Cognition, immune functions and outcome of affective disorders: electro-physiological studies

Aim of the study and current knowledge:
Mechanisms within the etiopathogenesis of depression are far from being suffi-ciently understood. Genetic, endocrine immunological alterations as well as exo-genic (drugs or virus) and cognitive/psychological factors appear to be involved.
A number of authors demonstrated changes of immune functions in depression. However, the findings were different. Some authors described immune suppres-sion, others immune activation in major depression (e.g. Irwin et al. 1990; Leser-man et al. 1997, for review: Dantzer et al. 2007). Furtheremore, neuromodulatory proteins (e.g. S100B) were found to correlate with cognitive aspects of affective disorders (Hetzel et al. 2005; Dietrich et al. 2004; Zhang et al. 2009). Cognitive alterations in depression involve executive functions, attentional, memory process-ing as well as the emotional/cognition-coupling. Nevertheless, there is little knowl-edge on how immune functions and S100B influence cognitive and emotional functions in affective disorders and their outcome. This knowledge, however, is important for the understanding of the different outcome of subtypes of affective disorders and the development of new treatment options.

To clarify the underlying mechanisms and to test how immune functions and S100B influence cognitive and emotional functions, especially electrophysiological correlates (event-related potentials = ERPs), and the outcome of affective disorders the following investigation will be performed within this project:
40 patients with a depressive episode of an affective disorder (20 with a bipolar and 20 with a monopolar recurrent affective disorder) and 20 control subjects will be investigated 3 times. One major investigation (including all clinical, blood and serological parameters as well as cognitive measures, especially ERPs) will be performed in the depressive status, follow-up investigations after clinical remission (about 1-3 month after hospital treatment) and also 1 year later. Optional MRI investigations (e.g. voxel-based morphometry) should be performed in a selected group of patients.
The major hypothesis of the project is that the amount of serum IL-2, IL-6, TNF, BDNF and S100B correlate with specific cognitive deficits (and correlating changes of certain ERP-components, like the N1, N2 or P300) and the outcome of depression. The prospective evaluation of these and clinical parameters helps to understand major differences in the outcome of affective disorders.

Status of own scientific work:
Relevant research in our department regarding this project include studies and articles on the neurobiology of affective disorders and on the use of electrophysiological methods (ERPs) to substantive emotional and cognitive processes in patients with affective disorders and healthy subjects. Furthermore, the role of S100B for cognitive functions in depression and new treatment strategies in affective and other major psychiatric disorders are subject of our research (see reference list with *).

Methods:
Structured clinical interview, outcome measures, definition of subgroup,
Clinical scales to assess symptoms (e.g., BDI, SCL-90R, CGI),
Cognitive testing, EEG and Event-related potentials (ERPs, see below), will be performed at the AMEOS Klinikum Hildesheim

Specific blood measures which will be analysed in
Münster, Dept. of Psychiatry (Immunological measures, see below)

Cerebral MRI-scan (e.g., voxel-based morphometry, spectrometry) can be performed at the Dept. of Neuroradiology, MHH

Literature:

*# Arolt V, Peters M, Erfurth A, Wiesmann M, Missler U, Rudolf S, Kirchner H, Rothermundt M. S100B and response to treatment in major depression: a pilot study. Eur Neuropsychopharmacol. 2003 Aug; 13(4): 235-9

* Bode L, Dietrich DE, Stoyloff R, Emrich HM, Ludwig H. Amantadine and human Borna disease vi-rus in vitro and in an infected patient with bipolar depression. Lancet. 1997; 349(9046):178-9.

* Bode L, Reckwald P, Severus WE, Stoyloff R, Ferszt R, Dietrich DE, Ludwig H. Borna disease vi-rus-specific circulating immune complexes, antigenemia, and free antibodies – the key marker trip-let determining infection and prevailing in severe mood disorders. Mol Psychiatry. 2001; 6(4):481-91

* Dantzer R, Bluthé, RM, Castanon N, Kelly KW, Konsman JP, Laye S, Lestage J, Parnet P. Cyto-kines, Sickness Behavior, and Depression. In: Ader R. Psychoneuroimmunology, 4E, Volume 1, 281-318

* Dietrich DE, Bode L. Human Borna disease virus-infection and its therapy in affective disorders. APMIS Suppl. 2008;(124):61-5. Review

* Dietrich DE, Emrich HM, Waller C, Wieringa BM, Johannes S, Munte TF. Emotion/cognition-coupling in word recognition memory of depressive patients: an event-related potential study. Psy-chiatry Res. 2000; 96(1):15-29.

*# Dietrich DE, Hauser U, Peters M, Zhang Y, Wiesmann M, Hasselmann M, Rudolf S, Jüngling O, Kirchner H, Münte TF, Arolt V, Emrich HM, Johannes S, Rothermundt M. Target evaluation process-ing correlates with serum levels of nerve tissue protein S100B in patients with remitted major de-pression. Neurosci Lett. 2004; 354(1):69-73.

* Dietrich DE, Kleinschmidt A, Hauser U, Schneider U, Spannhuth CW, Kipp K, Huber TJ, Wieringa BM, Emrich HM, Johannes S. Word recognition memory before and after successful treatment of depression. Pharmacopsychiatry. 2000 Nov;33(6):221-8.

* Dietrich DE, Schedlowski M, Bode L, Ludwig H, Emrich HM. A viro-psycho-immunological dis-ease-model of a subtype affective disorder. Pharmacopsychiatry. 1998; 31(3):77-82.

* Dietrich DE, Zhang Y, Bode L, Münte TF, Hauser U, Schmorl P, Richter-Witte C, Gödecke-Koch T, Feutl S, Schramm J, Ludwig H, Johannes S, Emrich HM. Brain potential amplitude varies as a function of Borna disease virus-specific immune complexes in obsessive-compulsive disorder. Mol Psychiatry. 2005;10(6):515, 519-20.

* Dima D, Dietrich DE, Dillo W, Emrich HM. Impaired top-down processes in schizophrenia: A DCM study of ERPs. Neuroimage. 2010 Jan 4. [Epub ahead of print]

* Emrich HM, Dietrich DE. Remembering, forgetting and depression. Time-conceptual implications of affective disorders. Fortschr Neurol Psychiatr. 2000 Apr;68(4):150-7. Review. German.

*# Hetzel G, Moeller O, Evers S, Erfurth A, Ponath G, Arolt V, Rothermundt M. The astroglial protein S100B and visually evoked event-related potentials before and after antidepressant. Psychophar-macology (Berl) 2005 Mar; 178(2-3): 161-6. Epub 2004 Aug 14.

Irwin M, Patterson T, Smith TL, Caldwell C, Brown SA, Gillin JC, Grant I. Reduction of immune function in life stress and depression. Biol Psychiatry. 1990; 27(1):22-30.

* Johannes S, Wieringa BM, Nager W, Rada D, Dengler R, Emrich HM, Münte TF, Dietrich DE. Discrepant target detection and action monitoring in obsessive-compulsive disorder. Psychiatry Res. 2001 Nov 30;108(2):101-10.

* Karoutzou G, Emrich HM, Dietrich DE. The myelin-pathogenesis puzzle in schizophrenia: a litera-ture review. Mol Psychiatry. 2008 Mar;13(3):245-60. Epub 2007 Oct 9. Review

Leserman J, Petitto JM, Perkins DO, Folds JD, Golden RN, Evans DL. Severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus-infected men. A 2-year follow-up study. Arch Gen Psychiatry. 1997; 54(3):279-85.

* Ohlmeier MD, Prox V, Zhang Y, Zedler M, Ziegenbein M, Emrich HM, Dietrich DE. Effects of methylphenidate in ADHD adults on target evaluation processing reflected by event-related poten-tials. Neurosci Lett. 2007 Sep 13;424(3):149-54. Epub 2007 Aug 6.

Pascual-Marqui et al. Low resolution electromagnetic tomography: a new method for localizing elec-trical activity in the brain. Int J Psychophysiol 1994; 18(1):49-65

Pizzagalli et al. Brain electrical tomography in depression: the importance of symptom severity, anxiety, and melancholic features. Biol Psychiatry 2002; 52(2):73-85

* Prox V, Dietrich DE, Zhang Y, Emrich HM, Ohlmeier MD. Attentional processing in adults with ADHD as reflected by event-related potentials. Neurosci Lett. 2007 Jun 4;419(3):236-41. Epub 2007 Apr 8.

*# Rothermundt M, Ponath G, Hetzel G, Dietrich DE, Arolt V. The Influence of neuronal restructuring on the course of depressive disorders. European Psychiatry, 2005: S115.

* Szycik GR, Münte TF, Dillo W, Mohammadi B, Samii A, Emrich HM, Dietrich DE. Audiovisual inte-gration of speech is disturbed in schizophrenia: an fMRI study. Schizophr Res. 2009 May;110(1-3):111-8. Epub 2009 Mar 19.

* Zhang Y, Feutl S, Hauser U, Richter-Witte C, Schmorl P, Emrich HM, Dietrich DE. Clinical corre-lates of word recognition memory in obsessive-compulsive disorder: an event-related potential study. Psychiatry Res. 2008 Apr 15;162(3):262-72. Epub 2008 Mar 4.

* Zhang Y, Hauser U, Conty C, Emrich HM, Dietrich DE. Familial risk for depression and p3b com-ponent as a possible neurocognitive vulnerability marker. Neuropsychobiology. 2007;55(1):14-20. Epub 2007 Jun 8.

* Zhang Y, Lehmann M, Shobeiry A, Höfer D, Johannes S, Emrich HM, Dietrich DE. Effects of quetiapine on cognitive functions in schizophrenic patients: a preliminary single-trial ERP analysis. Pharmacopsychiatry. 2009 Jul;42(4):129-34. Epub 2009 Jul

* Zhang Y, Rothermundt M, Peters M, Wiesmann M, Hoy L, Arolt V, Emrich HM, Dietrich DE. S100B serum levels and word memory processing in remitted major depression as reflected by brain potentials. Neuropsychobiology. 2009;59(3):172-7. Epub 2009 May 20.