Philipp S. Baumann

Structural connectomics in brain diseases

Imaging the connectome in vivo has become feasible through the integration of several rapidly developing fields of science and engineering, namely magnetic resonance imaging and in particular diffusion MRI on one side, image processing and network theory on the other side. This framework brings in vivo brain imaging closer to the real topology of the brain, contributing to narrow the existing gap between our understanding of brain structural organization on one side and of human behavior and cognition on the other side. Given the seminal technical progresses achieved in the last few years, it may be ready to tackle even greater challenges, namely exploring disease mechanisms. In this review we analyze the current situation from the technical and biological perspectives. First, we critically review the technical solutions proposed in the literature to perform clinical studies. We analyze for each step (i.e. MRI acquisition, network building and network statistical analysis) the advantages and potential limitations. In the second part we review the current literature available on a selected subset of diseases, namely, dementia, schizophrenia, multiple sclerosis and others, and try to extract for each disease the common findings and main differences between reports.

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne): implementation of an early intervention programme for psychosis in Switzerland

In a survey conducted in the Lausanne catchment area in 2000, we could estimate on the basis of file assessment that first‐episode psychosis (FEP) patients had psychotic symptoms for more than 2 years before treatment and that 50% did not attend any outpatient appointment after discharge from hospital. In this paper, we describe the implementation of a specialized programme aimed at improving engagement and quality of treatment for early psychosis patients in the Lausanne catchment area in Switzerland.

Characterizing the connectome in schizophrenia with diffusion spectrum imaging

Schizophrenia is a complex psychiatric disorder characterized by disabling symptoms and cognitive deficit. Recent neuroimaging findings suggest that large parts of the brain are affected by the disease, and that the capacity of functional integration between brain areas is decreased. In this study we questioned (i) which brain areas underlie the loss of network integration properties observed in the pathology, (ii) what is the topological role of the affected regions within the overall brain network and how this topological status might be altered in patients, and (iii) how white matter properties of tracts connecting affected regions may be disrupted. We acquired diffusion spectrum imaging (a technique sensitive to fiber crossing and slow diffusion compartment) data from 16 schizophrenia patients and 15 healthy controls, and investigated their weighted brain networks. The global connectivity analysis confirmed that patients present disrupted integration and segregation properties. The nodal analysis allowed identifying a distributed set of brain nodes affected in the pathology, including hubs and peripheral areas. To characterize the topological role of this affected core, we investigated the brain network shortest paths layout, and quantified the network damage after targeted attack toward the affected core. The centrality of the affected core was compromised in patients. Moreover the connectivity strength within the affected core, quantified with generalized fractional anisotropy and apparent diffusion coefficient, was altered in patients. Taken together, these findings suggest that the structural alterations and topological decentralization of the affected core might be major mechanisms underlying the schizophrenia dysconnectivity disorder. Hum Brain Mapp, 36:354–366, 2015.

Genetic Polymorphism Associated Prefrontal Glutathione and Its Coupling With Brain Glutamate and Peripheral Redox Status in Early Psychosis

BACKGROUND Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. METHODS Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. RESULTS Significantly lower [GSHmPFC] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSHmPFC] and blood GPx activities correlate positively in controls (P = .021), but negatively in patients (P = .039). In GCLC low-risk genotypes, [GlumPFC] are lower in patients, while it is not the case for high-risk genotypes. CONCLUSIONS GCLC high-risk genotypes are associated with low [GSHmPFC], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.

High b-value diffusion-weighted imaging: A sensitive method to reveal white matter differences in schizophrenia

Over the last 10 years, diffusion-weighted imaging (DWI) has become an important tool to investigate white matter (WM) anomalies in schizophrenia. Despite technological improvement and the exponential use of this technique, discrepancies remain and little is known about optimal parameters to apply for diffusion weighting during image acquisition. Specifically, high b-value diffusion-weighted imaging known to be more sensitive to slow diffusion is not widely used, even though subtle myelin alterations as thought to happen in schizophrenia are likely to affect slow-diffusing protons. Schizophrenia patients and healthy controls were scanned with a high b-value (4000 s/mm(2)) protocol. Apparent diffusion coefficient (ADC) measures turned out to be very sensitive in detecting differences between schizophrenia patients and healthy volunteers even in a relatively small sample. We speculate that this is related to the sensitivity of high b-value imaging to the slow-diffusing compartment believed to reflect mainly the intra-axonal and myelin bound water pool. We also compared these results to a low b-value imaging experiment performed on the same population in the same scanning session. Even though the acquisition protocols are not strictly comparable, we noticed important differences in sensitivities in the favor of high b-value imaging, warranting further exploration.

N-acetylcysteine in a Double-Blind Randomized Placebo-Controlled Trial: Toward Biomarker-Guided Treatment in Early Psychosis

Abstract Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Age at the time of exposure to trauma modulates the psychopathological profile in patients with early psychosis.

OBJECTIVE To examine the potential differential impact of childhood trauma, according to the age at the time of exposure, on the psychopathological profile of patients with early psychosis treated in a specialized 3-year program during the early phase of the disease. METHODS 196 subjects with early psychosis aged 18-35 years were followed up prospectively over 36 months of treatment between 2004 and 2010. Patients who had faced at least 1 experience of abuse (physical, sexual, or emotional) or neglect (physical or emotional) were classified according to age at the time of the first exposure (early trauma: before 12 years of age; late trauma: from age 12 through 16 years) and then compared with unexposed patients (nontrauma). The level of symptoms was assessed using the Positive and Negative Syndrome Scale, the Young Mania Rating Scale, and the Montgomery-Asberg Depression Rating Scale. RESULTS Exposure to 1 or more forms of trauma before 16 years of age was present in 31.63% of patients. Comparisons over the 3 years of treatment with the nontrauma patients revealed that (1) patients with early trauma showed consistently higher levels of positive (P = .006), depressive (P = .001), manic (P = .006), and negative (P = .029) symptoms and (2) patients with late trauma showed only more negative symptoms (P = .029). CONCLUSIONS These results suggest that the age at the time of exposure to trauma has a modulating effect on symptoms in patients with early psychosis. Various biological and psychological hypotheses can be proposed to explain this observation, and they need to be investigated in an experimental setting in order to develop therapeutic avenues.

Assertive outreach for "difficult to engage" patients: A useful tool for a subgroup of patients in specialized early psychosis intervention programs.

PURPOSE Most specialized Early Psychosis (EP) programs include assertive outreach (AO) principles, either for all patients or as an intensive case management (ICM) subprogram in selected situations. The objective of this study is to examine prevalence, characteristics and outcomes of patients who needed additional ICM in a specialized EP program. METHODS In a 3-year prospective naturalistic study of 229 consecutive EP patients treated at TIPP-Lausanne we compared characteristics of those who needed ICM and those who did not. RESULTS 60 (26.2%) TIPP patients needed ICM. At baseline, ICM-patients showed a poorer academic premorbid functioning (p=0.019); lower level of insight (p<0.001); had a previous history of alcohol (p=0.043) and cannabis (p=0.040) use. ICM-patients were less likely to be adherent to medication during the early phase of treatment but differences disappeared during follow-up. ICM-patients showed globally a poorer functional level and higher level of positive and negative symptoms during the follow-up. CONCLUSIONS About one quarter of EP patients needed a combination of ICM and assertive outreach. Despite the high treatment adherence in both groups, psychotic symptoms remained higher in ICM-patients. In a real live setting with limited resources, combination of ICM and AO in selected situations seems a valid solution.

Insight et comportements violents dans une cohorte de patients souffrant de premiers épisodes de psychose

Objectives: An important proportion of patients with first episode psychosis behave in a violent, hetero-aggressive manner. This study aims to explore the association between insight and violent behavior (VB), and insight evolution in the follow-up period. Method: The study was carried out with a prospective cohort of 265 patients recruited from the early treatment and intervention for psychotic disorders program, and followed for a 3-year period. Insight assessing is based on a 3-item scale and the insight item in Positive and Negative Syndrome Scale (PANSS). VBs were evaluated by case managers, information from forensic services and through a record of VBs noted during hospitalization. Univariate and multivariate logistic regression analyses, t-tests and correlations were conducted. Results: The significant effect of insight as a factor associated with VBs that was found in univariate analyses disappears after controlling for the effect of positive symptoms, substance addiction diagnosis, impulsivity and treatment compliance. Conclusion: If patient insight in their illness develops positively during treatment, our results suggest that the risk of VBs occurring is not influenced by insight level. On the other hand, it is significantly linked to substance abuse and impulsivity, which might implicate focusing on these 2 dimensions in preventive strategies. Insight impact on VB should be further explored in more focused prospective analyses.Objectifs: Une proportion importante de patients présentant un premier épisode psychotique commettent des actes violents hétéro-agressifs. L’objectif de cette étude est d’explorer l’association entre insight et comportement violent (CV) et l’évolution de l’insight durant la période de suivi. Méthode: L’étude est conduite sur une cohorte prospective de 265 patients recrutés au sein du programme de traitement et d’intervention précoce dans les troubles psychotiques et suivis sur une période de 3 ans. L’évaluation de l’insight est basée sur une échelle d’insight en 3 points et l’item de l’insight à la Positive and Negative Syndrome Scale (PANSS). Les CV ont été évalués par les case-managers, par les informations provenant des services forensiques et par l’intermédiaire d’un relevé des CV en cours d’hospitalisation. Des analyses de régression logistique uni-variées et multi-variées, des tests-t et des corrélations ont été réalisés. Résultats: L’effet significatif de l’insight comme facteur associé aux CV trouvé dans les analyses uni-variées disparaît après avoir contrôlé l’effet des symptômes positifs, du diagnostic de dépendance aux substances, de l’impulsivité et de l’adhésion au traitement. Conclusion: Si la prise de conscience des patients à l’égard de leur maladie évolue positivement au cours du traitement, nos résultats suggèrent que le risque de survenue de CV n’est pas influencé par le degré d’insight. Il est par contre significativement lié à l’abus de substances et à l’impulsivité, impliquant de cibler ces deux dimensions dans les stratégies préventives. L’impact de l’insight sur le CV doit être l’objet d’analyses prospectives plus précises.