Frederik M. van der Veen

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.

Acute tryptophan depletion attenuates brain-heart coupling following external feedback

External and internal performance feedback triggers neural and visceral modulations such as reactions in the medial prefrontal cortex and insulae or changes of heart period (HP). The functional coupling of neural and cardiac responses following feedback (cortico-cardiac connectivity) is not well understood. While linear time-lagged within-subjects correlations of single-trial EEG and HP (cardio-electroencephalographic covariance tracing, CECT) indicate a robust negative coupling of EEG magnitude 300 ms after presentation of an external feedback stimulus with subsequent alterations of heart period (the so-called N300H phenomenon), the neurotransmitter systems underlying feedback-evoked cortico-cardiac connectivity are largely unknown. Because it has been shown that acute tryptophan depletion (ATD), attenuating brain serotonin (5-HT), decreases cardiac but not neural correlates of feedback processing, we hypothesized that 5-HT may be involved in feedback-evoked cortico-cardiac connectivity. In a placebo-controlled double-blind cross-over design, 12 healthy male participants received a tryptophan-free amino-acid drink at one session (TRP−) and a balanced amino-acid control-drink (TRP+) on another and twice performed a time-estimation task with feedback presented after each trial. N300H magnitude and plasma tryptophan levels were assessed. Results indicated a robust N300H after TRP+, which was significantly attenuated following TRP−. Moreover, plasma tryptophan levels during TRP+ were correlated with N300H amplitude such that individuals with lower tryptophan levels showed reduced N300H. Together, these findings indicate that 5-HT is important for feedback-induced covariation of cortical and cardiac activity. Because individual differences in anxiety have previously been linked to 5-HT, cortico-cardiac coupling and feedback processing, the present findings may be particularly relevant for futures studies on the relationship between 5-HT and anxiety.

Effects of Acute Tryptophan Depletion on Mood and Facial Emotion Perception Related Brain Activation and Performance in Healthy Women with and without a Family History of Depression

The present study examined the effects of acute tryptophan (Trp) depletion (ATD), a well-recognized method to lower central serotonin (5-HT) metabolism, on brain activation during a facial emotion perception task. Brain activation was measured using fMRI, and healthy female volunteers with a positive family history of unipolar depression (FH+) were compared to healthy female volunteers without such a history (FH−). Participants viewed two morphed faces and were instructed to choose between the faces based either on the intensity of the emotional expression (direct task) or the gender of the face (incidental task). In the FH+ group, depletion led to the expected lowering of mood, which partly determined the effect of depletion on performance and brain activation. A stronger mood lowering effect was associated with less accurate performance on faces expressing a negative emotion in the incidental task and a stronger right amygdala response to fearful faces in comparison to happy faces. These results were explained in terms of a mood-induced bias leading to a stronger impact of the expressed negative emotion which subsequently leads to more interference in the incidental task and a stronger amygdala response. It was concluded that the effects of ATD on mood, performance, and brain activation in a facial emotion perception task depend on family history of depression. Performance and brain activation partly depend on the effect of ATD on mood.

The effect of acute tryptophan depletion on the BOLD response during performance monitoring and response inhibition in healthy male volunteers

RationaleSerotonin (5-HT) was implicated in both clinical and experimental studies in flexible, goal-directed behavior. However, the way in which 5-HT manipulations affect brain activation patterns underlying different subprocesses of cognitive flexibility remains largely unknown.ObjectivesThe aim of this study was to investigate the effect of a transient lowering of 5-HT on brain activation during performance monitoring and response inhibition.Materials and methodsWe used acute tryptophan depletion (ATD), a well-known method to reduce central 5-HT, to investigate the effect of a transient lowering of 5-HT on the blood-oxygen-level dependent (BOLD) response in an event-related functional MRI study. Thirteen healthy male volunteers performed a modified Go/NoGo task in a counterbalanced, placebo-controlled, within-subject design.ResultsATD significantly lowered plasma tryptophan but did not affect mood and cognitive performance. ATD decreased the BOLD response in the dorsomedial prefrontal cortex (BA 8) during performance monitoring. ATD did not affect the BOLD response during response inhibition.ConclusionsThis study provides more evidence for the suggested role of 5-HT in performance monitoring. Because ATD studies have revealed inconsistent effects of ATD on performance and on brain activation, it was suggested that gender and personality traits are important variables to take into account for future research.

Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task

Acute tryptophan depletion (ATD), a well-recognized method to lower central serotonin levels, was used to examine the effects of lower central serotonin levels on memory function in healthy males. Functional Magnetic Resonance Imaging (fMRI) was used to examine changes in brain activation during the encoding and the retrieval phase of a visual verbal episodic memory task. ATD led to more positively rated words in the encoding phase and to poorer recognition of these positively rated words in the retrieval phase. Furthermore, encoding was accompanied by enhanced brain activation in occipital, middle and superior frontal, anterior and posterior cingulate and striatal areas. Retrieval attempt was accompanied by enhanced activation in the cuneus, inferior occipital gyrus and inferior and middle frontal areas. Retrieval success was accompanied by activation in an extensive network including frontal, parietal, temporal, cingulate, striatal and cerebellar areas. In the encoding phase ATD attenuated activation in the right hippocampus and ATD did not affect brain activity in the retrieval phase. These results show that serotonin is important in long term memory processes, and that serotonin acts on the encoding phase and not on the retrieval phase.

Effects of aging on recognition of intentionally and incidentally stored words: An fMRI study

Functional magnetic resonance imaging (fMRI) was used to gain more insight in the mechanism underlying a decline in recognition memory function with age. Twelve young (23-27 years) and 12 older (63-67 years) healthy men performed two types of word encoding tasks, in which words were either incidentally or intentionally encoded for storage in memory. After a 30min delay, participants performed a recognition task. Older participants were less accurate and slower than young on the recognition task. In the both groups, successful retrieval was accompanied by activation in the left inferior frontal gyrus, left precentral gyrus and right cerebellum. Older participants showed additional activity in the bilateral medial prefrontal gyrus and right parahippocampal gyrus. Correlational analyses showed that only the additional parahippocampal activation correlated positively with task performance in the older but not young participants, suggesting that activation in this area served the purpose of functional compensation. The additional activation in the medial prefrontal cortex, on the other hand, was explained in terms of increased conflict, that is, reduced distinction between target and distracter words leading to increased simultaneous activity of both response tendencies. In a comparison between incidentally and intentionally remembered words the young group showed additional activation in the right middle occipital gyrus. This last result was explained in terms of strategic differences between the young and older group.

Verbal and spatial working memory in older individuals: A positron emission tomography study

Recent reviews of a substantial number of studies have partially resolved questions concerning the brain regions used by working memory for manipulation and representation. We report a large single experiment in middle-aged to older adults (n = 89), classified by hypertensive status. Our design addresses the question of regions related to manipulation and representation, most particularly comparing spatial and verbal working memory. A control, memory search, and 2-back running memory task were performed with identical stimuli and responses during whole-brain 15O water positron emission tomography (PET) scans. Letter or spatial position instructions created verbal or spatial working memory versions of the tasks. We assessed agreement with the literature using regions of interest that were defined by clusters of activation empirically derived from the literature by Wager and Smith (Wager, T.D. and Smith, E.E., Neuroimaging studies of working memory: a meta-analysis, Cognitive, Affective and Behavioral Neuroscience, 3 (2003) 255-274). Our results largely confirmed conclusions from the review on the organization of working memory into dorsal prefrontal manipulation and ventrolateral prefrontal maintenance areas and representation in dorsal and ventral paths. Specific verbal versus spatial comparisons were also concordant with prior work establishing posterior lateralized representation for different contents by working memory. The similarity of results between this older sample and results derived by others from younger participants is notable.

The anterior cingulate cortex responds differently to the validity and valence of feedback in a time-estimation task

This study examined the role of the medial frontal cortex in the processing of valence and validity of performance feedback using a time-estimation paradigm. Participants had to produce 1s intervals followed by positive and negative feedback that could be valid or invalid (i.e., related or unrelated to task performance). Performance results showed that participants used the validity information to adjust their time estimations to negative feedback. The rostral cingulate zone (RCZ) was more active after valid feedback than after invalid feedback, but was insensitive to the valence of the feedback. The rostral anterior cingulate cortex (rACC), posterior cingulate and right superior frontal gyrus, however, appeared to be primarily sensitive to the valence of the feedback; being more active after positive feedback. The results are discussed along the lines of the ACCs cognitive and affective subdivisions and their structural and functional connections.

Dissociation between medial frontal negativity and cardiac responses in the ultimatum game: Effects of offer size and fairness

In the present study, we examined the role of fairness and offer size on brain and cardiac responses in the ultimatum game (UG). Twenty healthy volunteers played the role of responder in a computerized version of the UG in which the fairness and size of the offers were systematically varied. Both fairness and size of the offer influenced the acceptance rates in a predictable way, leading to fewer accepted unfair and low offers. Only unfair high, but not unfair low offers were accompanied by a medial frontal negativity. An unexpected stronger cardiac deceleration to fairer offers was found, which was not affected by the size of the offers. Cardiac and electrocortical measures showed a different relation with performance, and both measures were correlated only modestly. This dissociation between cardiac responses and brain potentials is discussed in terms of a possible differential sensitivity to effects of stimulus probability and violation of the social rules.

Acute tryptophan depletion in healthy males attenuates phasic cardiac slowing but does not affect electro-cortical response to negative feedback

RationaleRecent studies have shown that serotonin might be involved in performance monitoring, although the results have been inconclusive. Inconsistent results might be related to the type of pharmacological manipulation and the used behavioral and physiological measures.ObjectivesThe present study aimed at further specifying the role of serotonin in performance monitoring.Materials and methodsThe effect of serotonin on performance monitoring was studied by using acute tryptophan depletion (ATD), a well-known method to transiently lower central serotonin levels. Twenty healthy male volunteers performed a time-estimation task and their event-related brain potential (ERP), behavioral, and cardiac responses to feedback stimuli were measured. Furthermore, subjective mood and amino-acid levels were determined.ResultsAs expected, ATD did not affect mood and lowered tryptophan levels. ATD attenuated cardiac slowing to negative feedback but did not affect responses to positive feedback, ERPs, and performance measures.ConclusionsThe data point in the direction of a dissociation between cardiac and electro-cortical responses. Cardiac responses appear to be more sensitive to changes in serotonin metabolism and appear to reflect different aspects of the feedback stimulus. The phasic cardiac response appears to be an important measure that provides additional information about the impact of feedback stimuli and serotonergic functioning.