Purkinje cells (PCs) mediate adaptive cerebellar output through inhibitory control of the cerebellar nuclei. Because many PCs converge, their influence on target neurons likely depends on population activity. However, despite a large literature on individual PC relationships with behavior, little is known about how multiple PCs collaborate to influence movement. In simultaneously recorded PCs during mouse forelimb reach behavior, we found that different kinematic variables correlated either with PC firing rates or covariance: reach velocity and deceleration correlated with firing rates, while the coordination of these kinematic variables, which influences reach amplitudes, was related to covariance. In a model, physiological levels of PC covariance elevated nuclear firing rates, which could promote faster reach deceleration than the same conditions with low covariance. These findings suggest a role for coherent PC population activity to coordinate movement.

Exercise-based physical therapy is effective for managing Achilles tendinopathy. Despite these successes, up to 45% of patients do not respond to therapy. The mechanisms differentiating patients who improve and those who do not remain unclear, although differences in pre-rehabilitation pain, tendon structure and function might explain this individual variability. The aim was to explore differences in pain, structure, and functional changes between patients with and without meaningful self-perceived resolution following a 12-week eccentric rehabilitation protocol for Achilles tendinopathy. Thirty-seven patients with chronic midportion Achilles tendinopathy (28 M/9F; 46 ± 12 years) followed a 12-week eccentric rehabilitation protocol. Functional and structural measurements and questionnaires were assessed pre- and post-intervention to evaluate pain, tendon structure, and function. A blinded medical doctor classified treatment response based on patient-perceived resolution, grouping participants into those with meaningful improvement (N = 28) and those without (N = 9). Patients without meaningful improvement had significantly higher VISA-A scores, greater free Achilles tendon stiffness, and higher pain-onset hopping repetitions (all p < 0.05) pre-intervention compared to those who reported meaningful improvement. After 12 weeks of rehabilitation, VISA-A and pain-onset hopping repetitions showed significant effects for time (p = 0.010; p = 0.024), group (p = 0.022; p = 0.003), and interaction (p = 0.032; p = 0.002). Tendon stiffness, maximal voluntary contraction, and palpation pain changed significantly over time (p = 0.009; p = 0.016; p = 0.044, respectively). Achilles tendon loading during dynamic exercises showed no between-group differences (all p > 0.05). Higher baseline functioning was linked to reduced improvement following rehabilitation, indicating that baseline functional status may influence treatment outcomes. Recognizing such baseline differences could help predict patient-perceived resolution and guide individualized interventions.

The central nervous system (CNS) can effectively control body movements despite environmental changes. While much is known about adaptation to external environmental changes, less is known about responses to internal bodily changes. This study investigates how the CNS adapts to long-term alterations in the musculoskeletal system using a tendon transfer model in nonhuman primates (Macaca fuscata). We surgically relocated finger flexor and extensor muscles to examine how the CNS adapts its strategy for finger movement control by measuring muscle activities during grasping tasks. Two months post-surgery, the monkeys demonstrated significant recovery of grasping function despite the initial disruption. Our findings suggest a two-phase CNS adaptation process: an initial phase enabling function with the transferred muscles, followed by a later phase abandoning this enabled function and restoring a control strategy that, while potentially less conflicted than the maladaptive state, resembled the original pattern, possibly representing a 'good enough' solution. These results highlight a multi-phase CNS adaptation process with distinct time constants in response to sudden bodily changes, offering potential insights into understanding and treating movement disorders.

BackgroundThe International Headache Society has proposed new treatment goals for migraine prevention in real world, as a way to set higher standards of care. This study provides the first assessment of the proportion of individuals achieving them after 6 months of migraine-specific treatment with anti-CGRP monoclonal antibodies (MAbs).MethodsThis was a prospective, real-world, European multicenter study, including adults with migraine treated with anti-CGRP MAbs (EUREkA cohort). We assessed the proportions of individuals in each treatment goal category-migraine freedom (no monthly migraine days [MMD]); optimal control (< 4 MMD), modest control (4-6 MMD); insufficient control (>6 MMD)-after 6 months of treatment. We also assessed the proportion of individuals with ≥50% reduction in MMD in the insufficient control group.ResultsOf the 5818 individuals in the EUREkA cohort, 4963 had 6 months data. Of these, 82.3% (4086/4963) were females and the median age was 48.0 [40.0-55.0] years. At baseline, the median monthly headache days [MHD] and MMD were 20.0 [13.3-28.0] and 15.0 [10.0-20.0], respectively. All participants were classified as having insufficient headache control (>6 MMD) at baseline. At month 6, 6.9% (342/4963) had migraine freedom, 22.9% (1137/4963) optimal control, 24.6% (1223/4963) modest control and 45.6% (2261/4963) insufficient control. In the insufficient control group, 27.1% (613/2261) had ≥50% reduction in MMD.ConclusionsHigh standards of care, defined as optimal disease control or even migraine freedom, are achieved in real-world settings with anti-CGRP MAbs in approximately 30% of individuals with a high migraine burden. These findings highlight the need to expand global access to these treatments. Future studies should explore whether initiating migraine-specific preventive treatments earlier could further reduce residual migraine days in responders, enabling a larger proportion of patients to achieve optimal disease control.

Abnormal calcium deposits in areas of the brain that control movement, including basal ganglia and cerebellum, are the hallmark of Fahr's syndrome. This report highlights the importance of clinicians being vigilant regarding behavioral and neuropsychiatric symptoms when evaluating cases of dystonia. These important clues indicate underlying inherited and neurodegenerative disorders.

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are progressive neurodegenerative disorders characterized by alpha-synuclein pathology. As current therapies largely target symptoms, there is a clear need for disease-modifying treatments. Emerging evidence links these disorders to glucose metabolism dysregulation, suggesting antidiabetic agents may hold therapeutic potential.

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behavior, and the motor cortex (MC), which executes movement. A hallmark of primate brain evolution is PFC expansion accompanied by a posterior displacement of the MC. Retinoic acid (RA) signaling has emerged as a key regulator of PFC specification and expansion. However, the mechanisms that spatially confine RA signaling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we defined an RA-associated gene regulatory network (RA-GRN) in the developing human PFC and identified MEIS2 , which encodes a transcription factor linked to intellectual disability and autism spectrum disorder (ASD), as its key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories toward motor-like molecular and connectional features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signaling itself, is markedly reduced in the developing medial prefrontal cortex (mPFC). These findings revealed a conserved autoregulatory loop: RA → MEIS2 → ALDH1A3 → RA that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signaling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to psychiatric disorders.