External awareness and GABA-A multimodal imaging study combining fMRI and [¹⁸F]flumazenil-PET

Abstract

Awareness is an essential feature of the human mind that can be directed internally, that is, toward our self, or externally, that is, toward the environment. The combination of internal and external information is crucial to constitute our sense of self. Although the underlying neuronal networks, the so-called intrinsic and extrinsic systems, have been well-defined, the associated biochemical mechanisms still remain unclear. We used a well-established functional magnetic resonance imaging (fMRI) paradigm for internal (heartbeat counting) and external (tone counting) awareness and combined this technique with [(18)F]FMZ-PET imaging in the same healthy subjects. Focusing on cortical midline regions, the results showed that both stimuli types induce negative BOLD responses in the mPFC and the precuneus. Carefully controlling for structured noise in fMRI data, these results were also confirmed in an independent data sample using the same paradigm. Moreover, the degree of the GABAA receptor binding potential within these regions was correlated with the neuronal activity changes associated with external, rather than internal awareness when compared to fixation. These data support evidence that the inhibitory neurotransmitter GABA is an influencing factor in the differential processing of internally and externally guided awareness. This in turn has implications for our understanding of the biochemical mechanisms underlying awareness in general and its potential impact on psychiatric disorders.

Neural overlap between resting state and self-relevant activity in human subcallosal cingulate cortex – Single unit recording in an intracranial study

“…It could also be that on a population level, as opposed to single-unit level, modulation of SCC neurons in response to self-relevant stimuli does exist, and was simply not detected using our methods. Future studies should not only test for externally-generated contents but also internally-generated contents like internal thoughts or stimuli from the body (Vanhaudenhuyse et al, 2011;Wiebking et al, 2014). If our assumption is correct, one would expect high self-specific internal thoughts or personally relevant bodily stimuli to show a similar pattern as observed here.…”

Resting state glutamate predicts elevated pre-stimulus alpha during self-relatedness: A combined EEG-MRS study on “rest-self overlap”

“…This finding is not only in line with previous EEG investigations of glutamate (Lally et al, 2014), it also suggests that glutamate can influence indirectly, via pre-stimulus state, subsequent stimulus-induced activity: first, glutamate mediates pre-stimulus state activity and then resting state activity modulates stimulusinduced activity. This is unlike the case with GABA, which appears to influence directly stimulus-induced activity Wiebking et al, 2014). In sum, glutamate's influence on stimulus-related behavior, as, for instance, whether a stimulus is judged to be high or low self-related, is indirect, not direct.…”

“…Based upon the rest-self overlap considerations adumbrated above, we hypothesized that glutamate in the PACC-but not in the other regionswould mediate elevated pre-stimulus alpha power at frontal regions for stimuli that subjects assessed as high self-related. Our group has abundant experience in combining MRS with other imaging modalities (Duncan et al, 2011Enzi et al, 2012;Hayes et al, 2013;Northoff, 2007;Wiebking et al, 2014); this experience enabled us to link prestimulus (e.g., prior to stimulus presentation or perception) activity levels (as measured in EEG) to biochemical modulation by resting state glutamate concentration (as measured in MRS).…”

GABA in the insula — a predictor of the neural response to interoceptive awareness

“…A well-established paradigm for functional magnetic resonance imaging (fMRI) was used (Wiebking et al, 2010, 2012), that consisted of a target task to induce IA (heartbeat counting), a closely matched control task to induce exteroceptive awareness (EA, tone counting), and fixation periods. In a separate session, measures of GABA and Glx concentrations from a voxel located in the target region, the left insula, were obtained in the same healthy participants using magnetic resonance spectroscopy (MRS).…”