Prodromal period of psychosis: diagnostic criteria.

OBJECTIVE: Aim: To study the psychopathological mechanisms of the development of the prodromal stage of psychosis in order to identify risk factors for the formation of psychosis. PATIENTS AND METHODS: Materials and Methods: In this research 137 patients with newly diagnosed psychosis were examined: 65 patients with a diagnosis of paranoid schizophrenia; 72 patients - with a diagnosis of acute polymorphic psychotic disorder. RESULTS: Results: According to the analysis of symptoms using the PANSS, the absence of signs of an anxious state, conceptual disorganization of thinking, emotional withdrowal are reliable signs of PPP in PS, and unusual thought content, absence of signs of stereotyped thinking, tension, anxiety, and hallucinations are reliable signs of PPP in APPD. According to the analysis of symptoms using the SOPS, unusual thought content/delusional ideas, bizarre thinking, social anhedonia, suspiciousness/persecutory ideas, decrease in expressiveness of emotions are reliable signs of PPP in PS, and bizarre thinking, impaired tolerance to normal stress, sleep disturbance, perceptual abnormalities/hallucinations, trouble with focus and attention are reliable signs of PPP in APPD. CONCLUSION: Conclusions: In the process of studying the clinical-psychopathological and pathopsychological aspects of the development of the PPP, a number of risk factors for the formation of psychosis were identified. We found that he most important diagnostic signs of PPP in PS patients are: stereotyped thinking, social isolation, disorganizational thinking disorders, passive-apathetic social detachment, suspiciousness. The most informative prodromal symptoms of HP in PS patients are: conceptual disorganization of thinking, bizzare thinking, social isolation, suspiciousness/persecutory ideas, reduced expression of emotions.

Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p<0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p<0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study.

Background: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer's disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use. Objective: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population. Methods: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms. Results: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function. Conclusions: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP.

Eight-month intensive meditation-based intervention improves refractory hallucinations and delusions and quality of life in male inpatients with schizophrenia: a randomized controlled trial.

AIM: This study investigated the impact of an 8-month daily-guided intensive meditation-based intervention (iMI) on persistent hallucinations/delusions and health-related quality of life (QoL) in male inpatients with schizophrenia with treatment-refractory hallucinations and delusions (TRHDs). METHODS: A randomized controlled trial assigned 64 male inpatients with schizophrenia and TRHD equally to an 8-month iMI plus general rehabilitation program (GRP) or GRP alone. Assessments were conducted at baseline and the third and eighth months using the Positive and Negative Syndrome Scale (PANSS), 36-Item Short Form-36 (SF-36), and Five Facet Mindfulness Questionnaire (FFMQ). Primary outcomes measured PANSS reduction rates for total score, positive symptoms, and hallucinations/delusions items. Secondary outcomes assessed PANSS, SF-36, and FFMQ scores for psychotic symptoms, health-related QoL, and mindfulness skills, respectively. RESULTS: In the primary outcome, iMI significantly improved the reduction rates of PANSS total score, positive symptoms, and hallucination/delusion items compared with GRP at both the third and eighth months. Treatment response rates (≥25% reduction) for these measures significantly increased in the iMI group at the eighth month. Concerning secondary outcomes, iMI significantly reduced PANSS total score and hallucination/delusion items, while increasing scores in physical activity and mindfulness skills at both the third and eighth months compared with GRP. These effects were more pronounced with an 8-month intervention compared with a 3-month intervention. CONCLUSIONS: An iMI benefits patients with TRHDs by reducing persistent hallucinations/delusions and enhancing health-related QoL. Longer iMI duration yields superior treatment outcomes.

Psychopathology and psychosocial functioning among young people with first-episode psychosis and/or first-presentation borderline personality disorder.

BACKGROUND: One in five young people with first-episode psychosis (FEP) also presents with borderline personality disorder (BPD) features. Among people diagnosed with BPD, auditory verbal hallucinations occur in 29-50 % and delusions in 10-100 %. Co-occurrence of psychotic symptoms and BPD is associated with greater clinical severity and greater difficulty accessing evidence based FEP care. This study aimed to investigate psychotic symptoms and psychosocial functioning among young people presenting to an early intervention mental health service. METHOD: According to the presence or absence of either FEP or BPD, 141 participants, aged 15-25 years, were assigned to one of four groups: FEP, BPD, combined FEP + BPD, or clinical comparison (CC) participants with neither FEP nor BPD. Participants completed semi-structured diagnostic interviews and interviewer and self-report measures of psychopathology and psychosocial functioning. RESULTS: The FEP + BPD group had significantly more severe psychopathology and poorer psychosocial functioning than the FEP group on every measure, apart from intensity of hallucinations. Comparing the FEP or BPD groups, the BPD group had greater psychopathology, apart from intensity of psychotic symptoms, which was significantly greater in the FEP group. These two groups did not significantly differ in their overall psychosocial functioning. Compared with CC young people, both the FEP + BPD and BPD groups differed significantly on every measure, with medium to large effect sizes. CONCLUSIONS: Young people with co-occurring FEP and BPD experience more severe difficulties than young people with either diagnosis alone. This combination of psychosis and severe personality pathology has been longitudinally associated with poorer outcomes among adults and requires specific clinical attention.

Interplay between childhood trauma, bodily self-disturbances, and clinical phenomena in schizophrenia spectrum disorders: A network analysis.

BACKGROUND: Bodily self-disturbances have long been considered central to schizophrenia. Exposure to childhood trauma has been linked to the development of both psychosis and bodily self-disturbances, yet little work has examined the role of bodily self-disturbances in the relationship between childhood trauma and schizophrenia symptomatology. This study uses network analysis to bridge this gap. METHODS: Networks were constructed to examine relationships between schizophrenia symptoms (Positive and Negative Symptom Scale; PANSS), bodily self-disturbances (Perceptual Aberration Scale; PAS), and self-reported exposure to childhood trauma (Childhood Trauma Questionnaire, Short-Form; CTQ-SF) in 152 people with a schizophrenia-spectrum disorder. Shortest path and bridge analyses were conducted to assess the role of bodily self-disturbances in linking childhood trauma to schizophrenia symptomatology. Three networks were constructed: 1) PAS, childhood trauma, and PANSS sub-scale composites (positive, negative, general); 2) PAS, childhood trauma, and positive symptoms, 3) PAS, childhood trauma, and distress symptoms. RESULTS: Shortest path analysis revealed that bodily self-disturbances were on the shortest path between childhood trauma and positive and general symptoms (Network 1), between trauma and hallucinations (Network 2), and between trauma and depression (Network 3). Bodily self-disturbances were also found to serve as a bridge between childhood trauma and positive symptoms of schizophrenia, particularly delusions and hallucinations. CONCLUSIONS: Using a novel, data-driven approach, we showed that bodily self-disturbances play a key role in linking childhood trauma to positive and co-morbid affective symptoms of schizophrenia. Threat experiences (i.e., abuse) specifically relate to bodily self-disturbances and psychotic symptoms.

Sleep-Related Hallucinations.

The diagnostic category of sleep-related hallucinations (SRH) replaces the previous category of Terrifying Hypnagogic Hallucinations in the 2001 edition of International Classification of Sleep Disorders-R. Hypnagogic and hypnopompic hallucinations (HHH) that occur in the absence of other symptoms or disorder and, within the limits of normal sleep, are most likely non-pathological. By contrast, complex nocturnal visual hallucinations (CNVH) may reflect a dimension of psychopathology reflecting different combinations of etiologic influences. The identification and conceptualization of CNVH is relatively new, and more research is needed to clarify whether CNVH share common mechanisms with HHH.

Abnormal effective connectivity of reward network in first-episode schizophrenia with auditory verbal hallucinations.

OBJECTIVE: Auditory verbal hallucinations (AVHs) in schizophrenia is proved to be associated with dysfunction of mesolimbic-cortical circuits, especially during abnormal salient and internal verbal resource monitoring processing procedures. However, the information flow among areas involved in coordinated interaction implicated the pathophysiology of AVHs remains unclear. METHODS: We used spectral dynamic causal modeling (DCM) to quantify connections among eight critical hubs of reward network in 86 first-episode drug-naïve schizophrenia patients with AVHs (AVH), 93 patients without AVHs (NAVH), and 88 matched normal controls (NC) using resting-state functional magnetic resonance imaging. Group-level connection coefficients, between-group differences and correlation analysis between image measures and symptoms were performed. RESULT: DCM revealed weaker effective connectivity (EC) from right ventral striatum (RVS) to ventral tegmental area (VTA) in AVH compared to NAVH. AVH showed stronger EC from left anterior insula (AI) to RVS, stronger EC from RVS to anterior cingulate cortex (ACC), and stronger EC from VTA to posterior cingulate cortex (PCC) compared to NC. The correlation analysis results were mostly visible in the negative correlation between EC from right AI to ACC and positive sub-score, P1 sub-score, and P3 sub-score of PNASS in group-level. CONCLUSION: These findings suggest that neural causal interactions between the reward network associated with AVHs are disrupted, expanding the evidence for potential neurobiological mechanisms of AVHs. Particularly, dopamine-dependent salience attribution and top-down monitoring impairments and compensatory effects of enhanced excitatory afferents to ACC, which may provide evidence for a therapeutic target based on direct in vivo of AVHs in schizophrenia.

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.

Visual hallucinations induced by Ganzflicker and Ganzfeld differ in frequency, complexity, and content.

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.

Casting shadows of perception: An exploration of visual hallucinations.

ABSTRACT: Hallucinations can be caused by biological, psychological, neurological, ophthalmological, and environmental factors. This article discusses a selection of the various conditions that can present with visual disturbances and hallucinations including schizophrenia, HIV, neurosyphilis, hyperammonemia, migraine, substance use, brain tumors, sleep disturbances, thyroid disorders, delirium, ophthalmologic conditions, and Lewy body dementia, providing an overview of the differential diagnosis of visual hallucinations. The mechanisms by which these conditions can lead to hallucinations are also discussed, and insight into the recommended medical workup for each is provided.

The Diagnostic Spectrum of Sexual Hallucinations.

ABSTRACT: Sexual hallucinations are little known, yet often extremely burdening, phenomena. In this systematic review, we summarize what is known about their phenomenology, prevalence, etiopathology, ensuing distress, and treatment options. Sexual hallucinations can be experienced as genital or orgasmic sensations, although other sensory modalities can also be involved. With the notable exception of orgasmic auras in the context of epilepsy, sexual hallucinations tend to be distressing and embarrassing in nature. Our analysis of 79 studies (together describing 390 patients) indicates that sexual hallucinations are more frequent in women than in men, with a sex ratio of 1.4:1, and that they are most prevalent in schizophrenia spectrum disorders, with rates ranging from 1.4% in recently admitted patients to 44% in chronically hospitalized patients. Other underlying conditions include epilepsy, the incubus phenomenon (possibly the most prevalent cause in the general population, associated with sleep paralysis), narcolepsy, and sedative use. As regards the sedative context, we found more medicolegal than purely medical cases, which sadly underlines that not all sexually explicit sensations experienced in anesthesia practice are indeed hallucinations. In the absence of evidence-based treatment protocols for sexual hallucinations, practice-based guidelines tend to focus on the underlying condition. Further research is needed, especially in the fields of substance abuse, posttraumatic stress disorder, and borderline personality disorder, where only anecdotal information on sexual hallucinations is available. Moreover, awareness of sexual hallucinations among health professionals needs to be improved in order to facilitate counseling, diagnosis, and treatment.

Temporal hyper-connectivity and frontal hypo-connectivity within gamma band in schizophrenia: A resting state EEG study.

OBJECTIVE: The brain network serves as the physiological foundation for information processing of the brain. Many studies have reported abnormalities of gamma oscillations in Schizophrenia. The aim of this study was to investigate the gamma-band connectivity in Schizophrenia patients. METHODS: We recorded the resting state electroencephalogram (EEG) for 15 schizophrenia patients with refractory auditory hallucinations and 14 healthy controls, with eyes open and closed. The brain network was constructed based on weighted phase lag index for gamma band. Whole scalp metrics (clustering coefficient, global efficiency and local efficiency) and local region metrics (degree and betweenness centrality) in the frontal and temporal lobes were computed. Correlation analyses between network metrics and symptom scales were examined to find associations with symptom severity. RESULTS: Schizophrenia patients had larger global efficiency and local efficiency (p < 0.05) with eyes closed, probably representing greater brain activity and information exchange. For degree and betweenness centrality, schizophrenia patients showed an increase (p < 0.05) in the temporal lobe but a decrease (p < 0.05) in the frontal lobe with eyes closed and open, potentially account for the patients' symptoms such as hallucinations and thought disorders. Local efficiency and frontal lobe degree were positively and negatively correlated with the scales, respectively (both p < 0.05). CONCLUSIONS: Altered connectivity of the resting state brain network has been revealed and may be associated with the core symptoms of schizophrenia. Our study provides promising evidence for the investigation of the pathological basis of Schizophrenia and could aid in objective diagnosis.

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.

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.

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.