Transcranial focused ultrasound to human rIFG improves response inhibition through modulation of the P300 onset latency
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eLife assessment
This important study reports on the causal role of the inferior frontal gyrus (IFG) in behavioral control. Transcranial ultrasonic stimulation is used to stimulate the IFG in a stop-signal task. The results are compelling while the analyses remain incomplete and some claims are unsubstantiated.
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Abstract
Response inhibition in humans is important to avoid undesirable behavioral action consequences. Neuroimaging and lesion studies point to a locus of inhibitory control in the right inferior frontal gyrus (rIFG). Electrophysiology studies have implicated a downstream event-related potential from rIFG, the fronto-central P300, as a putative neural marker of the success and timing of inhibition over behavioral responses. However, it remains to be established whether rIFG effectively drives inhibition and which aspect of P300 activity uniquely indexes inhibitory control—ERP timing or amplitude. Here, we dissect the connection between rIFG and P300 for inhibition by using transcranial-focused ultrasound (tFUS) to target rIFG of human subjects while they performed a Stop-Signal task. By applying tFUS simultaneously with different task events, we found behavioral inhibition was improved, but only when applied to rIFG simultaneously with a ‘stop’ signal. Improved inhibition through tFUS to rIFG was indexed by faster stopping times that aligned with significantly shorter N200/P300 onset latencies. In contrast, P300 amplitude was modulated during tFUS across all groups without a paired change in behavior. Using tFUS, we provide evidence for a causal connection between anatomy, behavior, and electrophysiology underlying response inhibition.
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eLife assessment
This important study reports on the causal role of the inferior frontal gyrus (IFG) in behavioral control. Transcranial ultrasonic stimulation is used to stimulate the IFG in a stop-signal task. The results are compelling while the analyses remain incomplete and some claims are unsubstantiated.
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Reviewer #1 (Public Review):
The authors set out to determine the causal influence of the rIFG on stop-signal inhibition by using the innovative method of focused ultrasound to modulate this area during a stop-signal task. They report that tFUS during the stop signal only (and not the go) affected the probability of making a stop (only for long SSD) and reduced reaction time. tFUS also looked to affect some ERP components thus lending 'causal' evidence for the role of rIFG in stopping behavior and N200/P300 dynamics. The background and premise seem solid, the experimental design looks appropriate with good controls however, I do not think the authors' conclusions are supported. The methods are difficult to understand, and lack citations (background for performing these analyses/pre-processing) - some are listed but not in the reference …
Reviewer #1 (Public Review):
The authors set out to determine the causal influence of the rIFG on stop-signal inhibition by using the innovative method of focused ultrasound to modulate this area during a stop-signal task. They report that tFUS during the stop signal only (and not the go) affected the probability of making a stop (only for long SSD) and reduced reaction time. tFUS also looked to affect some ERP components thus lending 'causal' evidence for the role of rIFG in stopping behavior and N200/P300 dynamics. The background and premise seem solid, the experimental design looks appropriate with good controls however, I do not think the authors' conclusions are supported. The methods are difficult to understand, and lack citations (background for performing these analyses/pre-processing) - some are listed but not in the reference list - but also leave out important methodology and detail. Despite the fact that there are many statistical tests in the results there are none for their main conclusions that the P300 latency indexes stop-signal inhibition - this is only descriptive. Individuals with expertise in the field of stop signal inhibition are encouraged to read this pre-print to gauge the veracity of the authors' conclusions and the appropriateness of their methodology.
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Reviewer #2 (Public Review):
The authors investigated a central component of adaptive and flexible human behaviour: our ability to stop ongoing action plans. This ability is under prefrontal control, with an important contribution of the right inferior prefrontal gyrus (rIFG). This is a well-studied system, yet providing causal evidence, especially at an electrophysiological level, has proven challenging. In this study the authors use a novel non-invasive brain stimulation technique, transcranial ultrasonic stimulation (TUS), to selectively stimulate the rIFG and record behavioural and electrophysiological changes in the context of a stop-signal task.
The principal finding of this work is that following TUS over rIFG, participants are faster to respond to a stop signal when successfully inhibiting a planned action program. This faster …
Reviewer #2 (Public Review):
The authors investigated a central component of adaptive and flexible human behaviour: our ability to stop ongoing action plans. This ability is under prefrontal control, with an important contribution of the right inferior prefrontal gyrus (rIFG). This is a well-studied system, yet providing causal evidence, especially at an electrophysiological level, has proven challenging. In this study the authors use a novel non-invasive brain stimulation technique, transcranial ultrasonic stimulation (TUS), to selectively stimulate the rIFG and record behavioural and electrophysiological changes in the context of a stop-signal task.
The principal finding of this work is that following TUS over rIFG, participants are faster to respond to a stop signal when successfully inhibiting a planned action program. This faster stop-inhibition was reflected both in behaviour and evoked responses as measured with electroencephalography.
The spatial specificity of the TUS stimulation allows strong inferences on selective targeting. The inclusion of two control groups, one receiving stimulation over an active control site, and the other receiving a non-stimulating sham condition, makes the specificity of the observed effect convincing.
The EEG analyses are advanced, exploiting robust data-cleaning and selection approaches to allow strong inferences for analyses in sensor space. Through careful trial-matching and dynamic time-warping, the effects of primary interest - responses evoked by stopping behaviour - could be isolated from those evoked by the go-cue and go-response.
The manuscript focusses on the latency of the electrophysiological response (ERP). Indeed, an earlier P300 ERP is expected considering that TUS over rIFG led to an earlier stop-signal-reaction time (SSRT). However, as the SSRT is inferred from a model fit on the probability of go-responses as a function of the stop-signal delay (more often failing to inhibit go-responses when the stop-signal arrives late), the empirical observation of a latency shift in the closely related P300 ERP is valuable.
It is less clear how the P300 ERP itself relates to the TUS stimulation over rIFG, considering that this ERP has a well-established mid-frontal topology, while rIFG is in the lateral prefrontal cortex. The authors suggest that in the context of stopping control, rIFG is positioned upstream from the mid-frontal regions. However, previous work has revealed an inverse temporal and causal relationship, where rIFG contributions follow those of preSMA (e.g. Neubert et al., 2010, PNAS).
Behavioural changes, especially those dependent on attention and a speeded response, are commonly driven by non-specific cues, such as auditory, somatosensory, or multi-modal cues. This is a major confounding factor for all brain stimulation paradigms. TUS is no exception. Pulsed TUS protocols, such as the 1000 Hz pulsed protocol employed here, are very likely to be accompanied by an auditory confound. In the condition of interest in this experiment, TUS is delivered together with the visual stop-signal, creating a multimodal cue. In the main analyses (figures 3 and 4) this is only contrasted against conditions where the stop-signal is unimodal (visual) only, creating a multi-modal vs. uni-modal contrast.
Indeed, the critical comparison to allow the strongest inference is not between stop-TUS vs. go-TUS, nor between stop-TUS vs. no-TUS, but between the two TUS sites: rIFG-TUS vs rS1-TUS in the stop condition. The inclusion of the S1-TUS condition in this study is therefore highly valuable, although this contrast was implemented as a between-group design, and no assessment of confound matching between rIFG-TUS and S1-TUS is reported. Perhaps more importantly, the main analyses and figures (e.g. figure 3), do not include this comparison. In fact, the data from the TUS control-site group are not included in any analyses of evoked potentials (EEG) at all (e.g. figure 4), even though this is the main focus of the study.
The title of the study is "Transcranial focused ultrasound to rIFG improves response inhibition through modulation of the P300 onset latency". The discussion reads "P300 latency modulation occurred only in the rIFG group". It is not straightforward to see how this conclusion is supported without including a control site in the analyses. Further, the reported difference in onset latency is based on a visual inspection of the data, not on a quantified statistical analysis ("visually contrasting SS-US difference waveforms across tFUS conditions (Fig. 4B, upper right) revealed P300 onsets shifted earlier during Stop-tFUS"). Visual inspection of the same figure might also highlight a clear difference in ERP amplitude, in addition to latency. Lastly, the suggestion of a directional mediation effect ("improves response inhibition through modulation of the P300 onset latency") is only supported by a correlational analysis relating P300 onset latency with the estimated stop-signal-reaction-time.
In summary, by advancing transcranial ultrasonic stimulation to study prefrontal control, this work signifies a paradigm shift towards using interventional tools in cognitive neuroscience. The specificity and precision that ultrasound stimulation provides, with reduced discomfort as compared to TMS, are urgently needed to support a refined and causal understanding of the neural circuits underlying human cognition. The central claims of this study are partially supported by the data presented and might benefit from quantitatively comparing the effects of TUS over the region of interest and the control site.
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