7T 1H MRS Research Articles

Acute gabapentin administration in healthy adults. A double-blind placebo-controlled study using transcranial magnetic stimulation and 7T 1H-MRS

Gamma-aminobutyric acid (GABA) and glutamate are the primary neurotransmitters responsible for modulating excitatory and inhibitory signalling within the human brain. Dysfunctional GABAergic and glutamatergic signalling has been identified as a key factor in a range of neuropsychiatric conditions; hence measurement and modulation of these neurometabolites is important for improving our understanding of neuropsychiatric conditions and treatment options. Gabapentin (GBP) is one of several drugs developed to increase GABA levels and is routinely prescribed for conditions such as epilepsy and neuralgia. While animal and human studies indicate that GBP can elevate GABA levels, its exact mechanisms of action are not fully understood, although animal studies indicate that GBP does not have a direct effect upon GABAergic receptors.To investigate the impact of acute GBP administration in the human motor system we used two complimentary approaches – transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). MRS and TMS measures of GABA have repeatedly been found to be uncorrelated and are likely to reflect different pools of synaptic and extra synaptic GABA, hence, measuring both within the same participants allows for an in-depth assessment of GBP effects.Despite significantly increased ratings of fatigue and tiredness within the GBP group, we failed to find any statistically significant changes in our MRS or TMS measures of GABA. Measures of MRS Glutamate (glu) and glutamine (gln) were also not affected by the administration of GBP. These findings are important as they run counter to previous work, and suggest that the effect of an acute dose of GBP is likely to be subject to substantial individual variation, with timing of measures particularly likely to impact observed effects. These findings have implications for the use of acute GBP dosing as a means to explore GABAergic function in health and disease.

Early Life Stress Increases Brain Glutamate and Induces Neurobehavioral Manifestations in Rats.

Early life stress (ELS) is associated with an increased risk of developing depression and anxiety disorders. Disturbances of the neurobiological glutamatergic system are implicated in depression; however, the long-term effects of ELS on glutamate (Glu) metabolites remain unclear. Our study used 7T proton magnetic resonance spectroscopy (7T 1H MRS) to detect metabolic Glu in a rat model to investigate maternal deprivation (MD)-induced ELS. MD was established in Sprague-Dawley rats by periodic separation from mothers and peers. Changes in the hippocampal volume and Glu metabolism were detected by 7T 1H MRS after testing for depression-like behavior via open field, sucrose preference, and Morris water maze tests. Adult MD offspring exhibited depression-like behavior. Compared to the control, the MD group exhibited reduced ratio of central activity time to total time and decreased sucrose consumption (p < 0.05). MD rats spent less time in the fourth quadrant, where the platform was originally placed, in the Morris water maze test. According to 7T 1H MRS, hippocampus of MD rats had elevated Glu and glutamate + glutamine (Glu+Gln) levels compared with the control group hippocampi, but Gln, γ-aminobutyric acid (GABA), and glutamate + glutamine (Glu+Gln) in the prefrontal cortex of MD rats showed a downward trend. Depression-like behavior and cognition deficits related to ELS may induce region-specific changes in Glu metabolism in the prefrontal cortex and hippocampus. The novel, noninvasive 7T 1H MRS-identified associations between Glu levels and ELS may guide future clinical studies.

P.192 The association between stress-induced changes in prefrontal GABA levels and heart rate variability: a 7T 1H-MRS study

P.192 The association between stress-induced changes in prefrontal GABA levels and heart rate variability: a 7T 1H-MRS study

Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7T

BackgroundMagnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and neurometabolites in patients with major depression across the lifespan. The application of 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD). MethodsNine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T 1H-MRS at baseline and after 10-12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling. ResultsBaseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels after Citalopram treatment were observed in a subset of LLD patients. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms. LimitationsSample size. ConclusionsThese preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response.

Alcohol consumption is associated with reduced creatine levels in the hippocampus of older adults

Besides its well established susceptibility to ageing, the hippocampus has also been shown to be affected by alcohol consumption. Proton spectroscopy (1H-MRS) of the hippocampus, particularly at high-field 7T MRI, may further our understanding of these associations. Here, we aimed to examine how hippocampal metabolites varied with age and alcohol consumption. Hippocampal metabolite spectra were acquired in 37 older adults using 7T 1H-MRS, from which we determined the absolute concentration of N-acetylaspartate (NAA), creatine, choline, myo-inositol, glutamate and glutamine. Thirty participants (mean age = 70.4 ± 4.7 years) also had self-reported data on weekly alcohol consumption. Total choline inversely correlated with age, although this did not survive multiple comparisons correction. Crucially, adults with a higher weekly alcohol consumption had significantly lower levels of creatine, suggesting a deficit in their hippocampal metabolism. These findings add to an increasing body of evidence linking alcohol to hippocampal function.

Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis.

The main objective of this study was to utilize high field (7T) in vivo proton magnetic resonance imaging to increase the ability to detect metabolite changes in people with ALS, specifically, to quantify levels of glutamine and glutamine separately. The second objective of this study was to correlate metabolic markers with clinical outcomes of disease progression. 13 ALS participants and 12 age-matched healthy controls (HC) underwent 7 Tesla MRI and MRS. Single voxel MR spectra were acquired from the left precentral gyrus using a very short echo time (TE = 5 ms) STEAM sequence. MRS data was quantified using LCModel and correlated to clinical outcome markers. N-acetylaspartate (NAA) and total NAA (tNA, NAA + NAAG) were decreased by 17% in people with ALS compared to HC (P = 0.004 and P = 0.005, respectively) indicating neuronal injury and/or loss in the precentral gyrus. tNA correlated with disease progression as measured by forced vital capacity (FVC) (P = 0.014; Rρ = 0.66) and tNA/tCr correlated with overall functional decline as measured by worsening of the ALS Functional Rating Scale-Revised (ALSFRS-R) (P = 0.004; Rρ = -0.74). These findings underscore the importance of NAA as a reliable biomarker for neuronal injury and disease progression in ALS. Glutamate (Glu) was 15% decreased in people with ALS compared to HC (P = 0.02) while glutamine (Gln) concentrations were similar between the two groups. Furthermore, the decrease in Glu correlated with the decrease in FVC (P = 0.013; Rρ = 0.66), a clinical marker of disease progression. The decrease in Glu is most likely driven by intracellular Glu loss due to neuronal loss and degeneration. Neither choline containing components (Cho), a marker for cell membrane turnover, nor myo-Inositol (mI), a suspected marker for neuroinflammation, showed significant differences between the two groups. However, mI/tNA was correlated with upper motor neuron burden (P = 0.004, Rρ = 0.74), which may reflect a relative increase of activated microglia around motor neurons. In summary, 7T 1H MRS is a powerful non-invasive imaging technique to study molecular changes related to neuronal injury and/or loss in people with ALS.

The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study

Gamma-aminobutyric acid (GABA) and glutamate are implicated in numerous neuropsychiatric and substance abuse conditions, but their spectral overlap with other resonances makes them a challenge to quantify in humans. Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known. We conducted a gabapentin (900 mg) challenge in healthy human subjects to confirm and explore its effects on GABA and glutamate concentrations, respectively, and to test the ability of single voxel localized proton magnetic resonance spectroscopy (¹H-MRS) to reliably measure GABA and glutamate in the visual cortex at the ultra-high magnetic field of 7 Tesla. Reproducibility of GABA and glutamate measurements was determined in a comparison group without drug twice within day and 2 weeks apart. Although GABA concentration changes were small both within day (average 5.6%) and between day (average 4.8%), gabapentin administration was associated with an average increase in GABA concentration of 55.7% (6.9-91.0%). Importantly, drug-induced change in GABA levels was inversely correlated to the individual's baseline GABA level (R²=0.72). Mean glutamate concentrations did not change significantly with or without drug administration. In conclusion, localized ¹H-MRS at 7 Tesla can be successfully applied to the measurement of GABA concentration and is sensitive to acute drug-induced changes in cortical GABA. Whether baseline GABA concentrations predict clinical efficacy of gabapentin is an area worthy of exploration.