0404
Dynamic changes of glutamate detected by functional MR spectroscopy in human visual cortex in regions with positive and negative BOLD response1Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany, 2Berlin Center for Advanced Neuroimaging, Charité Universitätsmedizin, Berlin, Germany, 3Max Planck Institute for Biological Cybernetics, Tuebingen, Germany
Synopsis
Dynamic changes of metabolite concentrations have been presented in human visual cortex in response to stimulus that induce a positive BOLD response (PBR). The present study compares the metabolic profile of the positive and the negative bold response (NBR). The application of different fMRS block designs showed a significant increase in Glutamate (+7.3%) during the PBR stimulation paradigm in agreement with previous studies and a decrease (-6.6%) during the NBR, which provides new information about its underlaying mechanisms.
Purpose
In recent years, several functional magnetic resonance spectroscopy (fMRS) studies have been performed to characterize the relationship between neuronal activation and energy or neurotransmitter metabolism. Dynamic changes of metabolite concentrations in the human brain were successfully detected at 7T in response to visual, motor, or auditory stimulation1–4 during prolonged stimulus in the order of minutes. More recently, event-related designs with shorter stimulation periods have been presented to eliminate any possible habituation or adaptation effect and increase the temporal resolution. 5,6 A direct comparison of the changes observed at different stimulus length could provide a better understanding of the nature of the observed neurotransmitter changes (i.e. functional or metabolic). Previous fMRS studies focused on the neurochemical mechanisms accompanying the Positive BOLD Response (PBR). In functional imaging, understanding of the often observed Negative BOLD Response (NBR) has recently attracted increasing interest, and initial results suggest different hemodynamic mechanisms associated with excitatory and inhibitory tasks.7 Similarly, we hypothesize that areas with PBR and NBR may also show distinct metabolic signatures that might be detectable by fMRS.Methods
9 healthy volunteers (4 women, age 23-31 years) participated in the fMRS study. Scans were performed on a 7T system (Siemens, Erlangen, Germany) using a 32-channel head coil. The PBR and NBR stimuli consisted of a full-field radial 25.5% grey/black flickering checkerboard8 and a centered small circle flickering checkerboard9, respectively (Figure 1). An additional colored fixation point was changing randomly to track the attention of the volunteers via a response button press. A block design (5 repetitions) with alternation of 30 sec of rest and 30 sec of stimulus during gradient-echo EPI scanning (TE 30 ms, TR 2 sec) was used as a functional localizer. A standard SPM12 processing scheme was employed to obtain BOLD activation maps. Localization of a single 8ml voxel for fMRS was done by co-registration of the thresholded BOLD activation/deactivation map to an MP-RAGE anatomical image (Figure 1).
A semi-LASER sequence (TE=40ms, TR=4sec, 16-step phase cycle) was used for fMRS (320 repetitions, 22:22 min). For each of the two voxel positions (PBR and NBR) first- and second-order shims were adjusted using FAST(EST)MAP,10,11 and a water-unsuppressed spectrum (64 repetitions, 4:46 min) was acquired while presenting the same paradigm to study the BOLD effect on the water resonance as an additional verification of a correct voxel positioning. The OFF/ON block lengths employed for fMRS were 32 sec (“short-blocks”) and 5.3 min (“long-blocks”) for the PBR and 5.3 min for the NBR. Metabolite quantification was performed with LCModel,12 (Figure 2) employing water as internal reference as well as ratios relative to creatine to avoid potential bias from variation of the linewidth due to the BOLD effect. Raw spectra were channel combined with a singular value decomposition (SVD) method13 and phase and Eddy-current corrected implemented in Matlab. Spectra were then averaged in REST vs. STIM blocks (i.e., 160 averages per condition) for each of the 3 paradigms. Additionally, a moving average of 64 repetitions shifted in steps of 6 repetitions was applied to the “long-blocks” paradigm to generate smooth time courses consisting of 64 points (Figure 3).
Results
A significant increase in glutamate (+7.3%, p = 0.011) was found in the group average with the 32-sec OFF/ON “short-block” paradigm generating a PBR (Figure 4). For the long stimulation blocks, the overall glutamate increase was reduced with an average increase by +3.5% (insignificant) that is consistent with previously published results employing similar block durations.1,2,3 The variation in glutamate levels was inverted with the paradigm leading to NBR yielding a decreased glutamate level during stimulation (−6.6%).Discussion
We observed a stable increase of glutamate levels in areas showing a PBR to visual stimulation. While most previous fMRS studies had relied on stimulation over several minutes, the block length could be matched to those typically used in fMRI studies to achieve a direct comparison of the dynamic hemodynamic and metabolic responses. The direction of the observed glutamate change is consistent with the assumption of an excitatory response in line with previously observed BOLD and CBV changes. The opposite trend was observed in areas with inhibitory responses (NBR) indicating reductions of glutamate levels. GABA changes to the excitatory and inhibitory stimuli demonstrated an opposite trend as compared to the alterations in glutamate levels; however, the variations were of the order of the experimental error and did not reach significance. Further investigations should, thus, include editing techniques, such as MEGA-PRESS.14Acknowledgements
Funded through EU Marie Curie ITN “TRANSACT”. The authors of this abstract would like to thank Mr. Giapitzakis I.A and Dr. Anke Henning from MR Spectroscopy and Ultra-High Field Methodology Group (Max Planck Institute for Biological Cybernetics) for sharing parts of their post-processing routines.References
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