Renaud Jardri

Neuroimaging Auditory Hallucinations in Schizophrenia: From Neuroanatomy to Neurochemistry and Beyond

Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future studies.

The multimodal connectivity of the hippocampal complex in auditory and visual hallucinations

Hallucinations constitute one of the most representative and disabling symptoms of schizophrenia. Several Magnetic Resonance Imaging (MRI) findings support the hypothesis that distinct patterns of connectivity, particularly within networks involving the hippocampal complex (HC), could be associated with different hallucinatory modalities. The aim of this study was to investigate HC connectivity as a function of the hallucinatory modality, that is, auditory or visual. Two carefully selected subgroups of schizophrenia patients with only auditory hallucinations (AH) or with audio-visual hallucinations (A+VH) were compared using the following three complementary multimodal MRI methods: resting state functional MRI, diffusion MRI and structural MRI were used to analyze seed-based Functional Connectivity (sb-FC), Tract-Based Spatial Statistics (TBSS) and shape analysis, respectively. Sb-FC was significantly higher between the HC, the medial prefrontal cortex (mPFC) and the caudate nuclei in A+VH patients compared with the AH group. Conversely, AH patients exhibited a higher sb-FC between the HC and the thalamus in comparison with the A+VH group. In the A+VH group, TBSS showed specific higher white matter connectivity in the pathways connecting the HC with visual areas, such as the forceps major and the inferior-fronto-occipital fasciculus than in the AH group. Finally, shape analysis showed localized hippocampal hypertrophy in the A+VH group. Functional results support the fronto-limbic dysconnectivity hypothesis of schizophrenia, while specific structural findings indicate that plastic changes are associated with hallucinations. Together, these results suggest that there are distinct connectivity patterns in patients with schizophrenia that depend on the sensory-modality, with specific involvement of the HC in visual hallucinations.

Visual Hallucinations in the Psychosis Spectrum and Comparative Information From Neurodegenerative Disorders and Eye Disease

Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications.

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.

An 11-year-old boy with drug-resistant schizophrenia treated with temporo-parietal rTMS.

Very early onset schizophrenia is a psychiatric syndrome in children under 13 years of age that is characterized by a very poor prognosis, due to frequent resistance to treatment. We report here the case of a hospitalized 11-year-old child (YP), with a positive diagnosis of very early onset schizophrenia for the past 2 years (positive K-SADS-DSM-IV), without any previous sign of pervasive developmental disorder. YP experienced verbal auditory hallucinations, a delusion of alien control and heteroaggressive behaviour. Antipsychotic drugs were unsuccessful and furthermore, provoked severe acute dystonia. A 72-h EEG recording, an anatomical MRI brain scan and a complete set of metabolic analyses, were all negative. However, using data-driven analysis, we observed that YP’s functional MRI scan revealed bilateral neural activity in the auditory cortex during auditory verbal hallucinations (Figure 1). Ten sessions of fMRI-guided, low frequency (1 Hz), repeated trans-cranial magnetic stimulation (rTMS) over the left temporo-parietal cortex, were successful in stopping the verbal auditory hallucinations (Auditory Hallucination Rating Scale 47%). The improvement obtained with rTMS was maintained by repeating the sessions every 5 weeks. The clinical improvement was confirmed by a significant improvement of adaptative functions (Children’s Global Assessment Scale þ40%), and the fact that YP was able to go back home and attend school. Thereby, YP was able to receive education about his illness and to follow regular psychotherapeutic sessions. rTMS has been used for hallucinations in adults, and in children with attentional deficits and hyperactivity. To our knowledge, however, this is the first published case demonstrating the efficacy of fMRI-guided rTMS in the treatment of verbal auditory hallucinations in a child with schizophrenia. These results require replication.

Imagining One's Own and Someone Else's Body Actions: Dissociation in Anorexia Nervosa

Background Patients with anorexia nervosa (AN) usually report feeling larger than they really are. This body overestimation appears to be related not only to the patient’s body image but also to an abnormal representation of the body in action. In previous work on a body-scaled anticipation task, anorexic patients judged that they could not pass through a door-like aperture even when it was easily wide enough - suggesting the involvement of the body schema. In the present study, we sought to establish whether this erroneous judgment about action is specifically observed when it concerns one’s own body or whether it is symptomatic of a general impairment in perceptual discrimination. Methods Twenty-five anorexic participants and 25 control participants were presented with a door-like aperture. They had to judge whether or not the aperture was wide enough for them to pass through (i.e. first-person perspective, 1PP) and for another person present in the testing room to pass through (i.e. third-person perspective, 3PP). Results We observed a higher passability ratio (i.e. the critical aperture size to shoulder width ratio) in AN patients for 1PP but not for 3PP. Moreover, the magnitude of the passability ratio was positively correlated not only with the extent of the patient’s body and eating concerns but also with the body weight prior to disease onset. Our results suggest that body overestimation can affect judgments about the capacity for action but only when they concern the patient’s own body. This could be related to impairments of the overall network involved in the emergence of the body schema and in one’s own perspective judgments. Conclusion Overestimation of the body schema might occur because the central nervous system has not updated the new, emaciated body, with maintenance of an incorrect representation based on the patient’s pre-AN body dimensions.

Resting-State Functional Connectivity of the Nucleus Accumbens in Auditory and Visual Hallucinations in Schizophrenia

Both auditory hallucinations (AH) and visual hallucinations may occur in schizophrenia. One of the main hypotheses underlying their occurrence involves the increased activity of the mesolimbic pathway, which links the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). However, the precise contribution of the mesolimbic pathway in hallucinations across various sensory modalities has not yet been explored. We compared the resting-state functional connectivity (rs-FC) of the NAcc among 16 schizophrenia patients with pure AH, 15 with both visuoauditory hallucinations (VAH), and 14 without hallucinations (NoH). A between-group comparison was performed using random-effects ANCOVA (rs-FC of the bilateral NAcc as the dependent variable, groups as the between-subjects factor, age and Positive and Negative Syndrome Scale scores as covariates; q(false discovery rate [FDR]) < .05). Compared to the NoH group, the AH group exhibited significantly enhanced NAcc rs-FC with the left temporal superior gyrus, the cingulate gyri, and the VTA, whereas the VAH group, compared to the AH group, exhibited significantly enhanced NAcc rs-FC with the bilateral insula, putamen, parahippocampal gyri, and VTA. The strength in rs-FC between the NAcc and the VTA appeared to be positively associated with the presence of hallucinations, but the NAcc FC patterns changed with the complexity of these experiences (ie, 0, 1, or 2 sensory modalities), rather than with severity. This might support the aberrant salience hypothesis of schizophrenia. Moreover, these findings suggest that future clinical and neurobiological studies of hallucinations should evaluate not only the global severity of symptoms but also their sensorial features.

The arcuate fasciculus in auditory-verbal hallucinations: A meta-analysis of diffusion-tensor-imaging studies

Auditory-verbal hallucinations (AVHs) are associated with an impaired connectivity of large-scale networks. To examine the relationship between white-matter integrity and AVHs, we conducted a meta-analysis of diffusion-tensor-imaging studies that compared patients with schizophrenia and AVHs with matched healthy controls (HCs). Five studies were retained gathering 256 DTI data points, divided into AVHs (n=106) and HCs (n=150). The meta-analysis demonstrated a reduced fractional anisotropy in the left Arcuate Fasciculus (AF) of hallucinators (hg= -0.42; CI[-0.69,-0.16]; p<10(-3)). The current meta-analysis confirmed disruptions of white matter integrity in the left AF bundle of schizophrenia patients with AVHs.

From Phenomenology to Neurophysiological Understanding of Hallucinations in Children and Adolescents

Typically reported as vivid, multisensory experiences which may spontaneously resolve, hallucinations are present at high rates during childhood. The risk of associated psychopathology is a major cause of concern. On the one hand, the risk of developing further delusional ideation has been shown to be reduced by better theory of mind skills. On the other hand, ideas of reference, passivity phenomena, and misidentification syndrome have been shown to increase the risk of self-injury or heteroaggressive behaviors. Cognitive psychology and brain-imaging studies have advanced our knowledge of the mechanisms underlying these early-onset hallucinations. Notably, specific functional impairments have been associated with certain phenomenological characteristics of hallucinations in youths, including intrusiveness and the sense of reality. In this review, we provide an update of associated epidemiological and phenomenological factors (including sociocultural context, social adversity, and genetics, considered in relation to the psychosis continuum hypothesis), cognitive models, and neurophysiological findings concerning hallucinations in children and adolescents. Key issues that have interfered with progress are considered and recommendations for future studies are provided.

Assessing fetal response to maternal speech using a noninvasive functional brain imaging technique.

Evidence for cortical sensory activation in the human fetus at the beginning of the third trimester of pregnancy was provided in a recent imaging study. Although hearing is functional before birth, it is not clear whether recognition of the mothers voice is learned in utero or rapidly following delivery. We developed an original fMRI procedure that allows for the specific exploration of fetal brain response to auditory stimuli. This procedure provides the first in vivo evidence for the development of maternal voice recognition in utero between 33 and 34 weeks of gestation. This methodology could have crucial implications in the study of fetal cognition.