We investigated the role of cortical GABA in the ATL on semantic memory and its neuroplasticity. Our results provide strong evidence that regional GABA levels increase following inhibitory cTBS in human associative cortex, specifically in the ATL, a representational semantic hub. Notably, the observed increase was specific to the ATL and semantic processing, as it was not observed in the control region (vertex) and not associated with control processing (visuospatial processing). Our study also found that the magnitude of cTBS-modulated GABA changes at the individual level was associated with their changes in ATL activity during semantic processing. Furthermore, our data confirmed and replicated our previous findings that GABA concentrations in the ATL shape task-related cortical activity and semantic task performance. In other words, individuals with greater semantic performance exhibit selective activity in the ATL due to higher concentrations of inhibitory GABA. GABAergic inhibition can sharpen activated distributed semantic representations through lateral inhibition, leading to improved semantic acuity38, which aligns with theories on representational sharpening in visual perception43,44. Importantly, our data revealed, for the first time, a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic function, by explaining individual differences in semantic task performance and cTBS responsiveness. Understanding the link between neurochemistry and semantic memory is an important step in understanding individual differences in semantic behaviour and could guide therapeutic interventions to restore semantic abilities in clinical settings.
To the best of our knowledge, this is the first study to demonstrate that (1) cTBS modulates both regional GABA concentrations and cortical activity in human higher cognition - semantic memory, and that (2) changes in GABA levels are closely linked to changes in regional activity induced by cTBS. These results suggests that GABAergic activity may be the mechanism by which cTBS induces long-lasting after-effects on cortical excitability, leading to behavioural changes. Previous studies in animals and humans have also suggested that cTBS can induce LTD-like effects on cortical synapses and is associated with the GABAergic system in the cortex45–50. Another study employing MRS found that cTBS increased regional GABA concentrations at the primary motor cortex in healthy subjects51. These findings suggest that cTBS activates a population of cortical GABAergic interneurons, leading to the increase in GABAergic activity52,53. As a major inhibitory neurotransmitter, GABA has been shown to have a negative correlation with BOLD signal changes5,54. Previous, we demonstrated this negative relationship between ATL GABA levels and BOLD signal changes in the ATL during semantic processing38, indicating a potential role of GABA in shaping the functions/computations of the cortex. Here, we further demonstrated that increase in GABA induced by cTBS was negatively correlated with the reduction of BOLD signal responses in the ATL following cTBS, during semantic processing. Our findings suggest a crucial role for GABAergic inhibition in the ATL shaping the local neural functioning underpinning semantic memory and its neuroplasticity. The GABAergic inhibition confines the propagation of excitatory signalling, thereby maintaining the functional organization of the cortex55, and the modulation of cortical GABAergic inhibition drives experience-dependent plasticity in cognition10,56.
GABA exists in two distinct neuronal pools: cytoplasmic GABA, which is involved in metabolism, and vesicular GABA, which plays a role in inhibitory synaptic neurotransmission57. In addition to intracellular GABA, extracelluar GABA exerts tonic inhibition through extra-synaptic GABAA receptors58. MRS is capable of detecting the total concentration of GABA in the voxel of interest, but it cannot differentiate between different pools of GABA59,60. Some studies have suggested that MRS-measured GABA signals reflect GABAergic tonic inhibition rather than synaptic GABA signalling61,62 whereas other studies have failed to replicate this relationship63,64. A recent study has shown a link between MRS-measured GABA and phasic synaptic GABAergic activity65. Although findings of previous studies have been mixed, changes in GABA levels observed in this study may reflect cTBS-modulated GABAergic neurotransmission, which encompass both tonic and synaptic GABAergic activity. This GABAergic activity shapes the selective response profiles of neurons in the cortex9.
Inverted U-shaped models have been previously considered in the field of neuroscience, specifically in terms of the relationship between the concentration of neurotransmitters such as dopamine, acetylcholine and noradrenaline, and the level of neural activity66–69. Recent studies suggest that this relationship also applies to behaviour, where moderate levels of neural activity are linked to the optimal performance (for a reveiw, see 70). For example, Ferri et al.71 showed an inverted U-shaped relationship between excitation and inhibition balance and multisensory integration, where extreme values impair functionality while intermediate values enhance it, even in healthy individuals. Our findings revealed a non-linear relationship between GABA levels in the anterior temporal lobe and semantic function, indicating that individual variations in semantic task performance can be explained by an inverted-U-shape pattern (Fig. 4A). Specifically, for relatively greater levels of GABA in the ATL, with lower task-induced regional activity, were associated with better semantic processing in healthy participants38. That is, individuals with better semantic memory abilities show more specific cortical activity in the ATL, which is linked to higher concentrations of inhibitory GABA. Extreme levels of GABA can be found in studies with dementia patients and pharmacological studies with GABA agonists. Recent studies have reported decreased GABA levels in Alzheimer’s disease72,73 and frontotemporal dementia74,75 in relation to their cognitive impairments such as memory and language. In fact, GABA agonists like midazolam have been found to improve a verbal generation in anxiety patients by increasing GABAergic function76. On the other hand, healthy participants who received GABA supplementation (such as baclofen) have been found to have decreased task performance77. Overall, optimal, elevated levels of GABA in the ATL may aid in refining stimulated widespread semantic representations through local inhibitory processes.
This inverted U-shaped model could also explain inter-individual variability in cTBS-induced neuroplasticity in the ATL in semantic processing. Our data demonstrated that cTBS over ATL increased regional GABA concentrations, but there was inter-individual variability in GABA level changes in response to cTBS (Fig. 2). Our previous investigation40 showed that the pre-interventional neurochemical state was crucial in predicting cTBS-induced changes in semantic memory. Specifically, cTBS over the ATL inhibited the semantic task performance (i.e., reduced accuracy) of individuals with initially higher concentration of GABA in the ATL, linked to better semantic capacity. However, cTBS had a null or even facilitatory effect on individuals with lower semantic ability with relatively lower GABA levels in the ATL. This study suggests that individuals with higher GABA levels in the ATL were more likely to respond to cTBS, exhibiting inhibitory effects on semantic task performance (responders), while individuals with lower GABA concentrations and lower semantic ability were less likely to respond or even showed facilitatory effects after ATL cTBS (non-responders). The current study revealed a non-linear, inverted-U-shape relationship between GABA levels in the ATL and semantic function, by explaining individual differences in semantic task performance and cTBS responsiveness. As regional GABA increases after cTBS, responders with the optimal level of GABA in the ATL would show poorer semantic performance, whereas non-responders could exhibit no changes or even better semantic performance with GABA increase (Fig. 4B). This relationship is similar to the inverted U-shaped relationship between dopamine action in the prefrontal cortex (PFC) and cognitive control, whereby moderate levels of dopamine lead to optimal cognitive performance78. The effects of dopaminergic drug on PFC function also depend on baseline levels of working memory performance (for a review, see 67), explaining the effects of dopaminergic drugs on cognitive performance in individuals with varying working memory capacities79–81.
Although we expected changes in task performance during semantic processing following cTBS, we only found relatively weak inhibitory effects in semantic task performance – the attenuation of a generalised practice effect. Participants showed practice effects in the second task, except for the semantic task after ATL cTBS. We have demonstrated that sufficient task practice (i.e., 120 trials) was required to detect rTMS-induced behavioural changes in semantic processing34. The lack of behavioural changes in response to cTBS may be attributed to the fact that the task practice only involved 20 trials for each task.
Our findings provide novel evidence of a direct link from neurochemical modulations to cortical responses in the brain, highlighting substantial individual variability in semantic memory and plasticity. In addition, the current study represents an important replication and extension of previous findings regarding the role of GABAergic inhibition in semantic memory. These results offer fundamental insights into the mechanisms underlying the maintenance and alteration of functional cortical organization in response to perturbations. Our study has important implications for the development of personalized therapeutic interventions aimed at modulating neurochemical systems to restore or enhance higher cognitive function in humans.