Trajectory Modeling and Response Prediction in Transcranial Magnetic Stimulation for Depression.

Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by better and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modelling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models can predict clinical outcomes. We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression (TRD), across multiple coils and protocols. We then compared the predictive power of those models. LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52-0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 - 0.94], but likewise, not before. In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.

Psychometric validation and clinical correlates of an experiential foraging task.

Measuring the function of decision-making systems is a central goal of computational psychiatry. Individual measures of decisional function could be used to describe neurocognitive profiles that underpin psychopathology and offer insights into deficits that are shared across traditional diagnostic classes. However, there are few demonstrably reliable and mechanistically relevant metrics of decision making that can accurately capture the complex overlapping domains of cognition whilst also quantifying the heterogeneity of function between individuals. The WebSurf task is a reverse-translational human experiential foraging paradigm which indexes naturalistic and clinically relevant decision-making. To determine its potential clinical utility, we examined the psychometric properties and clinical correlates of behavioural parameters extracted from WebSurf in an initial exploratory experiment and a pre-registered validation experiment. Behaviour was stable over repeated administrations of the task, as were individual differences. The ability to measure decision making consistently supports the potential utility of the task in predicting an individual's propensity for response to psychiatric treatment, in evaluating clinical change during treatment, and in defining neurocognitive profiles that relate to psychopathology. Specific aspects of WebSurf behaviour also correlate with anhedonic and externalising symptoms. Importantly, these behavioural parameters may measure dimensions of psychological variance that are not captured by traditional rating scales. WebSurf and related paradigms might therefore be useful platforms for computational approaches to precision psychiatry.

Engagement of the contralateral limb can enhance the facilitation of motor output by loud acoustic stimuli.

When intense sound is presented during light muscle contraction, inhibition of the corticomotoneuronal pathway is observed. During action preparation, this effect is reversed, with sound resulting in excitation of the corticomotoneuronal pathway. We investigated how the combined maintenance of a muscle contraction during preparation for a ballistic action impacts the magnitude of the facilitation of motor output by a loud acoustic stimulus (LAS), a phenomenon known as the StartReact effect. Participants executed ballistic wrist flexion movements and a LAS was presented simultaneously with the imperative signal in a subset of trials. We examined whether the force level or muscle used to maintain a contraction during preparation for the ballistic response impacted reaction time and/or the force of movements triggered by the LAS. These contractions were sustained either ipsilaterally or contralaterally to the ballistic response. The magnitude of facilitation by the LAS was greatest when low-force flexion contractions were maintained in the limb contralateral to the ballistic response during preparation. There was little change in facilitation when contractions recruited the contralateral extensor muscle or when they were sustained in the same limb that executed the ballistic response. We conclude that a larger network of neurons that may be engaged by a contralateral sustained contraction prior to initiation may be recruited by the LAS, further contributing to the motor output of the response. These findings may be particularly applicable in stroke rehabilitation, where engagement of the contralesional side may increase the benefits of a LAS to the functional recovery of movement.NEW & NOTEWORTHY The facilitation of reaction time, force, and vigor of a ballistic action by loud acoustic stimuli can be enhanced by the maintenance of a sustained contraction during preparation. This enhanced facilitation is observed when the sustained contraction is maintained with low force contralaterally and congruently with the ballistic response. This increased facilitation may be particularly applicable to rehabilitative applications of loud acoustic stimuli in improving the functional recovery of movement after neurological conditions such as stroke.

Premovement inhibition can protect motor actions from interference by response-irrelevant sensory stimulation.

KEY POINTS: Suppression of corticospinal excitability is reliably observed during preparation for a range of motor actions, leading to the belief that this preparatory inhibition is a physiologically obligatory component of motor preparation. The neurophysiological function of this suppression is uncertain. We restricted the time available for participants to engage in preparation and found no evidence for preparatory inhibition. The function of preparatory inhibition can be inferred from our findings that sensory stimulation can disrupt motor output in the absence of preparatory inhibition, but enhance motor output when inhibition is present. These findings suggest preparatory inhibition may be a strategic process which acts to protect prepared actions from external interference. Our findings have significant theoretical implications for preparatory processes. Findings may also have a pragmatic benefit in that acoustic stimulation could be used therapeutically to facilitate movement, but only if the action can be prepared well in advance. ABSTRACT: Shortly before movement initiation, the corticospinal system undergoes a transient suppression. This phenomenon has been observed across a range of motor tasks, suggesting that it may be an obligatory component of movement preparation. We probed whether this was also the case when the urgency to perform a motor action was high, in a situation where little time was available to engage in preparatory processes. We controlled the urgency of an impending motor action by increasing or decreasing the foreperiod duration in an anticipatory timing task. Transcranial magnetic stimulation (TMS; experiment 1) or a loud acoustic stimulus (LAS; experiment 2) were used to examine how corticospinal and subcortical excitability were modulated during motor preparation. Preparatory inhibition of the corticospinal tract was absent when movement urgency was high, though motor actions were initiated on time. In contrast, subcortical circuits were progressively inhibited as the time to prepare increased. Interestingly, movement force and vigour were reduced by both TMS and the LAS when movement urgency was high, and enhanced when movement urgency was low. These findings indicate that preparatory inhibition may not be an obligatory component of motor preparation. The behavioural effects we observed in the absence of preparatory inhibition were induced by both TMS and the LAS, suggesting that accessory sensory stimulation may disrupt motor output when such stimulation is presented in the absence of preparatory inhibition. We conclude that preparatory inhibition may be an adaptive strategy which can serve to protect the prepared motor action from external interference.

Cumulative distribution functions: An alternative approach to examine the triggering of prepared motor actions in the StartReact effect.

There has been much debate concerning whether startling sensory stimuli can activate a fast-neural pathway for movement triggering (StartReact) which is different from that of voluntary movements. Activity in sternocleidomastoid (SCM) electromyogram is suggested to indicate activation of this pathway. We evaluated whether SCM activity can accurately identify trials which may differ in their neurophysiological triggering and assessed the use of cumulative distribution functions (CDFs) of reaction time (RT) data to identify trials with the shortest RTs for analysis. Using recent data sets from the StartReact literature, we examined the relationship between RT and SCM activity. We categorised data into short/longer RT bins using CDFs and used linear mixed-effects models to compare potential conclusions that can be drawn when categorising data on the basis of RT versus on the basis of SCM activity. The capacity of SCM to predict RT is task-specific, making it an unreliable indicator of distinct neurophysiological mechanisms. Classification of trials using CDFs is capable of capturing potential task- or muscle-related differences in triggering whilst avoiding the pitfalls of the traditional SCM activity-based classification method. We conclude that SCM activity is not always evident on trials that show the early triggering of movements seen in the StartReact phenomenon. We further propose that a more comprehensive analysis of data may be achieved through the inclusion of CDF analyses. These findings have implications for future research investigating movement triggering as well as for potential therapeutic applications of StartReact.

Neural gain induced by startling acoustic stimuli is additive to preparatory activation.

Loud acoustic stimuli presented during movement preparation can shorten reaction time and increase response forcefulness. We examined how efferent connectivity of an agonist muscle to reticulospinal and corticospinal pathways, and the level of prepared movement force, affect reaction time and movement execution when the motor response is triggered by an intense acoustic stimulus. In Experiment 1, participants executed ballistic wrist flexion and extension movements of low and high force in response to visual stimuli. A loud acoustic stimulus (LAS; 105 dBa) was presented simultaneously with the visual imperative stimulus in probe trials. In Experiment 2, participants executed ballistic wrist flexion movements ranging from 10%-50% of maximum voluntary contraction with a LAS presented in probe trials. The shortening of response initiation was not affected by movement type (flexion or extension) or prepared movement force. Enhancement of response magnitude, however, was proportionally greater for low force movements and for the flexor muscle. Changes in peak force induced by the intense acoustic stimulus indicated that the neural activity introduced to motor program circuits by acoustic stimulation is additive to the voluntary neural activity that occurs due to movement preparation, rather than multiplicative.