Thalamic contributions to psychosis susceptibility: Evidence from co-activation patterns accounting for intra-seed spatial variability (µCAPs).

The temporal variability of the thalamus in functional networks may provide valuable insights into the pathophysiology of schizophrenia. To address the complexity of the role of the thalamic nuclei in psychosis, we introduced micro-co-activation patterns (µCAPs) and employed this method on the human genetic model of schizophrenia 22q11.2 deletion syndrome (22q11.2DS). Participants underwent resting-state functional MRI and a data-driven iterative process resulting in the identification of six whole-brain µCAPs with specific activity patterns within the thalamus. Unlike conventional methods, µCAPs extract dynamic spatial patterns that reveal partially overlapping and non-mutually exclusive functional subparts. Thus, the µCAPs method detects finer foci of activity within the initial seed region, retaining valuable and clinically relevant temporal and spatial information. We found that a µCAP showing co-activation of the mediodorsal thalamus with brain-wide cortical regions was expressed significantly less frequently in patients with 22q11.2DS, and its occurrence negatively correlated with the severity of positive psychotic symptoms. Additionally, activity within the auditory-visual cortex and their respective geniculate nuclei was expressed in two different µCAPs. One of these auditory-visual µCAPs co-activated with salience areas, while the other co-activated with the default mode network (DMN). A significant shift of occurrence from the salience+visuo-auditory-thalamus to the DMN + visuo-auditory-thalamus µCAP was observed in patients with 22q11.2DS. Thus, our findings support existing research on the gatekeeping role of the thalamus for sensory information in the pathophysiology of psychosis and revisit the evidence of geniculate nuclei hyperconnectivity with the audio-visual cortex in 22q11.2DS in the context of dynamic functional connectivity, seen here as the specific hyper-occurrence of these circuits with the task-negative brain networks.

Alterations in the volume and shape of the basal ganglia and thalamus in schizophrenia with auditory hallucinations.

Different lines of evidence indicate that the structure and physiology of the basal ganglia and the thalamus is disturbed in schizophrenia. However, it is unknown whether the volume and shape of these subcortical structures are affected in schizophrenia with auditory hallucinations (AH), a core positive symptom of the disorder. We took structural MRI from 63 patients with schizophrenia, including 36 patients with AH and 27 patients who had never experienced AH (NAH), and 51 matched healthy controls. We extracted volumes for the left and right thalamus, globus pallidus, putamen, caudate and nucleus accumbens. Shape analysis was also carried out. When comparing to controls, the volume of the right globus pallidus, thalamus, and putamen, was only affected in AH patients. The volume of the left putamen was also increased in individuals with AH, whereas the left globus pallidus was affected in both groups of patients. The shapes of right and left putamen and thalamus were also affected in both groups. The shape of the left globus pallidus was only altered in patients lacking AH, both in comparison to controls and to cases with AH. Lastly, the general PANSS subscale was correlated with the volume of the right thalamus, and the right and left putamen, in patients with AH. We have found volume and shape alterations of many basal ganglia and thalamus in patients with and without AH, suggesting in some cases a possible relationship between this positive symptom and these morphometric alterations.

Thalamic nuclei volume differences in schizophrenia patients and healthy controls using probabilistic mapping: A comparative analysis.

AIM: We aimed to investigate potential discrepancies in the volume of thalamic nuclei between individuals with schizophrenia and healthy controls. METHODS: The imaging data for this study were obtained from the MCICShare data repository within SchizConnect. We employed probabilistic mapping technique developed by Iglesias et al. (2018). The analytical component entailed volumetric segmentation of the thalamus using the FreeSurfer image analysis suite. Our analysis focused on evaluating the differences in the volumes of various thalamic nuclei groups within the thalami, specifically the anterior, intralaminar, medial, posterior, lateral, and ventral groups in both the right and left thalami, between schizophrenia patients and healthy controls. We employed MANCOVA to analyse these dependent variables (volumes of 12 distinct thalamic nuclei groups), with diagnosis (SCZ vs. HCs) as the main explanatory variable, while controlling for covariates such as eTIV and age. RESULTS: The assumptions of MANCOVA, including the homogeneity of covariance matrices, were met. Specific univariate tests for the right thalamus revealed significant differences in the medial (F[1, 200] = 26.360, p < 0.001), and the ventral groups (F[1, 200] = 4.793, p = 0.030). For the left thalamus, the medial (F[1, 200] = 22.527, p < 0.001); posterior (F[1, 200] = 8.227, p = 0.005), lateral (F[1, 200] = 7.004, p = 0.009), and ventral groups (F[1, 200] = 9.309, p = 0.003) showed significant differences. CONCLUSION: These findings suggest that particular thalamic nuclei groups in both the right and left thalami may be most affected in schizophrenia, with more pronounced differences observed in the left thalamic nuclei. FUNDINGS: The authors received no financial support for the research.

Robust hierarchically organized whole-brain patterns of dysconnectivity in schizophrenia spectrum disorders observed after personalized intrinsic network topography.

BACKGROUND: Spatial patterns of brain functional connectivity can vary substantially at the individual level. Applying cortical surface-based approaches with individualized rather than group templates may accelerate the discovery of biological markers related to psychiatric disorders. We investigated cortico-subcortical networks from multi-cohort data in people with schizophrenia spectrum disorders (SSDs) and healthy controls (HC) using individualized connectivity profiles. METHODS: We utilized resting-state and anatomical MRI data from n = 406 participants (n = 203 SSD, n = 203 HC) from four cohorts. Functional timeseries were extracted from previously defined intrinsic network subregions of the striatum, thalamus, and cerebellum as well as 80 cortical regions of interest, representing six intrinsic networks using (1) volume-based approaches, (2) a surface-based group atlas approaches, and (3) Personalized Intrinsic Network Topography (PINT). RESULTS: The correlations between all cortical networks and the expected subregions of the striatum, cerebellum, and thalamus were increased using a surface-based approach (Cohen's D volume vs. surface 0.27-1.00, all p < 10-6 ) and further increased after PINT (Cohen's D surface vs. PINT 0.18-0.96, all p < 10-4 ). In SSD versus HC comparisons, we observed robust patterns of dysconnectivity that were strengthened using a surface-based approach and PINT (Number of differing pairwise-correlations: volume: 404, surface: 570, PINT: 628, FDR corrected). CONCLUSION: Surface-based and individualized approaches can more sensitively delineate cortical network dysconnectivity differences in people with SSDs. These robust patterns of dysconnectivity were visibly organized in accordance with the cortical hierarchy, as predicted by computational models.

Macroscale Thalamic Functional Organization Disturbances and Underlying Core Cytoarchitecture in Early-Onset Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia is a polygenetic mental disorder with heterogeneous positive and negative symptom constellations, and is associated with abnormal cortical connectivity. The thalamus has a coordinative role in cortical function and is key to the development of the cerebral cortex. Conversely, altered functional organization of the thalamus might relate to overarching cortical disruptions in schizophrenia, anchored in development. STUDY DESIGN: Here, we contrasted resting-state fMRI in 86 antipsychotic-naive first-episode early-onset schizophrenia (EOS) patients and 91 typically developing controls to study whether macroscale thalamic organization is altered in EOS. Employing dimensional reduction techniques on thalamocortical functional connectome (FC), we derived lateral-medial and anterior-posterior thalamic functional axes. STUDY RESULTS: We observed increased segregation of macroscale thalamic functional organization in EOS patients, which was related to altered thalamocortical interactions both in unimodal and transmodal networks. Using an ex vivo approximation of core-matrix cell distribution, we found that core cells particularly underlie the macroscale abnormalities in EOS patients. Moreover, the disruptions were associated with schizophrenia-related gene expression maps. Behavioral and disorder decoding analyses indicated that the macroscale hierarchy disturbances might perturb both perceptual and abstract cognitive functions and contribute to negative syndromes in patients. CONCLUSIONS: These findings provide mechanistic evidence for disrupted thalamocortical system in schizophrenia, suggesting a unitary pathophysiological framework.

Advanced brain age correlates with greater rumination and less mindfulness in schizophrenia.

BACKGROUND: Individual variation in brain aging trajectories is linked with several physical and mental health outcomes. Greater stress levels, worry, and rumination correspond with advanced brain age, while other individual characteristics, like mindfulness, may be protective of brain health. Multiple lines of evidence point to advanced brain aging in schizophrenia (i.e., neural age estimate > chronological age). Whether psychological dimensions such as mindfulness, rumination, and perceived stress contribute to brain aging in schizophrenia is unknown. METHODS: We estimated brain age from high-resolution anatomical scans in 54 healthy controls (HC) and 52 individuals with schizophrenia (SZ) and computed the brain predicted age difference (BrainAGE-diff), i.e., the delta between estimated brain age and chronological age. Emotional well-being summary scores were empirically derived to reflect individual differences in trait mindfulness, rumination, and perceived stress. Core analyses evaluated relationships between BrainAGE-diff and emotional well-being, testing for slopes differences across groups. RESULTS: HC showed higher emotional well-being (greater mindfulness and less rumination/stress), relative to SZ. We observed a significant group difference in the relationship between BrainAge-diff and emotional well-being, explained by BrainAGE-diff negatively correlating with emotional well-being scores in SZ, and not in HC. That is, SZ with younger appearing brains (predicted age < chronological age) had emotional summary scores that were more like HC, a relationship that endured after accounting for several demographic and clinical variables. CONCLUSIONS: These data reveal clinically relevant aspects of brain age heterogeneity among SZ and point to case-control differences in the relationship between advanced brain aging and emotional well-being.

Large-Scale Thalamocortical Triple Network Dysconnectivities in Patients With First-Episode Psychosis and Individuals at Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Aberrant thalamocortical connectivity and large-scale network interactions among the default mode network (DMN), salience network (SN), and executive control network (ECN) (ie, triple networks) have been regarded as critical in schizophrenia pathophysiology. Despite the importance of network properties and the role of the thalamus as an integrative hub, large-scale thalamocortical triple network functional connectivities (FCs) in different stages of the psychotic disorder have not yet been reported. STUDY DESIGN: Thirty-nine first-episode psychosis (FEP) patients, 75 individuals at clinical high risk (CHR) for psychosis, 46 unaffected relatives (URs) of schizophrenia patients with high genetic loading, and 110 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Modular community detection was used to identify cortical and thalamic resting-state networks, and thalamocortical network interactions were compared across the groups. STUDY RESULTS: Thalamic triple networks included higher-order thalamic nuclei. Thalamic SN-cortical ECN FC was greater in the FEP group than in the CHR, UR, and HC groups. Thalamic DMN-cortical DMN and thalamic SN-cortical DMN FCs were greater in FEP and CHR participants. Thalamic ECN-cortical DMN and thalamic ECN-cortical SN FCs were greater in FEP patients and URs. CONCLUSIONS: These results highlight critical modulatory functions of thalamic triple networks and the shared and distinct patterns of thalamocortical triple network dysconnectivities across different stages of psychotic disorders. The current study findings suggest that large-scale thalamocortical triple network dysconnectivities may be used as an integrative biomarker for extending our understanding of the psychosis pathophysiology and for targeting network-based neuromodulation therapeutics.

Negative symptoms are associated with modularity and thalamic connectivity in schizophrenia.

Negative symptoms, including avolition, anhedonia, asociality, blunted affect and alogia are associated with poor long-term outcome and functioning. However, treatment options for negative symptoms are limited and neurobiological mechanisms underlying negative symptoms in schizophrenia are still poorly understood. Diffusion-weighted magnetic resonance imaging scans were acquired from 64 patients diagnosed with schizophrenia and 35 controls. Global and regional network properties and rich club organization were investigated using graph analytical methods. We found that the schizophrenia group had higher modularity, clustering coefficient and characteristic path length, and lower rich connections compared to controls, suggesting highly connected nodes within modules but less integrated with nodes in other modules in schizophrenia. We also found a lower nodal degree in the left thalamus and left putamen in schizophrenia relative to the control group. Importantly, higher modularity was associated with greater negative symptoms but not with cognitive deficits in patients diagnosed with schizophrenia suggesting an alteration in modularity might be specific to overall negative symptoms. The nodal degree of the left thalamus was associated with both negative and cognitive symptoms. Our findings are important for improving our understanding of abnormal white-matter network topology underlying negative symptoms in schizophrenia.

Thalamocortical connectivity and its relationship with symptoms and cognition across the psychosis continuum.

BACKGROUND: Coordination between the thalamus and cortex is necessary for efficient processing of sensory information and appears disrupted in schizophrenia. The significance of this disrupted coordination (i.e. thalamocortical dysconnectivity) to the symptoms and cognitive deficits of schizophrenia is unclear. It is also unknown whether similar dysconnectivity is observed in other forms of psychotic psychopathology and associated with familial risk for psychosis. Here we examine the relevance of thalamocortical connectivity to the clinical symptoms and cognition of patients with psychotic psychopathology, their first-degree biological relatives, and a group of healthy controls. METHOD: Patients with a schizophrenia-spectrum diagnosis (N = 100) or bipolar disorder with a history of psychosis (N = 33), their first-degree relatives (N = 73), and a group of healthy controls (N = 43) underwent resting functional MRI in addition to clinical and cognitive assessments as part of the Psychosis Human Connectome Project. A bilateral mediodorsal thalamus seed-based analysis was used to measure thalamocortical connectivity and test for group differences, as well as associations with symptomatology and cognition. RESULTS: Reduced connectivity from mediodorsal thalamus to insular, orbitofrontal, and cerebellar regions was seen in schizophrenia. Across groups, greater symptomatology was related to less thalamocortical connectivity to the left middle frontal gyrus, anterior cingulate, right insula, and cerebellum. Poorer cognition was related to less thalamocortical connectivity to bilateral insula. Analyses revealed similar patterns of dysconnectivity across patient groups and their relatives. CONCLUSIONS: Reduced thalamo-prefrontal-cerebellar and thalamo-insular connectivity may contribute to clinical symptomatology and cognitive deficits in patients with psychosis as well as individuals with familial risk for psychotic psychopathology.

Neuroanatomical subtypes of schizophrenia and relationship with illness duration and deficit status.

BACKGROUND: The heterogeneity of schizophrenia (SCZ) regarding psychopathology, illness trajectory and their inter-relationships with underlying neural substrates remain incompletely understood. In a bid to reduce illness heterogeneity using neural substrates, our study aimed to replicate the findings of an earlier study by Chand et al. (2020). We employed brain structural measures for subtyping SCZ patients, and evaluate each subtype's relationship with clinical features such as illness duration, psychotic psychopathology, and additionally deficit status. METHODS: Overall, 240 subjects (160 SCZ patients, 80 healthy controls) were recruited for this study. The participants underwent brain structural magnetic resonance imaging scans and clinical rating using the Positive and Negative Syndrome Scale. Neuroanatomical subtypes of SCZ were identified using "Heterogeneity through discriminative analysis" (HYDRA), a clustering technique which accounted for relevant covariates and the inter-group normalized percentage changes in brain volume were also calculated. RESULTS: As replicated, two neuroanatomical subtypes (SG-1 and SG-2) were found amongst our patients with SCZ. The subtype SG-1 was associated with enlargements in the third and lateral ventricles, volume increase in the basal ganglia (putamen, caudate, pallidum), longer illness duration, and deficit status. The subtype SG-2 was associated with reductions of cortical and subcortical structures (hippocampus, thalamus, basal ganglia). CONCLUSIONS: These replicated findings have clinical implications in the early intervention, response monitoring, and prognostication of SCZ. Future studies may adopt a multi-modal neuroimaging approach to enhance insights into the neurobiological composition of relevant subtypes.

Alterations in the volume of thalamic nuclei in patients with schizophrenia and persistent auditory hallucinations.

The thalamus is a subcortical structure formed by different nuclei that relay information to the neocortex. Several reports have already described alterations of this structure in patients of schizophrenia that experience auditory hallucinations. However, to date no study has addressed whether the volumes of specific thalamic nuclei are altered in chronic patients experiencing persistent auditory hallucinations. We have processed structural MRI images using Freesurfer, and have segmented them into 25 nuclei using the probabilistic atlas developed by Iglesias and collaborators (Iglesias et al., 2018). To homogenize the sample, we have matched patients of schizophrenia, with and without persistent auditory hallucinations, with control subjects, considering sex, age and their estimated intracranial volume. This rendered a group number of 41 patients experiencing persistent auditory hallucinations, 35 patients without auditory hallucinations, and 55 healthy controls. In addition, we have also correlated the volume of the altered thalamic nuclei with the total score of the PSYRATS, a clinical scale used to evaluate the positive symptoms of this disorder. We have found alterations in the volume of 8 thalamic nuclei in both cohorts of patients with schizophrenia: The medial and lateral geniculate nuclei, the anterior, inferior, and lateral pulvinar nuclei, the lateral complex and the lateral and medial mediodorsal nuclei. We have also found some significant correlations between the volume of these nuclei in patients experiencing auditory hallucinations, and the total score of the PSYRATS scale. Altogether our results indicate that volumetric alterations of thalamic nuclei involved in audition may be related to persistent auditory hallucinations in chronic schizophrenia patients, whereas alterations in nuclei related to association cortices are evident in all patients. Future studies should explore whether the structural alterations are cause or consequence of these positive symptoms and whether they are already present in first episodes of psychosis.

Common abnormal connectivity in first-episode and chronic schizophrenia in pre- and post-central regions: Implications for neuromodulation targeting.

Schizophrenia is a neurodevelopmental disorder manifesting differing impairments at early onset and chronic disease stages. Brain imaging research suggests a core pathological region in patients with first-episode schizophrenia is Broca's area. With disease progression, alterations in thalamic connectivity becomes more prevalent. Understanding the common circuitry underlying pathology in these two groups might highlight a critical common network and novel targets for treatment. In this study, 937 subject samples were collected including patients with first-episode schizophrenia and those with chronic schizophrenia. We used hypothesis-based voxel-level functional connectivity analyses to calculate functional connectivity using the left Broca's area and thalamus as regions of interest in those with first-episode and chronic schizophrenia, respectively. We show for the first time that in both patients with first-episode and chronic schizophrenia the greatest functional connectivity disruption ended in the pre- and postcentral regions. At the early-onset stage, the core brain region is abnormally connected to pre- and postcentral areas responsible for mouth movement, while in the chronic stage, it expanded to a wider range of sensorimotor areas. Our findings suggest that expanding the focus on the low-order sensory-motor systems beyond high-order cognitive impairments in schizophrenia may show potential for neuromodulation treatment, given the relative accessibility of these cortical regions and their functional and structural connections to the core region at different stages of illness.

Frontotemporal thalamic connectivity in schizophrenia and schizotypal personality disorder.

Schizotypal personality disorder (SPD) resembles schizophrenia, but with attenuated brain abnormalities and the absence of psychosis. The thalamus is integral for processing and transmitting information across cortical regions and widely implicated in the neurobiology of schizophrenia. Comparing thalamic connectivity in SPD and schizophrenia could reveal an intermediate schizophrenia-spectrum phenotype to elucidate neurobiological risk and protective factors in psychosis. We used rsfMRI to investigate functional connectivity between the mediodorsal nucleus (MDN) and pulvinar, and their connectivity with frontal and temporal cortical regions, respectively in 43 healthy controls (HCs), and individuals in the schizophrenia-spectrum including 45 psychotropic drug-free individuals with SPD, and 20 individuals with schizophrenia-related disorders [(schizophrenia (n = 10), schizoaffective disorder (n = 8), schizophreniform disorder (n = 1) and psychosis NOS (n = 1)]. Individuals with SPD had greater functional connectivity between the MDN and pulvinar compared to individuals with schizophrenia. Thalamo-frontal (i.e., between the MDN and rostral middle frontal cortex) connectivity was comparable in SPD and HCs; in SPD greater connectivity was associated with less symptom severity. Individuals with schizophrenia had less thalamo-frontal connectivity and thalamo-temporal (i.e., pulvinar to the transverse temporal cortex) connectivity compared with HCs. Thalamo-frontal functional connectivity may be comparable in SPD and HCs, but abnormal in schizophrenia, and that this may be protective against psychosis in SPD.

Thalamocortical dysrhythmia in patients with schizophrenia spectrum disorder and individuals at clinical high risk for psychosis.

Thalamocortical dysrhythmia (TCD) is a model characterized by abnormal resting-state thalamic oscillatory patterns where the alpha rhythm is replaced by cross-frequency coupling of low- and high-frequency rhythms. Although disrupted thalamic function is a suggested important pathophysiological mechanism underlying schizophrenia, knowledge regarding the TCD model in schizophrenia spectrum disorder (SSD) patients and individuals at clinical high risk (CHR) for psychosis is limited. A total of 169 SSD patients, 106 individuals at CHR for psychosis, and 105 healthy controls (HCs) underwent resting-state electroencephalography recordings. We performed mean global field power (MGFP) spectral analysis between 1 and 49 Hz as well as source-level theta phase-gamma amplitude coupling (TGC) analysis and compared resting-state oscillatory patterns across groups. Correlations between altered TGC values and psychotic symptom severity in the patient group were investigated. Spectral MGFP of low- and high-frequencies was larger in the SSD and CHR groups than in the HC group. The TGC of SSD patients was greater than that of HCs in the right frontal, right parietal, and left and right limbic lobes. Greater TGC in the right frontal and limbic lobes was associated with positive symptom severity in SSD patients. However, TGC in the CHR group was comparable to that in the HCs and was smaller than that in the SSD group in widespread cortical regions. The TCD pattern may be apparent after frank psychotic disorder onset in tandem with overt positive symptoms. A psychosis-risk state without overt psychotic symptoms could be characterized by abnormally increased low- and high-frequency activities with relatively preserved TGC.

Imbalance Between Prefronto-Thalamic and Sensorimotor-Thalamic Circuitries Associated with Working Memory Deficit in Schizophrenia.

BACKGROUND: Thalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia. METHODS: Both n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis. RESULTS: During both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d' score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively. CONCLUSIONS: The thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function.

Thalamic and striato-pallidal volumes in schizophrenia patients and individuals at risk for psychosis: A multi-atlas segmentation study.

Despite previous neuroimaging studies demonstrating morphological abnormalities of the thalamus and other subcortical structures in patients with schizophrenia, the potential role of the thalamus and its subdivisions in the pathophysiology of this illness remains elusive. It is also unclear whether similar changes of these structures occur in individuals at high risk for psychosis. In this study, magnetic resonance imaging was employed with the Multiple Automatically Generated Templates (MAGeT) brain segmentation algorithm to determine volumes of the thalamic subdivisions, the striatum (caudate, putamen, and nucleus accumbens), and the globus pallidus in 62 patients with schizophrenia, 38 individuals with an at-risk mental state (ARMS) [4 of whom (10.5%) subsequently developed schizophrenia], and 61 healthy subjects. Cognitive function of the patients was assessed by using the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). Thalamic volume (particularly the medial dorsal and ventral lateral nuclei) was smaller in the schizophrenia group than the ARMS and control groups, while there were no differences for the striatum and globus pallidus. In the schizophrenia group, the reduction of thalamic ventral lateral nucleus volume was significantly associated with lower BACS score. The pallidal volume was positively correlated with the dose of antipsychotic treatment in the schizophrenia group. These results suggest that patients with schizophrenia, but not those with ARMS, exhibit volume reduction in specific thalamic subdivisions, which may underlie core clinical features of this illness.

A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.

Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.

Grey matter connectome abnormalities and age-related effects in antipsychotic-naive schizophrenia.

BACKGROUND: Convergent evidence is increasing to indicate progressive brain abnormalities in schizophrenia. Knowing the brain network features over the illness course in schizophrenia, independent of effects of antipsychotic medications, would extend our sight on this question. METHODS: We recruited 237 antipsychotic-naive patients with schizophrenia range from 16 to 73 years old, and 254 healthy controls. High-resolution T1 weighted images were obtained with a 3.0T MR scanner. Grey matter networks were constructed individually based on the similarities of regional grey matter measurements. Network metrics were compared between patient groups and healthy controls, and regression analyses with age were conducted to determine potential differential rate of age-related changes between them. FINDINGS: Nodal centrality abnormalities were observed in patients with untreated schizophrenia, particularly in the central executive, default mode and salience networks. Accelerated age-related declines and illness duration-related declines were observed in global assortativity, and in nodal metrics of left superior temporal pole in schizophrenia patients. Although no significant intergroup differences in age-related regression were observed, the pattern of network metric alternation of left thalamus indicated higher nodal properties in early course patients, which decreased in long-term ill patients. INTERPRETATIONS: Global and nodal alterations in the grey matter connectome related to age and duration of illness in antipsychotic-naive patients, indicating potentially progressive network organizations mainly involving temporal regions and thalamus in schizophrenia independent from medication effects. FUNDING: The National Natural Science Foundation of China, Sichuan Science and Technology Program, the Fundamental Research Funds for the Central Universities, Post-Doctor Research Project, West China Hospital, Sichuan University , the Science and Technology Project of the Health Planning Committee of Sichuan, Postdoctoral Interdisciplinary Research Project of Sichuan University and 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Structural alterations in brainstem, basal ganglia and thalamus associated with parkinsonism in schizophrenia spectrum disorders.

The relative roles of brainstem, thalamus and striatum in parkinsonism in schizophrenia spectrum disorder (SSD) patients are largely unknown. To determine whether topographical alterations of the brainstem, thalamus and striatum contribute to parkinsonism in SSD patients, we conducted structural magnetic resonance imaging (MRI) of SSD patients with (SSD-P, n = 35) and without (SSD-nonP, n = 64) parkinsonism, as defined by a Simpson and Angus Scale (SAS) total score of ≥ 4 and < 4, respectively, in comparison with healthy controls (n = 20). FreeSurfer v6.0 was used for segmentation of four brainstem regions (medulla oblongata, pons, superior cerebellar peduncle and midbrain), caudate nucleus, putamen and thalamus. Patients with parkinsonism had significantly smaller medulla oblongata (p = 0.01, false discovery rate (FDR)-corrected) and putamen (p = 0.02, FDR-corrected) volumes when compared to patients without parkinsonism. Across the entire patient sample (n = 99), significant negative correlations were identified between (a) medulla oblongata volumes and both SAS total (p = 0.034) and glabella-salivation (p = 0.007) scores, and (b) thalamic volumes and both SAS total (p = 0.033) and glabella-salivation (p = 0.007) scores. These results indicate that brainstem and thalamic structures as well as basal ganglia-based motor circuits play a crucial role in the pathogenesis of parkinsonism in SSD.

Omega-3 fatty acids during adolescence prevent schizophrenia-related behavioural deficits: Neurophysiological evidences from the prenatal viral infection with PolyI:C.

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35-49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2-ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.