Böker Bösiger

Fakultäten » Medizinische Fakultät » Psychiatrische Universitätsklinik » Psychiatrie, Psychotherapie und Psychosomatik, Klinik für » Prof. Dr. Daniel Hell (emeritiert) » Böker Bösiger

Completed research project

Title / Titel Neural Activity and GABA/Glutamate in Prefrontal Cortex: A Combined fMRI/MRS-Study
PDF Abstract (PDF, 14 KB)
Summary / Zusammenfassung Major depression can be characterized by co-occurrence of emotional and cognitive symptoms. As revealed in functional imaging emotional symptoms are closely related with hyperactivation in ventromedial prefrontal cortex (VMPFC). Hyperactivation in VMPFC is accompanied by concurrent hypoactivation in ventro/dorsolateral prefrontal cortex (VLPFC/DLPFC). However exact neural correlates of cognitive symptoms remain unclear.
Moreover origin of concurrent hyper- and hypoactivation in prefrontal cortex is currently not known. Alteration in levels of neurotransmitter like GABA and Glutamate may play a crucial role in functional dysregulation of ventral prefrontal cortex in depression. However investigations directly linking hyper/hypoactivation and GABA/Glutamate in ventral prefrontal cortex are still lacking in both healthy and depressive subjects.

Working Hypothesis
First emotional stimulation may induce hyperactivation in VMPFC while cognitive stimulation may rather lead to hypoactivation in VLPFC/DLPFC in depressive patients.
Second levels of GABA and Glutamate in ventral prefrontal cortex may be altered in depressive patients showing decreased GABA and increased Glutamate.

First patterns of neural activity in ventral prefrontal cortex shall be investigated during emotional and cognitive stimulation in healthy and depressive subjects using functional magnetic resonance imaging (fMRI).
Second levels of GABA and Glutamate in ventral prefrontal cortex shall be investigated in the same subjects using 1h magnetic resonance in vivo spectroscopy (MRS).

Experimental Design and Methods
30 healthy controls and 20 unipolar acute depressive patients shall be investigated with both fMRI and MRS.
fMRI will be performed during emotional (i.e. presentation of pictures) and cognitive (i.e. judgement of pictures) stimulation. Analysis will focus on pattern of hyper- and hypoactivation in ventral prefrontal cortex including VMPFC and VLPFC.
MRS serves for investigation of levels of GABA and Glutamate/Glutamine in ventral prefrontal cortex. Exact regional localization of MRS will be oriented on neural activity in ventral prefrontal cortex as elucidated in fMRI.
In addition to comparison between healthy and depressive subjects analysis will focus on correlation between psychopathological symptoms, neural activity and levels of GABA/Glutamate using covariation and regression analyses.

Expected value of the proposed project
First, using fMRI, the project will reveal differential neural pattern in prefrontal cortex during emotional and cognitive stimulation in both healthy and depressive subjects. As such distinct kinds of symptoms i.e. emotional and cognitive may be related with specific neural substrates in depression.
Second, using MRS, the project will reveal neural metabolism of inhibitory/excitatory (GABA/Glutamate) transmitters in those prefrontal cortical regions being activated during emotional and cognitive stimulation. As such potential causes for altered neural activity in prefrontal cortex in depression may be revealed.
Third, combining fMRI and MRS, the project may contribute to elucidation of specific functional and metabolic “diagnostic markers” for emotional and cognitive symptoms in major depression thus showing potential clinical relevance.

Preliminary results of the study in healthy subjects: (1) Direct comparison between emotional judgement with expectancy and emotional judgement without expectancy showed relative signal decreases in OMPFC; in contrast, relative signal increases were detected in right VLPFC and right DLPFC; (2) as shown in separate comparisons with baseline, relative signal decreases in OMPFC were due to true signal decreases in emotional judgement with expectancy and true signal increases in emotional judgement without ecpectancy; (3) relative signal increases in right VLPFC and right DLPFC were revealed as true signal increases during emotional judgement with expectancy when compared to baseline.
Patients showed (1) reduced signal decreases in the VMPFC/PACC and reduced signal increases in the left DLPFC during both the affective (i.e. picture viewing) and the cognitive (i.e. picture judgment) component of emotion processing. ; (2) an abnormal correlation pattern of both regions with subjective ratings of negative emotional valences in patients when compared to healthy subjects. ; (3) a significant correlation of signal changes in the VMPFC (and the right amygdala) with symptom severity of depression. Taken together, our findings confirm recent models of abnormal relationship between ventral and dorsal prefrontal cortical function in MDD. They therefore indicate abnormal reciprocal modulation between VMPFC/PACC and DLPFC during emotion processing in unipolar depression.
Conclusion: The results are in accordance with the functional mechanisms of modulation by reversal and reciprocal modulation. Psychologically, these mechanisms might subserve representation of reward and reward-related function. Psychopathologically, disturbances in modulation by reversal might account for the inability of depressive patients to shift their expectations from negative to positive emotions.
Publications / Publikationen Walter, M., Henning, A., Grimm, S., Schulte, R.F., Beck, J., Dydak, U., Schnepf, B., Boeker, H., Boesiger, P., Northoff, D. (2008, in press) The relationship between aberrant neuronal activation patterns in the pregenual anterior cingulated, altered glutamatergic metabolism and anhedonia in Major Depression. Archives of General Psychiatry

Grimm S., Beck J., Schüpbach D., Hell D., Boesiger P., Bermphol F., Niehaus L., Boeker H., Northoff G. (2008) Imbalance between left and right dorsolateral prefrontal cortex in major depression is linked to negative emotional judgment. An fMRI study in severe major depressive disorder. Biological Psychiatry 63: 369 - 376

Northoff G., Walter M., Schulte R.F., Beck J., Dydak U., Henning, A., Boeker H., Grimm S., Boesiger P. (2007) Gaba concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nature Neuroscience 10 (12): 1515 - 1517

Grimm S., Schmidt C.F., Bermpohl F., Heinzel A., Dahlem Y., Wyss M., Hell D., Boesiger P., Boeker H., Northoff G. (2006) Segregated neural representation of distinct emotion dimensions in the prefrontal cortex – an fMRI study.
NeuroImage 30 (1): 325 - 340

Northoff G., Boeker H., Grimm S., Schmidt C., Bermpohl F., Heinzel A., Hell D.,
Boesiger P. (2006) Affective judgment and beneficial decision making: Ventromedial prefrontal activity correlates with performance in the Iowa Gambling Task.
Human Brain Mapping 27: 572 - 587

Böker H., Northoff G. (2005) Desymbolisierung in der schweren Depression und das
Problem der Hemmung: Ein neuropsychoanalytisches Modell der Störung des emotionalen Selbstbezuges Depressiver. Psyche Z Psychoanal 59: 964-989

Boeker H., Beck J., Grimm S., Hell D., Schulte R., Boesiger P., Northoff G. (2005) Neuropsychology, Psychopathology and Self- models of Depressed Patients. World Journal of Biological Psychiatry 6, Suppl.1: 21

Grimm S., Northoff G., Beck J., Schmidt C., Boesiger P., Hell D., Boeker H. (2005) Neural Activity in Prefrontal Cortex and Cognitive Symptoms in Depression. The World Journal of Biological Psychiatry 6, Suppl.1: 22

Grimm S., Northoff G., Boeker H., Schmidt C., Schulte R., Richter A., Beck J., Boesiger P. (2004). The neural correlates of abnormal expectancy: A fMR/ neuropsychological study in major depression. European Psychiatry 19, Suppl. 1: 151

Keywords / Suchbegriffe Major Depression, human brain metabolism, brain activation, prefrontal cortex, GABA/Glutamate, functional magnetic resonance imaging (fMRI), 1h magnetic resonance in vivo spectroscopy (MRS), “diagnostic markers”
Project leadership and contacts /
Projektleitung und Kontakte
Prof. Dr. med. Heinz Böker (Project Leader)
Prof. Dr. Peter Bösiger (Project Leader)
Prof. Dr. med. Daniel Hell
Other links to external web pages
Funding source(s) /
Unterstützt durch
Universität Zürich (position pursuing an academic career), Forschungskredit der Universität Zürich, SNF (Personen- und Projektförderung), Foundation
SNF: 3100-100'830Stiftung zur Förderung der wissenschaftlichen Forschung an der Universität ZürichHartmann- Müller- StiftungGebert- Rüf- StiftungHartmann- Müller- Stiftung
In collaboration with /
In Zusammenarbeit mit
Prof. Dr. Peter Bösiger
Institute of Biomedical Engineering
University and ETH Zurich
Prof. Dr. med. Dr. phil. habil. Georg Northoff
Psychiatric University Hospital
University of Magdeburg
Duration of Project / Projektdauer Jan 2004 to Dec 2009