Neurobiochemistry

Prof. Dr. Stefan Smesny

About

Prof. Smesny’s group has been working since 20 years in the field of neurobiochemistry and neurometabolism. The spectrum of used methods includes voxel-based morphometry, proton and phosporous-MR spectroscopy, enzyme kinetics in phospholipid metabolism (phospholipase A2) and antioxidative stress defense (e.g. glutathione, SOD, catalase, tocopherol), the investigation of polyunsaturated membrane fatty acid (PUFA) profile, as well as the investigation of diverse makers of neurodevelopment (e.g. BDNF), inflammation cascade (e.g. prostaglandins, niacin sensitivity), and neuroimmune system (IL-6, sIL-2R, s-ICAM1, S100B). Among others his group contributed research in all stages of psychotic disorders and manifest schizophrenia. His main focus during the last decade is the ultra-high risk for psychosis state. Using diverse combinations of the above named peripheral and MR-based techniques, his group investigated potential markers of transition to acute psychosis, diagnostic categorization, early intervention strategies and potential indicators for specific trajectories. He aimed to elucidate pathomechanisms of the transition to psychosis phase and to influence transition risk and outcome using PUFA supplementation as a low-risk prevention and early intervention strategy.

Within several multicenter RCT his group collaborated among others with Orygen - The National Centre of Excellence in Youth Mental Health in Melbourne, Australia (The NEURAPRO-North America, EURope, Australia PROdrome Study: A multicenter RCT of Treatment Strategies for Symptomatic Patients at Ultra-High Risk for Early Progression to Schizophrenia and Other Psychotic Disorders) and the Department of Child and Adolescent Psychiatry in Vienna, Austria (Vienna Fish Oil RCT) – all research sponsered by the Stanley Foundation.

The research projects of Prof. Smesny’s group were all supported by grants of the German Research Foundation (SM 68/6-1; DFG SM68/3-1; DFG SM68/1-1).

Team

Dr. Kerstin Langbein
Dr. Constantin Siegert
Dr. Susanne Straube
Marlene Machnik

Projects

PRESCIENT – PREdiction SCIENTific Global Consortium – (previously named as Clinical High Risk-Australia (CHR CHR-Aus)

The overarching aim of the proposed program of research is to better characterise and improve prediction of outcomes in the clinical high risk (CHR) for psychosis clinical population. This will lead to substantial benefits for clinical care (using dynamic risk calculators to estimate risk of a range of outcomes for individual patients, informing personalized treatment strategy), healthcare services (informing decision-making regarding allocation of resources), and for research in this field (stratification of samples for treatment trials, directing the engagement of treatment targets, and refining aetiological models). The broad aim will be achieved by leveraging a recently established national network of early psychosis service systems across Australia, including EPPIC and PACE at Orygen, to recruit, comprehensively assess and follow a large sample of CHR patients, with international partners as the group at Jena recruiting an independent sample for validation purposes and to test generalisability of findings across healthcare settings.

Specific aims are to:

Use the AEPCC national platform to consolidate a network of CHR recruitment centres (CHR-Aus) organised according to a ‘hub and spoke’ model, with Orygen functioning as the central hub in Melbourne with other centres as spokes across the country. CHR-AUS will recruit across Orygen clinical services and 6 national hYEPP programs. In total, this consists of 12 recruitment clinics across Australia. As a further recruitment pool, if required, the research team has access to the national infrastructure of 110 (soon to be 150) headspace youth mental health services. Across the CHR-Aus network, 1000 CHR patients and 300 clinical comparison patients will be recruited over a two-year period, receive multimodal assessments (clinical, neurocognitive, neurophysiological, biological, neuroimaging, speech, digital momentary assessments), a subset of which will be repeated longitudinally. The sample will be followed for two years to determine a full range of clinical and functional outcomes (conversion to psychotic disorder, persistent and incident non-psychotic disorders, non-remission of CHR status, persistent negative symptoms, full recovery, functional outcome.
In collaboration with the NIMH Steering Committee and the Data Processing, Analysis and Coordination Center (DPACC), use this large new CHR dataset with a wide range of multimodal data to:
1. Test the external validity of existing and forthcoming prediction models in the field.
2. Implement the model with strongest performance as an online risk calculator that is scalable nationally and internationally and able to be calibrated for service setting (primary vs specialist settings) and availability of type of data (e.g. clinical data alone, clinical data plus neurophysiological data, polygenic risk score, etc).
3. Develop new, more refined prediction models and risk calculators using recent conceptual and methodological advances (e.g., dynamic prediction, probabilistic multimodal modelling) and exploratory biomarkers. These tools will be usable clinically in real time to ‘step up’ interventions as risk is enriched over time (based on clinical trajectory, treatment response and incoming biomarker information).
4. Examine how specific the identified biopsychosocial features and predictive models are to the CHR population by comparing these with a matched help-seeking clinical comparison group.
Recruit an independent CHR sample (n=340) in international centres (Singapore, Korea, Hong Kong, Netherlands, Denmark, Germany (Jena), Switzerland, United Kingdom) for external validation of models generated in the Australian network (2c) to ensure generalizability of findings. This international network of sites and research specialisation will provide the clinical research infrastructure for future treatment trials in this clinical population informed by findings of the current program of work.
Meanwhile, two recruitment networks have been funded – the Australian network (CHR-Aus) and a US-based network called ProNET. NIMH have also funded a US-based Data Processing, Analysis and Coordination Centre (DPACC). The NIMH is working closely with a group called the Foundation for the National Institute of Health (FNIH), who are responsible for linking the recruitment networks with various project partners (pharmaceutical companies, the FDA, NAMI, the Wellcome Trust, etc.).
NIMH and the FNIH aim to harmonize the data collection across the two recruitment networks, i.e. the types of assessments, the measures used, the biospecimens collected, the frequency of assessments, etc. The aim is ultimately to be able to pool the data collected across the two networks to achieve greater accuracy/statistical power in prediction analyses and then move towards targeted treatment trials.

Effects of emotion-focused vs cognitive interventions of schema therapy on emotion regulation deficits in females suffering borderline personality disorder – interrelations between clinical efficacy, connectivity in the executive control and salience network and local glutamate/GABA metabolism
RE 1123/24-1 | SM 68/5-1

Research area: Neuroscience, Psychotherapy, Medical Physics

Field of work: H-MR-Spectroscopy, resting state functional MRI, emotion regulation deficits in borderline personality disorder; influence of intervention type of psychotherapy on clinical outcome, function in key networks and neurotransmitter metabolism
Anticipated total duration: The project is designed for 36 months; 01/04/2021 – 31/03/2024;

The major aim of this proposal is to compare the effects of emotion focused (experiential) and cognitive interventions of schema therapy (ST) on emotion regulation deficits in females with borderline personality disorder (BPD) according to DSM-V (alternative model) criteria. In a randomized, single-blinded parallel-group design clinical effects as well as effects on connectivity and neurotransmitter metabolism will be compared. While the 9-weeks treatment protocol of particular interest includes emotion focused interventions (ST-EF, n=60) such as chair dialogs, imagery rescripting or role play, the control condition (ST-AC, n=60) is restricted to cognitive interventions, e.g. psychoeducation or pro/contra discussions.

Resting-state functional MR imaging (rs-fMRI) and MEGA-PRESS 1H-MR spectroscopy will be applied before/after 3 weeks of familiarization/diagnostics (T0-T1) and before/after the treatment protocols (T1-T2) to investigate effects on the connectivity in executive control (ECN) and salience (SN) networks and on the glutamate (Glx) and GABA metabolism in key regions (ECN dorsolat. prefrontal cortex, DLPFC; SN anteromed. cingulate cortex, aMCC). The biological aberrations at T0 as compared to healthy controls (n=60) and treatment effects (T1-T2, n≥40 in each condition) on these aberrations will be linked to clinical effects measured by an extensive test battery with particular interest on emotion regulation, and specified by the Reliable Change Index (RCI). For longitudinal data mixed model analysis will be performed. Skin conductance as a correlate of vegetative activation will be used to quantify the intensity of emotional activation during therapeutic sessions.

Main questions are (i) whether the emotion regulation deficit in patients co-occurs with a specific pattern of Glx and GABA concentrations at aMCC and DLPFC and respective aberrations of functional connectivity within the ECN and SN. Depending on the deficit (measured by ERI, FSVV), we hypothezise a pattern of glutamatergic hyper- and/or GABA-ergic hypofunction in the aMCC, glutamatergic hypo- and/or GABA-ergic hyperfunction in the DLPFC and abnormal RSFC in the ECN and SN at T0. (ii) whether both treatment conditions cause different clinical effects on emotion regulation capabilities and other core symptoms of BPD (expressed by individual RCIs). We hypothesize that clinical effects of the treatment conditions differ in size/pattern, in terms of emotion regulation in favor of the ST-EF condition. (iii) whether these patterns of clinical improvement are linked to the changes of neurobiological aberrations (core issue of the proposal). We hypothesize that in particular ST-EF induced clinical effects on emotion regulation and other core BPD symptoms are interrelated with specific patterns of ST-EF induced changes of neurobiological parameters. (iv) We also hypothesize that the pattern of clinical improvement as defined by RCI can be predicted by the pattern of neurobiological aberrations at T1.

Key words: personality disorder, borderline personality disorder, brain, neurotransmitter, functional brain connectivity, proton MR-spectroscopy, resting-state functional MR imaging, glutamate, GABA, treatment effects, schema therapy, psychotherapy, follow-up investigation

Multicenter projects with participation of the AG of Prof. Smesny

PRESCIENT – PREdiction SCIENTific Global Consortium – (previously named as Clinical High Risk-Australia (CHR CHR-Aus)

Head: Prof. Barnaby Nelson (Orygen Youth Health, Centre for Youth Mental Health, The University of Melbourne, Australia)

Time Frame: 07/21 – 06/24

Sponsor: NIMH via ORYGEN Youth Health Research Centre

Volume (site Jena): 600.000,00 US$

The NEURAPRO (North America, EURope, Australia PROdrome) Study: A multicenter RCT of Treatment Strategies for Symptomatic Patients at Ultra-High Risk for Early Progression to Schizophrenia and Other Psychotic Disorders.

name side study:
The influence of omega-3 fatty acid supplementation on cerebral membrane metabolism and glutamatergic neurotransmission: a combined 31P/1H-MR-spectroscopy study at 3T.

Head: Prof. Patrick McGorry (Orygen Youth Health, Centre for Youth Mental Health, The University of Melbourne, Australia)

Time Frame: 11/11 – 04/16

Sponsor: Stanley Foundation, Grant ID # 07TGF-1102 via ORYGEN Youth Health Research Centre

Volume: 198.291, 44 €

Grants

Time frame: 01/04/2021 – 31/03/2024

Sponsor: German Research Foundation (DFG) SM 68/6-1

Volume: 195.414,00 €

Brain structural alterations within the first two yours of schizophrenic illness – neurobiological unterbinnings.

Time frame: 11/09 – 11/14

Sponsor: DFG SM68/3-1

Volume: 222.030,00 €

Alterations of lipid metabolism througout the body in individuals suffering schizophrenia –
correlations between cerebral and peripheral biochemical/metabolic alterations.

Time frame: 08/00 – 07/02

Sponsor: DFG SM68/1-1

Volume: 177.164,00 €

The inflammation cascade during development and course of schizophrenic illness.

Time frame: 07/08 – 06/09

Sponsor: BMBF über Interdisziplinäres Zentrum für Klinische Forschung (IZKF), University of Jena

Volume: 55.200,00 €

Neurodegeneration in dementia – investigations on the basis of phospholipid metabolism using Phospholipase A2-activity in CSF.

Time frame: 01/02 – 12/03

Sponsor: BMBF-Nachwuchsförderung über IZKF, University of Jena

Volume: 15.200,00 DM

Associations between cerebral and peripheal biological parameters of lipid and inflammation metabolism in schizophrenia – investigations using 31P-MR-spectroscopy (2D-CSI) and the niacin skin test.

Time frame: 1999 – 2001

Förderung: BMBF-Nachwuchsförderung, IZKF, University Hospital Jena

Volume: 12.000,00 DM

Publications

Schmidt, M., Rossetti, A.C., Brandwein, C., Riva, M.A., Gass, P., Elsner, P., Hesse-Macabata, J., Milleit, B., Smesny, S. Brain Derived Neurotrophic Factor Deficiency is associated withCognitive Impairment and Elevated Phospholipase A2 Activity in Plasma of Mice. Neuroscience 2021, in press
Smesny, S., Berberich, D., Gussew A., Schönfeld, N., Langbein, K., Walther, M., Reichenbach, J.R. Alterations of neurometabolism in the dorsolateral prefrontal cortex and thalamus in transition to psychosis patients change under treatment as usual – a two years follow-up 1H/31P-MR-spectroscopy study. Schizophr Res 2021, in press.
Smesny, S., Gussew, A., Schack, S., Langbein, K., Wagner, G., Reichenbach, J.R., 2020. Neurometabolic patterns of an "at risk for mental disorders" syndrome involve abnormalities in the thalamus and anterior midcingulate cortex. Schizophr Res 2021, in press.
Amminger, G.P., Nelson, B., Markulev, C., Yuen, H.P., Schafer, M.R., Berger, M., Mossaheb, N., Schlogelhofer, M., Smesny, S., Hickie, I.B., Berger, G.E., Chen, E.Y.H., de Haan, L., Nieman, D.H., Nordentoft, M., Riecher-Rossler, A., Verma, S., Thompson, A., Yung, A.R., McGorry, P.D. The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youths at Ultra-High Risk for Psychosis. Biol Psychiatry 2020, 87(3), 243-252.
Smesny S, Große J, Gussew A, Langbein K, Schönfeld N, Wagner G, Valente M, Reichenbach J. Prefrontal glutamatergic emotion regulation is disturbed in cluster B and C personality disorders – A combined 1H/31P-MR spectroscopic study. J Affect Dis 2018; 227: 688-697.
Langbein, K., Hesse, J., Gussew, A., Milleit, B., Lavoie, S., Amminger, G.P., Gaser, C., Wagner, G., Reichenbach, J.R., Hipler, U.C., Winter, D., Smesny, S., 2018. Disturbed glutathione antioxidative defense is associated with structural brain changes in neuroleptic-naive first-episode psychosis patients. Prostaglandins Leukot Essent Fatty Acids 2018, 136, 103-110.
Langbein K, Schmidt U, Schack S, Biesel NJ, Rudzok M, Amminger GP, Sauer H, Smesny S. State marker properties of niacin skin sensitivity in ultra-high risk groups for psychosis – an optical reflection spectroscopy study. Schizophr Res 2018;192: 377-384.
Smesny S, Milleit B, Schaefer MR, Hesse J, Schloegelhofer M, Langbein K, Hipler UC, Berger M, Cotter DR, Sauer H, McGorry PD, Amminger GP. Effects of omega-3 PUFA on endothelial pro-inflammatory markers in adolescent individuals at ultra-high risk for psychosis - results of the randomized controlled Vienna Omega-3 study. Schizophr Res 2017; 188: 110-117.
Langbein K, Hesse J, Gussew A, Milleit B, Lavoie S, Amminger GP, Wagner G, Reichenbach J, Hipler UC, Smesny S. Activation of glutathione antioxidative defense associated with structural brain changes and glutamate regulation deficits – correlates of negative symptomatology in untreated first-episode schizophrenia? Prostaglandins Leukotrienes and Essential Fatty Acids 2017, in press.
McNamara RK, Szeszko PR, Smesny S, Ikuta T, DeRosse P, Vaz FM, et al. Polyunsaturated fatty acid biostatus, phospholipase A2 activity and brain white matter microstructure across adolescence. Neuroscience. 2017;343:423-33.
McGorry PD, Nelson B, Markulev C, Yuen HP, Schäfer MR, Mossaheb N, Schlögelhofer M, Smesny S, Hickie IB, Berger B, Chen EYH, de Haan L, Nieman DH, Nordentoft M, Riecher-Rössler A, Verma S, Thompson A, Yung AR, Amminger GP. Effect of omega-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial. JAMA psychiatry. 2017;74(1):19-27.
Berger ME, Smesny S, Kim SW, Davey C, Rice S, Sarnyai Z, Schlögelhofer M, Schäfer MR, Berk M, McGorry PD, Amminger GP. Omega-6 to omega-3 polyunsaturated fatty acid ratio and subsequent mood disorders in young people with at-risk mental states: a 7-year longitudinal study. Transl Psychiatry 2017;7, e1220.
Smesny S and Valente M. Variables Setting, gleiche Akzeptanz – Wie schematherapeutische Behandlungselemente in stationäre und tagesklinische Settings implementiert werden können. Verhaltenstherapie und Verhaltensmedizin 2016, 37 (4), 450-465
Smesny S and Berger GE, Schäfer MR, Milleit B, Hipler UC, Milleit C, Klier CM, Schlögelhofer M, Holub M, Holzer I, Berk M, McGorry PD, Sauer H, Amminger GP. Increased niacin sensitivity in individuals at ultra-high risk for psychosis, its association with transition status, polyunsaturated fatty acids and intracellular PLA2 activity. PLOS One, 2016;11(2):e0148429. rg
Milleit B, Smesny S, Rothermundt M, Preul C, Schroeter ML, von Eiff C, Ponath G, Milleit C, Sauer H, Gaser C (2016) Serum S100B protein is specifically related to white matter changes in schizophrenia. Frontiers in Cellular Neuroscience, 2016; 10:33. rg
Nenadic I, Dietzek M, Schonfeld N, Lorenz C, Gussew A, Reichenbach JR, Sauer H, Gaser C, Smesny S. Brain structure in people at ultra-high risk of psychosis, patients with first-episode schizophrenia, and healthy controls: a VBM study. Schizophr Res 2015, 161:169-76.
Nenadic I, Maitra R, Basu S, Dietzek M, Schönfeld N, Lorenz C, Gussew A, Reichenbach JR, Sauer H, Gaser C, Smesny S. Hippocampal metabolism and brain structure in neuroleptic-naive ultra high-risk subjects and first-episode schizophrenia. European Neuropsychopharmacology 2015, accepted 13.05.2015
Smesny S and Gussew A, Nenadic I, Biesel NJ, Schack S, Walther M, Rzanny R, Milleit B, Gaser C, Sobanski T, Schultz CC, Amminger P, Hipler UC, Sauer H, Reichenbach JR. Glutamatergic dysfunction linked to energy and membrane lipid metabolism in frontal and anterior cingulate cortices of never treated first-episode schizophrenia patients. Schizophrenia Res 2015, accepted 06.07.2015.
Smesny S, Milleit B, Schaefer MR, Hipler UC, Milleit C, Wiegand C, Hesse J, Klier CM, Holub M, Holzer I, Berger GE, Berk M, McGorry PD, Sauer H, Amminger GP. Effects of omega-3 PUFA on the vitamin E and glutathione antioxidant defense system in individuals at ultra-high risk of psychosis. Prostaglandins Leukotrienes and Essential Fatty Acids 2015. accepted 14.07.2015
Nenadic I, Dietzek M, Langbein K, Rzanny R, Gussew A, Reichenbach JR, Smesny S. Superior temporal metabolic changes related to auditory hallucinations: a P-MR spectroscopy study in antipsychotic-free schizophrenia patients. Brain Struct Funct 2014 219(5):1869-72.
Smesny S, Milleit B, Hipler UC, Milleit C, Schäfer MR, Klier CM, Holub M, Holzer I, Berger GE, Otto M, Nenadic I, Berk M, McGorry PD, Sauer H, Amminger PG. Omega-3 fatty acid supplementation changes intracellular phospholipase A2 activity and membrane fatty acid profiles in individuals at ultra-high risk for psychosis. Molecular Psychiatry 2014;19(3):317-324.
Nenadic I, Dietzek M, Langbein K, Rzanny R, Gussew A, Reichenbach JR, Smesny S. Effects of olanzapine on 31P MRS metabolic markers in schizophrenia. Hum Psychopharmacol Clin 2013; 28(1): 91-93.
Smesny S, Schmelzer CEH, Hinder A, Köhler A, Schneider C, Rudzok M, Schmidt U, Milleit B, Milleit C, Nenadic I, Sauer H, Neubert RHH, Fluhr JW. Skin ceramide alterations in first-episode schizophrenia indicate abnormal sphingolipid metabolism. Schizophr Bull 2013; 39(4): 933-941.
Smesny S, Langbein K, Rzanny R, Gussew A, Burmeister HP, Reichenbach JR and Sauer H Antipsychotic drug effects on left prefrontal phospholipid metabolism: a follow-up 31P-2D-CSI study of haloperidol and risperidone in acutely ill chronic schizophrenia patients. Schizophr Res 2012; 138(2-3): 164-170. (IF 4.590; 2012)
Nenadic I, Langbein K, Weisbrod M, Maitra R, Rzanny R, Gussew A, Reichenbach JR, Sauer H, Smesny S. 31P-MR spectroscopy in monozygotic twins discordant for schizophrenia or schizoaffective disorder. Schizophr Res 2012; 134(2-3): 296-297.
Smesny S, Kunstmann C, Kunstmann S, Willhardt I, Lasch J, Yotter RA, Proffitt TM, Kerr M, Marculev C, Milleit B, Milleit C, Nenadic I, Amminger GP, McGorry PD, Sauer H, and Berger GE. Phospholipase A(2) activity in first episode schizophrenia: associations with symptom severity and outcome at week 12. World J Biol Psychiatry 2011; 12(8): 598-607.
Sand PG, Domani M, Smesny S. Critical reappraisal of a catechol-O-methyltransferase transversion variant in schizophrenia. Biol Psychiatry 2010; 67(7): e41-42; author reply e43-44.
Smesny S, Baur K, Rudolph N, Sauer N. Alterations of niacin skin sensitivity in recurrent unipolar depressive disorder. J Affect Disord 2010; 124(3): 335-340.
Smesny S, Milleit B, Nenadic I,, Kinder D, Lasch J, Willhardt I, Sauer H and Gaser C Phospholipase A2 activity is associated with structural brain changes in schizophrenia. Neuroimage 2010; 52(4): 1314-1327.