M Wylezinska

Polarity-Sensitive Modulation of Cortical Neurotransmitters by Transcranial Stimulation

Transcranial direct current stimulation (tDCS) modulates cortical excitability and is being used for human studies more frequently. Here we probe the underlying neuronal mechanisms by measuring polarity-specific changes in neurotransmitter concentrations using magnetic resonance spectroscopy (MRS). MRS provides evidence that excitatory (anodal) tDCS causes locally reduced GABA while inhibitory (cathodal) stimulation causes reduced glutamatergic neuronal activity with a highly correlated reduction in GABA, presumably due to the close biochemical relationship between the two neurotransmitters.

Reduction in Occipital Cortex γ-Aminobutyric Acid Concentrations in Medication-Free Recovered Unipolar Depressed and Bipolar Subjects

BACKGROUND Studies using proton magnetic resonance spectroscopy (MRS) have indicated that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in occipital cortex. Cortical levels of glutamate (Glu) may be increased, although these data are less consistent. The aim of this study was to use MRS to determine whether changes in GABA and Glu levels were present in patients with mood disorders who had recovered and were no longer taking medication. METHODS An [1H]-MRS was used to measure levels of GABA, of the combined concentration of Glu and glutamine (Gln), and of N-acetylaspartate (NAA) in occipital cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression (n = 15), bipolar disorder (n = 16), and a group of healthy controls (n = 18). RESULTS Occipital levels of GABA and NAA were significantly lower in recovered depressed and bipolar subjects than in healthy controls, whereas Glu +Gln concentrations were higher. CONCLUSIONS Our data suggest that recovered unmedicated subjects with a history of mood disorder have changes in cortical concentrations of GABA, NAA, and Glu +Gln. These biochemical abnormalities may be markers of a trait vulnerability to mood disorder, rather than neurochemical correlates of an abnormal mood state.

Thalamic neurodegeneration in relapsing-remitting multiple sclerosis

Objective: To define the extent of neuronal injury and loss in thalamic gray matter in patients with relapsing-remitting (RR) MS and to characterize how these neuronal pathologic changes are related to disease duration. Methods: The authors studied 14 patients with RRMS (Expanded Disability Status Scale score, mean 3.25, range 2.0 to 6.0) and 14 (8 men, 6 women) age-matched healthy controls. Structural MR and MRS studies were performed in a single scanning session using a 3T MR system. Results: N-acetylaspartate (NAA) concentrations (a measure of the apparent neuronal density) were decreased approximately 11% in the thalami of the patients with RRMS relative to controls (p < 0.05). The patients with RRMS also had an almost 25% lower mean normalized thalamic volume than controls (p < 0.005). Decreases in thalamic NAA concentration correlated strongly with thalamic volume loss for individual patients (r = 0.85, p < 0.01). Both the NAA concentration (r = −0.48, p = 0.044) and normalized thalamic volume (r = −0.60, p = 0.01) were correlated inversely with disease duration. There was a trend for a correlation between the thalamic NAA/creatine (Cr) ratio and the NAA/Cr in the frontal normal-appearing white matter (r = 0.56, p < 0.08). Conclusions: The reduction of both NAA concentration and thalamic volume suggests that a neurodegenerative component may contribute to the pathology of MS even in the earlier RR stage. The trend toward a relationship between thalamic NAA/Cr and distant normal-appearing white matter changes implies that there may be a common mechanism for the white matter axonal loss and thalamic neuronal injury.

Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients

Studies using proton magnetic resonance spectroscopy (1H-MRS) indicate that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in the occipital cortex. The aim of this study was to use 1H-MRS to determine if changes in occipital and frontal cortical GABA levels were present in patients with a history of depression who had recovered and were no longer taking medication. We used 1H-MRS to measure levels of GABA in both occipital cortex and anterior cingulate cortex/prefrontal cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression. Levels of GABA in both occipital and anterior cingulate cortex were significantly lower in recovered depressed subjects than healthy controls. Our data provide preliminary evidence that a history of recurrent depression is associated with decreased GABA levels in anterior cingulate cortex and occipital cortex. These changes could represent part of the neurobiological vulnerability to recurrent depressive episodes.

Discordant white matter N-acetylasparate and diffusion MRI measures suggest that chronic metabolic dysfunction contributes to axonal pathology in multiple sclerosis.

Diffusion MRI and magnetic resonance spectroscopic measurements of selectively neuronally localised N-acetylaspartate (NAA) both have been used widely to assess white matter integrity and axonal loss. We have tested directly the relationship between changes in diffusion MRI parameters and NAA concentrations in the corpus callosum (CC) in an in vivo study of patients with MS. Fifteen MS patients (median EDSS 2.5, range 1-4) were studied with T(1) anatomical, T(2)-weighted, and diffusion-sensitised MRI and PRESS single-voxel MRS. A recently described method, tract-based spatial statistics (TBSS) [Smith, S.M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T.E., Mackay, C.E. et al., 2006. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage 31, 1487-1505] also was used to perform exploratory voxelwise whole-brain analysis of white matter diffusion fractional anisotropy (FA). We found a strong correlation between callosal size and both mean FA (r=0.68, p<0.005) (related specifically to changes in the radial tensor component) and mean inter-hemispheric motor tract connectivity probability (r=0.74, p<0.001). TBSS confirmed that the diffusion anisotropies of white matter voxels specifically within the callosum were correlated with the callosal size. Individual patient global T(2) lesion volumes were correlated with both the probability of callosal connectivity (r=-0.69, p<0.005) and fractional anisotropy across the callosum (r=-0.76, p<0.001). However, absolute concentrations of NAA from the voxel showed no correlation with callosal cross-sectional area, mean connectivity or fractional anisotropy within the callosal pathway. We conclude that diffusion MRI shows changes consistent with sensitivity to axonal loss, but that relative NAA changes are not necessarily related directly to this. Axonal metabolic function, independent of structural integrity, may be a major determinant of NAA measures in MS.

Tryptophan depletion does not lower brain GABA levels in healthy volunteers.

The ascending serotonin (5-HT) innervation of the cortex preferentially targets gamma-aminobutyric acid (GABA) inter-neurons and 5-HT-GABA interactions may be important in the pathophysiology of depression and the actions of antidepressant drugs (see Taylor et al. 2003). Consistent with the latter suggestion, treatment of depressed patients with selective serotonin re-uptake inhibitors (SSRIs) increases cortical GABA levels as measured by proton magnetic resonance spectroscopy (MRS) (Sanacora et al. 2002) and a similar trend was recently reported after venlafaxine treatment of subjects with cocaine dependence (Streeter et al. 2005). In healthy subjects, a single intravenous administration of the SSRI, citalopram (Bhagwager et al. 2004) increased GABA levels in occipital cortex. This latter finding suggests that an acute increase in 5-HT neurotransmission can increase cortical GABA activity in humans as it does in animals (Taylor et al. 2003). The aim of the present study was to explore 5-HT-GABA interactions in humans further by determining the effect of acutely lowering brain 5-HT neurotransmission on cortical GABA levels as measured by MRS. To lower brain 5-HT function, we used the paradigm of tryptophan depletion that diminishes 5-HT neurotransmission by restricting the availability of the 5-HT precursor, tryptophan, to the brain (see Booij et al. 2003). Twelve healthy subjects (seven male, five female) mean age 34 years (range 21–62 years) underwent testing in a double-blind, random order, cross-over design receiving either a balanced mixture of amino acids (102 g) or the same mixture from which tryptophan (2.3 g) was omitted. The composition and preparation of the amino acid mixture is described in detail in Smith et al. (1997). The mixture was administered after an overnight fast and 5 h later, subjects underwent MRS scanning. Subjects gave informed written consent to the investigation that was approved by the local ethics committee. MRS was performed on a Varian INOVA 3T scanner. Measurements were taken from a 3×3×2 cm voxel located in the occipitalparietal lobe, selected using T1 weighted axial scout images, using point resolved spectroscopy (PRESS). The MEGA-PRESS sequence (TR=3 s, TE=68 ms, 128 averages, sweep width=2 kHz, 1,024 complex points, acquisition time=6.4 min) was used for simultaneous localisation, water suppression and J-difference editing of the 3.0 ppm GABA resonance which also contains coedited contributions from homocarnosine and macromolecules (MM). Resultant spectra were analysed with LCModel using a basis set of model spectra derived from phantom measurements made at room temperature and pH 7.04–7.20 (Provencher 1993; Shen et al. 2002). To account for the contribution of MM to the spectra, a preinversion (TI=800 ms) was added to the MEGA-PRESS sequence to null the metabolite signal. Simulated MM basis functions, derived from the edited metabolite-nulled spectra, were included in the basis set (Mescher et al. 1998). Creatine (Cr) was measured using standard PRESS (TR=3 s, TE=68 ms, 32 averages) and used as an internal reference. As noted previously (Booij et al. 2003), the tryptophanfree mixture was associated with a substantial lowering of mean±SEM plasma tryptophan values relative to the balanced mixture (balanced mixture; baseline, 10.1± 0.96 μg/ml vs +5 h, 16.9±0.42 μg/ml: tryptophan-free mixture; baseline, 10.2±0.42 μg/ml vs +5 h, 2.6±0.49 μg/ S. Selvaraj . M. Wylezinska . J. Evans . P. Jezzard . P. M. Matthews . P. J. Cowen University Department of Psychiatry, Warneford Hospital, Oxford and Centre for Functional Magnetic Imaging of the Brain, John Radcliffe Hospital, Oxford, UK