A web-based adapted physical activity program (e-APA) versus health education program (e-HE) in patients with schizophrenia and healthy volunteers: study protocol for a randomized controlled trial (PEPSY V@Si).

Patients with schizophrenia (SZ) have a high level of cardiovascular morbidity and some clinical symptoms of illness remain resistant to pharmacological approaches. A large number of studies support the effectiveness of physical activity (PA) in SZ. The aims of this trial is to assess the effects of a remote, web-based adapted PA program (e-APA) compared to a health education program (e-HE) on brain plasticity in SZ and healthy volunteers (HV) and on psychiatric, neurocognitive, circadian and physical variables. The study is an interventional, multicenter, randomized open-label trial. Forty-two SZ will be randomized to either the active group (e-APA, N = 21) or nonactive group (e-HE, N = 21), and 21 HV will be matched to SZ according to age, gender, and level of PA in both e-APA and e-HE groups. Interventions will consist of 32 sessions (2 × 60 min/week, for 16 weeks) via supervised home-based videoconferencing. Cerebral magnetic resonance imaging, psychiatric symptoms, neurocognitive and circadian rhythms assessments as well as physical tests and biological analyses will be assessed at baseline and 16 weeks after the intervention. To our knowledge, this is the first study aiming to evaluate the efficacy of APA delivered by supervised home-based videoconferencing in SZ. Moreover, using multimodal MRI, this study could clarify the pathophysiological mechanisms underlying the efficacy of APA. Finally, this innovative approach might also increase participation in long-term PA since PA-based programs are known to have low adherence and early dropout. Trial registration: ClinicalTrials.gov identifier: NCT03261817. Registered on 16 August 2017.

A new 3-hit mouse model of schizophrenia built on genetic, early and late factors.

Whether the etiology of schizophrenia remains unknown, its multifactorial aspect is conversely now well admitted. However, most preclinical models of the disease still rely on a mono-factorial construction and do not allow discover unequivocal treatments, particularly for negative and cognitive symptoms. The main interaction factors that have been implicated in schizophrenia are a genetic predisposition and unfavorable environmental factors. Here we propose a new animal model combining a genetic predisposition (1st hit: partial deletion of MAP-6 (microtubule-associated protein)) with an early postnatal stress (2nd hit: 24 h maternal separation at post-natal day 9), and a late cannabinoid exposure during adolescence (3rd hit: tetrahydrocannabinol THC from post-natal day 32 to 52; 8 mg/kg/day). The 2-hit mice displayed spatial memory deficits, decreased cortical thickness and fractional anisotropy of callosal fibers. The 3-hit mice were more severely affected as attested by supplementary deficits such a decrease in spontaneous activity, sociability-related behavior, working memory performances, an increase in anxiety-like behavior, a decrease in hippocampus volume together with impaired integrity of corpus callosum fibers (less axons, less myelin). Taken together, these results show that the new 3-hit model displays several landmarks mimicking negative and cognitive symptoms of schizophrenia, conferring a high relevance for research of new treatments. Moreover, this 3-hit model possesses a strong construct validity, which fits with gene x environment interactions hypothesis of schizophrenia. The 2-hit model, which associates maternal separation with THC exposure in wild-type mice gives a less severe phenotype, and could be useful for research on other forms of psychiatric diseases.

Anatomical Connectivity of the Visuospatial Attentional Network in Schizophrenia: A Diffusion Tensor Imaging Tractography Study.

OBJECTIVE: In healthy individuals, the visuospatial attentional network consists of frontoparietal bundles; however, the anatomical organization of this network in persons with schizophrenia remains largely unknown. Using diffusion tensor imaging-based tractography, the authors investigated the white matter integrity and volume of frontoparietal and frontotemporo-occipital bundles in the right and left hemispheres and studied their structural asymmetry in persons with schizophrenia and in healthy individuals. METHODS: This study included 34 participants with schizophrenia and 69 healthy individuals. Integrity parameters and volume were calculated in the three branches of the superior longitudinal fasciculus (SLF I, II, and III), the inferior longitudinal fasciculus, and the inferior fronto-occipital fasciculus in both hemispheres. RESULTS: In the SLF II and SLF III of the right hemisphere, healthy individuals showed greater integrity, compared with participants with schizophrenia. Both groups presented increased integrity in the SLF III of the right hemisphere, compared with the SLF III of the left hemisphere, but only healthy individuals had this pattern regarding the SLF II. Bundle volumes did not differ between groups. CONCLUSIONS: This study is the first to describe the structural hemispheric lateralization and organization of the visuospatial attentional network in persons with schizophrenia. The main findings indicate loss of integrity in the SLF II, associated with loss of asymmetry in participants with schizophrenia, compared with healthy individuals, suggesting a potential substrate of attentional deficits.

Corpus callosum microstructural and macrostructural abnormalities in schizophrenia according to the stage of disease.

Corpus callosum (CC) volume and surface (macrostructural) studies remain controversial and have not considered the illness duration (ID) systematically. Regardless of ID, some CC macrostructural studies have shown no difference between SZ patients and healthy controls (HC), whereas others have reported macrostructural abnormalities in SZ. Conversely, CC microstructural studies are more in agreement with alterations in CC integrity regardless of the patients' ID, but the direction and degree of these abnormalities over time remain unknown. Moreover, no study has explored both the micro- and macrostructure of the CC in SZ by considering the stage of disease. Both CC micro- and macrostructural data were investigated in 43 SZ patients and compared between two patient groups (21 patients with a short ID and 22 with a long ID) and HC (23 participants) using diffusion tensor and structural imaging. CC microstructural alterations were detected in both SZ groups compared to the HC group, without differences between the SZ groups. In contrast, CC macrostructural alterations were only found in the long ID group. CC microstructural alterations might be detected in schizophrenia at an early stage, without an increase of magnitude thereafter, while CC macrostructural alterations might become apparent at later stages of the illness.

Effects of low- and high-frequency repetitive transcranial magnetic stimulation on long-latency auditory evoked potentials.

Long-latency auditory event potentials (LLAEPs) involving local and global auditory processes have been investigated to examine the impact of low-frequency (LF) and high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) on the cortical excitability of the temporal cortex. We hypothesized that both stimulation frequencies have the same modulation effect, in accordance with clinical data showing a reduction in auditory verbal hallucinations (AVHs) after LF and HF temporal rTMS in patients with schizophrenia. With 30 right-handed healthy volunteer participants enrolled in a crossover trial, we analyzed LLAEPs before and after LF- and HF-rTMS of the left temporal cortex. While we observed no changes in latencies, we did observe a similar inhibitory action of both rTMS frequencies on LLAEP amplitudes. Analysis of surface potential maps and cortical generators revealed some differences regarding auditory processes: HF-rTMS produced earlier, more diffuse, and more right-lateralized effects than LF-rTMS. Beyond a local impact, rTMS exerted a remote modulation influence on the frontal cortex that might be involved in attentional processes. This association could explain the therapeutic effect of temporal HF-rTMS on AVH.

High-Frequency Neuronavigated rTMS in Auditory Verbal Hallucinations: A Pilot Double-Blind Controlled Study in Patients With Schizophrenia.

INTRODUCTION: Despite extensive testing, the efficacy of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of temporo-parietal targets for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia is still controversial, but promising results have been reported with both high-frequency and neuronavigated rTMS. Here, we report a double-blind sham-controlled study to assess the efficacy of high-frequency (20 Hz) rTMS applied over a precise anatomical site in the left temporal region using neuronavigation. METHODS: Fifty-nine of 74 randomized patients with schizophrenia or schizoaffective disorders (DSM-IV R) were treated with rTMS or sham treatment and fully evaluated over 4 weeks. The rTMS target was determined by morphological MRI at the crossing between the projection of the ascending branch of the left lateral sulcus and the superior temporal sulcus (STS). RESULTS: The primary outcome was response to treatment, defined as a 30% decrease of the Auditory Hallucinations Rating Scale (AHRS) frequency item, observed at 2 successive evaluations. While there was no difference in primary outcome between the treatment groups, the percentages of patients showing a decrease of more than 30% of AHRS score (secondary outcome) did differ between the active (34.6%) and sham groups (9.1%) (P = .016) at day 14. DISCUSSION: This controlled study reports negative results on the primary outcome but demonstrates a transient effect of 20 Hz rTMS guided by neuronavigation and targeted on an accurate anatomical site for the treatment of AVHs in schizophrenia patients.

Fronto-subcortical functional connectivity in patients with schizophrenia and bipolar disorder during a verbal fluency task.

OBJECTIVES: Impairments in language production are common of schizophrenia (SZ) and bipolar disorder (BD). Identifying distinct functional connectivity (FC) patterns in SZ and BD may provide biomarkers for their diagnoses. METHODS: Forty-nine participants (15 SZ, 14 BD and 20 healthy controls (HC)) underwent a verbal fluency task consisting of mentally generating verbs in French, alternated with periods of silence. Functional network allowed identifying activation clusters: the medio-frontal cluster (MFC), the left subcortical cluster (LSCC) and the left fronto-lateral cluster (LFLC). FC was calculated between the average blood oxygen level-dependent signal time series in each cluster. Analyses of covariance were performed to test group differences on FC among the three paired-seed regions. RESULTS: SZ presented a significant reduced FC compared to HC within two paired-seed regions between the LFLC and the LSCC and between the MFC and the LSCC while BD were not significantly different from HC. SZ compared to BD exhibited a reduced FC within one paired-seed region between the MFC and the LSCC. There was no group effect between the MFC and the LFLC. CONCLUSIONS: A specific medio-prefronto-striato-thalamic functional dysconnectivity may be implicated in the pathophysiology of schizophrenia. This reduced fronto-subcortical FC could be a functional brain biomarker of schizophrenia.

Relationships between corpus callosum and language lateralization in patients with schizophrenia and bipolar disorders.

OBJECTIVES: The question of whether there is a continuum or a dichotomy among patients with schizophrenia (SZ) and bipolar disorders (BD) has not been clearly resolved and remains a challenge. Thus, the identification of specific biomarkers of these disorders might be helpful. The present study investigated the volume of the corpus callosum (CC) and functional lateralization for language as potential biomarkers and their relationships in SZ and BD. METHODS: The study included 20 patients with SZ, 20 patients with BD and 40 healthy controls (HC). A functional lateralization index (FLI) was computed for each participant within the language comprehension network. For each participant, the volume of the total CC and those of three subregions were extracted. These variables and their anatomo-functional relationships were investigated. RESULTS: In comparison to HC, SZ patients presented a decreased leftward lateralization for language, whereas this was not found in BD patients. However, as compared to SZ patients and HC, BD patients showed a reduction in CC volume associated with a lower leftward lateralization for language. CONCLUSIONS: Our study revealed that SZ patients displayed a reduction of the leftward functional lateralization for language; however, no reduction of CC volume was observed, whereas BD patients presented a decreased volume of the CC associated with a lower leftward asymmetry for language. The results of our study detected distinct anomalies in both SZ and BD that may be considered as specific biomarkers of these disorders related to neurodevelopmental models.

Abnormalities of language pathways in schizophrenia patients with and without a lifetime history of auditory verbal hallucinations: A DTI-based tractography study.

OBJECTIVES: Auditory verbal hallucinations (AVHs) are frequently observed in patients with schizophrenia (SZ) and could be the result of white matter (WM) fibre abnormalities involved in speech production/comprehension and perception. We evaluated WM integrity changes in SZ with (SZ+) and without (SZ-) lifetime AVHs compared to healthy controls (HCs), using diffusion tensor imaging-based tractography, with a novel focus on the structural connectivity within both intra- and interhemispheric fasciculi. METHODS: The study included 27 SZ+, 12 SZ- and 34 HCs. Fractional anisotropy (FA) and mean and radial diffusivities (MD and RD) were extracted in each participant in two left interhemispheric fasciculi and in the interhemispheric auditory pathway (IAP) to test integrity differences among groups. RESULTS: SZ- and SZ + compared to HCs presented increased diffusivities and/or decreased FA in the interhemispheric fasciculi. Decreased FA was significant only between SZ + and HCs for the IAP. CONCLUSIONS: In this first comparison of integrity changes within both intra- and interhemispheric fasciculi, abnormalities in the intrahemispheric fasciculi were observed in both SZ- and SZ+, but an alteration in the IAP was seen only in SZ+. These results suggest that the IAP may be more involved in patients with AVHs-proneness.

Left-hemisphere lateralization for language and interhemispheric fiber tracking in patients with schizophrenia.

BACKGROUND: It has been suggested that the degree of hemispheric specialization (HS) depends on the structural connectivity between the two hemispheres, that is to say the corpus callosum (CC). Studies, performed only on healthy participants, investigated this anatomo-functional relationship. Nevertheless, it has never been studied in schizophrenia. We therefore propose to study the anatomo-functional relationships between the integrity of interhemispheric connectivity and leftward functional lateralization for language in patients with schizophrenia compared with healthy participants, driven by a multimodal approach combining fMRI and DTI-based fiber tractography. We hypothesized that reduced leftward functional lateralization for language in patients with schizophrenia could be related to a callosal hypoconnectivity. MATERIALS AND METHODS: Seventeen patients based on the DSM-IV, and 17 controls were included. The functional laterality index and interhemispheric diffusion values between homologue temporal regions, belonging to the language network, were individually extracted in order to study the anatomo-functional relationships. RESULTS: In the patients, higher mean and radial diffusivity (RD) values (thicker myelin sheaths) were associated with less leftward lateralization. In contrast, the controls presented higher RD values and lower fractional anisotropy values (axonal loss) with more leftward lateralization. CONCLUSIONS: Our study revealed a relationship between the CC and the HS for language, but did not provide evidence clarifying the direction of the relationship between callosal connectivity and functional lateralization for language. In particular, the present findings showed that the loss of integrity in interhemispheric callosal fibers was associated with reduced leftward cerebral dominance for language in patients with schizophrenia.

Functional and structural brain asymmetries in patients with schizophrenia and bipolar disorders.

OBJECTIVES: This study aimed to compare the functional and gray matter asymmetries in patients with schizophrenia (SZ), patients with bipolar disorders (BD), and healthy controls (HCs) to test whether decreased leftward functional hemispheric lateralization and gray matter volume asymmetry could mark the boundary between schizophrenia and bipolar disorder. METHODS: A total of 31 right-handed SZ and 20 right-handed BD underwent a session of functional MRI with a speech listening paradigm. Participants were matched with HCs for gender, age, and education. Functional laterality indices (FLI) and gray matter volume asymmetry indices (GVAI) were computed from the individual functional language network. Correlations between the FLI and GVAI indices were also examined. RESULTS: SZ exhibited significantly decreased leftward functional hemispheric lateralization whereas BD did not. The GVAIs did not differ significantly between SZ and HCs or between BD and HCs. There were positive correlations between GVAIs and FLIs in all groups. CONCLUSIONS: Loss of laterality for language comprehension with retention of gray matter volume asymmetry indicates that gray matter loss alone will not account for the pathophysiology of schizophrenia. Impaired leftward functional hemispheric lateralization for language but not gray matter volume asymmetry can be considered a biomarker of SZ.

Changes in cortical thickness in 6-year-old children open their mind to a global vision of the world.

Even if objectively presented with similar visual stimuli, children younger than 6 years of age exhibit a strong attraction to local visual information (e.g., the trees), whereas children older than 6 years of age, similar to adults, exhibit a visual bias toward global information (e.g., the forest). Here, we studied the cortical thickness changes that underlie this bias shift from local to global visual information. Two groups, matched for age, gender, and handedness, were formed from a total of 30 children who were 6 years old, and both groups performed a traditional global/local visual task. The first group presented a local visual bias, and the other group presented a global visual bias. The results indicated that, compared with the local visual bias group, children with a global visual bias exhibited (1) decreased cortical thickness in the bilateral occipital regions and (2) increased cortical thickness in the left frontoparietal regions. These findings constitute the first structural study that supports the view that both synaptic pruning (i.e., decreased cortical thickness) and expansion mechanisms (i.e., increased cortical thickness) cooccur to allow healthy children to develop a global perception of the visual world.

Left fronto-temporal dysconnectivity within the language network in schizophrenia: an fMRI and DTI study.

Schizophrenia is a mental disorder characterized by language disorders. Studies reveal that both a functional dysconnectivity and a disturbance in the integrity of white matter fibers are implicated in the language process in patients with schizophrenia. Here, we investigate the relationship between functional connectivity within a language-comprehension network and anatomical connectivity using fiber tracking in schizophrenia. We hypothesized that patients would present an impaired functional connectivity in the language network due to anatomical dysconnectivity. Participants comprised 20 patients with DSM-IV schizophrenia and 20 healthy controls who were studied with functional magnetic resonance imaging and diffusion tensor imaging. The temporal correlation coefficient and diffusion values between the left frontal and temporal clusters, belonging to the language network, were individually extracted, in order to study the relationships of anatomo-functional connectivity. In patients, functional connectivity was positively correlated with fractional anisotropy, but was negatively correlated with radial diffusivity and/or mean diffusivity, in the left arcuate fasciculus and part of the inferior occipitofrontal fasciculus, determined as the fronto-temporal tracts. Our findings indicate a close relationship between functional and anatomical dysconnectivity in patients with schizophrenia. The disturbance in the integrity of the left fronto-temporal tracts might be one origin of the functional dysconnectivity in the language-comprehension network in schizophrenia.

Functional and white matter abnormalities in the language network in patients with schizophrenia: a combined study with diffusion tensor imaging and functional magnetic resonance imaging.

BACKGROUND: Schizophrenia is a mental disorder characterized by functional abnormalities in the language network. Anatomical white matter (WM) abnormalities (volume and integrity) have also been reported for this pathology. Nevertheless, few studies have investigated anatomo-functional relationships in schizophrenia, and none has focused on the language comprehension network in relation to various diffusion parameters. We hypothesized that the WM abnormalities that are reflected by several diffusion parameters underlie functional deficits in the language network. METHODS: Eighteen DSM-IV patients with schizophrenia and 18 healthy controls without any significant differences in sex, age, or level of education were included. First, functional brain activation within the language network was estimated. Then, using diffusion tensor imaging, fractional anisotropy (FA), radial diffusivity (RD), and mean diffusivity (MD) values were extracted within WM regions adjacent to this network and their anatomo-functional relationships were investigated. RESULTS: Compared with healthy participants, both functional and diffusion deficits were observed in patients with schizophrenia. Primarily, an altered diffusion-functional relationship was observed in patients in the left middle temporal region: functional activations were positively correlated with FA, but were negatively correlated with RD. CONCLUSIONS: Our findings indicate a close relationship between diffusion and functional deficits in patients with schizophrenia, suggesting that WM integrity disturbance might be one cause of functional alterations in the language network in patients with schizophrenia. Thus, the present multimodal study improves our understanding of the pathophysiology of schizophrenia.

Functional hemispheric lateralization for language in patients with schizophrenia.

BACKGROUND: It is widely reported that patients with schizophrenia exhibit decreased hemispheric lateralization. However, no study has evaluated relationships between the hemispheric anatomical and functional asymmetry in language areas. The present study aimed to determine whether decreased leftward hemispheric lateralization could be related to asymmetry of the grey matter volume in patients with schizophrenia. This investigation was the first to use a functional index of laterality to analyze the global functional network specifically involved in the language task. METHODS: Twenty-seven right-handed patients with schizophrenia and 54 right-handed control subjects underwent a session of a functional magnetic resonance imaging (fMRI) with a speech listening paradigm. Functional laterality indices (FLI) were calculated (Wilke, M. and Lidzba, K., 2007. LI-tool: a new toolbox to assess lateralization in functional MR-data. J Neurosci Methods. 163, 128-136). The indices of asymmetry in the volume of grey matter (GVAIs) were computed from the functional language network. RESULTS: Patients with schizophrenia exhibited significantly decreased leftward hemispheric lateralization. There was a positive correlation between GVAIs and FLIs in healthy subjects, while no such correlation was seen in patients with schizophrenia. DISCUSSION: This study reports for the first time a significant relationship between the anatomical and functional asymmetry in healthy subjects, but not in patients with schizophrenia. While decreased leftward functional lateralization for language was observed in patients with schizophrenia compared to the control group, this functional abnormality was not related to asymmetry in the volume of grey matter.

Septohippocampal pathways contribute to system consolidation of a spatial memory: sequential implication of GABAergic and cholinergic neurons.

Studies of the neuropharmacological substrates of spatial memory formation have focused on the contribution of septohippocampal pathways. Although these pathways include, among others, cholinergic and GABAergic fibers innervating the hippocampus, research has essentially been oriented towards the role of their cholinergic component. Recently, a few studies investigated the role of GABAergic septohippocampal projections. These only focused on almost immediate or recent memory and yielded discrepant results. GABAergic lesions impaired learning or had no effects. Given the role of the hippocampus in memory consolidation and the potential modulatory influence of the septum on hippocampal function, it is relevant to study the role of the septohippocampal interface in memory stabilization. We performed investigations with relatively selective lesions of GABAergic (using oxerin-saporin) or/and cholinergic (using 192 IgG-saporin) medial septum/vertical limb of the diagonal band of Broca (MS/vDBB) neurons in rats, and assessed acquisition of a spatial memory and its subsequent recall in the water maze. Following a 6-day training phase during which all groups improved performance to comparable levels, retention was tested 1, 5, or 25 days later. At the 1-day delay, all groups performed above chance and did not differ significantly among each other. At the 5-day delay, only rats with GABAergic or combined lesions exhibited a retention deficit. At the 25-day delay, all three lesion groups performed at chance level; in these groups, performance was significantly lower than that found in sham-operated rats. Immunochemical and histochemical verifications of the lesion extent/selectivity showed extensive GABAergic damage after intraseptal orexin-saporin infusions or cholinergic damage after 192 IgG-saporin infusions, with relatively limited damage to the other neurotransmitter system. Our data show that GABAergic and cholinergic septohippocampal neurons both contribute to memory stabilization, and could do so in a sequential way: GABAergic processes could be engaged at an earlier stage than cholinergic ones during system consolidation of a spatial memory.