Ultra-high Field Magnetic Resonance Spectroscopy Research Articles

GABAergic inhibition in human hMT+ predicts visuo-spatial intelligence mediated through the frontal cortex.

The prevailing opinion emphasizes fronto-parietal network (FPN) is key in mediating general fluid intelligence (gF). Meanwhile, recent studies show that human MT complex (hMT+), located at the occipito-temporal border and involved in 3D perception processing, also plays a key role in gF. However, the underlying mechanism is not clear, yet. To investigate this issue, our study targets visuo-spatial intelligence, which is considered to have high loading on gF. We use ultra-high field magnetic resonance spectroscopy (MRS) to measure GABA/Glu concentrations in hMT+ combining resting-state fMRI functional connectivity (FC), behavioral examinations including hMT+ perception suppression test and gF subtest in visuo-spatial component. Our findings show that both GABA in hMT+ and frontal-hMT+ functional connectivity significantly correlate with the performance of visuo-spatial intelligence. Further, serial mediation model demonstrates that the effect of hMT+ GABA on visuo-spatial gF is fully mediated by the hMT+ frontal FC. Together our findings highlight the importance in integrating sensory and frontal cortices in mediating the visuo-spatial component of general fluid intelligence.

GABAergic inhibition in human hMT+ predicts visuo-spatial intelligence mediated through the frontal cortex

The prevailing opinion emphasizes fronto-parietal network (FPN) is key in mediating general fluid intelligence (gF). Meanwhile, recent studies show that human MT complex (hMT+), located at the occipito-temporal border and involved in 3D perception processing, also plays a key role in gF. However, the underlying mechanism is not clear, yet. To investigate this issue, our study targets visuo-spatial intelligence, which is considered to have high loading on gF. We use ultra-high field magnetic resonance spectroscopy (MRS) to measure GABA/Glu concentrations in hMT+ combining resting-state fMRI functional connectivity (FC), behavioral examinations including hMT+ perception suppression test and gF subtest in visuo-spatial component. Our findings show that both GABA in hMT+ and frontal-hMT+ functional connectivity significantly correlate with the performance of visuo-spatial intelligence. Further, serial mediation model demonstrates that the effect of hMT+ GABA on visuo-spatial gF is fully mediated by the hMT+ frontal FC. Together our findings highlight the importance in integrating sensory and frontal cortices in mediating the visuo-spatial component of general fluid intelligence.

Magnetic Resonance Spectroscopy (MRS) in Alzheimer's Disease.

MRS is a noninvasive technique to measure different metabolites in the brain. Changes in the levels of certain metabolites can be used as surrogate markers for Alzheimer's disease. They can potentially be used for diagnosis, prediction of prognosis, or even assessing response to treatment.There are different techniques for MRS acquisitions including STimulated Echo Acquisition Mode (STEAM) and Point Resolved Spectroscopy (PRESS). In terms of localization, single or multi-voxel methods can be used. Based on current data: 1. NAA, marker of neuronal integrity and viability, reduces in AD with longitudinal changes over the time as the disease progresses. There are data claiming that reduction of NAA is associated with tau accumulation, early neurodegenerative processes, and cognitive decline. Therefore, it can be used as a stage biomarker for AD to assess the severity of the disease. With advancement of disease modifying therapies, there is a potential role for NAA in the future to be used as a marker of response to treatment. 2. mI, marker of glial cell proliferation and activation, is associated with AB pathology and has early changes in the course of the disease. The NAA/mI ratio can be predictive of AD development with high specificity and can be utilized in the clinical setting to stratify cases for further evaluation with PET for potential treatments. 3. The changes in the level of other metabolites such as Chol, Glu, Gln, and GABA are controversial because of the lack of standardization of MRS techniques, current technical limitations, and possible region specific changes. 4. Ultrahigh field MRS and more advanced techniques can overcome many of these limitations and enable us to measure more metabolites with higher accuracy. 5. Standardization of MRS techniques, validation of metabolites' changes against PET using PET-guided technique, and longitudinal follow-ups to investigate the temporal changes of the metabolites in relation to other biomarkers and cognition will be crucial to confirm the utility of MRS as a potential noninvasive biomarker for AD.

Neurochemistry-enriched dynamic causal models of magnetoencephalography, using magnetic resonance spectroscopy

We present a hierarchical empirical Bayesian framework for testing hypotheses about neurotransmitters’ concertation as empirical prior for synaptic physiology using ultra-high field magnetic resonance spectroscopy (7T-MRS) and magnetoencephalography data (MEG). A first level dynamic causal modelling of cortical microcircuits is used to infer the connectivity parameters of a generative model of individuals’ neurophysiological observations. At the second level, individuals’ 7T-MRS estimates of regional neurotransmitter concentration supply empirical priors on synaptic connectivity. We compare the group-wise evidence for alternative empirical priors, defined by monotonic functions of spectroscopic estimates, on subsets of synaptic connections. For efficiency and reproducibility, we used Bayesian model reduction (BMR), parametric empirical Bayes and variational Bayesian inversion. In particular, we used Bayesian model reduction to compare alternative model evidence of how spectroscopic neurotransmitter measures inform estimates of synaptic connectivity. This identifies the subset of synaptic connections that are influenced by individual differences in neurotransmitter levels, as measured by 7T-MRS. We demonstrate the method using resting-state MEG (i.e., task-free recording) and 7T-MRS data from healthy adults. Our results confirm the hypotheses that GABA concentration influences local recurrent inhibitory intrinsic connectivity in deep and superficial cortical layers, while glutamate influences the excitatory connections between superficial and deep layers and connections from superficial to inhibitory interneurons. Using within-subject split-sampling of the MEG dataset (i.e., validation by means of a held-out dataset), we show that model comparison for hypothesis testing can be highly reliable. The method is suitable for applications with magnetoencephalography or electroencephalography, and is well-suited to reveal the mechanisms of neurological and psychiatric disorders, including responses to psychopharmacological interventions.

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

Neurochemical abnormalities in patients with type 1 Gaucher disease on standard of care therapy.

Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P < .015). Glutamate concentration was also lower in the putamen in GD1 (P = .01). Glucose + taurine concentration was significantly higher in PWM (P = .04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P < .001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. SYNOPSIS: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.

Learning to optimize perceptual decisions through suppressive interactions in the human brain

Translating noisy sensory signals to perceptual decisions is critical for successful interactions in complex environments. Learning is known to improve perceptual judgments by filtering external noise and task-irrelevant information. Yet, little is known about the brain mechanisms that mediate learning-dependent suppression. Here, we employ ultra-high field magnetic resonance spectroscopy of GABA to test whether suppressive processing in decision-related and visual areas facilitates perceptual judgments during training. We demonstrate that parietal GABA relates to suppression of task-irrelevant information, while learning-dependent changes in visual GABA relate to enhanced performance in target detection and feature discrimination tasks. Combining GABA measurements with functional brain connectivity demonstrates that training on a target detection task involves local connectivity and disinhibition of visual cortex, while training on a feature discrimination task involves inter-cortical interactions that relate to suppressive visual processing. Our findings provide evidence that learning optimizes perceptual decisions through suppressive interactions in decision-related networks.

182 - Noninvasively Measured Human Brain Glutathione and Ascorbate Concentrations in Healthy Aging and in Alzheimer's Disease

Numerous studies have found lower levels of antioxidants in the blood and cerebrospinal fluid of elderly adults. Oxidative stress is involved in Alzheimer’s disease (AD) pathogenesis and progression. Increased sensitivity of magnetic resonance technology has made it possible to noninvasively quantify concentrations of the antioxidants glutathione (GSH) and ascorbate (Asc) in intact human brain. Ultra-high field magnetic resonance spectroscopy (MRS) was used to measure concentrations of GSH and ascorbate in the occipital cortex (OCC) and posterior cingulate cortex (PCC) of seventeen young adults, sixteen cognitively normal older adults, and eight patients with AD. The short-echo-time MRS approach inherently retained numerous resonances, from which a profile of 15 neurochemicals was measured. For the first time, the concentration of GSH was found to be lower (p = 0.02) in the OCC of the elderly in a way that is not contingent upon the transverse relaxation rate. Healthy aging tended to impact neurochemicals associated with excitotoxicity (i.e. N-acetylaspartate) in the OCC, whereas those more closely linked to reactive astrogliosis (i.e.,myo-inositol, creatine and choline) were impacted in the PCC. The concentration of Asc was lower (p = 0.005) in the PCC of the patients with AD than in the healthy older adults. This is the first time human brain Asc has been studied noninvasively in patients with AD. In patients, one of the neurochemicals associated with reactive astrogliosis (myo-inositol) was higher in the OCC and two were higher in the PCC (i.e., myo-inositol and choline). Taken together, these outcomes show that both aging and AD impact brain regions differentially. These findings fill part of the gap in understanding how the brain deteriorates throughout aging and AD. Ultra-high field ultra-short-echo-time MRS supplies hitherto missing steps along the pathway to preventing and treating cognitive decline, i.e. means to identify which antioxidant is compromised, in which brain region, in whom, and whether intervention can achieve normalization.

An Ultra-High Field Magnetic Resonance Spectroscopy Study of Post Exercise Lactate, Glutamate and Glutamine Change in the Human Brain.

During strenuous exercise there is a progressive increase in lactate uptake and metabolism into the brain as workload and plasma lactate levels increase. Although it is now widely accepted that the brain can metabolize lactate, few studies have directly measured brain lactate following vigorous exercise. Here, we used ultra-high field magnetic resonance spectroscopy of the brain to obtain static measures of brain lactate, as well as brain glutamate and glutamine after vigorous exercise. The aims of our experiment were to (a) track the changes in brain lactate following recovery from exercise, and (b) to simultaneously measure the signals from brain glutamate and glutamine. The results of our experiment showed that vigorous exercise resulted in a significant increase in brain lactate. Furthermore, both glutamate and glutamine were successfully resolved, and as expected, although contrary to some previous reports, we did not observe any significant change in either amino acid after exercise. We did however observe a negative correlation between glutamate and a measure of fitness. These results support the hypothesis that peripherally derived lactate is taken up by the brain when available. Our data additionally highlight the potential of ultra-high field MRS as a non-invasive way of measuring multiple brain metabolite changes with exercise.

Non‐invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by (1) H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1(154Q/2Q) line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1(154Q/2Q) mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1(154Q/2Q) mice displayed very mild cerebellar pathology even at 39weeks, however, were distinguished from wild types by MRS starting at 6weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12weeks in Sca1(154Q/2Q) mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology. We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.

Initial experience with seven tesla magnetic resonance spectroscopy of hypothalamic GABA during hyperinsulinemic euglycemia and hypoglycemia in healthy humans

Hypothalamic GABA signaling has been shown to regulate the hormonal response to hypoglycemia in animals. The hypothalamus is a challenging brain region for magnetic resonance spectroscopy (MRS) due to its small size and central location. To investigate the feasibility of measuring GABA in the hypothalamus in humans, ultra-high field MRS was used. GABA levels in the hypothalamus and occipital cortex (control region) were measured in healthy volunteers during euglycemia and hypoglycemia at 7 tesla using short-echo STEAM (TE = 8 ms, TR = 5 s). Hypothalamic GABA levels were quantified with a mean within-session test-retest coefficient of variance of 9%. Relatively high GABA levels were observed in the hypothalamus compared with other brain regions. Hypothalamic GABA levels were 3.5 ± 0.3 µmol/g during euglycemia (glucose 89 ± 6 mg/dL) vs. 3.0 ± 0.4 µmol/g during hypoglycemia (glucose 61 ± 3 mg/dL) (P = 0.06, N = 7). In the occipital cortex, GABA levels remained constant at 1.4 ± 0.4 vs.1.4 ± 0.3 µmol/g (P = 0.3, N = 5) as glucose fell from 91 ± 4 to 61 ± 4 mg/dL. GABA concentration can be quantified in the human hypothalamus and shows a trend toward decrease in response to an acute fall in blood glucose. These methods can be used to further investigate role of GABA signaling in the counterregulatory response to hypoglycemia in humans.