Can a failure in the error-monitoring system explain unawareness of memory deficits in Alzheimer's disease?

Unawareness of memory deficits is an early manifestation in patients with Alzheimer's disease (AD), which often delays diagnosis. This intriguing behavior constitutes a form of anosognosia, whose neural mechanisms remain largely unknown. We hypothesized that anosognosia may depend on a critical synaptic failure in the error-monitoring system, which would prevent AD patients from being aware of their own memory impairment. To investigate, we measured event-related potentials (ERPs) evoked by erroneous responses during a word memory recognition task in two groups of amyloid positive individuals with only subjective memory complaints at study entry: those who progressed to AD within the five-year study period (PROG group), and those who remained cognitively normal (CTRL group). A significant reduction in the amplitude of the positivity error (Pe), an ERP related to error awareness, was observed in the PROG group at the time of AD diagnosis (vs study entry) in intra-group analysis, as well as when compared with the CTRL group in inter-group analysis, based on the last EEG acquisition for all subjects. Importantly, at the time of AD diagnosis, the PROG group exhibited clinical signs of anosognosia, overestimating their cognitive abilities, as evidenced by the discrepancy scores obtained from caregiver/informant vs participant reports on the cognitive subscale of the Healthy Aging Brain Care Monitor. To our knowledge, this is the first study to reveal the emergence of a failure in the error-monitoring system during a word memory recognition task at the early stages of AD. This finding, along with the decline of awareness for cognitive impairment observed in the PROG group, strongly suggests that a synaptic dysfunction in the error-monitoring system may be the critical neural mechanism at the origin of unawareness of deficits in AD.

Resting-state functional magnetic resonance imaging of the cerebellar vermis in patients with Parkinson's disease and visuospatial disorder.

PURPOSE: Visuospatial disorders (VSDs) are common in Parkinson's disease (PD). VSDs may involve cerebellar vermis, but evidence from functional connectivity (FC) studies is lacking. Here we compared FC between cerebellar vermis and the entire brain between PD patients with or without VSD, and between patients and healthy controls. METHODS: Resting-state 3.0-T functional magnetic resonance imaging was performed on 19 controls, 31 PD patients with VSD and 12 PD patients without VSD. Correlations in brain network were calculated between eight regions of interest in the cerebellar vermis (I-VIII) and other voxels in the brain, and voxel-based FC was analyzed. Patients were assessed in terms of cognitive function as well as motor and non-motor symptoms. RESULTS: In both types of patients, cerebellar vermis VIII, IX and X showed positive FC with the default-mode network (DMN), executive control network and sensorimotor network. Cerebellar vermis I and II showed positive FC with the visual network and DMN in controls, but negative FC in PD patients without VSD. Cerebellar vermis X showed negative FC with lobules VIII and IX of the left cerebellar hemisphere in controls, but positive FC in PD patients with VSD. CONCLUSION: Positive FC connecting the cerebellar vermis VIII and X with associated brain networks in PD patients with VSD may be compensatory activation. PD may involve disruption of functional coupling between the cerebellar vermis and cerebral cortex.

The Motor Unawareness Assessment (MUNA): A new tool for the assessment of Anosognosia for hemiplegia.

Introduction: Anosognosia for hemiplegia (AHP) is a condition in which patients with paralysis are unaware of their motor deficits. Research into AHP is important for improving its treatment and providing insight into the neurocognitive mechanism of motor awareness. Unfortunately, most studies use assessments with widely recognized limitations.The study aims at developing a psychometrically validated assessment of AHP.Method: We developed a 40-item Motor Unawareness Assessment (MUNA) and administered it to 131 right-hemisphere stroke patients. Principal Component Analysis (PCA) was used to identify the underlying factor structure. Receiver Operating Characteristics (ROC) analysis was used to determine diagnostic cutoffs, and Area Under the Curve (AUC) analysis used to assess these cutoffs. Relationships with demographic, clinical and neuropsychological variables were explored.Results: Five factors were identified: explicit motor awareness, implicit motor awareness, impaired sense of ownership, agency and illusory movement, and emotional reactions. Established cutoffs had excellent sensitivity and specificity. Clinical, neuropsychological and demographic variables did not predict overall MUNA score but were related to specific subcomponents.Conclusion: The MUNA can differentiate various facets of AHP and provides a detailed profile of (un)awareness. The MUNA can therefore provide robust assessment for research purposes and assist clinicians when developing targeted rehabilitation.

Subcortical deafness as a subtype of auditory agnosia after injury of bilateral auditory radiations caused by two cerebrovascular accidents - normal auditory brainstem responses with I-VII waves and abolished consciousness of hearing.

BACKGROUND: In central auditory disorders caused by damage of the cerebral hemispheres, there are cortical deafness and auditory agnosia. Although clinical cases of cortical deafness have been reported, little is known about the hearing problems and localized lesions associated with cortical deafness. AIMS/OBJECTIVES: The aims of our research are to elucidate lesion sites associated with cortical deafness and to clarify why patients with cerebral lesions are not aware of any sound at all. MATERIALS AND METHODS: Three patients diagnosed as having total loss of hearing participated in this study. We conducted pure-tone audiometry, speech audiometry, distortion product otoacoustic emission (DPOAE), auditory brainstem response (ABR), and brain magnetic resonance imaging (MRI) to diagnose cortical deafness with aphasia tests of these patients. RESULTS: Our studies showed that waves VI and VII as well as waves I to V have normal peak latencies in ABRs in all three patients. In brain MRI, we found complete damage of proximal parts of bilateral auditory radiations in the three patients. CONCLUSIONS: We propose 'subcortical deafness' as a subtype of auditory agnosia.

Superior Parietal Lobule: A Role in Relative Localization of Multiple Different Elements.

Simultanagnosia is an impairment in processing multiple visual elements simultaneously consecutive to bilateral posterior parietal damage, and neuroimaging data have specifically implicated the superior parietal lobule (SPL) in multiple element processing. We previously reported that a patient with focal and bilateral lesions of the SPL performed slower than controls in visual search but only for stimuli consisting of separable lines. Here, we further explored this patient's visual processing of plain object (colored disk) versus object consisting of separable lines (letter), presented in isolation (single object) versus in triplets. Identification of objects was normal in isolation but dropped to chance level when surrounded by distracters, irrespective of eccentricity and spacing. We speculate that this poor performance reflects a deficit in processing objects' relative locations within the triplet (for colored disks), aggravated by a deficit in processing the relative location of each separable line (for letters). Confirming this, performance improved when the patient just had to detect the presence of a specific colored disk within the triplets (visual search instruction), while the inability to identify the middle letter was alleviated when the distracters were identical letters that could be grouped, thereby reducing the number of ways individual lines could be bound.

Vestibular agnosia in traumatic brain injury and its link to imbalance.

Vestibular dysfunction, causing dizziness and imbalance, is a common yet poorly understood feature in patients with TBI. Damage to the inner ear, nerve, brainstem, cerebellum and cerebral hemispheres may all affect vestibular functioning, hence, a multi-level assessment-from reflex to perception-is required. In a previous report, postural instability was the commonest neurological feature in ambulating acute patients with TBI. During ward assessment, we also frequently observe a loss of vertigo sensation in patients with acute TBI, common inner ear conditions and a related vigorous vestibular-ocular reflex nystagmus, suggesting a 'vestibular agnosia'. Patients with vestibular agnosia were also more unbalanced; however, the link between vestibular agnosia and imbalance was confounded by the presence of inner ear conditions. We investigated the brain mechanisms of imbalance in acute TBI, its link with vestibular agnosia, and potential clinical impact, by prospective laboratory assessment of vestibular function, from reflex to perception, in patients with preserved peripheral vestibular function. Assessment included: vestibular reflex function, vestibular perception by participants' report of their passive yaw rotations in the dark, objective balance via posturography, subjective symptoms via questionnaires, and structural neuroimaging. We prospectively screened 918 acute admissions, assessed 146 and recruited 37. Compared to 37 matched controls, patients showed elevated vestibular-perceptual thresholds (patients 12.92°/s versus 3.87°/s) but normal vestibular-ocular reflex thresholds (patients 2.52°/s versus 1.78°/s). Patients with elevated vestibular-perceptual thresholds [3 standard deviations (SD) above controls' average], were designated as having vestibular agnosia, and displayed worse posturography than non-vestibular-agnosia patients, despite no difference in vestibular symptom scores. Only in patients with impaired postural control (3 SD above controls' mean), whole brain diffusion tensor voxel-wise analysis showed elevated mean diffusivity (and trend lower fractional anisotropy) in the inferior longitudinal fasciculus in the right temporal lobe that correlated with vestibular agnosia severity. Thus, impaired balance and vestibular agnosia are co-localized to the inferior longitudinal fasciculus in the right temporal lobe. Finally, a clinical audit showed a sevenfold reduction in clinician recognition of a common peripheral vestibular condition (benign paroxysmal positional vertigo) in acute patients with clinically apparent vestibular agnosia. That vestibular agnosia patients show worse balance, but without increased dizziness symptoms, explains why clinicians may miss treatable vestibular diagnoses in these patients. In conclusion, vestibular agnosia mediates imbalance in traumatic brain injury both directly via white matter tract damage in the right temporal lobe, and indirectly via reduced clinical recognition of common, treatable vestibular diagnoses.

Perceptual post-effects of left neck muscle vibration with visuo-haptic feedback in healthy individuals: A potential approach for treating spatial neglect.

Among the techniques used to reduce spatial neglect's symptoms, left neck muscle vibration (NMV) is alluring because it does not require the patient's attentional co-operation. The aim of this study was to determine the type of NMV-associated feedback that induced the most intense and longest-lasting egocentric post-effects. Eighty-seven healthy individuals were randomly assigned to four intervention groups: "neck muscle vibration, blindfolded" (NMV), "neck muscle vibration with vision" (NMV + V), "neck muscle vibration and visual finger-pointing" (NMV + P), and "visual finger-pointing" (P). An eyes-closed finger-pointing subjective straight-ahead (SSA) test was carried out before the intervention, immediately afterwards, and 30 min afterwards. The results showed that only the NMV + P intervention induced a lasting leftward bias of SSA. In addition, the deviation reported in this intervention group differed significantly from those observed in the other interventions. The combination of visuo-haptic feedback and neck-somatosensory stimulation may enable a full, lasting intermodal recalibration, which could be potentiated by the attention level engaged during voluntary pointing. These outcomes highlighted that the NMV technique could easily integrate into routine occupational therapy sessions for treating various aspects of neglect disorders.

Asymmetric Bálint's syndrome with multimodal agnosia, bilateral agraphesthesia, and ineffective kinesthetic reading due to subcortical hemorrhage in the left parieto-occipito-temporal area.

We report a patient with asymmetric Bálint's syndrome (predominantly right-sided oculomotor apraxia and simultanagnosia and optic ataxia for the right hemispace), and multimodal agnosia (apperceptive visual agnosia and bilateral associative tactile agnosia) with accompanying right hemianopia, bilateral agraphesthesia, hemispatial neglect, global alexia with unavailable kinesthetic reading, and lexical agraphia for kanji (Japanese morphograms), after hemorrhage in the left parieto-occipito-temporal area. The coexistence of tactile agnosia, bilateral agraphesthesia, and ineffective kinesthetic reading suggests that tactile-kinesthetic information can be interrupted because of damage to the fiber connection from the parietal lobe to the occipito-temporal area, leading to these tactually related cognitive impairments.

The size-weight illusion in visual form agnosic patient DF.

The size-weight illusion is a perceptual illusion where smaller objects are judged as heavier than equally weighted larger objects. A previous informal report suggests that visual form agnosic patient DF does not experience the size-weight illusion when vision is the only available cue to object size. We tested this experimentally, comparing the magnitudes of DF's visual, kinesthetic and visual-kinesthetic size-weight illusions to those of 28 similarly-aged controls. A modified t-test found that DF's visual size-weight illusion was significantly smaller than that of controls (zcc = -1.7). A test of simple dissociation based on the Revised Standardized Difference Test found that the discrepancy between the magnitude of DF's visual and kinesthetic size-weight illusions was not significantly different from that of controls (zdcc = -1.054), thereby failing to establish a dissociation between the visual and kinesthetic conditions. These results are consistent with previous suggestions that visual form agnosia, following ventral visual stream damage, is associated with an abnormally reduced size-weight illusion. The results, however, do not confirm that this reduction is specific to the use of visual size cues to predict object weight, rather than reflecting more general changes in the processing of object size cues or in the use of predictive strategies for lifting.

A case of mirror image agnosia and mirrored self-misidentification syndrome in schizophrenia without dementia or structural abnormalities.

Delusional misidentification syndrome (DMS) is an umbrella term encompassing a variety of disorders. One rare form of DMS is the delusional misidentification of one's own reflection, known as "mirrored self-misidentification syndrome". In "mirror image agnosia", the ability to identify the image of self and/or others in the mirror is lost, while the ability to identify the mirror itself is preserved. To our knowledge, mirror image agnosia has never been described in a patient with schizophrenia. Herein we present a case of a patient with schizophrenia with severe delusions of both mirrored self-misidentification and mirror image agnosia without any structural abnormalities or dementia.

Association Between Motor Subtype and Visuospatial and Executive Function in Mild-Moderate Parkinson Disease.

OBJECTIVE: To compare participants with Parkinson disease (PD) motor subtypes, postural instability and gait difficulty (PIGD) (n=46) and tremor dominant (TD) (n=28), in cognitive and motor-cognitive assessments with the purpose of identifying associations between subtype and visuospatial, whole-body spatial, inhibition and/or switching, and planning and/or organizational aspects of cognitive and motor-cognitive function. DESIGN: Retrospective cohort study. Fisher exact test was used for categorical variables, while 2-sample independent t tests were used to analyze continuous variables. SETTING: Assessments took place at Emory University. PARTICIPANTS: Participants (N=72) were 40 years and older, had a clinical diagnosis of PD, exhibited 3 of the 4 cardinal signs of PD, had shown benefit from antiparkinsonian medications, and were in Hoehn and Yahr stages I-IV. Participants could walk 3 m or more with or without assistance. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Balance and mobility tests included Fullerton Advanced Balance Scale and the time needed to turn 360 degrees. Cognitive assessments included Montreal Cognitive Assessment, Brooks Spatial Memory Task, Color-Word Interference Test, Tower of London, Trail Making Test, Corsi Blocks, Serial 3s Subtraction, and Body Position Spatial Task. Motor-cognitive function measures included Four Square Step Test and Timed Up and Go. RESULTS: Participants with PIGD performed lower than those with TD symptoms on mental status (P=.005), spatial memory (P=.027), executive function (P=.0001-.034), and visuospatial ability (P=.048). CONCLUSIONS: Findings suggest that PIGD subtype is linked to greater deficits in spatial cognition, attentional flexibility and organizational planning, and whole-body spatial memory domains. These findings support the need for more personalized approaches to clinically managing PD.

The effect of Virtual Reality on evoked potentials following painful electrical stimuli and subjective pain.

BACKGROUND: Virtual reality (VR) has been shown to reduce pain, however outcome parameters of previous studies have primarily been of a subjective nature and susceptible to bias. This study investigated the effect of VR on cortical processing of evoked potentials (EPs) and subjectively reported pain. Additionally, we explored whether subjects' demographic and personal characteristics modulated the effect of VR analgesia. METHODS: Three VR conditions were compared in a randomized cross-over study of 30 healthy volunteers: Passive VR (i.e. no interaction possible with the virtual world), active VR (interactive virtual environment) and no VR (black screen). Subjects received noxious electrical stimuli at random intervals during all conditions. EPs, recorded at Cz, were extracted time locked to stimuli. Pain scores were reported after each condition. RESULTS: Active VR significantly decreased pain scores and amplitudes of N1 and P3. Passive VR had no analgesic effect. Age was significantly correlated to pain scores, with older subjects demonstrating larger effects of VR. Gender, game experience, and susceptibility for immersion, did not influence VR analgesia. CONCLUSION: Active VR decreases pre-perceptual and perceptual brain activity following painful electrical stimuli, corresponding with reduced pain experience. VR has potential to serve as a non-pharmacologic treatment for pain, particularly in elderly patients.

Reduced tactile acuity in chronic low back pain is linked with structural neuroplasticity in primary somatosensory cortex and is modulated by acupuncture therapy.

Prior studies have shown that patients suffering from chronic Low Back Pain (cLBP) have impaired somatosensory processing including reduced tactile acuity, i.e. reduced ability to resolve fine spatial details with the perception of touch. The central mechanism(s) underlying reduced tactile acuity are unknown but may include changes in specific brain circuitries (e.g. neuroplasticity in the primary somatosensory cortex, S1). Furthermore, little is known about the linkage between changes in tactile acuity and the amelioration of cLBP by somatically-directed therapeutic interventions, such as acupuncture. In this longitudinal neuroimaging study, we evaluated healthy control adults (HC, N â€‹= â€‹50) and a large sample of cLBP patients (N â€‹= â€‹102) with structural brain imaging (T1-weighted MRI for Voxel-Based Morphometry, VBM; Diffusion Tensor Imaging, DTI) and tactile acuity testing using two-point discrimination threshold (2PDT) over the lower back (site of pain) and finger (control) locations. Patients were evaluated at baseline and following a 4-week course of acupuncture, with patients randomized to either verum acupuncture, two different forms of sham acupuncture (designed with or without somatosensory afference), or no-intervention usual care control. At baseline, cLBP patients demonstrated reduced acuity (greater 2PDT, P â€‹= â€‹0.01) over the low back, but not finger (P â€‹= â€‹0.29) locations compared to HC, suggesting that chronic pain affects tactile acuity specifically at body regions encoding the experience of clinical pain. At baseline, Gray Matter Volume (GMV) was elevated and Fractional Anisotropy (FA) was reduced, respectively, in the S1-back region of cLBP patients compared to controls (P â€‹< â€‹0.05). GMV in cLBP correlated with greater 2PDT-back scores (ρ â€‹= â€‹0.27, P â€‹= â€‹0.02). Following verum acupuncture, tactile acuity over the back was improved (reduced 2PDT) and greater improvements were associated with reduced S1-back GMV (ρ â€‹= â€‹0.52, P â€‹= â€‹0.03) and increased S1-back adjacent white matter FA (ρ â€‹= â€‹-0.56, P â€‹= â€‹0.01). These associations were not seen for non-verum control interventions. Thus, S1 neuroplasticity in cLBP is linked with deficits in tactile acuity and, following acupuncture therapy, may represent early mechanistic changes in somatosensory processing that track with improved tactile acuity.

Anton's Syndrome associated with autotopagnosia.

We describe an unusual case of a 68-year-old male affected by cerebral amyloid angiopathy and cortical blindness associated with Anton's syndrome. In addition, our patient presented with autotopagnosia, a form of agnosia characterized by loss of body spatial representation. Neuropsychological assessment evidenced cognitive impairment. Magnetic Resonance Imaging showed hemorrhagic foci in the left occipital and right occipito-parietal lobe, paratrigonal white matter, and post-ischemic parenchymal gliosis. The pattern-reversal of visual evoked potentials were indicative bilateral visual pathway of integrity of the. After a neurological damage, patients could show a denial of their own deficit; however, the association between anosognosia and autotopagnosia represents a rare neurological condition. The simultaneous onset of unusual neuropsychological syndromes could be related to involvement of a complex brain network.

Long-term cognitive disability after traumatic brain injury: Contribution of the DEX relative questionnaires.

Executive functions are high-level cognitive processes commonly impaired after severe traumatic brain injury (sTBI), which may be associated with persistent anosognosia. The dysexecutive questionnaire (DEX) was designed to assess different domains of executive functioning in daily life. Two versions of the DEX exist (DEX-S completed by the patient, DEX-O completed by a relative) to compare cognitive complaints and patient's awareness. This work was aimed at studying the relevance of DEX-O for assessing daily-life limitations, the persistence of anosognosia and its association with global disability (GOSE) and magnetic resonance imaging (MRI) markers of brain alterations. Sixty-three patients (and relatives) were included within 63.4 months (±20.7) after sTBI. DEX-S and DEX-O scores were significantly positively correlated. We obtained significant correlations between DEX-S and episodic memory and phasic alert but not with executive assessment, GOSE and diffusion MRI markers. DEX-O was significantly correlated with executive function, episodic memory, attention (phasic alert sustained and divided attention), with the GOSE and the volume of the body of the corpus callosum (MRI marker). Anosognosia score (DEX-O minus DEX-S) correlated with mean diffusivity measure. These results highlight the clinical interest of DEX-O in assessing long-term disability.

Understanding Anosognosia for Hemiplegia After Stroke.

BACKGROUND: Anosognosia for hemiplegia (AHP) after stroke is a complex cognitive behavioral disorder that removes awareness of one-sided paralysis (hemiplegia). As a result, stroke survivors afflicted with AHP may be more likely to have unrealistic expectations for stroke rehabilitation, display unsafe behaviors and experience falls, and ultimately suffer the physical and psychological consequences of frequent falling. OBJECTIVE: The purpose of this article is to describe AHP by discussing anosognosia within the context of contemporary theoretical understandings, examining current imaging evidence of the disorder, and summarizing emerging interventions designed to reinstate self-awareness in anosognosic patients. METHOD: Systematic review with a focus on defining and describing AHP based on human experimental studies was conducted within a 10-year period. RESULTS: Eleven studies were identified. The content and foci of the 11 studies fell into one of three categories: theory testing, imaging evidence, and interventions for individuals with AHP.

The Phenomenology of Acute Anosognosia for Hemiplegia.

OBJECTIVE: After attempting to move a plegic limb, patients with anosognosia for hemiplegia (AHP) may claim that limb movement occurred, even though the limb remained motionless. The authors investigated the characteristics, natural history, and anatomical basis of AHP phenomenology. METHODS: Twenty-nine right-hemisphere stroke patients with acute anosognosia for hemiplegia (AHP) were prospectively assessed for the presence and characteristics of movement claims and observable behavior during movement attempts. RESULTS: AHP was transient, with the condition resolving in 68% of patients by 1 week. Patients made movement claims during 31% of unilateral movement attempts and 50% of bilateral movement attempts. Movement claims were idiosyncratic, lacked internal consistency within individual patients, and even dissociated from explicit denial, as several patients made movement claims after they began to explicitly acknowledge hemiplegia. Observable behavior during movement attempts revealed allochiria (moving the right arm instead of the left) in 31% of patients, signs of implicit knowledge of weakness in 24%, and intact intention in 34%. Lesion analysis revealed that allochiria was associated with inferior right parietal lobe damage. CONCLUSIONS: These results highlight that heterogeneity, phenomenological complexity, and transience are hallmarks of AHP. This advances clinical AHP assessment by showing that assessment of performance, rather than just verbal response, uncovers multiple dimensions of AHP. Allochiria emerges as an anatomically distinct subcomponent of the disorder. These findings also have theoretical implications, because they do not lend support to unitary pathogenic models proposing that illusions of movement or impaired intention form the basis of AHP. Most patients rapidly improve, which should invigorate the search for typical compensatory mechanisms underlying spontaneous recovery.

Recovery from tactile agnosia: a single case study.

In a patient suffering from tactile agnosia a comparison was made (using the ABABAB paradigm) between three blocks of neuropsychological rehabilitation sessions involving off-line anodal transcranial direct current stimulation (anodal-tDCS) and three blocks of rehabilitation sessions without tDCS. During the blocks with anodal-tDCS, the stimulation was administered in counterbalanced order to two sites: i) the perilesional parietal area (specific stimulation) and ii) an occipital area far from the lesion (nonspecific stimulation).Rehabilitation associated with anodal-tDCS (in particular in the perilesional areas) is more efficacious than without stimulation.