TMS-induced plasticity improving cognitive control in OCD I: Clinical and neuroimaging outcomes from a randomised trial of rTMS for OCD.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment option for obsessive-compulsive disorder (OCD). The neurobiological mechanisms of rTMS in OCD have, however, been incompletely characterized. We compared clinical outcomes and changes in task-based brain activation following three different rTMS stimulation protocols, all combined with exposure and response prevention (ERP). Methods: In this three-arm proof-of-concept randomized controlled clinical trial, 61 treatment-refractory adult OCD patients received 16 sessions of rTMS immediately prior to ERP over 8 weeks, with task-based functional MRI (tb-fMRI) scans and clinical assessments pre- and post-treatment. Patients received either: high frequency (HF) rTMS to the left dorsolateral prefrontal cortex (DLPFC) (n=19 (6M/13F)); HF rTMS to the left pre-supplementary motor area (preSMA) (n=23 (10M/13F)); or control rTMS to the vertex (n=19 (6M/13F)). Changes in tb-fMRI activation pre-post treatment were compared using both a Bayesian region-of-interest and a general linear model whole-brain approach. Results: Mean OCD symptom severity decreased significantly in all treatment groups (delta=- 10.836, p<0.001, 95% CI [-12.504, -9.168]), with no differences between groups. Response rate in the entire sample was 57.4%. Groups receiving DLPFC or preSMA rTMS showed, respectively, a decrease in planning and error processing task-related activation after treatment that was associated with symptom improvement, while individuals in the vertex rTMS group with greater symptom improvement showed an increase in inhibition-related activation. Conclusions: PreSMA and DLPFC rTMS combined with ERP led to significant symptom improvement related to activation decreases in targeted task networks, although we observed no differences in symptom reduction between groups. This trial was registered at clinicaltrials.gov ( NCT03667807 ).

Repetitive transcranial magnetic stimulation for obsessive-compulsive disorder: A systematic review and pairwise/network meta-analysis.

Background We evaluated the efficacy and safety of repetitive transcranial magnetic stimulation (rTMS) for obsessive-compulsive disorder (OCD), and ranked the relative efficacy of different stimulation protocols. Methods We performed a search for randomised, sham-controlled trials of rTMS for OCD. The primary analysis included both a pairwise meta-analysis and a series of frequentist network meta-analyses (NMA) of OCD symptom severity. Secondary analyses were carried out on relevant clinical factors and safety. Results 21 studies involving 662 patients were included. The pairwise meta-analysis showed that rTMS for OCD is efficacious across all protocols (Hedges' g=-0.502 [95%CI= -0.708, -0.296]). The first NMA, with stimulation protocols clustered only by anatomical location, showed that both dorsolateral prefrontal cortex (dlPFC) stimulation and medial frontal cortex stimulation were efficacious. In the second NMA, considering each unique combination of frequency and location separately, low frequency (LF) pre-supplementary motor area (preSMA) stimulation, high frequency (HF) bilateral dlPFC stimulation, and LF right dlPFC stimulation were all efficacious . LF right dlPFC was ranked highest in terms of efficacy, although the corresponding confidence intervals overlapped with the other two protocols. Limitations Evidence base included mostly small studies, with only a few studies using similar protocols, giving a sparse network. Studies were heterogeneous, and a risk of publication bias was found. Conclusions rTMS for OCD was efficacious compared with sham stimulation. LF right dlPFC, HF bilateral dlPFC and LF preSMA stimulation were all efficacious protocols with significant and comparable clinical improvements. Future studies should further investigate the relative merits of these three protocols.

Action Intentions, Predictive Processing, and Mind Reading: Turning Goalkeepers Into Penalty Killers.

The key to action control is one's ability to adequately predict the consequences of one's actions. Predictive processing theories assume that forward models enable rapid "preplay" to assess the match between predicted and intended action effects. Here we propose the novel hypothesis that "reading" another's action intentions requires a rich forward model of that agent's action. Such a forward model can be obtained and enriched through learning by either practice or simulation. Based on this notion, we ran a series of studies on soccer goalkeepers and novices, who predicted the intended direction of penalties being kicked at them in a computerized penalty-reading task. In line with hypotheses, extensive practice in penalty kicking improved performance in penalty reading among goalkeepers who had extensive prior experience in penalty blocking but not in penalty kicking. A robust benefit in penalty reading did not result from practice in kinesthetic motor imagery of penalty kicking in novice participants. To test whether goalkeepers actually use such penalty-kicking imagery in penalty reading, we trained a machine-learning classifier on multivariate fMRI activity patterns to distinguish motor-imagery-related from attention-related strategies during a penalty-imagery training task. We then applied that classifier to fMRI data related to a separate penalty-reading task and showed that 2/3 of all correctly read penalty kicks were classified as engaging the motor-imagery circuit rather than merely the attention circuit. This study provides initial evidence that, in order to read our opponent's action intention, it helps to observe their action kinematics, and use our own forward model to predict the sensory consequences of "our" penalty kick if we were to produce these action kinematics ourselves. In sum, it takes practice as a penalty kicker to become a penalty killer.

Fast and slow errors: Logistic regression to identify patterns in accuracy-response time relationships.

Understanding error and response time patterns is essential for making inferences in several domains of cognitive psychology. Crucial insights on cognitive performance and typical behavioral patterns are disclosed by using distributional analyses such as conditional accuracy functions (CAFs) instead of mean statistics. Several common behavioral error patterns revealed by CAFs are frequently described in the literature: response capture (associated with relatively fast errors), time pressure or urgency paradigms (slow errors), or cue-induced speed-accuracy trade-off (evenly distributed errors). Unfortunately, the standard way of computing CAFs is problematic, because accuracy is averaged in RT bins. Here we present a novel way of analyzing accuracy-RT relationships on the basis of nonlinear logistic regression, to handle these problematic aspects of RT binning. First we evaluate the parametric robustness of the logistic regression CAF through parameter recovery. Second, we apply the function to three existing data sets showing that specific parametric changes in the logistic regression CAF can consistently describe common behavioral patterns (such as response capture, time pressure, and speed-accuracy trade-off). Finally, we discuss potential modifications for future research.

Correction to: Fast and slow errors: Logistic regression to identify patterns in accuracy-response time relationships.

This paper originally published with incorrect figures, it has been corrected.

Repetitive transcranial magnetic stimulation over inferior frontal cortex impairs the suppression (but not expression) of action impulses during action conflict.

In the recent literature, the effects of noninvasive neurostimulation on cognitive functioning appear to lack consistency and replicability. We propose that such effects may be concealed unless dedicated, sensitive, and process-specific dependent measures are used. The expression and subsequent suppression of response capture are often studied using conflict tasks. Response-time distribution analyses have been argued to provide specific measures of the susceptibility to make fast impulsive response errors, as well as the proficiency of the selective suppression of these impulses. These measures of response capture and response inhibition are particularly sensitive to experimental manipulations and clinical deficiencies that are typically obfuscated in commonly used overall performance analyses. Recent work using structural and functional imaging techniques links these behavioral outcome measures to the integrity of frontostriatal networks. These studies suggest that the presupplementary motor area (pre-SMA) is linked to the susceptibility to response capture whereas the right inferior frontal cortex (rIFC) is associated with the selective suppression of action impulses. Here, we used repetitive transcranial magnetic stimulation (rTMS) to test the causal involvement of these two cortical areas in response capture and inhibition in the Simon task. Disruption of rIFC function specifically impaired selective suppression of conflicting action tendencies, whereas the anticipated increase of fast impulsive errors after perturbing pre-SMA function was not confirmed. These results provide a proof of principle of the notion that the selection of appropriate dependent measures is perhaps crucial to establish the effects of neurostimulation on specific cognitive functions.

Lateral frontal pole and relational processing: Activation patterns and connectivity profile.

The functional contribution of the lateral frontal cortex to behavior has been discussed with reference to several higher-order cognitive domains. In a separate line of research, recent studies have focused on the anatomical organization of this part of the brain. These different approaches are rarely combined. Here, we combine previous work using anatomical connectivity that identified a lateral subdivision of the human frontal pole and work that suggested a general role for rostrolateral prefrontal cortex in processing higher-order relations, irrespective of the type of information. We asked healthy human volunteers to judge the relationship between pairs of stimuli, a task previously suggested to engage the lateral frontal pole. Presenting both shape and face stimuli, we indeed observed overlapping activation of the lateral prefrontal cortex when subjects judged relations between pairs. Using resting state functional MRI, we confirmed that the activated region's whole-brain connectivity most strongly resembles that of the lateral frontal pole. Using diffusion MRI, we showed that the pattern of connections of this region with the main association fibers again is most similar to that of the lateral frontal pole, consistent with the observation that it is this anatomical region that is involved in relational processing.

TMS over M1 reveals expression and selective suppression of conflicting action impulses.

Goal-directed action control comes into play when selecting between competing action alternatives. Response capture reflects the susceptibility of the motor system to incitement by task-irrelevant action impulses; the subsequent selective suppression of incorrect action impulses aims to counteract response capture and facilitate the desired response. The goal of this experiment was to clarify physiological mechanisms of response capture and suppression of action impulses during conflict at the level of the motor system. We administered single-pulse TMS at various intervals preceding speeded choice responses. The correct response side was designated by stimulus color, whereas stimulus location (which could match or conflict with response side) was to be ignored. TMS pulses triggered motor evoked potential and silent period, providing sensitive indices of cortico-spinal excitation and inhibition. Motor evoked potential data showed the typical progressive increase in cortico-spinal motor excitability leading up to the imminent (correct) response, which started earlier on nonconflict than on conflict trials. On conflict trials, the irrelevant stimulus location captured the incorrect response, as expressed by an early and transient rise in excitability. Silent period data showed that, already early during the response process, inhibition of the incorrect response was stronger for conflict than for nonconflict trials. Furthermore, inhibition decreased over time for nonconflict trials facilitating the imminent correct response while maintaining higher levels of inhibition on conflict trials. In conclusion, dynamic patterns of cortico-spinal excitability provide unique physiological evidence for the expression and selective suppression of action impulses captured by competing action alternatives.

Paired-pulse transcranial magnetic stimulation reveals probability-dependent changes in functional connectivity between right inferior frontal cortex and primary motor cortex during go/no-go performance.

The functional role of the right inferior frontal cortex (rIFC) in mediating human behavior is the subject of ongoing debate. Activation of the rIFC has been associated with both response inhibition and with signaling action adaptation demands resulting from unpredicted events. The goal of this study is to investigate the role of rIFC by combining a go/no-go paradigm with paired-pulse transcranial magnetic stimulation (ppTMS) over rIFC and the primary motor cortex (M1) to probe the functional connectivity between these brain areas. Participants performed a go/no-go task with 20% or 80% of the trials requiring response inhibition (no-go trials) in a classic and a reversed version of the task, respectively. Responses were slower to infrequent compared to frequent go trials, while commission errors were more prevalent to infrequent compared to frequent no-go trials. We hypothesized that if rIFC is involved primarily in response inhibition, then rIFC should exert an inhibitory influence over M1 on no-go (inhibition) trials regardless of no-go probability. If, by contrast, rIFC has a role on unexpected trials other than just response inhibition then rIFC should influence M1 on infrequent trials regardless of response demands. We observed that rIFC suppressed M1 excitability during frequent no-go trials, but not during infrequent no-go trials, suggesting that the role of rIFC in response inhibition is context dependent rather than generic. Importantly, rIFC was found to facilitate M1 excitability on all low frequent trials, irrespective of whether the infrequent event involved response inhibition, a finding more in line with a predictive coding framework of cognitive control.