Brain Sciences

Background: Multiple sclerosis (MS) lacks a single invariant phenotypic core. Patients accumulate heterogeneous combinations of sensory, motor, cognitive, and autonomic impairments over time, reflecting lesions that are disseminated in time and space. Standard scales such as the Expanded Disability Status Scale (EDSS) distribute disability across functional systems, but do not explicitly represent MS phenotype as a mixture of latent symptom modules. Methods: We analyzed 4617 de-identified neurology progress notes from 577 patients with MS at a single academic medical center. A large language model (GPT-5.2) categorized each note with respect to 17 non-mutually-exclusive neurological phenotype features, and note-level features were aggregated to patient-level binary vectors. Non-negative matrix factorization (NMF) was applied to generate three-, four-, and five-module solutions. For each rank, we computed approximate variance captured, relative reconstruction error, and module-level feature loadings. In the preferred four-module solution, we derived patient-level module percentages, identified highly dominant (≥55%) and archetypal (≥70%) module profiles, and quantified admixture using Shannon entropy and the effective number of modules. Results: Three-, four-, and five-module NMF solutions showed similar approximate variance captured (52.7–54.3%) and reconstruction error (0.47–0.53), but the four-module solution provided the clearest clinical interpretation. The four latent modules were sensory-visual-pain, ataxic-spastic-falls, cognitive-psychologic-fatigue, and autonomic-bladder-bowel, aligning closely with established functional systems in MS. Most patients exhibited admixed phenotypes, with module entropies ranging from 0 (single-module dominance) to 1.386 (equal mixture) and effective modules spanning approximately 1 to 4. Using pre-specified thresholds, 154 patients (26.6%) were highly dominant in a single module and 72 (12.5%) were archetypal; these purer phenotypes were most often in the sensory-visual-pain module. Conclusions: MS phenotypic diversity in routine clinical practice can be parsimoniously represented as mixtures of four latent symptom modules rather than as positions along a single severity axis. Most patients show substantial admixture of sensory, motor, cognitive, and autonomic involvement, but a minority exhibit relatively pure or strongly dominant module patterns. This modular representation provides an interpretable framework for quantifying MS phenotype and for generating testable hypotheses about MS subtypes whose biological relevance remains to be established.

Mastication is a fundamental rhythmic motor behavior controlled by a brainstem central pattern generator (CPG) located within the pontine and medullary reticular formations. Coordinated activation of jaw-opening and jaw-closing muscles is generated by this network and continuously refined through sensory feedback from periodontal mechanoreceptors and muscle spindles, together with descending inputs from the cortical masticatory area (CMA), basal ganglia, and cerebellum. Thus, mastication is regulated by distributed neural circuits rather than a single central locus. At the cellular level, the rhythmic activity of the masticatory CPG depends on the coordinated action of voltage-gated and ligand-gated ion channels. Recent electrophysiological and computational studies have identified candidate conductances that are proposed to underlie rhythm generation. Persistent sodium currents are proposed to facilitate burst initiation, whereas T-type calcium channels are thought to promote burst activation through post-inhibitory rebound. HCN channels may contribute to rhythmic timing, while calcium-activated potassium channels are thought to participate in burst termination. This review summarizes the hierarchical neural control of mastication and the biophysical mechanisms by which ion channels shape CPG rhythmogenesis. It also discusses the impact of channelopathies and neurodegenerative disorders on masticatory function, highlighting potential ion-channel-targeted therapeutic approaches for temporomandibular disorders, bruxism, and impaired mastication.

Stereotactic radiosurgery (SRS) delivers high doses of focused ionizing radiation (IR) to a defined target while sparing surrounding tissues. The delivery of focused doses of IR has proven to be an effective modality for the treatment of brain tumors, cerebrovascular lesions, and primary neuropathic pain conditions. More recently, the emerging concept of “radiomodulation” to rewire neural circuitry through the delivery of focused IR to specific neural relay centers has emerged as an alternative way to treat neurological conditions, such as essential tremor, trigeminal neuralgia, and psychiatric illnesses. In this article, we performed a scoping review of the existing data supporting the ability of focused doses of ionizing radiation to achieve modulation of neural circuits for the treatment of neurological conditions. We review the current understanding of the neurophysiological mechanisms of radiomodulation, the gaps in knowledge limiting its widespread use for in-human applications and stress the unmet need for ongoing research to rigorously prove that radiomodulation may be the “final frontier” as a non-invasive, non-pharmacological, versatile, and tunable modality for the treatment of a multitude of neurological conditions.