Review
Associations of regional GABA and glutamate with intrinsic and extrinsic neural activity in humans—A review of multimodal imaging studies

https://doi.org/10.1016/j.neubiorev.2014.07.016Get rights and content

Highlights

  • Integrating functional and biochemical imaging increasingly important.

  • Review of published GABA/glutamate studies in humans to date.

  • GABA consistently negatively correlated with functional responses.

  • Glutamate consistently positively correlated with between-region synchrony.

  • Methodological and interpretative issues remain to be addressed.

Abstract

The integration of multiple imaging modalities is becoming an increasingly well used research strategy for studying the human brain. The neurotransmitters glutamate and GABA particularly lend themselves towards such studies. This is because these transmitters are ubiquitous throughout the cortex, where they are the key constituents of the inhibition/excitation balance, and because they can be easily measured in vivo through magnetic resonance spectroscopy, as well as with select positron emission tomography approaches. How these transmitters underly functional responses measured with techniques such as fMRI and EEG remains unclear though, and was the target of this review. Consistently shown in the literature was a negative correlation between GABA concentrations and stimulus-induced activity within the measured region. Also consistently found was a positive correlation between glutamate concentrations and inter-regional activity relationships, both during tasks and rest. These findings are outlined along with results from populations with mental disorders to give an overview of what brain imaging has suggested to date about the biochemical underpinnings of functional activity in health and disease. We conclude that the combination of functional and biochemical imaging in humans is an increasingly informative approach that does however require a number of key methodological and interpretive issues be addressed before can meet its potential.

Introduction

Neuroimaging techniques, especially functional magnetic resonance imaging (fMRI), have provided much insight into the functional anatomy and neural networks of the brain. Whilst the vast majority of studies in this vein have concentrated on stimulus-induced activity, more recently the role of the brain's intrinsic activity (often described as its resting-state activity) has also shifted into focus (see for instance Northoff et al., 2010a, Raichle, 2009). The brain's intrinsic activity can be characterised by its apparent organisation into various neural networks, such as the default-mode network (DMN), salience, and sensorimotor networks, amongst others (Smith et al., 2009). Although much work has been done to understand both such stimulus-induced and intrinsic activity, the exact biochemical mechanisms supporting them remain to the explored in humans.

Neural activity in general is constituted to a large degree by the excitation–inhibition balance (EIB). Whilst the EIB has been extensively investigated at the cellular level of neural activity, it remains less well described at the regional. Most importantly, the EIB is closely related to the activities of glutamate and GABA (γ-aminobutyric acid) as, respectively, the brain's main excitatory and inhibitory neurotransmitters (see Isaacson and Scanziani, 2011, Lauritzen et al., 2012, Logothetis, 2008 for excellent discussions of the EIB). Recent imaging studies have indicated that the resting state concentration of GABA in regions such as the medial prefrontal cortex (mPFC), visual cortex, and motor cortex, modulate stimulus-induced activity intra-regionally, with concomitant inter-regional effects. In contrast to GABA, there is less available human neuroimaging evidence for the involvement of glutamate in the modulation of either intrinsic or stimulus-induced activity, though this appears to be a promising avenue of research (see for example Duncan et al., 2011, Enzi et al., 2012, Falkenberg et al., 2012, Schmaal et al., 2012). Taken together, these imaging studies point towards the central role of GABA and glutamate in the various regions of the brain's neural activity.

In addition to the healthy brain, we may also learn from abnormal alterations in GABA and glutamate in disorders of consciousness such as vegetative state and psychiatric disorders such as depression and schizophrenia (Alcaro et al., 2010, Brambilla et al., 2003, Broyd et al., 2009, Walter et al., 2009). Note, however, that healthy and pathological brain properties are not directly comparable and so the illustrative comparison of the two should not be over-interpreted. For example, depression can be characterised by abnormally elevated resting state activity and decreased stimulus-induced activity in the perigenual anterior cingulate cortex (pgACC), which psychopathologically may be related to symptoms of increased self-focus (Northoff et al., 2011), and which biochemically may be linked to an abnormal modulation of activity resulting from an altered glutamate–GABA relationship (Alcaro et al., 2010, Walter et al., 2009). These observations not only support the central role of GABA and glutamate balance as an underlying mechanism influencing both intrinsic and stimulus-induced activity across brain regions, but may also suggest that GABA and glutamate play a role in the constitution of the higher functions such as self and consciousness that are abnormally altered in these disorders.

The overall aim of this review is to provide an overview of current evidence from human neuroimaging regarding the role of the glutamate and GABA transmitter systems in brain function. The associations revealed by these experiments provide initial clues in humans towards what mechanisms may underlie the different brain processes studies (although importantly, on the whole, remain at a correlational stage). The focus shall be on findings from healthy participants and shall include work carried out using a range of imaging techniques, including magnetic resonance spectroscopy (MRS), positron emission tomography (PET), magnetoencephalography (MEG), and fMRI. It may be noted that each of these techniques provides measures of somewhat different aspects of neural activity. In general, BOLD (blood oxygen level dependent) fMRI is sensitive to processes related to neuronal inputs (Logothetis, 2008), EEG reflects voltage changes resulting from the synchronous firing of groups of neurons (Elul, 1971, Nunez and Snirivasan, 2006), and MEG the effects of synchronous post-synaptic activity (Hari et al., 2010). These differences must be borne in mind when interpreting the results described.

The literature shall be reviewed in line with two main themes:

  • (A)

    Extrinsic activity: Human imaging findings regarding the role of GABA and glutamate in the mediation and modulation of stimulus-induced neural responses to stimuli.

  • (B)

    Intrinsic activity: Human imaging findings regarding the role of GABA and glutamate in the mediation and modulation of ongoing neural activity that occurs in isolation from any particular stimulus.

Integrated within these sections, additional evidence as to the roles of GABA and glutamate in the human brain from studies of disease shall be briefly described and related to the functioning of the neurotypical brain. Finally, an overall discussion shall attempt to link the different strands of evidence and relate them to more general questions of brain function. This section shall also attempt to summarise some potential methodological and interpretive points that may be raised about the literature to date.

Section snippets

Extrinsic activity

Experimental stimuli can range from simple sensory inputs to complex psychological tasks. To date, studies combining biochemical and functional imaging measures have investigated stimulus-induced activity across this range of complexity, although with a leaning towards basic sensory processing. The following section shall be structured along anatomical lines, beginning with results related to the sensory cortices, through cortical midline structures, the insula, and other regions.

Intrinsic activity

As well as task-related responses, the relationship between biochemistry and the ongoing intrinsic activity of the brain is of key interest. A consistent finding across a number of species (Mantini et al., 2011, Nasrallah et al., 2013) is that the patterns of such intrinsic activity, generally as measured during rest but also during task states, are organised into a set of large scale networks that show correlated ongoing activity (Smith et al., 2009). Out of these, that consisting of anterior

Discussion

Combined functional and biochemical results have been reported from a number of brain regions and in a wide range of psychological task contexts. In addition, biochemical changes in different brain disorders have provided information that is broadly aligned with the results gained from healthy participants. Taking this body of evidence together a number of discussion points emerge.

Conclusion

The combination of functional and biochemical imaging in humans is an increasingly informative approach that does however require a number of key issues be addressed before can meet its potential. As reviewed here, studies to date have begun to further elucidate the associations between a range of physiological and psychological processes in the brain in health and disease. Difficult questions remain, however, as to how to best interpret results gained using the different biochemical imaging

Acknowledgements

The authors would like to thank Dave Hayes for the brain schemata used in Fig. 1. This work was supported by grants to G.N. from the Canadian Institutes of Health Research (CIHR).

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