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The LDAEP as a Potential Biomarker for Central Serotonergic Activity: Challenges to Overcome


Wyss, Christine. The LDAEP as a Potential Biomarker for Central Serotonergic Activity: Challenges to Overcome. 2015, University of Zurich, Faculty of Arts.

Abstract

Biological indicators for neurotransmitter activity are of great interest for a better understanding of the pathophysiology of psychiatric disorders. The monoaminergic neurotransmitter serotonin, in particular, plays an important role in the aetiology of many mental disorders. Serotonin has homeo- static effects on brain functioning by regulating the general excitability of neurons, and thus plays a role in modulating perception and behaviour. The loudness dependence of auditory evoked potentials (LDAEP) is a measure of the excitability of neurons in the auditory cortex during the processing of tones of different intensities. Due to a strong serotonergic innervation of the primary auditory cortex it is assumed that serotonin has modulatory effects on these brain areas. A strong LDAEP is thought to reflect a weak serotonergic activity and vice versa.
The LDAEP has been successfully applied in several fields of research. One of its most promising applications is the prediction of treatment responses. However, the LDAEPs validity has been challenged. Particularly, research on some clinical diagnoses is constrained by an inherent heteroge- neous symptom constellation within clinical diagnoses based on ICD-10 or DSM-V. It is therefore necessary to assess the symptoms with dimensional measures in order to give evidence to the underlying biological abnormalities. On the other hand, no standardized protocols exist for the application and analysis of the LDAEP. Basically, in order to measure the electrophysiological response of the auditory cortex, dipole source analysis, distributed imaging methods (LORETA) and single electrode estimation have been applied. However, results obtained with different approaches show major inconsistencies.
The aim of the present thesis was to progress in the search of biomarkers suitable for a daily clinical use. So far, findings in schizophrenia research using LDAEP are inconsistent and lack comparability due to the above-mentioned methodological issues. Study I conducted within this thesis investigated patients with schizophrenia by means of LDAEP taking dimensional measures of the symptoms into account. Patients showed higher LDAEP values compared to healthy controls, indicating a lower serotonergic activity. Moreover, predominant negative symptoms were associated with the LDAEP. These findings are in line with other studies, which showed a dysfunctional serotonergic neurotrans- mission in the genesis of negative symptoms. Study II examined the underlying neural generators during loudness processing using magnetoencephalography (MEG). Magnetic field tomography analysis revealed additional activation of brain regions outside of the auditory cortex. Time course analysis further specified that tones with high intensities were processed within hundreds of millisec- onds from the primary auditory cortex as well as the primary somatosensory cortex via the posterior cingulate cortex into the premotor cortex. These findings have strong implications on the compara- bility of the different analysis approaches.
In summary, in search of clinical biomarkers it is important to shed light on possible influences of methodological factors in order to improve their reliability and validity. Their application in daily clinical practice would lead to more precise diagnoses and improve treatment strategies by enabling a better prediction of therapeutic outcome.

Abstract

Biological indicators for neurotransmitter activity are of great interest for a better understanding of the pathophysiology of psychiatric disorders. The monoaminergic neurotransmitter serotonin, in particular, plays an important role in the aetiology of many mental disorders. Serotonin has homeo- static effects on brain functioning by regulating the general excitability of neurons, and thus plays a role in modulating perception and behaviour. The loudness dependence of auditory evoked potentials (LDAEP) is a measure of the excitability of neurons in the auditory cortex during the processing of tones of different intensities. Due to a strong serotonergic innervation of the primary auditory cortex it is assumed that serotonin has modulatory effects on these brain areas. A strong LDAEP is thought to reflect a weak serotonergic activity and vice versa.
The LDAEP has been successfully applied in several fields of research. One of its most promising applications is the prediction of treatment responses. However, the LDAEPs validity has been challenged. Particularly, research on some clinical diagnoses is constrained by an inherent heteroge- neous symptom constellation within clinical diagnoses based on ICD-10 or DSM-V. It is therefore necessary to assess the symptoms with dimensional measures in order to give evidence to the underlying biological abnormalities. On the other hand, no standardized protocols exist for the application and analysis of the LDAEP. Basically, in order to measure the electrophysiological response of the auditory cortex, dipole source analysis, distributed imaging methods (LORETA) and single electrode estimation have been applied. However, results obtained with different approaches show major inconsistencies.
The aim of the present thesis was to progress in the search of biomarkers suitable for a daily clinical use. So far, findings in schizophrenia research using LDAEP are inconsistent and lack comparability due to the above-mentioned methodological issues. Study I conducted within this thesis investigated patients with schizophrenia by means of LDAEP taking dimensional measures of the symptoms into account. Patients showed higher LDAEP values compared to healthy controls, indicating a lower serotonergic activity. Moreover, predominant negative symptoms were associated with the LDAEP. These findings are in line with other studies, which showed a dysfunctional serotonergic neurotrans- mission in the genesis of negative symptoms. Study II examined the underlying neural generators during loudness processing using magnetoencephalography (MEG). Magnetic field tomography analysis revealed additional activation of brain regions outside of the auditory cortex. Time course analysis further specified that tones with high intensities were processed within hundreds of millisec- onds from the primary auditory cortex as well as the primary somatosensory cortex via the posterior cingulate cortex into the premotor cortex. These findings have strong implications on the compara- bility of the different analysis approaches.
In summary, in search of clinical biomarkers it is important to shed light on possible influences of methodological factors in order to improve their reliability and validity. Their application in daily clinical practice would lead to more precise diagnoses and improve treatment strategies by enabling a better prediction of therapeutic outcome.

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Additional indexing

Item Type:Dissertation
Referees:Jäncke Lutz, Kawohl Wolfram, Quednow Boris B
Communities & Collections:06 Faculty of Arts > Institute of Psychology
Dewey Decimal Classification:150 Psychology
Uncontrolled Keywords:DoktoratPsych Erstautor
Language:English
Date:2015
Deposited On:30 Nov 2015 15:39
Last Modified:08 Dec 2017 15:24
Number of Pages:86
Free access at:Related URL. An embargo period may apply.
Related URLs:http://www.recherche-portal.ch/ZAD:default_scope:ebi01_prod010427139

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