Volume 147, Issue 9, September 2024

This scientific commentary refers to ‘Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy’ by Kim et al. (https://doi.org/10.1093/brain/awae190).

This scientific commentary refers to ‘The interictal suppression hypothesis is the dominant differentiator of seizure onset zones in focal epilepsy’ by Doss et al. (https://doi.org/10.1093/brain/awae189).

This scientific commentary refers to ‘Frontotemporal lobar degeneration targets brain regions linked to expression of recently evolved genes’ by Pasquini et al. (https://doi.org/10.1093/brain/awae205).

This scientific commentary refers to ‘Artificial intelligence classifies primary progressive aphasia from connected speech’ by Rezaii et al. (https://doi.org/10.1093/brain/awae196).

Cristina Kroon and Britta Eickholt discuss current barriers to effective science communication and propose strategies to overcome them.

On behalf of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, Bagnato et al. present a consensus statement which provides guidance for the radiological definition and measurement of chronic active lesions in people with multiple sclerosis, and which identifies remaining gaps in knowledge.

The success of COVID-19 mRNA vaccines has rekindled interest in mRNA as a cost-effective means of delivering therapeutic proteins. Monfrini et al. explore potential applications of mRNA therapies for neurological monogenic loss-of-function diseases, and highlight some of the possibilities and challenges in this rapidly advancing field.

Chen et al. review the cerebrovascular contribution of apolipoprotein E to Alzheimer’s disease pathogenesis and propose a three-hit hypothesis outlining potential mechanisms. They then discuss possible therapeutic approaches for targeting apolipoprotein E-associated cerebrovascular pathology.

Kucewicz et al. review the role of high frequency gamma and ripple oscillations in human memory and cognition, and propose that these fast activity bursts track coordinated firing of neuronal assemblies across the brain during the formation and recall of memory traces.

Brain-specific somatic mosaicism can induce intractable epilepsy in childhood, but the mutation threshold that leads to brain dysfunction is unknown. Kim et al. induce different mosaic burdens in FCD II mice and find that 8000–9000 mutant neurons are sufficient to disrupt normal brain function and trigger epileptic seizures.

Spontaneous activity in dorsal root ganglion neurons is a key driver of neuropathic pain. Using cultured dorsal root ganglion neurons, Li et al. show that this spontaneous activity can be reversibly suppressed by an inhibitor of MNK signalling. These findings support the development of MNK inhibitors for the treatment of neuropathic pain.

Babu et al. evaluate the safety, pharmacokinetics, and pharmacodynamic activity of apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis in a randomized, biomarker-end-point trial. CNS penetrance and successful target engagement, plus favourable safety and tolerability, support further testing in a clinical efficacy trial.

Successful surgical treatment of epilepsy traditionally relies on identification of seizure onset zones. Network analyses may improve identification, but it is unclear which motif is best. Here, Doss et al. show that the network motif suggested by the interictal suppression hypothesis is the most robust for identifying seizure onset zones.

See Lagarde et al. (https://doi.org/10.1093/brain/awae256) for a scientific commentary on this article.

Del Vecchio et al. use stereo-EEG to shed light on the role of the frontal lobes in the processing of observed emotional expressions. They test the two predominant theories of face processing by combining intracranial recording, electrical stimulation, and effective connectivity tracing in surgical patients.

Frontotemporal lobar degeneration (FTLD) erodes brain functions that have evolved relatively recently in humans, such as language and social behaviour. Pasquini et al. explore whether brain regions targeted by FTLD are linked to expression of genes that have undergone positive selection during human evolution.

See Shen et al. (https://doi.org/10.1093/brain/awae267) for a scientific commentary on this article.

Chu et al. identify specific atrophy networks associated with different clinical subtypes of frontotemporal dementia, and with apathy and disinhibition. The findings will aid the selection of future neuromodulation targets for the treatment of frontotemporal dementia.

Perivascular macrophages are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Bohannon et al. show that a brain-penetrant colony-stimulating factor 1 receptor kinase inhibitor depletes brain perivascular macrophages but not microglia and reduces brain viral load in SIV-infected rhesus macaques.

Rezaii et al. used large language models to analyse patient speech samples, and found that the three variants of primary progressive aphasia (PPA) emerged as natural clusters. They then identified language features distinctive for each cluster, resulting in a classifier with 97.9% accuracy in distinguishing PPA clusters and healthy controls.

See Hillis (https://doi.org/10.1093/brain/awae242) for a scientific commentary on this article.

Using fibre microdissections in postmortem human brains and population-based fibre tractography, Skandalakis et al. show that the ventral tegmental area participates in an intricate network involving limbic, striatal, basal forebrain, and prefrontal circuits. These findings can inform personalized DBS approaches for neuropsychiatric disorders.

Huynh et al. investigate why Huntington’s disease and schizophrenia share many features, including white matter loss, hyperexcitability and synaptic dysfunction. They find that glial progenitor cells—necessary for white matter and synaptic maintenance—are similarly defective in each disease, with shared abnormalities in differentiation.

Peripheral nerve insulation requires an intricate relationship between neurons and Schwann cells which is highly dependent on lipids. Prior et al. show how an excess of the PMP22 protein dysregulates the storage of lipids and their incorporation into the plasma membrane of Schwann cells, giving rise to Charcot–Marie–Tooth disease type 1A.

Biallelic mutations in SORD, which encodes the enzyme sorbitol dehydrogenase, cause a recessive motor-predominant neuropathy. Rebelo et al. generate a rat model of SORD neuropathy which closely mimics the human phenotype, and show that the animals have increased levels of sorbitol in serum, CSF and peripheral nerve.

Record et al. present the genetic breakdown for 1515 patients with Charcot-Marie-Tooth disease assessed at a single specialist inherited neuropathy centre. Whole genome sequencing contributed to a ‘solved’ rate of 76.9%, enhancing a diagnostic strategy based on phenotype-driven analysis and a multidisciplinary team approach.

Vincristine-induced pain is a common side effect of vincristine chemotherapy and can be dose-limiting. By establishing an animal model, Nascimento de Lima et al. show that Na_v1.8 channels contribute to vincristine-induced pain, and that deletion of Na_v1.8 in DRG neurons delays the onset of this pain.

Kim et al. study the function of RIM4, a member of a key family of scaffolding proteins. Mice lacking RIM4 in cerebellar Purkinje cells display spontaneous episodes of motor impairment that mimic behaviours observed in patients with paroxysmal dystonia, suggesting an essential role for RIM4 in Purkinje cell physiology.

Paß et al. present a mouse model which mimics the lifelong accumulation of mitochondrial DNA mutations in nigral dopaminergic neurons in humans. The mice show normal motor function in old age, despite severe loss of nigral dopaminergic neurons, due to a compensatory increase in synaptic terminals originating from the surviving neurons.

Using a novel technique to wirelessly record neural signals from already-implanted deep-brain stimulators in patients with Parkinson's disease in an outpatient setting, Soh et al. show that the subthalamic nucleus—known for its role in motor control—also exerts control over non-motoric, attentional processes.

Brain injury is common in very low birthweight infants. Bahari et al. explore whether neuronal membrane salt and water co-transporters play a role in the neuronal response to injury, and whether manipulation of co-transporters could have therapeutic potential.

Gene therapy can improve vision in patients with the retinal disease Leber’s congenital amaurosis. Ashtari et al. reveal a shift in visual processing towards the retinotectal pathway in affected individuals, and show that gene therapy partly reinstates visual transmission through the geniculostriate pathway.

Mycobacterium tuberculosis causes pulmonary tuberculosis and tuberculosis meningitis, but the mechanisms by which the latter develops are unknown. Spatola et al. show that antibodies against Mycobacterium tuberculosis in the brain may play a role in the development and severity of tuberculosis meningitis.