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Immunological Changes and Brain Function over a Psychotic-Depressive Spectrum
Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0002-0201-273X
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Psychotic and depressive disorders are severe psychiatric disorders that contribute significantly to the global burden of disease. They are distinct disorders with different symptom profiles according to both the Diagnostic and Statistical Manual and the International Classification of Diseases. However, these disorders share commonalities in various aspects, such as high comorbidity, prevalence of subclinical symptoms, and shared genetics. Furthermore, both disorders have been associated with a dysregulated immune system functioning.

In this thesis, we aimed to identify common biological dimensions of both depression and psychosis by first investigating proteins related to immune system activation in depression and psychosis separately, and then identifying biological underpinnings of psychotic-like symptoms in depression.Specifically, we first assessed in major depressive disorder central nervous system levels of metabolites along the kynurenine pathway, a pathway that is regulated by the immune system and implicated in depressive and psychotic disorders (paper I). We found an imbalance between neuroprotective versus neurotoxic metabolites in blood and decreased levels of a neuroprotective metabolite in cerebrospinal fluid of patients with depression.

Next, we assessed patterns of proteins implicated in immune-system function that distinguish first episode psychosis and healthy controls (paper II). Results indicate prominent changes in patients compared to controls, partially replicating previous findings and partially highlighting proteins that have not previously been assessed in psychosis.

Lastly, we investigated psychotic-like symptoms in patients with major depressive disorder, finding a relation to immune system markers (paper III) and changes in connectivity between brain structures that integrate information about the physical body and autobiographic information into a sense of self (paper IV).

In summary, the results from this thesis suggest that both in major depressive disorder and first episode psychosis there might be a dysregulation of the immune system and closely related systems such as the kynurenine pathway. These commonalities could further underlie the prevalence of subclinical psychotic-like symptoms in major depressive disorder. Ultimately, a better understanding of the underlying biological mechanisms of psychiatric disorders and, transdiagnostically, their symptoms will help formulate empiricallyinformed frameworks to guide clinical diagnostic processes and treatments.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2023. , p. 87
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1867
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:liu:diva-198464DOI: 10.3384/9789180753098ISBN: 9789180753081 (print)ISBN: 9789180753098 (electronic)OAI: oai:DiVA.org:liu-198464DiVA, id: diva2:1804796
Public defence
2023-11-24, Berzeliussalen, Building 463, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Note

Funding agencies: Drottning Silvias Jubileumsfond, Fonden för Psykisk Hälsa, Swedish Research Council, Region Östergötland (ALF), Medical Research Council of Southeast Sweden (ALF), Horizon 2020, Warren Foundation, Johnson & Johnson Innovation, National Institutes of Health, MD Anderson Cancer Support Grant, The Finnish Society of Sciences, Hjärnfonden, Liv and Hälsa Foundation, Finska Läkarsällskapet, Magnus Ehrnrooth Foundation, Sigrid Jusélius Foundation, Minerva Foundation, European Regional Development Fund, Estonian Research Foundation

Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2023-12-28Bibliographically approved
List of papers
1. Peripheral and central kynurenine pathway abnormalities in major depression
Open this publication in new window or tab >>Peripheral and central kynurenine pathway abnormalities in major depression
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2022 (English)In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 101, p. 136-145Article in journal (Refereed) Published
Abstract [en]

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.

Place, publisher, year, edition, pages
Academic Press Inc - Elsevier Science, 2022
Keywords
Major depressive disorder; Kynurenine pathway; Inflammation; Central nervous system; Brain volumetry; Structural magnetic resonance imaging; Cerebrospinal fluid
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-183765 (URN)10.1016/j.bbi.2022.01.002 (DOI)000761260700005 ()34999196 (PubMedID)
Note

Funding Agencies|Johnson & Johnson Innovation; Swedish Medical Research CouncilSwedish Medical Research Council (SMRC)European Commission [2017-00875, 2013-07434, 2019-01138]; ALF Grants, Region Ostergotland; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 CA193522, R01 NS073939]; MD Anderson Cancer Support Grant [P30 CA016672]

Available from: 2022-03-24 Created: 2022-03-24 Last updated: 2023-10-13
2. Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients
Open this publication in new window or tab >>Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients
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2023 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 326Article in journal (Refereed) Published
Abstract [en]

Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.

Place, publisher, year, edition, pages
Springer, 2023
National Category
Psychiatry
Identifiers
urn:nbn:se:liu:diva-198695 (URN)10.1038/s41398-023-02627-8 (DOI)001088122700001 ()
Funder
Swedish Research CouncilEuropean Regional Development Fund (ERDF)
Note

Funding agencies: Supported by H2020-MSCA-RISE-2016 (EU Grant no: 73479), The Finnish Society of Sciences and Letters, The Swedish Research Council (2018-02623, 2019-05820), Region Östergötland (LIO-795611, LIO-897641), Region South-East Sweden (FORSS807001, FORSS-849051, Swedish Brain Foundation (Hjärnfonden), Liv and Hälsa Foundation, Finska Läkaresällskapet, Magnus Ehrnrooth Foundation, Sigrid Jusélius Foundation, Minerva Foundation, European Regional Development Fund (Project No.2014-2020.4.01.15-0012), and Estonian Research Foundation (PUT PRG685). Open access funding provided by Linköping University. 

Available from: 2023-10-23 Created: 2023-10-23 Last updated: 2024-01-17
3. Functional Connectivity Between Extrastriate Body Area and Default Mode Network Predicts Depersonalization Symptoms in Major Depression: Findings From an A Priori Specified Multinetwork Comparison
Open this publication in new window or tab >>Functional Connectivity Between Extrastriate Body Area and Default Mode Network Predicts Depersonalization Symptoms in Major Depression: Findings From an A Priori Specified Multinetwork Comparison
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2019 (English)In: Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, ISSN 2451-9022, Vol. 4, no 7, p. 627-635Article in journal (Refereed) Published
Abstract [en]

Background

Depersonalization/derealization disorder is a dissociative disorder characterized by feelings of unreality and detachment from the self and surroundings. Depersonalization/derealization disorder is classified as a primary disorder, but depersonalization symptoms are frequently observed in mood and anxiety disorders. In the context of major depressive disorder (MDD), depersonalization symptoms are associated with greater depressive severity as indexed by treatment resistance, inpatient visits, and duration of depressive episodes. In the current investigation, we tested four network-based, neural-functional hypotheses of depersonalization in MDD. These hypotheses were framed in terms of functional relationships between 1) extrastriate body area and default mode network (DMN); 2) hippocampus and DMN; 3) medial prefrontal cortex and ventral striatum; and 4) posterior and anterior insular cortex.

Methods

We conducted functional magnetic resonance imaging during resting state on 28 female patients with MDD and 27 control subjects with no history of a psychiatric disorder. Functional connectivity between seed and target regions as specified by our network-level hypotheses was computed and correlated with scores on the Cambridge Depersonalization Scale. We used a conservative, unbiased bootstrapping procedure to test the significance of neural-behavioral correlations observed under each of the four models tested.

Results

Of the four neural-functional models of depersonalization symptoms tested, only the model proposing that reduced connectivity between the extrastriate body area and DMN predicts higher levels of depersonalization symptoms in MDD was confirmed.

Conclusions

Our results indicate that depersonalization/derealization disorder symptoms in patients with depression are related to reduced functional connectivity between brain regions that are proposed to support processing of body-related (extrastriate body area) and autobiographical (DMN) information.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Default mode network; Depersonalization/derealization disorder; Extrastriate body area; Functional connectivity; Major depressive disorder
National Category
Psychiatry
Identifiers
urn:nbn:se:liu:diva-162355 (URN)10.1016/j.bpsc.2019.03.007 (DOI)000494424200006 ()31103548 (PubMedID)2-s2.0-85065575555 (Scopus ID)
Note

Funding Agencies|Warren Foundation; Swedish Research CouncilSwedish Research Council; Region Ostergotland

Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2023-10-13Bibliographically approved

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Paul, Elisabeth R.

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