GABA Concentration in Posterior Cingulate Cortex Predicts Putamen Response during Resting State fMRI

Shah NJ (2014) GABA Concentration in Posterior Cingulate Cortex Predicts Putamen Response during Resting State fMRI. PLoS ONE 9(9): e106609. doi:10.1371/journal.pone.0106609 GABA Concentration in Posterior Cingulate Cortex Predicts Putamen Response during Resting State fMRI Jorge Arrubla 0 Desmond H. Y. Tse 0 Christin Amkreutz 0 Irene Neuner 0 N. Jon Shah 0 Yu-Feng Zang, Hangzhou Normal University, China 0 1 Institute of Neuroscience and Medicine 4, INM 4, Forschungszentrum J u lich, Ju lich, Germany , 2 Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University , Aachen, Germany , 3 JARA - BRAIN - Translational Medicine, RWTH Aachen University , Aachen, Germany , 4 Department of Neurology, RWTH Aachen University , Aachen , Germany The role of neurotransmitters in the activity of resting state networks has been gaining attention and has become a field of research with magnetic resonance spectroscopy (MRS) being one of the key techniques. MRS permits the measurement of c-aminobutyric acid (GABA) and glutamate levels, the central biochemical constituents of the excitation-inhibition balance in vivo. The inhibitory effects of GABA in the brain have been largely investigated in relation to the activity of resting state networks in functional magnetic resonance imaging (fMRI). In this study GABA concentration in the posterior cingulate cortex (PCC) was measured using single voxel spectra acquired with standard point resolved spectroscopy (PRESS) from 20 healthy male volunteers at 3 T. Resting state fMRI was consecutively measured and the values of GABA/Creatine+ Phosphocreatine ratio (GABA ratio) were included in a general linear model matrix as a step of dual regression analysis in order to identify voxels whose neuroimaging metrics during rest were related to individual levels of the GABA ratio. Our data show that the connection strength of putamen to the default-mode network during resting state has a negative linear relationship with the GABA ratio measured in the PCC. These findings highlight the role of PCC and GABA in segregation of the motor input, which is an inherent condition that characterises resting state. - Data Availability: The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. According to the authors ethical approval, granted by the Ethics Committee of the RWHT Aachen University to the Forschungszentrum Ju lich, data and results presented in this manuscript will be available upon request via the corresponding author: Prof. N. Jon Shah. Funding: Jorge Arrubla and Desmond Tse are supported by the Marie Curie Initial Training Network Methods in Neuroimaging (MC-ITN-238593). N. Jon Shah is funded in part by the Helmholtz Alliance ICEMED - Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Network Fund of the Helmholtz Association. Jorge Arrubla, Irene Neuner, and N. Jon Shah are also funded in part through the EU FP7 project TRIMAGE (Grant no. 602621). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Resting state has become an emerging field of research the understanding of which has brought new insights into brain function. The concept of resting state arose from positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies in which the focus moved from stimuli-related brain responses to the spontaneous fluctuations of activity when the brain is not engaged in any particular task [13]. It was thereby discovered that there exists a high correlation and temporal synchrony of the fMRI blood oxygen level-dependence (BOLD) series among relatively distant brain regions [3]. The analysis of resting state data is possible through independent component analysis (ICA) [4], where the low-frequency patterns of the resting state networks (RSN) are characterised and identified. The defaultmode network (DMN) has gained particular interest due to its relationship with neurological and psychiatric conditions [513] as well as with normal aging [14]. The canonical DMN comprises precuneus, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), medial prefrontal cortex (MPfC) and lateral parietal inferior gyri (LPIG) [2,5,15]. The DMN is thought to characterise basal neural activity [16,17] and has been linked to self-referential thought, introspection and integration of cognitive and emotional processing [18]. The DMN shows strong activity during rest, as well as rapid deactivation during externally directed tasks [19]. The DMN is also believed to represent an introspectively oriented mode of the mind which provides readiness and alertness to changes in the external and internal environment [15]. The posterior components of the DMN, precuneus and PCC, seem to act as an intrinsic mediatory node of this network [20,21]. Hagmann et al. [21] used diffusion imaging techniques to demonstrate the existence of a highly connected, complex brain network consisting of the posterior components of the DMN, and showed it to be highly activated at rest. Those regions showed a substantial correspondence between structural connectivity and resting-state functional connectivity. The PCC has been extensively described as an evaluative region [22], and includes Brodmann areas 29, 30, 23, and 31. This region is involved in spatial orientation and memory and it is likely that connections between posterior cingulate and parahippocampal cortices contribute to these processes [22]. Although PCC has been widely investigated, there is no consensus regarding its function [8]. The main functional characterisation of the PCC results from studies which investigate its role within the DMN [23]. PCC is implicated in awareness [24] and internally directed thoughts [13], which is supported by increased PCC activity during internally directed thoughts or during retrieval of autobiographical memories. Importantly, the PCC is one of the areas exhibiting significantly higher activity at rest, as it has been demonstrated by PET and arterial spin labelling [25]. Connectivity studies also demonstrate that the PCC is one of the regions with the highest local functional connectivity in resting conditions [26]. The role of neurotransmitter concentration in the activity of RSN is still not well understood and is an active field of research in magnetic resonance spectroscopy (MRS) [27]. MRS permits the measurement of c-aminobutyric acid (GABA) and glutamate levels, the central biochemical constituents of the excitationinhibition balance in vivo. In this sense, the presence of intraregional and trans-regional neuro-biochemical modulation has been proposed [27]. The latter means that the concentration of a biochemical constituent, as measured by MRS, may predict activity in either the same region, i (...truncated)