Team Krebs

Pathophysiology of Psychiatric disorders :Development and Vulnerability

Psychiatric disorders result from complex interactions between genetic and/or developmental vulnerability and late environmental factors. Our previous results support a developmental form of schizophrenia (SCZ), in the continuum of autism spectrum disorders (ASD), and suggest that rare variants and developmental markers are useful for stratifying patients in order to propose personalized therapeutic strategies (Girard 2015, Gay 2013; Martinez 2017). We also identified, for the first time, dynamic epigenetic changes during psychosis onset, and provide new pathways to explore for disease-modifying strategies, namely oxidative stress regulation, axon guidance, and inflammatory pathways (Chan 2015 ; Kebir 2017). In addition, we identified Hipp/PFC connectivity as a hub for modeling stress disorders (anxiety, depression), psychosis, and SCZ, and provide new means for identifying therapeutic targets (Godsil, 2015 ; Magalhães 2017, Rame 2016).

Our project aims at deciphering the processes underlying the onset and outcome of psychotic disorders, taking into account the developmental and/or genetic background. We will follow a reversible translational strategy in humans and in rodent models (i) at the molecular level (biomarkers, epigenetic regulation) and cellular level, by using a novel in vitro model, developed with A Hosmalin (Institut Cochin), that provides monocyte-derived-neuronal-like-cells (MDN) from peripheral blood; (ii) at the system level (imaging, cognitive models) focusing on hippocampo-prefrontal (HpPf) networks.

These studies should help identifying new personalized and preventive therapeutic strategies in early stages of schizophrenia spectrum disorders.

5 main publications

Demars F, Kebir O, Marzo A, Iftimovici A, Schramm C, Krebs MO, Chaumette B. Dysregulation of peripheral expression of the YWHA genes during conversion to psychosis. Sci Rep. 2020 Jun 17;10(1):9863. doi: 10.1038/s41598-020-66901-1.

Tripathi A, Spedding M, Schenker E, Didriksen M, Cressant A, Jay TM. Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress. Transl Psychiatry. 2020 Jan 28;10(1):41. doi: 10.1038/s41398-020-0687-z.

Kebir O*, Chaumette B*, Rivollier F, Miozzo F, Lemieux Perreault LP, Barhdadi A, Provost S, Plaze M, Bourgin J, Gaillard R, Mezger V, Dubé MP, Krebs MO. Methylomic changes during conversion to psychosis. Mol Psychiatry. 2017 Apr;22(4):512-518. doi: 10.1038/mp.2016.53. PubMed PMID: 27113994; PubMed Central PMCID: PMC5378806. *Contributed equally.

Chaumette B, Kebir O, Pouch J, Ducos B, Selimi F; ICAAR study group, Gaillard R, Krebs MO. Longitudinal Analyses of Blood Transcriptome During Conversion to Psychosis. Schizophr Bull. 2019 Jan 1;45(1):247-255. doi: 10.1093/schbul/sby009.

Dickens AM, Sen P, Kempton MJ, Barrantes-Vidal N, Iyegbe C, Nordentoft M, Pollak T, Riecher-Rössler A, Ruhrmann S, Sachs G, Bressan R, Krebs MO, Amminger GP, de Haan L, van der Gaag M, Valmaggia L, Hyötyläinen T; EU-GEI High Risk Study Group, Orešič M, McGuire P. Dysregulated Lipid Metabolism Precedes Onset of Psychosis. Biol Psychiatry. 2021 Feb 1;89(3):288-297. doi: 10.1016/j.biopsych.2020.07.012. Epub 2020 Jul 25. PMID: 32928501

The team’s projects aim to:

•   improve subgrouping of severe psychiatric disorders by focusing on the developmental anomalies and on treatment resistant disorders
•   identify early biomarkers and predictors of outcomes
•   explore the influence of environmental precipitating (stress, fear, substance use, aging) and protective factors (cognitive training) on vulnerable conditions
•   explore the neural and cognitive basis of specific dimensions in order to propose specific therapeutics.

Thanks to our in-house expertise and established collaborations we are using and developing:

•   multi-modal objective phenotyping (clinical and cognitive profiling, neurophysiological, sensorimotor and oculomotor exploration, and brain imaging explorations)
•   cutting edge whole genome molecular approaches exploring genetic, epigenetic and proteomic
•   bioinformatics analyses to address the challenge of heterogeneous large-scale data integration
•   in vivo rodents models to explore the neural underpinnings of psychiatric conditions with behavioral analysis coupled to:
► optogenetics
► multichannel electrophysiology
                         ►   pharmacology
•   in-vitro cellular models such as monocytes derived neuron-like cells and computational models to characterize pharmacological modulation
•   new cognitive exploration and remediation programs

The team comprises 7 PIs and 37 other researchers such as PhD students, post-docs, research assistants, and clinicians that are dedicated to research only part-time.
Our research develops around four main axes shaping also four subdivisions of the team:

1) Disentangling early developmental alterations from adult psychosis

Team members	Prof Marie-Odile KREBS, MD, PhD	Professor of Psychiatry
	Dr Alain DERVAUX, MD PhD	Psychiatrist and Clinical researcher
	Dr Pauline CHASTE, MD PhD	Psychiatrist and Clinical researcher
	Dr Gwenaelle LE PEN, PhD Olivier GAY, MD	Researcher (CR1 INSERM) Head resident and PhD student
	Dr Gilles MARTINEZ, MD	Head resident and PhD student
	Dr Macarena CUENCA, MD	Psychiatrist and Clinical researcher
	Me Charlotte ALEXANDRE	Psychologist, PhD student
Selected recent publications:	Alexandre C, Chaumette B, Martinez G, Christa L, Dupont J.M., Kebir O, Gaillard R, Amado I, Krebs M.O. (2015) Paradoxical improvement of schizoprenic symptoms by a dopaminergic agonist : an example of personalized psychiatry in a CNV carrying patient. Biol Psychiatry, S0006-3223(15)00813-6 Kebir O, Chaumette B, Fatjó-Vilas M, Ambalavanan A, Ramoz N, Xiong L, Mouaffak F, Millet B, Jaafari N, DeLisi LE, Levinson D, Joober R, Fañanás L, Rouleau G, Dubertret C, Krebs MO (2014) Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia. Schizophr Res. 160(1-3):97-103. Cachia A, Amad A, Brunelin J, Krebs MO, Plaze M, Thomas P, Jardri R. (2015) Deviations in cortex sulcation associated with visual hallucinations in schizophrenia. Mol Psychiatry 20(9):1101-7. Gay O, Plaze M, Oppenheim C, Mouchet-Mages S, Gaillard R, Olié JP, Krebs MO, Cachia A (2013) Cortex Morphology in First-Episode Psychosis Patients With Neurological Soft Signs. Schizophrenia Bull 39(4):820-9. Girard S, Gauthier J, Noreau N, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O, Thibodeau P, Bachand I, Bao JYJ, Tong AMY, Lin CH, Millet B, Jaafari N, Joober R, Dion PA, Lok Si, Krebs MO, Rouleau GA (2011) Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 43(9):860-3. Le Pen G, Jay TM and Krebs MO (2011) Effect of antipsychotics on spontaneous hyperactivity and hypersensitivity to mk-801-induced hyperactivity in rats prenatally exposed to methylazoxymethanol. J Psychopharmacol. 25(6):822-35. Tarabeux J¬, Champagne N, Brustein E, Hamdan FF, Julie Gauthier J , Lapointe M, Maios C, Piton A, Spiegelman D, Henrion E, S2D team, Millet B, Rapoport JL, DeLisi LE, Joober R, Fathalli F, Fombonne E, Mottron L, Forget-Dubois N, Boivin M, Michaud JL, Lafrenière RG, Drapeau P, Krebs MO, Rouleau GA. (2010) De Novo Truncating Mutation in KIF17 Associated with Schizophrenia. Biol Psychiatry 68(7):649-56.

2) Exploring the neural basis of symptoms to personalize therapeutic strategies

Team members	Prof Raphaël GAILLARD, MD PhD		Professor of Psychiatry
	Dr Isabelle AMADO, MD PhD		Psychiatrist and clinical researcher
	Dr Marion PLAZE, MD PhD		Psychiatrist and clinical researcher
	Dr Pierre DE MARICOURT, MD Dr Catherine DOYEN, MD		Psychiatrist and clinical researcher Psychiatrist and clinical researcher
	Dr Thierry GALLARDA, MD		Psychiatrist and clinical researcher
	Mrs Simona CALDANI		Psychologist, PhD student
	Dr Rita Dadi, MD		Psychiatrist and clinical researcher
	Mrs Célia MAM LAM FOOK		Psychologist, PhD student
	Dr Alexandre SALVADOR, MD		Head resident, PhD student
	Dr Sarah SMADJA, MD		Head resident, PhD student
	Dr Fabien VINCKIER, MD PhD		Head resident and clinical researcher
	Dr Eirini RARI, PhD		Psychologistand clinical researcher
Selected recent publications:		Plaze M, Mangin JF, Paillère-Martinot ML, Artiges E, Olié JP, Krebs MO, Gaillard R, Martinot JL, Cachia A. "Who is talking to me?" - Self-other attribution of auditory hallucinations and sulcation of the right temporoparietal junction. Schizophr Res. 2015 Oct 10. pii: S0920-9964(15)30011-6. doi: 10.1016/j.schres.2015.10.011 [in press] Vinckier F, Gaillard R, Palminteri S, Rigoux L, Salvador A, Fornito A, Adapa R, Krebs MO, Pessiglione M, Fletcher PC. Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade. Mol Psychiatry. 2015 Jun 9. doi: 10.1038/mp.2015.73. [Epub ahead of print] Vinckier F, Cohen L, Oppenheim C, Salvador A, Picard H, Amado I, Krebs MO, Gaillard R. Reading impairment in schizophrenia: Dysconnectivity within the visual system. Neuropsychologia. 2014 Jan;53:187-96. Sperduti M, Martinelli P, Kalenzaga S, Devauchelle AD, Lion S, Malherbe C, Gallarda T, Amado I, Krebs MO, Oppenheim C, Piolino P. Don't be Too Strict with Yourself! Rigid Negative Self-Representation in Healthy Subjects Mimics the Neurocognitive Profile of Depression for Autobiographical Memory. Front Behav Neurosci. 2013 May 21;7:41. Landgraf S, Amado I, Brucks M, Krueger F, Krebs MO, van der Meer E. Inflexible information acquisition strategies mediate visuo-spatial reasoning in stabilized schizophrenia patients. World J Biol Psychiatry. 2011 Dec;12(8):608-19.

3) Gene-environment interactions: epigenetic and rare variants

Team members	Dr Oussama KEBIR, MD PhD	Psychiatrist and clinical researcher
	Dr Boris CHAUMETTE, MD	Resident and PhD student
	Dr Julie ROBLIN, MD	Psychiatrist and clinical researcher
	Dr Nicolas BAUP, MD PhD	Psychiatrist and clinical researcher
	Dr Claire GAUTHIER, MD	Head resident clinical researcher
	Dr Fabrice RIVOLLIER, MD	Psychiatrist and clinical researcher
Selected recent publications:	Millan MJ, Andrieux A, Bartzokis G, Cadenhead K, Dazzan P, Fusar-Poli P, Gallinat J, Giedd J, Grayson D, Heinrichs M, Kahn R, Krebs MO, Leboyer M, Lewis D, Marin O, Marin P, Meyer-Lindenberg A, McGorry P, McGuire P, Owen MJ, Patterson P, Sawa A, Spedding M, Uhlhaas P, Vaccarino F, Wahlestedt C and Weinberger D : Altering the course of schizophrenia: progress and perspectives, Nat Rev Drug Disc, in press. Kebir O, Chaumette B, Fatjó-Vilas M, Ambalavanan A, Ramoz N, Xiong L, Mouaffak F, Millet B, Jaafari N, DeLisi LE, Levinson D, Joober R, Fañanás L, Rouleau G, Dubertret C, Krebs MO. Family-based association study of common variants, rare mutation study and epistatic interaction detection in HDAC genes in schizophrenia. Schizophr Res. 2014 Dec;160(1-3):97-103. European Network of National Networks studying Gene-Environment Interactions in Schizophrenia (EU-GEI), van Os J, et al. Identifying gene-environment interactions in schizophrenia: contemporary challenges for integrated, large-scale investigations. Schizophr Bull. 2014 Jul;40(4):729-36.

4) Lifetime perspective of neuroplasticity: critical periods and the stress response

Team members	Dr Thérèse JAY, PhD	Research director (group coordinator)
	Dr Gwenaëlle LE PEN, PhD	Researcher (CR1 INSERM)
	Dr Julie BOURGIN, MD PhD	Psychiatrist and clinical researcher
	Dr Mathilde KAZES, MD PhD	Psychiatrist
	Dr David BARRIERE, PhD	Post-doc
	Dr Claire DABAN, PhD	Psychologist
	Mr Adam Eckmier	PhD student
	Mr Marco POMPILI	PhD student
	Mrs Clémentine VINCENT	PhD student
	Mrs Alice OPPETIT	Resident and MSc student
	Mrs Mélanie CHAYET	Psychologist
	Mr Zbigniew ZIELINSKI	Research assistant
Selected recent publications:	Renard J, Vitalis T, Rame M, Krebs MO, Lenkei Z, Le Pen G, Jay TM (2015) Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex. Eur Neuropsychopharmacol. S0924-977X(15)00355-7 Chaumette, B., Kebir, O., Mam-Lam-Fook, C., Morvan, Y., Bourgin, J., Godsil, B.P., Plaze M., Gaillard, R., Jay, T. M., Krebs, MO (2015) Salivary cortisol in early psychosis: new findings and meta-analysis. Psychoneuroendocrinology 63:262-270 Bourgin J, Cachia A, Boumezbeur F, Djemaï B, Bottlaender M, Duchesnay E, Mériaux S, Jay TM (2015) Hyper-responsivity to stress in rats is associated with a large increase in amygdala volume. A 7T MRI study. Eur Neuropsychopharmacol 25(6):828-35 Godsil BP, Bontempi B, Mailliet F, Delagrange P, Spedding M, Jay TM (2015) Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction. Mol Psychiatry 20: 1420-1427 Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal prefrontal pathway: the link in psychiatric disorders? Eur Neuropsychopharmacol 23(10):1165-81

PsyCARE Project – Preventing psychosis through personalized care

Led by Prof. Marie-Odile Krebs(Université de Paris/GHU Paris/Inserm)

http://psy-care.fr/

Schizophrenia and chronic psychosis are among the most disabling disorders affecting adolescents and young adults. They involve cognitive impairment and reduced vocational achievement and quality of life.

Recent studies have shown that early psychosis is a window of opportunity to prevent the onset of the disease or its progression to chronicity.

Therefore, the background hypothesis of PsyCARE (“Preventing psychosis through personalized care”) is that promoting neuroprotection and neuroplasticity will improve individual levels of resilience and attenuate the negative impact of early developmental disorders when facing stressors during the critical period of brain development during adolescence (between 12-25 years old).

The main goal of PsyCARE is to improve early intervention in psychosis by providing a new set of easy-to-share tools to:

• Facilitate access to care
• Improve early detection;
• Provide personalised therapeutic programs.

These early and personalised strategies will enable to tailor therapies to the individual from the earliest stages of the disorder.

To fulfil this ambitious objective, the PsyCARE project aims at :

- Identifying biomarkers (genetic, epigenetic, metabolic, imaging) to improve diagnosis, disease stage detection and prediction of functional outcome;

- Identifying a list of targets for disease-modifying strategies;

-Providing and validating:

→ new portable tools for digital phenotyping in routine practice, including motor assessment, automatic text and speech analysis;

→ an application for personalised cognitive training;

→ a new patient-focused application facilitating case management and patient engagement (PsyCARE App);

→ a Decision Support System (DSS) that will guide the customised treatment strategy

- Developing an innovative PsyCARE data collection and integration platform tailored to research in psychiatry and mental health care;

- Providing a knowledge dissemination and training toolkit to improve awareness and transfer PsyCARE results to medical practice.

PsyCARE therapeutic strategies will be tested on a large scale in a multicentric clinical trial of 500 patients with early signs of psychosis to assess the effect of this early and personalized composite care. Particular attention will be paid to implementing the results of PsyCARE on a national scale and studying their impact on the healthcare system and the care pathway.

The project is structured in 9 workpackages:

Workpackage 1: Identifying biomarkers to guide therapeutic interventions (Leaders: O. Kébir and B. Chaumette, GHU Paris/Inserm)

Workpackage 2: Identifying imaging markers to guide therapeutic interventions (Leader: R. Jardri, CHRU Lille)

Workpackage 3: Using novel digital tools for clinical and neurocognitive phenotyping (Leaders: J. Charlet, Sorbonne University and P. Lindberg, Inserm)

Workpackage 4: Multimodal data analysis (Leader: E. Duchesnay, CEA)

Workpackage 5: Design and implementation of the PsyCARE platform (Leader: P. Boutinaud, Fealinx)

Workpackage 6: PsyCARE digital intervention tools for better cognition and promotion of engagement (Leader: E. Chevallier, Apycare)

Workpackage 7: Validating the effect of personalized treatment strategies on functional outcome in early psychosis (Leader: M.O. Krebs, GHU/University of Paris/Inserm)

Workpackage 8: Facilitating the wide-scale implementation of PsyCARE results (Leader: K. Chevreul, AP-HP)

Workpackage 9: Project coordination and dissemination of results (Leader: M.O. Krebs, GHU/University of Paris/Inserm)

The PsyCARE project is led by Prof. Marie-Odile Krebs (University of Paris), who is head of unit at the Hospital University Group (‘Groupe Hospitalo-Universitaire’- GHU) Paris Psychiatry and Neurosciences and is coordinated by the INSERM. The project is funded by the ‘Research in Hospital and University’ (RHU) in health action within the program ‘Investissements d'Avenir’ promoted by the French government and monitored by the Agence Nationale de la Recherche (ANR). It is the first RHU project in the field of psychiatry. It started in January 2020 for a total duration of 5 years, with a funding of 8.8 million euros. PsyCARE gathers a national consortium from the Institute of Psychiatry (https://institutdepsychiatrie.org/), which includes academic experts in neuroscience and bioinformatics, and clinical centres of excellence in the field of psychosis (‘Transition network' - réseau Transition), with innovative companies partnership. The project is carried by the Institute of Psychiatry and Neurosciences of Paris (IPNP - INSERM / University of Paris) and by the GHU Paris Psychiatry and Neurosciences.

At the IPNP, in addition to Pr. Marie-Odile Krebs team, the project also involves Dr. Pavel Lindberg (J-L Mas team) as well as Dr. Arnaud Cachia and Pr. Catherine Oppenheim (Oppenheim team).

Partners	Scientific leader	Description
INSERM	Pr. Marie-Odile Krebs	Coordinator – Public sector
GHU Paris Psychiatrie & Neurosciences	Pr. Marie-Odile Krebs	Public sector
CEA Neurospin	Dr. Edouard DUCHESNAY	Public sector
CHU de Lille	Pr. Renaud JARDRI	Public sector
SORBONNE Université	Dr. Jean CHARLET	Public sector
CHRU de Brest	Pr. Michel WALTER	Public sector
AP-HP	Pr. Corinne ALBERTI	Public sector
Université de Caen	Pr. Sonia DOLLFUS	Public sector
FEALINX	Dr. Philippe BOUTINAUD	Private company
SASU Apycare	Dr. Emmanuel CHEVALLIER	Private company
Digital & Ethics	Dr. Feten BEN FREDJ	Private company