Jimmy Jensen

The Formation of Abnormal Associations in Schizophrenia: Neural and Behavioral Evidence

It is hypothesized that due to an abnormal functioning of the reward system patients with schizophrenia form context-inappropriate associations. It has been shown that the dopamine target regions, especially the ventral striatum, are critical in the formation of reward associations. We wanted to examine how the ventral striatum responds as patients learn reward-related associations and how this neural response is linked to objective and subjective behavioral measures. Functional magnetic resonance imaging (fMRI) Blood oxygen level dependent (BOLD) responses were examined using aversive Pavlovian learning in 13 medicated patients with schizophrenia and 13 matched healthy controls. Colored circles served as conditioned stimulus (CS+) while a loud, individually adjusted, noise served as the unconditioned stimulus. Circles of another color served as neutral comparators (CS−). Subjective indices were assessed by a post-scan self-report, and galvanic skin responses (GSR) were used as objective measures of associative learning. fMRI data were analyzed using a random effects model in SPM2. Patients showed inappropriately strong activations in the ventral striatum in response to the neutral stimulus (CS−) as compared to the healthy controls. Consistent with this neural evidence of aberrant learning, patients also showed evidence of abnormal learning by self-report and as indexed by GSR. The main finding here is that patients with schizophrenia, when exposed to neutral stimuli in a threatening situation, show an abnormal pattern of learning. The aberrant activations and response are consistent with the idea that patients aberrantly assign motivational salience to neutral stimuli, and this process may be one of the aberrations that predisposes them to psychosis.

Separate brain regions code for salience vs. valence during reward prediction in humans

Predicting rewards and avoiding aversive conditions is essential for survival. Recent studies using computational models of reward prediction implicate the ventral striatum in appetitive rewards. Whether the same system mediates an organisms response to aversive conditions is unclear. We examined the question using fMRI blood oxygen level‐dependent measurements while healthy volunteers were conditioned using appetitive and aversive stimuli. The temporal difference learning algorithm was used to estimate reward prediction error. Activations in the ventral striatum were robustly correlated with prediction error, regardless of the valence of the stimuli, suggesting that the ventral striatum processes salience prediction error. In contrast, the orbitofrontal cortex and anterior insula coded for the differential valence of appetitive/aversive stimuli. Given its location at the interface of limbic and motor regions, the ventral striatum may be critical in learning about motivationally salient stimuli, regardless of valence, and using that information to bias selection of actions. Inc. Hum Brain Mapp, 2007.

Temporal Difference Modeling of the Blood-Oxygen Level Dependent Response During Aversive Conditioning in Humans: Effects of Dopaminergic Modulation

BACKGROUND The prediction error (PE) hypothesized by the temporal difference model has been shown to correlate with the phasic activity of dopamine neurons during reward learning and the blood-oxygen level dependent (BOLD) response during reward and aversive conditioning tasks. We hypothesized that dopamine would modulate the PE related signal in aversive conditioning and that haloperidol would reduce PE related activity, while an acute dose of amphetamine would increase PE related activity in the ventral striatum. METHODS Healthy participants took an acute dose of amphetamine, haloperidol, or placebo. We used functional magnetic resonance imaging (fMRI) to measure the BOLD signal while they carried out an aversive conditioning task, using cutaneous electrical stimulation as the unconditioned stimulus (US) and yellow and blue circles as conditioned stimulus (CS+ and CS-, respectively). RESULTS Prediction error related BOLD activity was seen only in the ventral striatum in the placebo subjects. The subjects given amphetamine showed a wider network of PE related BOLD activity, including the ventral striatum, globus pallidus, putamen, insula, anterior cingulate, and substantia nigra/ventral tegmental area. Haloperidol subjects did not show PE related activity in any of these regions. CONCLUSIONS Our results provide the first demonstration that the modulation of dopamine transmission affects both the physiological correlates and PE related BOLD activity during aversive learning.

THE HUMAN AMYGDALA IS INVOLVED IN GENERAL BEHAVIORAL RELEVANCE DETECTION: EVIDENCE FROM AN EVENT-RELATED FUNCTIONAL MAGNETIC RESONANCE IMAGING Go-NoGo TASK

The amygdala is classically regarded as a detector of potential threat and as a critical component of the neural circuitry mediating conditioned fear responses. However, it has been reported that the human amygdala responds to multiple expressions of emotions as well as emotionally neutral stimuli of a novel, uncertain or ambiguous nature. Thus, it has been proposed that the function of the amygdala may be of a more general art, i.e. as a detector of behaviorally relevant stimuli [Sander D, Grafman J, Zalla T (2003) The human amygdala: an evolved system for relevance detection. Rev Neurosci 14:303-316]. To investigate this putative function of the amygdala, we used event related functional magnetic resonance imaging (fMRI) and a modified Go-NoGo task composed of behaviorally relevant and irrelevant letter and number stimuli. Analyses revealed bilateral amygdala activation in response to letter stimuli that were behaviorally relevant as compared with letters with less behavioral relevance. Similar results were obtained for relatively infrequent NoGo relevant stimuli as compared with more frequent Go stimuli. Our findings support a role for the human amygdala in general detection of behaviorally relevant stimuli.

CACNA1C risk variant and amygdala activity in bipolar disorder, schizophrenia and healthy controls

Objectives Several genetic studies have implicated the CACNA1C SNP rs1006737 in bipolar disorder (BD) and schizophrenia (SZ) pathology. This polymorphism was recently found associated with increased amygdala activity in healthy controls and patients with BD. We performed a functional Magnetic Resonance Imaging (fMRI) study in a sample of BD and SZ cases and healthy controls to test for altered amygdala activity in carriers of the rs1006737 risk allele (AA/AG), and to investigate if there were differences across the diagnostic groups. Methods Rs1006737 was genotyped in 250 individuals (N = 66 BD, 61 SZ and 123 healthy controls), all of Northern European origin, who underwent an fMRI negative faces matching task. Statistical tests were performed with a model correcting for sex, age, diagnostic category and medication status in the total sample, and then in each diagnostic group. Results In the total sample, carriers of the risk allele had increased activation in the left amygdala. Group-wise analyses showed that this effect was significant in the BD group, but not in the other diagnostic groups. However, there was no significant interaction effect for the risk allele between BD and the other groups. Conclusions These results indicate that CACNA1C SNP rs1006737 affects amygdala activity during emotional processing across all diagnostic groups. The current findings add to the growing body of knowledge of the pleiotropic effect of this polymorphism, and further support that ion channel dysregulation is involved in the underlying mechanisms of BD and SZ.

Working memory networks and activation patterns in schizophrenia and bipolar disorder : comparison with healthy controls

BACKGROUND Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits. AIMS To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals. METHOD Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations. RESULTS Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder. CONCLUSIONS The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.

Aberrant Effective Connectivity in Schizophrenia Patients during Appetitive Conditioning

It has recently been suggested that schizophrenia involves dysfunction in brain connectivity at a neural level, and a dysfunction in reward processing at a behavioral level. The purpose of the present study was to link these two levels of analyses by examining effective connectivity patterns between brain regions mediating reward learning in patients with schizophrenia and healthy, age-matched controls. To this aim, we used functional magnetic resonance imaging and galvanic skin recordings (GSR) while patients and controls performed an appetitive conditioning experiment with visual cues as the conditioned (CS) stimuli, and monetary reward as the appetitive unconditioned stimulus (US). Based on explicit stimulus contingency ratings, conditioning occurred in both groups; however, based on implicit, physiological GSR measures, patients failed to show differences between CS+ and CS− conditions. Healthy controls exhibited increased blood-oxygen-level dependent (BOLD) activity across striatal, hippocampal, and prefrontal regions and increased effective connectivity from the ventral striatum to the orbitofrontal cortex (OFC BA 11) in the CS+ compared to the CS− condition. Compared to controls, patients showed increased BOLD activity across a similar network of brain regions, and increased effective connectivity from the striatum to hippocampus and prefrontal regions in the CS− compared to the CS+ condition. The findings of increased BOLD activity and effective connectivity in response to the CS− in patients with schizophrenia offer insight into the aberrant assignment of motivational salience to non-reinforced stimuli during conditioning that is thought to accompany schizophrenia.

Effect of relevance on amygdala activation and association with the ventral striatum.

While the amygdala historically has been implicated in emotional stimuli processing, recent data suggest a general role in parceling out the relevance of stimuli, regardless of their emotional properties. Using functional magnetic resonance imaging, we tested the relevance hypothesis by investigating human amygdala responses to emotionally neutral stimuli while manipulating their relevance. The task was operationalized as highly relevant if a subsequent opportunity to respond for a reward depended on response accuracy of the task, and less relevant if the reward opportunity was independent of task performance. A region of interest analysis revealed bilateral amygdala activations in response to the high relevance condition compared to the low relevance condition. An exploratory whole-brain analysis yielded robust similar results in bilateral ventral striatum. A subsequent functional connectivity analysis demonstrated increased connectivity between amygdala and ventral striatum for the highly relevant stimuli compared to the less relevant stimuli. These findings suggest that the amygdalas processing profile goes beyond detection of emotions per se, and directly support the proposed role in relevance detection. In addition, the findings suggest a close relationship between amygdala and ventral striatal activity when processing relevant stimuli. Thus, the results may indicate that human amygdala modulates ventral striatum activity and subsequent behaviors beyond that observed for emotional cues, to encompass a broader range of relevant stimuli.

Further evidence for the impact of a genome-wide-supported psychosis risk variant in ZNF804A on the Theory of Mind Network.

The single-nucleotide polymorphism (SNP) rs1344706 in ZNF804A is one of the best-supported risk variants for psychosis. We hypothesized that this SNP contributes to the development of schizophrenia by affecting the ability to understand other people’s mental states. This skill, commonly referred to as Theory of Mind (ToM), has consistently been found to be impaired in schizophrenia. Using functional magnetic resonance imaging, we previously showed that in healthy individuals rs1344706 impacted on activity and connectivity of key areas of the ToM network, including the dorsomedial prefrontal cortex, temporo-parietal junction, and the posterior cingulate cortex, which show aberrant activity in schizophrenia patients, too. We aimed to replicate these results in an independent sample of 188 healthy German volunteers. In order to assess the reliability of brain activity elicited by the ToM task, 25 participants performed the task twice with an interval of 14 days showing excellent accordance in recruitment of key ToM areas. Confirming our previous results, we observed decreasing activity of the left temporo-parietal junction, dorsomedial prefrontal cortex, and the posterior cingulate cortex with increasing number of risk alleles during ToM. Complementing our replication sample with the discovery sample, analyzed in a previous report (total N=297), further revealed negative genotype effects in the left dorsomedial prefrontal cortex as well as in the temporal and parietal regions. In addition, as shown previously, rs1344706 risk allele dose positively predicted increased frontal–temporo-parietal connectivity. These findings confirm the effects of the psychosis risk variant in ZNF804A on the dysfunction of the ToM network.

Dopamine-induced changes in neural network patterns supporting aversive conditioning

The aim of the present paper is to assess the effects of altered dopamine (DA) transmission on the functional connectivity among brain regions mediating aversive conditioning in humans. To this aim, we analyzed a previous published data set from a double-blind design combined with functional magnetic resonance imaging (fMRI) recordings in which healthy volunteers were randomly assigned to one of three drug groups: amphetamine (an indirect DA agonist), haloperidol (DA D2 receptor antagonist), and placebo. Participants were exposed to an aversive classical conditioning paradigm using cutaneous electrical stimulation as the unconditioned stimulus (US), and visual cues as the conditioned stimuli (CS) where one colour (CS+) was followed by the US in 33% of the trials and another colour (CS-) had no consequences. All participants reported awareness of stimulus contingencies. Group analysis of fMRI data revealed that the left ventral striatum (VS) and amygdala activated in response to the CS+ in all the three groups. Because of their activation patterns and documented involvement in aversive conditioning, both regions were used as seeds in the functional connectivity analysis. To constrain the functional networks obtained to relate to the conditioned response, we also correlated seed activity with the Galvanic Skin Response (GSR). In the placebo group, the right ventral tegmental area/substantia nigra (VTA/SN), bilateral caudate, right parahippocampal gyrus, left inferior parietal lobule (IPL), bilateral postcentral gyrus, bilateral middle frontal (BA 46), orbitofrontal, and ventromedial prefrontal cortices (PFC, BA 10/11) correlated with the VS and amygdala seeds in response to the CS+ compared to the CS-. Enhancing dopamine transmission via amphetamine was associated with reduced task differences and significant functional connectivity for both CS+ and CS- conditions between the left VS seed and regions modulated by DA, such as the left VTA/SN, right caudate, left amygdala, left middle frontal gyrus (BA 46), and bilateral ventromedial PFC (BA 10). Blocking dopamine transmission via haloperidol was associated with significant functional connectivity across an alternate network of regions including the left amygdala seed and the right insula, the left ACC (BA 24/32), bilateral IPL (BA 40), precuneus (BA 7), post-central gyrus, middle frontal gyrus (BA 46), and supplementary motor area (SMA, BA 6) to the CS+ versus the CS-. These data provide insight into the distinct effects of DA agents on the functional connectivity between striatal, limbic, and prefrontal areas.