Right inferior frontal gyrus damage is associated with impaired initiation of inhibitory control, but not its implementation
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eLife assessment
This study takes a fresh view of the hypothesis that right inferior frontal gyrus is critical in inhibitory control in humans, as assessed by the widely-used stop signal task. It applies recent development in modeling and EEG measures in patients with focal brain damage, yielding causal insights. It will be of interest to neuroscientists and clinical researchers who study the brain basis of response control. Reviewers found this to be a strong, hypothesis-driven study that makes new progress on an important topic.
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Abstract
Inhibitory control is one of the most important control functions in the human brain. Much of our understanding of its neural basis comes from seminal work showing that lesions to the right inferior frontal gyrus (rIFG) increase stop-signal reaction time (SSRT), a latent variable that expresses the speed of inhibitory control. However, recent work has identified substantial limitations of the SSRT method. Notably, SSRT is confounded by trigger failures: stop-signal trials in which inhibitory control was never initiated. Such trials inflate SSRT, but are typically indicative of attentional, rather than inhibitory deficits. Here, we used hierarchical Bayesian modeling to identify stop-signal trigger failures in human rIFG lesion patients, non-rIFG lesion patients, and healthy comparisons. Furthermore, we measured scalp-EEG to detect β-bursts, a neurophysiological index of inhibitory control. rIFG lesion patients showed a more than fivefold increase in trigger failure trials and did not exhibit the typical increase of stop-related frontal β-bursts. However, on trials in which such β-bursts did occur, rIFG patients showed the typical subsequent upregulation of β over sensorimotor areas, indicating that their ability to implement inhibitory control, once triggered, remains intact. These findings suggest that the role of rIFG in inhibitory control has to be fundamentally reinterpreted.
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eLife assessment
This study takes a fresh view of the hypothesis that right inferior frontal gyrus is critical in inhibitory control in humans, as assessed by the widely-used stop signal task. It applies recent development in modeling and EEG measures in patients with focal brain damage, yielding causal insights. It will be of interest to neuroscientists and clinical researchers who study the brain basis of response control. Reviewers found this to be a strong, hypothesis-driven study that makes new progress on an important topic.
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Reviewer #1 (Public Review):
The core question addressed by this study is whether right IFC damage disrupts stop-signal task performance because it plays a key role in response inhibition per se, or because it is crucial for attending to the need to engage response inhibition. A relatively large sample of patients with damage including right IFC, as well as lesioned and healthy control groups, were assessed on the stop-signal task accompanied by scalp EEG. The behavioral data were analyzed using hierarchical Bayesian modeling. Right IFC damage was associated with more trials where 'stopping' was not initiated, while an EEG hallmark of inhibitory control was present in trials where stopping initiation did occur, arguing that rIFG damage disrupts attention to the stop signal, rather than the inhibition that follows.
This is an interesting …
Reviewer #1 (Public Review):
The core question addressed by this study is whether right IFC damage disrupts stop-signal task performance because it plays a key role in response inhibition per se, or because it is crucial for attending to the need to engage response inhibition. A relatively large sample of patients with damage including right IFC, as well as lesioned and healthy control groups, were assessed on the stop-signal task accompanied by scalp EEG. The behavioral data were analyzed using hierarchical Bayesian modeling. Right IFC damage was associated with more trials where 'stopping' was not initiated, while an EEG hallmark of inhibitory control was present in trials where stopping initiation did occur, arguing that rIFG damage disrupts attention to the stop signal, rather than the inhibition that follows.
This is an interesting study testing a well-defined hypothesis relevant to competing views of the brain basis of inhibitory control. The experimental design is sophisticated and the analysis was preregistered. The acquisition of both behavioral and EEG data in lesion patients provides converging evidence and supports causal inference.
Interpretation of the results hinges on accepting that a hierarchical Bayesian model is appropriate for discriminating trials where stopping was 'triggered' from trials where there was no trigger. Likewise, we need to accept the EEG frontal beta burst pattern is an indicator of response inhibition. Both of these methodological elements have support from existing literature, although I don't think either of these has been applied in chronic focal lesion patients, so there may be technical issues to consider in their interpretation. Finally, as with most human lesion studies, caution should be applied in interpreting the critical lesion location: in this sample, the effects might relate to insula damage, or to white matter disruption within the ventrolateral/lateral frontal lobe or between those regions and subcortical regions. However, these provisos do not detract from the key finding that damage somewhere in these areas affected initiation/attentional processes rather than response control per se.
The results are more consistent with an attentional account of right IFG (or more broadly, right ventral frontal lobe) contributions to stop-signal task performance; this is provocative in light of current views of prefrontal contributions to inhibitory control, although in line with a wider literature implicating right frontoparietal circuitry in selective attention. As the authors suggest, a sharp distinction between attention and inhibition may be somewhat artificial: these processes may be closely interrelated in speeded tasks requiring response interruption. However, the present study cleverly tackles the challenge of disentangling them, applying recent modeling and EEG distinctions with interesting results.
The findings are helpful in further sharpening ideas regarding the neural basis of response control. They also have potential theoretical implications and perhaps direct experimental application in clinical-applied research on disorders of inhibitory control.
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Reviewer #2 (Public Review):
The present manuscript revisits the perennial (and important) question of which role the right IFG (rIFG) plays exactly in response inhibition. It does so using a stop-signal task in a patient group with lesions focused on rIFG, as well as a matched healthy control group, along with a group of control patients with lesions outside of the rIFG, and again a matched healthy control group. The behavioral data are analyzed with a novel parametric modeling approach that allows characterizing the distributions of Go RTs as well as the stop-signal reaction time (SSRT). Crucially, in the present form, it also accounts for so-called trigger failures, a long-known (but nearly equally long mostly ignored) phenomenon describing the failure to even initiate an inhibitory process (rather than the latency of this process …
Reviewer #2 (Public Review):
The present manuscript revisits the perennial (and important) question of which role the right IFG (rIFG) plays exactly in response inhibition. It does so using a stop-signal task in a patient group with lesions focused on rIFG, as well as a matched healthy control group, along with a group of control patients with lesions outside of the rIFG, and again a matched healthy control group. The behavioral data are analyzed with a novel parametric modeling approach that allows characterizing the distributions of Go RTs as well as the stop-signal reaction time (SSRT). Crucially, in the present form, it also accounts for so-called trigger failures, a long-known (but nearly equally long mostly ignored) phenomenon describing the failure to even initiate an inhibitory process (rather than the latency of this process being too long to succeed). Not accounting for trigger failures is known to inflate SSRT, and conceptually, they have been linked more to attentional processes than specifically to response inhibition. Here it is shown that behavioral deficits in rIFG patients are more strongly related to trigger failures than to the SSRT. This is elegantly complemented by the EEG data, where it is shown that mid-frontal beta bursts are strongly reduced in the rIFG group, but not in the others. Finally, it is shown that these mid-frontal beta bursts lead to corresponding beta bursts over the motor cortex. Importantly, this is also still the case for the rIFG patient group on successful stop trials where such mid-frontal beta bursts happened.
The present work has many strong elements. The use of a targeted patient group, with additional control groups, gets this research closer to causality than e.g. a pure EEG study could. The employed methods (computational modeling, beta bursts) are all cutting-edge and very appropriate, and the results form a coherent story, which is interpreted appropriately. The manuscript is also clear, yet very succinct, which at times might come at some cost towards following the details of the analysis and results, in particular, and some additional analyses might further strengthen the authors' claims. For example, there seems to be no reference to a traditional, non-parametric SSRT estimate, the size of the reduction of which by accounting for trigger failures might be a better metric of how central accounting for trigger failures is, rather than the five-fold TF increase in this group over the others (all of which have very low percentages, which put also a manifold increase into perspective). Maybe also more generally, the conceptual distinction between initiation and actual implementation of inhibition could be further sharpened, including with reference to the residual SSRT group effect from the parametric analysis, which is still quite sizable.
Given its innovative approach and important findings, the present results will undoubtedly have a major impact on the field of response inhibition, which is also relevant to the clinical domain.
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