Real-time fMRI neurofeedback modulates induced hallucinations and underlying brain mechanisms.

Hallucinations can occur in the healthy population, are clinically relevant and frequent symptoms in many neuropsychiatric conditions, and have been shown to mark disease progression in patients with neurodegenerative disorders where antipsychotic treatment remains challenging. Here, we combine MR-robotics capable of inducing a clinically-relevant hallucination, with real-time fMRI neurofeedback (fMRI-NF) to train healthy individuals to up-regulate a fronto-parietal brain network associated with the robotically-induced hallucination. Over three days, participants learned to modulate occurrences of and transition probabilities to this network, leading to heightened sensitivity to induced hallucinations after training. Moreover, participants who became sensitive and succeeded in fMRI-NF training, showed sustained and specific neural changes after training, characterized by increased hallucination network occurrences during induction and decreased hallucination network occurrences during a matched control condition. These data demonstrate that fMRI-NF modulates specific hallucination network dynamics and highlights the potential of fMRI-NF as a novel antipsychotic treatment in neurodegenerative disorders and schizophrenia.

Impact of motor dysfunction on neuropsychiatric symptom profile in patients with autopsy-confirmed Alzheimer's disease.

Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer's Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer's Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Dynamic predictive templates in perception.

Hallucinations are vivid and transient experiences of objects, such as images or sounds, that occur in the absence of a corresponding stimulus.1,2,3,4,5,6,7,8,9 To understand the neurocomputational mechanisms of hallucinations, cognitive neuroscience has focused on experiments that induce false alarms (FAs) in healthy participants,1,2,3,4,5,9 psychosis-prone individuals,1,3,4 and patients diagnosed with schizophrenia.5 FAs occur when participants make decisions about difficult-to-detect stimuli and indicate the presence of a signal that was, in fact, not presented. Since FAs are, at heart, reports, they must meet two criteria to serve as an experimental proxy for hallucinations: first, FAs should reflect perceptual states that are characterized by specific contents10,11,12 (criterion 1). Second, FAs should occur on a timescale compatible with the temporal dynamics of hallucinations13,14 (criterion 2). In this work, we combined a classification image approach15 with hidden Markov models16 to show that FAs can match the perceptual and temporal characteristics of hallucinations. We asked healthy human participants to discriminate visual stimuli from noise and found that FAs were more likely to occur during an internal mode of sensory processing, a minute-long state of the brain during which perception is strongly biased toward previous experiences17 (serial dependency). Our results suggest that hallucinations are driven by dynamic predictive templates that transform noise into transient, coherent, and meaningful perceptual experiences.

Shared and distinct cortical morphometric alterations in five neuropsychiatric symptoms of Parkinson's disease.

Neuropsychiatric symptoms (including anxiety, depression, apathy, impulse-compulsive behaviors and hallucinations) are among the most common non-motor features of Parkinson's disease. Whether these symptoms should be considered as a direct consequence of the pathophysiologic mechanisms of Parkinson's disease is controversial. Morphometric similarity network analysis and epicenter mapping approach were performed on T1-weighted images of 505 patients with Parkinson's disease and 167 age- and sex-matched healthy participants from Parkinson's Progression Markers Initiative database to reveal the commonalities and specificities of distinct neuropsychiatric symptoms. Abnormal cortical co-alteration pattern in patients with neuropsychiatric symptoms was in somatomotor, vision and frontoparietal regions, with epicenters in somatomotor regions. Apathy, impulse-compulsive behaviors and hallucinations shares structural abnormalities in somatomotor and vision regions, with epicenters in somatomotor regions. In contrast, the cortical abnormalities and epicenters of anxiety and depression were prominent in the default mode network regions. By embedding each symptom within their co-alteration space, we observed a cluster composed of apathy, impulse-compulsive behaviors and hallucinations, while anxiety and depression remained separate. Our findings indicate different structural mechanisms underlie the occurrence and progression of different neuropsychiatric symptoms. Based upon these results, we propose that apathy, impulse-compulsive behaviors and hallucinations are directly related to damage of motor circuit, while anxiety and depression may be the combination effects of primary pathophysiology of Parkinson's disease and psychosocial causes.

Structural brain differences in patients with schizophrenia spectrum disorders with and without auditory verbal hallucinations.

Schizophrenia spectrum disorders (SSD) are debilitating, with auditory verbal hallucinations (AVHs) being a core characteristic. While gray matter volume (GMV) reductions are commonly replicated in SSD populations, the neural basis of AVHs remains unclear. Using previously published data, this study comprises two main analyses, one of GMV dissimilarities between SSD and healthy controls (HC), and one of GMV differences specifically associated with AVHs. Structural brain images from 71 adults with (n = 46) and without (n = 25) SSD were employed. Group differences in GMVs of the cortex, anterior cingulate (ACC), superior temporal gyrus (STG), hippocampi, and thalami were assessed. Additionally, volumes of left Heschl's gyrus (HG) in a subgroup experiencing AVHs (AVH+, n = 23) were compared with those of patients who did not (AVH-, n = 23). SSD patients displayed reduced GMVs of the cortex, ACC, STG, hippocampi, and thalami compared to HC. AVH+ had significantly reduced left HG volume when compared to AVH-. Finally, a right-lateralized ventral prefrontal cluster was found to be uniquely associated with AVH severity. This study corroborates previous findings of GMV reductions in SSD cohorts. Chiefly, our secondary analysis suggests that AVHs are associated with language areas and their contralateral homologues.

Auditory illusions and Post-traumatic stress disorder: Sound test in a case-control study.

Post-Traumatic Stress Disorder (PTSD) is a prevalent and disabling disorder with a high degree of comorbidity. Clinical studies have focused on hallucinations, which could be associated with the severity of the disorder and treatment resistance. Auditory illusions have received little attention so far, possibly because they are particularly difficult to assess. However, they may impact functioning, and underdiagnosis could impair prognosis. To provide a clearer understanding of PTSD psychopathology, this paper proposes to focus on these auditory illusions. A monocentric case-control study was conducted on 30 subjects with PTSD and 30 controls, based on an original design. False recognitions were estimated during a sound test created with a vocoder. Additionally, differences in emotional valence, dissociation, hyperarousal, and reliving were assessed. The study found that individuals with PTSD experience a higher frequency of auditory illusions compared to healthy controls (65% versus 20%, p < 0.001). Additionally, the emotional valence of these illusions was more negative in individuals with PTSD than in controls. The study also identified a correlation between dissociation symptoms, hyperarousal and reliving with auditory illusions. These findings are in line with neurobiological studies of PTSD, as well as cognitive predictive models, and support the hypothesis of a significant prevalence of auditory illusions in PTSD. Like hallucinations, auditory illusions may be influenced by dissociation. Although these results are preliminary, they suggest a need for further investigation into auditory illusions in PTSD and their effect on prognosis.

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.

Variability in white matter structure relates to hallucination proneness.

Hallucinations are a prominent transdiagnostic psychiatric symptom but are also prevalent in individuals who do not require clinical care. Moreover, persistent psychosis-like experience in otherwise healthy individuals may be related to an increased risk to transition to a psychotic disorder. This suggests a common etiology across clinical and non-clinical individuals along a multidimensional psychosis continuum that may be detectable in structural variations of the brain. The current diffusion tensor imaging study assessed 50 healthy individuals (35 females) to identify possible differences in white matter associated with hallucination proneness (HP). This approach circumvents potential confounds related to medication, hospitalization, and disease progression common in clinical individuals. We determined how HP relates to white matter structure in selected association, commissural, and projection fiber pathways putatively linked to psychosis. Increased HP was associated with enhanced fractional anisotropy (FA) in the right uncinate fasciculus, the right anterior and posterior arcuate fasciculus, and the corpus callosum. These findings support the notion of a psychosis continuum, providing first evidence of structural white matter variability associated with HP in healthy individuals. Furthermore, alterations in the targeted pathways likely indicate an association between HP-related structural variations and the putative salience and attention mechanisms that these pathways subserve.

Targeting the superior temporal gyrus with real-time fMRI neurofeedback: A pilot study of the indirect effects on self-referential processes in schizophrenia.

BACKGROUND: Individuals with schizophrenia (SZ) and auditory hallucinations (AHs) display a distorted sense of self and self-other boundaries. Alterations of activity in midline cortical structures such as the prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) during self-reference as well as in the superior temporal gyrus (STG) have been proposed as neuromarkers of SZ and AHs. METHODS: In this randomized, participant-blinded, sham-controlled trial, 22 adults (18 males) with SZ spectrum disorders (SZ or schizoaffective disorder) and frequent medication-resistant AHs received one session of real-time fMRI neurofeedback (NFB) either from the STG (n = 11; experimental group) or motor cortex (n = 11; control group). During NFB, participants were instructed to upregulate their STG activity by attending to pre-recorded sentences spoken in their own voice and downregulate it by ignoring unfamiliar voices. Before and after NFB, participants completed a self-reference task where they evaluated if trait adjectives referred to themselves (self condition), Abraham Lincoln (other condition), or whether adjectives had a positive valence (semantic condition). FMRI activation analyses of self-reference task data tested between-group changes after NFB (self>semantic, post>pre-NFB, experimental>control). Analyses were pre-masked within a self-reference network. RESULTS: Activation analyses revealed significantly (p < 0.001) greater activation increase in the experimental, compared to the control group, after NFB within anterior regions of the self-reference network (mPFC, ACC, superior frontal cortex). CONCLUSIONS: STG-NFB was associated with activity increase in the mPFC, ACC, and superior frontal cortex during self-reference. Modulating the STG is associated with activation changes in other, not-directly targeted, regions subserving higher-level cognitive processes associated with self-referential processes and AHs psychopathology in SZ. CLINICALTRIALS: GOV: Rt-fMRI Neurofeedback and AH in Schizophrenia; https://clinicaltrials.gov/study/NCT03504579.

Innovative strategies for managing hallucinations by exploring effects of tDCS on source monitoring abilities.

This randomised, crossover, sham-controlled study explored the neural basis of source-monitoring, a crucial cognitive process implicated in schizophrenia. Left superior temporal gyrus (STG) and dorsolateral prefrontal cortex (DLPFC) were the key focus areas. Thirty participants without neurological or psychological disorders underwent offline sham and active tDCS sessions with specific electrode montage targeting the left STG and DLPFC. Source-monitoring tasks, reality monitoring (Hear-Imagine), internal source-monitoring (Say-Imagine), and external source monitoring (Virtual-Real) were administered. Paired t-test and estimation statistics was performed with Graphpad version 10.1.0. The Benjamini-Hochberg procedure was employed to control the false discovery rate in multiple hypothesis testing. A significant improvement in internal source monitoring tasks (p = 0.001, Cohen's d = 0.97) was observed, but reality monitoring tasks demonstrated moderate improvement (p = 0.02, Cohen's d = 0.44). The study provides insights into the neural mechanisms of source monitoring in healthy individuals and proposes tDCS as a therapeutic intervention, laying the foundation for future studies to refine tDCS protocols and develop individualized approaches to address source monitoring deficits in schizophrenia.

Prediction, perception, and psychosis: Application of associative learning theories to schizophrenia research.

In recent years, there have been significant advances in our understanding of the positive symptoms of schizophrenia, such as hallucinations and delusions. This progress has been significantly aided by the use of associative learning-based approaches in human subjects and preclinical animal models. Here, we first review experimental research focusing on the abnormal processing of absent stimuli using three different conditioning phenomena: conditioned hallucinations, mediated conditioning, and trace conditioning. We then review studies investigating the ability to reduce focal processing of physically present but informationally redundant stimuli using habituation, latent inhibition, and blocking. The results of these different lines of research are then summarized within the framework of Wagner's (1981) standard operating procedures model, an associative learning model with explicit reference to the internal representations of both present and absent stimuli. Within this framework, the central deficit associated with positive symptoms can be described as a failure to suppress the focal processing of both absent stimuli and present but irrelevant stimuli. This can explain the wide range of results obtained in different experimental settings. Finally, we briefly discuss the role of the hippocampus and its interaction with dopaminergic transmission in the emergence of such abnormal stimulus representations and learning. Overall, we hope that the theoretical framework and empirical findings offered by the associative learning approach will continue to facilitate and integrate analyses of schizophrenia conducted at the psychological and behavioral levels on the one hand, and at the neural and molecular levels on the other, by serving as a useful interface between them. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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

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

The phenomenological nature of schizophrenia and disorder of selfhood.

Schizophrenia continues its resistance to the pathogenetic understanding. We believe that one of the reasons is an oblivion of schizophrenia's characteristic Gestalt expressive of its psychopathological structure. In this article we argue for a crucial role of disorders of selfhood in the constitution of this Gestalt. First, we present a phenomenological account of the self. This is followed by an exposition of basic complaints in schizophrenia which are reflective of a disordered selfhood and which often date back to childhood. We then present characteristic features of the schizophrenic psychosis with its phenomenon of "double bookkeeping". Hallucinations, delusions and double bookkeeping are all associated with the instability of the self. Finally, we briefly address characteristic aspects of the encounter with a schizophrenia patient and argue that self-disorders play an important diagnostic role. We conclude by emphasizing the role of phenomenology in psychiatric research.

Hallucination Proneness Alters Sensory Feedback Processing in Self-voice Production.

BACKGROUND: Sensory suppression occurs when hearing one's self-generated voice, as opposed to passively listening to one's own voice. Quality changes in sensory feedback to the self-generated voice can increase attentional control. These changes affect the self-other voice distinction and might lead to hearing voices in the absence of an external source (ie, auditory verbal hallucinations). However, it is unclear how changes in sensory feedback processing and attention allocation interact and how this interaction might relate to hallucination proneness (HP). STUDY DESIGN: Participants varying in HP self-generated (via a button-press) and passively listened to their voice that varied in emotional quality and certainty of recognition-100% neutral, 60%-40% neutral-angry, 50%-50% neutral-angry, 40%-60% neutral-angry, 100% angry, during electroencephalography (EEG) recordings. STUDY RESULTS: The N1 auditory evoked potential was more suppressed for self-generated than externally generated voices. Increased HP was associated with (1) an increased N1 response to the self- compared with externally generated voices, (2) a reduced N1 response for angry compared with neutral voices, and (3) a reduced N2 response to unexpected voice quality in sensory feedback (60%-40% neutral-angry) compared with neutral voices. CONCLUSIONS: The current study highlights an association between increased HP and systematic changes in the emotional quality and certainty in sensory feedback processing (N1) and attentional control (N2) in self-voice production in a nonclinical population. Considering that voice hearers also display these changes, these findings support the continuum hypothesis.

Effects of expectations and sensory unreliability on voice detection - A preregistered study.

The phenomenon of "hearing voices" can be found not only in psychotic disorders, but also in the general population, with individuals across cultures reporting auditory perceptions of supernatural beings. In our preregistered study, we investigated a possible mechanism of such experiences, grounded in the predictive processing model of agency detection. We predicted that in a signal detection task, expecting less or more voices than actually present would drive the response bias toward a more conservative and liberal response strategy, respectively. Moreover, we hypothesized that including sensory noise would enhance these expectancy effects. In line with our predictions, the findings show that detection of voices relies on expectations and that this effect is especially pronounced in the case of unreliable sensory data. As such, the study contributes to our understanding of the predictive processes in hearing and the building blocks of voice hearing experiences.

Hypoactivation of the language network during auditory imagery contributes to hallucinations in Schizophrenia.

Auditory verbal hallucinations (AVHs) involve perceptions, often voices, in the absence of external stimuli, and rank among the most common symptoms of schizophrenia. Metrical stress evaluation requires determination of the stronger syllable in words, and therefore requires auditory imagery, of interest for investigation of hallucinations in schizophrenia. The current functional magnetic resonance imaging study provides an updated whole-brain network analysis of a previously published study on metrical stress, which showed reduced directed connections between Broca's and Wernicke's regions of interest (ROIs) for hallucinations. Three functional brain networks were extracted, with the language network (LN) showing an earlier and shallower blood-oxygen-level dependent (BOLD) response for hallucinating patients, in the auditory imagery condition only (the reduced activation for hallucinations observed in the original ROI-based results were not specific to the imagery condition). This suggests that hypoactivation of the LN during internal auditory imagery may contribute to the propensity to hallucinate. This accords with cognitive accounts holding that an impaired balance between internal and external linguistic processes (underactivity in networks involved in internal auditory imagery and overactivity in networks involved in speech perception) contributes to our understanding of the biological underpinnings of hallucinations.

Recent social stress and severity of auditory hallucinations.

BACKGROUND AND HYPOTHESIS: Hearing voices is a common and often distressing experience for people with psychosis, and many individuals experience medication-resistant auditory verbal hallucinations (AVH). Psychosocial interventions are often employed to address distress over hearing voices. However, although links have been made between adverse social experiences and psychosis broadly, no work has yet delineated the relationship between day-to-day social stress and hallucination severity. We aimed to define that relationship in both clinical and non-clinical voice-hearers. STUDY DESIGN: A sample of 278 participants with a history of hearing voices was selected from the Yale Control Over Perceptual Experiences (COPE) Project. They were administered self-report measures of recent stress and recent auditory experiences within a cross-sectional design. Regression models were used to evaluate whether self-reported aspects of recent stress-and social stress in particular-were related to recent frequency of and distress over hearing voices. Related demographics and clinical characteristics were included as covariates. STUDY RESULTS: A significant relationship was observed between recent social stress and both recent frequency of and distress over hearing voices. While other aspects of recent stress were also related to recent distress over voices, social stressors uniquely predicted distress over voice-hearing, beyond the influence of other stressors. Depressive symptom severity was also related to distress over voices. CONCLUSIONS: Results suggest that daily social stress may be an important consideration and a potential treatment target for individuals experiencing clinical distress over auditory hallucinations.

Towards the DSM-6: Results of a Survey of Experts on the Reintroduction of First-Rank Symptoms as Core Criteria of Schizophrenia and on Redefining Hallucinations.

BACKGROUND: Diagnostic criteria for mental disorders are subject to change. This is particularly true for schizophrenia, whose diagnostic criteria in the current DSM-5 bear little resemblance to what Kraepelin once named "dementia praecox" and Bleuler termed "the schizophrenias." The present study reports results from a survey of experts on two core topics of schizophrenia: (a) whether subsequent editions of the DSM should once again give the Schneiderian first-rank symptoms (FRS; eg, thought broadcasting) the prominent role they had in the DSM-IV and (b) whether the currently quite narrow definition of hallucinations in the DSM-5 requiring them to be vivid and clear and have the full force and impact of normal perceptions should be broadened to incorporate perceptual-like phenomena that the individual can differentiate from proper perceptions but still perceives as real and externally generated. HYPOTHESIS: The aim of the survey was to learn about experts' opinions with no clear hypotheses. STUDY DESIGN: International experts on schizophrenia were recruited via various sources and invited to participate in a short online survey. The final sample comprised 136 experts with a subgroup of 53 experts with verified identity and at least 6 years of clinical and/or research experience. STUDY RESULTS: Slightly more experts voted in favor (49.3%) of returning FRS to the prominent role they had in earlier versions of the DSM than against (34.6%). Approximately four out of five experts agreed that the definition of hallucinations in the DSM should be expanded. According to the results, alongside internal symptoms that are phenomenologically indistinguishable from true perceptions, sensory intrusions that the holder is convinced were inserted from another source (ie, not self-generated) should be included in the definition. CONCLUSIONS: While a large majority of experts recommend a change in the definition of hallucinations, the experts' opinions on FRS are more mixed. We hope that this article will stimulate future studies targeting the diagnostic relevance of these symptoms and encourage discussion about the definition of core psychotic symptoms and the diagnostic criteria for the upcoming edition of the DSM.