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Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that may modulate cortical excitability, metabolite concentration, and human behaviour. The supplementary motor area (SMA) has been largely ignored as a potential target for tDCS neurorehabilitation but is an important region in motor compensation after brain injury with strong efferent connections to the primary motor cortex (M1). The objective of this work was to measure tissue metabolite changes in the human motor cortex immediately following tDCS. We hypothesized that bihemispheric tDCS would change levels of metabolites involved in neuromodulation including N-acetylaspartate (NAA), glutamate (Glu), and creatine (tCr). In this single-blind, randomized, cross-over study, fifteen healthy adults aged 21–60 participated in two 7T MRI sessions, to identify changes in metabolite concentrations by magnetic resonance spectroscopy. Immediately after 20 minutes of tDCS, there were no significant changes in metabolite levels or metabolite ratios comparing tDCS to sham. However there was a trend toward increased NAA/tCr concentration (p = 0.08) in M1 under the stimulating cathode. There was a strong, positive correlation between the change in the absolute concentration of NAA and the change in the absolute concentration of tCr (p<0.001) suggesting an effect of tDCS. Both NAA and creatine are important markers of neurometabolism. Our findings provide novel insight into the modulation of neural metabolites in the motor cortex immediately following application of bihemispheric tDCS.

In the dysconnection hypothesis, psychosis is caused by NMDA hypofunction resulting in aberrant network connectivity. Combining a cognitive-control task, functional magnetic resonance spectroscopy, and functional magnetic resonance imaging, we tested this hypothesis in the salience network of 20 first-episode psychosis (FEP) and 20 healthy control (HC) subjects.Across groups, glutamate concentration in the dorsal anterior cingulate cortex (dACC) was associated with higher and lower inhibitory connectivity in the dACC and in the anterior insula (AI) respectively. Crucially, glutamate concentration correlated negatively with the inhibitory influence on the excitatory neuronal population in the dACC of FEP subjects. Furthermore, aberrant computational parameters of the cognitive-control task performance were associated with aberrant inhibitory connections. Finally, the strength of connections from the dACC to the AI correlated negatively with severity of social withdrawal. These findings support a link between glutamate-mediated cortical disinhibition, deficits in effective connectivity, and computational performance in psychosis.

A short echo time (T ) is commonly used for brain glutamate measurement by H MRS to minimize drawbacks of long T such as signal modulation due to J evolution and T relaxation. However, J coupling causes the spectral patterns of glutamate to change with T , and the shortest achievable T may not produce the optimal glutamate measurement. The purpose of this study was to determine the optimal T for glutamate measurement at 7 T using semi-LASER (localization by adiabatic selective refocusing). Time-domain simulations were performed to model the T dependence of glutamate signal energy, a measure of glutamate signal strength, and were verified against measurements made in the human sensorimotor cortex (five subjects, 2 × 2 × 2 cm voxel, 16 averages) on a 7 T MRI scanner. Simulations showed a local maximum of glutamate signal energy at T = 107 ms. In vivo, T = 105 ms produced a low Cramér-Rao lower bound of 6.5 ± 2.0% across subjects, indicating high-quality fits of the prior knowledge model to in vivo data. T = 105 ms also produced the greatest glutamate signal energy with the smallest inter-subject glutamate-to-creatine ratio (Glu/Cr) coefficient of variation (CV), 4.6%. Using these CVs, we performed sample size calculations to estimate the number of participants per group required to detect a 10% change in Glu/Cr between two groups with 95% confidence. 13 were required at T = 45 ms, the shortest achievable echo time on our 7 T MRI scanner, while only 5 were required at T = 105 ms, indicating greater statistical power. These results indicate that T = 105 ms is optimum for in vivo glutamate measurement at 7 T with semi-LASER. Using long T decreases power deposition by allowing lower maximum RF pulse amplitudes in conjunction with longer RF pulses. Importantly, long T minimizes macromolecule contributions, eliminating the requirement for acquisition of separate macromolecule spectra or macromolecule fitting techniques, which add additional scan time or bias the estimated glutamate fit.

Background: Vitamin D deficiency and altered body composition are common in Alzheimer’s disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-β exposure and glutamate toxicity. Objective: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. Methods: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The vitamin D-deficient group (n = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n = 14), while the other had both memantine and 10 IU/g vitamin D (n = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. Results: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p <  0.01) and absolute skeletal tissue mass (9.3% increase, p <  0.05) and volume (9.2% increase, p <  0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. Conclusion: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD.

23Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that 24 may modulate cortical excitability, metabolite concentration, and human behaviour. The 25 supplementary motor area (SMA) has been largely ignored as a potential target for tDCS 26 neurorehabilitation but is an important region in motor compensation after brain injury with 27 strong efferent connections to the primary motor cortex (M1). The objective of this work was to 28 measure tissue metabolite changes in the human motor cortex immediately following tDCS. We 29 hypothesized that bihemispheric tDCS would change levels of metabolites involved in 30 neuromodulation including N-acetylaspartate, glutamate, and creatine. In this single-blind, 31 randomized, cross-over study, fifteen healthy adults aged 21-60 participated in two 7T MRI 32 sessions, to identify changes in metabolite concentrations by magnetic resonance spectroscopy. 33Immediately after 20 minutes of tDCS, there were no significant changes in metabolite levels or 34 metabolite ratios comparing tDCS to sham. However there was a trend toward increased 35 NAA/tCr concentration (p=0.08) in M1 under the stimulating cathode. There was a strong, 36 positive correlation between the change in the absolute concentration of NAA and the change in 37 the absolute concentration of tCr (p<0.001) suggesting an effect of tDCS. Both NAA and 38 creatine are important markers of neurometabolism. Our findings provide novel insight into the 39 modulation of neural metabolites in the motor cortex immediately following application of 40 bihemispheric tDCS. 2 42 3 65 concentration of phosphocreatine in the left temporo-frontal region following anodal tDCS to the 66 left dorsolateral prefrontal cortex (17). In another study, 2mA of anodal tDCS to the right 67 parietal cortex caused an increase in both Glx and total N-aceytl-aspartate (NAA + NAAG) 68 relative to sham, measured from the parietal cortex (10), while a study by Stagg and colleagues 69 found that 1 mA of cathodal stimulation to left M1 decreased Glx under the electrode(7). Other 70 studies have found no effect. For example, Kim et. al. found no changes after 1.5 mA of 71 cathodal tDCS to left M1 in any metabolite measured under the stimulating electrode (18). 72 Similarly, using 1mA of current in an M1-M1 bihemispheric montage, Tremblay et. al. found no 73 significant changes in any metabolite in left M1 (19). These conflicting results are difficult to 74 interpret, and leads to uncertainty with regards to the implementation of an optimum stimulation 75 paradigm. 76 The application of tDCS to improve motor performance and recovery in neurological 77 disorders requires optimization of stimulation parameters. Bihemispheric tDCS can enhance both 78 behaviour and physiological responses in healthy and neurologically injured individuals (20-22). 79The supplementary motor area (SMA) has proven to be an important area of the brain during the 80 execution of bimanual hand movements (23), and plays a compensatory role durin...