Abstract Background The neurobiology underlying treatment-resistant schizophrenia (TRS) has not been fully elucidated1. This project provides a preliminary dissection of the neurobiological underpinnings of cognitive dysfunction in schizophrenia (SCZ), such as the disorganization factor, as a core clinical and pathophysiological correlate of TRS2. In this context, TRS shows putative unique neuroimaging correlates compared to treatment-responsive schizophrenia (non-TRS)3, probably related to specific functional disconnection patterns, with an emergent involvement of the Fusiform Gyrus (FG). Aims & Objectives This study aims to reveal the potential links between the aberrant functional connectivity of the FG and the disruption of cognitive performance rated through the proxy domain of disorganization in TRS. The objective of this study is to identify a functional biomarker that may predict the response to antipsychotics in schizophrenia. Methods We enrolled 49 patients with SCZ (34 M, 15 F, age 37.5 ±9.7 years), along with 55 healthy controls (HC) (30 M, 25 F, age 42.4 ±15.7 years) matched in age and sex. Patients were classified as TRS (N= 22) or non-TRS (N= 27), paired with demographic and clinical variables. The clinical features were evaluated using PANSS and the 5-factor model. T-test for PANSS scores was performed using SPSS software (p< 0.01). All subjects underwent a 3T resting-state functional magnetic resonance imaging (rs-fMRI) brain scan, and the data were processed using the CONN toolbox with a seed-to-voxel connectivity analysis approach, testing a functional connectivity (FC) map of the fusiform gyrus between the groups (HC vs. SZ and TRS vs. non-TRS). The statistical significance level was set at (p< 0.05 FWER corrected). Results TRS patients showed significantly higher scores compared with non-TRS in the PANSS 5-factor model Positive (p= 0.007), Negative (p= 0.006), and Disorganization factors (p= 0.001). Considering the FG, a cluster of increased FC in TRS compared with non-TRS patients emerged in the right putamen (p=0.005). Discussion & Conclusion TRS is associated with a cluster of increased rs-FC in FG seed within the right putamen and a more severe disorganization feature compared to non-TRS, suggesting an aberrant connectivity preferentially affected in TRS. Further studies may contribute to identifying functional biomarkers of altered connectivity in schizophrenia to predict the pharmacological response to antipsychotics. References 1. Iasevoli F, Avagliano C, D'Ambrosio L, Barone A, Ciccarelli M, De Simone G, Mazza B, Vellucci L, de Bartolomeis A. Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal. Biomedicines. 2023 Mar 14;11(3):895. doi: 10.3390/biomedicines11030895. PMID: 36979877; PMCID: PMC10046109. 2. Barone A, De Prisco M, Altavilla B, Avagliano C, Balletta R, Buonaguro EF, Ciccarelli M, D'Ambrosio L, Giordano S, Latte G, Matrone M, Milandri F, Francesco DN, Vellucci L, de Bartolomeis A. Disorganization domain as a putative predictor of Treatment Resistant Schizophrenia (TRS) diagnosis: A machine learning approach. J Psychiatr Res. 2022 Nov;155:572-578. doi: 10.1016/j.jpsychires.2022.09.044. Epub 2022 Sep 29. PMID: 36206601. 3. Iasevoli F, D'Ambrosio L, Ciccarelli M, Barone A, Gaudieri V, Cocozza S, Pontillo G, Brunetti A, Cuocolo A, de Bartolomeis A, Pappatà S. Altered Patterns of Brain Glucose Metabolism Involve More Extensive and Discrete Cortical Areas in Treatment-resistant Schizophrenia Patients Compared to Responder Patients and Controls: Results From a Head-to-Head 2-[18F]-FDG-PET Study. Schizophr Bull. 2023 Mar 15;49(2):474-485. doi: 10.1093/schbul/sbac147. PMID: 36268829; PMCID: PMC10016407.

Glutamatergic system, the main stimulating system of the brain, plays an important role in the pathogenesis of schizophrenia. Hippocampus, a structure crucial for memory and cognitive functions and rich in glutamatergic neurons, is a natural object of interest in studies on psychoses. Sarcosine, a glycine transporter (GlyT-1) inhibitor influences the function of NMDA receptor and glutamate-dependent transmission.The aim of the study was to assess the effects of sarcosine on metabolism parameters in the left hippocampus in patients with schizophrenia. Assessments were performed using proton nuclear magnetic resonance (1H NMR) spectroscopy (1.5T).Fifty patients diagnosed with schizophrenia (DSM-IV-TR), with dominant negative symptoms, in stable clinical condition and stable antipsychotics doses were treated either with sarcosine (n = 25) or placebo (n = 25). Spectroscopic parameters were evaluated within groups and between two groups before and after 6-month intervention. All patients were also assessed with the Positive and Negative Syndrome Scale (PANSS).In the sarcosine group, after 6-month treatment, we found significant decrease in hippocampal Glx/Cr (Glx-complex of glutamate, glutamine and GABA, Cr-creatine) and Glx/Cho (Cho-choline), while N-acetylaspartate (NAA), myo-inositol (mI), Cr and Cho parameters remained stable along the study and also did not differ significantly between both groups.This is the first study showing that a pharmacological intervention in schizophrenia, particularly augmentation of the antypsychotic treatment with sarcosine, may reverse the pathological increase in glutamatergic transmission in the hippocampus. The results confirm involvement of glutamatergic system in the pathogenesis of schizophrenia and demonstrate beneficial effects of GlyT-1 inhibitor on the metabolism in the hippocampus and symptoms of schizophrenia.

The dopamine neurotransmitter regulates important neural pathways and its action in the brain is very complex. When dopaminergic neurons make synapses on spiny neurons of the striatum nucleus, they tune the responsiveness of glutamatergic synapses by means of the dopamine D1 and D2 receptors. We studied the effect of dopamine D1 receptors on glutamatergic synapse of GABAergic spiny neurons in striatum nucleus where they are located on the neck of the same spine. The action of dopamine consists essentially in promoting the phosphorylation of AMPA and NMDA receptors thus increasing the Excitatory Post Synaptic Current peak amplitude. The consequence is a cooperative effect of glutamatergic and dopaminergic synapses for the regulation of the GABAergic neuronal code. The mechanisms by which the phosphorylation induces the increase of the EPSC amplitude still remain unclear although the lack of this regulation can be involved in several pathologies as, for example, the Parkinson's disease. We tested, by computational experiments based on our model of glutamatergic synapse, three parameters of the synaptic function that could be involved in dopamine action: (a) time binding of glutamate to receptors; (b) open probability of the receptors; and (c) single receptor conductance. For different reasons, any of the three parameters could be responsible of the increased EPSC-dopamine-dependent. Our computational results were compared and discussed with experimental results found in literature. Although for our model both the open probability and the single receptor conductance can reproduce the phosphorylation effect of dopamine, we argue that the dopamine effect consists essentially in an increase of the single receptor conductance due to a 3D rearrangement of the phosphorylated receptors.

We investigated the added value of combining information from direction-encoded color (DEC) maps with high-resolution structural magnetic resonance imaging scans (T1-weighted images [T1WIs]) to improve the identification of regions of interest (ROIs) for fiber tracking during preoperative planning for patients with brain tumors.The dataset included 42 patients with gliomas and 10 healthy subjects from the Human Connectome Project. For identification of the ROIs, we combined the structural information from high-resolution T1WIs and the directional information from DEC maps. To test our hypothesis, we examined the interrater and intrarater agreement.We identified specific ROIs to extract the main white matter bundles. The directional information from the DEC maps combined with the T1WIs (T1WI–DEC maps) had significantly facilitated ROI identification in patients with brain tumors, especially patients in whom the tracts had been displaced by the mass effect of the tumor. Fiber tracking using the combined T1WI–DEC maps showed significantly greater inter- and intrarater agreement compared with using either T1WI or DEC maps alone.Combining the information from diffusion-derived color-encoded maps with high-resolution anatomical details from structural imaging (T1WI–DEC map), especially in patients with brain tumors, could be useful for accurate identification of the ROIs.

Abstract Background Schizophrenia has been conceptualized both as synaptic plasticity and a functional connectivity disorder. Data on brain connectivity can be rendered in the form of network models. In our study we want to evaluate a particular kind of the structural and functional interaction between region of interest (ROI) relevant to schizophrenia pathophysiology: we evaluated the expression of Immediate Early Gene (IEG), Homer1a (H1a), in the different ROI and its functional interaction after Haloperidol (antipsychotic drug) acute administration. H1a is an IEG expressed in an activity-dependent manner, coding for a protein involved in the activity-induced reorganization of glutamatergic synapses. Methods Sprague-Dawley rats were randomly assigned to two treatment groups (n=23), receiving vehicle (NaCl 0.9%; VEH) or haloperidol 0.8 mg/kg (HAL) i.p. injection. H1a induction was evaluated using in situ hybridization. Signal intensity analysis was performed in 34 ROIs in the cortex, in the caudate-putamen and the nucleus accumbens. Student’s t-test was used to detect treatment effects. A signal correlation analysis was performed, computing all possible pairwise Pearson correlations among ROIs separately in the two groups. Using significant correlations, two networks were created for HAL and VEH groups, and their network, node, and edge properties were assessed. Results Bonferroni-corrected Student’s t-tests revealed statistically significant differences between the two treatment groups. Haloperidol significantly induced Homer1a gene expression compared to vehicle in all ROIs of the striatum (dmCP: p<.0001, t=9.089, df=44; dlCP: p<.0001, t=10.684, df=44; vlCP: p<.0001, t=10.870, df=44; vmCP: p<.0001, t=9.760, df=44; AcCo: p<.0001, t=8,573, df= 44; AcSh: p<.0001, t=6.615, df=44), a result that is consistent with our previous observations. No significant statistical differences were detected among cortical ROIs explored. Correlations between dmCP-AcSh, dlCP-AcSh, vlCP-AcCo, vlCP-AcSh and vmCP-AcSh were significantly different between the VEH and the HAL group (p<.01); correlations between I-vlCP and dlCP-AcCo were also significantly different between the two treatment groups (p<.05); the I-dlCP and I-vmCP showed a trend towards significance. Discussion Haloperidol acute administration led to a modification of the gene expression pattern in the brain regions considered herein, and consequently to differential functional connectivity. The observed disruption in the functional correlations of the nucleus accumbens may play a role in the affective, motivational and emotional consequences of haloperidol administration, with the loss of functional correlations with the lateral subregions of the caudate-putamen being potentially more relevant to the motor side-effects of haloperidol. These functional connectivity changes are potentially related to neural activity and synaptic plasticity within the glutamate system and may play a role in antipsychotic therapeutic and side effects. As far as we know, this is the first network analysis study on after haloperidol acute treatment of a gene deeply correlated to dendritic spine architecture.

The dynamic response mechanism of Candidatus Accumulibacter clades to environmental factors in enhanced biological phosphorus removal (EBPR) was unclear. This study investigated the relationship between the transcriptional responses of Candidatus Accumulibacter clades and environmental dynamics. Results suggested that Candidatus Accumulibacter clade IIA only responded in initial 20 and 30 min of P-release and P-uptake stage, respectively, and was also the first clade to stop responding among the six Candidatus Accumulibacter clades. Clade IIC and IID responded at rising stage of P-release and P-uptake rate. Clade IA and IIB responded at decreasing stage of P-release and P-uptake rate. The transcriptional response duration of clade IIF was the longest, which constantly responded throughout anaerobic, anoxic and oxic phase. The transcriptional responses of Candidatus Accumulibacter clades to environmental dynamics revealed the microorganisms actually working in P-release and P-uptake, and gave a new insight into the transcriptional responses related to the EBPR performance.