Ulrike M. Krämer

Dopamine Agonist Increases Risk Taking but Blunts Reward-Related Brain Activity

The use of D2/D3 dopaminergic agonists in Parkinsons disease (PD) may lead to pathological gambling. In a placebo-controlled double-blind study in healthy volunteers, we observed riskier choices in a lottery task after administration of the D3 receptor-preferring agonist pramipexole thus mimicking risk-taking behavior in PD. Moreover, we demonstrate decreased activation in the rostral basal ganglia and midbrain, key structures of the reward system, following unexpected high gains and therefore propose that pathological gambling in PD results from the need to seek higher rewards to overcome the blunted response in this system.

The Impact of Catechol-O-Methyltransferase and Dopamine D4 Receptor Genotypes on Neurophysiological Markers of Performance Monitoring

Dynamic adaptations of ones behavior by means of performance monitoring are a central function of the human executive system, that underlies considerable interindividual variation. Converging evidence from electrophysiological and neuroimaging studies in both animals and humans hints at the importance of the dopaminergic system for the regulation of performance monitoring. Here, we studied the impact of two polymorphisms affecting dopaminergic functioning in the prefrontal cortex [catechol-O-methyltransferase (COMT) Val108/158Met and dopamine D4 receptor (DRD4) single-nucleotide polymorphism (SNP)-521] on neurophysiological correlates of performance monitoring. We applied a modified version of a standard flanker task with an embedded stop-signal task to tap into the different functions involved, particularly error monitoring, conflict detection and inhibitory processes. Participants homozygous for the DRD4 T allele produced an increased error-related negativity after both choice errors and failed inhibitions compared with C-homozygotes. This was associated with pronounced compensatory behavior reflected in higher post-error slowing. No group differences were seen in the incompatibility N2, suggesting distinct effects of the DRD4 polymorphism on error monitoring processes. Additionally, participants homozygous for the COMT Val allele, with a thereby diminished prefrontal dopaminergic level, revealed increased prefrontal processing related to inhibitory functions, reflected in the enhanced stop-signal-related components N2 and P3a. The results extend previous findings from mainly behavioral and neuroimaging data on the relationship between dopaminergic genes and executive functions and present possible underlying mechanisms for the previously suggested association between these dopaminergic polymorphisms and psychiatric disorders as schizophrenia or attention deficit hyperactivity disorder.

Altered Resting State Brain Networks in Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder affecting dopaminergic neurons in the substantia nigra leading to dysfunctional cortico-striato-thalamic-cortical loops. In addition to the characteristic motor symptoms, PD patients often show cognitive impairments, affective changes and other non-motor symptoms, suggesting system-wide effects on brain function. Here, we used functional magnetic resonance imaging and graph-theory based analysis methods to investigate altered whole-brain intrinsic functional connectivity in PD patients (n = 37) compared to healthy controls (n = 20). Global network properties indicated less efficient processing in PD. Analysis of brain network modules pointed to increased connectivity within the sensorimotor network, but decreased interaction of the visual network with other brain modules. We found lower connectivity mainly between the cuneus and the ventral caudate, medial orbitofrontal cortex and the temporal lobe. To identify regions of altered connectivity, we mapped the degree of intrinsic functional connectivity both on ROI- and on voxel-level across the brain. Compared to healthy controls, PD patients showed lower connectedness in the medial and middle orbitofrontal cortex. The degree of connectivity was also decreased in the occipital lobe (cuneus and calcarine), but increased in the superior parietal cortex, posterior cingulate gyrus, supramarginal gyrus and supplementary motor area. Our results on global network and module properties indicated that PD manifests as a disconnection syndrome. This was most apparent in the visual network module. The higher connectedness within the sensorimotor module in PD patients may be related to compensation mechanism in order to overcome the functional deficit of the striato-cortical motor loops or to loss of mutual inhibition between brain networks. Abnormal connectivity in the visual network may be related to adaptation and compensation processes as a consequence of altered motor function. Our analysis approach proved sensitive for detecting disease-related localized effects as well as changes in network functions on intermediate and global scale.

Tit-for-tat: The neural basis of reactive aggression

Aggressive behavior is a basic form of human social interaction, yet little is known about its neural substrates. We used a laboratory task to investigate the neural correlates of reactive aggression using functional magnetic resonance imaging. The task is disguised as a reaction-time competition between the subject and two opponents and entitles the winner to punish the loser. It seeks to elicit aggression by provocation of the subject. As each single trial in this task is separated into a decision phase, during which the severity of the prospective punishment of the opponent is set, and an outcome phase, during which the actual punishment is applied or received, the paradigm enables us to analyze the neural events during each of these phases. Specific neural responses in areas related to negative affect, cognitive control and reward processing provide additional information about the cognitive, emotional and motivational processes underlying reactive aggressive behavior and afford us with the possibility to test and expand theories on aggression such as the General Aggression Model.

The Effects of COMT (Val108/158Met) and DRD4 (SNP −521) Dopamine Genotypes on Brain Activations Related to Valence and Magnitude of Rewards

Peoples sensitivity to reinforcing stimuli such as monetary gains and losses shows a wide interindividual variation that might in part be determined by genetic differences. Because of the established role of the dopaminergic system in the neural encoding of rewards and negative events, we investigated young healthy volunteers being homozygous for either the Valine or Methionine variant of the catechol-O-methyltransferase (COMT) codon 158 polymorphism as well as homozygous for the C or T variant of the SNP -521 polymorphism of the dopamine D4 receptor. Participants took part in a gambling paradigm featuring unexpectedly high monetary gains and losses in addition to standard gains/losses of expected magnitude while undergoing functional magnetic resonance imaging at 3 T. Valence-related brain activations were seen in the ventral striatum, the anterior cingulate cortex, and the inferior parietal cortex. These activations were modulated by the COMT polymorphism with greater effects for valine/valine participants but not by the D4 receptor polymorphism. By contrast, magnitude-related effects in the anterior insula and the cingulate cortex were modulated by the D4 receptor polymorphism with larger responses for the CC variant. These findings emphasize the differential contribution of genetic variants in the dopaminergic system to various aspects of reward processing.

Genetic Variability in the Dopamine System (Dopamine Receptor D4, Catechol-O-Methyltransferase) Modulates Neurophysiological Responses to Gains and Losses

BACKGROUND Interindividual variability in the processing of reward might be partially explained by genetic differences in the dopamine system. Here, we study whether brain responses (event-related potentials [ERPs], oscillatory activity) to monetary gains and losses in normal human subjects are modulated as a function of two dopaminergic polymorphisms (catechol-O-methyltransferase [COMT] valine [Val]158methionine [Met], dopamine receptor D4 [DRD4] single nucleotide polymorphism [SNP] -521). METHODS Forty participants homozygous for the different alleles of both polymorphisms were selected from a larger population to assess the main effects and interactions. Based on the phasic/tonic dopamine hypothesis, we expected increased brain responses to losses and gains in participants homozygous for the Val/Val variant of the COMT polymorphism (related to higher enzyme activity). RESULTS The medial frontal negativity (MFN) of the ERP and the increase in beta power for gains were enhanced for participants homozygous for the COMT ValVal allele when compared with homozygous MetMet participants. In contrast, no modulations in gain- and loss-related brain activity were found to be a function of the DRD4 SNP -521 polymorphism. CONCLUSIONS The results demonstrate the role of the COMT Val/Met polymorphism in the processing of reward, consistent with theoretical explanations that suggest the possible role of dopamine in the MFN and beta power increase generation. In addition, the present results might agree with the phasic/tonic dopamine theory that predicts higher phasic dopamine responses in ValVal participants.

The role of the lateral prefrontal cortex in inhibitory motor control

Research on inhibitory motor control has implicated several prefrontal as well as subcortical and parietal regions in response inhibition. Whether prefrontal regions are critical for inhibition, attention or task-set representation is still under debate. We investigated the influence of the lateral prefrontal cortex (PFC) in a response inhibition task by using cognitive electrophysiology in prefrontal lesion patients. Patients and age- and education-matched controls performed in a visual Stop-signal task featuring lateralized stimuli, designed to challenge either the intact or lesioned hemisphere. Participants also underwent a purely behavioral Go/Nogo task, which included a manipulation of inhibition difficulty (blocks with 50 vs. 80% go-trials) and a Change-signal task that required switching to an alternative response. Patients and controls did not differ in their inhibitory speed (stop-signal and change-signal reaction time, SSRT and CSRT), but patients made more errors in the Go/Nogo task and showed more variable performance. The behavioral data stress the role of the PFC in maintaining inhibitory control but not in actual inhibition. These results support a dissociation between action cancellation and PFC-dependent action restraint. Laplacian transformed event-related potentials (ERPs) revealed reduced parietal activity in PFC patients in response to the stop-signals, and increased frontal activity over the intact hemisphere. This electrophysiological finding supports altered PFC-dependent visual processing of the stop-signal in parietal areas and compensatory activity in the intact frontal cortex. No group differences were found in the mu and beta decrease as measures of response preparation and inhibition at electrodes over sensorimotor cortex. Taken together, the data provide evidence for a central role of the lateral PFC in attentional control in the context of response inhibition.

Decreased limbic and increased fronto-parietal connectivity in unmedicated patients with obsessive-compulsive disorder

Obsessive‐compulsive disorder (OCD) is characterized by recurrent intrusive thoughts and ritualized, repetitive behaviors, or mental acts. Convergent experimental evidence from neuroimaging and neuropsychological studies supports an orbitofronto‐striato‐thalamo‐cortical dysfunction in OCD. Moreover, an over excitability of the amygdala and over monitoring of thoughts and actions involving the anterior cingulate, frontal and parietal cortex has been proposed as aspects of pathophysiology in OCD. We chose a data driven, graph theoretical approach to investigate brain network organization in 17 unmedicated OCD patients and 19 controls using resting‐state fMRI. OCD patients showed a decreased connectivity of the limbic network to several other brain networks: the basal ganglia network, the default mode network, and the executive/attention network. The connectivity within the limbic network was also found to be decreased in OCD patients compared to healthy controls. Furthermore, we found a stronger connectivity of brain regions within the executive/attention network in OCD patients. This effect was positively correlated with disease severity. The decreased connectivity of limbic regions (amygdala, hippocampus) may be related to several neurocognitive deficits observed in OCD patients involving implicit learning, emotion processing and expectation, and processing of reward and punishment. Limbic disconnection from fronto‐parietal regions relevant for (re)‐appraisal may explain why intrusive thoughts become and/or remain threatening to patients but not to healthy subjects. Hyperconnectivity within the executive/attention network might be related to OCD symptoms such as excessive monitoring of thoughts and behavior as a dysfunctional strategy to cope with threat and uncertainty. Hum Brain Mapp 35:5617–5632, 2014.

Extra tree forests for sub-acute ischemic stroke lesion segmentation in MR sequences.

BACKGROUND To analyse the relationship between structure and (dys-)function of the brain after stroke, accurate and repeatable segmentation of the lesion area in magnetic resonance (MR) images is required. Manual delineation, the current gold standard, is time consuming and suffers from high intra- and inter-observer differences. NEW METHOD A new approach is presented for the automatic and reproducible segmentation of sub-acute ischemic stroke lesions in MR images in the presence of other pathologies. The proposition is based on an Extra Tree forest framework for voxel-wise classification and mainly intensity derived image features are employed. RESULTS A thorough investigation of multi-spectral variants, which combine the information from multiple MR sequences, finds the fluid attenuated inversion recovery sequence to be both required and sufficient for a good segmentation result. The accuracy can be further improved by adding features extracted from the T1-weighted and the diffusion weighted sequences. The use of other sequences is discouraged, as they impact negatively on the results. COMPARISON WITH EXISTING METHODS Quantitative evaluation was carried out on 37 clinical cases. With a Dice coefficient of 0.65, the method outperforms earlier published methods. CONCLUSIONS The approach proves especially suitable to differentiate between new stroke and other white matter lesions based on the FLAIR sequence alone. This, and the high overlap, renders it suitable for automatic screening of large databases of MR scans, e.g. for a subsequent neuropsychological investigation. Finally, each features importance is assessed in detail and the approachs statistical dependency on clinical and image characteristics is investigated.

Self-Assessment of Individual Differences in Language Switching

Language switching is omnipresent in bilingual individuals. In fact, the ability to switch languages (code switching) is a very fast, efficient, and flexible process that seems to be a fundamental aspect of bilingual language processing. In this study, we aimed to characterize psychometrically self-perceived individual differences in language switching and to create a reliable measure of this behavioral pattern by introducing a bilingual switching questionnaire. As a working hypothesis based on the previous literature about code switching, we decomposed language switching into four constructs: (i) L1 switching tendencies (the tendency to switch to L1; L1-switch); (ii) L2 switching tendencies (L2-switch); (iii) contextual switch, which indexes the frequency of switches usually triggered by a particular situation, topic, or environment; and (iv) unintended switch, which measures the lack of intention and awareness of the language switches. A total of 582 Spanish–Catalan bilingual university students were studied. Twelve items were selected (three for each construct). The correlation matrix was factor-analyzed using minimum rank factor analysis followed by oblique direct oblimin rotation. The overall proportion of common variance explained by the four extracted factors was 0.86. Finally, to assess the external validity of the individual differences scored with the new questionnaire, we evaluated the correlations between these measures and several psychometric (language proficiency) and behavioral measures related to cognitive and attentional control. The present study highlights the importance of evaluating individual differences in language switching using self-assessment instruments when studying the interface between cognitive control and bilingualism.