Is treatment-resistant schizophrenia associated with distinct neurobiological callosal connectivity abnormalities?

Abstract Background. Resistance to antipsychotic treatment affects up to 30% of patients with schizophrenia. Although the time course of development of treatment-resistant schizophrenia (TRS) varies from patient to patient, the reasons for these variations remain unknown. Growing evidence suggests brain dysconnectivity as a significant feature of schizophrenia. In this study, we compared fractional anisotropy (FA) of brain white matter between TRS and non–treatment-resistant schizophrenia (non-TRS) patients. Our central hypothesis was that TRS is associated with reduced FA values. Methods. TRS was defined as the persistence of moderate to severe symptoms after adequate treatment with at least two antipsychotics from different classes. Diffusion-tensor brain MRI obtained images from 34 TRS participants and 51 non-TRS. Whole-brain analysis of FA and axial, radial, and mean diffusivity were performed using Tract-Based Spatial Statistics (TBSS) and FMRIB’s Software Library (FSL), yielding a contrast between TRS and non-TRS patients, corrected for multiple comparisons using family-wise error (FWE) < 0.05. Results. We found a significant reduction in FA in the splenium of corpus callosum (CC) in TRS when compared to non-TRS. The antipsychotic dose did not relate to the splenium CC. Conclusion. Our results suggest that the focal abnormality of CC may be a potential biomarker of TRS.

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Plasma dopa decarboxylase activity in treatment-resistant recent-onset psychosis patients

Therapeutic Advances in Psychopharmacology ◽

10.1177/2045125319872341 ◽

2019 ◽

Vol 9 ◽

pp. 204512531987234

Author(s):

Marieke van der Pluijm ◽

Arjen L. Sutterland ◽

André B. P. van Kuilenburg ◽

Lida Zoetekouw ◽

Lieuwe de Haan ◽

...

Keyword(s):

Surrogate Marker ◽

Clinical Problem ◽

Dopa Decarboxylase ◽

Antipsychotic Treatment ◽

Decarboxylase Activity ◽

Treatment Resistant ◽

Significant Group ◽

Adequate Treatment ◽

Recent Onset ◽

Potential Biomarker

Treatment resistance (TR) in psychosis is a major clinical problem. A biomarker predicting TR against conventional antipsychotic drugs would be relevant, potentially reducing unnecessary delay to adequate treatment with clozapine. Dopa decarboxylase (DDC) activity in the striatum, measured with positron emission tomography, is elevated in responders, but not in treatment-resistant patients. Plasma DDC activity could be a surrogate marker for DDC brain activity, and thus a potential biomarker that could be used in daily clinical practice. Therefore, we determined plasma DDC activity in 40 male patients with recent-onset psychosis, of whom the majority had started treatment, whereby 21 turned out to be treatment responders and 19 treatment resistant during follow up. We observed no significant group differences. Furthermore, symptom severity was not associated with plasma DCC activity. We did observe a trend level difference in the distribution of plasma DDC activity across categories of medication, with subsequent post hoc analysis showing lower DDC activity in risperidone-using patients. This may suggest that risperidone could influence plasma DDC activity. Based on these results, plasma DDC activity does not appear to be a promising biomarker for TR in recent-onset psychosis patients who are already receiving antipsychotic treatment.

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Age-Related Variations in Regional White Matter Volumetry and Microstructure During the Post-adolescence Period: A Cross-Sectional Study of a Cohort of 1,713 University Students

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2021.692152 ◽

2021 ◽

Vol 15 ◽

Author(s):

Ami Tsuchida ◽

Alexandre Laurent ◽

Fabrice Crivello ◽

Laurent Petit ◽

Antonietta Pepe ◽

...

Keyword(s):

White Matter ◽

University Students ◽

Diffusion Tensor ◽

Brain Mri ◽

Mean Diffusivity ◽

High Angular Resolution ◽

White Matter Volume ◽

Matter Volume ◽

Brain White Matter ◽

Age Related

Human brain white matter undergoes a protracted maturation that continues well into adulthood. Recent advances in diffusion-weighted imaging (DWI) methods allow detailed characterizations of the microstructural architecture of white matter, and they are increasingly utilized to study white matter changes during development and aging. However, relatively little is known about the late maturational changes in the microstructural architecture of white matter during post-adolescence. Here we report on regional changes in white matter volume and microstructure in young adults undergoing university-level education. As part of the MRi-Share multi-modal brain MRI database, multi-shell, high angular resolution DWI data were acquired in a unique sample of 1,713 university students aged 18–26. We assessed the age and sex dependence of diffusion metrics derived from diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in the white matter regions as defined in the John Hopkins University (JHU) white matter labels atlas. We demonstrate that while regional white matter volume is relatively stable over the age range of our sample, the white matter microstructural properties show clear age-related variations. Globally, it is characterized by a robust increase in neurite density index (NDI), and to a lesser extent, orientation dispersion index (ODI). These changes are accompanied by a decrease in diffusivity. In contrast, there is minimal age-related variation in fractional anisotropy. There are regional variations in these microstructural changes: some tracts, most notably cingulum bundles, show a strong age-related increase in NDI coupled with decreases in radial and mean diffusivity, while others, mainly cortico-spinal projection tracts, primarily show an ODI increase and axial diffusivity decrease. These age-related variations are not different between males and females, but males show higher NDI and ODI and lower diffusivity than females across many tracts. These findings emphasize the complexity of changes in white matter structure occurring in this critical period of late maturation in early adulthood.

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White Matter Integrity Predicts Delay Discounting Behavior in 9- to 23-Year-Olds: A Diffusion Tensor Imaging Study

Journal of Cognitive Neuroscience ◽

10.1162/jocn.2009.21107 ◽

2009 ◽

Vol 21 (7) ◽

pp. 1406-1421 ◽

Cited By ~ 119

Author(s):

Elizabeth A. Olson ◽

Paul F. Collins ◽

Catalina J. Hooper ◽

Ryan Muetzel ◽

Kelvin O. Lim ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

White Matter ◽

Delay Discounting ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Imaging Study ◽

Temporal Lobes ◽

Brain White Matter ◽

Independent Effects ◽

Age Range

Healthy participants (n = 79), ages 9–23, completed a delay discounting task assessing the extent to which the value of a monetary reward declines as the delay to its receipt increases. Diffusion tensor imaging (DTI) was used to evaluate how individual differences in delay discounting relate to variation in fractional anisotropy (FA) and mean diffusivity (MD) within whole-brain white matter using voxel-based regressions. Given that rapid prefrontal lobe development is occurring during this age range and that functional imaging studies have implicated the prefrontal cortex in discounting behavior, we hypothesized that differences in FA and MD would be associated with alterations in the discounting rate. The analyses revealed a number of clusters where less impulsive performance on the delay discounting task was associated with higher FA and lower MD. The clusters were located primarily in bilateral frontal and temporal lobes and were localized within white matter tracts, including portions of the inferior and superior longitudinal fasciculi, anterior thalamic radiation, uncinate fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, and splenium of the corpus callosum. FA increased and MD decreased with age in the majority of these regions. Some, but not all, of the discounting/DTI associations remained significant after controlling for age. Findings are discussed in terms of both developmental and age-independent effects of white matter organization on discounting behavior.

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Abstract 14258: Modulation of Kynurenine Pathway to Prevent Brain Injury After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Circulation ◽

10.1161/circ.144.suppl_2.14258 ◽

2021 ◽

Vol 144 (Suppl_2) ◽

Author(s):

Aurora Magliocca ◽

Carlo Perego ◽

Francesca Motta ◽

Giulia Merigo ◽

Francesca M Fumagalli ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Diffusion Tensor ◽

Neuroprotective Effect ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Kynurenine Pathway ◽

Baseline Heart Rate ◽

Brain White Matter ◽

Fluoro Jade B

Introduction: Kynurenine pathway (KP) is emerging as one of the potential components affecting cardiac arrest (CA) outcomes. The aim of this study is to evaluate the effects of KP inhibition through genetic deletion of the rate-limiting enzyme of the KP, indoleamine-2,3-dyoxygenase (IDO) on survival and neurological outcome after CA. Methods and Results: Sixteen adult male wild-type (WT) and IDO-deleted (IDO -/- ) mice were subjected to 8 min untreated CA followed by resuscitation. At baseline heart rate and mean arterial pressure (MAP) did not differ among groups. At the time of return of spontaneous circulation, 30 and 60 min later, MAP was higher in the IDO -/- group compared to the WT one (p=0.0005). IDO -/- mice showed higher survival compared to WT at 7 days after CA (68.5% in IDO -/- vs 37.5% in WT; log rank p=0.036). Neurological function was higher in IDO -/- than in WT mice during the 7 days following CA (p=0.0124). IDO -/- mice also showed an improved locomotor function compared to WT mice (p=0.037). Brain magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) sequences showed a reduction in fractional anisotropy in the external capsule of the corpus callosum in WT mice compared to IDO -/- mice at 7 days after resuscitation (p=0.015). We then treated additional IDO -/- mice with L-kyn 15 min before CA, to revert the IDO -/- phenotype. Brain MRI with diffusion-weighted imaging (DWI) sequences and histological analysis were performed 24h after CA in WT, IDO -/- , and IDO -/- +L-Kyn mice. Brain MRI revealed restriction of water diffusivity 24h after CA in WT mice. IDO-deletion reduced water diffusion abnormalities while the beneficial effect was reverted in the L-kyn group (p=0.01). Degenerating neurons in the frontal cortex, represented as Fluoro-Jade B positive cells, were more numerous in WT compared to IDO -/- mice; L-kyn halted this IDO deletion-induced reduction in degenerating cells (p=0.05). Conclusion: KP inhibition improves survival and neurological outcome after CA. The neuroprotective effect of IDO-deletion was associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema. Reversal of these beneficial effects by L-kyn administration in IDO -/- mice further confirm the KP role in CA outcome.

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Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia

The British Journal of Psychiatry ◽

10.1192/bjp.bp.110.083907 ◽

2011 ◽

Vol 199 (4) ◽

pp. 275-280 ◽

Cited By ~ 25

Author(s):

Takefumi Suzuki ◽

Gary Remington ◽

Tamara Arenovich ◽

Hiroyuki Uchida ◽

Ofer Agid ◽

...

Keyword(s):

Antipsychotic Medication ◽

Time Course ◽

Rating Scale ◽

Antipsychotic Treatment ◽

Treatment Resistant ◽

Item Score ◽

Double Blind ◽

The Mean ◽

Meta Regression ◽

Item Scores

BackgroundImprovements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia.AimsTo address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia.MethodRandomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of meta-regression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment.ResultsStudy duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0–76%). The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression – Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356).ConclusionsOur findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early. More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.

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Progressive alterations of perilesional brain tissue after Gamma Knife stereotactic radiosurgery: a diffusion tensor imaging study

Innovative Neurosurgery ◽

10.1515/ins-2014-0009 ◽

2015 ◽

Vol 3 (1-2) ◽

Author(s):

Herwin Speckter ◽

José Bido ◽

Giancarlo Hernandez ◽

Diones Rivera ◽

Luis Suazo ◽

...

Keyword(s):

Diffusion Tensor Imaging ◽

Brain Tissue ◽

Gamma Knife ◽

Time Course ◽

Diffusion Tensor ◽

Statistical Significance ◽

Mean Diffusivity ◽

Imaging Study ◽

Vascular Lesion ◽

Cerebral White Matter

AbstractTo search for microstructural lesions of normal-appearing cerebral white matter surrounding a tumor or a vascular lesion, after single-fraction stereotactic Gamma Knife (GK) radiosurgery.In 43 patients with different brain lesions, magnetic resonance including diffusion tensor imaging (DTI) was performed before and after GK radiosurgery and change of parameters was measured in areas surrounding the lesion.Outside the lesion, there was an increase in mean diffusivity (MD) and radial diffusivity (RD) between 2.1% and 3.4% in the 15–10 Gy and in the 10–5 Gy perilesional isodose volumes, which reached statistical significance (pairedWe report some minor, but nevertheless significant changes in DTI parameters in normal-appearing perilesional brain tissue after GK radiosurgery progressing with time, which partially may be induced by the radiation itself and partially may be due to indirect effects of lesion reactions to the radiation. Follow-up studies are necessary for further characterization of these changes and assessment of their time course.

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Spatial Gradient of Microstructural Changes in Normal-Appearing White Matter in Tracts Affected by White Matter Hyperintensities in Older Age

10.1101/412064 ◽

2018 ◽

Author(s):

Susana Muñoz Maniega ◽

Rozanna Meijboom ◽

Francesca M. Chappell ◽

Maria C. Valdés Hernández ◽

John M. Starr ◽

...

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Pathological Process ◽

Spatial Gradient ◽

Microstructural Changes ◽

Normal Appearing White Matter ◽

Brain White Matter ◽

Lothian Birth Cohort

AbstractBrain white matter hyperintensities (WMH), common in older adults, may contribute to cortical disconnection and cognitive dysfunction. The presence of WMH within white matter (WM) tracts indicates underlying microstructural WM changes that may also affect the normal-appearing WM (NAWM) of a tract. We performed an exploratory study using diffusion magnetic resonance imaging of 52 healthy participants from the Lothian Birth Cohort 1936 (age 72.2 ± 0.7 years) selected to include a range of WMH burden, to quantify microstructural changes of tracts intersecting WMH. We reconstructed tracts using automated tractography and identified intersections with WMH. Tissue volumes and water diffusion tensor parameters (mean diffusivity (MD) and fractional anisotropy (FA)) were established for tract-WMH and tract-NAWM. MD and FA were also measured for tract-NAWM at 2 mm incremental distances from the tract-WMH edge, and from the edge of nearby, non-intersecting, WMH. We observed microstructural changes in tract-WMH suggestive of tissue damage. Tract-NAWM also showed a spatial gradient of FA and MD abnormalities, which diminished with distance from the tract-WMH. Nearby WMH lesions, not directly crossed by the tract, also affected tract microstructure with a similar pattern. Additionally, both FA and MD changes in tract-NAWM were predicted by FA and MD changes respectively in tract-WMH. FA was also predicted by tract-WMH overlap volume, whereas MD was better predicted by whole-brain WMH load. These results suggest that tract-NAWM microstructure is affected by the pathological process underlying WMH, when WMH are either within or near to the tract. The changes in NAWM tract tissue may indicate future lesion progression and may play an important role in cognitive ageing.

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18F-AV1451 PET imaging and white matter changes in progressive supranuclear palsy

10.1101/19000596 ◽

2019 ◽

Author(s):

Nicolas Nicastro ◽

Patricia Vazquez Rodriguez ◽

Maura Malpetti ◽

William Richard Bevan-Jones ◽

P. Simon Jones ◽

...

Keyword(s):

White Matter ◽

Progressive Supranuclear Palsy ◽

Pet Imaging ◽

Diffusion Tensor ◽

Brain Mri ◽

Mean Diffusivity ◽

White Matter Integrity ◽

Tau Pathology ◽

Cross Sectional ◽

White Matter Changes

ABSTRACTIntroductionProgressive supranuclear palsy (PSP) is characterized by deposition of straight filament tau aggregates in the grey matter of deep nuclei and cerebellum. White matter changes are increasingly documented as a feature of degenerative parkinsonism. We therefore examined the relationship between tau pathology (assessed via 18F-AV1451 positron emission tomography) and white matter integrity (using diffusion tensor imaging, DTI) in PSP.MethodsTwenty-three people with clinically probable PSP-Richardson’s syndrome (age 68.8 ± 5.8 years, 39% female) and 23 controls underwent structural 3T brain MRI including DTI. Twenty-one patients also underwent 18F-AV145 PET imaging. DTI group comparisons were performed using Fractional Anisotropy (FA), Mean Diffusivity (MD) and Radial Diffusivity (RD). Voxel-wise white matter integrity was correlated with 18F-AV1451 binding in typical subcortical PSP regions of interest (i.e. putamen, pallidum, thalamus and midbrain). DTI and 18F-AV1451 imaging measures were correlated with clinical impairment.ResultsWidespread DTI changes in PSP subjects relative to controls (family-wise error FWE p<0.01) were observed. In PSP, higher 18F-AV1451 binding correlated with reduced white matter integrity in the bilateral internal capsule, corona radiata, and superior longitudinal fasciculus (FWE p<0.05). Association between cognitive impairment (ACER score) and white matter deficits were found in the genu of corpus callosum and cingulum (p<0.005).ConclusionThis cross-sectional study demonstrates an association between in vivo proxy measures of tau pathology and white matter degeneration in PSP. Longitudinal studies and more specific PET probes for non-Alzheimer tauopathies are warranted to assess the complex interplay between microstructural changes and protein deposition in PSP.

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A Diffusion Tensor Imaging Study on the Phonology-related Pathways in Cantonese-mandarin Bilinguals.

10.21203/rs.3.rs-1168282/v1 ◽

2021 ◽

Author(s):

Xiaoyu Xu ◽

Yuying Jin ◽

Ning Pan ◽

Muqing Cao ◽

Jin Jing ◽

...

Keyword(s):

White Matter ◽

Phonological Processing ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Imaging Study ◽

Brain White Matter ◽

The Mean ◽

The Right ◽

Long Term Experience

Abstract Cantonese and Mandarin are logographic languages, and the phonology is the main difference between the two languages. It is unclear whether long-term experience of Cantonese-Mandarin bilingualism will shape different brain white matter structures of pathways related to phonological processing. 30 Cantonese-Mandarin bilinguals and 30 Mandarin monolinguals completed diffusion-weighted imaging (DWI) scans and phonological processing tasks. The tractography and TBSS were used to investigate the structural differences in the bilateral superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and inferior fronto-occipital fasciculus (IFOF) between Cantonese-Mandarin bilinguals and Mandarin monolinguals. Post-hoc correlation analysis was conducted to investigate the relationship between the different structures with phonological processing skills. Compared to the Mandarin monolinguals, the Cantonese-Mandarin bilinguals had higher fractional anisotropy (FA) along the left ILF, higher mean diffusivity (MD) in the clusters along the temporoparietal segment of SLF (tSLF), as well as higher axial diffusivity (AD) in the right tSLF, IFOF, bilateral ILF. The mean AD of the different voxels in the right IFOF and the mean FA of the different voxels in the left ILF were positively correlated with the inverse efficiency score (IES) of the Cantonese auditory and Mandarin visual rhyming judgment tasks respectively within the bilingual group. Long-term experience of Cantonese-Mandarin bilinguals shape different brain white matter structures including right tSLF, IFOF, bilateral ILF. The bilinguals’ white matter showed higher diffusivity, especially in the axonal direction, than the monolinguals. These changes were related to bilinguals’ phonological processing.

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Abstract P64: Longitudinal Brain Structural Changes After Stroke

Stroke ◽

10.1161/str.52.suppl_1.p64 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Kyle C Kern ◽

Clinton B Wright ◽

Richard Leigh

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Stroke Volume ◽

Brain Atrophy ◽

Structural Changes ◽

Diffusion Tensor ◽

Brain Mri ◽

Mean Diffusivity ◽

Intracranial Volume ◽

Post Stroke

Background: Stroke causes focal and diffuse structural brain changes that may contribute to subsequent cognitive decline and dementia. We hypothesize that MRI structural measures can detect continued cerebral degeneration over the first year after stroke. We identify predictors for progression of brain atrophy, leukoaraiosis and diffusion tensor imaging (DTI) metrics. Methods: Patients with ischemic stroke were enrolled prospectively in an observational study that included serial brain MRI. Patients underwent MRI FLAIR and DTI at the time of acute stroke and were followed for at least 9 months with multiple MRIs between 30 days and 15 months post-stroke. We used FLAIR to measure brain atrophy as the percent brain parenchymal fraction (BPF) of the total intracranial volume (TICV) and white matter hyperintensity volume (WMHV) as a percentage of TICV. DTI was used to calculate Peak Skeletonized Mean Diffusivity (PSMD), a global measure of white matter integrity previously validated in cerebral small vessel disease. Longitudinal changes in BPF, WMHV or PSMD were measured from 30 days post-stroke onward using linear regression models that included age, stroke volume, baseline BPF and WMHV as predictors. Results: Twenty-six patients had a median of 4 follow-ups over 9-15 months. Median age was 74 years (range 51-84) and 38% were women. Mean stroke volume was 4.5cc (0 - 30cc). Mean BPF was 78% (72 - 86%) and mean baseline WMHV was 1.1% (0.1 - 3.9%). BPF was associated with age and declined by 0.7% per year (t(111) = 2.7, p = 0.007). Progression was associated with baseline BPF (t(111) = -3.4, p < 0.001). WMHV in the non-stroke hemisphere was associated with age and increased by 0.10% per year (t(87) = -5.8, p < 0.001). Accumulation was associated with age (t(87) = 5.8, p < 0.001). PSMD was associated with baseline WMHV and had a relative increase of 1.9% per year in the non-stroke hemisphere and 4.5% in the stroke hemisphere (t(174) = -2.1, p = 0.03). Progression was associated with age (t(174) = 2.3, p = 0.03) and stroke volume (t(174) = 2.4, p = 0.02). Conclusions: During the months after ischemic stroke, BPF, WMHV and PSMD can detect persistent structural changes that may reflect later phases of stroke injury or ongoing contributions of aging, silent ischemia, or neurodegeneration.

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