Evidence indicates that such hyperactivity arises in part from dysfunctional GABAergic interneurons, and post-mortem anatomical studies confirm substantial hippocampal parvalbumin-positive and somatostatin-positive interneuron loss in victims of the disease 13 , 14 , Consistent with this view, animal models of schizophrenia show that disrupting GABAergic inhibition in the hippocampus by transgenic or pharmacological manipulations reliably reproduces hippocampal hyperactivity and volume loss, along with behavioral phenomena paralleling symptoms present in this disorder 21 , Interestingly, abnormally elevated hippocampal activity also occurs in post-traumatic stress disorder and major depression, and this pattern predicts both flashback intensity and depressive rumination 10 , 16 , 17 , 18 , In both of these disorders, impaired GABAergic inhibition in the hippocampus could contribute to these symptoms, possibly by a cascade of processes initiated by stress Indeed, animal models of anxiety often focus on compromised GABAergic inhibition in the hippocampus, which produces symptoms consistent with a dysregulation in affective control, including impaired extinction of conditioned fear 24 , 25 , 26 , Together, these findings suggest that a deficit of GABAergic inhibition local to the hippocampus contributes to problems controlling a spectrum of intrusive memories and thoughts, although the pathogenesis of this deficit and its specific manifestations across disorders may vary.
The basic link between hippocampal GABA and the capacity to control unwanted thoughts, however, remains unexplored.
Here we test a novel hypothesis about how hippocampal GABA supports this core feature of voluntary control over the contents of awareness. We hypothesized that GABAergic inhibition in the hippocampus forms a critical link in a fronto-hippocampal inhibitory control pathway that suppresses unwanted thoughts.
Observations from both human neuroimaging and rodent electrophysiology motivate this hypothesis. Human imaging studies indicate that when individuals are given a reminder to an unwanted thought and try to suppress the thought from awareness, the right dorsolateral prefrontal cortex DLPFC acts, via polysynaptic pathways 28 , to downregulate hippocampal activity, inducing forgetting of suppressed content 29 , 30 , 31 , 32 , 33 , 34 , This provides a systems level model for how thought suppression occurs.
Rodent electrophysiology, on the other hand, demonstrates that tonically disinhibiting GABAergic interneuron networks in the hippocampus desynchronizes hippocampal rhythms, reducing overall activity and impairing memory function 36 , Taken together, these observations raise the possibility that suppressing retrieval to stop an unwanted thought recruits a fronto-hippocampal inhibitory control pathway that engages this hippocampal GABAergic mechanism.
Specifically, prefrontal control signals may tonically increase activity in local hippocampal interneuron networks, inhibiting and desynchronizing principal cell activity throughout the hippocampus, impairing retrieval and disrupting memory. If this hypothesis is correct, diminished GABAergic tone local to the hippocampus may mute the inhibitory impact of control signals originating from DLPFC, compromising the ability to suppress unwanted content.
The Mechanism of Meaning
This same deficit of GABAergic tone may also cause abnormally elevated hippocampal activity hippocampal hyperactivity , explaining the recurring association between this feature and intrusive symptomatology. This multimodal neuroimaging strategy provided, within the same individuals, co-localized in vivo measures of hippocampal BOLD response and GABA concentration. To establish whether hippocampal GABA plays a functionally specific role in inhibiting thoughts, participants also performed a motor action inhibition task 39 , 40 while fMRI was acquired, providing an index of inhibitory control over actions rather than thoughts.
We, therefore, sought to determine whether hippocampal GABA selectively enables the control of unwanted thoughts, and if this arises because hippocampal GABA alters the impact of the putative fronto-hippocampal inhibitory control pathway. We found that higher GABA concentrations local to the hippocampus predicted superior forgetting of the thoughts that people tried to suppress, and, critically, the ability of the prefrontal cortex to exert long-range control over hippocampal retrieval processes.
Our findings are consistent with the possibility that hippocampal GABA may play an important role in enabling the prefrontal cortex to suppress unwanted thoughts. 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 content 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 38 , 41 , 42 , 43 , These hemodynamic and behavioral effects occur with a broad range of stimuli, including neutral or unpleasant words 29 , 30 , 31 , 38 , 42 , visual objects 34 , neutral or unpleasant scenes 32 , 33 , 41 , 43 , 44 , autobiographical memories 45 , and person-specific fears about their future Critically, populations that suffer from persistent intrusive thoughts such as those with post-traumatic stress disorder PTSD 44 , depression 46 , 47 , and anxiety 48 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 individuals 49 and in PTSD 44 , scores on clinical scales of ruminative thinking 50 and anxiety 35 , 48 , and measures of the general ability to control intrusive thoughts in daily life 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.
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 function Domain-specific modulation during thought and action suppression. Thought suppression modulated bilateral hippocampal HIP activity. Action-stopping-modulated activity in primary motor cortex M1 , lateralized to the left contralateral to hand hemisphere.
Color bars demarcate T -statistics. Error bars represent SEM. Alternating with blocks of the TNT task, participants also performed the SS task, a well-established procedure for measuring the inhibition of motor actions 39 , 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 contexts Critically, action stopping and thought suppression preferentially modulated the left M1 and hippocampus, respectively Fig.
In a Region M1 vs. Hippocampus by Modality Thoughts vs. Actions by Task Inhibition vs. 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.
We next tested whether our hemodynamic and behavioral measures of thought suppression were related to hippocampal GABA. To do so, we employed 1 H 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 metabolites 56 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. As a control, we also measured GABA in the primary visual cortex, a region outside the proposed pathway Supplementary Fig.
Blue line: raw metabolite spectra for an example subject. Black line: residuals after fitting. Both plots use identical scaling. Colors indicate minimum blue and maximum red height of spectral contours arbitrary units. 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 removed 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 1 H 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 concentration 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 interneurons 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 inhibition 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.
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. 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 task 20 e.
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. 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.
This relationship could, for example, reflect GABAergic integrity throughout the broader fronto-hippocampal pathway supporting the suppression of unwanted thoughts 28 , 29 , 30 , 31 , 32 , 33 , 34 , 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.
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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. 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 retrieval 65 , 66 , 67 , 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 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 inhibition 36 , 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. 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. 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.
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.
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 memory 70 , Conversely, in humans, experimentally reducing local GABA concentrations in motor cortex facilitates motor plasticity and increases co-localized BOLD response 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.
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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. 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 pathways 28 , to the hippocampus, integrating these regions in a task-dependent manner 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 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.
To test this possibility, we first used psychophysiological interaction PPI analysis 67 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.
Error bars represent standard error of the mean. This connectivity effect thus showed high anatomical specificity. These clusters overlapped at the juncture of Brodmann Area BA 46, 9, and 10 in right middle frontal gyrus Fig.
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.
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.
Control partial correlation analyses confirmed that this relationship was not driven by variation in participant sex, hippocampal gray matter content, or hippocampal glutamate concentrations. This approach enabled us to determine whether connectivity patterns differed depending on local hippocampal GABA, independent of GABA in other regions.