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BACKGROUND: Schizophrenic patients tend to attribute internal events to external agents, a bias that may be linked to positive symptoms. We investigated the effect of emotional valence on the cognitive bias.MethodMale schizophrenic subjects (n=30) and an experimenter alternatively produced neutral and negative words. The subject then decided whether he or the experimenter had generated the item. RESULTS: External misattributions were more common than self-misattributions, and the bias was greater for patients with active hallucinations and delusions relative to patients in remission. Actively psychotic patients but not patients in remission were more likely to generate external misattributions with negative relative to neutral words. CONCLUSIONS: Affective modulation of the externalizing cognitive bias in source monitoring is evident in patients with hallucinations and delusions. [ABSTRACT FROM AUTHOR]

Introduction: Hearing impairment is associated with dementia. We aimed to clarify the association between hearing impairment and future cognitive test performance measured by the Montreal Cognitive Assessment Scale (MoCA), adjusted for confounders, avoiding reverse causation through long follow-up., Methods: We used the Norwegian population-based longitudinal cohort study, The Trøndelag Health Study (HUNT). At baseline, we invited all residents 20+ for an audiometric hearing assessment, and at 20+ years follow-up, we cognitively assessed all persons 70+ including MoCA adjusted for hearing impairment. We analyzed the association using linear regression., Results: We included 6879 persons (mean 56.1 years, standard deviation 6.2). At follow-up, the MoCA score was -0.25 (95% confidence interval [CI] -0.35, -0.14), per 10 dB increase in hearing threshold and for persons < 85 years, -0.31 (95% CI -0.42, -0.20)., Discussion: This study finds a long-term association between hearing impairment and dose related reduced cognitive performance, particularly in those aged < 85., Clinical Trial Registration: ID NCT04284384, hearing impairment as a risk factor for dementia in older adults., Highlights: Hearing loss predicts long-term cognitive decline measured by MoCA over 20+ years. Long follow-up is crucial to avoid reverse causation in the hearing-cognition relationship. A 10 dB hearing threshold increase is linked to a 0.25-point reduction in MoCA score. Strongest cognitive decline associations are seen in people aged below 85 years. The association remained after excluding hearing-dependent tasks in the MoCA., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objective: People with adult-onset hearing loss (AoHL) are at increased dementia risk. In this study, we explore potential aetiological mechanisms by synthesising the evidence on the association between AoHL and neuropathological, cerebrospinal fluid (CSF), blood and imaging biomarkers of dementia., Methods: We systematically searched electronic databases from inception to 30 April 2024 for cross-sectional and longitudinal studies, including quantitative data on the association between AoHL and dementia biomarkers. Study quality was assessed with the Mixed Methods Appraisal Tool (MMAT)., Results: Sixty-six studies reporting 63 cross-sectional and 10 longitudinal analyses were included. Twenty-one studies met all MMAT quality criteria. We report a narrative synthesis due to the heterogeneity of the included studies. In CSF-based or blood-based assays or imaging, five out of six cross-sectional analyses found that AoHL was associated with elevated in vivo tau levels, whilst four out of 17 reported a link with elevated in vivo β-amyloid measures. One longitudinal analysis identified an association between AoHL and a steeper increase of CSF tau, but not Aβ 42 , levels over time. Twenty-five out of 44 cross-sectional and six out of nine longitudinal analyses identified associations between AoHL and grey matter atrophy of the temporal regions, particularly the medial temporal lobe. Studies using other biomarkers had inconsistent findings., Conclusions: AoHL was usually associated with more temporal regions grey matter atrophy both cross-sectionally and longitudinally, and elevated in vivo tau but not β-amyloid. Increasing atrophy and higher tau, leading to decreased cognitive reserve may be how hearing loss increases dementia risk., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Age-related hearing loss and mild cognitive impairment (MCI) independently increase dementia risk. The Ageing and Cognitive Health Evaluation in Elders randomised controlled trial (RCT) found hearing aids reduce cognitive decline in high-risk older adults with poor hearing., Methods: This pilot RCT in London memory clinics randomised people with MCI (aged ≥55, untreated hearing loss defined as Pure Tone Average 0.5-4 KHz between 25-70 dB) into two groups. The intervention group received 4 sessions of hearing aid fitting and support. The control group received healthy ageing education and a GP letter recommending audiological referral. Both were followed for 6 months. Primary outcomes were recruitment (feasibility target: 50%; 95% CI: 39%-61%) and retention (feasibility target: 80%; 95% CI: 71%-89%); intervention completion (≥2 visits) and hearing aid use (acceptability target: 80%; 95% CI: 71%-89%) for the intervention group and 50% difference between arms (95% CI: 31%-69%). Secondary outcomes included hearing aid fitting, cognition and other measures., Results: From October 2018 to March 2020, 58 participants were recruited (29 per group, 95% [86%-99%]). Twenty-four participants were fitted with hearing aids in the intervention arm, and 6 in the control arm (difference: 62% [42%-82%]). At 6 months, retention was 81% [69%-90%]. Hearing intervention completion (≥2 visits) was achieved by 24 (83%). Daily hearing aid use was reported by 18 (75%) intervention versus 5 (22%) control participants, a difference of 53% [29%-77%]., Conclusion: Randomisation of people with MCI to a personalised hearing intervention versus control is feasible. These findings support proceeding to a fully-powered multicentre RCT., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Competing Interests: Declaration of interests SA declares grants from the Indian Council for Medical Research (2022–25), the Government of Karnataka (2022–23), Rotary Bangalore Midtown (2022–23), Lowes Services India (2022–25), and Wellcome Trust (2023–26); payment for expert testimony received by Indian Council of Medical Research and Ashoka University; and a travel grant paid by University College London for being part of the Lancet Commission. SB declares grants from National Institute for Health and Care Research (NIHR), Economic and Social Research Council, Engineering and Physical Science Research Council, Canadian Institute for Health Research, the Alzheimer's Association, the Alzheimer's Society, Health Education England, Alzheimer's Association, Alzheimer's Society, and Health Education England. He has held the following positions: Non-Executive Director Somerset NHS Foundation Trust, Trustee of the Alzheimer's Society, Executive Dean of the University of Plymouth, and Pro-Vice Chancellor of the University of Nottingham. AB acts as a consultant for Lilly, TauRx Pharmaceuticals, and Eisai and carries out medico–legal work for solicitors. NCF declares consulting fees from F Hoffmann-La Roche, Eli Lilly, Ionis, Biogen, and Siemens; participation in data safety monitoring or advisory board for Biogen; and being a member of the Research Strategy Council for the Alzheimer's Society. LNG declares owning tailored activity programme licences. MK declares grants from Wellcome Trust (221854/Z/20/Z), the Medical Research Council (R024227), the National Institute on Aging (R01AG062553, R01AG056477), and the Academy of Finland (350426). KYL declared fellowship from Medical Research Council. EBL receives grants from the National Institutes of Health (NIH) and royalties from UpToDate. GL declares support for the manuscript from the Alzheimer's Society, the Alzheimer's Society UK, and UK Research and Innovation, who gave grants to pay for travel and accommodation. She is supported by the University College London Hospitals' NIHR Biomedical Research Centre, by North Thames NIHR Applied Research Collaboration, and as an NIHR Senior Investigator and has grants from NIHR Health Technology Assessment, NIHR Programme Grants for Applied Research, the Alzheimer's Association, the Norwegian Research Council, and Wellcome, outside of the submitted work. She works with the Alzheimer's Society as a member of the Research Strategy Council and is a trustee of Nightingale Hammerson care homes. KR declares grants from Canadian Institutes of Health Research, the Canadian Frailty Network, and Research Nova Scotia; royalties from Biotest, Qu Biologics, AstraZeneca UK, BioAge Labs, Congenica, Icosavax, KCR, Faraday Pharmaceuticals, Synairgen Research, Enanta Pharmaceuticals, Pfizer, Boehringer Ingelheim International, Fresenius Kabi Deutschland, Baycrest Geriatric Care, and Shanghai Ark Biopharmaceutical; payment or honoraria from University of British Columbia, Fraser Health Authority, McMaster University, Chinese Medical Association, Wake Forest University Medical School Centre, University of Omaha, and Atria Institute; participation on data safety or advisory board for EpiPharma; and leadership of the Canadian Consortium on Neurodegeneration in Dementia, Cap Breton University, and Nova Scotia Health. KS declares support from the Japan Society for the Promotion of Science fund (22H03352, 21KK0168, 16KK0059). LSS declares support from Della Martin Foundation, the NIH (P30 AG066530, R01 AG051346, R01 AG062687, R01 AG051346, R01 AG055444, P01 AG052350, R01 AG053267, R01 AG074983, R01 AG063826), Abbott, Biohaven, Biogen, Eisai, and Eli Lilly and consulting fees from AC Immune, Cortexyme, Alpha-cognition, BioVie, Athira, Eli Lilly/Avid, Corium, Lundbeck, Merck, Muna Therapeutics, Novo-Nordisk, Neurim, NeuroDiagnostics, Ono, Otsuka, Roche/Genentech, Cognition, Lighthouse, GW Research, ImmunoBrain, and Bristol Myers Squibb. AS declares grants from Wellcome Trust, the Alzheimer's Association, Brain Canada, and the NIHR. YY declares support from the National Natural Science Foundation of China (72374013) and the National Key R&D Program of China (2023YFB4603200, 2023YFC3606400). SW declares an NIHR doctoral training fellowship. GS has participated on advisory boards for the following pharmaceutical companies manufacturing drugs against Alzheimer's disease: Biogen, Roche, and Eisai. LG is an inventor of a training program for health and human service professionals in an evidence-based tailored activity intervention, the Tailored Activity Program; she and her respective universities are entitled to fees. All other authors declare no competing interests.

Background: Hearing impairment is strongly associated with future dementia. No studies have reported objectively measured hearing impairment in a cohort with a long period of follow-up (>20 years), and few have reported follow-up over 10 years. Hence, there is a need for high quality studies with sufficient follow-up time and data to account for reverse causality and confounding. We aimed to address this knowledge gap., Methods: This cohort study used individual participant data from The Trøndelag Health Study (HUNT) in Norway. All current residents aged at least 20 years in the former Norwegian Nord-Trøndelag County were invited to participate in four decennial surveys: HUNT1 (1984-1986), HUNT2 (1995-1997), HUNT3 (2006-2008), and HUNT4 (2017-2019) with individuals aged at least 70 years included in a substudy, known as HUNT4 70+. Here, we report the findings of this substudy. HUNT4 70+ comprised 7135 participants who were assessed for dementia using the Diagnostic and Statistical Manual of Mental Disorders 5 criteria and who had audiometry between 1996 and 1998. The primary objective was to investigate, with gold standard audiometric testing and dementia diagnostic assessment, whether hearing impairment was an independent risk factor for all-cause dementia. The secondary objective was to investigate if a risk also applied to Alzheimer dementia and non-Alzheimer dementia. We analysed the association using Poisson regression and adjusted for confounders. This study is registered with ClinicalTrials.gov (NCT04284384)., Findings: At baseline, 1058 (15%) individuals had acquired hearing impairment with a hearing threshold of at least 25 decibel (dB) and, at follow-up, 1089 (15%) had dementia. In the total group, people with hearing impairment had a relative risk (RR) 1.04 (95% confidence interval (CI) 1.00-1.09) per 10 dB increase in hearing thresholds. For individuals younger than 85 years at follow-up the RR was 1.12 (95% CI 1.05-1.21). Associations between hearing impairment and Alzheimer dementia and non-Alzheimer dementia were similar. There was no association for individuals aged at least 85 years., Interpretation: We found a moderate association between objectively measured hearing impairment and dementia in the younger age group (<85 years). The findings of no association in the older age group (≥85 years) might be due to the competing risk of death. The present study adds to the literature showing that acquired hearing impairment is a risk for dementias over a period which is too long for reverse causation, and with thorough consideration of confounders. Further research is needed to investigate associations between the different aetiologies of hearing loss and dementia subtypes, and risk differences for sexes., Funding: The Norwegian National Centre for Ageing and Health with a grant from Health South-East., Competing Interests: SGC has in the last 36 months received grants for research in dementia prevention, including by treating hearing loss, from UK NIHR, grant for dementia risk assessment from Dunhill Medical Trust—UK Charity, and grant for research in dementia prevention, including by treating hearing loss, from Alzheimer’s Research UK—Charity. FL has in the last 36 months received research grants pertaining to hearing loss from National Institutes of Health, research grants pertaining to hearing loss from Eleanor Schwartz Charitable Foundation, consulting fees as consultant on topics related to hearing loss from Frequency Therapeutics and Apple Inc., personal fees as expert witness for the plaintiff in a class action lawsuit against an insurance company in Washington state pertaining to litigation relating to the insurance company’s policy of non-coverage for hearing aids, is a scientific advisory board member for Fondation Pour L’Audition, is a scientific advisory board member (possible stock options pending continued role on the SAB), is a volunteer board of the nonprofit AccessHears, received donation in-kind from Sonova to Johns Hopkins University for hearing technologies used in the NIH-funded ACHIEVE trial, and is director of a public health research center funded in part by a philanthropic donation from Cochlear Ltd., to the Johns Hopkins Bloomberg School of Public Health. GL has since the initial planning of the work received payment made to the institutions University College London Hospitals’ National Institute for Health Research (NIHR), and Biomedical Research Centre, North Thames NIHR Applied Research Collaboration, and as an NIHR Senior Investigator to support academics to work. GS has participated in advisory boards for Biogen, Eisai and Roche concerning antidementia drugs. All other authors declare no competing interests., (© 2023 The Authors.)

Competing Interests: We declare no competing interests. The views expressed in this publication are those of the authors and not necessarily those of the National Institute for Health and Care Research (NIHR) or the Department of Health and Social Care. GL and SGC are supported by NIHR programme grants and by University College London Hospital NIHR Biomedical Research Centre. GL is supported by the NIHR Health Technology Assessment programme and by the NIHR Applied Research Collaboration North Thames and as an NIHR senior investigator.

Close links exist between vestibular function and cognition. Dual-task (DT) tests may have ecological validity to assess the impact of daily life cognitive-motor demands in people with vestibular dysfunction (PwVD), functional gait and falls risk. The present paper aimed at building predictive models for functional gait under DT conditions, while clarifying the impact of vestibular dysfunction, individual characteristics, varying task types and motor-cognitive demands. Case-controlled observational study with 39 PwVD and 62 healthy participants. The Functional Gait Assessment (FGA), with and without an additional motor, numeracy, or literacy task, was completed. Multiple linear regression was used to fit models to predict FGA under single and DT performance. Dual task cost (DTC, %) was calculated to assess DT interference on FGA performance using the equation: 100*(single task score-dual task score)/single-task score. Following Bonferroni corrections for multiple comparisons (corrected alpha level of 0.003), PwVD had poorer performance than controls for all FGA conditions (p < 0.001), motor (- 3.94%; p = 0.002) and numeracy (- 22.77%; p = 0.001) DTCs and spatial working memory (p = 0.002). The literacy DTC was marginally significant (- 19.39% p = 0.005). FGA single and DT motor, numeracy, and literacy models explained 76%, 76%, 66% and 67% of the variance respectively for PwVD. Sustained attention, visual memory and sex contributed to all models; short-term visual recognition memory, balance confidence, and migraine contributed to some models. Cognitive performance is impaired in PwVD. Motor, numeracy and literacy tasks impair functional gait performance. Cognitive assessment and FGA with a numeracy or literacy cognitive component should be included within assessment protocols and considered in the provision of targeted interventions for PwVD., (© 2023. The Author(s).)

Background: midlife hearing loss is a potentially modifiable risk factor for dementia. Addressing comorbid hearing loss and cognitive impairment in services for older adults may offer opportunities to reduce dementia risk., Objective: to explore current practice and views amongst UK professionals regarding hearing assessment and care in memory clinics and cognitive assessment and care in hearing aid clinics., Methods: national survey study. Between July 2021 and March 2022, we distributed the online survey link via email and via QR codes at conferences to professionals working in National Health Service (NHS) memory services and audiologists working in NHS and private adult audiology services. We present descriptive statistics., Results: 135 professionals working in NHS memory services and 156 audiologists (68% NHS, 32% private sector) responded. Of those working in memory services, 79% estimate that >25% of their patients have significant hearing difficulties; 98% think it useful to ask about hearing difficulties and 91% do so; 56% think it useful to perform a hearing test in clinic but only 4% do so. Of audiologists, 36% estimate that >25% of their older adult patients have significant memory problems; 90% think it useful to perform cognitive assessments, but only 4% do so. Main barriers cited are lack of training, time and resources., Conclusions: although professionals working in memory and audiology services felt addressing this comorbidity would be useful, current practice varies and does not generally address it. These results inform future research into operational solutions to integrating memory and audiology services., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Sleep disturbances affect 38% of care home residents living with dementia. They are often treated with medication, but non-pharmacological interventions may be safer and effective yet more difficult to implement. In the SIESTA study (Sleep problems In dEmentia: interviews with care home STAff) we explored care home staffs' experience of managing sleep disturbances in their residents living with dementia., Methods: We conducted one-to-one semi-structured interviews in four UK care homes, and purposively recruited a maximum variation sample of 18 nurses and care assistants, who were each interviewed once. We used a topic guide and audio-recorded the interviews. Two researchers independently analysed themes from transcribed interviews., Results: Staff used a range of techniques that often worked in improving or preventing residents' sleep disturbance. During the daytime, staff encouraged residents to eat well, and be physically active and stimulated to limit daytime sleep. In the evening, staff settled residents into dark, quiet, comfortable bedrooms often after a snack. When residents woke at night, they gave them caffeinated tea or food, considered possible pain and discomfort, and reassured residents they were safe. If residents remained unsettled, staff would engage them in activities. They used telecare to monitor night-time risk. Staff found minimising daytime napping difficult, described insufficient staffing at night to attend to reorient and guide awake residents and said residents frequently did not know it was night-time., Conclusions: Some common techniques, such as caffeinated drinks, may be counterproductive. Future non-pharmacological interventions should consider practical difficulties staff face in managing sleep disturbances, including struggling to limit daytime napping, identifying residents' night-time needs, day-night disorientation, and insufficient night-time staffing., Competing Interests: LW reports that the analyses in this paper were undertaken as part of their ESRC funded PhD studentship. SGC reports receiving research funding from Alzheimer’s Research UK Grant, European Research Council and Dunhill Medical Trust. GL reports participating on the Lancet Healthy Longevity Board and receiving research funding from Alzheimer’s Society, Wellcome trust, and NIHR. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: People living with dementia in care homes often have sleep disturbances, but little is known about incidence and importance., Methods: We interviewed 1483 participants in 97 care homes and report prevalence, 1-year incidence, and baseline associations of clinically significant sleep disturbance in people with dementia., Results: Baseline prevalence of clinically significant sleep disturbance was 13.7% (200/1460); 31.3% (457/1462) had them at least once over 16 months. One-year incidence was 25.2%. At baseline, residents with sleep disturbance had lower quality of life (mean difference -4.84; 95% confidence interval [CI] -6.53 to -3.16) and were more frequently prescribed sleep medications (odds ratio 1.75; CI 1.17 to 2.61) than other residents., Discussion: Approximately one-third of care home residents with dementia have or develop sleep disturbances over 1 year. These are associated with lower quality of life and prescription of sedatives, which may have negative outcomes; therefore, it is important to develop effective treatments., Competing Interests: LW reports that the analyses in this paper were undertaken as part of their ESRC‐funded PhD studentship. SGC reports receiving research funding from Alzheimer's Research UK Grant, European Research Council and Dunhill Medical Trust. JAB reports voluntary work on data safety monitoring boards and receiving research funding from NIHR and MRC. SDK reports no‐cost access to a digital sleep intervention (Sleepio, Big Health Ltd.) in clinical trial research. GL reports participating on the Lancet Healthy Longevity Board and receiving research funding from Alzheimer's Society, Wellcome trust, and NIHR., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Aims: To identify cognitive tests that best differentiate between Posterior Cortical Atrophy (PCA) and typical Alzheimer's Disease (tAD), as well as PCA and healthy control (HC) participants., Method: Medline, PsycInfo and Web of Science were systematically searched using terms related to PCA, tAD, and cognitive testing. Seventeen studies were identified, including 441 PCA, 391 tAD, and 284 HC participants. Standardised effect sizes of mean scores were calculated to measure performance differences on cognitive tests for PCA versus tAD and PCA versus HC groups. Meta-analyses used a random effects model., Results: The most discriminating cognitive tests for PCA and tAD presentations were measures of visuospatial function and verbal memory. Large, significant effect sizes were produced for all measures of visuospatial function, most notably for Rey-Osterrieth Copy (Hedges' g = -2.79), VOSP Fragmented letters (Hedges' g = -1.73), VOSP Dot Counting (Hedges' g = -1.74), and VOSP Cube Analysis (Hedges' g = -1.98). For measures of verbal memory, the RAVLT delay and Digit Span Backwards produced significant medium effects (Hedges' g = .62 and -.56, respectively)., Conclusion: Establishing a common framework for testing individuals with PCA has important implications for diagnosis and treatment, and forms a practical objective for future research. Findings from this meta-analysis suggest that measures of visuospatial function and verbal memory would form an important part of this framework., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Objectives: This research aims to validate a modified visually based Montreal Cognitive Assessment for hearing-aid users (MoCA-HA). This population should be the target of cognitive screening due to high risk of developing dementia., Design: Case-control study., Setting: The participants were recruited from referral hearing-aid center and memory clinic in central London, United Kingdom., Participant: 75 hearing-aid users were recruited. Of these, thirty were cognitively intact controls with hearing impairment (NC-HI); thirty had mild cognitive impairment with hearing impairment (MCI-HI); fifteen had dementia with hearing impairment (D-HI)., Measurements: The baseline characteristics and analysis of the MoCA-HA for the NC-HI were recorded. The MoCA-HA performance of the MCI-HI cohort and D-HI cohort were also studied., Results: The cutpoint of <26 yields 93.3% sensitivity with 80% specificity in distinguishing MCI-HI from NC-HI. The specificity increased to 95.6% in screening for all cognitive impairment (MCI-HI and D-HI) from NC-HI., Conclusion: The MoCA-HA has been validated with a cutpoint which is comparable to the traditional MoCA. This tool may help clinicians to early identify older adult hearing-aid users for appropriate cognitive evaluation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Utoomprurkporn, Stott, Costafreda, North, Heatley and Bamiou.)

(1) Introduction: The validity of self-reported hearing disability measures has been assessed using their correlation with the pure-tone average (PTA) hearing loss for non-cognitively impaired adults. However, for people with cognitive impairment, factors in addition to the PTA can play a role in their self-reported difficulties. Patients with cognitive impairment may experience more hearing difficulties due to their brain processing sounds abnormally, irrespective of PTA. (2) Methods: Three groups of hearing aid users who had normal cognition, mild cognitive impairment and dementia were recruited. Self-reported hearing abilities were assessed with the modified Amsterdam inventory for auditory disability (mAIAD) and the speech, spatial and qualities of hearing scale (SSQ). (3) Results: The SSQ and mAIAD scores were highly correlated with each other for all three groups. However, a correlation with objective PTA was found in the normal cognition but not the cognitively impaired groups. Self-reported hearing scores were associated with cognitive scores for the dementia group (4) Discussion: In people with combined cognitive and hearing impairment, PTA alone may be a poor predictor of hearing abilities. Subjective hearing questionnaires together with hearing tests may provide a better understanding of their hearing difficulties.

Background: A large proportion of older adults assessed for cognitive impairment likely have hearing loss, potentially affecting accuracy of cognitive performance estimations. This study aimed to develop a hearing-impaired version of the Addenbrooke's Cognitive Examination-III (HI-ACE-III) and to assess whether the HI-ACE-III can accurately distinguish people with mild cognitive impairment (MCI) and dementia from cognitively intact controls., Methods: The HI-ACE-III was developed by converting verbal instructions into a visual, timed PowerPoint presentation. Seventy-four participants over the age of 60 years were classified into three groups: 29 had MCI, 15 had mild to moderate dementia and 30 were cognitively intact controls. Receiver operating characteristic (ROC) curves were graphed to test screening accuracy. Concurrent validity was examined through correlations between HI-ACE-III domain scores and relevant, visually presented standardized neuropsychological measures., Results: ROC analysis for dementia revealed an area under the curve (AUC) of 0.99, achieving excellent sensitivity (100%) and good specificity (93.3%) at an optimum cut-off of <87. The AUC for MCI was 0.86, achieving reasonable sensitivity (75.9%) and good specificity (86.7%) at an optimum cut-off of <92. HI-ACE-III subtests shared anticipated and statistically significant correlations with established measures of cognitive functioning. Internal consistency of the HI-ACE-III was excellent as verified with Cronbach's alpha (α = 0.904)., Conclusions: Preliminarily, the HI-ACE-III showed good reliability, validity and screening utility for MCI and dementia in older adults in a hearing-impairment context. The adapted HI-ACE-III may offer accurate and reliable indication of cognitive performance, supporting timely diagnosis and research examining links between hearing loss and cognitive decline., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: The potential economic value of interventions to prevent late-onset dementia is unknown. We modelled this for potentially modifiable risk factors for dementia., Methods: For this modelling study, we searched PubMed and Web of Science from inception to March 12, 2020, and included interventions that: successfully targeted any of nine prespecified potentially modifiable risk factors (hypertension, diabetes, hearing loss, obesity, physical inactivity, social isolation, depression, cigarette smoking, and less childhood education); had robust evidence that the intervention improved risk or risk behaviour; and are feasible to enact in an adult population. We established when in the life course each intervention would be delivered. We calculated dementia incidence reduction from annual incidence of dementia in people with each risk factor, and population attributable fraction for each risk, corrected for risk factor clustering, and how effectively the intervention controls the risk factor. We calculated the discounted value of lifetime health gain and effect on cost (including NHS, social care and carer costs) per person eligible for treatment. We estimated annual total expenditure on the fully operational intervention programme in England., Findings: We found effective interventions for hypertension, smoking cessation, diabetes prevention, and hearing loss. Treatments for stopping smoking and provision of hearing aids reduced cost. Treatment of hypertension was cost-effective by reference to standard UK thresholds. The three interventions when fully implemented would save £1·863 billion annually in England, reduce dementia prevalence by 8·5%, and produce quality-adjusted life-year gains. The intervention for diabetes was unlikely to be cost-effective in terms of effect on dementia alone., Interpretation: There is a strong case for implementing the three effective interventions on grounds of cost-effectiveness and quality-of-life gains, as well as for improvements in general health. The interventions have the potential to remain cost-saving or cost-effective even with variations in dementia incidence and costs and effectiveness of interventions., Funding: Economic and Social Research Council., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licence. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with dementia commonly have problems processing speech in the presence of competing background speech or noise. This difficulty can be present from the very early stages of dementia, and may be a preclinical feature of Alzheimer's disease., Purpose: This study investigates whether people with dementia perform worse on the dichotic digit test (DDT), an experimental probe of speech processing in the presence of competing speech, and whether test performance may predict dementia onset., Research Design: Systematic review and meta-analysis., Data Collection and Analysis: A literature search was conducted in Medline, Embase, Scopus, and Psycinfo. We included (1) studies that included people with a diagnosis of dementia and a healthy control group with no cognitive impairment; (2) studies that reported results from a DDT in a free-recall response task; and (3) studies that had the dichotic digit mean correct percentage score or right-ear advantage, as outcome measurements., Results: People with dementia had a lower DDT total score, with a pooled mean difference of 18.6% (95% confidence interval [CI]: 21.2-15.9). Patients with dementia had an increased right-ear advantage relative to controls with a pooled difference of 24.4% (95% CI: 21.8-27.0)., Conclusion: The DDT total scores are lower and the right-ear advantage increased in cognitively impaired versus normal control participants. The findings also suggest that the reduction of dichotic digit total score and increase of right-ear advantage progress as cognitive impairment increases. Whether abnormalities in dichotic digit scores could predict subsequent dementia onset should be examined in further longitudinal studies., Competing Interests: None., (American Academy of Audiology. This article is published by Thieme.)

As life expectancy increases, it is imperative that the elderly take advantage of the benefits of technology to remain active and independent. Mobile health applications are widely used nowadays as they promote a healthy lifestyle and self-management of diseases, opening new horizons in the interactive health service delivery. However, adapting these applications to the needs and requirements of the elderly is still a challenge. This article presents a smartphone application that is part of a multifactorial intervention to support older people with balance disorders. The application aims to enable users to self-evaluate their activity and progress, to communicate with each other and, through strategically selected motivational features, to engage with the system with undiminished interest for a long period of time. Mock-up interfaces were evaluated in semi-structured focus groups and interviews that were performed across three European countries. Further evaluation in the form of four pilot studies with 160 participants will be performed and qualitative and quantitative measures will be used to process the feedback about the use of the application., (Copyright © 2020 Androutsou, Kouris, Anastasiou, Pavlopoulos, Mostajeran, Bamiou, Genna, Costafreda and Koutsouris.)

Background: Older adults are at high risk of developing age-related hearing loss (HL) and/or cognitive impairment. However, cognitive screening tools rely on oral administration of instructions and stimuli that may be impacted by HL. This systematic review aims to investigate (a) whether people with HL perform worse than those without HL on the Montreal Cognitive Assessment (MoCA), a widely used screening tool for cognitive impairment, and what the effect size of that difference is (b) whether HL treatment mitigates the impact of HL., Method: We conducted a systematic review and meta-analysis including studies that reported mean MoCA scores and SDs for individuals with HL., Results: People with HL performed significantly worse on the MoCA (4 studies, N = 533) with a pooled mean difference of -1.66 points (95% confidence interval CI -2.74 to -0.58). There was no significant difference in MoCA score between the pre- vs post-hearing intervention (3 studies, N = 75). However, sensitivity analysis in the cochlear implant studies (2 studies, N = 33) showed improvement of the MoCA score by 1.73 (95% CI 0.18 to 3.28)., Conclusion: People with HL score significantly lower than individuals with normal hearing on the standard orally administered MoCA. Clinicians should consider listening conditions when administering the MoCA and report the hearing status of the tested individuals, if known, taking this into account in interpretation or make note of any hearing difficulty during consultations which may warrant onward referral. Cochlear implants may improve the MoCA score of individuals with HL, and more evidence is required on other treatments. J Am Geriatr Soc 68:-, 2020., (© 2020 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.)

Objectives: Nearly 40% of care home residents who are living with dementia also have symptoms of disturbed sleep. However, the impact of these disturbances is relatively unknown and is needed to indicate whether interventions are warranted; therefore, we aimed to investigate the impact., Design: One-to-one semi-structured interviews., Settings: Four UK care homes., Participants: We interviewed 18 nurses and care assistants about residents with sleep disturbances., Measurements: We used a topic guide to explore staff experience of sleep disturbance in residents with dementia. The interviews were audio recorded and transcribed and then analyzed thematically by two researchers independently., Results: Staff described that sleep disturbances in most, but not all, residents impacted negatively on the resident, other residents, staff, and relatives. Residents became more irritable or agitated if they had slept badly. They slept in the daytime after a bad night, which then increased their chances of being awake the following night. For some, being sleepy in the day led to falls, missing medication, drinks, and meals. Staff perceived hypnotics as having low efficacy, but increasing the risk of falls and drowsiness. Other residents were disturbed by noise, and staff described stress when several residents had sleep disturbance. Some of the strategies reported by staff to deal with sleep disturbances such as feeding or providing caffeinated tea at night might be counterproductive., Conclusions: Sleep disturbances in care home residents living with dementia negatively affect their physical and psychological well-being. These disturbances also disturb other residents and increase stress in staff.

Background: Brain-derived neurotrophic factor (BDNF) has an essential role in synaptic plasticity and neurogenesis. BDNF mediates amygdala-dependent learning for both aversive and appetitive emotional memories. The expression of BDNF in limbic regions is posited to contribute the development of depression, and amygdala responsivity is a potential marker of depressive state., Methods: The present study examined the relationship between platelet BDNF levels and amygdala volume and function in major depressive disorder (MDD). Participants were 23 MDD (mean age 38.9 years) and 23 healthy controls (mean age 38.8 years). All participants were recruited from the community. MDD participants were in a current depressive episode of moderate severity and medication-free. Amygdala responses were acquired during a functional MRI task of implicit emotional processing with sad facial expressions., Results: Significant correlation was observed between platelet BDNF levels and left amygdala responses, but no significant correlations were found with right amygdala responses or with amygdala volumes., Limitations: Interactions with neuroprotective as well as neurotoxic metabolites in the kyneurenine pathway were not examined., Conclusions: Relationship between BDNF levels and amygdala responsivity to emotionally salient stimuli in MDD could reflect the importance of BDNF in amygdala-dependent learning with clinical implications for potential pathways for treatment., Competing Interests: Declaration of Competing Interest The study had been funded in part by Eli Lilly and Company. CHYF had held recent research grants from Eli Lilly and Company and GlaxoSmithKline. MMR had held recent research grants from Eli Lilly and Company and had received consulting fees from Eli Lilly, Roche, Sunnovion, Stroke-Med. MMR report ownership interest in Pax Neuroscience, and MMR reports partial salary support via a Merit Award from the Veterans Administration. LBM was a former employee and stockholder of Eli Lilly and Company., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Hearing aid usage supports communication and independence; however, many do not use their hearing aids. This study explored the experiences of hearing aid use in adults with mild cognitive impairment or Alzheimer's disease., Methods: Participants completed semi-structured interviews which were analysed using thematic analysis. Ten people (six males, age range 75-86 years old) with mild cognitive impairment or Alzheimer's disease who had been fitted with hearing aids were recruited to the study., Results: We identified four major themes: (1) memory and other cognitive barriers to using hearing aids, (2) practical aspects of hearing aids, (3) benefits of hearing aids, and (4) ambivalence towards hearing aids., Conclusions: Participants perceived a significant impact of cognitive impairment on the experience of using hearing aids. This population may benefit from targeted strategies to support use of hearing aids. The findings from this study can inform future research to optimise use of hearing aids in this population., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Longitudinal neuroimaging studies in major depression have revealed cortico-limbic abnormalities which are modulated by treatment. We performed a systematic review and meta-analysis of psychotherapy treatment studies measuring neural function and metabolism using fMRI, PET, SPECT and MRS. Seventeen studies were included in the systematic review, total of 200 major depression participants (mean age 37.6 years), all medication free, and 116 healthy controls (mean age 36.4 years). Neuroimaging assessments were performed prior to initiation of treatment and following course of treatment. Treatment durations were: 16-30 weeks for CBT, 11 weeks for behavioral activation therapy, and up to 15 months for psychodynamic psychotherapy. The meta-analysis consisted of studies in which both groups had same serial scans and comparable tasks; total of 5 studies with visual presentation tasks of emotional stimuli: 55 patients (mean age: 38.7 years) and 55 healthy controls (mean age: 36.3 years). The meta-analysis revealed a significant group by time effect in left rostral anterior cingulate, in which patients showed increased activity following psychotherapy while healthy controls showed a decrease at follow up. Longitudinal treatment effects revealed reduced left precentral cortical activity in major depression. Findings could be indicative of improvements in emotion responsivity that may be achieved following psychotherapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The other race effect, also known as own race bias, refers to the enhanced ability to recognize faces belonging to one's own race relative to faces from another race. The other race effect is associated with increased amygdala response in healthy individuals. The amygdala is a key node in emotion processing which shows impaired functioning in depression and has been proposed to be a marker of depressive state. We investigated the impact of the other race effect on amygdala responses in depression., Methods: Participants were 30 individuals with major depression (mean age 39.4 years) and 23 healthy individuals (mean age: 38.8 years) recruited from the community. Participants were Asian, Black/African American and Caucasian. During a functional MRI scan, participants viewed Caucasian faces which displayed a range of sad expressions. A region of interest analysis of left and right amygdala responses was performed., Results: Increased bilateral amygdala responses were observed in response to the Caucasian face stimuli in participants who were Asian or Black/African American as compared to Caucasian participants in both healthy individuals and individuals with major depression. There was no significant group by race interaction effect., Conclusions: Increased amygdala responses associated with the other race effect were evident in both individuals with major depression and in healthy participants. Increased amygdala responses with the other race effect is a potential confound of the neural correlates of facial processing in healthy participants and in mental health disorders. The implications of the other race effect on impairments in interpersonal functioning in depression require further investigation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Impairments in verbal working memory are evident in major depression. Verbal working memory is comprised of the components of encoding, maintenance and retrieval. Whether the neural impairments are expressed in specific components, and how pharmacological therapy could modify the neural correlates are not well understood. We investigated the neural correlates of verbal working memory components in depression using the Sternberg task in a longitudinal magnetic resonance imaging study. Serial scans were acquired in 23 patients (mean age 39.8 years) during an acute depressive episode and following 12 weeks of pharmacological therapy with duloxetine and in 22 matched healthy controls (mean age 39.1 years) at the same time points. A significant group by time interaction was evident during the long maintenance phase, extending from the left middle frontal to the middle temporal and caudate regions, in which there was reduced activation in healthy participants at the follow -up scan but there were no changes in patients. Persistent neural engagement during the maintenance phase following treatment was revealed in major depression. The findings emphasize that impairments in verbal working memory may be initiated in the maintenance phase in major depression in order to sustain performance. Further research with larger sample size and using randomized, placebo-controlled double-blind studies are required to confirm our results.

Background: Use of antipsychotics to treat behavioural symptoms of dementia has been associated with increased risks of mortality and stroke. Little is known about individual patient characteristics that might be associated with bad or good outcomes., Aims: We examined the risperidone clinical trial data to look for individual patient characteristics associated with these adverse outcomes., Method: Data from all double-blind randomised controlled trials of risperidone in dementia patients (risperidone n = 1009, placebo n = 712) were included. Associations between characteristics and outcome were analysed based on crude incidences and exposure-adjusted incidence rates, and by time-to-event analyses using Cox proportional hazards regression. Interactions between treatment (risperidone or placebo) and characteristic were analysed with a Cox proportional hazards regression model with main effects for treatment and characteristic in addition to the interaction term., Results: Baseline complications of depression (treatment by risk factor interaction on cerebrovascular adverse event (CVAE) hazard ratio (HR): P = 0.025) and delusions (P = 0.043) were associated with a lower relative risk of CVAE in risperidone-treated patients (HR = 1.47 and 0.54, respectively) compared to not having the complication (HR = 5.88 and 4.16). For mortality, the only significant baseline predictor in patients treated with risperidone was depression, which was associated with a lower relative risk (P<0.001). The relative risk of mortality was increased in risperidone patients treated with anti-inflammatory medications (P = 0.021)., Conclusions: Only anti-inflammatory medications increased mortality risk with risperidone. The reduced risks of CVAE in patients with comorbid depression and delusions, and of mortality with depression, may have clinical implications when weighing the benefits and risks of treatment with risperidone in patients with dementia., (© The Royal College of Psychiatrists 2016.)

Background: At present, we do not have any biological tests which can contribute towards a diagnosis of depression. Neuroimaging measures have shown some potential as biomarkers for diagnosis. However, participants have generally been from the same ethnic background while the applicability of a biomarker would require replication in individuals of diverse ethnicities., Aims: We sought to examine the diagnostic potential of the structural neuroanatomy of depression in a sample of a wide ethnic diversity., Method: Structural magnetic resonance imaging (MRI) scans were obtained from 23 patients with major depressive disorder in an acute depressive episode (mean age: 39.8 years) and 20 matched healthy volunteers (mean age: 38.8 years). Participants were of Asian, African and Caucasian ethnicity recruited from the general community., Results: Structural neuroanatomy combining white and grey matter distinguished patients from controls at the highest accuracy of 81% with the most stable pattern being at around 70%. A widespread network encompassing frontal, parietal, occipital and cerebellar regions contributed towards diagnostic classification., Conclusions: These findings provide an important step in the development of potential neuroimaging-based tools for diagnosis as they demonstrate that the identification of depression is feasible within a multi-ethnic group from the community., Declaration of Interests: C.H.Y.F. has held recent research grants from Eli Lilly and Company and GlaxoSmithKline. L.M. is a former employee and stockholder of Eli Lilly and Company., Copyright and Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Diabetes is associated with macrovascular and microvascular complications and is a major risk factor for neurological and psychiatric disorders, such as dementia and depression. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) have distinct etiologies and pathophysiological effects while sharing a common endpoint of persistent hyperglycemia. Neuroimaging studies in T1DM have revealed reductions in numerous regions, including the parahippocampal and occipital regions, while in T2DM there have been numerous reports of hippocampal atrophy. This meta-analysis aimed to identify consistent regional abnormalities in cerebral structures in T1DM and T2DM respectively, and also to examine the impact of potential confounds, including age, depression and vascular risk factors. Neuroimaging studies of both voxel-based morphometry (VBM) data and volumetric data were included. Ten T1DM studies (n = 613 patients) and 23 T2DM studies (n = 1364 patients) fulfilled inclusion criteria. The T1DM meta-analysis revealed reduced bilateral thalamus grey matter density in adults. The T2DM meta-analysis revealed reduced global brain volume and regional atrophy in the hippocampi, basal ganglia, and orbitofrontal and occipital lobes. Moreover, hippocampal atrophy in T2DM was not modified by hypertension, although there were more marked reductions in younger patients relative to healthy controls. In conclusion, T1DM and T2DM demonstrated distinct cerebral effects with generalised and specific target areas of grey matter reduction. Thalamic atrophy in T1DM may be a substrate of associated cognitive deficits. In T2DM, global cerebral atrophy may reflect atherosclerotic factors, while hippocampal atrophy was an independent effect providing a potential common neuropathological etiology for the comorbidity of T2DM with dementia and depression.

Background: Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to the development of depression (major depressive disorder, MDD), but it is unclear whether neural effects observed in healthy individuals are sustained in MDD., Aims: To investigate BDNF Val66Met effects on key regions in MDD neurocircuitry: amygdala, anterior cingulate, middle frontal and orbitofrontal regions., Method: Magnetic resonance imaging scans were acquired in 79 persons with MDD (mean age 49 years) and 74 healthy volunteers (mean age 50 years). Effects on surface area and cortical thickness were examined with multiple comparison correction., Results: People who were Met allele carriers showed reduced caudal middle frontal thickness in both study groups. Significant interaction effects were found in the anterior cingulate and rostral middle frontal regions, in which participants in the MDD group who were Met carriers showed the greatest reduction in surface area., Conclusions: Modulatory effects of the BDNF Val66Met polymorphism on distinct subregions in the prefrontal cortex in MDD support the neurotrophin model of depression., (© The Royal College of Psychiatrists 2015.)

Background: Longitudinal neuroimaging studies of major depressive disorder (MDD) have most commonly assessed the effects of antidepressants from the serotonin reuptake inhibitor class and usually reporting a single measure. Multimodal neuroimaging assessments were acquired from MDD patients during an acute depressive episode with serial measures during a 12-week treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine., Methods: Participants were medication-free MDD patients (n = 32; mean age 40.2 years) in an acute depressive episode and healthy controls matched for age, gender, and IQ (n = 25; mean age 38.8 years). MDD patients received treatment with duloxetine 60 mg daily for 12 weeks with an optional dose increase to 120 mg daily after 8 weeks. All participants had serial imaging at weeks 0, 1, 8, and 12 on a 3 Tesla magnetic resonance imaging (MRI) scanner. Neuroimaging tasks included emotional facial processing, negative attentional bias (emotional Stroop), resting state functional MRI and structural MRI., Results: A significant group by time interaction was identified in the anterior default mode network in which MDD patients showed increased connectivity with treatment, while there were no significant changes in healthy participants. In the emotional Stroop task, increased posterior cingulate activation in MDD patients normalized following treatment. No significant group by time effects were observed for happy or sad facial processing, including in amygdala responsiveness, or in regional cerebral volumes. Reduced baseline resting state connectivity within the orbitofrontal component of the default mode network was predictive of clinical response. An early increase in hippocampal volume was predictive of clinical response., Conclusions: Baseline resting state functional connectivity was predictive of subsequent clinical response. Complementary effects of treatment were observed from the functional neuroimaging correlates of affective facial expressions, negative attentional bias, and resting state. No significant effects were observed in affective facial processing, while the interaction effect in negative attentional bias and individual group effects in resting state connectivity could be related to the SNRI class of antidepressant medication. The specificity of the observed effects to SNRI pharmacological treatments requires further investigation., Trial Registration: Registered at clinicaltrials.gov ( NCT01051466 ).

fMRI is increasingly implemented in the clinic to assess memory function. There are multiple approaches to memory fMRI, but limited data on advantages and reliability of different methods. Here, we compared effect size, activation lateralisation, and between-sessions reliability of seven memory fMRI protocols: Hometown Walking (block design), Scene encoding (block design and event-related design), Picture encoding (block and event-related), and Word encoding (block and event-related). All protocols were performed on three occasions in 16 patients with temporal lobe epilepsy (TLE). Group T-maps showed activity bilaterally in medial temporal lobe for all protocols. Using ANOVA, there was an interaction between hemisphere and seizure-onset lateralisation (P = 0.009) and between hemisphere, protocol and seizure-onset lateralisation (P = 0.002), showing that the distribution of memory-related activity between left and right temporal lobes differed between protocols and between patients with left-onset and right-onset seizures. Using voxelwise intraclass Correlation Coefficient, between-sessions reliability was best for Hometown and Scenes (block and event). The between-sessions spatial overlap of activated voxels was also greatest for Hometown and Scenes. Lateralisation of activity between hemispheres was most reliable for Scenes (block and event) and Words (event). Using receiver operating characteristic analysis to explore the ability of each fMRI protocol to classify patients as left-onset or right-onset TLE, only the Words (event) protocol achieved a significantly above-chance classification of patients at all three sessions. We conclude that Words (event) protocol shows the best combination of between-sessions reliability of the distribution of activity between hemispheres and reliable ability to distinguish between left-onset and right-onset patients., (© 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Background: Hippocampal abnormalities have been demonstrated in schizophrenia. It is unclear whether these abnormalities worsen with age, and whether they affect cognition and function., Aims: To determine whether hippocampal abnormalities in chronic schizophrenia are associated with age, cognition and socio-occupational function., Method: Using 3 T magnetic resonance imaging we scanned 100 persons aged 19-82 years: 51 were out-patients with stable schizophrenia at least 2 years after diagnosis and 49 were healthy volunteers matched for age and gender. Automated analysis was used to determine hippocampal volume and shape., Results: There were differential effects of age in the schizophrenia and control samples on total hippocampal volume (group × age interaction: F(1,95) = 6.57, P = 0.012), with steeper age-related reduction in the schizophrenia group. Three-dimensional shape analysis located the age-related deformations predominantly in the mid-body of the hippocampus. In the schizophrenia group similar patterns of morphometric abnormalities were correlated with impaired cognition and poorer socio-occupational function., Conclusions: Hippocampal abnormalities are associated with age in people with chronic schizophrenia, with a steeper decline than in healthy individuals. These abnormalities are associated with cognitive and functional deficits, suggesting that hippocampal morphometry may be a biomarker for cognitive decline in older patients with schizophrenia., (Royal College of Psychiatrists.)

Objective: Current pharmacologic treatments for a depressive episode in unipolar major depressive disorder (MDD) and bipolar depression are limited by low rates of remission. Residual symptoms include a persistent low mood and neurovegetative symptoms such as fatigue. The objective of this study was to examine the efficacy and tolerability of augmentation of first-line therapies with the novel stimulant-like agent modafinil in MDD and bipolar depression., Data Sources: MEDLINE/PubMed, PsycINFO, 1980-April 2013 were searched using the following terms: (modafinil or armodafinil) and (depressi* or depressed or major depressive disorder or major depression or unipolar or bipolar or dysthymi*). Inclusion criteria were as follows: randomized controlled trial (RCT) design, sample comprising adult patients (18-65 years) with unipolar or bipolar depression, diagnosis according to DSM-IV, ICD-10, or other well-recognized criteria, modafinil or armodafinil given as augmentation therapy in at least 1 arm of the trial, and publication in English in a peer-reviewed journal., Study Selection: Double-blind, randomized, placebo-controlled clinical trials of adjunctive treatment with modafinil or armodafinil of standard treatment for depressive episodes in MDD and bipolar depression were selected., Data Extraction: Two independent appraisers assessed the eligibility of the trials. A random-effects meta-analysis with DerSimonian-Laird method was used. Moderator effects were evaluated by meta-regression., Results: Data from 6 RCTs, with a total of 910 patients with MDD or bipolar depression, consisting of 4 MDD RCTs (n = 568) and 2 bipolar depression RCTs (n = 342) were analyzed. The meta-analysis revealed significant effects of modafinil on improvements in overall depression scores (point estimate = -0.35; 95% CI, -0.61 to -0.10) and remission rates (odds ratio = 1.61; 95% CI, 1.04 to 2.49). The treatment effects were evident in both MDD and bipolar depression, with no difference between disorders. Modafinil showed a significant positive effect on fatigue symptoms (95% CI, -0.42 to -0.05). The adverse events were no different from placebo., Conclusions: Modafinil is an effective augmentation strategy for acute depressive episodes, including for symptoms of fatigue, in both unipolar and bipolar disorders., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Neuroimaging research has substantiated the functional and structural abnormalities underlying psychiatric disorders but has, thus far, failed to have a significant impact on clinical practice. Recently, neuroimaging-based diagnoses and clinical predictions derived from machine learning analysis have shown significant potential for clinical translation. This review introduces the key concepts of this approach, including how the multivariate integration of patterns of brain abnormalities is a crucial component. We survey recent findings that have potential application for diagnosis, in particular early and differential diagnoses in Alzheimer disease and schizophrenia, and the prediction of clinical response to treatment in depression. We discuss the specific clinical opportunities and the challenges for developing biomarkers for psychiatry in the absence of a diagnostic gold standard. We propose that longitudinal outcomes, such as early diagnosis and prediction of treatment response, offer definite opportunities for progress. We propose that efforts should be directed toward clinically challenging predictions in which neuroimaging may have added value, compared with the existing standard assessment. We conclude that diagnostic and prognostic biomarkers will be developed through the joint application of expert psychiatric knowledge in addition to advanced methods of analysis.

Neuroticism is a robust personality trait that constitutes a risk factor for mood disorders. Neuroimaging findings related to neuroticism have been inconsistent across studies and hardly integrated in order to construct a model of the underlying neural correlates of neuroticism. The aim of the current meta-analysis was to provide a quantitative summary of the literature, using a parametric coordinate-based meta-analysis (PCM) approach. Data were pooled for emotion processing tasks investigating the contrasts (negative>neutral) and (positive>neutral) to identify brain regions that are consistently associated with neuroticism across studies. Significant negative and positive correlations with neuroticism were found only for the contrast (negative>neutral) after multiple comparisons correction. Differences in brain activation were found to be associated with neuroticism during fear learning, anticipation of aversive stimuli and the processing and regulation of emotion. The relationship between neuroticism and these three psychological processes and their corresponding neural correlates is discussed. Furthermore, the meta-analytic findings are incorporated into a general model of emotion processing in neuroticism., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Alexithymia is a personality trait characterized by difficulties in the experience and cognitive processing of emotions. It is considered a risk factor for a range of psychiatric and neurological disorders. Functional neuroimaging studies investigating the neural correlates of alexithymia have reported inconsistent results. To integrate previous findings, we conducted a parametric coordinate-based meta-analysis including fifteen neuroimaging studies on emotion processing in alexithymia. During the processing of negative emotional stimuli, alexithymia was associated with a diminished response of the amygdala, suggesting decreased attention to such stimuli. Negative stimuli additionally elicited decreased activation in supplementary motor and premotor brain areas and in the dorsomedial prefrontal cortex, possibly underlying poor empathic abilities and difficulties in emotion regulation associated with alexithymia. Positive stimuli elicited decreased activation in the right insula and precuneus, suggesting reduced emotional awareness in alexithymia regarding positive affect. Independent of valence, higher (presumably compensatory) activation was found in the dorsal anterior cingulate possibly indicating increased cognitive demand. These results suggest valence-specific as well as valence-independent effects of alexithymia on the neural processing of emotions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Polymorphisms in the serotonin transporter gene (5-HTTLPR) modulate amygdala activity in healthy individuals. Increased responses to negative stimuli in carriers of low transcription alleles have been proposed to contribute to the pathogenesis of depression. We sought to investigate the effects of genotype as well as diagnosis in patients with depression., Methods: Subjects with recurrent depression (n=67) and matched healthy controls (n=49) participated in a fMRI task of implicit processing of sad facial stimuli. Effects of biallelic (short (S) and long (L) alleles) and triallelic (including rs25531 A/G single nucleotide variation) models of 5-HTTLPR polymorphisms on amygdala activity and connectivity were investigated., Results: Significant effects were observed of both genotype and diagnosis on amygdala activity. Increased amygdala activity was associated with 5-HTTLPR genotype in low transcription allele carriers as well as with a diagnosis of depression. The connectivity analysis revealed a main effect of genotype with reduced connectivity to the subgenual region of the anterior cingulate in carriers of the low transcription alleles. There was also a main effect of diagnosis with reduced connectivity to the dorsal region of the anterior cingulate and to the dorsolateral prefrontal cortex in depression. There were no interaction effects between genotype and diagnosis in amygdala activity or connectivity., Conclusions: Significant independent effects of genotype and diagnosis on amygdala responsivity were revealed. The effects of genotype and diagnosis on amygdala connectivity showed a regional segregation, suggesting that 5-HTTLPR polymorphisms bias frontal-limbic connectivity while the development of depression involves more extensive neural disturbances. These findings point to the potential of connectivity maps as a diagnostic biomarker for depression., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Voxel-based morphometry (VBM) studies demonstrate grey matter volume (GMV) deficits in schizophrenia. This method is also applied for detecting associations between specific psychotic symptoms and brain structure, such as auditory verbal hallucinations (AVHs). However, due to differing methodological approaches, the available findings are inconsistent and difficult to integrate., Methods: We used a novel voxel-based meta-analytical method to provide a robust quantitative review of neuroanatomical abnormalities specifically associated with the hallucinatory phenomenon in the schizophrenic brain. We reviewed all VBM studies of AVHs in schizophrenia published until July 2011 (n = 9). A total of 438 patients with a diagnosis of schizophrenia were included (307 with AVHs). Using a random-effects parametric voxel-based meta-analysis, coordinates of 83 foci reported as significant in the source studies were extracted and computed to estimate the brain locations most consistently associated with AVHs., Results: Severity of AVHs was significantly associated with GMV reductions in the left (p = .022) and marginally with the right (p = .062) superior temporal gyri (STGs, including Heschl's gyri) across studies examining correlations with AVHs severity in patients (n = 8). Analysis of studies categorically comparing patients with and without AVHs did not reveal any significant findings, possibly due to the small number of studies using this approach (n = 3)., Conclusions: This meta-analysis implicates bilateral STG (including Heschl's gyri) as key areas of structural pathology in AVHs in schizophrenia. These findings support a model postulating that aberrations within neural systems involved at different levels of language processing are critical to AVHs in schizophrenia., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

We performed a systematic review and meta-analysis of neural predictors of response to the most commonly used, evidence based treatments in clinical practice, namely pharmacological and psychological therapies. Investigations of medication-free subjects suffering from a current major depressive episode who underwent positron emission tomography (PET) or functional or structural magnetic resonance imaging (MRI) scans prior to the initiation of treatment were reviewed. Results of 20 studies from 15 independent samples were included in the functional imaging meta-analysis and 9 studies from 6 independent samples in the structural neuroimaging meta-analysis. Regional activations with prognostic value include the well replicated finding that increased baseline activity in the anterior cingulate is predictive of a higher likelihood of improvement. As well, increased baseline activation in the insula and striatum is associated with higher likelihood of a poorer clinical response. Structural neuroimaging studies indicated that a decrease in right hippocampal volume is a statistically significant predictor of poorer treatment response. Overall, the predictive information that is measurable with brain imaging techniques is both multimodal and regionally distributed as it contains functional as well as structural correlates which encompass several brain regions within a frontostriatal-limbic network. To develop clinically relevant, prognostic markers will require high predictive accuracy at the level of the individual. Predicting clinical response will help to stratify patients and to identify at an early stage those patients who may require more intensive or combined therapies. We propose that structural and functional neuroimaging show significant potential for the development of prognostic markers of clinical response in the treatment of depression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Models describing the neural correlates of biased emotion processing in depression have focused on increased activation of anterior cingulate and amygdala and decreased activation of striatum and dorsolateral prefrontal cortex. However, neuroimaging studies investigating emotion processing in depression have reported inconsistent results. This meta-analysis integrates these findings and examines whether emotional valence modulates such abnormalities. A systematic literature search identified 26 whole-brain and 18 region-of-interest studies. Peak coordinates and effect sizes were combined in an innovative parametric meta-analysis. Opposing effects were observed in the amygdala, striatum, parahippocampal, cerebellar, fusiform and anterior cingulate cortex, with depressed subjects displaying hyperactivation for negative stimuli and hypoactivation for positive stimuli. Anterior cingulate activity was also modulated by facial versus non-facial stimuli, in addition to emotional valence. Depressed subjects also showed reduced activity in left dorsolateral prefrontal cortex for negative stimuli and increased activity in orbitofrontal cortex for positive stimuli. Emotional valence is a moderator of neural abnormalities in depression, and therefore a critical feature to consider in models of emotional dysfunction in depression., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The aim of coordinate-based meta-analysis is to provide valid quantitative summaries of the literature, while taking into account the specificities of neuroimaging data. Neuroimaging findings are usually reported as coordinates of effects surviving multiple comparison correction through statistical thresholding. Different studies may use widely differing censoring thresholds, ranging from strict family-wise corrections to more lenient "uncorrected"p-values. However, standard meta-analysis methods do not take into account these differences, as findings from studies with varying thresholds are treated as though they were equivalent. The present paper details a development in coordinate-based meta-analysis which addresses this limitation. Parametric coordinate-based meta-analysis (PCM) computes valid estimates from thresholded measurements, integrating significant findings with the information generated by subthreshold measurements to produce asymptotically unbiased meta-analytical summaries. The method is validated through simulated data, and demonstrated in a real data meta-analysis of structural differences in grey matter density in depression. PCM demonstrates a sensitivity that is comparable or superior to existing coordinate-based meta-analysis methods, and demonstrates high agreement between its estimates and those obtained from the meta-analysis of unthresholded manual volumetric measurements. PCM constitutes a powerful approach to meta-analysis, able to generate valid and unbiased effect-size summaries of studies with different statistical thresholds, and also allowing the integration of whole brain and region-of-interest studies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Reduced hippocampal volume has been consistently observed in major depressive disorder. Hippocampal volume loss is particularly evident in patients with recurrent and chronic depression. However, the reports in first episode depression have been mixed., Methods: We performed a random effects meta-analysis to establish whether hippocampal atrophy exists from disease onset. We included magnetic resonance imaging studies of hippocampal volume in patients with first episode major depressive disorder and matched healthy controls., Results: A total of 7 studies met our inclusion and exclusion criteria, representing independent observations in a total sample of 191 patients and 282 healthy controls. The cumulative analysis revealed hippocampal volume loss in patients with first episode depression relative to controls in both the left (standardised mean difference, SMD = -0.41, 95% Confidence Interval: [-0.78;-0.03], z = -2.14, p = 0.0321) and right (SMD = -0.53[-0.98;-0.09], z = -2.38, p = 0.0173) hippocampi. The average volume reduction was -4.0% in the left and -4.5% in the right hippocampus., Conclusions: Hippocampal volume loss in first episode depression is consistent with a neurodevelopmental model of depression, advocating hippocampal structure as a potential diagnostic neurobiomarker for depression., (Copyright © 2011 Elsevier B.V. All rights reserved.)

There is rapidly accumulating evidence that the application of machine learning classification to neuroimaging measurements may be valuable for the development of diagnostic and prognostic prediction tools in psychiatry. However, current methods do not produce a measure of the reliability of the predictions. Knowing the risk of the error associated with a given prediction is essential for the development of neuroimaging-based clinical tools. We propose a general probabilistic classification method to produce measures of confidence for magnetic resonance imaging (MRI) data. We describe the application of transductive conformal predictor (TCP) to MRI images. TCP generates the most likely prediction and a valid measure of confidence, as well as the set of all possible predictions for a given confidence level. We present the theoretical motivation for TCP, and we have applied TCP to structural and functional MRI data in patients and healthy controls to investigate diagnostic and prognostic prediction in depression. We verify that TCP predictions are as accurate as those obtained with more standard machine learning methods, such as support vector machine, while providing the additional benefit of a valid measure of confidence for each prediction., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The hippocampus is involved at the onset of the neuropathological pathways leading to Alzheimer's disease (AD). Individuals with mild cognitive impairment (MCI) are at increased risk of AD. Hippocampal volume has been shown to predict which MCI subjects will convert to AD. Our aim in the present study was to produce a fully automated prognostic procedure, scalable to high throughput clinical and research applications, for the prediction of MCI conversion to AD using 3D hippocampal morphology. We used an automated analysis for the extraction and mapping of the hippocampus from structural magnetic resonance scans to extract 3D hippocampal shape morphology, and we then applied machine learning classification to predict conversion from MCI to AD. We investigated the accuracy of prediction in 103 MCI subjects (mean age 74.1 years) from the longitudinal AddNeuroMed study. Our model correctly predicted MCI conversion to dementia within a year at an accuracy of 80% (sensitivity 77%, specificity 80%), a performance which is competitive with previous predictive models dependent on manual measurements. Categorization of MCI subjects based on hippocampal morphology revealed more rapid cognitive deterioration in MMSE scores (p<0.01) and CERAD verbal memory (p<0.01) in those subjects who were predicted to develop dementia relative to those predicted to remain stable. The pattern of atrophy associated with increased risk of conversion demonstrated initial degeneration in the anterior part of the cornus ammonis 1 (CA1) hippocampal subregion. We conclude that automated shape analysis generates sensitive measurements of early neurodegeneration which predates the onset of dementia and thus provides a prognostic biomarker for conversion of MCI to AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Impairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses., Methods: 104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis., Results: During the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls., Conclusions: In summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.

Background: Hippocampal atrophy is a well reported feature of major depressive disorder, although the evidence has been mixed. The present study sought to examine hippocampal volume and subregional morphology in patients with major depressive disorder, who were all medication-free and in an acute depressive episode of moderate severity., Methods: Structural magnetic resonance imaging scans were acquired in 37 patients (mean age 42 years) and 37 age, gender and IQ-matched healthy individuals. Hippocampal volume and subregional structural differences were measured by manual tracings and identification of homologous surface points to the central core of each hippocampus., Results: Both right (P=0.001) and left (P=0.005) hippocampal volumes were reduced in patients relative to healthy controls (n=37 patients and n=37 controls), while only the right hippocampus (P=0.016) showed a reduced volume in a subgroup of first-episode depression patients (n=13) relative to healthy controls. Shape analysis localised the subregional deformations to the subiculum and CA1 subfield extending into the CA2-3 subfields predominantly in the tail regions in the right (P=0.017) and left (P=0.011) hippocampi., Limitations: As all patients were in an acute depressive episode, effects associated with depressive state cannot be distinguished from trait effects., Conclusions: Subregional hippocampal deficits are present early in the course of major depression. The deformations may reflect structural correlates underlying functional memory impairments and distinguish depression from other psychiatric disorders., (Copyright 2010 Elsevier B.V. All rights reserved.)