The Core outcome Clubfoot (CoCo) study: relapse, with poorer clinical and quality of life outcomes, affects 37% of idiopathic clubfoot patients.

Aims: There is a lack of high-quality research investigating outcomes of Ponseti-treated idiopathic clubfeet and correlation with relapse. This study assessed clinical and quality of life (QoL) outcomes using a standardized core outcome set (COS), comparing children with and without relapse. Methods: A total of 11 international centres participated in this institutional review board-approved observational study. Data including demographics, information regarding presentation, treatment, and details of subsequent relapse and management were collected between 1 June 2022 and 30 June 2023 from consecutive clinic patients who had a minimum five-year follow-up. The clubfoot COS incorporating 31 parameters was used. A regression model assessed relationships between baseline variables and outcomes (clinical/QoL). Results: Overall, 293 patients (432 feet) with a median age of 89 months (interquartile range 72 to 113) were included. The relapse rate was 37%, with repeated relapse in 14%. Treatment considered a standard part of the Ponseti journey (recasting, repeat tenotomy, and tibialis anterior tendon transfer) was performed in 35% of cases, with soft-tissue release and osteotomies in 5% and 2% of cases, respectively. Predictors of relapse included duration of follow-up, higher initial Pirani score, and poor Evertor muscle activity. Relapse was associated with poorer outcomes. Conclusion: This is the first multicentre study using a standardized COS following clubfoot treatment. It distinguishes patients with and without relapse in terms of clinical outcomes and QoL, with poorer outcomes in the relapse group. This tool allows comparison of treatment methods and outcomes, facilitates information sharing, and sets family expectations. Predictors of relapse encourage us to create appropriate treatment pathways to reduce relapse and improve outcome.

A 'Hub and Spoke' Shared Care initiative for CTEV Ponseti service.

Aims: The Ponseti method is the gold standard treatment for congenital talipes equinovarus (CTEV), with the British Consensus Statement providing a benchmark for standard of care. Meeting these standards and providing expert care while maintaining geographical accessibility can pose a service delivery challenge. A novel 'Hub and Spoke' Shared Care model was initiated to deliver Ponseti treatment for CTEV, while addressing standard of care and resource allocation. The aim of this study was to assess feasibility and outcomes of the corrective phase of Ponseti service delivery using this model. Methods: Patients with idiopathic CTEV were seen in their local hospitals ('Spokes') for initial diagnosis and casting, followed by referral to the tertiary hospital ('Hub') for tenotomy. Non-idiopathic CTEV was managed solely by the Hub. Primary and secondary outcomes were achieving primary correction, and complication rates resulting in early transfer to the Hub, respectively. Consecutive data were prospectively collected and compared between patients allocated to Hub or Spokes. Mann-Whitney U test, Wilcoxon signed-rank test, or chi-squared tests were used for analysis (alpha-priori = 0.05, two-tailed significance). Results: Between 1 March 2020 and 31 March 2023, 92 patients (139 feet) were treated at the service (Hub 50%, n = 46; Spokes 50%, n = 46), of whom nine were non-idiopathic. All patients (n = 92), regardless of allocation, ultimately achieved primary correction, with idiopathic patients at the Hub requiring fewer casts than the Spokes (mean 4.0 (SD 1.4) vs 6.9 (SD 4.4); p < 0.001). Overall, 60.9% of Spokes' patients (n = 28/46) required transfer to the Hub due to complications (cast slips Hub n = 2; Spokes n = 17; p < 0.001). These patients ultimately achieved full correction at the Hub. Conclusion: The Shared Care model was found to be feasible in terms of providing primary correction to all patients, with results comparable to other published services. Complication rates were higher at the Spokes, although these were correctable. Future research is needed to assess long-term outcomes, parents' satisfaction, and cost-effectiveness.

A Diversity of Intrinsic Timescales Underlie Neural Computations.

Neural processing occurs across a range of temporal scales. To facilitate this, the brain uses fast-changing representations reflecting momentary sensory input alongside more temporally extended representations, which integrate across both short and long temporal windows. The temporal flexibility of these representations allows animals to behave adaptively. Short temporal windows facilitate adaptive responding in dynamic environments, while longer temporal windows promote the gradual integration of information across time. In the cognitive and motor domains, the brain sets overarching goals to be achieved within a long temporal window, which must be broken down into sequences of actions and precise movement control processed across much shorter temporal windows. Previous human neuroimaging studies and large-scale artificial network models have ascribed different processing timescales to different cortical regions, linking this to each region's position in an anatomical hierarchy determined by patterns of inter-regional connectivity. However, even within cortical regions, there is variability in responses when studied with single-neuron electrophysiology. Here, we review a series of recent electrophysiology experiments that demonstrate the heterogeneity of temporal receptive fields at the level of single neurons within a cortical region. This heterogeneity appears functionally relevant for the computations that neurons perform during decision-making and working memory. We consider anatomical and biophysical mechanisms that may give rise to a heterogeneity of timescales, including recurrent connectivity, cortical layer distribution, and neurotransmitter receptor expression. Finally, we reflect on the computational relevance of each brain region possessing a heterogeneity of neuronal timescales. We argue that this architecture is of particular importance for sensory, motor, and cognitive computations.

Visual fixation patterns during economic choice reflect covert valuation processes that emerge with learning.

Visual fixations play a vital role in decision making. Recent studies have demonstrated that the longer subjects fixate an option, the more likely they are to choose it. However, the role of evaluating stimuli covertly (i.e., without fixating them), and how covert evaluations determine where to subsequently fixate, remains relatively unexplored. Here, we trained monkeys to perform a decision-making task where they made binary choices between reward-predictive stimuli which were well-learned ("overtrained"), recently learned ("novel"), or a combination of both ("mixed"). Subjects were free to saccade around the screen and make a choice (via joystick response) at any time. Subjects rarely fixated both options, yet choice behavior was better explained by assuming the values of both stimuli governed choices. The first fixation latency was fast (∼150 ms) but, surprisingly, its direction was value-driven. This suggests covert evaluation of stimulus values prior to first saccade. This was particularly evident for overtrained stimuli. For novel stimuli, first fixations became increasingly value-driven throughout a behavioral session. However, this improvement lagged behind learning of accurate economic choices, suggesting separate processes governed their learning. Finally, mixed trials revealed a strong bias toward fixating the novel stimulus first but no bias toward choosing it. Our results suggest that the primate brain contains fast covert evaluation mechanisms for guiding fixations toward highly valuable and novel information. By employing such covert mechanisms, fixation behavior becomes dissociable from the value comparison processes that drive final choice. This implies that primates use separable decision systems for value-guided fixations and value-guided choice.

Reconciling persistent and dynamic hypotheses of working memory coding in prefrontal cortex.

Competing accounts propose that working memory (WM) is subserved either by persistent activity in single neurons or by dynamic (time-varying) activity across a neural population. Here, we compare these hypotheses across four regions of prefrontal cortex (PFC) in an oculomotor-delayed-response task, where an intervening cue indicated the reward available for a correct saccade. WM representations were strongest in ventrolateral PFC neurons with higher intrinsic temporal stability (time-constant). At the population-level, although a stable mnemonic state was reached during the delay, this tuning geometry was reversed relative to cue-period selectivity, and was disrupted by the reward cue. Single-neuron analysis revealed many neurons switched to coding reward, rather than maintaining task-relevant spatial selectivity until saccade. These results imply WM is fulfilled by dynamic, population-level activity within high time-constant neurons. Rather than persistent activity supporting stable mnemonic representations that bridge subsequent salient stimuli, PFC neurons may stabilise a dynamic population-level process supporting WM.

Selective Suppression of Local Interneuron Circuits in Human Motor Cortex Contributes to Movement Preparation.

Changes in neural activity occur in the motor cortex before movement, but the nature and purpose of this preparatory activity is unclear. To investigate this in the human (male and female) brain noninvasively, we used transcranial magnetic stimulation (TMS) to probe the excitability of distinct sets of excitatory inputs to corticospinal neurons during the warning period of various reaction time tasks. Using two separate methods (H-reflex conditioning and directional effects of TMS), we show that a specific set of excitatory inputs to corticospinal neurons are suppressed during motor preparation, while another set of inputs remain unaffected. To probe the behavioral relevance of this suppression, we examined whether the strength of the selective preparatory inhibition in each trial was related to reaction time. Surprisingly, the greater the amount of selective preparatory inhibition, the faster the reaction time was. This suggests that the inhibition of inputs to corticospinal neurons is not involved in preventing the release of movement but may in fact facilitate rapid reactions. Thus, selective suppression of a specific set of motor cortical neurons may be a key aspect of successful movement preparation.SIGNIFICANCE STATEMENT Movement preparation evokes substantial activity in the motor cortex despite no apparent movement. One explanation for the lack of movement is that motor cortical output in this period is gated by an inhibitory mechanism. This notion was supported by previous noninvasive TMS studies of human motor cortex indicating a reduction of corticospinal excitability. On the contrary, our data support the idea that there is a coordinated balance of activity upstream of the corticospinal output neurons. This includes a suppression of specific local circuits that supports, rather than inhibits, the rapid generation of prepared movements. Thus, the selective suppression of local circuits appears to be an essential part of successful movement preparation instead of an external control mechanism.

Autocorrelation structure at rest predicts value correlates of single neurons during reward-guided choice.

Correlates of value are routinely observed in the prefrontal cortex (PFC) during reward-guided decision making. In previous work (Hunt et al., 2015), we argued that PFC correlates of chosen value are a consequence of varying rates of a dynamical evidence accumulation process. Yet within PFC, there is substantial variability in chosen value correlates across individual neurons. Here we show that this variability is explained by neurons having different temporal receptive fields of integration, indexed by examining neuronal spike rate autocorrelation structure whilst at rest. We find that neurons with protracted resting temporal receptive fields exhibit stronger chosen value correlates during choice. Within orbitofrontal cortex, these neurons also sustain coding of chosen value from choice through the delivery of reward, providing a potential neural mechanism for maintaining predictions and updating stored values during learning. These findings reveal that within PFC, variability in temporal specialisation across neurons predicts involvement in specific decision-making computations.