Patterns of white matter microstructure in individuals at ultra-high-risk for psychosis: associations to level of functioning and clinical symptoms

BackgroundIndividuals at ultra-high-risk (UHR) for psychosis present with emerging symptoms and decline in functioning. Previous univariate analyses have indicated widespread white matter (WM) aberrations in multiple brain regions in UHR individuals and patients with schizophrenia. Using multivariate statistics, we investigated whole brain WM microstructure and associations between WM, clinical symptoms, and level of functioning in UHR individuals.MethodsForty-five UHR individuals and 45 matched healthy controls (HCs) underwent magnetic resonance diffusion tensor imaging (DTI) at 3 Tesla. UHR individuals were assessed with the Comprehensive Assessment of At-Risk Mental States, Scale for the Assessment of Negative Symptoms, and Social and Occupational Functioning Assessment Scale. Partial least-squares correlation analysis (PLSC) was used as statistical method.ResultsPLSC group comparisons revealed one significant latent variable (LV) accounting for 52% of the cross-block covariance. This LV indicated a pattern of lower fractional anisotropy (FA), axial diffusivity (AD), and mode of anisotropy (MO) concomitant with higher radial diffusivity (RD) in widespread brain regions in UHR individuals compared with HCs. Within UHR individuals, PLSC revealed five significant LVs associated with symptoms and level of functioning. The first LV accounted for 31% of the cross-block covariance and indicated a pattern where higher symptom score and lower level of functioning correlated to lower FA, AD, MO, and higher RD.ConclusionsUHR individuals demonstrate complex brain patterns of WM abnormalities. Despite the subtle psychopathology of UHR individuals, aberrations in WM appear associated with positive and negative symptoms as well as level of functioning.

Download Full-text

Disturbances in White Matter Integrity in the Ultra-High-Risk Psychosis State—A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm10112515 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2515

Author(s):

Katarzyna Waszczuk ◽

Katarzyna Rek-Owodziń ◽

Ernest Tyburski ◽

Monika Mak ◽

Błażej Misiak ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Diffusion Tensor ◽

Schizophrenia Spectrum Disorders ◽

Schizophrenia Spectrum ◽

Inferior Longitudinal Fasciculus ◽

Ultra High Risk ◽

Recent Developments ◽

And Function

Schizophrenia is a severe and disabling mental illness whose etiology still remains unclear. The available literature indicates that there exist white matter (WM) abnormalities in people with schizophrenia spectrum disorders. Recent developments in modern neuroimaging methods have enabled the identification of the structure, morphology, and function of the underlying WM fibers in vivo. The purpose of this paper is to review the existing evidence about WM abnormalities in individuals at ultra-high risk of psychosis (UHR) with the use of diffusion tensor imaging (DTI) available from the National Center for Biotechnology Information PubMed (Medline) and Health Source: Nursing/Academic Edition databases. Of 358 relevant articles identified, 25 papers published in the years 2008–2020 were ultimately included in the review. Most of them supported the presence of subtle aberrations in WM in UHR individuals, especially in the superior longitudinal fasciculus (SLF), the inferior longitudinal fasciculus (ILF), and the inferior fronto-occipital fasciculus (IFOF). These alterations may therefore be considered a promising neurobiological marker for the risk of psychosis. However, due to methodological discrepancies and the relative scarcity of evidence, further investigation is called for, especially into connectome analysis in UHR patients.

Download Full-text

Early Detection of Ultra High Risk for Psychosis in a Norwegian Catchment Area: The Two Year Follow-Up of the Prevention of Psychosis Study

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.573905 ◽

2021 ◽

Vol 12 ◽

Author(s):

Inge Joa ◽

Jone Bjornestad ◽

Jan Olav Johannessen ◽

Johannes Langeveld ◽

Helen J. Stain ◽

...

Keyword(s):

High Risk ◽

Early Detection ◽

Help Seeking ◽

Catchment Area ◽

Negative Symptoms ◽

Linear Mixed Model ◽

Mental States ◽

First Episode ◽

Ultra High Risk

Objectives: Most individuals experience a relatively long period of sub-clinical psychotic like symptoms, known as the ultra high risk (UHR) or at risk mental states (ARMS), prior to a first episode of psychosis. Approximately 95% of individuals who will later develop psychosis are not referred to specialized clinical services and assessed during the UHR phase. The study aimed to investigate whether a systematic early detection program, modeled after the successful early detection of psychosis program TIPS, would improve the detection of help-seeking UHR individuals. The secondary aim was to examine the rates and predictors of conversion to psychosis after 2 years.Method: The overall study design was a prospective (2012–2018), follow- up study of individuals fulfilling UHR inclusion criteria as assessed by the structural interview for prodromal syndromes (SIPS). Help-seeking UHR individuals were recruited through systematic early detection strategies in a Norwegian catchment area and treated in the public mental health services.Results: In the study period 141 UHR help-seeking individuals were identified. This averages an incidence of 7 per 100,000 people per year. The baseline assessment was completed by 99 of these and the 2 year psychosis conversion rate was 20%. A linear mixed-model regression analysis found that the significant predictors of conversion were the course of positive (0.038) and negative symptoms (0.017). Age was also a significant predictor and showed an interaction with female gender (<0.000).Conclusion: We managed to detect a proportion of UHR individuals in the upper range of the expected prediction by the population statistics and further case enrichment would improve this rate. Negative symptoms were significant predictors. As a risk factor for adverse functional outcomes and social marginalization, this could offer opportunities for earlier psychosocial intervention.

Download Full-text

Disrupted thalamo-orbitofrontal but not fronto-temporal white matter connectivity in people with schizotypal personality disorder

European Psychiatry ◽

10.1016/j.eurpsy.2016.01.082 ◽

2016 ◽

Vol 33 (S1) ◽

pp. S103-S103

Author(s):

T.Y. Lee ◽

S.N. Kim ◽

J.S. Kwon

Keyword(s):

White Matter ◽

Personality Disorder ◽

Negative Symptoms ◽

Diffusion Tensor ◽

Brain Regions ◽

Schizotypal Personality Disorder ◽

Cross Sectional ◽

Schizotypal Personality ◽

Competing Interest ◽

White Matter Connectivity

IntroductionDespite patients with schizophrenia showed the deficits in the fronto-temporal and thalamo-frontal connectivity, the white matter connectivity in patients with schizotypal personality disorder had not been systemically investigated.MethodsThis study involved 40 neuroleptic-naïve patients with schizotypal personality disorder (SPD), 60 patients with schizophrenia (SCZ), and 100 healthy controls (HC), and scanned on the 3T MRI scanner. Probablistic tractography was performed using the FATCAT software in AFNI. The target brain regions (bilateral lateral frontal, medial frontal, orbitofrontal, temporal and thalamus) were extracted from the automated segmentation and cortical parcellation. Cross-sectional comparisons in mean fractional anisotropy (FA) performed on the thalamo-lateral frontal, thalamo-medial frontal, thalamo-orbitofrontal, lateral frontal-temporal and orbitofrontal-temporal pathway. We also analyzed the relationship between the white matter pathway and the Positive and Negative Syndrome Scale and GAF.ResultsThe diffusion tensor imaging showed that SCZ and SPD had decreased FA in the left thalamo-orbitofrontal pathway. However, SPD showed no alteration in the fronto-temporal pathway, despite SCZ showed decreased FA in the left temporo-orbitofrontal pathway. In SCZ, there were significant correlations between FA value in the left temporo-orbitofrontal pathway and negative symptoms score in PANSS and GAF score. However, SPD showed the trend level relationship between the GAF score and FA value in the left temporo-orbitofrontal pathway.ConclusionThese results suggest that the deficits in thalamo-frontal connectivity may be a trait marker of schizophrenia spectrum disorder, and the deficits in fronto-temporal connectivity may play a key role towards the vulnerability of psychosis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Download Full-text

T18. EFFECTS OF COGNITIVE REMEDIATION ON WHITE MATTER IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS – A RANDOMIZED, CONTROLLED CLINICAL TRIAL

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.578 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S237-S238

Author(s):

Tina Kristensen ◽

Bjørn H Ebdrup ◽

Carsten Hjorthøj ◽

Rene C W Mandl ◽

Jayachandra Mitta Raghava ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Negative Symptoms ◽

Cognitive Remediation ◽

Attrition Rate ◽

Healthy Controls ◽

Whole Brain ◽

Ultra High Risk ◽

Secondary Outcomes ◽

Post Hoc

Abstract Background Individuals at ultra-high risk for psychosis (UHR) present with subtle white matter alterations, which have been associated with clinical and functional outcome. The effect of cognitive remediation on white matter (WM) in UHR-individuals has not been investigated. Methods In a randomized, clinical intervention-trial (FOCUS), UHR-individuals aged 18–40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation (CR) for 20 weeks. CR comprised 20 x 2-hour sessions of neurocognitive and social-cognitive training (SCIT). Primary outcome was whole brain fractional anisotropy (FA) derived from diffusion weighted imaging. Secondary outcomes pertained to regions of interest analyses. Planned post-hoc analyses explored dose-response effects of CR on WM. Main analyses of treatment effect of CR on primary and secondary outcomes were conducted using linear mixed models, assessing the interaction of timepoint by group (CR and TAU). Analyses were conducted according to the intention-to-treat principle. Results 111 UHR-individuals and 59 healthy controls were included. Attrition-rate was 30% at 6 months post-treatment follow-up. The CR group completed a mean of 12 hours of neurocognitive training. We found no effect of CR on whole-brain or regional FA. Planned post-hoc analyses revealed significant time*group (high- and low-attendance to CR) interactions in left superior corona radiata (p<0.01), left cingulum cingulate gyrus (P=0.03), and right superior longitudinal fasciculus (P<0,01), corrected. Specifically, when compared to UHR-individuals with high attendance (UHR-high >12 hours), those with low attendance (UHR-low <12 hours) had more co-morbid diagnoses, larger recreational smoking (nicotine and cannabis), more depressive and negative symptoms, and had significantly lower global FA at baseline, and showed a significant increase in FA after treatment. Furthermore, UHR-low displayed large effect-size (ES) improvements on depressive and negative symptoms, and moderate to large ES improvements in several cognitive functions (verbal fluency, verbal working memory, and processing speed). In contrast, UHR-high displayed large ES improvements in UHR-symptoms, and moderate ES improvement on social and occupational functioning. Discussion Contradicting our main hypothesis, we found no effect of CR on whole-brain or regional FA after six months. This may be explained by both the low number of neurocognitive training sessions and the attrition rate. The average of 12 hours of neurocognitive training is considerably lower than the recommended dosage of 25–30 hours necessary for cognitive improvements. The continuous need to develop feasible interventions and enhance adherence is stressed. Nevertheless, non-specific treatment may improve WM-integrity in UHR-individuals with lower global baseline FA in those with more severe psychopathology. The UHR-low subgroup exhibited improvements with large ES in levels of depressive and negative symptoms, as well as cognitive functions. We speculate, whether our results reflect that UHR-individuals with higher baseline FA (approaching the healthy controls), present with a preserved structural capacity for increased demands and new learning, while UHR-individuals characterized by lower FA at baseline may be more amendable to neuroplastic treatment-effects. The results support the value of subgrouping in a clinically heterogenous UHR-population, which also applies to examining WM integrity.

Download Full-text

White matter connectivity and psychosis in ultra-high-risk subjects: A diffusion tensor fiber tracking study

Psychiatry Research Neuroimaging ◽

10.1016/j.pscychresns.2009.10.008 ◽

2010 ◽

Vol 181 (1) ◽

pp. 44-50 ◽

Cited By ~ 48

Author(s):

Bart D. Peters ◽

Peter M. Dingemans ◽

Nienke Dekker ◽

Jorik Blaas ◽

Erik Akkerman ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Diffusion Tensor ◽

Fiber Tracking ◽

Ultra High Risk ◽

White Matter Connectivity

Download Full-text

Changes in negative symptoms are linked to white matter changes in superior longitudinal fasciculus in individuals at ultra-high risk for psychosis

Schizophrenia Research ◽

10.1016/j.schres.2021.09.014 ◽

2021 ◽

Vol 237 ◽

pp. 192-201

Author(s):

Tina D. Kristensen ◽

Louise B. Glenthøj ◽

Jayachandra M. Ragahava ◽

Warda Syeda ◽

Rene C.W. Mandl ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Negative Symptoms ◽

Superior Longitudinal Fasciculus ◽

White Matter Changes ◽

Ultra High Risk

Download Full-text

Distinct white-matter aberrations in 22q11.2 deletion syndrome and patients at ultra-high risk for psychosis

Psychological Medicine ◽

10.1017/s0033291716000970 ◽

2016 ◽

Vol 46 (11) ◽

pp. 2299-2311 ◽

Cited By ~ 10

Author(s):

G. Bakker ◽

M. W. A. Caan ◽

R. S. Schluter ◽

O. J. N Bloemen ◽

F. da Silva- Alves ◽

...

Keyword(s):

White Matter ◽

High Risk ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Superior Temporal Gyrus ◽

Risk Groups ◽

Deletion Syndrome ◽

Psychotic Symptoms ◽

Clinical Criteria ◽

Ultra High Risk

BackgroundPatients with a deletion at chromosome 22q11.2 (22q11DS) have 30% lifetime risk of developing a psychosis. People fulfilling clinical criteria for ultra-high risk (UHR) for psychosis have 30% risk of developing a psychosis within 2 years. Both high-risk groups show white-matter (WM) abnormalities in microstructure and volume compared to healthy controls (HC), which have been related to psychotic symptoms. Comparisons of WM pathology between these two groups may specify WM markers related to genetic and clinical risk factors.MethodFractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) were assessed using diffusion tensor magnetic resonance imaging (MRI), and WM volume with structural MRI, in 23 UHR patients, 21 22q11DS patients, and 33 HC.ResultsCompared to UHR patients 22q11DS patients had (1) lower AD and RD in corpus callosum (CC), cortical fasciculi, and anterior thalamic radiation (ATR), (2) higher FA in CC and ATR, and (3) lower occipital and superior temporal gyrus WM volume. Compared to HC, 22q11DS patients had (1) lower AD and RD throughout cortical fasciculi and (2) higher FA in ATR, CC and inferior fronto-occipital fasciculus. Compared to HC, UHR patients had (1) higher mean MD, RD, and AD in CC, ATR and cortical fasciculi, (2) no differences in FA.ConclusionsUHR and 22q11DS patients share a susceptibility for developing psychosis yet were characterized by distinct patterns of WM alterations relative to HC. While UHR patients were typified by signs suggestive of aberrant myelination, 22q11DS subjects showed signs suggestive of lower axonal integrity.

Download Full-text

Retrospective analysis of hemispheric structural network change as a function of location and size of glioma

Brain Communications ◽

10.1093/braincomms/fcaa216 ◽

2020 ◽

Author(s):

Shawn D’Souza ◽

Lisa Hirt ◽

David R Ormond ◽

John A Thompson

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Temporal Lobe ◽

Diffusion Tensor ◽

Brain Regions ◽

Structural Network ◽

Tumour Location ◽

The Impact ◽

Tractography Data ◽

Diffusion Tensor Imaging Tractography

Abstract Gliomas are neoplasms that arise from glial cell origin and represent the largest fraction of primary malignant brain tumours (77%). These highly infiltrative malignant cell clusters modify brain structure and function through expansion, invasion and intratumoral modification. Depending on the growth rate of the tumour, location and degree of expansion, functional reorganization may not lead to overt changes in behaviour despite significant cerebral adaptation. Studies in simulated lesion models and in patients with stroke reveal both local and distal functional disturbances, using measures of anatomical brain networks. Investigations over the last two decades have sought to use diffusion tensor imaging tractography data in the context of intracranial tumours to improve surgical planning, intraoperative functional localization, and post-operative interpretation of functional change. In this study, we used diffusion tensor imaging tractography to assess the impact of tumour location on the white matter structural network. To better understand how various lobe localized gliomas impact the topology underlying efficiency of information transfer between brain regions, we identified the major alterations in brain network connectivity patterns between the ipsilesional versus contralesional hemispheres in patients with gliomas localized to the frontal, parietal or temporal lobe. Results were indicative of altered network efficiency and the role of specific brain regions unique to different lobe localized gliomas. This work draws attention to connections and brain regions which have shared structural susceptibility in frontal, parietal and temporal lobe glioma cases. This study also provides a preliminary anatomical basis for understanding which affected white matter pathways may contribute to preoperative patient symptomology.

Download Full-text

Quantitative diffusion tensor imaging analysis does not distinguish pediatric canines with mucopolysaccharidosis I from control canines

The Neuroradiology Journal ◽

10.1177/1971400917718844 ◽

2017 ◽

Vol 30 (5) ◽

pp. 454-460

Author(s):

Dana M Middleton ◽

Jonathan Y Li ◽

Steven D Chen ◽

Leonard E White ◽

Patricia I Dickson ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Fractional Anisotropy ◽

Imaging System ◽

Diffusion Tensor ◽

Brain Regions ◽

Magnetic Resonance Imaging System ◽

Radial Diffusivity ◽

Mucopolysaccharidosis I ◽

Diffusivity Measurements

Purpose We compared fractional anisotropy and radial diffusivity measurements between pediatric canines affected with mucopolysaccharidosis I and pediatric control canines. We hypothesized that lower fractional anisotropy and higher radial diffusivity values, consistent with dysmyelination, would be present in the mucopolysaccharidosis I cohort. Methods Six canine brains, three affected with mucopolysaccharidosis I and three unaffected, were euthanized at 7 weeks and imaged using a 7T small-animal magnetic resonance imaging system. Average fractional anisotropy and radial diffusivity values were calculated for four white-matter regions based on 100 regions of interest per region per specimen. A 95% confidence interval was calculated for each mean value. Results No difference was seen in fractional anisotropy or radial diffusivity values between mucopolysaccharidosis affected and unaffected brains in any region. In particular, the 95% confidence intervals for mucopolysaccharidosis affected and unaffected canines frequently overlapped for both fractional anisotropy and radial diffusivity measurements. In addition, in some brain regions a large range of fractional anisotropy and radial diffusivity values were seen within the same cohort. Conclusion The fractional anisotropy and radial diffusivity values of white matter did not differ between pediatric mucopolysaccharidosis affected canines and pediatric control canines. Possible explanations include: (a) a lack of white matter tissue differences between mucopolysaccharidosis affected and unaffected brains at early disease stages; (b) diffusion tensor imaging does not detect any existing differences; (c) inflammatory processes such as astrogliosis produce changes that offset the decreased fractional anisotropy values and increased radial diffusivity values that are expected in dysmyelination; and (d) our sample size was insufficient to detect differences. Further studies correlating diffusion tensor imaging findings to histology are warranted.

Download Full-text