Functional network dynamics revealed by EEG microstates reflect cognitive decline in amyotrophic lateral sclerosis.

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.

A Systematic Review of Cognition in Cervical Dystonia.

Growing evidence points to a spectrum of non-motor symptoms, including cognitive difficulties that have a greater impact on functional outcomes and quality of life than motor symptoms in cervical dystonia (CD). Some cognitive impairments have been reported; however, findings are inconsistent, and described across mixed groups of dystonia. The current review aimed to examine the evidence for cognitive impairments in CD. MEDLINE, EMBASE, PsychINFO and Web of Science databases were searched. Studies were included if they met the following criteria (i) cross-sectional or longitudinal studies of adults with CD, (ii) where the results of standardised measures of cognitive or neuropsychological function in any form were assessed and reported, (iii) results compared to a control group or normative data, and (iv) were published in English. Results are presented in a narrative synthesis. Twenty studies were included. Subtle difficulties with general intellectual functioning, processing speed, verbal memory, visual memory, visuospatial function, executive function, and social cognition were identified while language, and attention and working memory appear to be relatively spared. Several methodological limitations were identified that should be considered when interpreting the evidence to describe a specific profile of cognitive impairment in CD. Clinical and research implications are discussed.

Re-evaluating patient communication and care in angiographically negative subarachnoid hemorrhage: Balancing realism and optimism.

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.

Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis.

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 (ß-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.

StrokeCog Markov Model: Projected Prevalent and Incident Cases of Stroke and Poststroke Cognitive Impairment to 2035 in Ireland.

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.

Cognitive reserve in amyotrophic lateral sclerosis (ALS): a population-based longitudinal study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is often associated with cognitive and/or behavioural impairment. Cognitive reserve (CR) may play a protective role in offsetting cognitive impairment. This study examined the relationship between CR and longitudinal change in cognition in an Irish ALS cohort. METHODS: Longitudinal neuropsychological assessment was carried out on 189 patients over 16 months using the Edinburgh cognitive and behavioural ALS screen (ECAS) and an additional battery of neuropsychological tests. CR was measured by combining education, occupation and physical activity data. Joint longitudinal and time-to-event models were fitted to investigate the associations between CR, performance at baseline and decline over time while controlling for non-random drop-out. RESULTS: CR was a significant predictor of baseline neuropsychological performance, with high CR patients performing better than those with medium or low CR. Better cognitive performance in high CR individuals was maintained longitudinally for ECAS, social cognition, executive functioning and confrontational naming. Patients displayed little cognitive decline over the course of the study, despite controlling for non-random drop-out. CONCLUSIONS: These findings suggest that CR plays a role in the presentation of cognitive impairment at diagnosis but is not protective against cognitive decline. However, further research is needed to examine the interaction between CR and other objective correlates of cognitive impairment in ALS.

Localization of Brain Networks Engaged by the Sustained Attention to Response Task Provides Quantitative Markers of Executive Impairment in Amyotrophic Lateral Sclerosis.

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.

Blood-brain barrier permeability imaging as a predictor for delayed cerebral ischaemia following subarachnoid haemorrhage. A narrative review.

BACKGROUND: Aneurysmal subarachnoid haemorrhage is associated with significant morbidity and mortality due to the myriad of complications contributing to early brain injury and delayed cerebral ischaemia. There is increasing interest in the exploration of the association between blood-brain barrier integrity and risks of delayed cerebral ischaemia and poor outcomes. Despite recent advances in cerebral imaging, radiographic imaging of blood-brain barrier disruption, as a biomarker for outcome prediction, has not been adopted in clinical practice. METHODS: We performed a narrative review by searching for articles describing molecular changes or radiological identification of changes in BBB permeability following subarachnoid haemorrhage (SAH) on MEDLINE. Preclinical studies were analysed if reported structural changes and clinical studies were included if they investigated for radiological markers of BBB disruption and its correlation with delayed cerebral ischaemia. RESULTS: There is ample preclinical evidence to suggest that there are structural changes in BBB permeability following SAH. The available clinical literature has demonstrated correlations between permeability imaging and outcomes following aneurysmal subarachnoid haemorrhage (aSAH). CONCLUSION: Radiological biomarkers offer a potential non-invasive prognostication tool and may also allow early identifications of patients who may be at risk of DCI.

Cognitive and behavioural impairment in amyotrophic lateral sclerosis.

PURPOSE OF REVIEW: The current review provides an up to date overview of the nature and progression of the cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS). Understanding these symptoms has implications for the management of the disease and the design of clinical trials, in addition to the support of patient and caregiver regarding mental capacity and end of life decision-making. RECENT FINDINGS: Cognitive and behavioural change in ALS are best characterized as the consequence of extensive network dysfunction. 35-45% of ALS patients present with mild-moderate cognitive impairment and comorbid dementia occurs in approximately 14% of patients, the majority of these meeting diagnostic criteria for frontotemporal dementia (FTD). Cognitive change in ALS manifests most commonly as executive dysfunction and language impairment. Behavioural change in the form of apathy, disinhibition, loss of sympathy and empathy, stereotyped behaviours and dietary changes occur. SUMMARY: Cognitive and behavioural impairment is an important feature of ALS, and reflects broad network dysfunction of frontostriatal and frontotemporal systems. Cognition and behaviour should be assessed early in the diagnostic process, and data driven approaches should be developed to enable reliable quantitative outcome assessment suitable for clinical trials.

Characteristic Increases in EEG Connectivity Correlate With Changes of Structural MRI in Amyotrophic Lateral Sclerosis.

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.

Patterned functional network disruption in amyotrophic lateral sclerosis.

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 ß-band), lateral/orbitofrontal (δ- to θ-band) and sensorimotor (ß-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 γl -band) and frontal (δ- and γl -band) regions, as well as decreased synchrony in the temporal and frontal (δ- to ß-band) and sensorimotor (ß-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.

Disclosure strategies in adults with epilepsy when telling, "I have epilepsy": The How2tell study.

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."

The Study of Language in the Amyotrophic Lateral Sclerosis - Frontotemporal Spectrum Disorder: a Systematic Review of Findings and New Perspectives.

Amyotrophic Lateral Sclerosis is a neurodegenerative disorder characterized primarily by motor network disruption. Extra-motor manifestations including executive functions, social cognition, and behavioral changes are now well recognized as important features of ALS, and are associated with frontotemporal and frontostriatal network disruption. However, the presence and characterization of language changes has received less attention. This systematic review characterizes the profile of reported language dysfunction in ALS. PRISMA guidelines were implemented to carry out and report the review. Current evidence suggests that areas of neuroanatomical disruption in ALS spread to language centers such as posterior, inferior frontal and superior temporal areas leading to deficits in word retrieval, syntactic and grammatical processing, and spelling. However, the majority of studies of language in ALS have been limited by the recruitment of small clinic-based prevalent samples and important questions remain regarding the incidence and progression of language impairment in ALS. Further studies from population-based incident cohorts will help to determine the range of language deficits in ALS, and how these relate to previously defined executive and behavioral sub-phenotypes.

A Systematic Review of Cognitive Outcomes in Angiographically Negative Subarachnoid Haemorrhage.

Clinical outcomes, including performance on cognitive assessment, in patients with angiographically negative subarachnoid haemorrhage (anSAH) are often interpreted as benign with a good prognostic trajectory. However, diffuse cognitive deficits have been reported within this patient cohort resulting from anSAH, albeit to a lesser extent when compared to other neurovascular events. We consider cognitive outcomes in relation to anSAH to systematically review reported deficits, with a view to quantify and categorise cognitive impairment in this cohort. Anxiety and depression were also included within this review, provided they were assessed alongside cognitive function. Performance deficits in attention and executive function are commonly reported, with set-shifting and interference tasks most commonly impaired in patients. Non-executive cognitive functions are negatively implicated also. Clinical implications and hypotheses relating to the source of these deficits are discussed. This review was formally registered with PROSPERO (CRD42017075294).

Becoming comfortable with "my" epilepsy: Strategies that patients use in the journey from diagnosis to acceptance and disclosure.

OBJECTIVE: Proponents of resilience theory have highlighted the importance of understanding the processes of resilience. The objective of the study was to explore how people with epilepsy reach a stage of being comfortable with their epilepsy. Identifying the processes used is important to developing effective self-management for people who are newly diagnosed with epilepsy. METHOD: A grounded theory approach involving forty-nine consenting adult people with epilepsy (18 years and over), was used to explore their first-hand experiences of coming to terms with their epilepsy. Data were collected using one-to-one interview to elicit in-depth personal accounts of people with epilepsy's experiences of adjusting to their diagnosis of epilepsy. Using grounded theory's systematic inductive-deductive process data of analysis, the core findings that emerged from the open coding and inductive phase were analyzed independently by two researchers to ensure that findings were verified and validated across the interview dataset. FINDINGS: Three core categories emerged as central to the journey that people experience after receiving their diagnosis of epilepsy towards becoming comfortable with their epilepsy. These were: i) meaning of "my" epilepsy diagnosis, to capture people with epilepsy's feelings, reactions and concerns after being diagnosed with epilepsy, ii) useful strategies, to identify what people with epilepsy did to become comfortable with their diagnosis, and iii) being comfortable with my epilepsy, to account for the frame of mind of people with epilepsy when they reach a point of accepting their diagnosis. DISCUSSION: The findings provide important insights into the personal experiences of people with epilepsy after receiving their diagnosis and identifies a range of strategies they find useful in helping them reach a position of acceptance and being 'comfortable with my epilepsy'.

Closing the tau loop: the missing tau mutation.

Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.

The effects of immunologic brainstem encephalopathy on cognitive function following awakening from a progressive autoimmune coma.

We describe a unique patient who experienced a progressive autoimmune coma from age 14 to 17. The patient awoke after treatment with immunosuppressant medication. Although alertness, verbalization, and mobilization markedly improved, the patient reported persistent cognitive difficulties. Neuropsychological assessment from age 21 showed impairments in selective attention, distractibility, and memory. Conversely, higher-order executive functions were preserved. Electrophysiological analysis also identified abnormal neural signatures of selective attention. Eighteen months after the neuropsychological assessment, voxel-based morphometry revealed reduced white matter in the medulla compared to controls. The findings are discussed in terms of the impact of brainstem encephalopathy on cognitive mechanisms.

Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a neuroimaging study of ALS motor phenotype heterogeneity and cortical focality.

BACKGROUND: Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS). OBJECTIVES: To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability. METHODS: We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability. RESULTS: Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions. CONCLUSIONS: Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS.