Abnormal Striatal Dopamine Transmission in Schizophrenia

Despite numerous revisions and reformulations, dopamine (DA) hypothesis of schizophrenia remains a pivotal neurochemical hypothesis of this illness. The aim of this review is to expose and discuss findings from positron emission tomography (PET) or single-photon-emission computed tomography (SPECT) studies investigating DA function in the striatum of medicated, drug-naïve or drug-free patients with schizophrenia and in individuals at risk compared with healthy volunteers. DA function was studied at several levels: i) at a presynaptic level where neuroimaging studies investigating DOPA uptake capacity clearly show an increase of DA synthesis in patients with schizophrenia; ii) at a synaptic level where neuroimaging studies investigating dopamine transporter availability (DAT) does not bring any evidence of dysfunction; iii) and finally, neuroimaging studies investigating DA receptor density show a mild increase of D2 receptor density in basic condition and, an hyperreactivity of DA system in dynamic condition. These results are discussed regarding laterality, sub-regions of striatum and implications for the at-risk population. Striatal DA abnormalities are now clearly demonstrated in patients with schizophrenia and at risk population and could constitute an endophenotype of schizophrenia. Subtle sub-clinical striatal DA abnormalities in at risk population could be a biomarker of transition from a vulnerability state to the expression of frank psychosis

Integrity of the arcuate fasciculus in patients with schizophrenia with auditory verbal hallucinations: A DTI-tractography study

AbstractAuditory verbal hallucinations (AVH) of schizophrenia are associated with a disrupted connectivity between frontal and temporoparietal language areas. We hypothesized that this dysconnectivity is underpinned by white matter abnormalities in the left arcuate fasciculus, the main fiber bundle connecting speech production and perception areas. We therefore investigated the relationship between AVH severity and the integrity of the arcuate fasciculus measured by diffusion tensor imaging (DTI) tractography in patients with schizophrenia.Thirty-eight patients with treatment-resistant schizophrenia were included: 26 presented with daily severe treatment-resistant AVH, 12 reported prominent negative symptoms and no AVH. Fractional anisotropy (FA) was measured along the length of the left and right anterior arcuate fasciculi and severity of AVH was assessed using P3 PANSS item.FA values were significantly higher in the left arcuate fasciculus in patients with AVH than in no AVH patients (F(1,35)=3.86; p=0.05). No difference was observed in the right arcuate fasciculus. There was a significant positive correlation between FA value in the left arcuate fasciculus and the severity of AVH (r=0.36; p=0.02). No correlation was observed between FA values and PANSS total score suggesting a specific relationship between AVH severity and the left arcuate fasciculus integrity.These results support the hypothesis of a relationship between left frontotemporal connectivity and AVH in patients with schizophrenia and suggest that whilst a disruption of frontotemporal connectivity might be present to ensure the emergence of AVH, more severe anatomical alterations may prevent the occurrence of AVH in patients with schizophrenia

La Schizophrénie (hypothèses physiopathologiques et modèles animaux)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Etude de la neurotransmission dopaminergique dans un modèle animal présumé de schizophrénie (la souris déficiente en protéine STOP)

LYON1-BU Santé (693882101) / SudocSudocFranceF

Du stade juvénile au stade adulte (évolution des troubles de la transmission dopaminergique chez les rats ayant subi la lésion néonatale de l hippocampe ventral et implications pour la physiopathologie de la schizophrénie)

Dans ce travail, nous avons développé le modèle de rat ayant subi une lésion néonatale de l hippocampe ventral (rat LNHV), un outil reconnu pour l étude de la schizophrénie. Nous avons validé l utilisation de l imagerie anatomique (IRM) comme outil permettant une détection fiable et précoce (avant la puberté) de la taille et la cible des lésions, pour remplacer l évaluation post mortem. Au niveau comportemental, nous avons montré que le nombre des anomalies qui sont associées à des troubles de la transmission dopaminergique augmente du stade juvénile à l âge adulte chez les animaux LNHV. Au niveau neurochimique, nous avons montré que les animaux LNHV présentent des altérations des efflux de dopamine au niveau mésocorticolimbique (noyau accumbens et cortex préfrontal) qui n apparaissent qu après la puberté. Nos résultats confirment l implication majeure de la dopamine dans la physiopathologie de la schizophrénie et soulignent l importance des facteurs qui pourraient précipiter l émergence de la maladie au moment de l adolescenceIn this work, we developed the model of rats with neonatal ventral hippocampal lesions (NVHL rats), a relevant tool for studying schizophrenia. We validated anatomic imaging (MRI) as a tool allowing an early and reliable detection of locus and extent of lesions instead of post mortem evaluation. At the behavioural level, we showed that the number of abnormalities associated with of dopaminergic transmission alterations increase from prepubertal stage to adult life in NVHL animals. At the neurochemical level, we showed that NVHL animals display alterations of dopamine effluxes measured in the mesocorticolimbic system (nucleus accumbens, prefrontal cortex) that emerge only after puberty. Our results strengthen the main implication of dopamine in the physiopathology of schizophrenia and emphasize the role of factors that could precipitate the onset of the disease in the late adolescenceLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Anodal tDCS targeting the left temporo-parietal junction disrupts verbal reality-monitoring

International audienceUsing transcranial direct current stimulation (tDCS) we aimed to investigate the causal role of the left temporo-parietal and prefrontal regions in source-monitoring. Forty-two healthy participants received tDCS while performing a verbal reality-monitoring task (requiring discrimination between imagined and heard words) and a verbal internal source-monitoring task (requiring discrimination between imagined and said words). In 2 randomized crossover studies, 21 participants received active and sham anodal tDCS applied over the left temporo-parietal junction (TPJ) and 21 participants received active and sham cathodal tDCS applied over the left prefrontal cortex (PFC). The reference electrode was placed over the right occipital region in both experiments. Active tDCS over the left TPJ decreased reality-monitoring performance but did not modulate internal source-monitoring performance. Participants were more likely to misattribute self-generated events to externally perceived events (externalization bias). Active tDCS over the left PFC did not modulate performance of participants in both tasks. In summary, anodal tDCS applied over the left TPJ, assumed to enhance cortical excitability, can alter reality-monitoring processes in healthy subjects. Such abnormal reality-monitoring performances have been reported in hallucinating patients with schizophrenia known to display hyperactivity of the left TPJ. Our results highlighted the role of the left TPJ in self/other recognition

Neurostimulation du cortex préfrontal dorsolatéral : quels effets sur la symptomatologie, l’humeur et les émotions dans la dépression et la schizophrénie ?

La stimulation magnétique transcrânienne répétée (rTMS) et la stimulation transcrânienne par courant continu (tDCS) sont des techniques de stimulation cérébrale non invasive actuellement utilisées comme solutions thérapeutiques dans plusieurs pathologies psychiatriques. Appliquées au niveau du cortex préfrontal dorsolatéral (CPFDL), elles ont montré leur efficacité pour diminuer les symptômes pharmacorésistants chez les patients déprimés et chez les patients schizophrènes avec symptômes négatifs prédominants (SN). Le CPFDL est une structure cérébrale impliquée dans l’expression de ces symptômes et dans d’autres processus dysfonctionnels de ces deux pathologies comme les processus émotionnels. Le but de cette revue est d’établir s’il existe ou non un lien entre l’amélioration clinique et la modulation des processus émotionnels suite à la stimulation du CPFDL dans ces deux pathologies. Les données collectées montrent que l’amélioration des processus émotionnels n’est pas en lien avec l’amélioration clinique ni chez les patients déprimés ni chez les patients SN. Notre revue suggère que bien que partageant des structures cérébrales communes, les réseaux cérébraux impliqués dans les processus émotionnels d’une part et les symptômes dépressifs ou les SN d’autre part seraient distincts.Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive brain stimulation techniques currently used as therapeutic tools in various psychiatric conditions. Applied over the dorsolateral prefrontal cortex (DLPFC), they showed their efficacy in reducing drug-resistant symptoms in patients with major depression and in patients with schizophrenia with predominantly negative symptoms. The DLPFC is a brain structure involved in the expression of these symptoms as well as in other dysfunctional functions observed in theses conditions such as emotional processes. The goal of this review is to establish whether or not a link exists between clinical improvements and modulation of emotional processes following the stimulation of the DLPFC in both conditions. The data collected show that improved emotional processes is not linked to a clinical improvement neither in patients with depression nor in patients with negative schizophrenia. Our results suggests that although sharing common brain structures, the brain networks involved in both symptoms and in emotional processes would be separate

A Polysomnographic and Cluster Analysis of Periodic Limb Movements in Sleep of Restless Legs Syndrome Patients with Psychiatric Conditions

Only survey studies have linked specific individual psychiatric disorders such as anxiety, depression and schizophrenia to Restless Legs Syndrome (RLS), Periodic Limb Movements in Sleep (PLMS) or both. We therefore aim to polysomnographically characterize sleep in a sample of physician-based, newly diagnosed cases of RLS with various ICD-10 psychiatric diagnoses. Retrospective analysis of data from a convenience sample of psychiatric patients (n = 43) per standard clinical sleep disorder cut-offs was conducted. Next, a cluster analysis was performed on the sleep data, taking into account the psychiatric diagnosis, comorbid non-psychiatric somatic problems and medication. We found that 37.2% of our sample showed clinically significant PLMS ≥ 15 and 76.5% exhibited an apnea hypopnea index (AHI) ≥ 5. Sleep structure was unaltered apart from the PLMS-related parameters. Two clusters were statistically identified: Cluster 1 primarily representing recurrent major depressive issues and Cluster 2 representing present but not predominant mood symptomatology as well as mixed disorders with personality problems. The known confounders were controlled. A PLMS index ≥ 15 was differentially distributed among the two clusters with Cluster 1: 10 out of 17 with PLMS index ≥ 15; Cluster 2: 1 out of 16 with PLMS index ≥15; whilst AHI was not different. Patients in Cluster 1 have a higher rate of periodic leg movements than patients in Cluster 2. This suggests that the high association with PLMS is primarily driven by affective disorders. Our findings warrant questioning of RLS symptomatology in patients with psychiatric conditions

Neuroanatomical correlates of reality monitoring in patients with schizophrenia and auditory hallucinations

International audienceBackground. Reality-monitoring process enables to discriminate memories of internally generated information from memories of externally derived information. Studies have reported impaired reality-monitoring abilities in schizophrenia patients with auditory hallucinations (AHs), specifically with an exacerbated externalization bias, as well as alterations in neural activity within frontotemporoparietal areas. In healthy subjects, impaired reality-monitoring abilities have been associated with reduction of the paracingulate sulcus (PCS). The current study aimed to identify neuroanatomical correlates of reality monitoring in patients with schizophrenia. Methods. Thirty-five patients with schizophrenia and AHs underwent a reality-monitoring task and a 3D anatomical MRI scan at 1.5 T. PCS lengths were measured separately for each hemisphere, and whole-brain voxel-based morphometry analyses were performed using the Computational Anatomy Toolbox (version 12.6) to evaluate the gray-matter volume (GMV). Partial correlation analyses were used to investigate the relationship between reality-monitoring and neuroanatomical outcomes (PCS length and GMV), with age and intracranial volume as covariates. Results. The right PCS length was positively correlated with reality-monitoring accuracy (Spearman's ρ = 0.431, p = 0.012) and negatively with the externalization bias (Spearman's ρ = À0.379, p = 0.029). Reality-monitoring accuracy was positively correlated with GMV in the right angular gyrus, whereas externalization bias was negatively correlated with GMV in the left supramarginal gyrus/superior temporal gyrus, in the right lingual gyrus and in the bilateral inferior temporal/fusiform gyri (voxel-level p < 0.001 and cluster-level p < 0.05, FDR-corrected). Conclusions. Reduced reality-monitoring abilities were significantly associated with shorter right PCS and reduced GMV in temporal and parietal regions of the reality-monitoring network in schizophrenia patients with AHs

Effects of Fronto-Temporal Transcranial Direct Current Stimulation on Auditory Verbal Hallucinations and Resting-State Functional Connectivity of the Left Temporo-Parietal Junction in Patients With Schizophrenia

Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20 min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring