De novo protein design by deep network hallucination.

There has been considerable recent progress in protein structure prediction using deep neural networks to predict inter-residue distances from amino acid sequences1-3. Here we investigate whether the information captured by such networks is sufficiently rich to generate new folded proteins with sequences unrelated to those of the naturally occurring proteins used in training the models. We generate random amino acid sequences, and input them into the trRosetta structure prediction network to predict starting residue-residue distance maps, which, as expected, are quite featureless. We then carry out Monte Carlo sampling in amino acid sequence space, optimizing the contrast (Kullback-Leibler divergence) between the inter-residue distance distributions predicted by the network and background distributions averaged over all proteins. Optimization from different random starting points resulted in novel proteins spanning a wide range of sequences and predicted structures. We obtained synthetic genes encoding 129 of the network-'hallucinated' sequences, and expressed and purified the proteins in Escherichia coli; 27 of the proteins yielded monodisperse species with circular dichroism spectra consistent with the hallucinated structures. We determined the three-dimensional structures of three of the hallucinated proteins, two by X-ray crystallography and one by NMR, and these closely matched the hallucinated models. Thus, deep networks trained to predict native protein structures from their sequences can be inverted to design new proteins, and such networks and methods should contribute alongside traditional physics-based models to the de novo design of proteins with new functions.

Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Abnormal higher-order network interactions in Parkinson's disease visual hallucinations.

Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby dysfunctional communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between-functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques-diffusion-map embedding and t-distributed stochastic neighbour embedding (t-SNE)-to resting state functional MRI data, in order to characterize the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy control subjects. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions, suggesting an additional layer of complexity in the functional brain network abnormalities implicated in hallucinations, which was not apparent in traditional functional connectivity analyses. Together, the results confirm abnormal brain organization associated with the hallucinating phenotype in Parkinson's disease and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.

Electrical stimulation induced self-related auditory hallucinations correlate with oscillatory power change in the default mode network.

Self-related information is crucial in our daily lives, which has led to the proposal that there is a specific brain mechanism for processing it. Neuroimaging studies have consistently demonstrated that the default mode network (DMN) is strongly associated with the representation and processing of self-related information. However, the precise relationship between DMN activity and self-related information, particularly in terms of neural oscillations, remains largely unknown. We electrically stimulated the superior temporal and fusiform areas, using stereo-electroencephalography to investigate neural oscillations associated with elicited self-related auditory hallucinations. Twenty-two instances of auditory hallucinations were recorded and categorized into self-related and other-related conditions. Comparing oscillatory power changes within the DMN between self-related and other-related auditory hallucinations, we discovered that self-related hallucinations are associated with significantly stronger positive power changes in both alpha and gamma bands compared to other-related hallucinations. To ensure the validity of our findings, we conducted controlled analyses for factors of familiarity and clarity, which revealed that the observed effects within the DMN remain independent of these factors. These results underscore the significance of the functional role of the DMN during the processing of self-related auditory hallucinations and shed light on the relationship between self-related perception and neural oscillatory activity.

Neural response properties predict perceived contents and locations elicited by intracranial electrical stimulation of human auditory cortex.

Intracranial electrical stimulation (iES) of auditory cortex can elicit sound experiences with a variety of perceived contents (hallucination or illusion) and locations (contralateral or bilateral side), independent of actual acoustic inputs. However, the neural mechanisms underlying this elicitation heterogeneity remain undiscovered. Here, we collected subjective reports following iES at 3062 intracranial sites in 28 patients (both sexes) and identified 113 auditory cortical sites with iES-elicited sound experiences. We then decomposed the sound-induced intracranial electroencephalogram (iEEG) signals recorded from all 113 sites into time-frequency features. We found that the iES-elicited perceived contents can be predicted by the early high-γ features extracted from sound-induced iEEG. In contrast, the perceived locations elicited by stimulating hallucination sites and illusion sites are determined by the late high-γ and long-lasting α features, respectively. Our study unveils the crucial neural signatures of iES-elicited sound experiences in human and presents a new strategy to hearing restoration for individuals suffering from deafness.

Effects of Hallucination Proneness and Sensory Resolution on Prior Biases in Human Perceptual Inference of Time Intervals.

Bayesian models of perception posit that percepts result from the optimal integration of new sensory information and prior expectations. In turn, prominent models of perceptual disturbances in psychosis frame hallucination-like phenomena as percepts excessively biased toward perceptual prior expectations. Despite mounting support for this notion, whether this hallucination-related prior bias results secondarily from imprecise sensory representations at early processing stages or directly from alterations in perceptual priors-both suggested candidates potentially consistent with Bayesian models-remains to be tested. Using modified interval timing paradigms designed to arbitrate between these alternative hypotheses, we show in human participants (16 females and 24 males) from a nonclinical population that hallucination proneness correlates with a circumscribed form of prior bias that reflects selective differences in weighting of contextual prior variance, a prior bias that is unrelated to the effect of sensory noise and to a separate index of sensory resolution. Our results thus suggest distinct mechanisms underlying prior biases in perceptual inference and favor the notion that hallucination proneness could reflect direct alterations in the representation or use of perceptual priors independent of sensory noise.SIGNIFICANCE STATEMENT Current theories of psychosis posit that hallucination proneness results from excessive influence of prior expectations on perception. It is not clear whether this prior bias represents a primary top-down process related to the representation or use of prior beliefs or instead a secondary bottom-up process stemming from imprecise sensory representations at early processing stages. To address this question, we examined interval timing behaviors captured by Bayesian perceptual-inference models. Our data support the notion that excessive influence of prior expectations associated with hallucination propensity is not directly secondary to sensory imprecision and is instead more consistent with a primary top-down process. These results help refine computational theories of psychosis and may contribute to the development of improved intervention targets.

Trial of Pimavanserin in Dementia-Related Psychosis.

BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Low-frequency rTMS induces modifications in cortical structural connectivity - functional connectivity coupling in schizophrenia patients with auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) are distinctive clinical manifestations of schizophrenia. While low-frequency repetitive transcranial magnetic stimulation (rTMS) has demonstrated potential in mitigating AVH, the precise mechanisms by which it operates remain obscure. This study aimed to investigate alternations in structural connectivity and functional connectivity (SC-FC) coupling among schizophrenia patients with AVH prior to and following treatment with 1 Hz rTMS that specifically targets the left temporoparietal junction. Initially, patients exhibited significantly reduced macroscopic whole brain level SC-FC coupling compared to healthy controls. Notably, SC-FC coupling increased significantly across multiple networks, including the somatomotor, dorsal attention, ventral attention, frontoparietal control, and default mode networks, following rTMS treatment. Significant alternations in SC-FC coupling were noted in critical nodes comprising the somatomotor network and the default mode network, such as the precentral gyrus and the ventromedial prefrontal cortex, respectively. The alternations in SC-FC coupling exhibited a correlation with the amelioration of clinical symptom. The results of our study illuminate the intricate relationship between white matter structures and neuronal activity in patients who are receiving low-frequency rTMS. This advances our understanding of the foundational mechanisms underlying rTMS treatment for AVH.

Illusory Responses across the Lewy Body Disease Spectrum.

OBJECTIVE: This study was undertaken to study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. METHODS: We studied illusory responses on the Noise Pareidolia Task in 300 participants (38 cognitively impaired LB, 65 cognitively unimpaired LB, 51 Alzheimer disease spectrum [AD-s], 146 controls). Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. RESULTS: Cognitively impaired LB participants were 12.3, 4.9, and 4.6 times more likely than control, cognitively unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex, and education, the probability of endorsing 1 or more illusory responses was 61% in the cognitively impaired LB group, compared to 26% in AD-s, 25% in cognitively unimpaired LB, and 12% in control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least 1 illusory response. INTERPRETATION: We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. ANN NEUROL 2023;93:702-714.

An integrative framework for perceptual disturbances in psychosis.

Perceptual disturbances in psychosis, such as auditory verbal hallucinations, are associated with increased baseline activity in the associative auditory cortex and increased dopamine transmission in the associative striatum. Perceptual disturbances are also associated with perceptual biases that suggest increased reliance on prior expectations. We review theoretical models of perceptual inference and key supporting physiological evidence, as well as the anatomy of associative cortico-striatal loops that may be relevant to auditory perceptual inference. Integrating recent findings, we outline a working framework that bridges neurobiology and the phenomenology of perceptual disturbances via theoretical models of perceptual inference.

Carbamazepine responsive episodic dystonia and hallucination due to pyruvate dehydrogenase E2 (DLAT) gene mutation.

Pyruvate Dehydrogenase (PDH) E2 deficiency due to Dihydrolipoamide acetyltransferase (DLAT) mutations is a very rare condition with only nine reported cases to date. We describe a 15-year-old girl with mild intellectual disability, paroxysmal dystonia and bilateral basal ganglia signal abnormalities on brain magnetic resonance imaging (MRI). Additionally, neurophysiological, imaging, metabolic and exome sequencing studies were performed. Routine metabolite testing, and GLUT1 and PRRT2 mutation analysis were negative. A repeat brain MRI revealed 'Eye-of-the-tiger-sign'. Exome sequencing identified homozygous valine to glycine alteration at amino acid position 157 in the DLAT gene. Bioinformatic and family analyses indicated that the alteration was likely pathogenic. Patient's dystonia was responsive to low-dose carbamazepine. On weaning carbamazepine, patient developed hallucinations which resolved after carbamazepine was restarted. PDH E2 deficiency due to DLAT mutation has a more benign course compared to common forms of PDH E1 deficiency due to X-linked PDHA1 mutations. All known cases of PDH E2 deficiency due to DLAT mutations share the features of episodic dystonia and intellectual disability. Our patient's dystonia and hallucinations responded well to low-dose carbamazepine.

Functional Brain Networks of Minor and Well-Structured Major Hallucinations in Parkinson's Disease.

BACKGROUND: Minor hallucinations (mHs) and well-structured major hallucinations (MHs) are common symptoms of Parkinson's disease (PD) psychosis. OBJECTIVES: To investigate the resting-state networks (RSNs) in patients with PD without hallucinations (PD-nH), with mH (PD-mH), and with MH (PD-MH). METHODS: A total of 73 patients with PD were enrolled (27 PD-nH, 23 PD-mH, and 23 PD-MH). Using seed-based functional connectivity analyses, we investigated the RSNs supposedly related to hallucinations in PD: the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), ventral attention network (VAN), and visual network (VN). We compared the cognitive function and RSN connectivity among the three groups. In addition, we performed a seed-to-seed analysis to examine the inter-network connectivity within each group using the corresponding RSN seeds. RESULTS: PD-MH group had lower test scores for attention and visuospatial functions compared with those in the other groups. The connectivity of the right intracalcarine cortex within the DAN was lower in the PD-MH group than in the others. The PD-mH and PD-MH groups showed higher connectivity in the left orbitofrontal cortex within DMN compared with the PD-nH group, whereas the connectivity was lower in the right middle frontal gyrus (MFG) within ECN, precuneus cortex within VAN, right middle temporal gyrus and precuneus cortex within DAN, and left MFG within VN. The PD-mH and PD-MH groups showed different inter-network connectivity between the five RSNs, especially regarding DAN connectivity. CONCLUSIONS: DAN dysfunction may be a key factor in the progression from mH to MH in patients with PD. © 2023 International Parkinson and Movement Disorder Society.

The experience of felt presence in a general population sample.

Felt presence is a widely occurring experience, but remains under-recognised in clinical and research practice. To contribute to a wider recognition of the phenomenon, we aimed to assess the presentation of felt presence in a large population sample (n = 10 447) and explore its relation to key risk factors for psychosis. In our sample 1.6% reported experiencing felt presence in the past month. Felt presence was associated with visual and tactile hallucinations and delusion-like thinking; it was also associated with past occurrence of adverse events, loneliness and poor sleep. The occurrence of felt presence may function as a marker for general hallucination proneness.

Aberrant Hippocampal Neuroregenerative Plasticity in Schizophrenia: Reactive Neuroblastosis as a Possible Pathocellular Mechanism of Hallucination.

Hallucination is a sensory perception that occurs in the absence of external stimuli during abnormal neurological disturbances and various mental diseases. Hallucination is recognized as a core psychotic symptom and is particularly more prevalent in individuals with schizophrenia. Strikingly, a significant number of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other neurological diseases like cerebral stroke and epileptic seizure also experience hallucination. While aberrant neurotransmission has been linked to the neuropathogenic events of schizophrenia, the precise cellular mechanism accounting for hallucinations remains obscure. Neurogenesis is a cellular process of producing new neurons from the neural stem cells (NSC)-derived neuroblasts in the brain that contribute to the regulation of pattern separation, mood, olfaction, learning, and memory in adulthood. Impaired neurogenesis in the hippocampus of the adult brain has been linked to stress, anxiety, depression, and dementia. Notably, many neurodegenerative disorders are characterized by the mitotic and functional activation of neuroblasts and cell cycle re-entry of mature neurons leading to a drastic alteration in neurogenic process, known as reactive neuroblastosis. Considering their neurophysiological properties, the abnormal integration of neuroblasts into the existing neural network or withdrawal of their connections can lead to abnormal synaptogenesis, and neurotransmission. Eventually, this would be expected to result in altered perception accounting for hallucination. Thus, this article emphasizes a hypothesis that aberrant neurogenic processes at the level of reactive neuroblastosis could be an underlying mechanism of hallucination in schizophrenia and other neurological diseases.

Robotically-induced auditory-verbal hallucinations: combining self-monitoring and strong perceptual priors.

BACKGROUND: Inducing hallucinations under controlled experimental conditions in non-hallucinating individuals represents a novel research avenue oriented toward understanding complex hallucinatory phenomena, avoiding confounds observed in patients. Auditory-verbal hallucinations (AVH) are one of the most common and distressing psychotic symptoms, whose etiology remains largely unknown. Two prominent accounts portray AVH either as a deficit in auditory-verbal self-monitoring, or as a result of overly strong perceptual priors. METHODS: In order to test both theoretical models and evaluate their potential integration, we developed a robotic procedure able to induce self-monitoring perturbations (consisting of sensorimotor conflicts between poking movements and corresponding tactile feedback) and a perceptual prior associated with otherness sensations (i.e. feeling the presence of a non-existing another person). RESULTS: Here, in two independent studies, we show that this robotic procedure led to AVH-like phenomena in healthy individuals, quantified as an increase in false alarm rate in a voice detection task. Robotically-induced AVH-like sensations were further associated with delusional ideation and to both AVH accounts. Specifically, a condition with stronger sensorimotor conflicts induced more AVH-like sensations (self-monitoring), while, in the otherness-related experimental condition, there were more AVH-like sensations when participants were detecting other-voice stimuli, compared to detecting self-voice stimuli (strong-priors). CONCLUSIONS: By demonstrating an experimental procedure able to induce AVH-like sensations in non-hallucinating individuals, we shed new light on AVH phenomenology, thereby integrating self-monitoring and strong-priors accounts.

Barriers and solutions to the adoption of translational tools for computational psychiatry.

Computational psychiatry is a field aimed at developing formal models of information processing in the human brain, and how alterations in this processing can lead to clinical phenomena. There has been significant progress in the development of tasks and how to model them, presenting an opportunity to incorporate computational psychiatry methodologies into large- scale research projects or into clinical practice. In this viewpoint, we explore some of the barriers to incorporation of computational psychiatry tasks and models into wider mainstream research directions. These barriers include the time required for participants to complete tasks, test-retest reliability, limited ecological validity, as well as practical concerns, such as lack of computational expertise and the expense and large sample sizes traditionally required to validate tasks and models. We then discuss solutions, such as the redesigning of tasks with a view toward feasibility, and the integration of tasks into more ecologically valid and standardized game platforms that can be more easily disseminated. Finally, we provide an example of how one task, the conditioned hallucinations task, might be translated into such a game. It is our hope that interest in the creation of more accessible and feasible computational tasks will help computational methods make more positive impacts on research as well as, eventually, clinical practice.

Wilhelm Mayer's follow-up study of Kraepelin's cases of paraphrenia: diagnostic validity in 1921.

As part of his lifelong effort to develop optimal nosologic categories for the non-affective delusional syndromes, in the 1913 8th edition of his textbook, Kraepelin proposed a new diagnosis of paraphrenia presenting with extensive bizarre delusions and auditory hallucinations but no prominent negative symptoms or personality deterioration. He tentatively suggested it was distinct from dementia praecox (DP). His proposal was met with controversy. In an attempt to resolve this matter, Wilhelm Mayer, working with Kraepelin in Munich, published in 1921 the result of a follow-up study of the 78 cases of paraphrenia on the basis of which Kraepelin had developed his new diagnosis. In the 74 cases with adequate follow-up, Mayer's final diagnoses were 43% DP, 38% paraphrenia, and 18% other. He also presented limited family data, suggesting co-aggregation of DP and paraphrenia. On the basis of these results, Mayer argued that paraphrenia was likely better considered to represent a form of DP and not an independent disorder. His opinion was accepted by nearly all subsequent authors. Mayer's work appeared nearly a half-century before the proposal of Robin and Guze for the validation of psychiatric disorders by follow-up and family studies. The idea of deciding psychiatric questions on empirical grounds-rather than on the prestige of debating parties-is not a recent discovery but can be traced to the roots of our current diagnostic system in the work of Emil Kraepelin and his associates.

Juvenile neuropsychiatric systemic lupus erythematosus: A specific clinical phenotype and proposal of a probability score.

OBJECTIVE: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic auto-immune disease involving several organs. Neuropsychiatric (NP) SLE (NPSLE) is frequent in j-SLE and associated with increased morbidity/mortality. Although NPSLE classification criteria exist, attributing NP features to j-SLE remains a major challenge. The study objective is to thoroughly describe j-NPSLE patients and assist in their diagnosis. METHODS: This is a 4-year retrospective monocentric study of j-SLE patients. NP events were attributed to j-SLE using standardised diagnostic criteria and multidisciplinary paediatric clinical expertise. Clinical features, brain magnetic resonance imaging (MRI)s and samples analysis including cerebrospinal fluid were assessed. A risk of j-NPSLE score was developed based on multivariable logistic regression analysis. RESULTS: Of 39 patients included, 44% were identified as having j-NPSLE. J-NPSLE diagnosis was established at the onset of j-SLE in 59% of patients. In addition to frequent kidney involvement (76%) and chilblains (65%), all j-NPSLE patients displayed psychiatric features: cognitive symptoms (82%), hallucinations (76%), depressed mood (35%), acute confused state (18%) and catatonia (12%). Neurological involvement was often mild and nonspecific, with headache (53%) in about half of the patients. The main features reported on brain MRI were nonspecific T2/FLAIR white matter hyperintensities (65%), and cerebral atrophy (88%). Upon immunosuppressive treatment, clinical improvement of NP features was observed in all j-NPSLE patients. The score developed to attribute j-NPSLE probability, guide further investigations and appropriate treatments is based on hallucinations, memory, sleep and renal involvement (Sensitivity: 0.95 Specificity: 0.85). Cerebrospinal fluid (CSF) neopterin assessment increases the score sensitivity and specificity. CONCLUSION: Physicians should carefully and systematically assess the presence of NP features at diagnosis and early stages of j-SLE. For j-NPSLE patients with predominant psychiatric features, a multidisciplinary collaboration, including psychiatrists, is essential for the diagnosis, management and follow-up.

Risk for Complicated Grief After the COVID-19 Death of a Marital Partner in Late Life.

OBJECTIVE: To identify 1) complicated grief symptom clusters among acutely-bereaved older adults who have lost a spouse to COVID-19 and 2) if spousal death due to COVID-19 increased risk of developing probable PGD METHODS: Eighty adults participating in a randomized controlled trial for depression prevention (mean age [± SD] = 70.4 [6.6]) completed the Inventory of Complicated Grief, every 3 months over a maximum of 15 months. Twenty-four percent (n = 19) of participants lost a spouse to COVID-19; 76% (n = 61) lost a spouse to other causes of death. Adjusted linear regression examined the associations between COVID-19 bereavement and six symptom clusters: yearning and preoccupation, anger and bitterness, shock and disbelief, estrangement from others, hallucinations, and behavior change. RESULTS: Compared to the non-COVID-19 group, the COVID-19 bereaved group reported greater shock and disbelief, hallucinations of the deceased, and estrangement from others. COVID-19 death was also associated with higher risk for probable prolonged grief disorder (PGD) at 12 months (odds ratio = 4.38, p = 0.027). CONCLUSIONS: Older adults who have lost a spouse to COVID-19 present with specific symptoms of distress and may eventually require clinical care for PGD.

Functional connectivity in Lewy body disease with visual hallucinations.

BACKGROUND AND PURPOSE: Visual hallucinations are a common, potentially distressing experience of people with Lewy body disease (LBD). The underlying brain changes giving rise to visual hallucinations are not fully understood, although previous models have posited that alterations in the connectivity between brain regions involved in attention and visual processing are critical. METHODS: Data from 41 people with LBD and visual hallucinations, 48 with LBD without visual hallucinations and 60 similarly aged healthy comparator participants were used. Connections were investigated between regions in the visual cortex and ventral attention, dorsal attention and default mode networks. RESULTS: Participants with visual hallucinations had worse cognition and motor function than those without visual hallucinations. In those with visual hallucinations, reduced functional connectivity within the ventral attention network and from the visual to default mode network was found. Connectivity strength between the visual and default mode network correlated with the number of correct responses on a pareidolia task, and connectivity within the ventral attention network with visuospatial performance. CONCLUSIONS: Our results add to evidence of dysfunctional connectivity in the visual and attentional networks in those with LBD and visual hallucinations.