Search

Examines the effect of forced delivery from nickel-titanium archwires on tooth movement. Indicators of the active turnover of deeper periodontal tissues; Effect of gingival inflammation on gingival crevicular fluid flow and chondroitin sulphate content; Biochemical changes in the extracellular matrix of perturbed tissues.

Objective: To evaluate mandibular tooth position changes following treatment with a lip bumper and fixed appliance. Specifically, we aimed to determine how space was obtained to align crowded lower incisors.

Angiographically negative subarachnoid hemorrhage (anSAH) has traditionally been considered a benign condition, mainly because of favorable outcomes in the acute stage in comparison to the often negative acute outcomes of aneurysmal subarachnoid hemorrhage. However, a growing body of research in recent years shows that anSAH often leads to cognitive impairments, emotional distress, and difficulties in resuming work or other daily life activities. Therefore, in this position paper, we call for a change in neurological care and a shift in patient communication, emphasizing the importance of addressing patient needs and fostering realistic expectations rather than solely focusing on the benign nature of the condition., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Recent electroencephalography (EEG) studies have shown that patterns of brain activity can be used to differentiate amyotrophic lateral sclerosis (ALS) and control groups. These differences can be interrogated by examining EEG microstates, which are distinct, reoccurring topographies of the scalp's electrical potentials. Quantifying the temporal properties of the four canonical microstates can elucidate how the dynamics of functional brain networks are altered in neurological conditions. Here we have analysed the properties of microstates to detect and quantify signal-based abnormality in ALS. High-density resting-state EEG data from 129 people with ALS and 78 HC were recorded longitudinally over a 24-month period. EEG topographies were extracted at instances of peak global field power to identify four microstate classes (labelled A-D) using K-means clustering. Each EEG topography was retrospectively associated with a microstate class based on global map dissimilarity. Changes in microstate properties over the course of the disease were assessed in people with ALS and compared with changes in clinical scores. The topographies of microstate classes remained consistent across participants and conditions. Differences were observed in coverage, occurrence, duration, and transition probabilities between ALS and control groups. The duration of microstate class B and coverage of microstate class C correlated with lower limb functional decline. The transition probabilities A to D, C to B and C to B also correlated with cognitive decline (total ECAS) in those with cognitive and behavioural impairments. Microstate characteristics also significantly changed over the course of the disease. Examining the temporal dependencies in the sequences of microstates revealed that the symmetry and stationarity of transition matrices were increased in people with late-stage ALS. These alterations in the properties of EEG microstates in ALS may reflect abnormalities within the sensory network and higher-order networks. Microstate properties could also prospectively predict symptom progression in those with cognitive impairments., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis ( n = 149) were compared to controls ( n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status ( n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming ( d = 0.91, P = 0.00001) and phonemic verbal fluency ( d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits ( d = -0.52, P = 0.005), lower conscientiousness ( d = 0.57, P = 0.003) and lower openness to experience personality traits ( d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion., Competing Interests: E.C., M.R., B.D., C.K., M.P.-G., M.D., R.L.McL., C.McH., S.A., and M.H. have no conflicts of interest to declare. N.P. serves as the associate editor of the International Journal of Neuroscience and has received speaker honoraria from Novartis. O.H. has received speaking honoraria from Janssen Cilag, Biogen Idec, Sanofi Aventis, Novartis and MerckSerono. She has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics and Sanofi Aventis. She serves as the editor-in-chief of the journal Amyotrophic Lateral Sclerosis and Frontotemporal Dementia., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Protein synthesis by the ribosome requires large-scale rearrangements of the 'small' subunit (SSU; ∼1 MDa), including inter- and intra-subunit rotational motions. However, with nearly 2000 structures of ribosomes and ribosomal subunits now publicly available, it is exceedingly difficult to design experiments based on analysis of all known rotation states. To overcome this, we developed an approach where the orientation of each SSU head and body is described in terms of three angular coordinates (rotation, tilt and tilt direction) and a single translation. By considering the entire RCSB PDB database, we describe 1208 fully-assembled ribosome complexes and 334 isolated small subunits, which span >50 species. This reveals aspects of subunit rearrangements that are universal, and others that are organism/domain-specific. For example, we show that tilt-like rearrangements of the SSU body (i.e. 'rolling') are pervasive in both prokaryotic and eukaryotic (cytosolic and mitochondrial) ribosomes. As another example, domain orientations associated with frameshifting in bacteria are similar to those found in eukaryotic ribosomes. Together, this study establishes a common foundation with which structural, simulation, single-molecule and biochemical efforts can more precisely interrogate the dynamics of this prototypical molecular machine., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (β-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: Cognitive impairment no dementia (CIND) and dementia are common stroke outcomes, with significant health and societal implications for aging populations. These outcomes are not included in current epidemiological models. We aimed to develop an epidemiological model to project incidence and prevalence of stroke, poststroke CIND and dementia, and life expectancy, in Ireland to 2035, informing policy and service planning., Methods: We developed a probabilistic Markov model (the StrokeCog model) applied to the Irish population aged 40 to 89 years to 2035. Data sources included official population and hospital-episode statistics, longitudinal cohort studies, and published estimates. Key assumptions were varied in sensitivity analysis. Results were externally validated against independent sources. The model tracks poststroke progression into health states characterized by no cognitive impairment, CIND, dementia, disability, stroke recurrence, and death., Results: We projected 69 051 people with prevalent stroke in Ireland in 2035 (22.0 per 1000 population [95% CI, 20.8-23.1]), with 25 274 (8.0 per 1000 population [95% CI, 7.1-9.0]) of those projected to have poststroke CIND, and 12 442 having poststroke dementia (4.0 per 1000 population [95% CI, 3.2-4.8]). We projected 8725 annual incident strokes in 2035 (2.8 per 1000 population [95% CI, 2.7-2.9]), with 3832 of these having CIND (1.2 per 1000 population [95% CI, 1.1-1.3]), and 1715 with dementia (0.5 per 1000 population [95% CI, 0.5-0.6]). Life expectancy for stroke survivors at age 50 was 23.4 years (95% CI, 22.3-24.5) for women and 20.7 (95% CI, 19.5-21.9) for men., Conclusions: This novel epidemiological model of stroke, poststroke CIND, and dementia draws on the best available evidence. Sensitivity analysis indicated that findings were robust to assumptions, and where there was uncertainty a conservative approach was taken. The StrokeCog model is a useful tool for service planning and cost-effectiveness analysis and is available for adaptation to other national contexts.

Objective: To investigate the incidence and nature of language change and its relationship to executive dysfunction in a population-based incident amyotrophic lateral sclerosis (ALS) sample, with the hypothesis that patterns of frontotemporal involvement in early ALS extend beyond areas of executive control to regions associated with language processing., Methods: One hundred seventeen population-based incident ALS cases without dementia and 100 controls matched by age, sex, and education were included in the study. A detailed assessment of language processing including lexical processing, word spelling, word reading, word naming, semantic processing, and syntactic/grammatical processing was undertaken. Executive domains of phonemic verbal fluency, working memory, problem-solving, cognitive flexibility, and social cognition were also evaluated., Results: Language processing was impaired in this incident cohort of individuals with ALS, with deficits in the domains of word naming, orthographic processing, and syntactic/grammatical processing. Conversely, phonological lexical processing and semantic processing were spared. Although executive dysfunction accounted in part for impairments in grammatical and orthographic lexical processing, word spelling, reading, and naming, primary language deficits were also present., Conclusions: Language impairment is characteristic of ALS at early stages of the disease and can develop independently of executive dysfunction, reflecting selective patterns of frontotemporal involvement at disease onset. Language change is therefore an important component of the frontotemporal syndrome associated with ALS., (© 2021 American Academy of Neurology.)

Introduction: Non-motor features of cervical dystonia (CD) have been identified, including depression, anxiety, and neuropsychological deficits. The aims were: to provide a clinical neuropsychological profile of CD patients with specific focus on social cognition; assess levels of psychological distress; and investigate the relationship between non-motor features of CD, including cognitive functioning, psychological distress, CD severity, pain, and health-related quality of life (HR-QoL)., Methods: A multi-domain neuropsychological assessment battery was administered to 46 participants with CD, examining cognitive and social cognitive domains. Clinical data on dystonia severity, pain, psychological distress and HR-QoL were collected., Results: The majority of participants with CD performed within the average range across most tests of cognition. Scores were significantly lower than standardized norms in social cognition, processing speed, and aspects of memory. High levels of anxiety (Hospital Anxiety and Depression Scale [HADS-A] ≥ 11, 30%) and depression (HADS-D ≥ 11; 29%) were observed. Psychological distress, CD severity, pain and HR-QoL were not significantly associated with neuropsychological functioning after controlling for multiple comparisons. Low HR-QoL was associated with higher levels of pain and psychological distress, but not severity of motor symptoms., Conclusion: Results indicate that psychological distress and deficits in cognitive and social cognitive functioning are likely distinct features of CD. While motor symptoms do not appear to impact HR-QoL, pain and psychological distress were associated with low HR-QoL. Findings highlight the importance of addressing non-motor symptoms in the treatment of CD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Diets low in seafood omega-3 polyunsaturated fatty acids (PUFAs) are very prevalent. Such diets have recently been ranked as the sixth most important dietary risk factor-1.5 million deaths and 33 million disability-adjusted life-years worldwide are attributable to this deficiency. Wild oily fish stocks are insufficient to feed the world's population, and levels of eicosapentaenoic acid and docosahexaenoic acid (DHA) in farmed fish have more than halved in the last 20 years. Here we report on a double-blinded, controlled trial, where 161 healthy normotensive adults were randomly allocated to eat at least three portions/week of omega-3-PUFA enriched (or control) chicken-meat, and to eat at least three omega-3-PUFA enriched (or control) eggs/week, for 6 months. We show that regular consumption of omega-3-PUFA enriched chicken-meat and eggs significantly increased the primary outcome, the red cell omega-3 index (mean difference [98.75% confidence interval] from the group that ate both control foods, 1.7% [0.7, 2.6]). Numbers of subjects with a very high-risk omega-3 index (index < 4%) were more than halved amongst the group that ate both enriched foods. Furthermore, eating the enriched foods resulted in clinically relevant reductions in diastolic blood pressure (- 3.1 mmHg [- 5.8, - 0.3]). We conclude that chicken-meat and eggs, naturally enriched with algae-sourced omega-3-PUFAs, may serve as alternative dietary sources of these essential micronutrients. Unlike many lifestyle interventions, long-term population health benefits do not depend on willingness of individuals to make long-lasting difficult dietary changes, but on the availability of a range of commonly eaten, relatively inexpensive, omega-3-PUFA enriched foods.

Background: Although considered a motor disorder, adult onset isolated focal dystonia has many non-motor symptoms. There is a paucity of neuropsychological research on cognitive processing in adult onset focal dystonia., Methods: We employed a battery of clinical and cognitive assessments, including basic and complex social cognition, and assessed 46 patients with adult-onset cervical dystonia, compared to 46 age-, sex-, education-, and premorbid IQ-matched healthy controls., Results: Significant between-group differences were observed in relation to measures of memory encoding, recall and recognition, as well as multimodal measures of basic Social Cognition (emotion recognition: face and prosody), but not complex Social Cognition (mentalising). There were no deficits observed in multimodal measures of executive function. Controlling for mood did not affect performance., Conclusion: In this multi-dimensional assessment of cognition in cervical dystonia, we report deficits in memory encoding, and in social cognition. Further investigation of social cognitive processes, memory, and sustained attention are required. Longitudinal studies are also needed to further delineate the role of psychological distress on cognitive outcomes and document the cognitive profile over time., Competing Interests: There are no other potential conflicts of interest for research relating to this article, for all authors., (© 2020 The Authors.)

Objective: To identify cortical regions engaged during the sustained attention to response task (SART) and characterize changes in their activity associated with the neurodegenerative condition amyotrophic lateral sclerosis (ALS)., Methods: High-density electroencephalography (EEG) was recorded from 33 controls and 23 ALS patients during a SART paradigm. Differences in associated event-related potential peaks were measured for Go and NoGo trials. Sources active during these peaks were localized, and ALS-associated differences were quantified., Results: Go and NoGo N2 and P3 peak sources were localized to the left primary motor cortex, bilateral dorsolateral prefrontal cortex (DLPFC), and lateral posterior parietal cortex (PPC). NoGo trials evoked greater bilateral medial PPC activity during N2 and lesser left insular, PPC and DLPFC activity during P3. Widespread cortical hyperactivity was identified in ALS during P3. Changes in the inferior parietal lobule and insular activity provided very good discrimination (AUROC > 0.75) between patients and controls. Activation of the right precuneus during P3 related to greater executive function in ALS, indicative of a compensatory role., Interpretation: The SART engages numerous frontal and parietal cortical structures. SART-EEG measures correlate with specific cognitive impairments that can be localized to specific structures, aiding in differential diagnosis., (© The Author(s) 2020. Published by Oxford University Press.)

Whereas the diagnosis of moderate and severe traumatic brain injury (TBI) is readily visible on current medical imaging paradigms (magnetic resonance imaging [MRI] and computed tomography [CT] scanning), a far greater challenge is associated with the diagnosis and subsequent management of mild TBI (mTBI), especially concussion which, by definition, is characterized by a normal CT. To investigate whether the integrity of the blood-brain barrier (BBB) is altered in a high-risk population for concussions, we studied professional mixed martial arts (MMA) fighters and adolescent rugby players. Additionally, we performed the linear regression between the BBB disruption defined by increased gadolinium contrast extravasation on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on MRI and multiple biomechanical parameters indicating the severity of impacts recorded using instrumented mouthguards in professional MMA fighters. MMA fighters were examined pre-fight for a baseline and again within 120 h post-competitive fight, whereas rugby players were examined pre-season and again post-season or post-match in a subset of cases. DCE-MRI, serological analysis of BBB biomarkers, and an analysis of instrumented mouthguard data, was performed. Here, we provide pilot data that demonstrate disruption of the BBB in both professional MMA fighters and rugby players, dependent on the level of exposure. Our data suggest that biomechanical forces in professional MMA and adolescent rugby can lead to BBB disruption. These changes on imaging may serve as a biomarker of exposure of the brain to repetitive subconcussive forces and mTBI.

The thalamus is a key cerebral hub relaying a multitude of corticoefferent and corticoafferent connections and mediating distinct extrapyramidal, sensory, cognitive and behavioural functions. While the thalamus consists of dozens of anatomically well-defined nuclei with distinctive physiological roles, existing imaging studies in motor neuron diseases typically evaluate the thalamus as a single structure. Based on the unique cortical signatures observed in ALS and PLS, we hypothesised that similarly focal thalamic involvement may be observed if the nuclei are individually evaluated. A prospective imaging study was undertaken with 100 patients with ALS, 33 patients with PLS and 117 healthy controls to characterise the integrity of thalamic nuclei. ALS patients were further stratified for the presence of GGGGCC hexanucleotide repeat expansions in C9orf72. The thalamus was segmented into individual nuclei to examine their volumetric profile. Additionally, thalamic shape deformations were evaluated by vertex analyses and focal density alterations were examined by region-of-interest morphometry. Our data indicate that C9orf72 negative ALS patients and PLS patients exhibit ventral lateral and ventral anterior involvement, consistent with the 'motor' thalamus. Degeneration of the sensory nuclei was also detected in C9orf72 negative ALS and PLS. Both ALS groups and the PLS cohort showed focal changes in the mediodorsal-paratenial-reuniens nuclei, which mediate memory and executive functions. PLS patients exhibited distinctive thalamic changes with marked pulvinar and lateral geniculate atrophy compared to both controls and C9orf72 negative ALS. The considerable ventral lateral and ventral anterior pathology detected in both ALS and PLS support the emerging literature of extrapyramidal dysfunction in MND. The involvement of sensory nuclei is consistent with sporadic reports of sensory impairment in MND. The unique thalamic signature of PLS is in line with the distinctive clinical features of the phenotype. Our data confirm phenotype-specific patterns of thalamus involvement in motor neuron diseases with the preferential involvement of nuclei mediating motor and cognitive functions. Given the selective involvement of thalamic nuclei in ALS and PLS, future biomarker and natural history studies in MND should evaluate individual thalamic regions instead overall thalamic changes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting motor function, with additional evidence of extensive nonmotor involvement. Despite increasing recognition of the disease as a multisystem network disorder characterised by impaired connectivity, the precise neuroelectric characteristics of impaired cortical communication remain to be fully elucidated. Here, we characterise changes in functional connectivity using beamformer source analysis on resting-state electroencephalography recordings from 74 ALS patients and 47 age-matched healthy controls. Spatiospectral characteristics of network changes in the ALS patient group were quantified by spectral power, amplitude envelope correlation (co-modulation) and imaginary coherence (synchrony). We show patterns of decreased spectral power in the occipital and temporal (δ- to β-band), lateral/orbitofrontal (δ- to θ-band) and sensorimotor (β-band) regions of the brain in patients with ALS. Furthermore, we show increased co-modulation of neural oscillations in the central and posterior (δ-, θ- and γ l -band) and frontal (δ- and γ l -band) regions, as well as decreased synchrony in the temporal and frontal (δ- to β-band) and sensorimotor (β-band) regions. Factorisation of these complex connectivity patterns reveals a distinct disruption of both motor and nonmotor networks. The observed changes in connectivity correlated with structural MRI changes, functional motor scores and cognitive scores. Characteristic patterned changes of cortical function in ALS signify widespread disease-associated network disruption, pointing to extensive dysfunction of both motor and cognitive networks. These statistically robust findings, that correlate with clinical scores, provide a strong rationale for further development as biomarkers of network disruption for future clinical trials., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Objective: To generate evidence-based knowledge about the strategies that adult people with epilepsy (PWEs) use in the process of telling others about their epilepsy., Methods: In-depth, one-to-one interviews explored PWEs' first-hand experiences of self-disclosure (or not), and grounded theory methods of inductive-deductive analysis were used to identify strategies used in disclosing. Interviews were audio-recorded, transcribed, coded, and independently recoded by two researchers using a coding framework specifically developed in this study. To account for maximum variation, PWEs (aged 18+ years) with different life experiences and situations relating to (1) gender, (2) age, (3) employment status, (4) personal relationships, (5) family relationship, (6) support group involvement, and (7) seizure frequency were included. Given the many variables and psychosocial issues associated with epilepsy, demographic details and validated measures including Quality of Life in Epilepsy-10-P, Coping Inventory of Stressful Situations-Adult, and Patient Health Questionnaire-9 were used to describe the characteristics of participants and to contextualize the results., Results: Forty-nine adults with epilepsy participated. Data analysis revealed six interrelated categories (with subcategories) of the strategies that PWEs reported using in the process of disclosure: (1) concerns about disclosing; (2) weighing up who and when to tell; (3) opportunities for telling; (4) moment of disclosure-how to construct the message; (5) tailoring the message to audience needs-altering the message when telling family members, partner, friends, children, or employer and workplace colleagues; and (6) managing reactions by making it ordinary., Significance: People with epilepsy use a range of different strategies during the process of disclosing their epilepsy. These strategies were used to inform the development of the How2tell multimedia self-management resource for PWEs on self-disclosure in everyday social and life situations. How2tell is designed to benefit PWEs by empowering them with practical information about the process of telling another person, "I have epilepsy.", (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Introduction: Amyotrophic lateral sclerosis (ALS) is a rapid and fatal motor disease marked by progressive physical impairment due to muscle weakness and wasting. It is multidimensional with many patients presenting with cognitive and/or behavioural impairment. Caregivers of patients with ALS, commonly non-paid immediate family members, often take primary responsibility for the complex care needs of patients in non-medicalised setting, and many as a consequence experience caregiver burden, anxiety, and/or depression., Methods and Analysis: This randomised controlled trial (RCT) will use randomisation to allocate n=75 caregivers of patients with ALS from the national ALS clinic into three groups with an equal distribution. The RCT consists of two intervention groups and a wait list control (treatment as usual [TAU]) group. The intervention arms of the trial consist of a 'mindfulness-based stress reduction' and 'building better caregivers' manualised group-based intervention, with 9 and 6 weekly sessions, respectively. The TAU group will have access to intervention at the end of the trial period. Primary outcomes are self-report questionnaires on anxiety and depression symptoms, with caregiver burden and quality of life considered secondary outcomes. Assessment will commence at baseline, immediately following the intervention period, and after a period of 12 weeks to assess the effectiveness and efficacy of participating in an intervention. Patient cognitive and behavioural data will also be considered. Means of treatment and control groups at Time 0 and 1 will be analysed using mixed model multivariate analysis of variance followed by analysis of variance, and treatment effect-sizes will be calculated. This RCT protocol is pre-results and has been registered with an international database resulting in an International Standard Randomised Controlled Trials Number (ISRCTN53226941)., Ethics and Dissemination: Ethics approval was obtained from the Beaumont Hospital Medical Research Ethics Committee. Results of the main trial will be submitted for publication in a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The association between long-chain omega-3 polyunsaturated fatty acids (PUFAs), brain health, cognitive function and mood has been the subject of intensive research. Marine-derived omega-3 PUFAs, such as docosahexaenoic acid and eicosapentaenoic acid, are highly concentrated in neuronal membranes and affect brain function. Many studies have found that consumption of omega-3 PUFAs is associated with lower risk of cognitive or mood dysfunction. However, other studies have demonstrated no beneficial effects. There appears to be inconsistent findings from both epidemiological and randomised controlled trial (RCT) studies. The aim of this review is to compile the previous literature and establish the efficacy of omega-3 PUFAs in enhancing cognitive performance and mood in healthy adults., Methods and Analysis: Prospective cohort studies, RCTs, controlled clinical trials, controlled before and after studies, interrupted time series with a minimum of 3 months duration will be eligible for inclusion. Studies on healthy adults over the age of 18, where the intervention/exposure of interest is omega-3 PUFAs will be included. The outcomes of interest are cognition and mood. Studies will be eligible for inclusion if they measure changes in cognitive function or mood, or the risk of developing cognitive or mood disorders using validated tools and assessments. Relevant search terms and keywords will be used to generate a systematic search in Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Scopus and the grey literature. Two independent reviewers will screen studies for eligibility. Risk of bias in cohort and non-randomised studies will be assessed using the ROBINS-I tool. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials will be used for RCTs. If there are sufficient data, a meta-analysis will be conducted., Ethics and Dissemination: This systematic review does not involve primary data collection and therefore formal ethical approval is not required. Results will be disseminated through peer reviewed publications, conference presentations and the popular press., Prospero Registration Number: CRD42018080800., Competing Interests: Competing interests: Several team members are affiliated with Devenish Nutrition, a company that is involved in the production of omega-3 PUFA-enriched food products. FOD is a PhD student funded by the Irish Research Council Employment Based Postgraduate scheme in partnership with Devenish Nutrition. HH is Food Innovation Director with Devenish Nutrition. JK is Food Innovation Manager with Devenish Nutrition. AS works with and has ownership interest with Devenish Nutrition., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cognitive impairment is a pervasive outcome of stroke, reported in over half of patients 6 months post-stroke and is associated with increased disability and a poorer quality of life. Despite the prevalence of post-stroke cognitive impairment, the efficacy of existing psychological interventions for the rehabilitation of cognitive impairment following stroke has yet to be established. The aim of this study is to identify psychological interventions from non-randomised studies that intended to improve post-stroke cognitive function and establish their efficacy., Design: Systematic review and meta-analysis of non-randomised studies of psychological interventions addressing post-stroke cognitive impairment., Data Sources: Electronic searches were performed in the Pubmed, EMBASE and PsycINFO databases, the search dating from inception to February 2017., Eligibility Criteria: All non-randomised controlled studies and quasi-randomised controlled trials examining psychological interventions to improve cognitive function following stroke were included, such as feasibility studies, pilot studies, experimental studies, and quasi-experimental studies. The primary outcome was cognitive function. The prespecified secondary outcomes were functional abilities in daily life and quality of life., Methods: The current meta-analyses combined the findings of seven controlled studies, examining the efficacy of psychological interventions compared with treatment-as-usual controls or active controls, and 13 one-group pre-post studies., Results: Results indicated an overall small effect on cognition across the controlled studies (Hedges' g=0.38, 95% CI=0.06 to 0.7) and a moderate effect on cognition across the one-group pre-post studies (Hedges' g=0.51, 95% CI=0.3 to 0.73). Specific cognitive domains, such as memory and attention also demonstrated a benefit of psychological interventions., Conclusions: This review provides support for the potential of psychological interventions to improve overall cognitive function post-stroke. Limitations of the study, in terms of risk of bias and quality of included studies, and future research directions are explored., Prospero Registration Number: CRD42017069714., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Primary lateral sclerosis (PLS) is a low incidence motor neuron disease which carries a markedly better prognosis than amyotrophic lateral sclerosis (ALS). Despite sporadic reports of extra-motor symptoms, PLS is widely regarded as a pure upper motor neuron disorder. The post mortem literature of PLS is strikingly sparse and very little is known of subcortical grey matter pathology in this condition., Methods: A prospective imaging study was undertaken with 33 PLS patients, 117 healthy controls and 100 ALS patients to specifically assess the integrity of subcortical grey matter structures and determine whether PLS and ALS have divergent thalamic, hippocampal and basal ganglia signatures. Volumetric, morphometric, segmentation and vertex-wise analyses were carried out in the three study groups to evaluate the integrity of thalamus, hippocampus, caudate, amygdala, pallidum, putamen and accumbens nucleus in each hemisphere. The hippocampus was further parcellated to characterise the involvement of specific subfields., Results: Considerable thalamic, caudate, and hippocampal atrophy was detected in PLS based on both volumetric and vertex analyses. Significant volume reductions were also detected in the accumbens nuclei. Hippocampal atrophy in PLS was dominated by dentate gyrus, hippocampal tail and CA4 subfield volume reductions. The morphometric comparison of ALS and PLS cohorts revealed preferential medial bi-thalamic pathology in PLS compared to the predominant putaminal degeneration detected in ALS. Another distinguishing feature between ALS and PLS was the preferential atrophy of the amygdala in ALS., Conclusions: PLS is associated with considerable subcortical grey matter degeneration and due to the extensive extra-motor involvement, it should no longer be regarded a pure upper motor neuron disorder. Given its unique pathological features and a clinical course which differs considerably from ALS, dedicated research studies and disease-specific therapeutic strategies are urgently required in PLS., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To localise and characterise changes in cognitive networks in Amyotrophic Lateral Sclerosis (ALS) using source analysis of mismatch negativity (MMN) waveforms., Rationale: The MMN waveform has an increased average delay in ALS. MMN has been attributed to change detection and involuntary attention switching. This therefore indicates pathological impairment of the neural network components which generate these functions. Source localisation can mitigate the poor spatial resolution of sensor-level EEG analysis by associating the sensor-level signals to the contributing brain sources. The functional activity in each generating source can therefore be individually measured and investigated as a quantitative biomarker of impairment in ALS or its sub-phenotypes., Methods: MMN responses from 128-channel electroencephalography (EEG) recordings in 58 ALS patients and 39 healthy controls were localised to source by three separate localisation methods, including beamforming, dipole fitting and exact low resolution brain electromagnetic tomography., Results: Compared with controls, ALS patients showed significant increase in power of the left posterior parietal, central and dorsolateral prefrontal cortices (false discovery rate = 0.1). This change correlated with impaired cognitive flexibility (rho = 0.45, 0.45, 0.47, p = .042, .055, .031 respectively). ALS patients also exhibited a decrease in the power of dipoles representing activity in the inferior frontal (left: p = 5.16 × 10 -6 , right: p = 1.07 × 10 -5 ) and left superior temporal gyri (p = 9.30 × 10 -6 ). These patterns were detected across three source localisation methods. Decrease in right inferior frontal gyrus activity was a good discriminator of ALS patients from controls (AUROC = 0.77) and an excellent discriminator of C9ORF72 expansion-positive patients from controls (AUROC = 0.95)., Interpretation: Source localization of evoked potentials can reliably discriminate patterns of functional network impairment in ALS and ALS subgroups during involuntary attention switching. The discriminative ability of the detected cognitive changes in specific brain regions are comparable to those of functional magnetic resonance imaging (fMRI). Source analysis of high-density EEG patterns has excellent potential to provide non-invasive, data-driven quantitative biomarkers of network disruption that could be harnessed as novel neurophysiology-based outcome measures in clinical trials., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a terminal progressive adult-onset neurodegeneration of the motor system. Although originally considered a pure motor degeneration, there is increasing evidence of disease heterogeneity with varying degrees of extra-motor involvement. How the combined motor and nonmotor degeneration occurs in the context of broader disruption in neural communication across brain networks has not been well characterized. Here, we have performed high-density crossectional and longitudinal resting-state electroencephalography (EEG) recordings on 100 ALS patients and 34 matched controls, and have identified characteristic patterns of altered EEG connectivity that have persisted in longitudinal analyses. These include strongly increased EEG coherence between parietal-frontal scalp regions (in γ-band) and between bilateral regions over motor areas (in θ-band). Correlation with structural MRI from the same patients shows that disease-specific structural degeneration in motor areas and corticospinal tracts parallels a decrease in neural activity over scalp motor areas, while the EEG over the scalp regions associated with less extensively involved extra-motor regions on MRI exhibit significantly increased neural communication. Our findings demonstrate that EEG-based connectivity mapping can provide novel insights into progressive network decline in ALS. These data pave the way for development of validated cost-effective spectral EEG-based biomarkers that parallel changes in structural imaging.

There is strong clinical, imaging and pathological evidence that neurodegeneration is associated with altered brain connectivity. While functional imaging (fMRI) can detect resting and activated states of metabolic activity, its use is limited by poor temporal resolution, cost and confounding vascular parameters. By contrast, electrophysiological (e.g. EEG/MEG) recordings provide direct measures of neural activity with excellent temporal resolution, and source localization methodologies can address problems of spatial resolution, permitting measurement of functional activity of brain networks with a spatial resolution similar to that of fMRI. This opens an exciting therapeutic approach focussed on pharmacological and physiological modulation of brain network activity. This review describes current neurophysiological approaches towards evaluating cortical network dysfunction in common neurodegenerative disorders. It explores how modern neurophysiologic tools can provide markers for diagnosis, prognosis, subcategorization and clinical trial outcome measures, and how modulation of brain networks can contribute to new therapeutic approaches., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess temporal trends in familial amyotrophic lateral sclerosis (FALS) incidence rates in an Irish population and to determine factors influencing FALS ascertainment., Methods: Population-based data collected over 23 years, using the Irish amyotrophic lateral sclerosis (ALS) register and DNA biobank, were analyzed and age-standardized rates of FALS and associated familial neuropsychiatric endophenotypes were identified., Results: Between 1994 and 2016, 269 patients with a family history of ALS from 197 unique families were included on the register. Using stringent diagnostic criteria for FALS, the mean age-standardized FALS incidence rate for the study period was 11.1% (95% confidence interval [CI], 8.8-13.4). The FALS incidence rate increased steadily from 5.2% in 1994 to 19.1% in 2016, an annual increase of 0.7% (95% CI, 0.5-0.9, p < 0.0001). Inclusion of the presence of neuropsychiatric endophenotypes within kindreds increased the FALS incidence rate to 30%. The incidence of FALS in newly diagnosed individuals from known families increased significantly with time, accounting for 50% of all FALS diagnoses by 2016. The mean annual rate of recategorization from "sporadic ALS" to "FALS" was 3% (95% CI, 2.6-3.8)., Conclusions: The true population-based rate of FALS is at least 20%. Inclusion of extended endophenotypes within kindreds increases the rate of FALS to 30%. Cross-sectional analysis of clinic-based cohorts and stringent definitions of FALS underestimate the true rate of familial disease. This has implications for genetic counseling and in the recognition of presymptomatic stages of ALS.

Objectives: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a debilitating terminal condition. Informal caregivers are key figures in ALS care provision. The physical, psychological and emotional impact of providing care in the home requires appropriate assistance and support. The objective of this analysis is to explore the needs of informal ALS caregivers across the caregiving course., Design: In an open-ended question as part of a semistructured interview, caregivers were asked what would help them in their role. Interviews took place on three occasions at 4-month to 6-month intervals. Demographic, burden and quality of life data were collected, in addition to the open-ended responses. We carried out descriptive statistical analysis and thematic analysis of qualitative data., Setting and Participants: Home interviews at baseline (n=81) and on two further occasions (n=56, n=41) with informal caregivers of people with ALS attending the National ALS/MND Clinic at Beaumont Hospital, Dublin, Ireland., Results: The majority of caregivers were family members. Hours of care provided and caregiver burden increased across the interview series. Thematic analysis identified what would help them in their role, and needs related to external support and services, psychological-emotional factors, patient-related behaviours, a cure and 'nothing'. Themes were interconnected and their prevalence varied across the interview time points., Conclusion: This study has shown the consistency and adaptation in what caregivers identified as helpful in their role, across 12-18 months of a caregiving journey. Support needs are clearly defined, and change with time and the course of caregiving. Caregivers need support from family, friends and healthcare professionals in managing their tasks and the emotional demands of caregiving. Identifying the specific needs of informal caregivers should enable health professionals to provide tailored supportive interventions., Competing Interests: Competing interests: OH is the Editor in Chief of the Amyotrophic Lateral Sclerosis and the Frontotemporal Degenerations journal, and is a member of the editorial board of the Journal of Neurology, Neurosurgery and Psychiatry., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Stroke is one of the primary causes of death and disability worldwide, leaving a considerable proportion of survivors with persistent cognitive and functional deficits. Despite the prevalence of poststroke cognitive impairment, there is no established treatment aimed at improving cognitive function following a stroke. Therefore, the aims of this systematic review are to identify psychological interventions intended to improve poststroke cognitive function and establish their efficacy., Methods and Analysis: A systematic review of non-randomised controlled studies that investigated the efficacy of psychological interventions aimed at improving cognitive function in stroke survivors will be conducted. Electronic searches will be performed in the PubMed, Embase and PsycINFO databases, the search dating from the beginning of the index to February 2017. Reference lists of all identified relevant articles will be reviewed to identify additional studies not previously identified by the electronic search. Potential grey literature will be reviewed using Google Scholar. Titles and abstracts will be assessed for eligibility by one reviewer, with a random sample of 50% independently double-screened by second reviewers. Any discrepancies will be resolved through discussion, with referral to a third reviewer where necessary. Risk of bias will be assessed with the Risk of Bias in Non-randomized Studies of Interventions tool. Meta-analyses will be performed if studies are sufficiently homogeneous. This review will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The quality of the evidence regarding cognitive function will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation., Ethics and Dissemination: This systematic review will collect secondary data only and as such ethical approval is not required. Findings will be disseminated through presentations and peer-reviewed publication. This review will provide information on the effectiveness of psychological interventions for poststroke cognitive impairment, identifying which psychological interventions are effective for improving poststroke cognitive function., Prospero Registration Number: CRD42017069714., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)