Cognition, hallucination severity and hallucination-specific insight in neurodegenerative disorders and eye disease.

Introduction: Hallucinations occur across neurodegenerative disorders, with increasing severity, poorer cognition and impaired hallucination-specific insight associated with worse outcomes and faster disease progression. It remains unclear how changes in cognition, temporal aspects of hallucinations, hallucination-specific insight and distress relate to each other.Methods: Extant samples of patients experiencing visual hallucinations were included in the analyses: Parkinson's Disease (n = 103), Parkinson's Disease Dementia (n = 41), Dementia with Lewy Bodies (n = 27) and Eye Disease (n = 113). We explored the relationship between factors of interest with Spearman's correlations and random-effect linear models.Results: Spearman's correlation analyses at the whole-group level showed that higher hallucination-specific insight was related to higher MMSE score (rs = 0.39, p < 0.001) and less severe hallucinations (rs = -0.28, p < .01). Linear mixed-models controlling for diagnostic group showed that insight was related to higher MMSE (p < .001), to hallucination severity (p = 0.003), and to VH duration (p = 0.04). Interestingly, insight was linked to the distress component but not the frequency component of severity. No significant relationship was found between MMSE and hallucination severity in these analyses.Conclusion: Our findings highlight the importance of hallucination-specific insight, distress and duration across groups. A better understanding of the role these factors play in VH may help with the development of future therapeutic interventions trans-diagnostically.

Visual mismatch negativity in Parkinson's psychosis and potential for testing treatment mechanisms.

Psychosis and visual hallucinations are a prevalent non-motor symptom of Parkinson's disease, negatively affecting patients' quality of life and constituting a greater risk for dementia. Understanding neural mechanisms associated to these symptoms is instrumental for treatment development. The mismatch negativity is an event-related potential evoked by a violation in a sequence of sensory events. It is widely considered an index of sensory change-detection. Reduced mismatch negativity response is one of the most replicated results in schizophrenia and has been suggested to be a superior psychosis marker. To understand whether this event-related potential component could be a similarly robust marker for Parkinson's psychosis, we used electroencephalography with a change-detection task to study the mismatch negativity in the visual modality in 20 participants with Parkinson's and visual hallucinations and 18 matched Parkinson's participants without hallucinations. We find that visual mismatch negativity is clearly present in participants with Parkinson's disease without hallucinations at both parieto-occipital and frontal sites, whereas participants with Parkinson's and visual hallucinations show reduced or no differences in the two waveforms, confirming the sensitivity of mismatch negativity to psychosis, even within the same diagnostic group. We also explored the relationship between hallucination severity and visual mismatch negativity amplitude, finding a negative correlation between visual hallucinations severity scores and visual mismatch negativity amplitude at a central frontal and a parieto-occipital electrodes, whereby the more severe or complex (illusions, formed visual hallucinations) the symptoms the smaller the amplitude. We have also tested the potential role of the serotonergic 5-HT2A cascade in visual hallucinations in Parkinson's with these symptoms, following the receptor trafficking hypothesis. We did so with a pilot study in healthy controls (N = 18) providing support for the role of the Gi/o-dependent pathway in the psychedelic effect and a case series in participants with Parkinson's and visual hallucinations (N = 5) using a double-blind crossover design. Positive results on psychosis scores and mismatch amplitude add further to the potential role of serotonergic modulation of visual hallucinations in Parkinson's disease.

Grey matter volume loss in Parkinson's disease psychosis and its relationship with serotonergic gene expression: A meta-analysis.

BACKGROUND: Neuroanatomical alterations underlying psychosis in Parkinson's Disease (PDP) remain unclear. We carried out a meta-analysis of MRI studies investigating the neural correlates of PDP and examined its relation with dopaminergic and serotonergic receptor gene expression. METHODS: PubMed, Web of Science and Embase were searched for MRI studies (k studies = 10) of PDP compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images and multiple linear regression analyses was used to examine the relationship between pooled estimates of grey matter volume (GMV) loss in PDP and D1/D2 and 5-HT1a/5-HT2a receptor gene expression estimates from Allen Human Brain Atlas. RESULTS: We observed lower grey matter volume in parietal-temporo-occipital regions (PDP n = 211, PDnP, n = 298). GMV loss in PDP was associated with local expression of 5-HT1a (b = 0.109, p = 0.012) and 5-HT2a receptors (b= -0.106, p = 0.002) but not dopaminergic receptors. CONCLUSION: Widespread GMV loss in the parieto-temporo-occipital regions may underlie PDP. Association between grey matter volume and local expression of serotonergic receptor genes may suggest a role for serotonergic receptors in PDP.

Cognitive and visual processing performance in Parkinson's disease patients with vs without visual hallucinations: A meta-analysis.

IMPORTANCE: Cognitive and visual impairments in Parkinson's Disease Psychosis (PDP) raise the question of whether a specific profile of impaired cognition and visual function is linked to vulnerability to visual hallucinations (VHs). Previous studies have limited sample sizes and only included a sub-sample of tests. This is the first meta-analysis quantifying visuo-cognitive impairments in PDP patients across a spectrum of tests and taking into account potential confounding factors such as levodopa medication, illness duration and general cognitive ability. OBJECTIVE: Compare visual processing and cognitive performance between PD patients with and without VHs (PDVH and PDnoVH). METHODS: Four databases (PubMed, PsychINFO, Scopus, WebOfScience) were searched for studies on visual and/or cognitive performance of PDnoVH and PDVH published up to 02/2020. For each task, means and SDs were extracted and standardized-mean-differences (SMDs) between-groups calculated. Effect-sizes (Hedges' g) were calculated for all comparisons and synthesized in random-effects meta-analyses with robust-variance-estimation (accounting for multiple correlated measures within each study per cognitive/visual domain). Publication bias was assessed with funnel plots and Egger intercept. RESULTS: N = 99 studies including 2508 PDVH patients (mean age 68.4 years) and 5318 PDnoVH (mean age 66.4 years) were included in the seven meta-analyses. PDVH patients performed worse than PDnoVH across all measures of cognition and visual processing, with the greatest between-group effect-sizes in executive functions, attention, episodic memory and visual processing. Study characteristics were not significantly associated with between-group differences in the domains investigated. Age-differences were significantly associated with performance differences in general cognition, working memory and executive functions. CONCLUSION: Models of PDVH need to incorporate a wider range of cognitive and processing domains than currently included. There is a need for studies disentangling the temporal relationship between cognitive/visual deficits and VHs as early identification of risk before the onset of VHs could mitigate later outcomes such as progression to dementia.

Mapping brain structural differences and neuroreceptor correlates in Parkinson's disease visual hallucinations.

Parkinson's psychosis (PDP) describes a spectrum of symptoms that may arise in Parkinson's disease (PD) including visual hallucinations (VH). Imaging studies investigating the neural correlates of PDP have been inconsistent in their findings, due to differences in study design and limitations of scale. Here we use empirical Bayes harmonisation to pool together structural imaging data from multiple research groups into a large-scale mega-analysis, allowing us to identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of morphometrics analysed show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and surrounding regions, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to the involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may be linked to the cortical changes.

Establishing links between abnormal eating behaviours and semantic deficits in dementia.

The hypothesis that semantic deficits in dementia may contribute in producing changes in eating preferences has never been experimentally investigated despite this association has been clinically observed. We administered tasks assessing semantic memory and the Appetite and Eating Habits Questionnaire (APEHQ) to 23 patients with dementia (behavioural frontotemporal dementia, primary progressive aphasia, and Alzheimer's disease) and to 21 healthy controls. We used voxel-based morphometry and diffusion tensor imaging to identify regions and white matter tracts of significant atrophy associated with the performance at the semantic tasks and the pathological scores at the APEHQ. We observed that the lower the patients' scores at semantic tasks, the higher their changes in eating habits and preferences. Both semantic disorders and eating alterations correlated with atrophy in the temporal lobes and white matter tracts connecting the temporal lobe with frontal regions such as the arcuate fasciculus, the cingulum, and the inferior longitudinal fasciculus. These results confirm that semantic deficits underlie specific eating alterations in dementia patients.

A GABA Interneuron Deficit Model of the Art of Vincent van Gogh.

Vincent van Gogh was one of the most influential artists of the Western world, having shaped the post-impressionist art movement by shifting its boundaries forward into abstract expressionism. His distinctive style, which was not valued by the art-buying public during his lifetime, is nowadays one of the most sought after. However, despite the great deal of attention from academic and artistic circles, one important question remains open: was van Gogh's original style a visual manifestation distinct from his troubled mind, or was it in fact a by-product of an impairment that resulted from the psychiatric illness that marred his entire life? In this paper, we use a previously published multi-scale model of brain function to piece together a number of disparate observations about van Gogh's life and art. In particular, we first quantitatively analyze the brushwork of his large production of self-portraits using the image autocorrelation and demonstrate a strong association between the contrasts in the paintings, the occurrence of psychiatric symptoms, and his simultaneous use of absinthe-a strong liquor known to affect gamma aminobutyric acid (GABA) alpha receptors. Secondly, we propose that van Gogh suffered from a defective function of parvalbumin interneurons, which seems likely given his family history of schizophrenia and his addiction to substances associated with GABA action. This could explain the need for the artist to increasingly amplify the contrasts in his brushwork as his disease progressed, as well as his tendency to merge esthetic and personal experiences into a new form of abstraction.

Food knowledge depends upon the integrity of both sensory and functional properties: a VBM, TBSS and DTI tractography study.

Food constitutes a fuel of life for human beings. It is therefore of chief importance that their recognition system readily identifies the most relevant properties of food by drawing on semantic memory. One of the most relevant properties to be considered is the level of processing impressed by humans on food. We hypothesized that recognition of raw food capitalizes on sensory properties and that of transformed food on functional properties, consistently with the hypothesis of a sensory-functional organization of semantic knowledge. To test this hypothesis, patients with Alzheimer's disease, frontotemporal dementia, primary progressive aphasia, and healthy controls performed lexical-semantic tasks with food (raw and transformed) and non-food (living and nonliving) stimuli. Correlations between task performance and local grey matter concentration (VBM) and white matter fractional anisotropy (TBSS) led to two main findings. First, recognition of raw food and living things implicated occipital cortices, typically involved in processing sensory information and, second, recognition of processed food and nonliving things implicated the middle temporal gyrus and surrounding white matter tracts, regions that have been associated with functional properties. In conclusion, the present study confirms and extends the hypothesis of a sensory and a functional organization of semantic knowledge.

How experience modulates semantic memory for food: evidence from elderly adults and centenarians.

In order to make sense of the objects we encounter in everyday life we largely rely on previous knowledge stored in our semantic memory. Semantic memory is considered dependent on lifelong experience and cultural knowledge. So far, a few studies have investigated the role of expertise on the organization of semantic memory, whereas life-long experience has largely been overlooked. In this study, we investigated this issue using food concepts. In particular, we administered different semantic tasks using food (natural and transformed) and non-food (living and non-living things) as stimuli to participants belonging to three different age cohorts (56-74, 75-91, 100-108), who were also asked to report on the dietary habits held throughout their life. In addition, we investigated to what extent psycholinguistic variables influence the semantic performance of different age cohorts. Results showed that Centenarians recognized natural food better than transformed food, while the other two groups showed the opposite pattern. According to our analyses, experience is responsible for this effect in Centenarians, as their dietary habits seem to suggest. Moreover, significant correlations between picture naming and age of acquisition, familiarity and frequency were observed. This study indicates that lifelong experience can shape conceptual knowledge of food concepts, and that semantic memory is less resilient to aging than initially thought.

Episodic memory for natural and transformed food.

It has been proposed that the conceptual knowledge of food and its putative subdivision into natural (i.e., fruit/vegetables) and transformed (i.e., food that underwent thermic or non-thermic processing) may follow the living/non-living distinction. In the present study, we investigated whether the advantage for living things compared to non-living things observed in episodic memory (the so-called animacy effect) extends to natural foods and transformed foods respectively. We pursued this issue in two experiments. In Experiment 1, we measured episodic memory for natural and transformed foods in young participants. In Experiment 2, we enrolled dementia-free centenarians, patients with Alzheimer's disease (DAT), Progressive primary aphasia (PPA), and healthy controls whose episodic memory was also tested for living/non-living things. Results showed that young participants had better recognition memory for transformed foods compared to natural foods. This difference disappeared in centenarians and patients. However, centenarians and PPA exhibited enhanced levels of false alarms (FA) with natural food, and DAT patients with both natural and transformed food. As far as the living/non-living distinction is concerned, the episodic memory for the living category appears more resilient to the decline compared to the non-living category in patients, particularly those with PPA. In conclusion, our study shows that transformed food is better remembered than natural food, suggesting that it is more salient and possibly relevant from an evolutionary perspective. The natural/transformed distinction appears susceptible to erosion only in the presence of a high degree of episodic memory impairment. These results offer novel insight on episodic memory of food, and also extend the current knowledge on the animacy effect in episodic memory.