The aim of this study was to elucidate and differentiate the influence of acute noradrenergic and serotonergic modulation onto brain activations during depressiveness-associated emotional information processing. Our main findings provide evidence for a selective focus of noradrenergic effects on the medial thalamic region and a more prominent dorso- and ventrolateral prefrontal focus of serotonergic effects. Medial and dorsolateral prefrontal regions were modulated by both citalopram and reboxetine, but with a preponderance of serotonergic effects. Other regions, such as the cingulate, known to be activated during the anticipation of emotional stimuli and involved in depressive information processing, were not found to be modulated differentially in our approach compared with placebo.
Primarily, the placebo sample can be regarded as a suitable basis for the comparison with the medication conditions, as it shows comparable activations with an earlier report (Herwig et al, 2007c
), particularly concerning the regions reported here to be modulated in the medication conditions. The chosen substances, citalopram and reboxetine, act as considerably selective reuptake inhibitors of serotonin and noradrenaline and have shown to be effective in the treatment of depressive disorders (for a comprehensive review on citalopram: Joubert et al, 2000
; on reboxetine: Kent, 2000
). In the treatment of depression, the antidepressant effects of all classical substances develop in the first place after repeated application and a duration of days to a few weeks (Katz et al, 2004
). Considered biological correlates of this delay of effect of selective reuptake inhibitors are considered to be adaptive changes in the balance of the transmitter systems with initial down-regulation or desensitization of inhibitory autoreceptors. Consecutively, a remodeling takes place at the synaptic and intracellular level, resulting in adaptive neuroplastic changes with increased neuroneogenesis (Nemeroff and Owens, 2002
; Berton and Nestler, 2006
; Schloss and Henn, 2004
). These changes occur at noradrenergic and serotonergic synapses, thus representing the sites of action of the reuptake transporters and accordingly of the reuptake-inhibiting drugs. The effects of single dose application of these antidepressant drugs occur at the same places. The sites of action of antidepressants within functional systems of the brain are so far not clearly characterized. Such knowledge could be valuable for the neurobiological differentiation of subtypes of patients with depressive disorders toward a more serotonergic or noradrenergic dysfunction, leading to a neurobiologically indicated treatment with a more effective response to rather noradrenergic or serotonergic acting antidepressants.
Therefore, we combined a pharmacological with a functional approach. We specifically enhanced the neurotransmission of noradrenaline and serotonin by acutely and selectively blocking the reuptake of the respective transmitters during an emotional task to identify the sites of action of both drugs by differences of brain activity compared with placebo. Considering priming or facilitating actions of these antidepressants, the modulation of brain activity should depend on the activation of the respective regions because of the task: the greater the activation by the task, the greater the influence of the reuptake inhibitor.
The noradrenergic and serotonergic modulated brain regions fit with known localizations of noradrenaline transporters (Kung et al, 2004
; Logan et al, 2007
; Schou et al, 2005
) and serotonin transporters (Varnas et al, 2004
; Laruelle et al, 1988
), although because of the widespread distribution of serotonergic and noradrenergic neurons and sites of innervation, this confirmation is rather a weak one concerning specificity, increasing the relevance of the additional functional approach.
Only a handful of recent studies have examined acute effects of serotonergic- or noradrenergic-reuptake inhibitors with functional MRI: McKie et al, 2005
infused citalopram and observed changes in brain activity compared with baseline during and after infusion in cortical (frontal, temporal, cingular, occipital) and subcortical (caudate, parahippocampal gyrus/amygdala, thalamus; deactivation in the pons) regions. In a study of Del-Ben et al, 2005
, subjects performed three tasks addressing behavioral inhibition, reinforcement processing, and covert emotional face recognition after infusion of citalopram. Citalopram caused changes in similar cortical (frontal, temporal, occipital) and subcortical (dorsal thalamic, amygdalar) regions. In a comparable approach, Anderson et al, 2007
found after infusion of citalopram increased activity in frontal, insular, and occipital regions as well as in the dorsal thalamus during the recognition of disgusted faces. A fourth study concentrated on the changes in amygdalar activity during infusion of citalopram with an emotional face processing task (Bigos et al, 2008
). Applying escitalopram, the s-enantiomer of citalopram, during a sustained attention task, Wingen et al, 2008
found increased activity only in right temporal regions, but decreased brain activity in thalamic, frontal, and premotor areas. A recent study (Murphy et al, 2009
) applied 20
mg citalopram 3
h before fMRI using the masked and unmasked emotional faces, revealing a reduced activity of the right amygdala after unmasked fearful faces. This reduction of amygdalar activity, although contradictory to the above-mentioned earlier findings in human beings (McKie et al, 2005
; Del-Ben et al, 2005
; Bigos et al, 2008
) and in animals (Burghardt et al, 2007
; Forster et al, 2006
), is not in a direct conflict with our results of a stronger modulation of the amygdala by noradrenergic reuptake inhibition.
Untill now, three studies used acutely applied reboxetine. During a categorization task with self-referential emotional words during fMRI, reboxetine induced changes in a fronto-parietal cortical network (Miskowiak et al, 2007
). The other studies focused on the amygdala during the perception of emotional facial movies (Onur et al, 2009
, Kukolja et al, 2008
), the former reporting additionally increased activations in frontal, cingular, and occipital brain regions.
In this study, serotonergic modulation during the anticipation of negative and unknown emotional stimuli affected prefrontal regions (right MidFG, SFG, DLPFC, left IFG), the dorsal striatum, and the midbrain. These regions have been shown to be involved in the anticipation of negative or unpleasant stimuli in many studies (eg, Abler et al, 2007
; Chua et al, 1999
; Nitschke et al, 2006
; Ploghaus et al, 1999
; Herwig et al, 2007a
; Jensen et al, 2003
) as well as in the anticipation of stimuli after an undecided cue (‘unknown' condition, Herwig et al, 2007c
; Critchley et al, 2001
). Most of these studies showed additional activations in the (extended) amygdalar region and in the cingulate cortex, both here not clearly modulated by serotonin. In our study, citalopram modulated both the processing of negative and positive emotional information. Though not primarily addressed in our study, citalopram modulated brain activations during the anticipation of positive stimuli in such a way that it provides a possible explanation why our analysis of the combined ‘pessimism contrast', including the comparison between the unknown and the negative condition with the positive anticipation period, revealed no differences. This points to increased activations because of serotonergic modulation in the same regions activated by the negative and unknown anticipation, which was not the case with placebo or with reboxetine. Accordingly, serotonin modulates regions involved in several cognitive–emotional functions such as response inhibition, motivational learning, valence appraisal, as well as varying effects on anxiety (acute application: increased anxiety, chronic SSRI: reduced anxiety), and mood (review: Cools et al, 2008
Earlier studies have identified noradrenergic modulation to act functionally more specific on attention and arousal (Berridge, 2008
; Aston-Jones et al, 1999
), additionally with possible implications in anxiety and fear processing (Onur et al, 2009
). In particular, the mediodorsal nucleus of the thalamus, which was in this study strongly activated by reboxetine, is known to be part of the ascending reticular activating system, the rostral continuation of the reticular formation (Van der Werf et al, 2002
). Medial thalamic regions further receive input from viscero-sensitive and pain mediating brainstem areas and are considered to form a relay within the visceroceptive pathway toward, for example, insular regions (Vogt, 2005
; Craig, 2002
). Our data of modulating influences of noradrenergic enhancement during the anticipation of negative and unknown stimuli in prefrontal, cingulate, temporal, parieto-occipital, and thalamic regions fit with the anatomical and neurochemical distribution of noradrenergic innervation in the brain with a lack of noradrenergic innervation in the striatum including the caudate (eg, Kung et al, 2004
; Wilson et al, 2003
; Schou et al, 2005
; Varnas et al, 2004
; Houle et al, 2000
Concerning the post-scanning rating of the emotional pictures, we found no significant influence of the medication. Earlier studies found influences of the acute administration of citalopram (eg, Harmer et al, 2003
; Bhagwagar et al, 2004
) and reboxetine (De Martino et al, 2008
; Miskowiak et al, 2007
) on some emotional paradigms; others, however, found no significant behavioral effects of acute doses of citalopram (Del-Ben et al, 2005
; Wingen et al, 2008
) and reboxetine (O'Carroll and Papps, 2003
) in emotional tasks.
From a systemic view, antidepressant medication was recently proposed to affect primarily basic emotion processing regions as the amygdala, rebalancing the dysfunctional interrelation to the prefrontal cortex in a bottom-up-mode (DeRubeis et al, 2008
). Our data expand this model by adding several prefrontal regions as well as thalamic and striatal areas as primary places of action of antidepressant substances. Thereby, citalopram may be suggested to act more on regions mediating behavior planning and executive control within the DLPFC (Fuster, 2000
) and cognitive–emotional integration in the VLPFC (Mayberg, 2003
). Reboxetine can be suggested to modulate viscero-sensitive afferences and arousal functions in medial thalamic regions (Vogt, 2005
; Berridge, 2008
; Aston-Jones et al, 1999
). All these functional domains can be considered to be affected in depression (DeRubeis et al, 2008
), as shown in our specific task (Herwig et al, 2009
). However, until now such findings neither provide a functional differentiation into subtypes of depression nor treatment response prediction.
With respect to the aim of improving therapy strategies for depression and of developing a personalized treatment approach in mind, future patients could be examined by fMRI with a task similar to ours to identify dysfunctional brain regions in the domain of emotion processing on the single subject level. According to this pattern, those antidepressants modulating the affected areas could be selected, which increases the activity in the respective dysfunctionally hyperactive region a dysfunctional signal in the sense of a pathological attractor for the information processing in the respective functional module. The modulatory antidepressant may thus promote neuroplastic adaptations representing the therapeutic effect. On the basis of our findings, hyperactivation in medial thalamic regions, for instance, might be better modulated with a noradrenaline-prone antidepressant. The principles of this approach may be a basis for personalized treatment based on neurobiological findings in psychiatric disorders.
Reflecting possible limitations of our study, we consider the relatively low number of analyzable subjects and scans with the analysis of 13–15 subjects corresponding to 26–30 scans in each comparison. However, the repeated-measures cross-over design of the study provided sufficient statistical power. Another specificity of our study is the lack of direct behavioral control or measure during the scan. We dispensed intentionally of any such direct behavioral measure, as the preparation and execution of an answer in any form would have been a distraction from the task and could have interfered with the addressed brain activities because of action preparation and cognitive evaluation. Participants confirmed their attention to the task in the interview after scanning. This was further verified by controlling individual brain activation in visual areas. Furthermore, the study was performed with healthy volunteers. The validity of the results for patients with depressive disorder still has to be shown.
In conclusion, the study presents a useful way of differentiating neurochemical subsystems involved in the processing of emotional information by combining functional imaging during an emotional task with an acute and specific pharmacological enhancement of serotonergic and noradrenergic neurotransmission in healthy subjects. This differentiation revealed common influences of both neurotransmitters (with a slight overweight of serotonergic effects) in medial and dorsolateral prefrontal regions during the anticipation of negatively and ‘unknown' (ambiguously) cued emotional stimuli. The bilateral medial thalamic region was selectively affected by noradrenergic modulation, unlike medial and dorsolateral prefrontal regions, which were primarily modulated by serotonergic enhancement. This combined method of pharmaco-fMRI points to regions, which in future could possibly be used to detect endophenotypes of depressive syndromes in patients responding primarily to serotonergic- or noradrenergic-acting antidepressants. Next steps in the development of a neurobiologically based administration of differential therapy in depression will be the application of these findings to depressed patients with a prospective view concerning the response to more noradrenergic or serotonergic acting antidepressants.