The Auditory Agnosias: a Short Review of Neurofunctional Evidence.

PURPOSE OF REVIEW: To investigate the neurofunctional correlates of pure auditory agnosia and its varieties (global, verbal, and nonverbal), based on 116 anatomoclinical reports published between 1893 and 2022, with emphasis on hemispheric lateralization, intrahemispheric lesion site, underlying cognitive impairments. RECENT FINDINGS: Pure auditory agnosia is rare, and observations accumulate slowly. Recent patient reports and neuroimaging studies on neurotypical subjects offer insights into the putative mechanisms underlying auditory agnosia, while challenging traditional accounts. Global auditory agnosia frequently results from bilateral temporal damage. Verbal auditory agnosia strictly correlates with language-dominant hemisphere lesions. Damage involves the auditory pathways, but the critical lesion site is unclear. Both the auditory cortex and associative areas are reasonable candidates, but cases resulting from brainstem damage are on record. The hemispheric correlates of nonverbal auditory input disorders are less clear. They correlate with unilateral damage to either hemisphere, but evidence is scarce. Based on published cases, pure auditory agnosias are neurologically and functionally heterogeneous. Phenotypes are influenced by co-occurring cognitive impairments. Future studies should start from these facts and integrate patient data and studies in neurotypical individuals.

Evolution of anosognosia in alzheimer's disease and its relationship to amyloid.

OBJECTIVE: Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer's disease (AD) that adversely affects a patient's safety and decision-making. However, there is a lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta-amyloid (Aß) burden in a large cohort (N = 1,070) of individuals across the disease spectrum. METHODS: Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aß deposition was measured at baseline using [18F]florbetapir positron emission tomographic imaging. RESULTS: Aß predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aß burden. Aß and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (-0.08 discrepant-points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (-0.23 discrepant-points/yr), reaching anosognosia 3.2 years before dementia onset. INTERPRETATION: Aß burden is associated with a progressive decrease in self-awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2020;87:267-280.

Anosognosia in patients with Alzheimer's disease: current perspectives.

Alzheimer's disease (AD) is a neurodegenerative disease characterised by neurocognitive impairments, especially memory impairment, as core symptoms linked to reductions in activities of daily life. As marginal symptoms, neuropsychiatric symptoms (NPSs) appear during the progressive course of the disease. A lack of self-awareness (anosognosia) of cognitive and functional impairments is often seen in patients with AD, and associations between anosognosia and other NPSs have been previously reported. To account for anosognosia pathogenesis neurocognitively, the cognitive awareness model (CAM) has been helpful for explaining the stream of events from sensory input to behavioural/affective and metacognitive outputs. According to CAM, there are three types of anosognosia: (i) primary anosognosia, (ii) executive anosognosia, and (iii) mnemonic anosognosia. These types of anosognosia are generated from different neurocognitive modulations leading to metacognitive outputs or behavioural/affective regulations. Primary anosognosia is considered to be caused by deficits in the metacognitive awareness system (MAS). While preserved MAS function is associated with milder depression and anxiety in AD, a severer depressive mood in patients with mild AD can inversely cause self-underestimation. The modulation of executive anosognosia is thought to be associated with dangerous/disinhibition behaviours and apathy among NPS sub-symptoms, via impairments of comparator mechanism (Cm) within the central executive system. Other neurobehavioral reactions linked to self-awareness include 'denying' and 'confabulation', and each of these reactions is thought to be affected by the MAS and a Cm. Denial of one's own memory impairments appears as a defensive reaction to protect against dysphoric feelings, and the confabulatory comment is instantly reaction constructed by fabrications according to misinterpretations of memory information about oneself. Similarly, the innovative development of a theoretical model (CAM) has contributed to explaining the mechanism of anosognosia and some neurobehavioral outputs from a neurocognitive perspective.

Anosognosia and default mode subnetwork dysfunction in Alzheimer's disease.

Research on the neural correlates of anosognosia in Alzheimer's disease varied according to methods and objectives: they compared different measures, used diverse neuroimaging modalities, explored connectivity between brain networks, addressed the role of specific brain regions or tried to give support to theoretical models of unawareness. We used resting-state fMRI connectivity with two different seed regions and two measures of anosognosia in different patient samples to investigate consistent modifications of default mode subnetworks and we aligned the results with the Cognitive Awareness Model. In a first study, patients and their relatives were presented with the Memory Awareness Rating Scale. Anosognosia was measured as a patient-relative discrepancy score and connectivity was investigated with a parahippocampal seed. In a second study, anosognosia was measured in patients with brain amyloid (taken as a disease biomarker) by comparing self-reported rating with memory performance, and connectivity was examined with a hippocampal seed. In both studies, anosognosia was consistently related to disconnection within the medial temporal subsystem of the default mode network, subserving episodic memory processes. Importantly, scores were also related to disconnection between the medial temporal and both the core subsystem (participating to self-reflection) and the dorsomedial subsystem of the default mode network (the middle temporal gyrus that might subserve a personal database in the second study). We suggest that disparity in connectivity within and between subsystems of the default mode network may reflect impaired functioning of pathways in cognitive models of awareness.

Profiles of visuospatial memory dysfunction in opioid-exposed and dependent populations.

BACKGROUND: Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. METHODS: We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. RESULTS: As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.

Pure topographical disorientation in novel environments without anterograde amnesia: a case study.

Topographical disorientation (TD) in novel environments is considered to be a part of anterograde amnesia. A 56-year-old woman presented with pure TD only in novel environments following limbic encephalitis. She could not remember directions inside the hospital on weekly outpatient visits; however, her verbal and visual anterograde memories were normal. In the test of learning photographs of scenes, faces, and objects, only her scores for landscapes were worse than those in healthy controls. These findings suggested that her TD specific to landscapes and directions in novel environments was caused by category-specific memory impairment related to bilateral hippocampal and parahippocampal dysfunction.

Computer-Based Cognitive Rehabilitation in Patients with Visuospatial Neglect or Homonymous Hemianopia after Stroke.

OBJECTIVES: The purpose of this pilot study was to investigate the feasibility and effects of computer-based cognitive rehabilitation (CBCR) in patients with symptoms of visuospatial neglect or homonymous hemianopia in the subacute phase following stroke. METHOD: A randomized, controlled, unblinded cross-over design was completed with early versus late CBCR including 7 patients in the early intervention group (EI) and 7 patients in the late intervention group (LI). EI received CBCR training immediately after inclusion (m = 19 days after stroke onset) for 3 weeks and LI waited for 3 weeks after inclusion before receiving CBCR training for 3 weeks (m = 44 days after stroke onset). RESULTS: CBCR improved visuospatial symptoms after stroke significantly when administered early in the subacute phase after stroke. The same significant effect was not found when CBCR was administered later in the rehabilitation. The difference in the development of the EI and LI groups during the first 3 weeks was not significant, which could be due to a lack of statistical power. CBCR did not impact mental well-being negatively in any of the groups. In the LI group, the anticipation of CBCR seemed to have a positive impact of mental well-being. CONCLUSION: CBCR is feasible and has a positive effect on symptoms in patients with visuospatial symptoms in the subacute phase after stroke. The study was small and confirmation in larger samples with blinded outcome assessors is needed.

The Effect of Continuous Theta-Burst Transcranial Magnetic Stimulation Combined with Prism Adaptation on the Neglect Recovery in Stroke Patients.

OBJECTIVES: This study was designed to investigate the effect of prism adaptation (PA) combined with continuous theta-burst transcranial magnetic stimulation (cTBS) on the neglect recovery of stroke patients with unilateral neglect. METHODS: A total of 14 stroke patients with unilateral neglect were randomly assigned to 2 groups including an intervention group undergone PA combined with cTBS over the left intact parietal cortex and a control group. PA combined with sham cTBS was perfomed for 2 weeks in 10 daily sessions. Before and after the intervention, patients were evaluated for visuospatial neglect measured using the Star Cancellation Test (SCT), Line Bisection Task (LBT), Figure Copying Test, and Clock Drawing Task. Neurological function was evaluated using the Modified Rankin Scale (MRS). RESULTS: Both groups (PA alone and PA+ cTBS) showed improvement in their neglected symptoms (measured by SCT, LBT, Figure Copying Test, and Clock Drawing Task), and in their disability in the neurological function (measured by MRS) (P< .05). CONCLUSIONS: The results of the present study showed that, transcranial magnetic stimulation did not increase the effect of PA on neglect symptoms in stroke patients.

Preserved Expert Object Recognition in a Case of Visual Hemiagnosia.

We examined a stroke patient (HWS) with a unilateral lesion of the right medial ventral visual stream, involving the right fusiform and parahippocampal gyri. In a number of object recognition tests with lateralized presentations of target stimuli, HWS showed significant symptoms of hemiagnosia with contralesional recognition deficits for everyday objects. We further explored the patient's capacities of visual expertise that were acquired before the current perceptual impairment became effective. We confronted him with objects he was an expert for already before stroke onset and compared this performance with the recognition of familiar everyday objects. HWS was able to identify significantly more of the specific ("expert") than of the everyday objects on the affected contralesional side. This observation of better expert object recognition in visual hemiagnosia allows for several interpretations. The results may be caused by enhanced information processing for expert objects in the ventral system in the affected or the intact hemisphere. Expert knowledge could trigger top-down mechanisms supporting object recognition despite of impaired basic functions of object processing. More importantly, the current work demonstrates that top-down mechanisms of visual expertise influence object recognition at an early stage, probably before visual object information propagates to modules of higher object recognition. Because HWS showed a lesion to the fusiform gyrus and spared capacities of expert object recognition, the current study emphasizes possible contributions of areas outside the ventral stream to visual expertise.

The Impact of Awareness of and Concern About Memory Performance on the Prediction of Progression From Mild Cognitive Impairment to Alzheimer Disease Dementia.

OBJECTIVE: To investigate the relationship of awareness of and concern about memory performance to progression from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. METHODS: Participants (n = 33) had a diagnosis of MCI at baseline and a diagnosis of MCI or AD dementia at follow-up. Participants were categorized as "Stable-MCI" if they retained an MCI diagnosis at follow-up (mean follow-up = 18.0 months) or "Progressor-MCI" if they were diagnosed with AD dementia at follow-up (mean follow-up = 21.6 months). Awareness was measured using the residual from regressing a participant's objective memory score onto their subjective complaint score (i.e., residual<0 indicates overestimation of performance). Concern was assessed using a questionnaire examining the degree of concern when forgetting. Logistic regression was used to determine whether the presence of these syndromes could predict future diagnosis of AD dementia, and repeated measures analysis of covariance tests were used to examine longitudinal patterns of these syndromes. RESULTS: Baseline anosognosia was apparent in the Progressor-MCI group, whereas participants in the Stable-MCI group demonstrated relative awareness of their memory performance. Baseline awareness scores successfully predicted whether an individual would progress to AD-dementia. Neither group showed change in awareness of performance over time. Neither group showed differences in concern about memory performance at baseline or change in concern about performance over time. CONCLUSION: These data suggest that anosognosia may appear prior to the onset of AD dementia, while anosodiaphoria likely does not appear until later in the AD continuum. Additionally, neither group showed significant changes in awareness or concern over time, suggesting that change in these variables may happen over longer periods.

Anosognosia in degenerative brain diseases: The role of the right hemisphere and of its dominance for emotions.

Earlier studies, which suggested that anosognosia of hemiplegia might be related to right hemisphere (RH) lesions did not control for the influence of confounding variables, such as aphasia, in patients with left-hemisphere lesions and unilateral neglect in those with RH lesions. These confounding variables are absent in patients with degenerative brain disease, where a prevalence of right-sided lesions is often associated with emotional and behavioural disturbances. This review, which can be considered a 'qualitative synthesis', aimed, therefore, to determine whether the unawareness phenomena observed in degenerative brain diseases are linked to the RH dominance for emotions. Results of the review confirmed that the neural correlates of anosognosia are often right lateralised in patients with degenerative brain diseases and that emotional disturbances are associated with right frontal lesions and anosognosia in the behavioural variant, i.e., frontotemporal dementia (bvFTD). However, they also showed that anosognosia is a heterogeneous phenomenon and that the role of right frontal lesions is much greater when the loss of insight concerns emotion-linked aspects of personality or behaviour than when it concerns particular aspects of cognition or memory.

Anosognosia in mild Alzheimer's disease is correlated with not only neural dysfunction but also compensation.

BACKGROUND: Anosognosia in Alzheimer's disease (AD) is a complicated, non-unitary phenomenon. In a clinical setting, patients with mild AD often preserve their awareness partially. We hypothesized that compensation, as well as neural dysfunction, could be correlated with anosognosia in mild AD. METHODS: The severity of anosognosia was evaluated using the Anosognosia Questionnaire for Dementia in 37 subjects with mild AD or mild cognitive impairment due to AD. The subjects also underwent single-photon emission computed tomography with N-isopropyl-p-[123 I]iodoamphetamine. Correlation between the severity of anosognosia and perfusion was assessed, and anosognosia (+) and (-) groups were compared. RESULTS: The severity of anosognosia was relatively mild; the mean Anosognosia Questionnaire for Dementia score was 6.76 ± 14.16. Subjects were divided into two groups: anosognosia (+) (n = 11) and anosognosia (-) (n = 26). In the single-photon emission computed tomography data analysis, the severity of anosognosia was correlated with both lower regional cerebral blood flows of the right prefrontal cortex and higher regional cerebral blood flows of the parietal cortex, especially the left temporo-parietal junction. CONCLUSIONS: Our results suggest that anosognosia in mild AD could be correlated with compensation as well as neural dysfunction. We speculate that this compensation may be related to the retrieval of outdated autobiographical memory.

Repressive Coping Does Not Contribute to Anosognosia in First-Diagnosis Patients With Alzheimer Disease.

Anosognosia is common in patients with Alzheimer disease (AD) even in early stages. Although neural correlates and the impact of cognitive dysfunctions have been described, possible psychodynamic processes such as a repressive coping style as described in other illnesses, have not been examined. Our study aimed to examine possible psychological influence factors on illness perception embracing a repressive coping style and cognitive functions in AD patients in the diagnostic process. Fifty-four subjects with mild AD diagnosed in our memory clinic were enrolled. Anosognosia was evaluated using a patient-caregiver discrepancy rating. All patients underwent comprehensive neuropsychological testing. In addition, characteristics of a repressive coping style were assessed. In total, 79.6% of our patients showed a lack of awareness at least to some degree. 33.3% of the patients were classified as repressors. Repressors and nonrepressors did not differ in cognition, or the unawareness score. Multivariate regression analysis showed that repressive coping style did not significantly contribute to anosognosia, but that verbal memory and naming ability had a strong influence. Although our data indicate that a high proportion of patients with mild AD show characteristics of repressive coping, this possible defense mechanism had no influence on the awareness of illness-related deficits measured by caregiver patient discrepancy.

Anosognosia and Its Relation to Psychiatric Symptoms in Early-Onset Alzheimer Disease.

BACKGROUND: We investigated differences in the prevalence of anosognosia and neuropsychiatric symptoms (NPSs) characteristics according to disease severity in patients with early-onset Alzheimer disease (EOAD). METHODS: We recruited 616 patients with EOAD. We subdivided participants into 2 groups based on the presence or absence of anosognosia and then again by Clinical Dementia Rating (CDR) scale. We compared the differences in the Neuropsychiatric Inventory (NPI) scores according to anosognosia and disease severity. RESULTS: The percentage of patients with anosognosia in each CDR group steadily increased as the CDR rating increased (CDR 0.5 8.6% vs CDR 1 13.6% vs CDR 2 26.2%). The NPI total score was significantly higher in patients with anosognosia in the CDR 0.5 and 1 groups; by contrast, it had no association in the CDR 2 group. Frontal lobe functions were associated with anosognosia only in the CDR 0.5 and 1 groups. After stratification by CDR, in the CDR 0.5 group, the prevalence of agitation ( P = .040) and appetite ( P = .013) was significantly higher in patients with anosognosia. In the CDR 1 group, patients with anosognosia had a significantly higher prevalence of delusions ( P = .032), hallucinations ( P = .048), and sleep disturbances ( P = .047). In the CDR 2 group, we found no statistical difference in the frequency of symptoms between patients with and without anosognosia. CONCLUSION: These results confirm that the prevalence of anosognosia as well as the individual NPS and cognitive functions associated with it differ according to EOAD severity.

Integrating the Constructs of Anosognosia and Metacognition: a Review of Recent Findings in Dementia.

The current review integrates recent findings regarding the construct of self-awareness in dementia from both clinical and cognitive perspectives. We present the predominant theoretical models of awareness and summarize both traditional and emerging approaches to assessing awareness from clinical and meta-cognitive perspectives. In this review, we focus primarily on findings from recent studies in anosognosia and meta-cognition in the context of neurodegenerative disease with special emphasis on Alzheimer's disease and frontotemporal dementia. Emerging trends in the study of awareness, including examination of the longitudinal course of anosognosia, and investigation of the neural substrates underlying meta-cognitive abilities are addressed. Finally, the practical importance of studying and assessing awareness from both theoretical and clinical angles is emphasized.

Mentalizing the body: spatial and social cognition in anosognosia for hemiplegia.

Following right-hemisphere damage, a specific disorder of motor awareness can occur called anosognosia for hemiplegia, i.e. the denial of motor deficits contralateral to a brain lesion. The study of anosognosia can offer unique insights into the neurocognitive basis of awareness. Typically, however, awareness is assessed as a first person judgement and the ability of patients to think about their bodies in more 'objective' (third person) terms is not directly assessed. This may be important as right-hemisphere spatial abilities may underlie our ability to take third person perspectives. This possibility was assessed for the first time in the present study. We investigated third person perspective taking using both visuospatial and verbal tasks in right-hemisphere stroke patients with anosognosia (n = 15) and without anosognosia (n = 15), as well as neurologically healthy control subjects (n = 15). The anosognosic group performed worse than both control groups when having to perform the tasks from a third versus a first person perspective. Individual analysis further revealed a classical dissociation between most anosognosic patients and control subjects in mental (but not visuospatial) third person perspective taking abilities. Finally, the severity of unawareness in anosognosia patients was correlated to greater impairments in such third person, mental perspective taking abilities (but not visuospatial perspective taking). In voxel-based lesion mapping we also identified the lesion sites linked with such deficits, including some brain areas previously associated with inhibition, perspective taking and mentalizing, such as the inferior and middle frontal gyri, as well as the supramarginal and superior temporal gyri. These results suggest that neurocognitive deficits in mental perspective taking may contribute to anosognosia and provide novel insights regarding the relation between self-awareness and social cognition.

Comparing triggers to visual disturbances among individuals with positive vs negative experiences of hallucinogen-persisting perception disorder (HPPD) following LSD use.

BACKGROUND AND OJECTIVE: Exploring differences in visual disturbances and triggers between Hallucinogen-Persisting-Perceptual-Disorder (HPPD) Type I ("positive/benign") and II ("negative/distressing"). METHODS: Forty individuals with HPPD and prior LSD use completed clinical questionnaires. RESULTS: The most common type of visual disturbances among individuals with HPPD I and II was slow movement of still objects and trailing phenomena, respectively. Those with HPPD I were more likely to report experiencing disturbances in dark environment, while looking at a still or moving object and during sexual intercourse. DISCUSSION AND CONCLUSIONS: HPPD I and II differ in terms of visual disturbances and triggers, possibly representing different phenomena existing on the same spectrum. SCIENTIFIC SIGNIFICANCE: Our study indicating differences in triggers to HPPD I and II adds to existing literature on differences in visual disturbances between the two subtypes. Further research elucidating additional differences between the subtypes of HPPD is needed. (Am J Addict 2017;26:568-571).

Cognitive and anatomical correlates of anosognosia in amnestic mild cognitive impairment and early-stage Alzheimer's disease.

BACKGROUND: Anosognosia is a common feature in Alzheimer's disease (AD). The brain substrates of anosognosia are not fully understood, and less is known about the cognitive substrates of anosognosia in prodromal and early stages of AD. METHODS: Fourty-seven patients with amnestic-type mild cognitive impairment (aMCI) (n = 26) and early-stage AD (n = 21) were included, and Clinical Insight Rating Scale and Anosognosia Questionnaire for Dementia (AQ-D) were used to assess anosognosia. A detailed neuropsychological battery was administered; each patient underwent a structural magnetic resonance imaging (MRI). Correlation between anosognosia and performance in individual cognitive domains as well as correlation between anosognosia and cortical thickness values in regions of interest were assessed. RESULTS: Performance of the anosognosic patients in Digit Ordering Test (DOT), Digit Span Backwards, and Clock Drawing Test (CDT) was significantly worse compared to non-anosognosic patients in the total study population and in the aMCI subgroup but not in AD group. AQ-D scores negatively correlated with Mini-Mental State Examination (MMSE), California Verbal Learning Test (CVLT), Digit Span Backwards and CDT scores in total group and MMSE, CVLT, DOT, and Digit Span Backwards scores in the aMCI group. No significant correlations were found between cortical thickness measurements and AQ-D scores in any of the patient populations. CONCLUSIONS: Anosognosia was associated with episodic memory, working memory, and executive functions in the total population and aMCI group, but no association was found in early-stage AD patients. Anosognosia in the early stages of AD may be related with non-structural changes such as hypoconnectivity rather than structural changes.

[Geriatric psychiatric home counseling for people with dementia and anosognosia : Results of a model project]. / Gerontopsychiatrische Hausbesuche bei Menschen mit Demenz und Anosognosie : Ergebnisse eines Modellprojekts.

BACKGROUND: Lack of awareness of an illness (anosognosia) is a common symptom in dementia and has a significant impact on the course of the disease. It is associated with dysfunctional interaction with caregivers. Due to unawareness patients are not able to accept diagnostic procedures or medical treatment and refuse any kind of support. Thus, they are not integrated into psychosocial networks and medical support. This has a significant impact on patient-centered care in a domestic environment. In this article a model project with home visits to patients with dementia and anosognosia is described. METHOD: A total of 55 home visits were carried out. The aim of this project was the integration into the existing healthcare services in order to safeguard the domestic environment. These visits focused on advice and information for the patients and their caregivers initiating the visits. Sociodemographic data of the patient cohort and the satisfaction of the caregiving relatives and general practitioners are presented. RESULTS: Subjects with dementia were found to be in advanced stages of the disease, caring situations were complex and required assistance. Caregivers showed a substantial burden in accordance with previous reports. CONCLUSION: New strategies are required to cope with anosognosia in patients with dementia and their caregivers. Even single home visits seem to be sufficient to initiate support for subjects with dementia and their relatives.