Convergent evidence indicates that apathy affects cognitive behavior in different neurological and psychiatric conditions. Studies of clinical populations have also suggested the primary involvement of the prefrontal cortex and the basal ganglia in apathy. These brain regions are interconnected at both the structural and functional levels and are deeply involved in cognitive processes, such as working memory and attention. However, it is unclear how apathy modulates brain processing during cognition and whether such a modulation occurs in healthy young subjects. To address this issue, we investigated the link between apathy and prefrontal and basal ganglia function in healthy young individuals. We hypothesized that apathy may be related to sub-optimal activity and connectivity in these brain regions.
Three hundred eleven healthy subjects completed an apathy assessment using the Starkstein’s Apathy Scale and underwent fMRI during working memory and attentional performance tasks. Using an ROI approach, we investigated the association of apathy with activity and connectivity in the DLPFC and the basal ganglia.
Apathy scores correlated positively with prefrontal activity and negatively with prefrontal-basal ganglia connectivity during both working memory and attention tasks. Furthermore, prefrontal activity was inversely related to attentional behavior.
These results suggest that in healthy young subjects, apathy is a trait associated with inefficient cognitive-related prefrontal activity, i.e., it increases the need for prefrontal resources to process cognitive stimuli. Furthermore, apathy may alter the functional relationship between the prefrontal cortex and the basal ganglia during cognition.
Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships.
Being in a social world requires an understanding of other people that is co-determined in its meaning by the situation at hand. Therefore, we investigated the underlying neural activation occurring when we encounter someone acting in angry or joyful situation. We hypothesized a dynamic interplay between the right insula, both involved in mapping visceral states associated with emotional experiences and autonomic control, and the bilateral superior temporal gyri (STG), part of the “social brain”, when facing angry vs. joyful situations. Twenty participants underwent a functional magnetic resonance imaging (fMRI) scanning session while watching video clips of actors grasping objects in joyful and angry situations. The analyses of functional connectivity, psychophysiological interaction (PPI) and dynamic causal modeling (DCM), all revealed changes in functional connectivity associated with the angry situation. Indeed, the DCM model showed that the modulatory effect of anger increased the ipsilateral forward connection from the right insula to the right STG, while it suppressed the contralateral one. Our findings reveal a critical role played by the right insula when we are engaged in angry situations. In addition, they suggest that facing angry people modulates the effective connectivity between these two nodes associated, respectively, with autonomic responses and bodily movements and human-agent motion recognition. Taken together, these results add knowledge to the current understanding of hierarchical brain network for social cognition.
anger; right insula; superior temporal gyri; social affective engagement; dynamic causal modeling
Earlier studies have demonstrated that emotional stimulation modulates attentional processing during goal-directed behavior and related activity of a brain network including the inferior frontal gyrus (IFG) and the caudate nucleus. However, it is not clear how emotional interference modulates behavior and brain physiology during variation in attentional control, a relevant question for everyday life situations in which both emotional stimuli and cognitive load vary. The aim of this study was to investigate the impact of negative emotions on behavior and activity in IFG and caudate nucleus during increasing levels of attentional control. Twenty two healthy subjects underwent event-related functional magnetic resonance imaging while performing a task in which neutral or fearful facial expressions were displayed before stimuli eliciting increasing levels of attentional control processing. Results indicated slower reaction time (RT) and greater right IFG activity when fearful compared with neutral facial expressions preceded the low level of attentional control. On the other hand, fearful facial expressions preceding the intermediate level of attentional control elicited faster behavioral responses and greater activity in the right and left sides of the caudate. Finally, correlation analysis indicated a relationship between behavioral correlates of attentional control after emotional interference and right IFG activity. All together, these results suggest that the impact of negative emotions on attentional processing is differentially elicited at the behavioral and physiological levels as a function of cognitive load.
attentional control; emotion; inferior frontal gyrus; caudate nucleus; fMRI
Background: Maternal care (MC) and dopamine modulate brain activity during emotion processing in inferior frontal gyrus (IFG), striatum and amygdala. Reuptake of dopamine from the synapse is performed by the dopamine transporter (DAT), whose abundance is predicted by variation in its gene (DAT 3′VNTR; 10 > 9-repeat alleles). Here, we investigated the interaction between perceived MC and DAT 3′VNTR genotype on brain activity during processing of aversive facial emotional stimuli.
Methods: Sixty-one healthy subjects were genotyped for DAT 3′VNTR and categorized in low and high MC individuals. They underwent functional magnetic resonance imaging while performing a task requiring gender discrimination of facial stimuli with angry, fearful or neutral expressions.
Results: An interaction between facial expression, DAT genotype and MC was found in left IFG, such that low MC and homozygosity for the 10-repeat allele are associated with greater activity during processing of fearful faces. This greater activity was also inversely correlated with a measure of emotion control as scored with the Big Five Questionnaire. Moreover, MC and DAT genotype described a double dissociation on functional connectivity between IFG and amygdala.
Conclusion: These findings suggest that perceived early parental bonding may interact with DAT 3′VNTR genotype in modulating brain activity during emotionally relevant inputs.
emotion; dopamine; maternal care; fMRI; amygdala; inferior frontal gyrus
Prefrontal behavior and activity in humans are heritable. Studies in animals demonstrate an interaction between dopamine D2 receptors and nicotinic acetylcholine receptors on prefrontal behavior but evidence in humans is weak. Therefore, we hypothesize that genetic variation regulating dopamine D2 and nicotinic acetylcholine receptor signaling impact prefrontal cortex activity and related cognition. To test this hypothesis in humans, we explored the interaction between functional genetic variants in the D2 receptor gene (DRD2, rs1076560) and in the nicotinic receptor α5 gene (CHRNA5, rs16969968) on both dorsolateral prefrontal cortex mediated behavior and physiology during working memory and on prefrontal gray matter volume.
A large sample of healthy subjects was compared for genotypic differences for DRD2 rs1076560 (G>T) and CHNRA5 rs16969968 (G>A) on prefrontal phenotypes, including cognitive performance at the N-Back task, prefrontal physiology with BOLD fMRI during performance of the 2-Back working memory task, and prefrontal morphometry with structural MRI.
We found that DRD2 rs1076560 and CHNRA5 rs16969968 interact to modulate cognitive function, prefrontal physiology during working memory, and prefrontal gray matter volume. More specifically, CHRNA5-AA/DRD2-GT subjects had greater behavioral performance, more efficient prefrontal cortex activity at 2Back working memory task, and greater prefrontal gray matter volume than the other genotype groups.
The present data extend previous studies in animals and enhance our understanding of dopamine and acetylcholine signaling in the human prefrontal cortex, demonstrating interactions elicited by working memory that are modulated by genetic variants in DRD2 and CHRNA5.
“Schizotypy” is a latent organization of personality related to the genetic risk for schizophrenia. Some evidence suggests that schizophrenia and schizotypy share some biological features, including a link to dopaminergic D2 receptor signaling. A polymorphism in the D2 gene (DRD2 rs1076560, guanine > thymine (G > T)) has been associated with the D2 short/long isoform expression ratio, as well as striatal dopamine signaling and prefrontal cortical activity during different cognitive operations, which are measures that are altered in patients with schizophrenia. Our aim is to determine the association of schizotypy scores with the DRD2 rs1076560 genotype in healthy individuals and their interaction with prefrontal activity during attention and D2 striatal signaling. A total of 83 healthy subjects were genotyped for DRD2 rs1076560 and completed the Schizotypal Personality Questionnaire (SPQ). Twenty-six participants underwent SPECT with [123I]IBZM D2 receptor radiotracer, while 68 performed an attentional control task during fMRI. We found that rs1076560 GT subjects had greater SPQ scores than GG individuals. Moreover, the interaction between schizotypy and the GT genotype predicted prefrontal activity and related attentional behavior, as well as striatal binding of IBZM. No interaction was found in GG individuals. These results suggest that rs1076560 GT healthy individuals are prone to higher levels of schizotypy, and that the interaction between rs1076560 and schizotypy scores modulates phenotypes related to the pathophysiology of schizophrenia, such as prefrontal activity and striatal dopamine signaling. These results provide systems-level qualitative evidence for mapping the construct of schizotypy in healthy individuals onto the schizophrenia continuum.
schizotypy; dopamine; DRD2; fMRI; SPECT
The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.
DRD2; dopamine; default mode network; functional magnetic resonance imaging; single-photon emission computerized tomography
Several studies investigated the neural and functional mechanisms underlying action observation in contexts with objects. However, actions seen in everyday life are often embedded in emotional contexts. The neural systems integrating emotion cues in action observation are still poorly understood. Previous findings suggest that the processing of both action and emotion information recruits motor control areas within the cerebello-thalamo-cortical pathways. It is therefore hard to determine whether social emotional contexts influence action processing via a direct modulation of motor representations coding for the observed action or via the affective state and implicit motor preparedness elicited in observers in response to emotional contexts. Here we designed a novel fMRI task to identify neural networks engaged by the affective appraisal of a grasping action seen in two different emotional contexts, while keeping the action kinematics constant. Results confirmed that observing the same acts of grasping but in different emotional contexts modulated activity in supplementary motor area, ventrolateral thalamus, anterior cerebellum. Moreover, changes in functional connectivity between left supplementary motor area and parahippocampus in different emotional contexts suggested a direct neural pathway through which emotional contexts may drive the neural motor system. Taken together, these findings shed new light on the malleability of motor system as a function of emotional contexts.
Earlier studies have shown widespread alterations of functional connectivity of various brain networks in schizophrenia, including the default mode network (DMN). The DMN has also an important role in the performance of cognitive tasks. Furthermore, treatment with second-generation antipsychotic drugs may ameliorate to some degree working memory (WM) deficits and related brain activity. The aim of this study was to evaluate the effects of treatment with olanzapine monotherapy on functional connectivity among brain regions of the DMN during WM. Seventeen patients underwent an 8-week prospective study and completed two functional magnetic resonance imaging (fMRI) scans at 4 and 8 weeks of treatment during the performance of the N-back WM task. To control for potential repetition effects, 19 healthy controls also underwent two fMRI scans at a similar time interval. We used spatial group-independent component analysis (ICA) to analyze fMRI data. Relative to controls, patients with schizophrenia had reduced connectivity strength within the DMN in posterior cingulate, whereas it was greater in precuneus and inferior parietal lobule. Treatment with olanzapine was associated with increases in DMN connectivity with ventromedial prefrontal cortex, but not in posterior regions of DMN. These results suggest that treatment with olanzapine is associated with the modulation of DMN connectivity in schizophrenia. In addition, our findings suggest critical functional differences in the regions of DMN.
default mode network; schizophrenia; antipsychotics; working memory; ventromedial prefrontal cortex; fMRI; Biological Psychiatry; Imaging; Clinical or Preclinical; Schizophrenia/Antipsychotics; Cognition; default mode network; ventromedial prefrontal cortex; fMRI; olanzapine
Individual variability in emotion processing may be associated with genetic variation as well as with psychological predispositions such as dispositional affect styles. Our previous fMRI study demonstrated that amygdala reactivity was independently predicted by affective-cognitive styles (phobic prone or eating disorders prone) and genotype of the serotonin transporter in a discrimination task of fearful facial expressions. Since the insula is associated with the subjective evaluation of bodily states and is involved in human feelings, we explored whether its activity could also vary in function of individual differences. In the present fMRI study, the association between dispositional affects and insula reactivity has been examined in two groups of healthy participants categorized according to affective-cognitive styles (phobic prone or eating disorders prone). Images of the faces of partners and strangers, in both painful and neutral situations, were used as visual stimuli. Interaction analyses indicate significantly different activations in the two groups in reaction to a loved one's pain: the phobic prone group exhibited greater activation in the left posterior insula. These results demonstrate that affective-cognitive style is associated with insula activity in pain empathy processing, suggesting a greater involvement of the insula in feelings for a certain cohort of people. In the mapping of individual differences, these results shed new light on variability in neural networks of emotion.
Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D2 receptor gene (DRD2, rs1076560, guanine>thymine - G>T) shifts splicing of the two protein isoforms (D2 short, D2S, mainly presynaptic, and D2 long, D2L) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced ‘emotion control’ compared with GT subjects. fMRI in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.
amygdala; DRD2; dopamine; emotion; fMRI; prefrontal cortex
A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser704Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser704Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser/Ser subjects exhibited greater engagement of the HF together with greater HF–dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser704Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.
DISC1; fMRI; gray matter; hippocampus; memory encoding; phenotypic variance
Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.
Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory.
Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.
Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.
Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case–control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.
dopamine; D2 receptor; working memory; prefrontal cortex; striatum
Earlier imaging studies in schizophrenia have reported abnormal amygdala and prefrontal cortex activity during emotion processing. We investigated with functional magnetic resonance imaging (fMRI) during emotion processing changes in activity of the amygdala and of prefrontal cortex in patients with schizophrenia during 8 weeks of olanzapine treatment. Twelve previously drug-free/naive patients with schizophrenia were treated with olanzapine for 8 weeks and underwent two fMRI scans after 4 and 8 weeks of treatment during implicit and explicit emotional processing. Twelve healthy subjects were also scanned twice to control for potential repetition effects. Results showed a diagnosis by time interaction in left amygdala and a diagnosis by time by task interaction in right ventrolateral prefrontal cortex. In particular, activity in left amygdala was greater in patients than in controls at the first scan during both explicit and implicit processing, while it was lower in patients at the second relative to the first scan. Furthermore, during implicit processing, right ventrolateral prefrontal cortex activity was lower in patients than controls at the first scan, while it was greater in patients at the second relative to the first scan. These results suggest that longitudinal treatment with olanzapine may be associated with specific changes in activity of the amygdala and prefrontal cortex during emotional processing in schizophrenia.
Amygdala; Antipsychotic drugs; Emotions; Functional magnetic resonance imaging; Schizophrenia
Dopamine modulation of neuronal activity during memory tasks identifies a non-linear inverted-U shaped function. Both the dopamine transporter (DAT) and dopamine D2 receptors (encoded by DRD2) critically regulate dopamine signaling in the striatum and in prefrontal cortex during memory. Moreover, in vitro studies have demonstrated that DAT and D2 proteins reciprocally regulate each other presynaptically. Therefore, we have evaluated the genetic interaction between a DRD2 polymorphism (rs1076560) causing reduced presynaptic D2 receptor expression and the DAT 3’-VNTR variant (affecting DAT expression) in a large sample of healthy subjects undergoing BOLD - fMRI during memory tasks and structural MRI. Results indicated a significant DRD2/DAT interaction in prefrontal cortex and striatum BOLD activity during both working memory and encoding of recognition memory. The differential effect on BOLD activity of the DAT variant was mostly manifest in the context of the DRD2 allele associated with lower presynaptic expression. Similar results were also evident for gray matter volume in caudate. These interactions describe a non-linear relationship between compound genotypes and brain activity or gray matter volume. Complementary data from striatal protein extracts from wild-type and D2 knock-out animals (D2R−/−) indicate that DAT and D2 proteins interact in vivo. Taken together, our results demonstrate that the interaction between genetic variants in DRD2 and DAT critically modulates the non-linear relationship between dopamine and neuronal activity during memory processing.
working memory; Recognition Memory; FMRI; Dopamine; Transport; D2; Receptor