Brain最新文献

Despite decades of development and clinical application, drug-resistant epilepsy occurs in 25%-30% of patients. One limiting factor in the success of antiseizure medications are challenges in mapping the neural effects of epilepsy drugs to seizure mechanisms in humans. Most antiseizure medications were developed in animal models and primarily target nano-scale structures like ion channels and receptors. However, they exert their effects and are typically measured in humans at the macro-scale using techniques like EEG and conventional functional MRI (fMRI). This disconnect between the mechanisms of pharmaceutical interventions and the clinical management of epilepsy leaves a critical gap in our understanding. This is because all seizures, even those of a generalized nature, appear to initiate in intermediate scale, local microcircuits and then propagate from that initial ictogenic zone. Invasive electrophysiological recordings in both animal models and humans have shown that one such microcircuit, cortical layers, and more specifically deep cortical layers, play a critical role in seizure generation in both generalized and focal epilepsies, serving as the critical link between nano-scale dysfunctions and the macro-scale activity observed in seizures. Laminar fMRI, a technique capable of resolving activity across cortical depths, offers a promising avenue to bridge this gap. By providing a non-invasive measure of laminar response alterations in humans, it could complement animal model and electrophysiological findings, offering novel insights into the layer-specific mechanisms of seizure generation and propagation in humans. This review discusses evidence for this concept, highlighting key findings from animal models and human intracranial recordings in this regard, and details how laminar fMRI may be able to refine our understanding of epilepsy at the microcircuit level. It concludes with a discussion regarding the possible role of laminar fMRI in improving surgical targeting for focal epilepsies, elucidating the mechanistic effects of antiseizure medications, and ultimately, targeting current and future epilepsy treatments.

Centronuclear myopathies (CNM) are rare congenital disorders characterized by muscle weakness and disorganization of myofibres. These conditions can result from dominant mutations in the DNM2 gene encoding the GTPase dynamin, making them potential targets for antisense therapy. Preclinical studies suggested decreasing DNM2 as a therapy but a recent clinical trial with antisense oligonucleotides did not effectively address the disease and showed some non-muscle toxicity. Here, to promote DNM2 downregulation in muscle versus other tissues, we used an exon skipping peptide-conjugated phosphorodiamidate morpholino (PPMO) targeting Dnm2 exon 6 splicing in the Dnm2R369W/+ mouse model for the moderate CNM form. Intravenous administration of PPMOs at an early age (4 weeks) significantly downregulated intact (i.e. normally spliced) Dnm2 mRNA (∼50%) and DNM2 protein levels in muscle. This intervention led to a rescue of muscle force, thereby preventing disease progression. PPMO administration at a later age (8 weeks), when mice demonstrated established phenotypes, efficiently decreased intact Dnm2 mRNA and protein levels in muscle, resulting in reversal of the disease phenotype and significant improvement in muscle force (from 11 mN/mg to nearly 16 mN/mg). Overall, our results indicate that PPMOs targeting Dnm2 splicing effectively decrease intact Dnm2 mRNA and protein levels in muscle and rescue muscle force in Dnm2R369W/+ mice, suggesting a promising translational approach for patients with DNM2 mutations and potentially other forms of CNM. More generally, it provides the concept of using the exon skipping strategy to decrease the protein expression of a target gene, rather than producing a shorter functional protein as is generally done.

Depression in people with multiple sclerosis (MS) is two to three times more frequent than in demographically matched people without MS. The MS-depression literature is large and has expanded exponentially over the past few years. This increase in new knowledge is the impetus for assessing whether there is now sufficient evidence to differentiate depression linked to multiple sclerosis from depression alone. Establishing the validity of MS-depression as a distinct diagnosis is important because it would enhance our understanding of the pathogenesis of depression in general, shed light on a clinical course that might diverge from what is expected from depression without MS, and suggest management strategies that may differ from those followed for people with depression alone. A review of the MS-depression literature from January 2018 to December 2024 (generating 114 papers for inclusion in the manuscript) reveals no unique, distinct MS-depression phenomenology. The factors encompassing predictive validity, namely the course of depression, employment, suicide, cognitive impairment and quality of life, are similar in kind but not severity between depressed people with and without MS. The paucity of randomized controlled trial psychotropic data in MS-related depression means it is unclear whether medication plus psychotherapy is the best treatment option for people with MS who are depressed, as it is in general population samples. In terms of construct validity, the posited immune signature of MS depression, namely an increased frequency of circulating CD4+CCR7low central memory T cells with a Th1 predilection, does not appear to be distinct from depression in the general population. There is considerable neuroimaging commonality, particularly in limbic regional involvement. The potential importance of the dopamine-rich ventral tegmental area in a putative MS depression neural circuit suggests a degree of specificity, but the absence of direct comparison between depressed people with and without MS hinders a more definite conclusion. As for personality factors and socio-economic status in depressed people with MS, the findings essentially overlap with the depression literature in the general population. There are, however, a couple of standout constructs suggesting the possibility of two distinct disorders: the equivocal data pertaining to a specific MS genetic diathesis to depression and the absence of a clear sex difference in depressed people with MS. Until these conundrums are explained, one cannot conclude with certainty that depression in people with and without MS is the same disorder. Further research comparing depressed people with and without MS is needed to understand why this difference may exist.