Distinct grey and white matter changes are associated with the phenomenology of visual hallucinations in Lewy Body Disease.

Visual hallucinations in Lewy body disease (LBD) can be differentiated based on phenomenology into minor phenomena (MVH) and complex hallucinations (CVH). MVH include a variety of phenomena, such as illusions, presence and passage hallucinations occurring at early stages of LBD. The neural mechanisms of visual hallucinations are largely unknown. The hodotopic model posits that the hallucination state is due to abnormal activity in specialized visual areas, that occurs in the context of wider network connectivity alterations and that phenomenology of VH, including content and temporal characteristics, may help identify brain regions underpinning these phenomena. Here we investigated both the topological and hodological neural basis of visual hallucinations integrating grey and white matter imaging analyses. We studied LBD patients with VH and age matched healthy controls (HC). VH were assessed using a North-East-Visual-Hallucinations-Interview that captures phenomenological detail. Then we applied voxel-based morphometry and tract based spatial statistics approaches to identify grey and white matter changes. First, we compared LBD patients and HC. We found a reduced grey matter volume and a widespread damage of white tracts in LBD compared to HC. Then we tested the association between CVH and MVH and grey and white matter indices. We found that CVH duration was associated with decreased grey matter volume in the fusiform gyrus suggesting that LBD neurodegeneration-related abnormal activity in this area is responsible for CVH. An unexpected finding was that MVH severity was associated with a greater integrity of white matter tracts, specifically those connecting dorsal, ventral attention networks and visual areas. Our results suggest that networks underlying MVH need to be partly intact and functional for MVH experiences to occur, while CVH occur when cortical areas are damaged. The findings support the hodotopic view and the hypothesis that MVH and CVH relate to different neural mechanisms, with wider implications for the treatment of these symptoms in a clinical context.

Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development.

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.

Exploring the relationship between perceived loneliness and subjective cognitive decline in older individuals.

OBJECTIVE: Loneliness has been associated to a greater risk of cognitive decline and dementia in older individuals. However, evidence on whether this association also exists for older individuals who complain of cognitive problems is limited. We conducted a survey to examine the association between subjective cognitive decline in the working memory domain, perceived loneliness, depression, anxiety, and stress in older individuals with different profiles. METHODS: A total of 302 healthy, old individuals completed 3 questionnaires to assess subjective cognitive problems in attention, executive functions, storage, depression, anxiety, stress, and perceived loneliness. RESULTS: We conducted a cluster analysis and 3 clusters of individuals with different profiles emerged. Individuals with greater subjective cognitive problems (cluster 1) in the attention and storage domains, reported higher perceived loneliness and stress but not depression. In contrast, individuals with the least subjective cognitive problems (cluster 3) in the storage domain, reported lower perceived loneliness. CONCLUSIONS: Individuals with higher subjective cognitive decline also report higher levels of perceived loneliness but not more depression than their peers. However, this correlation is present only for individuals with mild subjective cognitive decline (cluster 2). The implications for future research and interventions are discussed.

Multidimensional assessment of time perception along the continuum of Alzheimer's Disease and evidence of alterations in subjective cognitive decline.

Timing alterations occur in Alzheimer's disease (AD), even in early stages (mild cognitive impairment, MCI). Moreover, a stage named subjective cognitive decline (SCD), in which individuals perceive a change in cognitive performance not revealed by neuropsychological tests, has been identified as a preclinical phase of AD. However, no study to date has investigated different dimensions of time processing along the continuum from physiological to pathological aging, and whether timing alterations occur in SCD. Here a sample of participants with SCD, MCI, AD and healthy controls (HC) performed tasks assessing prospective duration estimation, production, reproduction, implicit temporal learning in conditions dependent from external cues (externally-cued learning, ECL) or independent from external cues (internally-based learning, IBL), retrospective duration estimation, the subjective experience of time and the temporal collocation of events. AD patients performed worse than HC and SCD in prospective timing, and in collocating events in time. The subjective experience of time did not differ between groups. Concerning temporal learning, AD performed worse in ECL than in IBL, whereas SCD performed worse in IBL than in ECL. SCD, MCI and AD patients all showed errors greater than HC in retrospective duration estimation. Results point to implicit temporal learning in externally-cued conditions and retrospective time estimation as possible early markers of cognitive decline.

The contribution of being physically active to successful aging.

Growing old involves changes in physical, psychological, and cognitive functions. Promoting physical and mental health has become one of the priorities for an aging population. Studies have demonstrated the benefits of engaging in regular physical activity. Here, we aimed to understand the relationships between physical activity and working memory complaints in attention, memory storage, and executive functions. We hypothesized that physical activity was negatively associated with complaints in working memory domains after controlling for socio-demographics and distress factors, such as anxiety, stress, and depression. Two hundred and twenty-three individuals aged between 65 and 100 years (74.84; SD = 7.74; 133 males) without self-reported neurological and/or psychiatric disorders completed a questionnaire on socio-demographic, with questions on physical activity and the Italian version of the working memory questionnaire (WMQ) and the DASS-21 measuring anxiety, stress, and depression. Results from three linear regression models showed that low physical activity was associated with complaints in attention (R2 = 0.35) and executive functions (R2 = 0.37) but not in memory storage (R2 = 0.28). Notably, age, gender, and total emotional distress (DASS score) were significant in all regression models. Our results suggested regular physical activity, even just walking, is crucial for maintaining efficient cognitive function. Theoretical and practical implications for engaging in physical activity programs and social aggregation during exercise are considered. Limitations are also presented.

The time squares sequences: a new task for assessing visuospatial working memory.

Introduction: Several studies have shown that the working memory is sensitive to temporal variations. We used a new visuospatial working memory task, the "Time Squares Sequences," to investigate whether implicit variations in stimuli presentation time affect task performance. Methods: A total of 50 healthy participants saw two sequences (S1 and S2) of seven white squares presented in a matrix of gray squares and assessed whether S2 matched S1. There were four conditions depending on the spatial position and the presentation time (i.e., timing) of the white squares in S1 and S2: two with the same (S1 fixed/S2 fixed and S1 variable/S2 variable) and two with different (S1 fixed/S2 variable and S1 variable/S2 fixed) presentation times. Results: Findings showed impaired performance when S1 had a fixed presentation time and S2 had a variable presentation time. Conclusion: These findings are attributed to increased cognitive load due to S2 timing difference, pointing to a monitoring process, sensitive to temporal variations.

The Spectrum of Neurological and Sensory Abnormalities in Gaucher Disease Patients: A Multidisciplinary Study (SENOPRO).

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient's initial classification.

The Effect of Cognitive Style on Individual Differences in Prismatic Adaptation: A Pilot Study.

Prism adaptation (PA) is a well-known and widely used technique for rehabilitating unilateral spatial neglect and studying sensory-motor plasticity. However, there is conflicting evidence in the literature regarding its effectiveness which may arise from differences in the type of prisms used, clinical characteristics of the patients, and the procedure used in training. Individual differences may play a role in PA effectiveness in rehabilitating neglect, affecting both its development and its effects. Field-dependent/independent cognitive style is a pervasive characteristic of individual functioning, affecting how environmental information is processed. Here, we tested the hypothesis that cognitive style plays a role in PA efficacy by submitting to a protocol of prism adaptation to 38 health participants, who were classified as field-dependent (FD, N = 19) or field-independent (FI, N = 19), by using the Embedded Figure Test. Results show that during the exposure phase, FI individuals needed a lesser number of pointing movements to reduce the deviation error than FD individuals. However, there are no differences in the extinction of sensory-motor and cognitive after-effects. These results suggest that prismatic adaptation is affected by individuals' cognitive style since FI individuals will need fewer trials to reach adaptation and this could explain why using this rehabilitation technique with a unique, standard protocol is not always effective.

Neural substrates of interoceptive sensibility: An integrated study in normal and pathological functioning.

In early studies interoception strictly referred to the awareness of visceral sensations, but recent theories have expanded this concept to denote the ongoing status of the body, including somatosensory feelings. Here, we integrated data from normal and pathological functioning to disclose neural underpinnings of interoceptive sensibility, taking into account the crucial distinction between visceral and somatosensory feelings. Twenty-seven healthy young individuals underwent structural MRI (including T1w images and DTI). Voxel-wise analyses of the gyrification index (GI) and fractional anisotropy (FA) data were performed to assess the relation between interoceptive sensibility and surface morphometry and anatomical connectivity. Thirty-three unilateral brain-damaged patients took part in this study for Voxel-Based Lesion-Symptom Mapping (VLSM) and track-wise hodological lesion-deficit analysis (TWH). All participants completed the Self-Awareness Questionnaire (SAQ), a self-report tool assessing interoceptive sensibility of visceral (F1) and somatosensory feelings (F2). Tract-Based Spatial Statistics showed that F2 was positively associated with FA in the bilateral anterior thalamic radiation, corticospinal tract, cingulum, forceps, inferior longitudinal, fronto-occipital, superior longitudinal, and uncinate fasciculi; no significant association was detected for F1. However, F1 was positively associated with GI in the left anterior cingulate cortex. VLSM showed that F1 mainly relies on the right posterior insula, whereas F2 is related mostly to subcortical nuclei and surrounding white matter in the right hemisphere. Accordingly, patients with disconnection of the anterior thalamic projection, corticospinal tract, inferior fronto-occipital, inferior longitudinal, uncinate and superior longitudinal fasciculus III showed lower scores on F2. Overall, results support the dissociation between interoceptive sensibility of visceral and somatosensory feelings.

Temporal learning in the suprasecond range: insights from cognitive style.

The acquisition of information on the timing of events or actions (temporal learning) occurs in both the subsecond and suprasecond range. However, although relevant differences between participants have been reported in temporal learning, the role of dimensions of individual variability in affecting performance in such tasks is still unclear. Here we investigated this issue, assessing the effect of field-dependent/independent cognitive style on temporal learning in the suprasecond range. Since different mechanisms mediate timing when a temporal representation is self-generated, and when it depends on an external referent, temporal learning was assessed in two conditions. Participants observed a stimulus across six repetitions and reproduced it. Unbeknownst to them, in an internally-based learning (IBL) condition, the stimulus duration was fixed within a trial, although the number of events defining it varied; in an externally-cued learning (ECL) condition, the stimulus was defined by the same number of events within each trial, although its duration varied. The effect of the reproduction modality was also assessed (motor vs. perceptual). Error scores were higher in IBL compared to ECL; the reverse was true for variability. Field-independent individuals performed better than field-dependent ones only in IBL, as further confirmed by correlation analyses. Findings provide evidence that differences in dimensions of variability in high-level cognitive functioning, such as field dependence/independence, significantly affect temporal learning in the suprasecond range, and that this effect depends on the type of temporal representation fostered by the specific task demands.

Working Memory in Navigational and Reaching Spaces in Typically Developing Children at Increasing School Stages.

BACKGROUND: Based on studies of children with motor disabilities on topographic working memory (TWM), no influence of age was reported. The only differences were in the degree of mobility and exploration of the environment. The more active a child was in exploring the environment, the less his/her TWM was poor. However, in typically developing children (TD), exploration of the environment increases with increasing age, and age-related effects have been described. Here, we aim at investigating TWM considering age in TD with the additional question of whether WM in the reaching space differed from that in the navigational space requiring body movements. We hypothesized that WM in both spaces would improve correspondingly with increasing age, assuming that the greater the autonomy in exploring the environment, the better TWM becomes. METHOD: 120 children (5-16 years old) performed the Corsi Block-Tapping test (CBT) and the Walking Corsi test (WalCT). RESULTS: Statistical analyses evidenced significantly increasing WalCT and CBT spans between each school stage, except in the CBT span between middle stage (MS) and upper stage (US). CBT spans were significantly higher than in the WalCT in the pre-school, lower stage, and MS, with the CBT span increasing until MS, which is sufficient for using spatial orientation strategies effectively. CONCLUSIONS: When navigation is gradually controlled, a child may be able to pay increasingly more attention to wayfinding and behavior in traffic. Since the US group even presented as good in the WalCT as young adults living in metropolitan environments, assuming that children may gain spatial orientation from having opportunities to move in their surroundings, this is also relevant for children with motor disabilities.

Where Am I? Searching for the Tangle in the Developmental Topographical Disorientation.

The Developmental Topographical Disorientation (DTD) is a pathological condition that impairs an individual's ability to orient in space, even in the most familiar environments. It is a lifelong selective condition in individuals without brain damage or without impaired general cognitive functions. Here, we aimed at characterizing 54 individuals with DTD identified in a previous study, aged between 18 and 35 years and assessed through a 4-year-long online survey. To this purpose, we compared them with 54 matched healthy participants. We described the demographics, sense of direction, town knowledge, navigational strategies, left-right confusion as well as agnosic disorders (for landmarks, faces and objects). This novel study attempts to characterize the phenotype of DTD, providing an important contribution to the worldwide definition of a condition that was first described only 13 years ago, but which, considering the growing number of cases complaining of the disorder, deserves continuous and increasing attention.

A multi-expert ensemble system for predicting Alzheimer transition using clinical features.

Alzheimer's disease (AD) diagnosis often requires invasive examinations (e.g., liquor analyses), expensive tools (e.g., brain imaging) and highly specialized personnel. The diagnosis commonly is established when the disorder has already caused severe brain damage, and the clinical signs begin to be apparent. Instead, accessible and low-cost approaches for early identification of subjects at high risk for developing AD years before they show overt symptoms are fundamental to provide a critical time window for more effective clinical management, treatment, and care planning. This article proposes an ensemble-based machine learning algorithm for predicting AD development within 9 years from first overt signs and using just five clinical features that are easily detectable with neuropsychological tests. The validation of the system involved both healthy individuals and mild cognitive impairment (MCI) patients drawn from the ADNI open dataset, at variance with previous studies that considered only MCI. The system shows higher levels of balanced accuracy, negative predictive value, and specificity than other similar solutions. These results represent a further important step to build a preventive fast-screening machine-learning-based tool to be used as a part of routine healthcare screenings.

Giant chess game enhances spatial navigational skills in 6-years-old children: preliminary findings.

The game of chess is a valuable extracurricular activity for children, with positive effects on their cognitive skills and academic achievements. We investigated the extent to which the Giant Chess Game (GCG) played on a giant chessboard enhances working memory in "navigational-vista" space and "reaching" space. We also assessed if the GCG enhances mental rotation skills. For 10 weeks, 15 children (GCG group) were involved in a giant chess class, while 15 gender and age-matched children were involved in standard didactics (control group-CG). Children were tested twice, before (T0) and after (T1) the GCG, by tasks aimed at measuring: visuo-spatial working memory (VSWM) in the navigational-vista space (Walking Corsi test); VSWM in the reaching space (Corsi Block-Tapping task); mental rotation (Rotating Flowers test). We found that the GCG group significantly improved its performance more than the CG in VSWM in both navigational-vista space and reaching space, as well as in mental rotation. Our results suggest that the GCG has positive effects on visuo-spatial abilities underlying topographical skills. Therefore, the training using GCG can help enhancing spatial ability and may have a role in contrasting the spreading of navigational deficits such as the Developmental Topographical Disorientation (DTD).

"Where am I?" A snapshot of the developmental topographical disorientation among young Italian adults.

In the last decade, several cases affected by Developmental Topographical Disorientation (DTD) have been described. DTD consists of a neurodevelopmental disorder affecting the ability to orient in the environment despite well-preserved cognitive functions, and in the absence of a brain lesion or other neurological or psychiatric conditions. Described cases showed different impairments in navigational skills ranging from topographic memory deficits to landmark agnosia. All cases lacked a mental representation of the environment that would allow them to use high-order spatial orientation strategies. In addition to the single case studies, a group study performed in Canada showed that the disorder is more widespread than imagined. The present work intends to investigate the occurrence of the disorder in 1,698 young Italian participants. The sample is deliberately composed of individuals aged between 18 and 35 years to exclude people who could manifest the loss of the ability to navigate as a result of an onset of cognitive decline. The sample was collected between 2016 and 2019 using the Qualtrics platform, by which the Familiarity and Spatial Cognitive Style Scale and anamnestic interview were administered. The data showed that the disorder is present in 3% of the sample and that the sense of direction is closely related to town knowledge, navigational strategies adopted, and gender. In general, males use more complex navigational strategies than females, although DTD is more prevalent in males than in females, in line with the already described cases. Finally, the paper discusses which protective factors can reduce DTD onset and which intervention measures should be implemented to prevent the spread of navigational disorders, which severely impact individuals' autonomy and social relationships.

Cerebellum-Cortical Interaction in Spatial Navigation and Its Alteration in Dementias.

The cerebellum has a homogeneous structure and performs different computational functions such as modulation/coordination of the communication between cerebral regions, and regulation/integration of sensory information. Albeit cerebellar activity is generally associated with motor functions, several recent studies link it to various cognitive functions, including spatial navigation. In addition, cerebellar activity plays a modulatory role in different cognitive domains and brain processes. Depending on the network involved, cerebellar damage results in specific functional alterations, even when no function loss might be detected. In the present review, we discuss evidence of brainstem degeneration and of a substantial reduction of neurons in nuclei connected to the inferior olivary nucleus in the early stages of Alzheimer's disease. Based on the rich patterns of afferences from the inferior olive nucleus to the cerebellum, we argue that the subtle alterations in spatial navigation described in the early stages of dementia stem from alterations of the neuromodulatory functions of the cerebellum.

Testing a Model of Human Spatial Navigation Attitudes towards Global Navigation Satellite Systems.

Global navigation satellite systems (GNSS) can provide better data quality for different purposes; however, some age groups might lie outside its use. Understanding the barriers to its adoption is of interest in different fields. This work aims at developing a measurement instrument of the adoption attitudes towards this technology and examining the relationship of variables such as age and gender. A UTAUT model was tested on 350 participants. The main results can be summarised as follows: (i) the proposed GNSS scale on human spatial navigation attitudes towards geopositioning technology showed optimal psychometric properties; (ii) although statistically significant differences were found in the Wayfinding Questionnaire (WQ) between men and women, these did not reach the level of statistical significance for the scores on attitudes towards GNSS; (iii) by testing a model on human spatial navigation attitudes towards geopositioning technology, it was possible to show a higher relationship with age in women.