Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla

Negative blood oxygenation-level dependent (BOLD) signal observed during task execution in functional magnetic resonance imaging (fMRI) can be caused by different mechanisms, such as a blood-stealing effect or neuronal deactivation. Electrophysiological recordings showed that neuronal deactivation underlies the negative BOLD observed in the occipital lobe during visual stimulation. In this study, the metabolic demand of such a response was studied by measuring local metabolite concentration changes during a visual checkerboard stimulation using functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. The results showed increases of glutamate and lactate concentrations during the positive BOLD response, consistent with previous fMRS studies. In contrast, during the negative BOLD response, decreasing concentrations of glutamate, lactate and gamma-aminobutyric acid (GABA) were found, suggesting a reduction of glycolytic and oxidative metabolic demand below the baseline. Additionally, the respective changes of the BOLD signal, glutamate and lactate concentrations of both groups suggest that a local increase of inhibitory activity might occur during the negative BOLD response.

Metabolic and hemodynamic changes in the activated human brain and cerebellar organisation measured by MRS/MRl at 7 Tesla

Yohan Boillat

Although less often investigated than the positive blood-oxygen-level-dependent (BOLD) signal, a negative BOLD signal has also been observed under certain conditions, which could have a neuronal origin. To further investigate the negative BOLD signal from a metabolic point of view, a functional 1H magnetic resonance spectroscopy (fMRS) study was conducted using visual stimulations to trigger a negative BOLD response. The latter was linked to decreases of [Glu] and [Lac] with also a decrease in GABA concentration. These results suggest that the negative BOLD signal is linked to a neuronal deactivation and maybe to a local increase of inhibitory activity. Although both glycolytic and oxidative metabolisms are involved during neuronal activity, it is still unclear how they are respectively modulated by the latter. To investigate this, a functional magnetic resonance imaging (fMRI)-fMRS study was carried out on participants performing a finger tapping task at either 1Hz, 2Hz or 3Hz. In addition to the BOLD signal, the CBF signal was also obtained. As previously observed, the BOLD and CBF signals increased for larger finger tapping frequencies confirming the overall increase of metabolic demand. [Glu] and [Lac] were used as biomarker of oxidative and glycolytic metabolisms, respectively. [Glu] changes were the largest for 3Hz while [Lac] changes were more important at 2Hz. These results highlights the different involvement of the two metabolic pathways. The positive BOLD signal differs in its timings and shape across brain regions. Using a high temporal resolution sequence combined with short stimulations, the positive BOLD responses of six motor regions, including the cerebellum, were extracted. The main difference between motor regions was the positive peak and undershoot amplitudes that were the smallest in the cerebellum, which also showed delayed onsets. In addition to the BOLD response, the cerebellum has some very specific characteristics such as the representation of body parts in both the anterior and posterior lobes. In order to obtain more precise and complete maps of the cerebellar somatotopy, an fMRI motor task was performed testing for the eyes, the tongue, the little fingers, the thumbs or the toes. The anterior lobe showed a consistent and robust somatotopic gradient with also the presence of such a gradient in the posterior lobe, albeit less obvious. These results show that multiple representations of the body are present in the cerebellum and organized in an orderly manner. In addition, the cerebellum can be parcellated based on several features like cell packing, olive fibre input or molecular biomarker. To test whether such tissue characteristics can be observed at macroscale level, T1 and T2* mapping was performed on cerebellar surfaces generated at three different cortical depths. T1 surfaces showed an alternation of lower and higher T1 values when going from the median to the lateral part of the cerebellar hemispheres with shorter T1 values observed in the deeper grey matter layers. T2* maps showed a similar longitudinal pattern, but no change related to the cortical depths. These patterns reflect potential myelin and iron content variations over the cerebellar cortex. Whether these tissue variations are linked to the somatotopic organization is not clear.

EPFL2020

Astrocytic and neuronal oxidative metabolism are coupled to the rate of glutamate-glutamine cycle in the tree shrew visual cortex

Anne Catherine Clerc, João Miguel das Neves Duarte, Rolf Gruetter, Nathalie Just, Gregor Rainer, Sarah Catherine Sonnay

Astrocytes play an important role in glutamatergic neurotransmission, namely by clearing synaptic glutamate and converting it into glutamine that is transferred back to neurons. The rate of this glutamate–glutamine cycle (VNT) has been proposed to couple to that of glucose utilization and of neuronal tricarboxylic acid (TCA) cycle. In this study, we tested the hypothesis that glutamatergic neurotransmission is also coupled to the TCA cycle rate in astrocytes. For that we investigated energy metabolism by means of magnetic resonance spectroscopy (MRS) in the primary visual cortex of tree shrews (Tupaia belangeri) under light isoflurane anesthesia at rest and during continuous visual stimulation. After identifying the activated cortical volume by blood oxygenation level-dependent functional magnetic resonance imaging, 1H MRS was performed to measure stimulation-induced variations in metabolite concentrations. Relative to baseline, stimulation of cortical activity for 20 min caused a reduction of glucose concentration by −0.34 ± 0.09 µmol/g (p < 0.001), as well as a −9% ± 1% decrease of the ratio of phosphocreatine-to-creatine (p < 0.05). Then 13C MRS during [1,6-13C]glucose infusion was employed to measure fluxes of energy metabolism. Stimulation of glutamatergic activity, as indicated by a 20% increase of VNT, resulted in increased TCA cycle rates in neurons by 12% ( math formula, p < 0.001) and in astrocytes by 24% ( math formula, p = 0.007). We further observed linear relationships between VNT and both math formula and math formula. Altogether, these results suggest that in the tree shrew primary visual cortex glutamatergic neurotransmission is linked to overall glucose oxidation and to mitochondrial metabolism in both neurons and astrocytes.

Wiley-Blackwell2018

The cellular bases of functional brain imaging: evidence for astrocyte-neuron metabolic coupling

Pierre Magistretti, Luc Pellerin

Signals detected with functional brain imaging techniques are based on the coupling between neuronal activity and energy metabolism. Positron emission tomography signals detect blood flow, oxygen consumption and glucose utilization associated with neuronal activity; the degree of blood oxygenation is thought to contribute to the signal detected with functional magnetic resonance imaging, whereas magnetic resonance spectroscopy identifies the spatiotemporal pattern of activity-dependent appearance of metabolic in termediates, such as glucose or lactate. Despite the technological sophistication of these brain imaging techniques, the precise mechanisms and cell types involved in coupling and in generating metabolic signals are still debated. Indeed, given the level of resolution achieved with these brain imaging techniques, it has not been feasible to monitor met abolic fluxes between the highly intermingled neuronal, glial, and vascular elements in the intact brain. This obstacle has been overcome in recent years by using purified cellular preparations of neurons and glia. These approaches have suggested a critical role for astrocytes in coupling neuronal activity to energy metabolism. Indeed, astrocytes possess receptors and reuptake sites for a variety of neurotransmitters, including glu tamate. In addition, astrocytic end-feet, which surround capillaries, are enriched in the specific glucose transporter GLUT-1. These features would be expected to allow astro cytes to sense synaptic activity and to couple it with energy metabolism. During activa tion, glutamate is the predominant neurotransmitter released by modality-specific excitatory pathways to a given cortical area; in vitro and in vivo data support a model in which glutamate would stimulate, during activation, an initial glycolytic processing of blood-borne glucose by astrocytes; this glutamate-dependent process would result in a transient lactate overproduction, followed by a recoupling phase during which lactate would be oxidized by neurons. Such a model is consistent with data recently obtained with functional brain imaging techniques

1997