The pathophysiology of visual hallucinations in Parkinson's disease has yet to be characterized. Although stimulus-driven ("bottom-up") processes are known to be impaired, the role of "top-down" processes remains to be determined. Distinguishing between conscious and non-conscious detections (i.e. access to consciousness) may be a valuable way of monitoring top-down processes. Conscious access to visual inputs was investigated to identify the neural substrates underlying susceptibility to hallucinations in Parkinson's disease. Seventeen healthy controls, 18 Parkinson's disease patients with minor visual hallucinations and 16 without were enrolled in the study. During functional magnetic resonance imaging, the participants performed a visual detection task. The detection threshold was significantly higher in each patient group than in healthy controls while the two groups of patients did not differ significantly. Compared with hallucination-free patients, patients with minor hallucinations displayed hyperactivation of prefrontal and right occipital cortices, and hypoactivation of the left cingulate, temporal and occipital cortices. During conscious access to visual inputs, the functional network in patients with visual hallucinations differed from that seen in patients without visual hallucinations. This suggests that the supremacy of top-down processes in visual information processing may enhance susceptibility to hallucinations in Parkinson's disease.

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.

Visual hallucinations can be phenomenologically divided into those of a simple or complex nature. Both simple and complex hallucinations can occur in pathological and non-pathological states, and can also be induced experimentally by visual stimulation or deprivation-for example using a high-frequency, eyes-open flicker (Ganzflicker) and perceptual deprivation (Ganzfeld). Here we leverage the differences in visual stimulation that these two techniques involve to investigate the role of bottom-up and top-down processes in shifting the complexity of visual hallucinations, and to assess whether these techniques involve a shared underlying hallucinatory mechanism despite their differences. For each technique, we measured the frequency and complexity of the hallucinations produced, utilising button presses, retrospective drawing, interviews, and questionnaires. For both experimental techniques, simple hallucinations were more common than complex hallucinations. Crucially, we found that Ganzflicker was more effective than Ganzfeld at eliciting simple hallucinations, while complex hallucinations remained equivalent across the two conditions. As a result, the likelihood that an experienced hallucination was complex was higher during Ganzfeld. Despite these differences, we found a correlation between the frequency and total time spent hallucinating in Ganzflicker and Ganzfeld conditions, suggesting some shared mechanisms between the two methodologies. We attribute the tendency to experience frequent simple hallucinations in both conditions to a shared low-level core hallucinatory mechanism, such as excitability of visual cortex, potentially amplified in Ganzflicker compared to Ganzfeld due to heightened bottom-up input. The tendency to experience complex hallucinations, in contrast, may be related to top-down processes less affected by visual stimulation.

Evidence from behavioral, electrophysiological and diffusion-weighted imaging studies suggest that schizophrenia patients suffer from deficiencies in bilateral brain communication, and this disruption may be related to the occurrence of auditory verbal hallucinations (AVH). To increase our understanding of aberrant inter-hemispheric communication in relation to AVH, we recruited two groups of first-episode schizophrenia patients: one group with AVH (N = 18 AVH patients) and one without hallucinations (N = 18 Non-AVH patients), and 20 healthy controls. All participants received T1 structural imaging and resting-state fMRI scanning. We adopted a newly developed index, voxel-mirrored homotopic connectivity (VMHC), to quantitatively describe bilateral functional connectivity. The whole-brain VMHC measure was compared among the three groups and correlation analyses were conducted between symptomology scores and neurological measures. Our findings suggest all patients shared abnormalities in parahippocampus and striatum. Aberrant bilateral connectivity of default mode network (DMN), inferior frontal gyrus and cerebellum only showed in AVH patients, whereas aberrances in superior temporal gyrus and precentral gyrus were specific to Non-AVH patients. Meanwhile, inter-hemispheric connectivity of DMN correlated with patients' symptomatology scores. This study corroborates that schizophrenia is characterized by inter-hemispheric dysconnectivity, and suggests the localization of such abnormalities may be crucial to whether auditory verbal hallucinations develop.

Our understanding of the neural correlates of auditory-verbal-hallucinations (AVH) has substantially increased during the last few years, but is far from sufficient. One current hypothesis, the interhemispheric miscommunication theory, is based on findings from fMRI, DTI and EEG, but there is only limited evidence so far concerning underlying functional coupling mechanisms. Here we report a 64-channel EEG study using lagged phase synchronization analysis and eLORETA source estimation to examine the functional connectivity between bilateral auditory cortices in the gamma-band in 26 schizophrenia patients (13 with and 13 without AVH) and 26 matched healthy controls (HC) while performing a dichotic listening task. We found a significantly reduced right-ear-advantage (REA) in AVH but not in non-AVH patients compared to HC. The major finding was significantly stronger gamma-band connectivity between bilateral auditory cortices during conscious perception of left (versus right) ear syllables in patients with AVH compared to HC and patients without AVH. A significant positive correlation was found between this connectivity alteration and the AVH symptom score in schizophrenia patients. These findings provide further support for the interhemispheric miscommunication hypothesis of AVH pathophysiology by indicating that aberrant gamma-band coupling between auditory cortices is related to the emergence of AVH in schizophrenia.

Auditory verbal hallucinations (AVH, 'hearing voices') are an important symptom of schizophrenia but their biological basis is not well understood. One longstanding approach proposes that they are perceptual in nature, specifically that they reflect spontaneous abnormal neuronal activity in the auditory cortex, perhaps with additional 'top down' cognitive influences. Functional imaging studies employing the symptom capture technique-where activity when patients experience AVH is compared to times when they do not-have had mixed findings as to whether the auditory cortex is activated. Here, using a novel variant of the symptom capture technique, we show that the experience of AVH does not induce auditory cortex activation, even while real speech does, something that effectively rules out all theories that propose a perceptual component to AVH. Instead, we find that the experience of AVH activates language regions and/or regions that are engaged during verbal short-term memory.

Auditory verbal hallucinations (AVH) in patients with schizophrenia are linked to abnormalities within a large cerebral network including frontal and temporal regions. Whilst abnormalities of frontal speech production and temporal speech perception regions have been extensively studied, alterations of the dorsolateral prefrontal cortex (DLPFC), a region critically involved in the pathophysiology of schizophrenia, have rarely been studied in relation to AVH. Using 1.5 T proton magnetic resonance spectroscopy, this study examined the relationship between right and left DLPFCs N-AcetylAspartate (NAA) levels and the severity of AVH in patients with schizophrenia. Twenty-seven male patients with schizophrenia were enrolled in this study, 15 presented daily treatment-resistant AVH (AVH+) and 12 reported no AVH (no-AVH). AVH+ patients displayed higher NAA levels in the right DLPFC than no-AVH patients (p = 0.033). In AVH+ patients, NAA levels were higher in the right DLPFC than in the left (p = 0.024). No difference between the right and left DLPFC was observed in no-AVH patients. There was a positive correlation between NAA levels in the right DLPFC and the severity of AVH (r = 0.404, p = 0.037). Despite limited by magnetic field strength, these results suggest that AVH may be associated with increased NAA levels in the right DLPFC in schizophrenia.

Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods across two unique samples to characterize the patterns of symptom organization. We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) participants from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all participants, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. MDS revealed relationships between items of SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 SANS clusters (asocial and apathy, speech and affect). Those reality distortion items which were furthest from auditory hallucinations had very weak to no relationship with hallucination severity. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes do not. This has important implications, not only for treatment, but also for research-particularly efforts to understand the neurocomputational and pathophysiological mechanism underlying delusions and hallucinations.

Auditory working memory impairments feature prominently in schizophrenia. However, the existence of altered and perhaps compensatory neural dynamics, sub-serving auditory working memory, remains largely unexplored. We compared the dynamics of induced high gamma power (iHGP) across cortex in humans during speech-sound working memory in individuals with schizophrenia (SZ) and healthy comparison subjects (HC) using magnetoencephalography (MEG). SZ showed similar task performance to HC while utilizing different brain regions. During encoding of speech sounds, SZ lacked the correlation of iHGP with task performance in posterior superior temporal gyrus (STGp) that was observed in healthy subjects. Instead, SZ recruited the visual word form area (VWFA) during both stimulus encoding and response preparation. Importantly, VWFA activity during encoding correlated with the magnitude of SZ hallucinations, task performance and an independent measure of verbal working memory. These findings suggest that VWFA plasticity is harnessed to compensate for STGp dysfunction in schizophrenia patients with hallucinations.

The ergot alkaloid ergotamine is produced by Claviceps purpurea, a parasitic fungus that commonly infects crops and pastures of high agricultural and economic importance. In humans and livestock, symptoms of ergotism include necrosis and gangrene, high blood pressure, heart rate, thermoregulatory dysfunction and hallucinations. However, ergotamine is also used in pharmaceutical applications to treat migraines and stop post-partum hemorrhage. To define its effects, metabolomic profiling of the brain was undertaken to determine pathways perturbed by ergotamine treatment. Metabolomic profiling identified the brainstem and cerebral cortex as regions with greatest variation. In the brainstem, dysregulation of the neurotransmitter epinephrine, and the psychoactive compound 2-arachidonylglycerol was identified. In the cerebral cortex, energy related metabolites isobutyryl-L-carnitine and S-3-oxodecanoyl cysteamine were affected and concentrations of adenylosuccinate, a metabolite associated with mental retardation, were higher. This study demonstrates, for the first time, key metabolomic pathways involved in the behavioural and physiological dysfunction of ergot alkaloid intoxicated animals.

Although chatbots such as ChatGPT can facilitate cost-effective text generation and editing, factually incorrect responses (hallucinations) limit their utility. This study evaluates one particular type of hallucination: fabricated bibliographic citations that do not represent actual scholarly works. We used ChatGPT-3.5 and ChatGPT-4 to produce short literature reviews on 42 multidisciplinary topics, compiling data on the 636 bibliographic citations (references) found in the 84 papers. We then searched multiple databases and websites to determine the prevalence of fabricated citations, to identify errors in the citations to non-fabricated papers, and to evaluate adherence to APA citation format. Within this set of documents, 55% of the GPT-3.5 citations but just 18% of the GPT-4 citations are fabricated. Likewise, 43% of the real (non-fabricated) GPT-3.5 citations but just 24% of the real GPT-4 citations include substantive citation errors. Although GPT-4 is a major improvement over GPT-3.5, problems remain.

Are synaesthetic experiences congenital and so hard-wired, or can a functional analogue be created? We induced an equivalent of form-colour synaesthesia using hypnotic suggestions in which symbols in an array (circles, crosses, squares) were suggested always to have a certain colour. In a Stroop type-naming task, three of the four highly hypnotizable participants showed a strong synaesthesia-type association between symbol and colour. This was verified both by their subjective reports and objective eye-movement behaviour. Two resembled a projector- and one an associator-type synaesthete. Participant interviews revealed that subjective experiences differed somewhat from typical (congenital) synaesthesia. Control participants who mimicked the task using cognitive strategies showed a very different response pattern. Overall, the results show that the targeted, preconsciously triggered associations and perceptual changes seen in association with congenital synaesthesia can rapidly be induced by hypnosis. They suggest that each participant's subjective experience of the task should be carefully evaluated, especially when studying hypnotic hallucinations. Studying such experiences can increase understanding of perception, automaticity, and awareness and open unique opportunities in cognitive neuroscience and consciousness research.

Patients with schizophrenia (ScZ) often show impairments in auditory information processing. These impairments have been related to clinical symptoms, such as auditory hallucinations. Some researchers have hypothesized that aberrant low-frequency oscillations contribute to auditory information processing deficits in ScZ. A paradigm for which modulations in low-frequency oscillations are consistently found in healthy individuals is the auditory continuity illusion (ACI), in which restoration processes lead to a perceptual grouping of tone fragments and a mask, so that a physically interrupted sound is perceived as continuous. We used the ACI paradigm to test the hypothesis that low-frequency oscillations play a role in aberrant auditory information processing in patients with ScZ (N = 23). Compared with healthy control participants we found that patients with ScZ show elevated continuity illusions of interrupted, partially-masked tones. Electroencephalography data demonstrate that this elevated continuity perception is reflected by diminished 3 Hz power. This suggests that reduced low-frequency oscillations relate to elevated restoration processes in ScZ. Our findings support the hypothesis that aberrant low-frequency oscillations contribute to altered perception-related auditory information processing in ScZ.

The Right Ear Advantage effect (REA) was explored in a white noise speech illusion paradigm: binaural white noise (WN) could be presented i) in isolation (WN condition), ii) overlapped to a voice pronouncing the vowel /a/ presented in the left ear (LE condition), iii) overlapped to a voice pronouncing the vowel /a/ presented in the right ear (RE condition). Participants were asked to report in which ear the voice has been perceived. The voice could be female or male, and it could be presented at 4 different intensities. Participants carried out the task correctly both in LE and in RE conditions. Importantly, in the WN condition the "right ear" responses were more frequent with respect to both the chance level and the "left ear" responses. A perceptual REA was confirmed both in LE and RE conditions. Moreover, when the voice was presented at low intensities (masked by WN), it was more frequently reported in the right than in the left ear ("illusory" REA). A positive correlation emerged between perceptual and illusory REA. Potential links of the REA effects with auditory hallucinations are discussed.

Studies comparing gray matter (GM) volume of schizophrenic patients with or without auditory verbal hallucinations (AVHs) to that of normal controls remain controversial. This project aims to investigate changes of GM volumes of drug-naïve schizophrenic patients with and without AVHs. Eighteen first episode schizophrenic (FES) patients with AVHs, 18 FES patients without AVHs, and 18 healthy controls were scanned using structural MRI. Voxel-based morphometry (VBM) analysis was conducted to investigate changes of GM volume among the three groups. Patients with and without AVHs exhibited reduced GM volumes relative to normal controls in the left superior temporal gyrus, frontal regions, cerebellum and caudate. Further analysis of the GM of subcortical structures found that patients with AVHs had reduced thalamic volume than healthy controls. No significant difference was found between patients with and without AVHs. Significant correlation was found between the total scores of the Positive and Negative Syndrome Scale and bilateral thalamic volume. ROC analysis of thalamic volumes of the patients with AVHs and normal controls showed that the area under the curve was 0.698 (P = 0.043). The decreased thalamic volumes might serve as a biomarker for discriminating FES AVHs patients from normals.

The default mode network (DMN) is suggested to play a pivotal role in schizophrenia; however, the dissociation pattern of functional connectivity of DMN subsystems remains uncharacterized in this disease. In this study, resting-state fMRI data were acquired from 55 schizophrenic patients and 53 matched healthy controls. DMN connectivity was estimated from time courses of independent components. The lateral DMN exhibited decreased connectivity with the unimodal sensorimotor cortex but increased connectivity with the heteromodal association areas in schizophrenics. The increased connectivity between the lateral DMN and right control network was significantly correlated with negative and anergia factor scores in the schizophrenic patients. The anterior and posterior DMNs exhibited increased and decreased connectivity with the right control and lateral visual networks, respectively, in schizophrenics. The altered DMN connectivity may underlie the hallucinations, delusions, thought disturbances, and negative symptoms involved in schizophrenia. Furthermore, DMN connectivity patterns could be used to differentiate patients from controls with 76.9% accuracy. These findings may shed new light on the distinct role of DMN subsystems in schizophrenia, thereby furthering our understanding of the pathophysiology of schizophrenia. Elucidating key disease-related DMN subsystems is critical for identifying treatment targets and aiding in the clinical diagnosis and development of treatment strategies.

Alzheimer's disease (AD) is a chronic neurodegenerative disease with significant financial costs and negative impacts on quality of life. Psychotic symptoms, i.e., the presence of delusions and/or hallucinations, is a frequent complication of AD. About 50% of AD patients will develop psychotic symptoms (AD with Psychosis, or AD + P) and these patients will experience an even more rapid cognitive decline than AD patients without psychosis (AD-P). In a previous analysis on medication records of 776 AD patients, we had shown that use of Vitamin D was associated with delayed time to psychosis in AD patients and Vitamin D was used more by AD-P than AD + P patients. To explore the potential molecular mechanism behind our findings, we applied systems pharmacology approaches to investigate the crosstalk between AD and psychosis. Specifically, we built protein-protein interaction (PPI) networks with proteins encoded by AD- and psychosis-related genes and Vitamin D-perturbed genes. Using network analysis we identified several high-impact genes, including NOTCH4, COMT, CACNA1C and DRD3 which are related to calcium homeostasis. The new findings highlight the key role of calcium-related signaling pathways in AD + P development and may provide a new direction and facilitate hypothesis generation for future drug development.

Psychosis is the most common neuropsychiatric side-effect of dopaminergic therapy in Parkinson's disease (PD). It is still unknown which factors determine individual proneness to psychotic symptoms. Schizotypy is a multifaceted personality trait related to psychosis-proneness and dopaminergic neurotransmission in healthy subjects. We investigated whether (1) PD patients exhibit lower schizotypy than controls and (2) dopamine-related neuropsychiatric side-effects can be predicted by higher schizotypy. In this cross-sectional study, we used the Oxford-Liverpool Inventory of Feelings and Experiences in 56 PD patients (12 women, mean ± sd age: 61 ± 11 years) receiving their usual dopaminergic medication and 32 age-matched healthy controls (n = 32; 18 women, mean ± sd age: 57 ± 6 years). We further compared schizotypy scores of patients with (n = 18, 32.1%) and without previously experienced psychosis. We found that patients exhibited lower schizotypy than controls. Further, patients with a history of psychosis exhibited higher schizotypy than patients without these symptoms. Using an information theoretic measure and a machine learning approach, we show that schizotypy yields the greatest predictive value for dopamine-associated hallucinations compared to other patient characteristics and disease related factors. Our results indicate an overlap between neural networks associated with schizotypy and the pathophysiology of PD and a relationship between schizotypy and psychotic side-effects of dopaminergic medication.

Large language models (LLMs) have shown potential in various applications, including clinical practice. However, their accuracy and utility in providing treatment recommendations for orthopedic conditions remain to be investigated. Thus, this pilot study aims to evaluate the validity of treatment recommendations generated by GPT-4 for common knee and shoulder orthopedic conditions using anonymized clinical MRI reports. A retrospective analysis was conducted using 20 anonymized clinical MRI reports, with varying severity and complexity. Treatment recommendations were elicited from GPT-4 and evaluated by two board-certified specialty-trained senior orthopedic surgeons. Their evaluation focused on semiquantitative gradings of accuracy and clinical utility and potential limitations of the LLM-generated recommendations. GPT-4 provided treatment recommendations for 20 patients (mean age, 50 years ± 19 [standard deviation]; 12 men) with acute and chronic knee and shoulder conditions. The LLM produced largely accurate and clinically useful recommendations. However, limited awareness of a patient's overall situation, a tendency to incorrectly appreciate treatment urgency, and largely schematic and unspecific treatment recommendations were observed and may reduce its clinical usefulness. In conclusion, LLM-based treatment recommendations are largely adequate and not prone to 'hallucinations', yet inadequate in particular situations. Critical guidance by healthcare professionals is obligatory, and independent use by patients is discouraged, given the dependency on precise data input.

The recommended antiviral drugs available for the treatment and prevention of influenza are neuraminidase inhibitors (NAIs). The aim of this study was to evaluate age-related clinical manifestations of adverse events (AEs) related to NAIs. FAERS and WebMD data were downloaded. The available NAIs selected for the analysis were oseltamivir, peramivir, zanamivir, and laninamivir. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), and the information component (IC) methods. In total, 16729 AEs from 4598 patients and 575 AEs from 440 patients in the FAERS and WebMD, respectively, were included in the analysis. In the FAERS, AEs were more common among those who were younger (<19 years) for zanamivir, while for those who were older (>65 years) for peramivir. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. Psychiatric disorders were most common in younger and older patients, while gastrointestinal disorders were most common in adult given oseltamivir in the WebMD. Adverse symptoms related to NAIs varied and depended on the drugs used and the age of the patient.