Mary C. Stephenson

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.

Investigating the electrophysiological basis of resting state networks using magnetoencephalography

In recent years the study of resting state brain networks (RSNs) has become an important area of neuroimaging. The majority of studies have used functional magnetic resonance imaging (fMRI) to measure temporal correlation between blood-oxygenation-level–dependent (BOLD) signals from different brain areas. However, BOLD is an indirect measure related to hemodynamics, and the electrophysiological basis of connectivity between spatially separate network nodes cannot be comprehensively assessed using this technique. In this paper we describe a means to characterize resting state brain networks independently using magnetoencephalography (MEG), a neuroimaging modality that bypasses the hemodynamic response and measures the magnetic fields associated with electrophysiological brain activity. The MEG data are analyzed using a unique combination of beamformer spatial filtering and independent component analysis (ICA) and require no prior assumptions about the spatial locations or patterns of the networks. This method results in RSNs with significant similarity in their spatial structure compared with RSNs derived independently using fMRI. This outcome confirms the neural basis of hemodynamic networks and demonstrates the potential of MEG as a tool for understanding the mechanisms that underlie RSNs and the nature of connectivity that binds network nodes.

Visualization of nigrosome 1 and its loss in PD Pathoanatomical correlation and in vivo 7 T MRI

Objective: This study assessed whether high-resolution 7 T MRI allowed direct in vivo visualization of nigrosomes, substructures of the substantia nigra pars compacta (SNpc) undergoing the greatest and earliest dopaminergic cell loss in Parkinson disease (PD), and whether any disease-specific changes could be detected in patients with PD. Methods: Postmortem (PM) midbrains, 2 from healthy controls (HCs) and 1 from a patient with PD, were scanned with high-resolution T2*-weighted MRI scans, sectioned, and stained for iron and neuromelanin (Perl), TH, and calbindin. To confirm the identification of nigrosomes in vivo on 7 T T2*-weighted scans, we assessed colocalization with neuromelanin-sensitive T1-weighted scans. We then assessed the ability to depict PD pathology on in vivo T2*-weighted scans by comparing data from 10 patients with PD and 8 age- and sex-matched HCs. Results: A hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense SNpc was identified in the HC brains on in vivo and PM T2*-weighted MRI. Location, size, shape, and staining characteristics conform to nigrosome 1. Blinded assessment by 2 neuroradiologists showed consistent bilateral absence of this nigrosome feature in all 10 patients with PD, and bilateral presence in 7/8 HC. Conclusions: In vivo and PM MRI with histologic correlation demonstrates that high-resolution 7 T MRI can directly visualize nigrosome 1. The absence of nigrosome 1 in the SNpc on MRI scans might prove useful in developing a neuroimaging diagnostic test for PD.

Investigating the Metabolic Changes due to Visual Stimulation using Functional Proton Magnetic Resonance Spectroscopy at 7 T

Proton magnetic resonance spectroscopy (1H-MRS) has been used to demonstrate metabolic changes in the visual cortex on visual stimulation. Small (2% to 11%) but significant stimulation induced increases in lactate, glutamate, and glutathione were observed along with decreases in aspartate, glutamine, and glycine, using 1H-MRS at 7 T during single and repeated visual stimulation. In addition, decreases in glucose and increases in γ-aminobutyric acid (GABA) were seen but did not reach significance. Changes in glutamate and aspartate are indicative of increased activity of the malate–aspartate shuttle, which taken together with the opposite changes in glucose and lactate, reflect the expected increase in brain energy metabolism. These results are in agreement with those of Mangia et al. In addition, increases in glutamate and GABA coupled with the decrease in glutamine can be interpreted in terms of increased activity of the neurotransmitter cycles. An entirely new observation is the increase of glutathione during prolonged visual stimuli. The similarity of its time course to that of glutamate suggests that it may be a response to the increased release of glutamate or to the increased production of reactive oxygen species. Together, these observations constitute the most detailed analysis to date of functional changes in human brain metabolites.

tDCS-induced alterations in GABA concentration within primary motor cortex predict motor learning and motor memory: a 7 T magnetic resonance spectroscopy study.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that alters cortical excitability in a polarity specific manner and has been shown to influence learning and memory. tDCS may have both on-line and after-effects on learning and memory, and the latter are thought to be based upon tDCS-induced alterations in neurochemistry and synaptic function. We used ultra-high-field (7 T) magnetic resonance spectroscopy (MRS), together with a robotic force adaptation and de-adaptation task, to investigate whether tDCS-induced alterations in GABA and Glutamate within motor cortex predict motor learning and memory. Note that adaptation to a robot-induced force field has long been considered to be a form of model-based learning that is closely associated with the computation and ‘supervised’ learning of internal ‘forward’ models within the cerebellum. Importantly, previous studies have shown that on-line tDCS to the cerebellum, but not to motor cortex, enhances model-based motor learning. Here we demonstrate that anodal tDCS delivered to the hand area of the left primary motor cortex induces a significant reduction in GABA concentration. This effect was specific to GABA, localised to the left motor cortex, and was polarity specific insofar as it was not observed following either cathodal or sham stimulation. Importantly, we show that the magnitude of tDCS-induced alterations in GABA concentration within motor cortex predicts individual differences in both motor learning and motor memory on the robotic force adaptation and de-adaptation task.

Increased GABA Contributes to Enhanced Control over Motor Excitability in Tourette Syndrome

Summary Tourette syndrome (TS) is a developmental neurological disorder characterized by vocal and motor tics [1] and associated with cortical-striatal-thalamic-cortical circuit dysfunction [2, 3], hyperexcitability within cortical motor areas [4], and altered intracortical inhibition [4–7]. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence in many individuals [1], who exhibit enhanced control over their volitional movements [8–11]. Importantly, control over motor outputs appears to be brought about by a reduction in the gain of motor excitability [6, 7, 12, 13]. Here we present a neurochemical basis for a localized gain control mechanism. We used ultra-high-field (7 T) magnetic resonance spectroscopy to investigate in vivo concentrations of γ-aminobutyric acid (GABA) within primary and secondary motor areas of individuals with TS. We demonstrate that GABA concentrations within the supplementary motor area (SMA)—a region strongly associated with the genesis of motor tics in TS [14]—are paradoxically elevated in individuals with TS and inversely related to fMRI blood oxygen level-dependent activation. By contrast, GABA concentrations in control sites do not differ from those of a matched control group. Importantly, we also show that GABA concentrations within the SMA are inversely correlated with cortical excitability in primary motor cortex and are predicted by motor tic severity and white-matter microstructure (FA) within a region of the corpus callosum that projects to the SMA within each hemisphere. Based upon these findings, we propose that extrasynaptic GABA contributes to a form of control, based upon localized tonic inhibition within the SMA, that may lead to the suppression of tics.

Applications of multi-nuclear magnetic resonance spectroscopy at 7T

AIM To discuss the advantages of ultra-high field (7T) for (1)H and (13)C magnetic resonance spectroscopy (MRS) studies of metabolism. METHODS Measurements of brain metabolites were made at both 3 and 7T using (1)H MRS. Measurements of glycogen and lipids in muscle were measured using (13)C and (1)H MRS respectively. RESULTS In the brain, increased signal-to-noise ratio (SNR) and dispersion allows spectral separation of the amino-acids glutamate, glutamine and γ-aminobutyric acid (GABA), without the need for sophisticated editing sequences. Improved quantification of these metabolites is demonstrated at 7T relative to 3T. SNR was 36% higher, and measurement repeatability (% coefficients of variation) was 4%, 10% and 10% at 7T, vs 8%, 29% and 21% at 3T for glutamate, glutamine and GABA respectively. Measurements at 7T were used to compare metabolite levels in the anterior cingulate cortex (ACC) and insula. Creatine and glutamate levels were found to be significantly higher in the insula compared to the ACC (P < 0.05). In muscle, the increased SNR and spectral resolution at 7T enables interleaved studies of glycogen ((13)C) and intra-myocellular lipid (IMCL) and extra-myocellular lipid (EMCL) ((1)H) following exercise and re-feeding. Glycogen levels were significantly decreased following exercise (-28% at 50% VO(2) max; -58% at 75% VO(2) max). Interestingly, levels of glycogen in the hamstrings followed those in the quadriceps, despite reduce exercise loading. No changes in IMCL and EMCL were found in the study. CONCLUSION The demonstrated improvements in brain and muscle MRS measurements at 7T will increase the potential for use in investigating human metabolism and changes due to pathologies.

Fat Emulsion Intragastric Stability and Droplet Size Modulate Gastrointestinal Responses and Subsequent Food Intake in Young Adults

Background: Intragastric creaming and droplet size of fat emulsions may affect intragastric behavior and gastrointestinal and satiety responses. Objectives: We tested the hypotheses that gastrointestinal physiologic responses and satiety will be increased by an increase in intragastric stability and by a decrease in fat droplet size of a fat emulsion. Methods: This was a double-blind, randomized crossover study in 11 healthy persons [8 men and 3 women, aged 24 ± 1 y; body mass index (in kg/m2): 24.4 ± 0.9] who consumed meals containing 300-g 20% oil and water emulsion (2220 kJ) with 1) larger, 6-μm mean droplet size (Coarse treatment) expected to cream in the stomach; 2) larger, 6-μm mean droplet size with 0.5% locust bean gum (LBG; Coarse+LBG treatment) to prevent creaming; or 3) smaller, 0.4-μm mean droplet size with LBG (Fine+LBG treatment). The participants were imaged hourly by using MRI and food intake was assessed by using a meal that participants consumed ad libitum. Results: The Coarse+LBG treatment (preventing creaming in the stomach) slowed gastric emptying, resulting in 12% higher gastric volume over time (P < 0.001), increased small bowel water content (SBWC) by 11% (P < 0.01), slowed appearance of the 13C label in the breath by 17% (P < 0.01), and reduced food intake by 9% (P < 0.05) compared with the Coarse treatment. The Fine+LBG treatment (smaller droplet size) slowed gastric emptying, resulting in 18% higher gastric volume (P < 0.001), increased SBWC content by 15% (P < 0.01), and significantly reduced food intake by 11% (P < 0.05, equivalent to an average of 411 kJ less energy consumed) compared with the Coarse+LBG treatment. These high-fat meals stimulated substantial increases in SBWC, which increased to a peak at 4 h at 568 mL (range: 150–854 mL; P < 0.01) for the Fine+LBG treatment. Conclusion: Manipulating intragastric stability and fat emulsion droplet size can influence human gastrointestinal physiology and food intake.

Methodology for improved detection of low concentration metabolites in MRS: optimised combination of signals from multi-element coil arrays.

State of the art magnetic resonance imaging (MRI) scanners are generally equipped with multi-element receive coils; 16 or 32 channel coils are common. Their development has been predominant for parallel imaging to enable faster scanning. Less consideration has been given to localized magnetic resonance spectroscopy (MRS). Multinuclear studies, for example (31)P or (13)C MRS, are often conducted with a single element coil located over the region of interest. (1)H MRS studies have generally employed the same multi-element coils used for MRI, but little consideration has been given as to how the spectroscopic data from the different channels are combined. In many cases it is simply co-added with detrimental effect on the signal to noise ratio. In this study, we derive the optimum method for combining multi-coil data, namely weighting with the ratio of signal to the square of the noise. We show that provided that the noise is uncorrelated, this is the theoretical optimal combination. The method is demonstrated for in vivo proton MRS data acquired using a 32 channel receive coil at 7T in four different brain areas; left motor and right motor, occipital cortex and medial frontal cortex.

Increased liver fat and glycogen stores after consumption of high versus low glycaemic index food: A randomized crossover study

To investigate the acute and longer‐term effects of low (LGI) versus high glycaemic index (HGI) diets on hepatic fat and glycogen accumulation and related blood measures in healthy volunteers.