Enhanced intensity dependence as a marker of low serotonergic neurotransmission in borderline personality disorder
Introduction
Impulsiveness is a central feature of borderline personality disorder (BPD), which manifests itself in severe self-harming behaviors (Linehan, 1993), in anger outbursts (American Psychiatric Association, 1994) and in criminal offences—at least in male subjects (Coid and Cordess, 1992, Herpertz et al., 2001). Therefore, concepts of serotonergic dysfunction of the CNS suggested for patients with a variety of inwardly and outwardly directed impulsive modes of behavior may also apply to BPD patients. Up to now there has been increasing evidence from pharmacological challenge tests and neuroimaging techniques (e.g. Coccaro et al., 1989, Hollander et al., 1994, Herpertz et al., 1997, de la Fuenta et al., 1997, Leyton et al., 1997, Rinne et al., 2000) that serotonergic transmission may actually be dysfunctional in BPD.
Electrophysiological observations of intra-individual stability of an augmenting/reducing (A/R) characteristic of the N1 and P2 amplitudes in response to stimuli of varying intensities in event-related potentials go back to the 1970s (Buchsbaum and Silverman, 1968, Silverman et al., 1969). The paradigm gained special impact with regard to personality dimensions, more specifically sensation seeking (Zuckerman et al., 1974, Mullins and Lukas, 1984), disinhibition (Stenberg et al., 1988), and impulsiveness (Barratt et al., 1987). The N1 represents early orienting to new external stimuli, whereas the P2 is related to very early aspects of selective attention in information processing. Meanwhile the augmenting/reducing concept has been found to be limited by a number of technical arguments (e.g. Connolly and Gruzelier, 1986). However, given the lack of competitors (Carrillo-de-la-Peña 1992) related paradigms have been increasingly applied in research on sensory stimulus processing in the human brain, such as the paradigms of “stimulus intensity modulation” (Blenner and Yingling, 1993), “stimulus intensity dependence” or “loudness dependency of auditory evoked potentials” for the acoustic modality (Hegerl and Juckel, 1993).
Due to the stable and continuous firing rate of its intracortical neuronal innervation pattern, the serotonergic system seems to be able to carry out tonic processing and modulation of sensory cortical processing (Jacobs and Azmitia, 1992). In search of a biological marker for central serotonergic functioning, the high serotonergic innervation of the primary auditory cortex (Lewis et al., 1986, Azmitia and Gannon, 1986) is of special interest for event-related potentials. Hegerl and Juckel (1993) postulated that the augmentation of the N1/P2 in its particular tangential dipole activity with increasing stimuli intensity (intensity dependence) is associated with low serotonergic neurotransmission and vice versa. This hypothesis was supported by data showing a negative correlation between the concentration of 5-HIAA in the CSF and the intensity dependence of sensory evoked potentials (von Knorring and Perris, 1981), extended by various animal studies (Ehlers et al., 1991, Pineda et al., 1991, Juckel et al., 1997, Juckel et al., 1999). On the other hand, the tryptophan depletion test—a pharmacological human challenge tool to induce a reduced serotonergic neurotransmission—did not sufficiently increase the loudness dependence of the N1/P2 (Dierks et al., 1999). Still, these negative findings may result from a methodological fact that in PET-studies (e.g. Nizhizawa et al., 1997), but particularly in cerebral fluid studies nadirs of tryptophan and its metabolites have longer latency windows than peripheral plasma tryptophan (e.g. Carpenter et al., 1998).
Early electrophysiological findings of augmenting response to visual evoked stimuli response from patients with affective disorder (Buschbaum et al., 1971, von Knorring et al., 1980), alcohol abuse (Pfefferbaum et al., 1979), autism or attention deficit disorder (Dykman et al., 1983, Bruneau et al., 1989) were followed by more sophisticated studies using AEP: Introduction of dipole source analysis in studies with patients with major depression (Hegerl et al., 1992, Gallinat et al., 2000) and other psychiatric disorders thought to be characterized by serotonergic dysfunction (Wang et al., 1996, Carillo-de-la-Pena et al., 2000, Tuchtenhagen et al., 2000) mostly indicated a strong intensity dependence. Moreover, several pharmacological studies following an enhanced stimulus intensity suggest a positive clinical response towards Selective-Serotonin-Reuptake-Inhibitors (SSRIs), lithium or other serotonin agonists as opposed to clinical non-responders (Buchsbaum et al., 1971; von Knorring, 1982; Dykman et al., 1983, Bruneau et al., 1989, Hegerl et al., 1992, Hegerl et al., 1996, Paige et al., 1994, Gallinat et al., 2000).
Furthermore, the application of dipole source analysis (Scherg and von Cramon, 1985) evoked potentials enables differention of the primary auditory cortex with its high serotonergic innervation from secondary auditory areas (Hegerl and Jackson, 1993). This non-invasive method allows localization of the main neuronal generators in the cortex by estimating intracerebral sources for surface scalp-recorded waveforms (Scherg et al., 1989). Two temporal sources were identified bilaterally for the N1/P2 component of AEP: a tangential dipole representing activity in the superior temporal plane in which the primary auditory cortex is situated and a radial dipole reflecting the evoked activity of the lateral part of the superior temporal gyrus corresponding to secondary areas (Scherg and von Cramon, 1985). In AEP the test–retest-stability of N1/P2 components was shown to be higher when measured by activity of the dipole source amplitudes than those of N1/P2 amplitudes of surface electrodes only (Hegerl et al., 1994, Carillo-de-la-Pena, 2001).
The aim of the study which used dipole analysis of the N1/P2 component of AEP was to test whether patients with BPD who are thought to be characterized by serotonergic dysfunction demonstrate enhanced loudness dependence in comparison to healthy controls. Since the concept of impulsiveness has been criticized of being rather heterogeneous (Newton et al., 1993, Herpertz and Sass, 1997) we planned to also apply a number of self-ratings to contribute to the clarification of the relationship of subfeatures of impulsiveness with stimulus intensity dependence.
Section snippets
Subjects
The study consecutively recruited female subjects only, ranging in age from 18 to 40, from our regular 12-week inpatient treatment program for BPD. The diagnosis of BPD was assessed by two experienced, specifically trained and independent raters (C.N., M.M.; inter-rater-reliabitiy 0.82) on the basis of DSM-IV and using a semi-structured standardized interview, the International Personality Disorder Examination (German version of IPDE; Loranger et al., 1996). In their past history, patients had
Source analysis of electrophysiological parameters
The dipole source model explained the data with a goodness of fit (GoF) of between 86.47% (S.D. 6.45) in 60 dB stimulus intensity data and 80.38% (S.D. 5.55) in 90 dB intensity data, including a stepwise decrease of the GoF reflecting stimulus intensity with a level of significance (T=3.81, P<0.01) when compared to the strongest stimulus intensity of 90 dB, indicating increasing noise at higher stimulus intensities. As far as the GoF was concerned, no difference was found between the groups:
Discussion
Enhanced intensity dependence of auditory evoked dipole source activity with increasing loudness in a group of 15 impulsive female BPD subjects as opposed to controls was demonstrated after multichannel-EEG recordings were carried out and followed by thorough dipole source analysis of the relevant N1/P2 tangential component. This increase in amplitudes of early intracranial source activity response to auditory event-related potentials is hypothesized to specifically indicate reduced
Acknowledgements
This work was supported with a special grant (START) from the Faculty of Medicine, Aachen. The authors would also like to thank H.-J. Kunert, A. Schuerkens and W. Kawohl for statistical and technical assistance.
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