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

Highlights

• Combines MRS and fMRI in healthy participants during interoceptive awareness

• Insula interoceptive activity positively correlated with GABA concentration.

• Insula interoceptive activity negatively correlated with depressed affect.

• Insula GABA negatively correlated with depressed affect.

• Provides link between insula interoception, GABA, and depression

Abstract

The insula has been identified as a key region involved in interoceptive awareness. Whilst imaging studies have investigated the neural activation patterns in this region involved in intero- and exteroceptive awareness, the underlying biochemical mechanisms still remain unclear.

In order to investigate these, a well-established fMRI task targeting interoceptive awareness (heartbeat counting) and exteroceptive awareness (tone counting) was combined with magnetic resonance spectroscopy (MRS). Controlling for physiological noise, neural activity in the insula during intero- and exteroceptive awareness was confirmed in an independent data sample using the same fMRI design.

Focussing on MRS values from the left insula and combining them with neural activity during intero- and exteroceptive awareness in the same healthy individuals, we demonstrated that GABA concentration in a region highly involved in interoceptive processing is correlated with neural responses to interoceptive stimuli, as opposed to exteroceptive stimuli. In addition, both GABA and interoceptive signal changes in the insula predicted the degree of depressed affect, as measured by the Beck Hopelessness Scale. On the one hand, the association between GABA concentration and neural activity during interoceptive awareness provides novel insight into the biochemical underpinnings of insula function and interoception. On the other, through the additional association of both GABA and neural activity during interoception with depressed affect, these data also bear potentially important implications for psychiatric disorders like depression and anxiety, where GABAergic deficits, altered insula function and abnormal affect coincide.

Introduction

A growing body of research has suggested that the insula cortex integrates the processing of various stimulus types (Craig, 2009). This includes stimuli that originate from both internally and externally to the body. Processing of such stimuli has been located within the insula and has been suggested to underlie our ability to be aware of our internal states (Craig, 2002), termed interoceptive awareness (IA). Imaging studies in humans of the insula have provided details of task-specific subdivisions within the region (Chang et al., 2012, Simmons et al., 2012), highlighting, for example, distinctions between the anterior and posterior insula (Farb et al., 2012). In addition, functional connectivity analyses have been used to identify networks of regions in the brain that have patterns of spontaneous activity that are correlated with that in the insula (Cauda et al., 2011, Deen et al., 2011). What remains unclear, however, is the neurochemistry that underlies task-induced activity in the insula in humans.

Studies regarding regions of the brain other than the insula have revealed links between task-evoked neural responses and a number of different neurotransmitters in humans. Concentrations of GABA (γ-aminobutyric acid) – the main inhibitory transmitter in the brain – in the visual cortex have been shown in a number of studies to be correlated with both the amplitude of the BOLD response to visual stimuli and with the particular dynamic properties of this response (i.e., the latency and width) (Donahue et al., 2010, Muthukumaraswamy et al., 2009, Muthukumaraswamy et al., 2012). Similarly, GABA concentrations in the medial prefrontal cortex (mPFC) also correlate with BOLD responses to stimuli (Northoff et al., 2007). At the same time, concentrations of glutamate – the primary excitatory transmitter – as measured in areas of the anterior cingulate have been shown to correlate with task-induced activity changes in multiple other brain regions during different tasks (Duncan et al., 2011, Falkenberg et al., 2012). Taken together, these prior results suggest that GABA and glutamate concentrations may be related to IA-related responses in the insula.

Under a prominent theory of emotions that views them as arising, in part, from bodily states, IA is linked closely to affective experience (Lamm and Singer, 2010). Support for this link comes from a growing body of research, including studies that show an anatomical overlap in the insula between emotional and interoceptive processing (Kelly et al., 2012, Terasawa et al., 2013, Zaki et al., 2012) and work that demonstrates a correlation between quality of emotional experience and bodily awareness (Dunn et al., 2010, Herbert et al., 2007, Pollatos et al., 2007a, Wiens, 2005). The link between IA activity in the insula and emotional experience suggests a role for the region in mood disorders, such as major depressive disorder (MDD), that are characterised by negative affect. Such an involvement of the insula in depression is supported by findings of altered functional responses in the region (Liotti et al., 2002, Paulus and Stein, 2010), as well as structural changes (Sprengelmeyer et al., 2011) and deficits in IA (Terhaar et al., 2012). In addition to such changes, MDD is associated with altered GABAergic and glutamatergic function in multiple brain regions (Alcaro et al., 2010, Zhao et al., 2012), whilst drugs acting on these systems have an antidepressant effect (Möhler, 2012, Sanacora et al., 2012). These combined factors suggest that IA in the insula may be related to depressive symptoms of negative affect and that this association is related to glutamate or GABA in the region. This remains to be investigated, however.

Based on these combined strands of IA, insula neurochemistry, and the relation between the insula and depressive symptoms, we examined whether the concentrations of GABA or glutamate and glutamine (Glu + Gln = Glx) can be related to neural activity in the insula during IA and to depressed affect. A well-established paradigm for functional magnetic resonance imaging (fMRI) was used (Wiebking et al., 2010, Wiebking et al., 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). A comparison voxel was placed in the mPFC. It was hypothesised that BOLD responses in the insula would be correlated with GABA concentrations in the same region and that these responses would be further correlated with depressed affect, as measured using the Beck Hopelessness scale (BHS) (Beck et al., 1974).