Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

The relationship between transliminality, hypnotic and imaginative suggestibility, and other personality traits.

To our knowledge, no study has directly examined the link between hypnotic response and the personality trait of transliminality (which is underpinned, for example, by magical ideation, mystical experience, fantasy proneness, absorption, hyperaesthesia). In order to further understand the correlates of suggestibility, the aim of the current project was to investigate whether transliminality is associated with hypnotic and imaginative suggestibility (considering: objective response, subjective response and involuntariness). Another aim was to assess the contribution of transliminality as a predictor of suggestibility when a range of previously studied personality trait measures were considered. Participants completed: the Revised Transliminality Scale, Tellegen Absorption Scale, Creative Experiences Questionnaire, and the Dissociative Experiences Scale II. To avoid context effects, where knowledge or measurement of one trait or ability might influence measurement of another, a separate standalone study was conducted where hypnotic and imaginative (without hypnosis) suggestibility screenings were carried out in-person in small groups using the modified Carleton University Responsiveness to Suggestion Scale. The merging of these two datasets enabled the analyses. Transliminality was weakly correlated with the imaginative suggestibility subjective response measure (r = 0.19). Likewise, weak correlations were found between transliminality and the hypnotic suggestibility response measures (objective, r = 0.21, subjective, r = 0.23, involuntariness, r = 0.24). The multiple regressions (forward selection) reflected the pattern of correlations, with no model for any of the variables, retaining more than a single significant predictor. In summary, this study combination, avoiding context effects, shows transliminality to be a weak predictor of response to suggestion.

Suggested visual hallucination without hypnosis enhances activity in visual areas of the brain.

This functional Magnetic Resonance Imaging (fMRI) study investigated high and low suggestible people responding to two visual hallucination suggestions with and without a hypnotic induction. Participants in the study were asked to see color while looking at a grey image, and to see shades of grey while looking at a color image. High suggestible participants reported successful alterations in color perception in both tasks, both in and out of hypnosis, and showed a small benefit if hypnosis was induced. Low suggestible people could not perform the tasks successfully with or without the hypnotic induction. The fMRI results supported the self report data, and changes in brain activity were found in a number of visual areas. The results indicate that a hypnotic induction, although having the potential to enhance the ability of high suggestible people, is not necessary for the effective alteration of color perception by suggestion.

Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions.

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

The neuroanatomical substrate of lexical-semantic decline in MCI APOE ε4 carriers and noncarriers.

Lexical-semantic competency in mild cognitive impairment (MCI) ε4 carriers was used as an endophenotype, and gray matter volume in MCI ε4 carriers/noncarriers and in noncarrier controls was compared. Residual gray matter volumes were correlated with age of acquisition values for words from a category fluency task, an index of semantic competency. MCI patients had significantly impoverished lexical-semantic output compared with controls, more marked in MCI ε4 carriers. Smaller volumes in the left hippocampus, bilateral regions of the uncus, and posterior cingulate cortex were associated with a tendency to retrieve earlier acquired words in the category fluency task in MCI ε4 carriers, whereas poor semantic performance in MCI noncarriers was associated with smaller volumes in the left uncus, bilateral regions of the parahippocampal gyrus, and hippocampus, and also in a large number of neocortical regions. There was a significant semantic competency by genotype interaction in the left perirhinal cortex, in a number of left frontal and temporal areas and in the right inferior parietal lobule and precuneus. MCI ε4 carriers, when compared with noncarriers, had lower gray matter volume values confined to the right precuneus and the cerebellum bilaterally, but the converse comparison showed that MCI noncarriers had lower values in extensive frontal, temporal, and parietal regions of the neocortex. Similar brain volumetric variations linked to genotype were found in minimal-to-mild AD. The results suggest a relatively specific impact of apolipoprotein E (APOE) ε4 burden and underline the value of linguistic assessment in preclinical diagnosis.

Multimodal Prediction of Alzheimer's Disease Severity Level Based on Resting-State EEG and Structural MRI.

While several biomarkers have been developed for the detection of Alzheimer's disease (AD), not many are available for the prediction of disease severity, particularly for patients in the mild stages of AD. In this paper, we explore the multimodal prediction of Mini-Mental State Examination (MMSE) scores using resting-state electroencephalography (EEG) and structural magnetic resonance imaging (MRI) scans. Analyses were carried out on a dataset comprised of EEG and MRI data collected from 89 patients diagnosed with minimal-mild AD. Three feature selection algorithms were assessed alongside four machine learning algorithms. Results showed that while MRI features alone outperformed EEG features, when both modalities were combined, improved results were achieved. The top-selected EEG features conveyed information about amplitude modulation rate-of-change, whereas top-MRI features comprised information about cortical area and white matter volume. Overall, a root mean square error between predicted MMSE values and true MMSE scores of 1.682 was achieved with a multimodal system and a random forest regression model.

A systematic review of the impacts of intergenerational engagement on older adults' cognitive, social, and health outcomes.

BACKGROUND: Intergenerational engagement could benefit health and wellbeing within an ageing population. This systematic review evaluated the impacts of intergenerational engagement on cognitive, social, and health outcomes in healthy older adults and older adults with mild cognitive impairment. RESEARCH DESIGN AND METHODS: Comprehensive literature searches were undertaken, with records filtered according to pre-registered criteria. Study quality was formally assessed, and a narrative synthesis of the findings produced. RESULTS: Forty-four studies were reviewed. Regarding quantitative evidence, 4 out of 8 studies found significant intergenerational engagement effects on cognitive outcomes, 15 of 24 on social outcomes, and 21 of 31 on health-related outcomes. Qualitative evidence was also important for understanding perceived impacts and experiences of intergenerational programmes. Only 11 studies fully met criteria for high quality research, of which the majority focused on social outcomes. DISCUSSION AND IMPLICATIONS: There are a range of potential benefits of intergenerational engagement, most notably regarding anxiety, generativity, cross-age attitudes, and physical activity. However, heterogeneity in programme context, sample design, dosage, and duration indicate that more research is required to enable wider implementation and generalisability. Scientific rigour in both quantitative and qualitative research should also be employed as far as possible, to provide the highest quality evidence.

Eigenvector alignment: Assessing functional network changes in amnestic mild cognitive impairment and Alzheimer's disease.

Eigenvector alignment, introduced herein to investigate human brain functional networks, is adapted from methods developed to detect influential nodes and communities in networked systems. It is used to identify differences in the brain networks of subjects with Alzheimer's disease (AD), amnestic Mild Cognitive Impairment (aMCI) and healthy controls (HC). Well-established methods exist for analysing connectivity networks composed of brain regions, including the widespread use of centrality metrics such as eigenvector centrality. However, these metrics provide only limited information on the relationship between regions, with this understanding often sought by comparing the strength of pairwise functional connectivity. Our holistic approach, eigenvector alignment, considers the impact of all functional connectivity changes before assessing the strength of the functional relationship, i.e. alignment, between any two regions. This is achieved by comparing the placement of regions in a Euclidean space defined by the network's dominant eigenvectors. Eigenvector alignment recognises the strength of bilateral connectivity in cortical areas of healthy control subjects, but also reveals degradation of this commissural system in those with AD. Surprisingly little structural change is detected for key regions in the Default Mode Network, despite significant declines in the functional connectivity of these regions. In contrast, regions in the auditory cortex display significant alignment changes that begin in aMCI and are the most prominent structural changes for those with AD. Alignment differences between aMCI and AD subjects are detected, including notable changes to the hippocampal regions. These findings suggest eigenvector alignment can play a complementary role, alongside established network analytic approaches, to capture how the brain's functional networks develop and adapt when challenged by disease processes such as AD.

Neuroanatomical and cognitive correlates of domain-specific anosognosia in early Alzheimer's disease.

Anosognosia in Alzheimer's disease (AD) is defined as a lack of awareness for cognitive deficits or severity of disease. Previous studies have highlighted the link between anosognosia and damage to prefrontal functioning, i.e., executive functions. This study investigated the neuropsychological and neurostructural substrates of domain specific anosognosia in early AD. Fifty-three patients with a clinical diagnosis of early-AD and a reliable informant were administered the Measurement of Anosognosia Instrument, a validated tool to quantify anosognosia. Linear models were devised to test the association between the patient-informant discrepancy scores in the memory and non-memory domains and clinical profiles inclusive of cognitive scores and maps of grey matter. Total anosognosia scores were associated with episodic memory, semantic memory, visuoconstructive skills and volume of the anterior cingulate cortex (ACC), lingual gyrus, fusiform gyrus and thalamus. Memory anosognosia was associated with episodic memory and visuoconstructive skills. Non-memory anosognosia was associated with episodic and semantic memory and with volume of the ACC, precentral gyrus, superior frontal gyrus, postcentral gyrus, fusiform gyrus and lingual gyrus. Known as a region responsible for self-regulation and monitoring, reduction of grey matter in the frontal lobe was highlighted as crucial for the presence of anosognosia. Based on our findings, we argue that specific regions based in the frontal lobe could contribute to the functioning of the mnemonic comparator systems postulated by theoretical models of anosognosia. The cross-domain variability of cognitive correlates indicates that various computational mechanisms are at play in the presence of anosognosia.

Revisiting Criteria for Psychosis in Alzheimer's Disease and Related Dementias: Toward Better Phenotypic Classification and Biomarker Research.

BACKGROUND: Psychotic symptoms are common in Alzheimer's disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. OBJECTIVE: To establish research criteria for the diagnosis of psychosis in AD. METHODS: The International Society to Advance Alzheimer's Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. RESULTS: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. CONCLUSION: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

What electrophysiology tells us about Alzheimer's disease: a window into the synchronization and connectivity of brain neurons.

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer's disease (AD), despite a surge in recent validated evidence. This position paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity, reflecting thalamocortical and corticocortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies.

Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's disease research has largely concentrated on the study of cognitive decline, but the associated behavioural and neuropsychiatric symptoms are of equal importance in the clinical profile of the disease. There is emerging evidence that regional differences in brain atrophy may align with variant disease presentations. The objective of this study was to identify the regions of decreased grey matter (GM) volume which were associated with specific neuropsychiatric behaviours in patients with mild Alzheimer's disease. Voxel-based morphometry was used to correlate GM derived from T(1)-weighted MRI images of 31 patients with mild Alzheimer's disease and specific neuropsychiatric symptoms and behaviours measured by the Neuropsychiatric Inventory. Delusions were associated with decreased GM density in the left frontal lobe, in the right frontoparietal cortex and in the left claustrum. Apathy was associated with GM density loss in the anterior cingulate and frontal cortex bilaterally, the head of the left caudate nucleus and in bilateral putamen. Agitation was associated with decreased GM values in the left insula, and in anterior cingulate cortex bilaterally. Neuropsychiatric symptoms of Alzheimer's disease seem to associate with neurodegeneration of specific neural networks supporting personal memory, reality monitoring, processing of reward, interoceptive sensations and subjective emotional experience. The study of neurodegenerative disorders such as Alzheimer's disease using voxel-based morphometry and other imaging modalities may further the understanding of the neural structures that mediate the genesis of abnormal behaviours.

Hypnotic induction decreases anterior default mode activity.

The 'default mode' network refers to cortical areas that are active in the absence of goal-directed activity. In previous studies, decreased activity in the 'default mode' has always been associated with increased activation in task-relevant areas. We show that the induction of hypnosis can reduce anterior default mode activity during rest without increasing activity in other cortical regions. We assessed brain activation patterns of high and low suggestible people while resting in the fMRI scanner and while engaged in visual tasks, in and out of hypnosis. High suggestible participants in hypnosis showed decreased brain activity in the anterior parts of the default mode circuit. In low suggestible people, hypnotic induction produced no detectable changes in these regions, but instead deactivated areas involved in alertness. The findings indicate that hypnotic induction creates a distinctive and unique pattern of brain activation in highly suggestible subjects.

The anatomical bases of semantic retrieval deficits in early Alzheimer's disease.

Semantic abilities deteriorate early in patients with Alzheimer's disease (AD) and their residual language is characterised by strong lexical effects such as the age of acquisition of words and their typicality. The anatomical bases of this early semantic degradation have not been fully explored. To clarify which neural structures, when atrophic, alter lexical-semantic function in patients with very mild AD, this study correlated the lexical attributes of words produced in a semantic fluency task with grey matter density values from 3D MRI scans of mild AD patients. The voxel-based analyses showed a significant correlation between the lexical attributes characterising residual linguistic production in early AD patients and the integrity of regions of the medial temporal lobes, especially in areas of the perirhinal and parahippocampal cortex. This correlation was present in both hemispheres. There were no correlations within these structures with scores on neuropsychological tests not involving semantic or episodic memory. The results have implications for the role of medial temporal structures in episodic and semantic retrieval and argue against a unitary function of these structures in respect of episodic and semantic memory processes. This evidence suggests that specialised regions within the hippocampal complex engage in processes of encoding and retrieval for both semantic and episodic memories.

Regional brain activity after prolonged cholinergic enhancement in early Alzheimer's disease.

This functional magnetic resonance imaging (fMRI) study examined changes in brain activation after prolonged (20 weeks) and stabilized treatment with the cholinesterase inhibitor galantamine in a small group of patients with very mild Alzheimer's disease (AD). Two cognitive activation paradigms were chosen: one requiring semantic association and the other relying on attention and requiring target detection. A group of age- and education-matched healthy controls was also scanned for comparison. A modest (but not statistically significant) improvement in behavioral scores after treatment was observed in both fMRI tasks. There were brain activation increases in the semantic association task after treatment, and the differences in brain activation present in the comparison of AD patients' baseline images with those of controls were not detectable after treatment. In the target detection task, regions that were activated in the elderly controls but not in the baseline images of the AD group also showed significant activation after treatment. Overall, however, the increases were modest and might reflect the heterogeneity of clinical response to treatment in this small group. Future pharmacological fMRI studies should include clinical response as a factor in the analysis of cholinergic enhancement effects in AD patients.

New directions in hypnosis research: strategies for advancing the cognitive and clinical neuroscience of hypnosis.

This article summarizes key advances in hypnosis research during the past two decades, including (i) clinical research supporting the efficacy of hypnosis for managing a number of clinical symptoms and conditions, (ii) research supporting the role of various divisions in the anterior cingulate and prefrontal cortices in hypnotic responding, and (iii) an emerging finding that high hypnotic suggestibility is associated with atypical brain connectivity profiles. Key recommendations for a research agenda for the next decade include the recommendations that (i) laboratory hypnosis researchers should strongly consider how they assess hypnotic suggestibility in their studies, (ii) inclusion of study participants who score in the middle range of hypnotic suggestibility, and (iii) use of expanding research designs that more clearly delineate the roles of inductions and specific suggestions. Finally, we make two specific suggestions for helping to move the field forward including (i) the use of data sharing and (ii) redirecting resources away from contrasting state and nonstate positions toward studying (a) the efficacy of hypnotic treatments for clinical conditions influenced by central nervous system processes and (b) the neurophysiological underpinnings of hypnotic phenomena. As we learn more about the neurophysiological mechanisms underlying hypnosis and suggestion, we will strengthen our knowledge of both basic brain functions and a host of different psychological functions.

Empirical evidence of neuroprotection by dual cholinesterase inhibition in Alzheimer's disease.

Brain grey matter density changes were quantified using voxel based morphometry in 26 patients with minimal to mild Alzheimer's disease (AD) treated with three cholinesterase inhibitors over 20 weeks. Patients whose drug treatment also inhibited butyrylcholinesterase did not show the widespread cortical atrophic changes in parietotemporal regions invariably reported in untreated AD patients, and which were detectable in the subgroups treated with selective acetylcholinesterase inhibition. This finding is the first empirical evidence that dual cholinesterase inhibition may have neuroprotective potential in AD.

Aging and the number sense: preserved basic non-symbolic numerical processing and enhanced basic symbolic processing.

Aging often leads to general cognitive decline in domains such as memory and attention. The effect of aging on numerical cognition, particularly on foundational numerical skills known as the number sense, is not well-known. Early research focused on the effect of aging on arithmetic. Recent studies have begun to investigate the impact of healthy aging on basic numerical skills, but focused on non-symbolic quantity discrimination alone. Moreover, contradictory findings have emerged. The current study aimed to further investigate the impact of aging on basic non-symbolic and symbolic numerical skills. A group of 25 younger (18-25) and 25 older adults (60-77) participated in non-symbolic and symbolic numerical comparison tasks. Mathematical and spelling abilities were also measured. Results showed that aging had no effect on foundational non-symbolic numerical skills, as both groups performed similarly [RTs, accuracy and Weber fractions (w)]. All participants showed decreased non-symbolic acuity (accuracy and w) in trials requiring inhibition. However, aging appears to be associated with a greater decline in discrimination speed in such trials. Furthermore, aging seems to have a positive impact on mathematical ability and basic symbolic numerical processing, as older participants attained significantly higher mathematical achievement scores, and performed significantly better on the symbolic comparison task than younger participants. The findings suggest that aging and its lifetime exposure to numbers may lead to better mathematical achievement and stronger basic symbolic numerical skills. Our results further support the observation that basic non-symbolic numerical skills are resilient to aging, but that aging may exacerbate poorer performance on trials requiring inhibitory processes. These findings lend further support to the notion that preserved basic numerical skills in aging may reflect the preservation of an innate, primitive, and embedded number sense.

Differentiating normal from pathological brain ageing using standard neuropsychological tests.

To diagnose Alzheimer's disease (AD) early, tests sensitive to neuropathology and insensitive to normal ageing are of greatest benefit. We used several neuropsychological tests to identify those best suited to distinguishing Mild Cognitive Impairment (MCI) and early AD from normal ageing. Impairments in long-term memory were found in older adults and these were even greater in MCI and AD. Older adults outperformed young controls on category fluency and produced later acquired and less familiar words. Older adults also outperformed both patient groups on this task producing more words which were significantly later acquired, less familiar and less typical. Decline in long-term memory appears nonspecific and in the early stage of AD cannot help the differentiation between normal and pathological brain ageing. Normal ageing has no negative effects on verbal fluency, and impairment on this task signals not only established AD, but also its prodromal MCI stage.

Awareness and confabulation.

OBJECTIVE: A single case study with control and normative data of a 74-year-old retired businessman with amnestic mild cognitive impairment, who had spontaneous confabulations concerning fantastic exploits and magical powers as well as déjà vécu experiences. METHODS AND RESULTS: His neuropsychological profile showed episodic memory impairment including deficits of recent episodic autobiographical memories and of recognition, but performance was within normal limits on tests assessing source memory for words, the ability to suppress irrelevant items on a continuous recognition memory task, and the detection of stimulus frequency. There were discrete impairments in an ad hoc test measuring his ability to detect and discriminate the source of a range of material including information derived from personal and public events, invented material, and episodes culled from his personal reading. Although his source memory for autobiographical information was normal, he attributed 20% of the invented material and personal readings and 15% of the public events either to his own experience or to that of someone he knew personally or to someone else. CONCLUSIONS: This evidence suggests that none of the current theoretical accounts of spontaneous confabulations is sufficiently explanatory. Instead, an argument is developed that both fantastic confabulation and déjà vécu arose from a more fundamental disorder of awareness.