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Deep brain stimulation is known to treat the symptoms of stiffness, slow movement, and tremor in people with Parkinson’s disease. Researchers are now a step closer to understanding exactly how this electrical stimulation of specific areas in the brain works.
©
James Fitzgerald
Phase-dependent closed-loop deep brain stimulation of the fornix provides bidirectional manipulation of hippocampal theta oscillations.
INTRODUCTION: Alzheimer's disease (AD) has very limited treatment options and therapies to prevent or reverse neurodegeneration remain elusive. Deep brain stimulation (DBS), whereby high-frequency pulses of electricity are delivered continuously to a specific part of the brain, has been trialled as an experimental treatment for AD. In AD patients, continuous, high frequency DBS targeted to the fornix (fx-DBS) has been shown to be safe, but not reliably effective across patients. In movement disorders, high-frequency DBS is thought to act as a virtual lesion, disrupting pathophysiological activity. In AD, it may be more advantageous to use stimulation to reinforce or rebuild oscillatory activities that are disrupted by the disease process. A primary candidate for such a target is the hippocampal theta oscillation, which provides a temporal framework for mnemonic processing and is altered in rodent models of AD. MATERIAL AND METHODS: We applied closed-loop electrical stimulation to the fornix of rats traversing a linear track, triggered by different phases of the ongoing theta oscillation in the hippocampal local field potential (LFP) using the OscillTrack algorithm. RESULTS: Stimulation at different target phases could robustly suppress or amplify the theta oscillation, and these effects were significantly larger than those caused by open-loop replay of the same stimulation pattern. Amplification of the theta oscillation could be achieved irrespective of the locomotor speed of the animal, showing that it did not result from a secondary effect of behavioural change. CONCLUSIONS: Our findings demonstrate that closed-loop fx-DBS is a viable method of modulating the amplitude of hippocampal theta oscillations that could be applied in human devices to provide a constructive intervention with the potential to boost memory circuit function in AD.
Nature documentaries vs. quiet rest: no evidence for an impact on event-related desynchronization during motor imagery and neurofeedback
Motor imagery (MI) in combination with neurofeedback (NF) has emerged as a promising approach in motor neurorehabilitation, facilitating brain activity modulation and promoting motor learning. Although MI-NF has been demonstrated to enhance motor performance and cortical plasticity, its efficacy varies considerably across individuals. Various context factors have been identified as influencing neurophysiological outcomes in motor execution and MI, however, their specific impact on event-related desynchronization (ERD), a key neurophysiological marker in NF, remains insufficiently understood. Previous research suggested that declarative interference following MI-NF may serve as a context factor hindering the progression of ERD. Yet, no significant changes in ERD within the mu and beta (8–30 Hz) frequency bands were observed across blocks in either a declarative interference or a control condition. This raises the question of whether the absence of ERD modulation could be attributed to the break task that was common to both declarative interference and control condition: watching nature documentaries immediately after MI blocks. To investigate this, we conducted a follow-up study replicating the original methodology while collecting new data. We compared NF-MI-ERD between groups with and without nature documentaries as a post-MI condition. Participants completed three sessions of kinesthetic MI-NF training involving a finger-tapping task over two consecutive days, with quiet rest as the post-MI condition (group quiet rest). 64-channel EEG data were analyzed from 17 healthy participants (8 females, 18–35 years, M and SD: 25.2 ± 4.2 years). Data were compared to a previously recorded dataset (group documentaries), in which 17 participants (10 females, 23–32 years, M and SD: 25.8 ± 2.5 years) watched nature documentaries after MI blocks. The results showed no significant main effects for blocks or group, though a session-by-group interaction was observed. Post-hoc tests, however, did not reveal significant differences in ERD development between the groups across individual blocks. These findings do not provide evidence that nature documentaries used as a post-MI condition negatively affect across-block development of NF-MI-ERD. This study highlights the importance of exploring additional context factors in MI-NF training to better understand their influence on ERD development.
High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.
An intronic G4C2 repeat expansion in the C9ORF72 gene is the major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence for both, loss of function and pathological gain of function disease mechanisms. We screened 96 200 small molecules in C9ORF72 patient iPS neurons for modulation of nuclear G4C2 RNA foci and identified 82 validated hits, including the Brd4 inhibitor JQ1 as well as novel analogs of Spliceostatin-A, a known modulator of SF3B1, the branch point binding protein of the U2-snRNP. Spliceosome modulation by these SF3B1 targeted compounds recruits SRSF1 to nuclear G4C2 RNA, mobilizing it from RNA foci into nucleocytoplasmic export. This leads to increased repeat-associated non-canonical (RAN) translation and ultimately, enhanced cell toxicity. Our data (i) provide a new pharmacological entry point with novel as well as known, publicly available tool compounds for dissection of C9ORF72 pathobiology in C9ORF72 ALS models, (ii) allowing to differentially modulate RNA foci versus RAN translation, and (iii) suggest that therapeutic RNA foci elimination strategies warrant caution due to a potential storage function, counteracting translation into toxic dipeptide repeat polyproteins. Instead, our data support modulation of nuclear export via SRSF1 or SR protein kinases as possible targets for future pharmacological drug discovery.
Neuroimaging-based data-driven subtypes of spatiotemporal atrophy due to Parkinson's disease.
Parkinson's disease is the second most common neurodegenerative disease. Despite this, there are no robust biomarkers to predict progression, and understanding of disease mechanisms is limited. We used the Subtype and Stage Inference algorithm to characterize Parkinson's disease heterogeneity in terms of spatiotemporal subtypes of macroscopic atrophy detectable on T1-weighted MRI-a successful approach used in other neurodegenerative diseases. We trained the model on covariate-adjusted cortical thicknesses and subcortical volumes from the largest known T1-weighted MRI dataset in Parkinson's disease, Enhancing Neuroimaging through Meta-Analysis consortium Parkinson's Disease dataset (n = 1100 cases). We tested the model by analyzing clinical progression over up to 9 years in openly-available data from people with Parkinson's disease from the Parkinson's Progression Markers Initiative (n = 584 cases). Under cross-validation, our analysis supported three spatiotemporal atrophy subtypes, named for the location of the earliest affected regions as: 'Subcortical' (n = 359, 33%), 'Limbic' (n = 237, 22%) and 'Cortical' (n = 187, 17%). A fourth subgroup having sub-threshold/no atrophy was named 'Sub-threshold atrophy' (n = 317, 29%). Statistical differences in clinical scores existed between the no-atrophy subgroup and the atrophy subtypes, but not among the atrophy subtypes. This suggests that the prime T1-weighted MRI delineator of clinical differences in Parkinson's disease is atrophy severity, rather than atrophy location. Future work on unravelling the biological and clinical heterogeneity of Parkinson's disease should leverage more sensitive neuroimaging modalities and multimodal data.
Collaborative care for pregnant women with eye conditions.
The management of ophthalmic conditions in pregnancy presents unique challenges that demand a nuanced approach. Significant knowledge gaps and practice variations persist, likely as a result of the infrequent nature of these issues in pregnancy, as well as the lack of crossover in the specialty training curriculum for both specialties. This commentary explores how multidisciplinary team (MDT) working can address these uncertainties to support shared decision-making and potentially improve outcomes in this vulnerable patient population. We highlight the need to involve ophthalmologists in obstetric MDTs, where appropriate, and the importance of establishing clear communication channels and referral pathways between both specialties and across hospitals in the region. We also share our experience of establishing these pathways locally, the feedback we have received from interdisciplinary educational initiatives to improve knowledge sharing, and possible future directions for this collaborative approach to help fill the evidence gap.
Practical routes to preregistration: a guide to enhanced transparency and rigour in neuropsychological research
Abstract Preregistration is the act of formally documenting a research plan before collecting (or at least before analysing) the data. It allows those reading a final research report to know which aspects of a study were decided before sight of the data, and which were added later. This enables informed evaluation of the severity with which scientific claims have been tested. We, as the British Neuropsychological Society Open Research Group, conducted a survey to explore awareness and adoption of open research practices within our field. Neuropsychology involves the study of relatively rare or hard-to-access participants, creating practical challenges that, according to our survey, are perceived as barriers to preregistration. We survey the available routes to preregistration, and suggest that the barriers are all surmountable in one way or another. However, there is a tension, in that higher levels of bias control require greater restriction over the flexibility of preregistered studies, but such flexibility is often essential for neuropsychological research. Researchers must therefore consider which route provides the right balance of rigour and pragmatic flexibility to render a preregistered project viable for them. By mapping out the issues and potential solutions, and by signposting relevant resources and publication routes, we hope to facilitate well-reasoned decision-making and empower neuropsychologists to enhance the transparency and rigour of their research. Although we focus neuropsychology, our guidance is applicable to any field that studies hard-to-access human samples, or involves arduous or expensive means of data collection.
Improving Outcomes in Survivors of Sepsis-The Transition from Secondary to Primary Care, and the Role of Primary Care: A Narrative Review.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The number of patients with sepsis requiring critical care admission is increasing. At the same time, overall mortality from sepsis is declining. With increasing survival to hospital discharge, there are an increasing number of sepsis survivors whose care needs shift from the acute to chronic care settings. Recently, the phrase "post-sepsis syndrome" has emerged to encompass the myriad of complications in patients recovering from sepsis. The aim of this narrative review is to provide a contemporary summary of the available literature on post-sepsis care and highlight areas of ongoing research. There are many incentives for improving the quality of survivorship following sepsis, including individual health-related outcomes (e.g., increased survival, enhanced physical and psychological health) and wider socio-economic benefits (e.g., reduced economic burden on the healthcare systems, reduced physical and psychological burden on carers, ability for individuals (and carers) to return to workforce). Modifiable factors influencing long-term outcomes can be in-hospital or after discharge, when primary care physicians play a pivotal role. Despite national and international guidance being available, this area has been under-recognised historically, despite its profoundly negative impact on both patients and their families or caregivers. Contributing factors likely include the lack of a formally recognised "disease" or pathology, the presence of challenging-to-treat symptoms such as fatigue, weakness and cognitive impairment, and the prevailing assumption that ongoing rehabilitation merely requires time. Our review will focus on the following areas: screening for new cognitive and physical impairments; optimisation of pre-existing comorbidities; transition to primary care; and palliative care. Primary care physicians may have a crucial role to play in improving outcomes in sepsis survivors, and candidate interventions include education on common complications of post-sepsis syndrome.
The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study
AbstractSpinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is ‘burnt out’ and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.
Regional contribution of vascular dysfunction in white matter dementia: clinical and neuropathological insights
The maintenance of adequate blood supply and vascular integrity is fundamental to ensure cerebral function. A wide range of studies report vascular dysfunction in white matter dementias, a group of cerebral disorders characterized by substantial white matter damage in the brain leading to cognitive impairment. Despite recent advances in imaging, the contribution of vascular-specific regional alterations in white matter dementia has been not extensively reviewed. First, we present an overview of the main components of the vascular system involved in the maintenance of brain function, modulation of cerebral blood flow and integrity of the blood–brain barrier in the healthy brain and during aging. Second, we review the regional contribution of cerebral blood flow and blood–brain barrier disturbances in the pathogenesis of three distinct conditions: the archetypal white matter predominant neurocognitive dementia that is vascular dementia, a neuroinflammatory predominant disease (multiple sclerosis) and a neurodegenerative predominant disease (Alzheimer’s). Finally, we then examine the shared landscape of vascular dysfunction in white matter dementia. By emphasizing the involvement of vascular dysfunction in the white matter, we put forward a hypothetical map of vascular dysfunction during disease-specific progression to guide future research aimed to improve diagnostics and facilitate the development of tailored therapies.
Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres
Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963–1.381), by 18.6% for index 0.7–1.5 (95% CI = 1.009–1.394) and by 21.1% for index >1.5 (95% CI = 1.040–1.409) compared to JCV negative patients. Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.