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Tractography of 5 white matter tracts. Sagittal view of the tractography of the inferior longitudinal fasciculus (green), the superior longitudinal fasciculus (blue), arcuate fasciculus (red), uncinate fasciculus (pink), and the cingulum bundle (yellow).
Source publication
Purpose:
Tractography is the most anatomically accurate method for delineating white matter tracts in the brain, yet few studies have examined multiple tracts using tractography in patients with schizophrenia (SCZ). We analyze 5 white matter connections important in the pathophysiology of SCZ: uncinate fasciculus, cingulum bundle (CB), inferior lo...
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Basal ganglia and the cerebellum are part of a densely interconnected network. While both subcortical structures process information in basically segregated loops that primarily interact in the neocortex, direct subcortical interaction has been recently confirmed by neuroanatomical studies using viral transneuronal tracers in non-human primate brai...
Citations
... The rationale for choosing manual tracts of interest estimation was that automated tract identification is often anatomically inaccurate in populations with significant damage to connections [83]. While manual approaches can be impractical with large cohorts and rely on human expertise, manual fiber bundle identification results in low values of true negatives [82] and has commonly been used with patient populations [84][85][86]. ...
Background:
Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are common in Veterans and linked to behavioral disturbances, increased risk of cognitive decline, and Alzheimer's disease.
Objective:
We studied the synergistic effects of PTSD and TBI on behavioral, cognitive, and neuroimaging measures in Vietnam war Veterans.
Methods:
Data were acquired at baseline and after about one-year from male Veterans categorized into: PTSD, TBI, PTSD+TBI, and Veteran controls without PTSD or TBI. We applied manual tractography to examine white matter microstructure of three fiber tracts: uncinate fasciculus (N = 91), cingulum (N = 87), and inferior longitudinal fasciculus (N = 95). ANCOVAs were used to compare Veterans' baseline behavioral and cognitive functioning (N = 285), white matter microstructure, amyloid-β (N = 230), and tau PET (N = 120). Additional ANCOVAs examined scores' differences from baseline to follow-up.
Results:
Veterans with PTSD and PTSD+TBI, but not Veterans with TBI only, exhibited poorer behavioral and cognitive functioning at baseline than controls. The groups did not differ in baseline white matter, amyloid-β, or tau, nor in behavioral and cognitive functioning, and tau accumulation change. Progression of white matter abnormalities of the uncinate fasciculus in Veterans with PTSD compared to controls was observed; analyses in TBI and PTSD+TBI were not run due to insufficient sample size.
Conclusions:
PTSD and PTSD+TBI negatively affect behavioral and cognitive functioning, while TBI does not contribute independently. Whether progressive decline in uncinate fasciculus microstructure in Veterans with PTSD might account for cognitive decline should be further studied. Findings did not support an association between PTSD, TBI, and Alzheimer's disease pathology based on amyloid and tau PET.
... Our finding might also suggest that inhibitory control deficits precede positive symptoms in psychosis. Further, consistent with the idea that RH findings may occur early in the course of illness and may reflect a neurodevelopment process, i.e., a failure of typical maturation, we note both a prior study of subjects at clinical high risk of psychosis that showed more pronounced abnormalities in WM microstructure in the right hemisphere [90] and a study showing microstructural abnormalities in the RH in early-course schizophrenia [91]. ...
Background
Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography.
Methods
Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively.
Results
We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions.
Conclusions
In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.
... В зарубежной литературе широко представлены данные об изменениях показателей диффузиифракционной анизотропии (ФА), аксиальной, радиальной диффузивности (diffusivity) и другихв структурах ГМ при шизофрении [5][6][7], корреляции показателей с клиническими данными и результатами нейропсихологического тестирования (например, наличием слуховых галлюцинаций, нарушений стройности ассоциативного процесса, персистирующих негативных симптомов [8][9][10][11]), оценки рабочей памяти и скорости мышления [6] и других функций, а также с результатами специфического анализа сетей с помощью теории графов [12] и анализа независимых компонент [13]. P.A. Geoffroy и соавт. ...
... В зарубежной литературе широко представлены данные об изменениях показателей диффузиифракционной анизотропии (ФА), аксиальной, радиальной диффузивности (diffusivity) и другихв структурах ГМ при шизофрении [5][6][7], корреляции показателей с клиническими данными и результатами нейропсихологического тестирования (например, наличием слуховых галлюцинаций, нарушений стройности ассоциативного процесса, персистирующих негативных симптомов [8][9][10][11]), оценки рабочей памяти и скорости мышления [6] и других функций, а также с результатами специфического анализа сетей с помощью теории графов [12] и анализа независимых компонент [13]. P.A. Geoffroy и соавт. ...
Background : inconsistency of the obtained results of research on the pathology of microstructural connectivity in schizophrenia on the basis of tractography, absence of clinical application of special MRI techniques justify the need to continue scientific search in this direction. Objective : to identify the features of microstructural pathology of the brain in paranoid schizophrenia. Patients and methods : 25 patients diagnosed with paranoid schizophrenia (F20.0) were included in the main group, 30 healthy subjects without neurological and somatic diseases made up the control group. Instrumental studies were carried out on a Philips Ingenia magnetic resonance tomograph (magnetic field strength 1.5 T) using a DTI pulse sequence. Subsequent processing was carried out using “DSI Studio” (software for the analysis of tractor data). Results and discussion : the resulting microstructural brain changes demonstrated differences in the microstructural connectivity of the brain in patients with paranoid schizophrenia compared to the control group. Significant connections were revealed (at the given parameters for constructing connectivity matrices) between the hippocampus and the cingulate gyrus, the hippocampus and thalamus, thalamus and structures of the striopallidar system, and the absence of significant connections between the amygdala in the main group compared to the control group. The results of graph theoretical analysis of neural network indicators of the brain demonstrated higher values of indicators of “clustering” and the “small world” coefficient, characteristic path length, transitivity, density, and lower values of the global efficiency indicator of the main group compared to the control group. Conclusion : the obtained results demonstrate microstructural semiotics of neural network changes of brain in paranoid schizophrenia. Changes in the connectivity of the hippocampus, thalamus, and amygdala appear to be important tractographic semiotic features of the microstructural pathology of the brain in paranoid schizophrenia. The study is one of the stages of the search for a method of objectification and detection of disruption of brain neuroplasticity processes in the endogenous pathology of the schizophrenic spectrum.
... Abnormal white matter microstructure also associates with cognitive deficits in schizophrenia, as evidenced by recent connectivity and connectome studies (Kochunov et al. 2017;Peng et al. 2020;Seitz et al. 2016;Wannan et al. 2022;Zeng et al. 2016). The structural connectome is a network representation of the brain, where cortical and subcortical regions define network nodes and white matter fibers inferred from tractography connect node pairs. ...
Schizophrenia has long been thought to be a disconnection syndrome and several previous studies have reported widespread abnormalities in white matter tracts in individuals with schizophrenia. Furthermore, reductions in structural connectivity may also impair communication between anatomically unconnected pairs of brain regions, potentially impacting global signal traffic in the brain. Therefore, we used different communication models to examine direct and indirect structural connections (polysynaptic) communication in large-scale brain networks in schizophrenia. Diffusion-weighted magnetic resonance imaging scans were acquired from 62 patients diagnosed with schizophrenia and 35 controls. In this study, we used five network communication models including, shortest paths, navigation, diffusion, search information and communicability to examine polysynaptic communication in large-scale brain networks in schizophrenia. We showed less efficient communication between spatially widespread brain regions particulary encompassing cortico-subcortical basal ganglia network in schizophrenia group relative to controls. Then, we also examined whether reduced communication efficiency was related to clinical symptoms in schizophrenia group. Among different measures of communication efficiency, only navigation efficiency was associated with global cognitive impairment across multiple cognitive domains including verbal learning, processing speed, executive functions and working memory, in individuals with schizophrenia. We did not find any association between communication efficiency measures and positive or negative symptoms within the schizophrenia group. Our findings are important for improving our mechanistic understanding of neurobiological process underlying cognitive symptoms in schizophrenia.
... Given the relationship between WM microstructure and cognition in healthy populations [69,85,86] and the previously described WM pathology in schizophrenia [23,[31][32][33][34][87][88][89], we applied regression-mediation analyses to elucidate the association between a diagnosis of schizophrenia, WM microstructure, and cognitive deficits. ...
Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).
... Previous studies utilizing a single-compartment diffusion tensor imaging model also reported reductions in the traditional FA metric in similar areas for psychotic ADO-BPD ( Barnea-Goraly et al., 2009;Frazier et al., 2007;Lagopoulos et al., 2013;Mahapatra et al., 2017;Roberts et al., 2016;Versace et al., 2010), and ADO-SCZ (Clark et al., 2012;Douaud et al., 2007;Drakesmith et al., 2016;Moran et al., 2015). Of note, these tracts (in particular, the corpus callosum) have also demonstrated the most consistent differences between healthy individuals and adult individuals with psychosis (Kelly et al., 2018), and our finding of widespread differences between the psychotic groups and HCs is in line with the previously published adult psychosis literature Kelly et al., 2018;Seitz et al., 2016;Seitz-Holland et al., 2021). ...
Background
While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need.
Methods
Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FA T ) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FA T and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence.
Results
Individuals with adolescent-onset psychosis exhibited pronounced FW and FA T abnormalities compared to HCs. FA T reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FA T was positively related to age.
Conclusions
We observe evidence for cellular (FA T ) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.
... Diffusion tensor imaging (DTI) provides unique information about white-matter microstructural properties that are useful in characterising pathophysiology in brain disorders [10]. Changes in fractional anisotropy (FA) and mean diffusivity (MD) are indicative of white-matter pathology [11]. Studies using dMRI have shown reduced FA and altered MD in individuals with schizophrenia relative to controls [12][13][14]. ...
White-matter abnormalities, including increases in extracellular free-water, are implicated in the pathophysiology of schizophrenia. Recent advances in diffusion magnetic resonance imaging (MRI) enable free-water levels to be indexed. However, the brain levels in patients with schizophrenia have not yet been systematically investigated. We aimed to meta-analyse white-matter free-water levels in patients with schizophrenia compared to healthy volunteers. We performed a literature search in EMBASE, MEDLINE, and PsycINFO databases. Diffusion MRI studies reporting free-water in patients with schizophrenia compared to healthy controls were included. We investigated the effect of demographic variables, illness duration, chlorpromazine equivalents of antipsychotic medication, type of scanner, and clinical symptoms severity on free-water measures. Ten studies, including five of first episode of psychosis have investigated free-water levels in schizophrenia, with significantly higher levels reported in whole-brain and specific brain regions (including corona radiata, internal capsule, superior and inferior longitudinal fasciculus, cingulum bundle, and corpus callosum). Six studies, including a total of 614 participants met the inclusion criteria for quantitative analysis. Whole-brain free-water levels were significantly higher in patients relative to healthy volunteers (Hedge’s g = 0.38, 95% confidence interval (CI) 0.07–0.69, p = 0.02). Sex moderated this effect, such that smaller effects were seen in samples with more females ( z = −2.54, p < 0.05), but antipsychotic dose, illness duration and symptom severity did not. Patients with schizophrenia have increased free-water compared to healthy volunteers. Future studies are necessary to determine the pathological sources of increased free-water, and its relationship with illness duration and severity.
... Diffusion tensor imaging (DTI) provides unique information about white-matter microstructural properties that are useful in characterising pathophysiology in brain disorders [10]. Changes in fractional anisotropy (FA) and mean diffusivity (MD) are indicative of white-matter pathology [11]. Studies using dMRI have shown reduced FA and altered MD in individuals with schizophrenia relative to controls [12][13][14]. ...
... Most dMRI studies have utilized the fractional anisotropy (FA) measure, and FA reductions are frequently interpreted as indicators of compromised WM (e.g., fiber density, myelination, or tract coherence) [4]. Earlier studies have reported widespread FA reductions across multiple WM areas [5][6][7] at all stages of SCZ [8][9][10][11][12][13]. ...
... Several smaller studies explored the relationship between symptoms and WM structure [10,[57][58][59], focusing on specific symptoms, tracts, and populations. However, results have been relatively inconsistent, and the existing evidence has not been convincing enough to demonstrate that symptoms are associated with WM tracts. ...
White matter (WM) abnormalities are repeatedly demonstrated across the schizophrenia time-course. However, our understanding of how demographic and clinical variables interact, influence, or are dependent on WM pathologies is limited. The most well-known barriers to progress are heterogeneous findings due to small sample sizes and the confounding influence of age on WM. The present study leverages access to the harmonized diffusion magnetic-resonance-imaging data and standardized clinical data from 13 international sites (597 schizophrenia patients (SCZ)). Fractional anisotropy (FA) values for all major WM structures in patients were predicted based on FA models estimated from a healthy population (n = 492). We utilized the deviations between predicted and real FA values to answer three essential questions. (1) “Which clinical variables explain WM abnormalities?”. (2) “Does the degree of WM abnormalities predict symptom severity?”. (3) “Does sex influence any of those relationships?”. Regression and mediator analyses revealed that a longer duration-of-illness is associated with more severe WM abnormalities in several tracts. In addition, they demonstrated that a higher antipsychotic medication dose is related to more severe corpus callosum abnormalities. A structural equation model revealed that patients with more WM abnormalities display higher symptom severity. Last, the results exhibited sex-specificity. Males showed a stronger association between duration-of-illness and WM abnormalities. Females presented a stronger association between WM abnormalities and symptom severity, with IQ impacting this relationship. Our findings provide clear evidence for the interaction of demographic, clinical, and behavioral variables with WM pathology in SCZ. Our results also point to the need for longitudinal studies, directly investigating the casualty and sex-specificity of these relationships, as well as the impact of cognitive resiliency on structure-function relationships.
... 43 Our findings are consistent with diffusion imaging studies in schizophrenia reporting reduced white matter integrity in general 25,[44][45][46] and reduced integrity of the cingulum bundle, a white matter tract that structurally connects regions of the DMN, specifically. 47 While FA is generally conceptualized as a non-specific marker of white matter integrity, other diffusion indices may yield additional information about the underlying pathophysiology. For example, preclinical studies have identified reduced AD in the corpus callosum as a potential marker of axonal damage. ...
Introduction
Only a few studies have comprehensively characterized DMN pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis patients (FEP), and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response.
Methods
Diffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response.
Results
We detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment.
Conclusion
Our study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.
