GABA Concentrations in the Anterior Cingulate Cortex Are Associated with Fear Network Function and Fear Recovery in Humans

Abstract

Relapse of fear after successful treatment is a common phenomenon in patients with anxiety disorders. Animal research suggests that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a key role in the maintenance of extinguished fear. Here, we combined magnetic resonance spectroscopy and functional magnetic resonance imaging to investigate the role of GABA in fear recovery in 70 healthy male participants. We associated baseline GABA levels in the dorsal anterior cingulate cortex (dACC) to indices of fear recovery as defined by changes in skin conductance responses (SCRs), blood oxygen level dependent responses, and functional connectivity from fear extinction to fear retrieval. The results showed that high GABA levels were associated with increased SCRs, enhanced activation of the right amygdala, and reduced amygdala-ventromedial prefrontal cortex connectivity during fear recovery. Follow-up analyses exclusively for the extinction phase showed that high GABA levels were associated with reduced amygdala activation and enhanced amygdala-ventromedial prefrontal cortex connectivity, despite the absence of correlations between GABA and physiological responses. Follow-up analyses for the retrieval phase did not show any significant associations with GABA. Together, the association between GABA and increases in SCRs from extinction to retrieval, without associations during both phases separately, suggests that dACC GABA primarily inhibits the consolidation of fear extinction. In addition, the opposite effects of GABA on amygdala activity and connectivity during fear extinction compared to fear recovery suggest that dACC GABA may initially facilitate extinction learning.

Neurochemical and brain functional changes in the ventromedial prefrontal cortex of first-episode psychosis patients: A combined functional magnetic resonance imaging—proton magnetic resonance spectroscopy study

“…Several lines of evidence have indicated that GABA concentrations in a variety of brain regions, including vmPFC (Jocham et al, 2012), amygdala (Levar et al, 2017), ACC (Northoff et al, 2007) and visual cortex (Muthukumaraswamy et al, 2009), predicted BOLD responses within the regions. Recent fMRI studies have shown that GABA level was inversely correlated with the strength of FC within motor and frontal-limbic networks (Delli Pizzi et al, 2017b; Levar et al, 2017; Stagg et al, 2014). It was suggested that higher GABA concentration in one region enhanced the inhibitory signaling within it (Delli Pizzi et al, 2017b).…”

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

“…In rodents, this area is responsible for the enhancement of contextual fear generalization after fear conditioning, and for the transfer of socially derived fear through its connections with the amygdala (Cullen et al 2015;Pisansky et al 2017;Allsop et al 2018). In humans, local GABAergic signaling in the ACC promotes fear extinction, which suggests that inhibition of the dorsal ACC may initially inhibit the retrieval of fear memories, and thus facilitates extinction learning (Levar et al 2017a(Levar et al , 2017b.…”

“…In the case of PTSD, interestingly, the activation of ACC, together with the vmPFC and hippocampus, is sexually dimorphic: men with PTSD exhibited increased activation in the left rostral dACC during extinction recall compared to women with PTSD (Shvil et al 2014;Yoon et al 2017). Further, animal and human studies (Cullen et al 2015;Levar et al 2017aLevar et al , 2017b have positioned the ACC as an important hub to trigger fear retrieval alongside the PL, and its inhibition might be a way to boost fear extinction.…”

Inhibitory and excitatory mechanisms in the human cingulate-cortex support reinforcement learning

“…Although it is much harder to assess excitation and inhibition in humans, the main contributors: Glutamate and GABA, can be accurately and reliably measured through Proton Magnetic Resonance Spectroscopy ( 1 H-MRS) [7][8][9]. Indeed, MRS-observed neurotransmitter levels reflect task-related activity with studies demonstrating sensitivity to baseline [10][11][12][13][14][15] and rapidly-modulating levels [16][17][18]. Most studies measured concentrations during rest and correlated it with later/previous behavior [13][14][15][19][20][21], yet some even measured during behavior [17,18,22].…”

“…Most studies measured concentrations during rest and correlated it with later/previous behavior [13][14][15][19][20][21], yet some even measured during behavior [17,18,22]. A few studies have correlated baseline (rest) levels with subsequent/prior learning metrics [11,12,23], and one has even examined changes during motor learning [16]. However, none have quantified neurotransmitter modulations during active reinforcement-learning.…”