Resting-state glutamate level in the anterior cingulate predicts blood-oxygen level-dependent response to cognitive control

Abstract

The dorsal anterior cingulate cortex (dACC) is a core structure for the governing of cognitive control, and recent studies have shown that interindividual differences in dACC anatomy are associated with corresponding differences in the ability for cognitive control. However, individuals differ not only in anatomical features of dACC, but also exhibit substantial variability regarding the biochemical characteristics of the dACC. In this study, we combined magnetic resonance spectroscopy ( 1 H-MRS) and functional magnetic resonance imaging (fMRI), finding that interindividual differences of glutamate levels in the dACC during resting-state predict the strength of the blood-oxygen level-dependent (BOLD) response to a task requiring cognitive control. This relationship was observed in the retrosplenial cortex, the orbitofrontal cortex, the inferior parietal lobe, and the basal ganglia. More specifically, individuals with low resting-state glutamate levels in the dACC showed an increased BOLD response when the task demands were high, whereas high-glutamate individuals showed the opposite pattern of an increased BOLD response when the task demands were low. Thus, we show here that individual variability of glutamate levels is directly related to how the brain implements cognitive control.dichotic listening | default-mode network | gamma-aminobutyric acid D espite the steadily increasing knowledge concerning the neuronal underpinnings of cognitive control processes, little is known regarding the underlying biochemistry. Glutamate is particularly interesting in this respect because it is the most important excitatory neurotransmitter in the brain and also acts as a substantial intermediate in cerebral energy metabolism (1). Glutamate functioning is known to be reduced in several psychiatric disorders associated with an impairment in cognitive control (2), and pharmacologically induced reduction of glutamate levels has been found to alter the blood-oxygen level-dependent (BOLD) response to cognitively demanding tasks (3, 4). Here, we investigate the effect of interindividual variations in levels of glutamate on cognitive control mechanisms in healthy subjects. As target region for this investigation, the dorsal anterior cingulate cortex (dACC) was chosen because it represents a core region for handling cognitive conflict (5) and regulating the engagement of cognitive control processes (6), in addition to having strong connections to the frontoparietal and frontostriatal executive and cognitive control networks (7-9). Furthermore, the dACC is rich in glutamatergic innervation (10), rendering it as the prime candidate for the investigation of how individual glutamate levels affect the neuronal implementation of cognitive control.Individual levels of glutamate were determined in a resting state (rsGlu) in 40 healthy adults, using proton magnetic resonance spectroscopy ( 1 H-MRS) from bilateral voxels located in the dACC (Fig. 1A). The auditory cognitive control paradigm for the functional MRI (fMRI) acquisition has been fre...

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

“…Most importantly, this correlation was biochemically, regionally, and neuronally specific: it applied to glutamate but not other metabolites; to the PACC, not other regions; and to pre-stimulus (e.g., prior to presentation or perception of the stimulus), not GLUTAMATE,ALPHA AND SELF 11 postonset (e.g., during stimulus presentation or perception) stimulus-related ERSP differences. Glutamate has been demonstrated to modulate resting state measures like the BOLD amplitude in fMRI (Enzi et al, 2012), and the PACC functional connectivity to cortical and subcortical regions (Duncan et al, 2011Falkenberg et al, 2012). These findings, however, left unresolved how glutamatergic modulation of resting state activity influences stimulus-induced activity, in general, and self-related stimuli, in particular.…”

“…Although inhibitory GABA has recently been shown to mediate EEG taskevoked measures like gamma band oscillations (Lally et al, 2014;Muthukumaraswamy, Edden, Jones, Swettenham, & Singh, 2009), studies on excitatory glutamate modulation of EEG measures have been reported less widely (for exceptions, see Lally et al, 2014; for animal studies, see MoralesVillagrán, Medina-Ceja, & López-Pérez, 2008). Glutamate is an excitatory transmitter that fMRI and magnetic resonance spectroscopy (MRS) analyses have shown to mediate resting state activity, including both intra-regional activity levels and trans-regional functional levels (Duncan, Enzi, Wiebking, & Northoff, 2011;Duncan et al, 2013;Enzi et al, 2012; also see Falkenberg, Westerhausen, Specht, & Hugdahl, 2012;Scheidegger et al, 2012). Such glutamatergic modulation of the resting state suggests that glutamate might mediate the influence of pre-stimulus state activity on stimulus-related activity.…”

The relationship between MEG and fMRI

“…Relatively few studies have assessed the role of glutamate in the BOLD response to a stimulus (Duncan et al, 2011, Falkenberg et al, 2012. Duncan et al (Duncan et al, 2011) found that glutamate levels in the perigenual ACC were positively correlated with BOLD signal change in the supragenual ACC.…”

“…Duncan et al (Duncan et al, 2011) found that glutamate levels in the perigenual ACC were positively correlated with BOLD signal change in the supragenual ACC. Falkenberg and colleagues (Falkenberg et al, 2012) measured basal glutamate in the left and right dorsal ACC and BOLD during an auditory cognitive control task.…”

Lisdexamfetamine Effects on Executive Activation and Neurochemistry in Menopausal Women with Executive Function Difficulties

“…The relationship between glutamate concentration and BOLD signal is not well established. One study found a positive correlation between dorsal anterior cingulate cortex (ACC) glutamate and BOLD during a cognitive control task in several regions including the retrosplenial cortex, orbitofrontal cortex, inferior parietal lobule, and basal ganglia (Falkenberg et al, 2012). Another study found a positive correlation between dorsomedial PFC glutamate and pregenual ACC BOLD during emotional processing (Stan et al, 2014).…”