Thought suppression engages a functionally specific pathway

Twenty-four healthy young adults performed adapted versions of the Think/No-Think (TNT)38 and stop signal (SS)39, 40 tasks, which were interleaved in a mixed block/event-related design (see Methods section). We focus first on the TNT task used to measure thought suppression. Prior to scanning, participants were drilled on a large set of word pairs, each one composed of a reminder and its associated thought. During scanning, on each trial, participants viewed one of these reminders, by itself. For each reminder, we cued participants either to retrieve its associated thought (Think trials), or instead to suppress its retrieval, stopping the thought from coming to mind at all (No-Think trials).

Previous work with the TNT paradigm establishes that suppressing retrieval of an associated thought downregulates hippocampal activity and impairs later memory for the suppressed content28,29,30,31,32,33,34,35, 38, 41,42,43,44. These hemodynamic and behavioral effects occur with a broad range of stimuli, including neutral or unpleasant words29,30,31, 38, 42, visual objects34, neutral or unpleasant scenes32, 33, 41, 43, 44, autobiographical memories45, and person-specific fears about their future35. Critically, populations that suffer from persistent intrusive thoughts such as those with post-traumatic stress disorder (PTSD)44, depression46, 47, and anxiety48 show significant deficits in suppression-induced forgetting. Individual differences in suppression-induced forgetting have been found to predict the frequency of naturally occurring traumatic intrusions in healthy individuals49 and in PTSD44, scores on clinical scales of ruminative thinking50 and anxiety35, 48, and measures of the general ability to control intrusive thoughts in daily life51. Together, these observations point to a general retrieval suppression mechanism that contributes to suppressing intrusive thoughts and suggest that these behavioral and hemodynamic effects index the efficiency of this mechanism.

To confirm these effects with the present stimuli, we compared BOLD responses between No-Think and Think trials in the anatomically defined right hippocampus region of interest (ROI)52, and found that performing No-Think trials significantly reduced activation in this region (t 23 = 3.34, p = 0.003; Fig. 1a). The same effect was observed in the left hippocampus (t 23 = 3.69, p = 0.001; Fig. 1a), though we focus on the right hippocampus ROI co-localized to our 1H MRS acquisition. Suppressing retrieval also impaired participants’ later memory for the suppressed items, demonstrating suppression-induced forgetting in this sample. Specifically, on a post-scan recall test, participants recalled No-think items less often (mean ± SEM: 59 ± 3%) than they recalled either Think items (65 ± 3%; t 23 = 2.2, p = 0.04) or Baseline items that they also learned, but that did not appear during the Think/No-Think phase (M = 65 ± 3%; t 23 = 2.5, p = 0.02). As previously shown42, the amount of suppression-induced forgetting significantly increased with larger BOLD reductions during No-Think trials, though only in posterior hippocampus (Robust correlation53: r = −0.56, t = −3.14, 95% boot-strapped confidence interval (CI) (−0.84 to −0.14)). Together, these neural and behavioral markers of how well people suppressed unwanted thoughts confirm prior evidence for the role of the hypothesized fronto-hippocampal inhibitory control pathway in this function29.

Fig. 1 Domain-specific modulation during thought and action suppression. a and b. Group (N = 24) whole-brain contrasts for No-Think < Think (top) and Stop < Go (bottom). Thought suppression modulated bilateral hippocampal (HIP) activity. Action-stopping-modulated activity in primary motor cortex (M1), lateralized to the left (contralateral to hand) hemisphere. Boxes illustrate HIP and M1 activations on a coronal slice in MNI space. Activations are derived from an uncorrected cluster-defining threshold (p < 0.001), with cluster level false discovery rate p < 0.05. Color bars demarcate T-statistics. (Middle panels) A priori region of interest (ROI) analyses: Group hemodynamic time-courses were attenuated in HIP by thought suppression (No-Think) and in M1 by action suppression (Stop) relative to Think and Go, respectively ***p < 0.001; **p < 0.01; *p < 0.05. c Modality-dependent hemodynamic attenuation in HIP (top) and M1 (bottom) was confirmed with a repeated measures ANOVA, which revealed an ROI by Modality interaction. Error bars represent SEM Full size image

Alternating with blocks of the TNT task, participants also performed the SS task, a well-established procedure for measuring the inhibition of motor actions39, 40 (see Methods section). We included the action-stopping task to contrast the effects of thought suppression with those of another widely studied inhibitory control task that should not rely on modulating hippocampal activity, but rather motor cortical activity. Prior to scanning, participants learned to press one of two buttons with their right index finger in response to differently colored circles. During scanning, participants performed a speeded motor response task that, on a minority of trials, required them to stop their motor action midstream if they received a stop signal. The right DLPFC (approximately Brodmann area 46) is thought to be critical for inhibitory control in a variety of cognitive task contexts54. To test whether this was indeed the case in our within-subjects study, we used an a priori ROI of the DLPFC (defined from a prior TNT study31) to extract BOLD response estimates during No-Think, Think, Stop, and Go trials. Consistent with a broad involvement in inhibitory control, DLPFC was significantly more engaged when either thoughts or actions needed to be inhibited (No-Think > Think, t 23 = 2.38, p = 0.026; Stop > Go, t 23 = 4.32, p < 0.001). To confirm that action-stopping targeted motor processes, we examined BOLD response in the hand lobule of left primary motor cortex (M1; defined with an independent localizer task; see Supplementary Methods). As predicted, when participants stopped a (right-handed) key press, we observed a significant downregulation of BOLD response in left M1 (t 23 = 10.02, p < 0.001; Fig. 1b), consistent with prior findings55. The stopping-induced reduction in BOLD response (Stop < Go) was significantly larger in the left than in the right hemisphere (t 23 = 2.38, p = 0.026), as would be expected, based on a right-handed key press response.

Critically, action stopping and thought suppression preferentially modulated the left M1 and hippocampus, respectively (Fig. 1c). In a Region (M1 vs. Hippocampus) by Modality (Thoughts vs. Actions) by Task (Inhibition vs. Non-Inhibition) analysis of variance (ANOVA), there was a significant three way interaction in both the left and right hemispheres (Left: F 1,23 = 78.29, p < 0.001; Right: F 1,23 = 13.56, p = 0.001). Suppressing retrieval (No-Think < Think) evoked larger negative BOLD responses in the hippocampus compared to M1 (Left: t 23 = 5.80, p < 0.001; Right: t 23 = 3.29, p = 0.003). By contrast, suppressing motor actions (Stop < Go) evoked larger negative BOLD responses in M1 relative to the hippocampus (Left: t 23 = 5.80, p < 0.001; Right: t 23 = 3.29, p = 0.003). These differing modulatory profiles support the possibility that stopping thoughts engages a distinct fronto-hippocampal pathway that is not engaged by stopping actions. If so, GABA concentrations local to the hippocampus may be selectively tied to stopping thoughts, and not to stopping processes in general.

Hippocampal GABA predicts successful thought suppression

We next tested whether our hemodynamic and behavioral measures of thought suppression were related to hippocampal GABA. To do so, we employed 1H MRS, a non-invasive imaging technique that provides sensitive measures of brain metabolites, such as GABA, by detecting the unique radio frequency signals arising from the hydrogen nuclear spins within these metabolites56 (Methods section). In a separate MRS session, we quantified resting GABA concentrations in the hippocampus, the proposed site of inhibition, and in the right DLPFC, the proposed source of the control signal driving inhibitory activity in the hippocampus (see Fig. 2). As a control, we also measured GABA in the primary visual cortex, a region outside the proposed pathway (Supplementary Fig. 1). We used pre-defined anatomical landmarks to position the MRS ROIs for the DLPFC31, hippocampus52, and primary visual cortex57, ensuring anatomical co-localization across subjects.

Fig. 2 1H MRS quantification of GABA concentrations. a–c Positions of the visual cortical, DLPFC, and hippocampus (HIP) voxels are displayed on sagittal (top row) and coronal (bottom row) slices extracted from an example subject’s tissue segmented structural scan. d An example of the 1H MRS spectra displayed in one dimension. Blue line: raw metabolite spectra for an example subject. Red line: ProFit basis functions for singlet (one-peak) metabolites, including Creatine (Cre), Choline (Cho), and N-acetyl aspartate (NAA). Black line: residuals after fitting. Note the GABA CH 2 methylene group at 2.28 PPM is invisible on the 1D plot. e and f Plotted for the DLPFC (N = 23) and HIP (N = 18) voxels are the fitted spectra (averaged overall subjects) of the same four metabolites, but now spread along two dimensions, the J-resolved axis (±20 Hz) plotted and the chemical shift axis (1.5–4 parts per million; p.p.m.). Both plots use identical scaling. Colors indicate minimum (blue) and maximum (red) height of spectral contours (arbitrary units). The GABA CH 2 methylene group is visible at 2.28 p.p.m. (diagonal lines) Full size image

After applying MRS quality control standards to the data (see Methods), the final sample sizes for the 1H MRS data were: Hippocampus (n = 18), DLPFC (n = 23), and visual cortex (n = 20). Mean GABA/Cre values (±SD) for the three MRS voxels were as follows: Hippocampus (0.185 ± 0.05), DLPFC (0.169 ± 0.02) and visual cortex (0.192 ± 0.05). GABA concentrations were not correlated across our ROIs, as determined by robust correlation analyses53: Hippocampus and DLPFC (r = −0.21, t < 1); Hippocampus and Visual Cortex, (r = −0.13, t < 1); DLPFC and Visual Cortex, (r = 0.04, t < 1). The mean GABA/Cre value of 0.18 across these ROIS matches the reported value from an independent study using the same 2D 1H MRS protocol (0.18)57, as well as reported values from three other studies using similar protocols (mean GABA/Cre across ROIs and studies: 0.18)58,59,60. These results suggest a level of reliability in GABA estimation close to that achieved by more frequently used 1H MRS acquisition protocols, such as MEGA-PRESS56. Mean glutamate/Cre values (±SD) for the three ROIs were as follows: Hippocampus (0.80 ± 0.17), DLPFC (1.19 ± 0.18), and visual cortex (1.07 ± 0.11). Mean gray matter concentration values (±SD) for the three ROIs were: Hippocampus (65.4 ± 5.29), DLPFC (28.4 ± 4.02), and visual cortex (48.9 ± 5.10).

To examine relationships of 1H MRS GABA with BOLD signal, and with behavior, we conducted a two-step procedure integrating robust correlation with partial correlation analyses. In the first step, we used a skipped correlation to derive a Pearson’s r-value on data with bivariate outliers removed53. Outliers were determined automatically via an algorithm that found the central point in the distribution of data using the mid-covariance determinant. Orthogonal distances were then computed to this point, and any data outside the bound defined by the ideal estimator of the interquartile range was removed53. In the second step, we used partial correlation to determine if any relationships observed in the robust estimation step were explained (or masked) by participant sex, the amount of gray matter volume captured by the 1H MRS voxel, or co-localized concentrations of glutamate. We controlled for participant sex and gray matter tissue content in each ROI because these variables can influence estimates of GABA concentration61. Glutamate concentration was controlled because of the relationship of glutamatergic principal cell metabolism with BOLD62 and GABA63. In both steps, inference of statistical significance was determined from 95% boot-strapped confidence intervals. These relationships are reported in Tables 1 and 2, and are described in the sections below.

Table 1 Intermodal relationships of hippocampal GABA Full size table

Table 2 Intermodal relationships of DLPFC and visual cortical GABA Full size table

Our main interest concerned whether task-induced changes in BOLD responses in the hippocampus were related to hippocampal GABA. Given the established role of the hippocampus in memory, mnemonic processes should drive changes in its activity, which in turn depends on the local population of GABAergic interneurons21. Prior work with non-human primates, combining fMRI with cortical electrophysiology, suggests that stimulus-induced negative BOLD responses in visual cortex arise, in part, due to increases in neuronal inhibition64. Moreover, in humans the magnitude of task-induced negative BOLD responses in anterior cingulate have been linked with co-localized 1H MRS estimates of GABA concentration58, 60. Together, these findings raise the possibility that negative BOLD responses in the hippocampus may also be linked with neuronal inhibition, and thus, co-localized 1H MRS estimates of GABA concentration. If so, our MRS measure of baseline GABA should predict reduced memory-driven BOLD responses arising during the Think/No-Think task. In contrast, our motor action inhibition task, despite requiring focused attention and inhibitory control, should not depend on hippocampal processing, and so baseline GABA may be less related to hippocampal BOLD signal during this task. The data confirmed these expectations (Table 1A): Robust correlation analyses demonstrated that hippocampal GABA significantly predicted hippocampal BOLD response magnitude during both the Think and No-Think conditions; it did not, however, predict BOLD during either the Go or Stop conditions. Partial correlation analyses confirmed that these relationships were not driven (or masked) by participant sex, hippocampal gray matter content, or hippocampal glutamate concentrations (Table 1A).

Although the foregoing patterns suggest a functionally specific role of hippocampal GABA in memory processes, it is important to determine whether this relationship survives even when any relationship between GABA and BOLD in non-memory tasks is accounted for. This control analysis is especially necessary given that action stopping, like thought suppression, also reduced hippocampal BOLD signal (right HIP: t 23 = 2.42, p = 0.02, left HIP: t 23 = 3.65, p = 0.001, Fig. 1c). Stopping-related reductions in hippocampal BOLD could signify that action stopping engages mechanisms similar to thought suppression to disrupt hippocampal function; alternatively, they may simply be a passive side effect of performing a difficult task20 (e.g., reduced afferent input to the hippocampus due to heightened task focus). In the former case, BOLD responses induced by both No-Think and Stop trials should share variance with hippocampal GABA, whereas in the latter case, the variance explained by thought suppression (active inhibition) should differ from that explained by action stopping (task difficulty) due to their differing mechanistic origins. To distinguish these two alternatives, we conducted a partial correlation analysis on the relationship between hippocampal GABA and BOLD response during No-Think trials that additionally controlled for BOLD response during Stop trials (Table 1A). We found that the relationship between hippocampal GABA and BOLD response during No-Think trials persisted even when controlling for Stop-induced BOLD response. We obtained a similar finding when we performed this analysis using Think and Go trials. These patterns suggest that BOLD response reductions during motor stopping likely have a different mechanistic origin, perhaps relating to task difficulty. They also confirm the functional specificity of hippocampal GABA/BOLD coupling to memory processes in the context of the Think/No-Think task: only memory task-related signals to the hippocampus drove changes in BOLD signal amplitude that scaled with resting concentrations of hippocampal GABA, such that the higher the hippocampal GABA, the lower the observed BOLD response during memory retrieval and memory suppression.

We next considered the possibility that the relationships between hippocampal GABA and BOLD measures were not specific to hippocampal GABA. This relationship could, for example, reflect GABAergic integrity throughout the broader fronto-hippocampal pathway supporting the suppression of unwanted thoughts28,29,30,31,32,33,34,35. If so, hippocampal BOLD responses should share variance with both hippocampal and DLPFC GABA concentrations. Alternatively, if the relationship is anatomically specific, hippocampal GABA should share unique variance with hippocampal BOLD responses. To distinguish these alternatives, we conducted a partial correlation analysis on the relationship between hippocampal GABA and BOLD responses during No-Think trials, additionally controlling for DLPFC GABA (Table 1A). Consistent with anatomical specificity, the relationship between hippocampal GABA and No-Think-induced BOLD response persisted, even when controlling for DLPFC GABA concentration. Anatomical specificity also held for the partial correlation between hippocampal GABA and BOLD responses during Think trials, controlling for DLPFC GABA. Finally, we examined whether DLPFC BOLD responses during the No-Think and Think conditions were correlated with DLPFC GABA. No relationships were observed, even when controlling for participant sex, DLPFC glutamate, and DLPFC gray matter concentrations (Table 2A). Moreover, whereas robust correlations on the visual cortical control ROI revealed a negative correlation between visual cortical GABA and co-localized BOLD during Think and No-Think trials, these relationships did not survive after controlling for participant sex, visual cortical glutamate, and visual cortical gray matter concentrations (Table 2D). Together, these findings suggest that hippocampal GABA is not simply a proxy for brain-wide GABA integrity, but rather captures region-specific variation, and that this variation is distinctively related to co-localized BOLD responses during memory retrieval and memory suppression.

The foregoing findings provide evidence for a functionally and anatomically specific relationship of GABA to memory tasks, whereby higher hippocampal GABA predicts reduced BOLD signal. Interestingly, we observed this relationship for both suppression and retrieval. Although we did not anticipate that hippocampal GABA would exhibit a negative relationship with retrieval-induced upregulation of hippocampal BOLD, this observation can be understood in retrospect. A key observation is that 1H MRS indices of bulk tissue GABA are unlikely to be tied to BOLD signal in any single task, but rather should be related to any psychological process that evokes high demand on local GABAergic interneuron populations. Retrieval processes during the Think condition likely also evoke increases in GABAergic interneuron activity. It is widely known, for example, that rhythmic firing of GABAergic interneurons in the hippocampus makes an essential contribution to the theta rhythm, which is believed to be critical for encoding and retrieval65,66,67,68. One speculation is that the observed relationship between GABA and retrieval-related BOLD signal reflects this key role of GABA interneurons, a possibility consistent with the fact that theta activity is sometimes associated with reduced BOLD signal (though the relationship of these variables is complex)69. This potential rhythmic engagement of hippocampal GABAergic interneurons in our retrieval task cannot be evaluated in the present data. Importantly, however, this speculated role of GABAergic interneurons in retrieval is functionally distinct from the increases in tonic inhibition36, 37 that we had hypothesized might underlie retrieval suppression, and the associated reduction in hippocampal BOLD signal.

Although the foregoing relationships between GABA and BOLD cannot, by themselves, distinguish the hypothesized tonic inhibition mechanism, our behavioral measures provide important information relevant to a distinct role of inhibition during thought suppression. If suppression engages GABAergic interneurons in a distinct manner, as we have hypothesized, baseline GABA measures should predict how effectively participants forget the thoughts they try to suppress. We tested this possibility by relating hippocampal GABA concentrations to performance on the final surprise recall test of the Think/No-Think paradigm (Methods section, Table 1B). Consistent with our initial hypothesis, a robust correlation analysis revealed that participants with higher hippocampal GABA exhibited better suppression of unwanted content, as reflected in higher suppression-induced forgetting (Baseline–No-Think). Hippocampal GABA did not, in contrast, predict retrieval-induced facilitation (r = −0.12, 95% CI: (−0.78 to 0.51)). We also did not observe a relationship between hippocampal GABA and pre-scan recall performance of the studied word pairs (r = −0.10, 95% CI: (−0.50 to 0.41)), indicating that the positive relationship between hippocampal GABA and suppression-induced forgetting is unlikely to be explained by a relationship between GABA and baseline learning success. To further interrogate the functional specificity of the relationship of hippocampal GABA to thought suppression, we examined whether hippocampal GABA predicted general indices of inhibitory control ability, as assessed with motor action-stopping speed on the SS Task (the stop signal reaction time). No such relationship was detected (Table 1B). Control partial correlation analyses confirmed that these relationships were not masked by participant sex, hippocampal gray matter content, or hippocampal glutamate concentrations. Together, these findings point to a specific relationship of hippocampal GABA to thought suppression, and not to general inhibitory control ability. Indeed, even when we accounted for individual variation in general inhibitory control ability (by including stop signal reaction time as a covariate in partial correlations), the hippocampal GABA-forgetting relationship was, if anything, strengthened (Table 1B).

We next tested whether suppression-induced forgetting was uniquely predicted by hippocampal GABA, or, was instead related to brain-wide GABA concentrations indexed from our three 1H MRS ROIs. To evaluate anatomical specificity, we conducted a partial correlation analysis that examined the relationship between hippocampal GABA and suppression-induced forgetting, while controlling for shared variance with DLPFC GABA. Critically, we found that the relationship between hippocampal GABA and suppression-induced forgetting persisted in this model (Table 1C). Moreover, we also directly tested whether DLPFC GABA itself predicted suppression-induced forgetting. We observed no such relationship, even when controlling for participant sex, DLPFC glutamate, and DLPFC gray matter concentration (Table 2B). GABA concentrations outside of the fronto-hippocampal pathway, in the visual cortical control ROI, also failed to account for significant variance in suppression-induced forgetting (Table 2E).

The foregoing findings suggest that GABA concentrations local to the hippocampus contribute to the persisting disruption of intrusive thoughts in healthy participants. Although the cellular mechanisms underlying the influence of GABA on memory cannot be established from MRS data, increased tonic inhibition has, in animal models, been found to attenuate synaptic plasticity, impairing memory70, 71. Conversely, in humans, experimentally reducing local GABA concentrations in motor cortex facilitates motor plasticity and increases co-localized BOLD response72. Taken together, these findings suggest that a suppression-related increase in tonic GABAergic inhibition could, in principle, disrupt plasticity in the hippocampus underlying episodic retention. More broadly, however, these findings are consistent with the hypothesis that although both retrieval and suppression are likely to engage hippocampal GABAergic inhibition networks, they do so in functionally distinct ways.

Reduced hippocampal GABA compromises prefrontal control

If intentionally suppressing thoughts engages hippocampal GABAergic networks in a functionally distinct manner, some mechanism must drive this activity. Prior effective connectivity analyses indicate that suppressing retrieval involves a goal-related signal that originates in right DLPFC and spreads downstream, via polysynaptic pathways28, to the hippocampus, integrating these regions in a task-dependent manner28,29,30,31,32,33,34,35, 41. If this fronto-hippocampal pathway provides afferent input that drives GABAergic processes during suppression, then how strongly DLPFC and hippocampus functionally integrate should depend on the availability of hippocampal GABA to implement retrieval stopping. Specifically, higher concentrations of hippocampal GABA should predict stronger negative DLPFC-hippocampal coupling. To test this possibility, we first used psychophysiological interaction (PPI) analysis67 to examine brain-wide task-dependent connectivity with the hippocampus, isolating all regions with which it shows suppression-related coupling (Supplementary Methods). The PPI thus enabled a whole-brain (data-driven) search for patterns of covariance with the hippocampus that differed significantly depending on whether participants retrieved thoughts (Think) or suppressed them (No-Think), after accounting for variance explained by main effects of task (No-Think, Think, Go, and Stop) and physiological (task-independent) correlations with the hippocampus (Fig. 3a).

Fig. 3 Hippocampal GABA predicts DLPFC-Hippocampal connectivity during thought suppression. a Schematic of psychophysiological interaction analysis (PPI) with hippocampal (HIP) seed and conditions modulating HIP connectivity. Significant PPI effects arose in right lateral prefrontal cortex: Brodmann’s area (BA) 46/9 (DLPFC) and BA45 (VLPFC), displayed as colored boundaries (see legend). b DLPFC activity during suppression (No-Think > Think) in the current (left) and in a prior study31 (right) overlapped with the PPI effects. c Functional connectivity: Suppression negatively modulated fronto-hippocampal coupling (PPI estimate, y axis), with the strength of negative coupling differing between low- and high-GABA subgroups (Independent samples t-test, *p < 0.05). Error bars represent standard error of the mean. d The six bidirectional dynamic causal models of the DLPFC–HIP network varied according to two parameters: Which Task modulated connectivity (horizontal lines: No-Think or Think) and source of Driving Input (Outer arrows: DLPFC, HIP, or BOTH). e Effective connectivity: for Low GABA participants, no clear evidence for a role of DLPFC in modulating connectivity emerged in any model. For high hippocampal GABA participants, model evidence (exceedence probabilities) favored a model with inputs to DLPFC driving the network and the No-Think task modulating connectivity Full size image

We observed task-dependent connectivity between the hippocampus and the right DLPFC (t 23 = 3.58, p = 0.034 after small volume FWE correction with an a priori DLPFC ROI31; Fig. 3a). Additional activations were detected in right inferior frontal gyrus, and in early visual cortex (at a more liberal uncorrected threshold, p < 0.005). This connectivity effect thus showed high anatomical specificity. We next projected onto the same cortical surface (A) the whole-brain main effect contrasts of retrieval suppression [No-Think > Think] observed in the current study, and (B) the study from which our a priori ROI is derived31. These clusters overlapped at the juncture of Brodmann Area (BA) 46, 9, and 10 in right middle frontal gyrus (Fig. 3b). Critically, these functional connectivity effects reflect negative modulation, that is, a task-dependent inversion of BOLD activity in hippocampus relative to DLPFC, consistent with our hypothesis that suppression-induced recruitment of right DLPFC signals retrieval suppression—and hence downregulation of BOLD activity—in the hippocampus (Fig. 3c). No regions expressing task-dependent positive modulation with the hippocampus were detected. These initial connectivity findings confirm that suppressing unwanted thoughts functionally integrates the right DLPFC and the hippocampus, consistent with a possible role of DLPFC in modulating unwanted hippocampal retrieval activity.

Of central interest, however, is whether the negative coupling observed between the DLPFC and hippocampus during suppression was associated with hippocampal GABA concentrations, as would be expected if local GABA contributed to inhibitory control. To assess this, we first tested with robust correlation analysis whether indices of DLPFC–hippocampal connectivity varied continuously with hippocampal GABA. Consistent with our hypothesis, individuals with higher hippocampal GABA exhibited stronger negative coupling of the DLPFC with the hippocampus (see Table 1C). Control partial correlation analyses confirmed that this relationship was not driven by variation in participant sex, hippocampal gray matter content, or hippocampal glutamate concentrations. The relationship also showed striking anatomical specificity within the fronto-hippocampal control pathway: A partial correlation analysis, controlling for DLPFC GABA, revealed that hippocampal GABA uniquely predicted PPI indices of connectivity with the DLPFC (Table 2C). We also examined whether DLPFC GABA was itself correlated with PPI indices of DLPFC connectivity. We observed no such relationship, even when controlling for participant’s sex, DLPFC glutamate, and DLPFC gray matter concentration (Table 2C). GABA concentrations in the visual cortical control ROI also failed to account for significant variance on the PPI indices of fronto-hippocampal coupling (Table 2F).

To further explore the anatomical specificity of hippocampal GABA to DLPFC-hippocampal coupling, we median split our sample into two subgroups with lower and higher hippocampal GABA concentrations (t 16 = 6.10, p = 0.00002). Crucially, these subgroups were matched on DLPFC (t 16 = 1.25, p = 0.23) and visual cortical GABA (t < 1), as well as on age, sex and several cognitive measures, including performance during initial word-pair training, motor response speed, and motor action inhibition (Supplementary Table 1). This approach enabled us to determine whether connectivity patterns differed depending on local hippocampal GABA, independent of GABA in other regions. We found that task-dependent DLPFC-hippocampal connectivity differed significantly between the high and low hippocampal GABA subgroups (t 16 = 2.39, p = 0.03): Whereas the high GABA subgroup showed negative coupling during retrieval suppression, the low GABA subgroup did not (Fig. 3c). Taken together, these findings are consistent with the hypothesis that suppressing unwanted thoughts engages GABAergic interneurons local to the hippocampus in a functionally distinct manner to implement an inhibitory control signal driven by DLPFC.

Although PPI analysis shows that condition-dependent coupling occurs between the DLPFC and the hippocampus, one cannot infer that suppression causes this integration or that the input driving hippocampal suppression originates in the DLPFC. To identify the causal dynamics of the proposed network, we used dynamic causal modeling, a Bayesian statistical framework for inferring effective connectivity between brain regions through a network composed of a small number of key brain regions68. We used a model space from a prior study31 that included the DLPFC and hippocampus as key regions. Briefly, the model space was defined by: (i) intrinsic bidirectional connections between the right DLPFC and the right hippocampus (modeling regional interactions that may be mediated polysynaptically), (ii) task-induced modulation of either the top-down connections from DLPFC to the hippocampus, bottom–up connections from the hippocampus to DLPFC, bidirectional connections, or no connections, and (iii) task-related input sources that drive activity in the network (e.g, No-Think and Think inputs driving activity either via the hippocampus, the DLPFC, or both). To further confirm the functional selectivity of the DLPFC-hippocampal pathway to suppressing unwanted thoughts, rather than to the broader process of inhibiting any type of response, we performed a parallel dynamic causal modeling analysis, using an analogous model space, but substituting the No-Think and Think conditions (parameters ii and iii) with the Stop and Go conditions of the stop-signal action inhibition task. We fit all of these models to the fMRI time series in each participant (Supplementary Methods).

Using this model space, we first evaluated the Think/No-Think task in the whole sample (N = 24). Replicating prior findings, we found the strongest evidence for models with bidirectional coupling between DLPFC and hippocampus31, 35 (Supplementary Notes). By contrast, when we performed a parallel analysis substituting the Think/No-Think task with the stop-signal action inhibition task (Stop, Go) we found no evidence that action-stopping modulated DLPFC-hippocampal connectivity (Supplementary Notes). Thus, the effective connectivity findings for the thought suppression and action inhibition tasks accord well with the hypothesis that DLPFC-hippocampal network dynamics support a function specific to thought suppression.