Longitudinal thalamic white and grey matter changes associated with visual hallucinations in Parkinson's disease.

OBJECTIVE: Visual hallucinations are common in Parkinson's disease (PD) and associated with worse outcomes. Large-scale network imbalance is seen in PD-associated hallucinations, but mechanisms remain unclear. As the thalamus is critical in controlling cortical networks, structural thalamic changes could underlie network dysfunction in PD hallucinations. METHODS: We used whole-brain fixel-based analysis and cortical thickness measures to examine longitudinal white and grey matter changes in 76 patients with PD (15 hallucinators, 61 non-hallucinators) and 26 controls at baseline, and after 18 months. We compared white matter and cortical thickness, adjusting for age, gender, time-between-scans and intracranial volume. To assess thalamic changes, we extracted volumes for 50 thalamic subnuclei (25 each hemisphere) and mean fibre cross-section (FC) for white matter tracts originating in each subnucleus and examined longitudinal change in PD-hallucinators versus non-hallucinators. RESULTS: PD hallucinators showed white matter changes within the corpus callosum at baseline and extensive posterior tract involvement over time. Less extensive cortical thickness changes were only seen after follow-up. White matter connections from the right medial mediodorsal magnocellular thalamic nucleus showed reduced FC in PD hallucinators at baseline followed by volume reductions longitudinally. After follow-up, almost all thalamic subnuclei showed tract losses in PD hallucinators compared with non-hallucinators. INTERPRETATION: PD hallucinators show white matter loss particularly in posterior connections and in thalamic nuclei, over time with relatively preserved cortical thickness. The right medial mediodorsal thalamic nucleus shows both connectivity and volume loss in PD hallucinations. Our findings provide mechanistic insights into the drivers of network imbalance in PD hallucinations and potential therapeutic targets.

Auditory hallucinations activate language and verbal short-term memory, but not auditory, brain regions.

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.

Beyond imagination: Hypnotic visual hallucination induces greater lateralised brain activity than visual mental imagery.

Hypnotic suggestions can produce a broad range of perceptual experiences, including hallucinations. Visual hypnotic hallucinations differ in many ways from regular mental images. For example, they are usually experienced as automatic, vivid, and real images, typically compromising the sense of reality. While both hypnotic hallucination and mental imagery are believed to mainly rely on the activation of the visual cortex via top-down mechanisms, it is unknown how they differ in the neural processes they engage. Here we used an adaptation paradigm to test and compare top-down processing between hypnotic hallucination, mental imagery, and visual perception in very highly hypnotisable individuals whose ability to hallucinate was assessed. By measuring the N170/VPP event-related complex and using multivariate decoding analysis, we found that hypnotic hallucination of faces involves greater top-down activation of sensory processing through lateralised neural mechanisms in the right hemisphere compared to mental imagery. Our findings suggest that the neural signatures that distinguish hypnotically hallucinated faces from imagined faces lie in the right brain hemisphere.

Ninety Years of Multiple Psychotic-Like and Spiritual Experiences in a Doctor Honoris Causa: A Case Report and Literature Review.

ABSTRACT: Psychotic experiences are common experiences shared by a considerable part of the world's population. Moreover, most of the individuals who report these experiences also report those called spiritual and dissociative phenomena. In specific culture and religious backgrounds, these experiences are frequently seen as a part of normal human experiences, usually called mediumship. We report a case of a famous Brazilian medium with 90 years of experiencing psychotic-like, dissociative and/or spiritual experiences, but coped well with the experiences and never sought psychiatric or psychological assistance. The medium received several honorific prizes, such as doctor honoris causa from different institutions, published more than 200 books, and ran a nonprofit organization that takes care of 5000 people daily. Finally, we review the literature on this topic and stress the urge for more research aiming to distinguish pathological and nonpathological psychotic experiences to avoid overmedicalization and iatrogenic treatments.

Hallucination, imagery, dreaming: reassembling stimulus-independent perceptions based on Edmund Parish's classic misperception framework.

Within the broad field of human perception lies the category of stimulus-independent perceptions, which draws together experiences such as hallucinations, mental imagery and dreams. Traditional divisions between medical and psychological sciences have contributed to these experiences being investigated separately. This review aims to examine their similarities and differences at the levels of phenomenology and underlying brain function and thus reassemble them within a common framework. Using Edmund Parish's historical work as a guiding tool and the latest research findings in the cognitive, clinical and computational sciences, we consider how different perspectives may be reconciled and help generate novel hypotheses for future research. This article is part of the theme issue 'Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation'.

Postural Control and Verbal and Visual Working Memory Correlates in Nonclinical Psychosis.

INTRODUCTION: Motor and cognitive abnormalities are well documented in psychosis spectrum disorders. Evidence suggests these deficits could be pronounced because of disruptions in the cerebellar-thalamic-cortical-cerebellar (CTCC) circuit, a network thought to be heavily implicated in motor and higher cognitive functioning. Although significant research has been done on this topic in individuals with schizophrenia and those at a clinical high risk for psychosis, much less is known about deficits at the lower end of the spectrum. METHODS: In this study, we extended the understanding of motor abnormalities across the psychosis continuum by examining postural sway deficits in the nonclinical psychosis (NCP) population. Furthermore, we linked these deficits to verbal and visual working memory. High-NCP (n = 37) and low-NCP control (n = 31) participants completed an instrumental balance task, highly sensitive to subtle variations in postural sway, along with a brief working memory battery. RESULTS: We found that high-NCP participants presented with increased postural sway area (i.e., worse postural control) relative to low-NCP controls on a difficult condition (with limited proprioceptive cues), but not on an easier condition. Furthermore, results indicated that the sway area was correlated with poorer performance on working memory tasks in the high-NCP group. CONCLUSION: These findings suggest that CTCC circuit abnormalities are present across the lower end of the psychosis spectrum and that they may be contributing to a range of motor and cognitive behaviors seen in the population. However, evidence suggests that the signs are subtle, and that sensitive assessment devices and challenging conditions may be necessary for detection.

Reading characters in voices: Ratings of personality characteristics from voices predict proneness to auditory verbal hallucinations.

People rapidly make first impressions of others, often based on very little information-minimal exposure to faces or voices is sufficient for humans to make up their mind about personality of others. While there has been considerable research on voice personality perception, much less is known about its relevance to hallucination-proneness, despite auditory hallucinations being frequently perceived as personified social agents. The present paper reports two studies investigating the relation between voice personality perception and hallucination-proneness in non-clinical samples. A voice personality perception task was created, in which participants rated short voice recordings on four personality characteristics, relating to dimensions of the voice's perceived Valence and Dominance. Hierarchical regression was used to assess contributions of Valence and Dominance voice personality ratings to hallucination-proneness scores, controlling for paranoia-proneness and vividness of mental imagery. Results from Study 1 suggested that high ratings of voices as dominant might be related to high hallucination-proneness; however, this relation seemed to be dependent on reported levels of paranoid thinking. In Study 2, we show that hallucination-proneness was associated with high ratings of voice dominance, and this was independent of paranoia and imagery abilities scores, both of which were found to be significant predictors of hallucination-proneness. Results from Study 2 suggest an interaction between gender of participants and the gender of the voice actor, where only ratings of own gender voices on Dominance characteristics are related to hallucination-proneness scores. These results are important for understanding the perception of characterful features of voices and its significance for psychopathology.

Hallucinations, somatic-functional disorders of PD-DLB as expressions of thalamic dysfunction.

Hallucinations, delusions, and functional neurological manifestations (conversion and somatic symptom disorders) of Parkinson's disease (PD) and dementia with Lewy bodies increase in frequency with disease progression, predict the onset of cognitive decline, and eventually blend with and are concealed by dementia. These symptoms share the absence of reality constraints and can be considered comparable elements of the PD-dementia with Lewy bodies psychosis. We propose that PD-dementia with Lewy bodies psychotic disorders depend on thalamic dysfunction promoting a theta burst mode and subsequent thalamocortical dysrhythmia with focal cortical coherence to theta electroencephalogram rhythms. This theta electroencephalogram activity, also called fast-theta or pre-alpha, has been shown to predict cognitive decline and fluctuations in Parkinson's disease with dementia and dementia with Lewy bodies. These electroencephalogram alterations are now considered a predictive marker for progression to dementia. The resulting thalamocortical dysrhythmia inhibits the frontal attentional network and favors the decoupling of the default mode network. As the default mode network is involved in integration of self-referential information into conscious perception, unconstrained default mode network activity, as revealed by recent imaging studies, leads to random formation of connections that link strong autobiographical correlates to trivial stimuli, thereby producing hallucinations, delusions, and functional neurological disorders. The thalamocortical dysrhythmia default mode network decoupling hypothesis provides the rationale for the design and testing of novel therapeutic pharmacological and nonpharmacological interventions in the context of PD, PD with dementia, and dementia with Lewy bodies. © 2019 International Parkinson and Movement Disorder Society.

Visual hallucinations, thalamocortical physiology and Lewy body disease: A review.

One of the core diagnostic criteria for Dementia with Lewy Bodies (DLB) is the presence of visual hallucinations. The presence of hallucinations, along with fluctuations in the level of arousal and sleep disturbance, point to potential pathological mechanisms at the level of the thalamus. However, the potential role of thalamic dysfunction in DLB, particularly as it relates to the presence of formed visual hallucinations is not known. Here, we review the literature on the pathophysiology of DLB with respect to modern theories of thalamocortical function and attempt to derive an understanding of how such hallucinations arise. Based on the available literature, we propose that combined thalamic-thalamic reticular nucleus and thalamocortical pathology may explain the phenomenology of visual hallucinations in DLB. In particular, diminished α7 cholinergic activity in the thalamic reticular nucleus may critically disinhibit thalamocortical activity. Further, concentrated pathological changes within the posterior regions of the thalamus may explain the predilection for the hallucinations to be visual in nature.

Absorption and spiritual experience: A review of evidence and potential mechanisms.

Some people seem to have a 'talent' for spiritual experience: they readily sense the presence of supernatural beings, receive special messages from God, and report intense feelings of self-transcendence, awe and wonder. Here we review converging strands of evidence to argue that the trait of 'absorption' captures a general proclivity for having spiritual experiences. Participants scoring highly on the Tellegen Absorption Scale report vivid experiences of hearing God's voice during prayer, intense mystical experiences in response to psychedelics or placebo brain-stimulation, and strong feelings of presence and transcendence when confronted with natural beauty, virtual reality, or music. Several mechanisms may help to explain the relationship between absorption and spiritual experience. We suggest that absorption captures an experiential mindset that intensifies inner and outer sensory experience in ways that reflect both prior expectation and novel sensory engagement. It seems to enable that which must be imagined to feel more real.

Auditory verbal hallucination and the auditory network: From molecules to connectivity.

Auditory verbal hallucinations (AVHs) frequently occur across multiple psychiatric diseases especially in schizophrenia (SCZ) patients. Functional imaging studies have revealed the hyperactivity of the auditory cortex and disrupted auditory-verbal network activity underlying AVH etiology. This review will firstly summarize major findings from both human AVH patients and animal models, with focuses on the auditory cortex and associated cortical/sub-cortical areas. Besides mesoscale connectivity or activity data, structure and functions at synaptic level will be discussed, in conjunction with molecular mechanisms. We have summarized major findings for the pathogenesis of AVH in SCZ patients, with focuses in the auditory cortex and prefrontal cortex (PFC). Those discoveries provide explanations for AVH from different perspectives including inter-regional connectivity, local activity in specific areas, structure and functions of synapse, and potentially molecular targets. Due to the uniqueness of AVH in humans, full replica using animals seems impossible. However, we can still extract useful information from animal SCZ models based on the disruption of auditory pathway during AVH episodes. Therefore, we will further interpolate the synaptic structures and molecular targets, whose dysregulation in SCZ models may be highly related with AVH episodes. As the last part, implications for future development of treatment strategies will be discussed.

Neurofeedback of core language network nodes modulates connectivity with the default-mode network: A double-blind fMRI neurofeedback study on auditory verbal hallucinations.

BACKGROUND: The experience of auditory verbal hallucinations in schizophrenia is associated with changes in brain network function. In particular, studies indicate altered functional coupling between nodes of the language and default mode networks. Neurofeedback based on real-time functional magnetic resonance imaging (rtfMRI) can be used to modulate such aberrant network connectivity. METHODS: We investigated resting-state connectivity changes after neurofeedback (NF) in 21 patients with schizophrenia and 35 healthy individuals. All participants underwent two days of neurofeedback training of important nodes of the left-hemispheric language network including the inferior frontal gyrus (IFG) and posterior superior temporal gyrus (pSTG). In a double-blind randomized cross-over design, participants learned to down- and up-regulate their brain activation in the designated target regions based on NF. Prior to and after each training day, a resting state measurement took place. RESULTS: Coupling between nodes of the language and the default mode network (DMN) selectively increased after down-as compared to up-regulation NF. Network analyses revealed more pronounced increases in functional connectivity between nodes of the language network and the DMN in patients compared to healthy individuals. In particular, down-regulation NF led to increased coupling between nodes of the language network and bilateral inferior parietal lobe (IPL) as well as posterior cingulate cortex (PCC)/precuneus in patients. Up-regulation strengthened connectivity with the medial prefrontal cortex (mPFC). Improved well-being four weeks after the training predicted increased functional coupling between the left IFG and left IPL. CONCLUSION: Modulatory effects emerged as increased internetwork communication, indicating that down-regulation NF selectively enhances coupling between language and DM network nodes in patients with AVH. RtfMRI NF may thus be used to modulate brain network function that is relevant to the phenomenology of AVH. Specific effects of self-regulation on symptom improvement have to be explored in therapeutic interventions.

THE NEUROPHENOMENOLOGY OF OUT-OF-BODY EXPERIENCES INDUCED BY HYPNOTIC SUGGESTIONS.

Inducing out-of-body experiences in hypnosis (H-OBEs) offers an almost unique opportunity to investigate them under controlled conditions. OBEs were induced as an imaginative task in a resting condition (I-OBE) or in hypnosis (H-OBE) in a group of 15 high hypnotizable subjects. A 32-channel EEG was recorded, and the spectral power and imaginary coherence of each frequency band and each couple of electrodes were calculated. At the end of each session, the Phenomenology of Consciousness Inventory (PCI) was administered to assess the phenomenological aspects of the subjects' experience. Significantly higher scores in the altered state, positive affect altered experience, and attention subdimensions of the PCI were reported in H-OBE than in I-OBE, which were associated with a significant decrease of power in beta and gamma band activity in right parieto-temporal derivations. These results suggest that the H-OBE may offer a useful experimental model of spontaneous OBEs.

Alterations of agency in hypnosis: A new predictive coding model.

Hypnotic suggestions can lead to altered experiences of agency, reality, and memory. The present work is primarily concerned with alterations of the sense of agency (SoA) following motor suggestions. When people respond to the suggestion that their arm is rising up all by itself, they usually have a feeling of passivity for their action. The mechanisms leading to such alterations of the SoA are still controversial. We propose a theoretical model based on the framework of predictive coding: The view that the brain constantly generates hypotheses that predict sensory input at varying levels of abstraction and minimizes prediction errors either by updating its prior hypotheses-perceptual inference-or by modifying sensory input through action-active inference. We argue that suggested motor behavior and the experience of passivity accompanying it can be accounted for in terms of active inference. We propose that motor suggestions optimize both proprioceptive predictions and actual proprioceptive evidence through attentional modulation. The comparison between predicted and actual sensory evidence leads to highly precise prediction errors that call for an explanation. The motor suggestion readily supplies such an explanation by providing a prior of nonagency to the subject. We present this model in detail and discuss how it relates to, and differs from, other recent models of hypnosis. We compare its predictions with the predictions derivable from these other models. We also discuss the potential application of our predictive account to reality and memory alterations in hypnosis and offer an explanation of interindividual differences in hypnotic suggestibility. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Functional MRI study in a case of Charles Bonnet syndrome related to LHON.

INTRODUCTION: Charles Bonnet syndrome is characterized by simple or complex visual hallucinations (VH) due to damage along the visual pathways. We report a functional MRI study of brain correlates of VH in the context of a severe optic atrophy in a patient with Leber's Hereditary Optic Neuropathy (LHON). CASE REPORT: A 62-year-old man was diagnosed with LHON (11778/ND4 mtDNA mutation) after subacute visual loss in left eye (right eye was amblyopic). One month later, he experienced VH of a few seconds consisting in "moving red and blue miniature cartoons". One year later VH content changed in colored mosaic (10-15 s duration), usually stress-related, and blue and white flashes (2-5 s), triggered by unexpected auditory stimuli. Audiometry revealed mild sensorineural hearing loss. Three block design functional MRI paradigms were administrated: 1) random "clap", 2) "checkerboard" and 3) non-random "beep". After random "claps" simple flashes were evoked with bilateral activation of primary and secondary visual cortex, cuneus, precuneus and insula. Neither hallucinations nor cortex activation were registered after "checkerboard" stimulation, due to the severe visual impairment. Primary and secondary auditory cortices were "beep"-activated, without eliciting VH by non-random "beep". CONCLUSIONS: The peculiarity of our case is that VH were triggered by random auditory stimuli, possibly due to a cross-modal plasticity between visual and auditory networks, likely influenced by the sensorineural deafness. Functional alterations of both networks in resting conditions have been demonstrated in LHON patients, even without an auditory deficit. Finally, the absence of VH triggered by expected stimuli is consistent with the "expectation suppression theory", based on increased neural activations after unexpected but not by predicted events.

Reduction in lower-alpha power during Ganzfeld flicker stimulation is associated with the production of imagery and trait positive schizotypy.

Light-flicker Ganzfeld (LFG) induces a lower to upper-alpha frequency shift. However, it is unclear how this neurophysiological response might relate to LFG-induced pseudo-hallucinatory phenomena. It is also unknown whether emotional states (e.g., fear) or traits associated with risk for psychosis (e.g., proneness to perceptual anomalies, ability to produce vivid mental imagery) affect such neurophysiological and/or perceptual responses to LFG. The present study investigated alpha sub-bands during LFG across several flicker frequencies, in relation to individual differences in propensity for Ganzfeld-induced imagery (GI), positive schizotypy and trait mental imagery, and in relation to manipulations of affective state. Given previously reported sex differences in risk for psychosis and response to Ganzfeld, the effect of sex on GI was also studied. Forty-six healthy adults (16 men) completed psychometric measures of trait mental imagery and positive schizotypy before undergoing three LFG (20 min each) conditions. In each condition, participants wore white-out goggles and listened to either mood-inducing soundscapes (fear, serenity) or pink noise (control) through headphones. Greatest propensity for GI arose between 13.1 and 16.0 Hz flicker, with a peak at 16.0 Hz flicker. Occipital lower-alpha was reduced for lower flicker frequencies (13.1-16.0 Hz) and was inversely associated with GI. Upper-alpha power was not significantly related to GI or to other measures. Fear-induction was associated with reduction in alpha power, but did not significantly affect GI. Men reported more GI than women. Findings support a role for cortical destabilisation, as reflected in reduced lower-alpha, in perceptual anomalies; and, by extension, LFG as an experimental model of liability for psychosis.

Musical hallucinations, musical imagery, and earworms: A new phenomenological survey.

Musical hallucinations (MH) account for a significant proportion of auditory hallucinations, but there is a relative lack of research into their phenomenology. In contrast, much research has focused on other forms of internally generated musical experience, such as earworms (involuntary and repetitive inner music), showing that they can vary in perceived control, repetitiveness, and in their effect on mood. We conducted a large online survey (N = 270), including 44 participants with MH, asking participants to rate imagery, earworms, or MH on several variables. MH were reported as occurring less frequently, with less controllability, less lyrical content, and lower familiarity, than other forms of inner music. MH were also less likely to be reported by participants with higher levels of musical expertise. The findings are outlined in relation to other forms of hallucinatory experience and inner music, and their implications for psychological models of hallucinations discussed.

Neurofeedback-Based Enhancement of Single-Trial Auditory Evoked Potentials: Treatment of Auditory Verbal Hallucinations in Schizophrenia.

Auditory verbal hallucinations depend on a broad neurobiological network ranging from the auditory system to language as well as memory-related processes. As part of this, the auditory N100 event-related potential (ERP) component is attenuated in patients with schizophrenia, with stronger attenuation occurring during auditory verbal hallucinations. Changes in the N100 component assumingly reflect disturbed responsiveness of the auditory system toward external stimuli in schizophrenia. With this premise, we investigated the therapeutic utility of neurofeedback training to modulate the auditory-evoked N100 component in patients with schizophrenia and associated auditory verbal hallucinations. Ten patients completed electroencephalography neurofeedback training for modulation of N100 (treatment condition) or another unrelated component, P200 (control condition). On a behavioral level, only the control group showed a tendency for symptom improvement in the Positive and Negative Syndrome Scale total score in a pre-/postcomparison ( t(4) = 2.71, P = .054); however, no significant differences were found in specific hallucination related symptoms ( t(7) = -0.53, P = .62). There was no significant overall effect of neurofeedback training on ERP components in our paradigm; however, we were able to identify different learning patterns, and found a correlation between learning and improvement in auditory verbal hallucination symptoms across training sessions ( r = 0.664, n = 9, P = .05). This effect results, with cautious interpretation due to the small sample size, primarily from the treatment group ( r = 0.97, n = 4, P = .03). In particular, a within-session learning parameter showed utility for predicting symptom improvement with neurofeedback training. In conclusion, patients with schizophrenia and associated auditory verbal hallucinations who exhibit a learning pattern more characterized by within-session aptitude may benefit from electroencephalography neurofeedback. Furthermore, independent of the training group, a significant spatial pre-post difference was found in the event-related component P200 ( P = .04).

Real-time fMRI neurofeedback to down-regulate superior temporal gyrus activity in patients with schizophrenia and auditory hallucinations: a proof-of-concept study.

Neurocognitive models and previous neuroimaging work posit that auditory verbal hallucinations (AVH) arise due to increased activity in speech-sensitive regions of the left posterior superior temporal gyrus (STG). Here, we examined if patients with schizophrenia (SCZ) and AVH could be trained to down-regulate STG activity using real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF). We also examined the effects of rtfMRI-NF training on functional connectivity between the STG and other speech and language regions. Twelve patients with SCZ and treatment-refractory AVH were recruited to participate in the study and were trained to down-regulate STG activity using rtfMRI-NF, over four MRI scanner visits during a 2-week training period. STG activity and functional connectivity were compared pre- and post-training. Patients successfully learnt to down-regulate activity in their left STG over the rtfMRI-NF training. Post- training, patients showed increased functional connectivity between the left STG, the left inferior prefrontal gyrus (IFG) and the inferior parietal gyrus. The post-training increase in functional connectivity between the left STG and IFG was associated with a reduction in AVH symptoms over the training period. The speech-sensitive region of the left STG is a suitable target region for rtfMRI-NF in patients with SCZ and treatment-refractory AVH. Successful down-regulation of left STG activity can increase functional connectivity between speech motor and perception regions. These findings suggest that patients with AVH have the ability to alter activity and connectivity in speech and language regions, and raise the possibility that rtfMRI-NF training could present a novel therapeutic intervention in SCZ.