fMRI capture of auditory hallucinations: Validation of the two-steps method.

Our purpose was to validate a reliable method to capture brain activity concomitant with hallucinatory events, which constitute frequent and disabling experiences in schizophrenia. Capturing hallucinations using functional magnetic resonance imaging (fMRI) remains very challenging. We previously developed a method based on a two-steps strategy including (1) multivariate data-driven analysis of per-hallucinatory fMRI recording and (2) selection of the components of interest based on a post-fMRI interview. However, two tests still need to be conducted to rule out critical pitfalls of conventional fMRI capture methods before this two-steps strategy can be adopted in hallucination research: replication of these findings on an independent sample and assessment of the reliability of the hallucination-related patterns at the subject level. To do so, we recruited a sample of 45 schizophrenia patients suffering from frequent hallucinations, 20 schizophrenia patients without hallucinations and 20 matched healthy volunteers; all participants underwent four different experiments. The main findings are (1) high accuracy in reporting unexpected sensory stimuli in an MRI setting; (2) good detection concordance between hypothesis-driven and data-driven analysis methods (as used in the two-steps strategy) when controlled unexpected sensory stimuli are presented; (3) good agreement of the two-steps method with the online button-press approach to capture hallucinatory events; (4) high spatial consistency of hallucinatory-related networks detected using the two-steps method on two independent samples. By validating the two-steps method, we advance toward the possible transfer of such technology to new image-based therapies for hallucinations. Hum Brain Mapp 38:4966-4979, 2017. © 2017 Wiley Periodicals, Inc.

Network dynamics during the different stages of hallucinations in schizophrenia.

The majority of patients with schizophrenia suffer from hallucinations. While the triple-network model, which includes the default mode network (DMN), the central executive network (CEN) and the salience network (SAL), has recently been applied to schizophrenia, how this framework could explain the emergence of hallucinations remains unclear. Therefore, complementary brain regions that have been linked to hallucinations, such as the left hippocampus, should also be considered and added to this model. Accordingly, the present study explored the effective connectivity across these four components (i.e., the quadripartite model) during the different stages of hallucinations. Twenty-five patients with schizophrenia participated in a single session of resting-state functional magnetic resonance imaging to capture hallucinatory experiences. Based on the participants' self-report of the psychosensory experiences that occurred during scanning, hallucinatory experiences were identified and divided into four stages: periods without hallucination ("OFF"), periods with hallucination ("ON"), transition periods between "OFF" and "ON", and the extinction of the hallucinatory experience ("END"). Using stochastic dynamic causal modeling analysis, this study first confirmed that the SAL played a critical and causal role in switching between the CEN and the DMN in schizophrenia. In addition, effective connectivity within the quadripartite model depended on the hallucinatory stage. In particular, "ON" periods were linked to memory-based sensory input from the hippocampus to the SAL, while "END" periods were associated with a takeover of the CEN in favor of a voluntary process. Finally, the pathophysiological and therapeutic implications of these findings are critically discussed. Hum Brain Mapp 37:2571-2586, 2016. © 2016 Wiley Periodicals, Inc.

The multiple neural networks of familiarity: A meta-analysis of functional imaging studies.

Recent research has demonstrated the critical role of the feeling of familiarity in recognition memory. Various neuroimaging paradigms have been developed to identify the brain regions that sustain the processing of familiarity; however, there is still considerable controversy about the functional significance of each brain region implicated in familiarity-based retrieval. Here, we focused on the differences between paradigms that assess familiarity, with or without the encoding phase. We used the activation likelihood estimation (ALE) algorithm to conduct a whole-brain meta-analysis of neuroimaging studies that involved a familiarity task. Sixty-nine studies, performed in healthy subjects to determine the specific functions of the identified regions in familiarity processing, were finally selected. Distinct subanalyses were performed according to the experimental procedures used in the original studies. The ALE clusters that were highlighted revealed common activations for paradigms with and without encoding in the prefrontal cortex and in the parietal cortex. Additionally, supplementary activations related to specific familiarity (i.e., without the encoding phase) were observed in the limbic system (i.e., the amygdala, hippocampus, cingulate cortex, and insula) and in the associative sensory areas. The differences in the reported findings for different procedures are possibly due to differences in the concept of familiarity. To aid the exploration of the neural correlates of familiarity in future studies, the strengths and weaknesses of these experimental procedures are critically discussed.

Incongruent object/context relationships in visual scenes: where are they processed in the brain?

Rapid object visual categorization in briefly flashed natural scenes is influenced by the surrounding context. The neural correlates underlying reduced categorization performance in response to incongruent object/context associations remain unclear and were investigated in the present study using fMRI. Participants were instructed to categorize objects in briefly presented scenes (exposure duration=100ms). Half of the scenes consisted of objects pasted in an expected (congruent) context, whereas for the other half, objects were embedded in incongruent contexts. Object categorization was more accurate and faster in congruent relative to incongruent scenes. Moreover, we found that the two types of scenes elicited different patterns of cerebral activation. In particular, the processing of incongruent scenes induced increased activations in the parahippocampal cortex, as well as in the right frontal cortex. This higher activity may indicate additional neural processing of the novel (non experienced) contextual associations that were inherent to the incongruent scenes. Moreover, our results suggest that the locus of object categorization impairment due to contextual incongruence is in the right anterior parahippocampal cortex. Indeed in this region activity was correlated with the reaction time increase observed with incongruent scenes. Representations for associations between objects and their usual context of appearance might be encoded in the right anterior parahippocampal cortex.

The neurodynamic organization of modality-dependent hallucinations.

The pathophysiology of hallucinations remains mysterious. This research aims to specifically explore the interaction between hallucinations and spontaneous resting-state activity. We used multimodal magnetic resonance imaging during hallucinations occurrence in 20 drug-free adolescents with a "brief psychotic disorder." They were furthermore compared with 20 matched controls at rest or during exteroceptive stimuli. Anatomical and functional symptom-mapping demonstrated reduced cortical thickness and increased blood oxygen level-dependent signal in modality-dependent association sensory cortices during auditory, visual, and multisensory hallucinations. On the contrary, primary-sensory-cortex recruitment was not systematic and was shown to be associated with increased vividness of the hallucinatory experiences. Spatiotemporal activity patterns in the default-mode network (DMN) during hallucinations and symptom-free periods in patients were compared with patterns measured in healthy individuals. A disengagement of the DMN was concomitant to hallucinations, as for exogenous stimulations in healthy participants. Specifically, spatial and temporal instabilities of the DMN correlated with the severity of hallucinations but persisted during symptom-free periods. These results suggest that hallucinatory experiences emerge from a spontaneous DMN withdrawal, providing a convincing model for hallucinations beyond the auditory modality.

Mapping brain structural differences and neuroreceptor correlates in Parkinson's disease visual hallucinations.

Parkinson's psychosis (PDP) describes a spectrum of symptoms that may arise in Parkinson's disease (PD) including visual hallucinations (VH). Imaging studies investigating the neural correlates of PDP have been inconsistent in their findings, due to differences in study design and limitations of scale. Here we use empirical Bayes harmonisation to pool together structural imaging data from multiple research groups into a large-scale mega-analysis, allowing us to identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of morphometrics analysed show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and surrounding regions, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to the involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may be linked to the cortical changes.

What can we learn from fMRI capture of visual hallucinations in Parkinson's disease?

With disease progression, patients with Parkinson's disease (PD) may have chronic visual hallucinations (VH). The mechanisms behind this invalidating non-motor symptom remain largely unknown, namely because it is extremely difficult to capture hallucination events. This study aimed to describe the patterns of brain functional changes when VH occur in PD patients. Nine PD patients were enrolled because of their frequent and chronic VH (> 10/day). Patients with severe cognitive decline (MMSE<18) were excluded. Patients were scanned during ON/OFF hallucinatory states and resting-state functional imaging (rs-fMRI) was performed. Data were analyzed in reference to the two-step method, which consists in: (i) a data-driven analysis of per-hallucinatory fMRI data, and (ii) selection of the components of interest based on a post-fMRI interview. The phenomenology of VH ranged from visual spots to distorting faces. First, at the individual level, several VH-related components of interest were identified and integrated in a second-level analysis. Using a random-effects self-organizing-group ICA, we evidenced increased connectivity in visual networks concomitant to VH, encompassing V2, V3 and the fusiform gyri bilaterally. Interestingly, the stability of the default-mode network (DMN) was found positively correlated with VH severity (Spearman's rho = 0.77, p = 0.05). By using a method that does not need online self-report, we showed that VH in PD patients were associated with functional changes in associative visual cortices, possibly linked with strengthened stability of resting-state networks.

Reward anticipation in schizophrenia: A coordinate-based meta-analysis.

Reward processing impairments have been linked with positive and negative symptoms of schizophrenia. Here, we performed a coordinate-based meta-analysis that combined eleven BOLD-fMRI studies comparing reward anticipation signals between schizophrenia patients and healthy controls. We observed a reduced difference in activation in schizophrenia patients within a frontal-striatal network. Meta-regressions revealed that this functional signature was linked to the severity of psychotic symptoms and persisted even after controlling for the dose of antipsychotic medications.

Clinical practice of rTMS reveals a functional dissociation between agency and hallucinations in schizophrenia.

We report here the case of a hospitalized 11 year-old boy (YP) with a positive diagnosis of 'Childhood Onset Schizophrenia'. YP experienced verbal-auditory hallucinations, a delusion of alien control and hetero-aggressive behaviour. Antipsychotic drugs were unsuccessful and furthermore provoked severe acute dystonia. fMRI-guided rTMS applied over several cortical regions provided the means to reveal for the first time a functional dissociation between auditory-verbal hallucinations and agency. These results demonstrate the efficacy of rTMS for young patients suffering from drug-resistant hallucinations but they furthermore question the physiopathology of the hallucinatory process by suggesting that agency and hallucinations may be sub-served by different neural networks.

Neural functional organization of hallucinations in schizophrenia: multisensory dissolution of pathological emergence in consciousness.

Although complex hallucinations are extremely vivid, painful symptoms in schizophrenia, little is known about the underlying mechanisms of multisensory integration in such a phenomenon. We investigated the neural basis of these altered states of consciousness in a patient with schizophrenia, by combining state of the art neuroscientific exploratory methods like functional MRI, diffusion tensor imaging, cortical thickness analysis, electrical source reconstruction and trans-cranial magnetic stimulation. The results shed light on the functional architecture of the hallucinatory processes, in which unimodal information from different modalities is strongly functionally connected to higher-order integrative areas.

Fetal cortical activation to sound at 33 weeks of gestation: a functional MRI study.

Hearing already functions before birth, but little is known about the neural basis of fetal life experiences. Recent imaging studies have validated the use of functional magnetic resonance imaging (fMRI) in pregnant women at 38-weeks of gestation. The aim of the present study was to examine fetal brain activation to sound, using fMRI at the beginning of the third trimester of pregnancy. 6 pregnant women between 28- and 34-weeks of gestation were scanned using a magnetic strength of 1.5 T, with an auditory stimulus applied to their abdomen. 3 fetuses with a gestational age of 33 weeks, showed significant activation to sound in the left temporal lobe, measured using a new data-driven approach (Independent Component Analysis for fMRI time series). Only 2 of these fetuses showed left temporal activation, when the standard voxel-wise analysis method was used (p=0.007; p=0.001). Moreover, motion parameters added as predictors of the General Linear Model confirmed that motion cannot account for the signal variance in the fetal temporal cortex (p=0.01). Comparison between the statistical maps obtained from MRI scans of the fetuses with those obtained from adults, made it possible to confirm our hypothesis, that there is brain activation in the primary auditory cortex in response to sound. Measurement of the fetal hemodynamic response revealed an average fMRI signal change of +3.5%. This study shows that it is possible to use fMRI to detect early fetal brain function, but also confirms that sound processing occurs beyond the reflexive sub-cortical level, at the beginning of the third trimester of pregnancy.

Implicit Recognition of Familiar and Unfamiliar Faces in Schizophrenia: A Study of the Skin Conductance Response in Familiarity Disorders.

OBJECTIVE: Familiarity is a subjective sensation that contributes to person recognition. This process is described as an emotion-based memory-trace of previous meetings and could be disrupted in schizophrenia. Consequently, familiarity disorders could be involved in the impaired social interactions observed in patients with schizophrenia. Previous studies have primarily focused on famous people recognition. Our aim was to identify underlying features, such as emotional disturbances, that may contribute to familiarity disorders in schizophrenia. We hypothesize that patients with familiarity disorders will exhibit a lack of familiarity that could be detected by a flattened skin conductance response (SCR). METHOD: The SCR was recorded to test the hypothesis that emotional reactivity disturbances occur in patients with schizophrenia during the categorization of specific familiar, famous and unknown faces as male or female. Forty-eight subjects were divided into the following 3 matched groups with 16 subjects per group: control subjects, schizophrenic people with familiarity disorder, and schizophrenic people without familiarity disorders. RESULTS: Emotional arousal is reflected by the skin conductance measures. The control subjects and the patients without familiarity disorders experienced a differential emotional response to the specific familiar faces compared with that to the unknown faces. Nevertheless, overall, the schizophrenic patients without familiarity disorders showed a weaker response across conditions compared with the control subjects. In contrast, the patients with familiarity disorders did not show any significant differences in their emotional response to the faces, regardless of the condition. CONCLUSION: Only patients with familiarity disorders fail to exhibit a difference in emotional response between familiar and non-familiar faces. These patients likely emotionally process familiar faces similarly to unknown faces. Hence, the lower feelings of familiarity in schizophrenia may be a premise enabling the emergence of familiarity disorders.

[Hallucinations and Parkinson's disease in the elderly: Pitfalls and medical care]. / Hallucinations et maladie de Parkinson du sujet âgé : pièges et prise en charge.

Hallucinations are common neuropsychiatric symptoms in Parkinson's disease (PD), with a significant prognosis impact. It is necessary to rule out other diagnoses that can be mentioned when hallucinations occur in old patients with PD. The various etiological factors must be systematically checked and can help for diagnosis. Medical care will be focused on treating the primary cause (medical or iatrogenic origin) and will privilege non-pharmacological strategies. Due to their frequent adverse effects, antipsychotic medication should be limited and started at low dose in old patients with multiple comorbidities. Clozapine and quetiapine have the highest level of recommendation in this indication. In the future, defining fMRI-based targets for noninvasive brain stimulation tools should pave the way for innovative non-pharmacological treatment of hallucinations.

Hallucinations and conscious access to visual inputs in Parkinson's disease.

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.

Categorical perception of familiarity: Evidence for a hyper-familiarity in schizophrenia.

Familiarity is a crucial aspect of recognition that may be perturbed in schizophrenia patients (SZP) and may lead to delusional disorders. However, there are no existing guidelines on how to assess and treat familiarity disorders in schizophrenia. Some experimental studies have investigated familiarity processing in SZP but have produced inconsistent results, which are likely a result of methodological issues. Moreover, these studies only assessed whether familiarity processing is preserved or impaired in SZP, but not the tendency of SZP to consider unfamiliar stimuli to be familiar. By using a familiarity continuum task based on the existence of the categorical perception effect, the objective of this study was to determine whether SZP present hyper- or hypo-familiarity. To this purpose, 15 SZP and 15 healthy subjects (HS) were presented with facial stimuli, which consisted of picture morphs of unfamiliar faces and faces that were personally familiar to the participants. The percentage of the familiar face contained in the morph ranged from 5 to 95%. The participants were asked to press a button when they felt familiar with the face that was presented. The main results revealed a higher percentage of familiarity responses for SZP compared with HS from the stimuli with low levels of familiarity in the morph and a lower familiarity threshold, suggesting a hyper-familiarity disorder in SZP. Moreover, the intensity of this "hyper-familiarity" was correlated with positive symptoms. This finding clearly suggests the need for a more systematic integration of an assessment of familiarity processing in schizophrenia symptoms assessments.

'What is more familiar than I? Self, other and familiarity in schizophrenia.

BACKGROUND: Familiarity disorders (FDs) critically impact social cognition in persons with schizophrenia. FDs can affect both relationships with people familiar to the patient and the patient's relationship with himself, in the case of a self-disorder. Skin conductance response (SCR) studies have shown that familiar and unknown faces elicit the same emotional response in persons with schizophrenia with FD. Moreover, in control subjects, one's own face and familiar faces have been shown to activate strongly overlapping neural networks, suggesting common processing. The aim of the present study was to determine whether the mechanisms involved in processing one's own and familiar faces are similarly impaired in persons with schizophrenia, suggesting a link between them. METHOD: Twenty-eight persons with schizophrenia were compared with twenty control subjects. Three face conditions were used: specific familiar, self and unknown. The task was to indicate the gender of the faces presented randomly on a screen during SCR recording. Face recognition was evaluated afterwards. RESULTS: Control subjects exhibited similar SCRs for the familiar and self-conditions, which were higher than the responses elicited by the unknown condition, whereas persons with schizophrenia exhibited no significant differences between the three conditions. CONCLUSION: Persons with schizophrenia have a core defect of both self and familiarity that is emphasised by the lack of an increased SCR upon presentation with either self or familiar stimuli. Familiarity with specific familiar faces and one's own face may be driven by the same mechanism. This perturbation may predispose persons with schizophrenia to delusions and, in particular, to general familiarity disorder.

Are neural correlates of visual consciousness retinotopic?

Some visual neurons code what we see, their defining characteristic being a response profile which mirrors conscious percepts rather than veridical sensory attributes. One issue yet to be resolved is whether, within a given cortical area, conscious visual perception relates to diffuse activity across the entire population of such cells or focal activity within the sub-population mapping the location of the perceived stimulus. Here we investigate the issue in the human brain with fMRI, using a threshold stimulation technique to dissociate perceptual from non-perceptual activity. Our results point to a retinotopic organisation of perceptual activity in early visual areas, with independent perceptual activations for different regions of visual space.

What visual illusions teach us about schizophrenia.

Illusion, namely a mismatch between the objective and perceived properties of an object present in the environment, is a common feature of visual perception, both in normal and pathological conditions. This makes illusion a valuable tool with which to explore normal perception and its impairments. Although still debated, the hypothesis of a modified, and typically diminished, susceptibility to illusions in schizophrenia patients is supported by a growing number of studies. The current paper aimed to review how illusions have been used to explore and reveal the core features of visual perception in schizophrenia from a psychophysical, neurophysiological and functional point of view. We propose an integration of these findings into a common hierarchical Bayesian inference framework. The Bayesian formalism considers perception as the optimal combination between sensory evidence and prior knowledge, thereby highlighting the interweaving of perceptions and beliefs. Notably, it offers a holistic and convincing explanation for the perceptual changes observed in schizophrenia that might be ideally tested using illusory paradigms, as well as potential paths to explore neural mechanisms. Implications for psychopathology (in terms of positive symptoms, subjective experience or behavior disruptions) are critically discussed.