contamination from glutamine (Gln), N‐acetylaspartate (NAA), and glutathione (GSH). The magnetization of Glu and tCr was extracted from spectral fitting of experimental and calculated spectra. Apparent T2 values of Glu and tCr were estimated as 201 ± 18 and 164 ± 12 ms for the medial prefrontal (PF) cortex, and 198 ± 22 and 169 ± 15 ms (mean ± SD, N = 5) for the left frontal (LF) cortex, respectively. With water segmentation data, the magnetization values of Glu and tCr of the two adjacent voxels, calculated from the T2 values and spectra following the thermal equilibrium magnetization, were combined to give the Glu and tCr concentrations as 10.37 ± 1.06 and 8.87 ± 0.56 mM for gray matter (GM), and 5.06 ± 0.57 and 5.16 ± 0.45 mM (mean ± SD, N = 5) for white matter (WM), respectively. Magn Reson Med, 2006.

Multi-component T1 relaxation and magnetisation transfer in peripheral nerve

We report here a study of longitudinal relaxation (T1) and magnetisation transfer (MT) in peripheral nerve. Amphibian sciatic nerve was maintained in vitro and studied at a magnetic field strength of 3 T. A CPMG pulse sequence was modified to include either a saturation pulse to measure T1 relaxation or an off-resonance RF irradiation pulse to measure MT. The resulting transverse relaxation (T2) spectra yielded four components corresponding to three nerve compartments, taken to result from myelinic, axonal, and inter-axonal water, and a fourth corresponding to the buffer solution water in which the nerve sample was bathed. Each nerve component was analysed for T1 relaxation and MT. All three nerve T2 components exhibited unique T1 relaxation and MT characteristics, providing further support for the assignment of the components to unique physical compartments of water. Numerical investigation of T1sat measurements of each of the three nerve T2 components indicates that while the two shorter-lived exhibit similar steady-state magnetisation transfer ratios (MTRs), their respective MT properties are quite different. Simulations demonstrate that mobile water exchange between these two components is not necessary to explain their similar steady-state MTR. In the context of the assignment of these two components to signal from myelinic and axonal water, this is to say that these two microanatomical regions of nerve may exhibit similar steady-state MTR characteristics despite possessing widely different MT exchange rates. Therefore, interpreting changes in MTR solely to reflect a change in degree of myelination could lead to erroneous conclusions.

Response of metabolites with coupled spins to the STEAM sequence

This article demonstrates that a numerical solution of the full quantum mechanical equations for all metabolites with coupled spins is an efficient and accurate means, first, of predicting the optimum STEAM sequence design for quantifying any target metabolite in brain, and, second, for providing the basis lineshapes and yields of these metabolites to facilitate their accurate quantification. Using as illustrations the weakly coupled AX3 system of lactate, the ABX aspartyl group of N‐acetylaspartate, which has only two strongly coupled spins, and the much larger strongly coupled AMNPQ glutamyl group of glutamate, the numerical solutions for the response to STEAM highlight the principal source of response variability, namely, the evolution of and transfer between zero quantum terms during the mixing time, TM. These highlights include the rapid oscillations of zero quantum terms due to the chemical shift difference of the coupled spins, the proliferation of oscillating zero order terms due to strong coupling, and the serendipitous smoothing of the response as the number of strongly coupled spins increases. The numerical solutions also demonstrate that the design of the selective 90° pulses is a far less critical factor in determining the response than was the case for the selective 180° pulses of the PRESS sequence (Thompson and Allen, Magn Reson Med 1999;41:1162–1169). The veracity of the method is demonstrated both in phantom solutions and in the parietal lobe of a normal human brain. Magn Reson Med 45:955–965, 2001.

Proton magnetic resonance spectroscopy measurement of brain glutamate levels in premenstrual dysphoric disorder.

BACKGROUND Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). METHODS Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. RESULTS A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. CONCLUSIONS The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.