Premier article (soumis) : Rôle du lobe temporal dans la physiopathologie des hallucinations auditives des patients schizophrènes

Dans cet article, nous réalisons une revue de la littérature transversale sur les lobes temporaux et leur implication dans la physiopathologie des HAs. Nous avons fait le choix dans ce travail de combiner des données issues des différentes techniques de neuroimagerie et de neurophysiologie. L’objectif principal de cette étude était de construire un modèle physiopathologique synthétique rendant compte de la complexité de la symptomatologie hallucinatoire, en compatibilité avec les données scientifiques actuelles.

TITLE

The involvement of the temporal lobe in auditory verbal hallucinations : an update

Authors

Frédéric HAESEBAERT, Jérôme BRUNELIN, Thierry d’AMATO, Mohamed SAOUD, Emmanuel POULET, Marie-Françoise SUAUD-CHAGNY

Affiliations

EA4615, Université Claude Bernard Lyon 1, F-69003 University of Lyon, Centre Hospitalier le Vinatier, Lyon, France

Correspondence:

Frederic.haesebaert@ch-le-vinatier.fr

Abstract

Introduction : Auditory hallucinations (AH) is a key symptom in schizophrenic population. Former studies and reviews involved temporal lobes in the pathophysiology of AH, but at our knowledge, none propose a multimodal study of the literature. We conduct a review focusing on neuroimaging and neurophysiological studies on AH and temporal lobe. We aimed to build a pathophysiological model of AH including the data retrieved.

Materials and methods: We conducted a MEDLINE (before november 2012) search in the English-language literature. The search terms were: hallucinat* AND ("schizophrenia") AND (("temporal lobe") OR ("auditory cortex")).

Results: we retained 81 articles after our selection. We retrieved data concerning anatomical abnormality in white (n=21) and grey mater (n=9). Most of the studies investigated functional abnormalities : “activation studies” (n=11), focusing on brain activity during AH, “trait markers studies” (n=14), revealing abnormalities in specific task in patients, 13 electrophysiological studies, “resting state” studies (n=8) and multimodal studies (n=5). We built a pathophysiological model according to these data integrating fronto-temporal dysconnectivity, early and later auditory process, memory retrieval, mulstisensoriality, emotion regulation and self/other distinction as factors influencing temporal lobe activation.

Discussion: This reviews permitted us to describe a synthetic pathophysiological model that explains a part of the clinical complexity of the AH phenomenon. It takes into account the variety of paradigms and technique investigating AH, which can also lead to heterogeneity of the results. This review draws perspectives to furthers works, in particular in the field of multimodal studies

1. Introduction

Auditory verbal hallucinations (AH) are a key feature in schizophrenia that extensively contribute to the burden of the disease. Some 50-70% of patients with schizophrenia will experience this symptom in their whole life (Andreasen et Flaum 1991). Despite advances in antipsychotic medication, AH remain in 25% of cases (S. S. Shergill, Murray, et McGuire 1998b). In the last decades, many studies investigating the pathophysiology of AH in schizophrenia highlight activations in the temporal lobes, especially in the left hemisphere (Jardri et al. 2011). The temporal lobe is a large anatomical region including at least Brodmann’s area 40, 41, 21 and 22 involved in the auditory and the linguistic networks (McGuire, Shah, et Murray 1993; Woodruff et al. 1997) The temporal lobe has been implicated in cognitive models of AH (Waters et al. 2012). Several authors have suggested that the temporal lobe is implicated in the self-other recognition system and that a failure in this system leading to misattribution of internal speech underlies AH (Jérôme Brunelin et al. 2007; Chris D Frith, Blakemore, et Wolpert 2000). Beyond studies on AH in schizophrenia, several synthetic reviews have confirmed anatomical and functional impairments in this region in subjects experiencing AH (Pearlson 1997; Sun et al. 2009) including patients with epilepsy (Elliott, Joyce, et Shorvon 2009) or even non-clinical populations (the specific case of the subjects called “voice hearers”, without any other symptom or functional disability) (Diederen, Van Lutterveld, et Sommer 2012).

Unfortunately, previous reviews on disrupted neural process in patients with AH have only focused on one imaging technique while the different neuroimaging and electrophysiological approaches can give us complementary information.

Here, we hypothesized that knowledge from all neuroimaging techniques can give us a more exhaustive point of view on the temporal lobe abnormalities and dysfunctions in hallucinators. Our final goal is to clarify the role of temporal lobe in AH and to propose an integrative comprehensive pathophysiologic model of AH in accordance with the most recent data. To achieve this goal, we conduct a systematic review in combining neuroimaging and neurophysiological studies in adult population with AH in schizophrenia. We focused our interest on anatomical and functional data concerning the temporal lobes and their connections.

2. Material and methods

We conducted a comprehensive MEDLINE (before november 2012) search in the English-language literature. The search terms were: hallucinat* AND ("schizophrenia") AND (("temporal lobe") OR ("auditory cortex")). This primary search was completed by hand-searched the references of all manuscripts for further relevant publications and manual article’s selection.

We excluded articles not concerning directly patients with schizophrenia, auditory hallucination and temporal lobe. We then excluded articles investigating AH in specific populations (early onset, late onset schizophrenia), case reports, clinical trials, review and metaanalysis although they will be helpful to contribute to our further discussion. We also choose to exclude post mortem studies (please see flowchart in Figure 1). After the exclusions described above, a total of 81 articles were taken into account into our review.

3. Results

We perform a qualitative analysis of the data extracted from the literature. The 81 retained articles were divided into anatomical and functional studies. Functional studies were separated depending on the neuroimaging or neurophysiological technique and/or paradigm used in the study.

3.1. Studies investigating anatomical abnormalities

Structural abnormalities involved in the pathogenesis of AH concern grey and white matter.

3.1.1. Grey matter abnormalities

Regarding grey matter abnormalities, 21 anatomical MRI studies were retained. Barta and colleagues (1990) reported for the first time in a sample of 15 patients a reduction in the volume of the left superior temporal gyrus (Barta et al. 1990). This reduction was correlated with the severity of AH, suggesting the direct implication of this region in the occurrence of AH. Despite two exceptions (DeLisi et al. 1994; Shin et al. 2005), all original reports confirmed a reduced volume of the left temporal lobe in patients with AH (see for instance (Flaum et al. 1995; Milev et al. 2003).

Thanks to technological advances in imaging techniques, recent studies have investigated which part of the temporal lobe is involved in AH. Involvement of the left anterior STG (Levitan, Ward, et Catts 1999; Rajarethinam et al. 2000), the left insula (Shapleske et al. 2002), the left transverse gyrus (Gaser et al. 2004), the left supramarginal gyrus (Heschl’s gyrus) (Gaser et al. 2004; Neckelmann et al. 2006; Neckelmann et al. 2006; Nenadic et al. 2010), the left inferior temporal gyrus (O’Daly et al. 2007), the angular gyrus (Nenadic et al. 2010).

Structural abnormalities in the left temporal lobe have also been associated with abnormalities in other regions within a distributed fronto-temporal network including frontal regions (Gaser et al. 2004) and the right temporal cortex (Nenadic et al. 2010). The left frontal volume loss positively correlated with severity of AH (Modinos et al. 2009).

3.1.2. Analyses of white matter

Regarding white matter abnormalities, anatomy and integrity of white matter tracts and bundles have been explored using diffusion tensor imaging (dTi). We retained 9 studies investigating the integrity of the superior longitudinal fasciculus and the arcuate fasciculus in patients with AH compared with healthy controls or with patients without AH.

All the studies, whatever the direction of fractional anisotropy (FA) modulation, concluded to an abnormal integrity in the fronto temporal connectivity in patients with AH. On the one hand, increased (especially on the left (Abdul-Rahman et al. 2012; Hubl et al. 2004) and decreased (Catani et al. 2011; de Weijer et al. 2011) FA have been found in the arcuate fasciculus in patients with AH. On the other hand, a correlation with AH severity and FA measured in the superior longitudinal fasciculi has been reported (Sukhwinder S Shergill et al. 2007), especially for the left frontal part in a study (Seok et al. 2007).

Other bundles, namely, the inferior fronto-occipital fasciculus (Szeszko et al. 2008) and the corpus calosum (Christoph Mulert et al. 2012) have been also reported to be abnormal in patients with AH.

Totally, a distributed brain network involving the left temporal lobe and its interconnected areas (especially the frontal lobe and the right temporal lobe) is abnormal in patients with AH.

Abnormalities are also observable in the anatomical bundle connecting these brain areas. This network beeing implicated in language processing and in corollary discharge process (Towle et al. 2008), it is conceivable that in such network might lead to aberrant auditory perceptions of spontaneous language production as suggested by cognitive works on AH (Chris D Frith, Blakemore, et Wolpert 2000).

3.2. Activation studies

We reviewed here 11 imaging studies using fMRI, PET, MEG and EEG designed to “catch” the hallucination symptom. Imaging data was acquired while the patient experiencing AH and compared with not hallucinating period or with patients without AH. Studies differ in the manner to determine if subject experiences AH during imaging acquisition. Ten of eleven, studies were designed with a button press paradigm where subjects have to a press a button when they experienced AH.

The first PET studies reported left temporal lobe hyperactivation during AH (McGuire, Shah, et Murray 1993; Suzuki et al. 1993) associated with abnormalities in other brain areas involved in language processing especially the Broca’s area (McGuire et al., 1993) and the anterior cingulum. These results were replicated and refined by Copolov and colleagues (Copolov et al. 2003) by demonstrating that, during hallucinating episode, the bilateral auditory cortices,. the left limbic regions, the right medial frontal and the right prefrontal regions were co-activated.

Results from studies using an fMRI button press paradigm are in the same line. Lennox and colleagues reported temporal cortex activations and involvement of prefrontal areas (Lennox et al. 2000). Recently, Hoffman and col. (Hoffman, Fernandez, et al. 2011; Hoffman, Pittman, et al. 2011) confirmed these results. They showed the brain activity associated to the action of pressing a button was not a bias by comparing fMRI data obtained in hallucinators and in HC asked to randomly use press button. Moreover, their studies showed an increase correlation between activity of the left inferior frontal gyrus and the right temporal lobe, with also an overactivvity of left temporal region during AH (Hoffman, Pittman, et al. 2011). The same team highlighted a higher functional connectivity between Wernicke area and the left inferior frontal gyrus and putamen (Hoffman, Fernandez, et al. 2011). In another paper, they revealed, by “press-button” capture, activation of insula and right temporal gyrus and deactivation of

anterior cingulate and parahippocampal gyrus (Hoffman et al. 2008) coinciding with the onset of AH. Using a complex button press paradigm with a post hallucination assessment of voice reality, Raij and colleagues explored the reality of voice (Raij et al. 2009). In such paradigm, they showed the involvement of the inferior frontal gyrus, the ventral striatum, the both auditory cortices, the posterior temporal lobe and the cingulate cortex.

Finally, despite Hoffman’s validation of the button press paradigm, another team attempted to avoid bias about hallucination awareness and using spatial ICA analysis combined with patients self reports, Van de ven and coll (van de Ven et al. 2005) confirmed the involvement of the both auditory cortex with activations linked to time course of auditory hallucinations.

We found only two neurophysiological studies in the domain of capture studies. One using EEG (Sritharan et al. 2005) in a button press paradigm and measuring electrode coherence . It revealed an increase of synchrony between the left and the right auditory cortices during AH and an increase in relative power in the left auditory cortex suggesting a dysfunction of auditory pathways. The second was an MEG study (Reulbach et al. 2007) also using button press paradigm showing an increase of dipoles activities in the fast frequency range during AH, concentrated in frontal and temporal regions.

In sum, we retained 11 studies that all showed an involvement of the temporal lobes in the AH phenomenon. All of them highlight the involvement of auditory pathways and language networks as suggested by the left predominance of brain abnormalities. Other structures involved in language production and perception seems to be involved in the pathogenesis of AH (i.e. Inferior frontal gyrus) with an increased (or decreased) fronto temporal connectivity, probably inducing aberrant perceptions of language percepts in hallucinating patients.

Deep brain structures including cortical areas (GPH, insula) and basal ganglia seem to be involved but their roles remain unclear in the activation maps.

3.3. Trait marker studies

We reviewed here imaging studies designed to investigate difference between hallucinators and non-hallucinators. These studies investigate traits in hallucinating patients whatever the hallucinated state. They outline the manner the brain of these patients treat information

comparing to themselves at a different clinical state or to other non AH comparison patients, or healthy controls. During these experience, the hallucinatory state is not controlled. These types of paradigms can also be useful to correlate a “trait marker” with symptom severity or other cognitive or symptomatic features in hallucinated patients. Several types of protocol have been used: recognition of self vs alien or external speech, comparison of brain activities during speaking, imaging or listening, working memory tests, word recognition tasks, and listening tasks. One of the first studies in this field was conducted by Woodruff and colleagues and dedicated to a comparison between patients with and without AH and HC (Woodruff et al. 1997). The study focused on the responses of the brain to speech. It brought out a reduced responsiveness to external speech in the patients experiencing AH. This reduced responsiveness in the temporal cortex was particularly observed in the right middle temporal gyrus. These results were replicated by Plaze and colleagues highlighting a lesser responsiveness of the left temporal lobe (superior region) in patients with AH than in non-hallucinating (Plaze et al. 2006). Further, Lawrie and colleagues reported a negative correlation between AH severity and connectivity of the left dorsolateral prefrontal cortex and the left temporal cortex (Lawrie et al. 2002). Other authors focused on the different brain pattern of activity depending of the nature of the stimulus (self, other, distored, undistorded, etc.) emphazing specificities in patients with AH in treating different types of stimuli. Patients with AH showed a different connectivity pattern between the left superior temporal area and the anterior cingulate for self speech (vs alien speech) (Mechelli et al. 2007) according to the mechanism could be involved in the faulty appraisal of inner speech in AH confusing it with external speech. Fu et al. corroborate this hypothesis showing a bilateral superior temporal activation associated to external misattribution rather than correct self attributions (Fu et al. 2008). Other used distorted vs undistorted feedback to a self generated speech and showed a greater response to undistorted feedback in patients with AH, unlike HC (Kumari et al. 2010). Simons compared the effects of listened vs imagined in HC and SCZ with AH speech and showed interactions between groups with a lack of attenuation of the left superior temporal gyrus during inner speech in patients with AH, probably reflecting a deficit of self monitoring abilities (Simons et al. 2010). Other types or protocols reported abnormalities involving the left temporal lobe: PET Scan studies showed modified activations pattern with less left temporal lobe activation with verbal memory task in patients with AH (Gur et al. 1994) and reduced activation of left temporal lobe during mismatch auditory stimuli in patients (Wible et al. 2001), both showing impairment in auditory processing. Other works showed aberrant brain responses in schizophrenic patients with excessive response to emotional external words

(frontal, temporal, insular, cingular and amygdalia, mainly in the right) (Sanjuan et al. 2007), less abilities to recruit the brain network involved in word processing or language working memory tasks (with less left frontal and temporal activation). This abnormal brain response correlated with severity of AH (Han et al. 2007; Wible et al. 2009) or last, a disability to activate brain process (including the right temporal lobe) involved in recognition of familiar voices (Zhang et al., 2008).

In sum, the studies investigating traits markers characteristics highlighted a lack of recruitment or aberrant recruitment of the temporal regions. Indeed, there is firstly a failure of structures, mainly left fronto temporal, involved in self / alien speech discrimination, with an overactivation for self stimuli defect and a lack of activation for the alien stimuli. On the other hand, we identify a series of processes that may incriminate the right and left temporal lobes failing patients hallucinated to discriminate the qualities of words or sentences (lexical fields, emotional valence, familiarity) mainly showing a lack of brain activation, excerpt for the emotional stimuli.

3.4. Electrophysiological studies

We reviewed here eletrophysiological studies investigating temporal lobes functioning in patients with auditory hallucinations. We reported results from studies using 3 kind of protocol: auditory evoked potential, auditory oddball studies and auditory steady state response.

3.4.1. Auditory evoked potentials studies

We found 6 studies in this field with different types of paradigms. Most of them focused on the N100m response reflecting pre-attentive processes that take place in the superior temporal gyri. The different authors reported an absence of modulation of this component usually found in HC. Ford and colleagues showed that schizophrenic patients fail to dampen this response when they produce an acoustic message (in a “talking” condition) compared to an externally produced message (J M Ford et al. 2001). Then the same group of authors highlighted a lack of increase of EEG fronto temporal coherence to acoustic stimuli during talking (vs. listening) in patients, corroborating the previous results (Judith M Ford et al. 2002). Further, they showed that the lack of N100 dampening was correlated with poor neural synchrony during the period preceding speech onset. This last perturbation was correlated to hallucinations severity (Judith M Ford et al. 2007). Moreover, they showed that different

qualities of the speech conducted to refine this results showing also a disability to damped the N100 in patients when triggered by altered self-voice or alien auditory feedback (Heinks-Maldonado et al. 2007). In a MEG study, the lack of N100m modulation was identify only on the in the left temporal lobe in patients with AH (Haesebaert et al. 2013) while an absence of dampening the P50m in a double stimuli paradigm was associated to the left hemisphere, and to auditory hallucination (with an inverse correlation between this ratio and hallucination severity) (Hirano et al. 2010).

3.4.2. Mismatch Negativity (MMN) Paradigm studies

We found 4 articles in this field. The aim of these studies was to investigate the neural response to an odd stimuli presented in a sequence of comparable stimulus. The MMN is known to be modified in numerous psychiatric diseases (Turetsky et al. 2007). MMN mainly involves fronto-temporal networks. It has been linked to auditory hallucinations severity especially in the left hemisphere with a correlation with AH score and amplitude of the MMN in left frontal electrodes (Hirayasu et al. 1998) with a reduced “normal” asymmetry also linked to AH (Youn et al. 2003). We found replications of the first results confirming MMN abnormalities and AH patients (Fisher, Labelle, et Knott 2008a), incriminating the left hemisphere (Youn et al. 2003) and especially the temporal electrodes (Fisher, Labelle, et Knott 2008b).

3.4.3. Auditory Steady State Response (ASSR) studies

ASSR is defined as the specific brain response to a 40 Hz binaural continuous stimulus reflecting auditory pathways integrity. Three articles were retrieved. Using EEG, Spencer et al. found an increase in the phase locking factor (measured in ASSR paradigm) in patients with AH (Spencer et al. 2009) whereas Mulert and colleagues found a decreased in sourced density in the right superior and middle temporal gyrus, with a reduction of interhemispheric phase locking for primary cortices (C. Mulert et al. 2011). These last authors found also a positive correlation between AH scores and phase synchronization between the primary cortices. It highlights a disturbed pattern of ASSR response in patients with AH. In a MEG study, Tsuchimoto and colleagues confirmed the AASR power reduction in AH patients and reported a correlation between 80 Hz left ASSR response and hallucination severity (Tsuchimoto et al. 2011). These 3 studies reported abnormal patterns of response but can be contradictory and so must be replicated.

In sum, neurophysiological studies highlight abnormalities in auditory pre-attentive processes involving fronto temporal networks (especially in the left hemisphere). These alterations are also involved in self-monitoring processing.

3.5. Resting state studies

Resting state consists in analyzing brain activity at rest. In this recent field, we found fMRI and PET studies. PET studies reported modification in language areas in patients with AH with a lower metabolism in auditory regions especially on the left (Cleghorn et al. 1992) and higher metabolism in the right homologue Broca area. Author also found correlation with AH severity and metabolism in the striatum and the anterior cingulate region. Gordon and colleagues confirmed the involvement of brain regions implicated in language observing a