Hidehiko Takahashi

When your gain is my pain and your pain is my gain : neural correlates of envy and schadenfreude

We often evaluate the self and others from social comparisons. We feel envy when the target person has superior and self-relevant characteristics. Schadenfreude occurs when envied persons fall from grace. To elucidate the neurocognitive mechanisms of envy and schadenfreude, we conducted two functional magnetic resonance imaging studies. In study one, the participants read information concerning target persons characterized by levels of possession and self-relevance of comparison domains. When the target persons possession was superior and self-relevant, stronger envy and stronger anterior cingulate cortex (ACC) activation were induced. In study two, stronger schadenfreude and stronger striatum activation were induced when misfortunes happened to envied persons. ACC activation in study one predicted ventral striatum activation in study two. Our findings document mechanisms of painful emotion, envy, and a rewarding reaction, schadenfreude.

Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study

We aimed to investigate the neural substrates associated with evaluative process of moral emotions. Using functional magnetic resonance imaging (fMRI), we examined the similarities and differences between evaluative process of guilt and that of embarrassment at the neural basis level. Study of the neural basis of judgments of moral emotions might contribute to a better understanding of the amoral behavior observed in neurological and psychiatric disorders. Nineteen healthy volunteers were studied. The participants read sentences carrying neutral, guilty, or embarrassing contents during the scans. Both guilt and embarrassment conditions commonly activated the medial prefrontal cortex (MPFC), left posterior superior temporal sulcus (STS), and visual cortex. Compared to guilt condition, embarrassment condition produced greater activation in the right temporal cortex (anterior), bilateral hippocampus, and visual cortex. Most of these regions have been implicated in the neural substrate of social cognition or Theory of Mind (ToM). Our results support the idea that both are self-conscious emotions, which are social emotions requiring the ability to represent the mental states of others. At the same time, our functional fMRI data are in favor of the notion that evaluative process of embarrassment might be a more complex process than that of guilt.

An fMRI study of differential neural response to affective pictures in schizophrenia.

Although emotional dysfunction is considered a fundamental symptom of schizophrenia, studies investigating the neural basis of emotional dysfunction in schizophrenia are few. Using functional magnetic resonance imaging (fMRI) and a task viewing affective pictures, we aimed to examine automatic emotional response and to elucidate the neural basis of impaired emotional processing in schizophrenia. Fifteen healthy volunteers and 15 schizophrenics were studied. During the scans, the subjects were instructed to indicate how each of the presented pictures made them feel. Whole brain activities in response to the affective pictures were measured by fMRI. Controls recruited the neural circuit including amygdaloid-hippocampal region, prefrontal cortex, thalamus, basal ganglia, cerebellum, midbrain, and visual cortex while viewing unpleasant pictures. Despite an equal behavioral result to controls, the patients showed less activation in the components of the circuit (right amygdala, bilateral hippocampal region, medial prefrontal cortex (MPFC), basal ganglia, thalamus, cerebellum, midbrain, and visual cortex). This study demonstrated functional abnormalities in the neural circuit of emotional processing in schizophrenia. In particular, decreased activation in the right amygdala and MPFC appears to be an important finding related to dysfunctional emotional behavior in schizophrenia.

Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C]DAA1106

Inflammatory/immunological process and glial contribution are suggested in the pathophysiology of schizophrenia. We investigated peripheral benzodiazepine receptors in brains of patients with chronic schizophrenia, which were reported to be located on mitochondria of glial cells, using [11C]DAA1106 with positron emission tomography. Fourteen patients and 14 age- and sex-matched normal controls participated in this study. PET data were analysed by two-tissue compartment model with metabolite-corrected plasma input. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. There was no significant difference between [11C]DAA1106 binding of the cortical regions of normal controls and patients with schizophrenia, whereas the patients showed a positive correlation between cortical [11C]DAA1106 binding and positive symptom scores. There was also a positive correlation between [11C]DAA1106 binding and duration of illness. Although the correlations need to be interpreted very cautiously, involvement of glial reaction process in the pathophysiology of positive symptoms or progressive change of schizophrenia might be suggested.

Differential Contributions of Prefrontal and Hippocampal Dopamine D1 and D2 Receptors in Human Cognitive Functions

Dopamine D1 receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D1 receptors induces an inverted U-shaped response, such that too little or too much D1 receptor stimulation impairs prefrontal functions. Less is known of the role of D2 receptors in cognition, but previous studies showed that D2 receptors in the hippocampus (HPC) might play some roles via HPC–PFC interactions. We measured both D1 and D2 receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D1 and D2 receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D1 receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D2 binding has no relation with any neuropsychological measures. Hippocampal D2 receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D1 receptor binding had no association with any memory and prefrontal functions. Hippocampal D2 receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC (“frontal lobe functions”), which are mainly subserved by PFC, via the HPC–PFC pathway. Our findings suggest that orchestration of prefrontal D1 receptors and hippocampal D2 receptors might be necessary for human executive function including working memory.

Effects of dopaminergic and serotonergic manipulation on emotional processing: A pharmacological fMRI study

Recent neuroimaging studies have demonstrated abnormal central emotional processing in psychiatric disorders. The dopamine (DA) systems and serotonin (5-HT) systems are the main target of psychopharmacotherapy. DA D2 receptor antagonists and selective serotonin reuptake inhibitors (SSRIs) are widely used in psychiatric practice. Investigating the effects of these drugs on emotional processing should lead to a better understanding of the pathophysiology and pharmacotherapy of neuropsychiatric disorders. We aimed to examine effects of dopaminergic and serotonergic manipulation on neural responses to unpleasant pictures in healthy volunteers using pharmacological fMRI. Thirteen healthy male subjects participated in a single-blind, randomized, placebo-controlled design study. Each subject participated in three fMRI sessions. In each session, participants were orally administered either 25 mg of sultopride or 50 mg of fluvoxamine or placebo prior to scanning, and neural responses to unpleasant and neutral pictures were recorded. Despite no significant differences being found in the subjective ratings of affective pictures across three sessions, compared to placebo, acute treatments of DA D2 receptor antagonists and SSRIs commonly attenuated the amygdala activity, although both treatments had slightly different modulatory effects on other components of the neural circuit of emotional processing. This study has shown that even acute treatment of drugs that manipulate neurotransmitter systems could affect brain activation associated with emotional processing in human brain. At the same time, our findings suggest that pharmacological fMRI could be a powerful tool for investigating the neurophysiological properties of drugs targeting neuropsychiatric disorders.

Men and women show distinct brain activations during imagery of sexual and emotional infidelity

Jealousy-related behaviors such as intimate partner violence and morbid jealousy are more common in males. Principal questionnaire studies suggest that men and women have different modules to process cues of sexual and emotional infidelity. We aimed to elucidate the neural response to sentences depicting sexual and emotional infidelity in men and women using functional magnetic resonance imaging. Although there was no sex difference in the self-rating score of jealousy for sexual and emotional infidelity, men and women showed different brain activation patterns in response to the two types of infidelity. During jealous conditions, men demonstrated greater activation than women in the brain regions involved in sexual/aggressive behaviors such as the amygdala and hypothalamus. In contrast, women demonstrated greater activation in the posterior superior temporal sulcus. Our fMRI results are in favor of the notion that men and women have different neuropsychological modules to process sexual and emotional infidelity. Our findings might contribute to a better understanding of the neural basis of the jealousy-related behaviors predominantly observed in males.

Memory and frontal lobe functions; possible relations with dopamine D2 receptors in the hippocampus.

Cerebral cortical regions are thought to be important for cognitive functions such as memory and executive function. Although the functional associations between dopamine D2 receptors and motor and cognitive functions have been extensively examined in the striatum using positron emission tomography (PET), the role of dopamine D2 receptors in extrastriatal regions has been unexplored. We aimed to investigate the relationship between dopamine D2 receptors in extrastriatal regions and the performance of a broad spectrum of cognitive functions including memory, language, attention, and executive function in healthy subjects. Extrastriatal dopamine D2 receptors were measured in 25 male subjects using PET with [(11)C]FLB457. After the PET scans, a battery of neuropsychological tests was administered to all subjects. We found that the binding potential (BP) of [(11)C]FLB457 in the hippocampus was positively correlated with memory function. Furthermore, BP of [(11)C]FLB457 in the hippocampus, but not in the prefrontal cortex, was associated with frontal lobe functions such as executive function and verbal fluency. Our findings suggest that dopamine D2 receptors in the hippocampus might affect the local hippocampal function, but also brain functions outside the hippocampus such as the prefrontal cortex.

The Role of Extrastriatal Dopamine D2 Receptors in Schizophrenia

Despite numerous studies on extrastriatal regions involved in schizophrenia, studies on the functional implications of dopamine (DA) D2 receptors in the extrastriatal regions, including the cortex and thalamus, are limited. We review postmortem and in vivo human imaging studies as well as animal studies, focusing on the function of extrastriatal DA D2 receptors and their role in the pathophysiology of schizophrenia. Based on recent findings, cortical DA D2 receptors may interact with the gamma-aminobutyric acid system to modulate DA transmission, and thalamic DA D2 receptors are likely to participate in sensory gating function into the prefrontal cortex. We have found decreased DA D2 receptors in the anterior cingulate cortex and thalamic subregions of patients with schizophrenia. These observations may suggest that alterations of extrastriatal DA D2 receptors are involved in dysregulation of DA transmission and sensory signals from the thalamus to the cortex. Excessive excitatory signals from the thalamus might flow into the cortical neurotransmission system, aggravating dysregulation of DA transmission in both the striatal and extrastriatal regions in schizophrenia. These notions suggest the need for future investigations of extrastriatal DA D2 receptor function to gain important clues regarding the pathogenesis and of possible treatments for schizophrenia.

Normal database of dopaminergic neurotransmission system in human brain measured by positron emission tomography.

The central dopaminergic system is of interest in the pathophysiology of schizophrenia and other neuropsychiatric disorders. Both pre- and postsynaptic dopaminergic functions can be estimated by positron emission tomography (PET) with different radiotracers. However, an integrated database of both pre- and postsynaptic dopaminergic neurotransmission components including receptors, transporter, and endogenous neurotransmitter synthesis has not yet been reported. In the present study, we constructed a normal database for the pre- and postsynaptic dopaminergic functions in the living human brain using PET. To measure striatal and extrastriatal dopamine D(1) and D(2) receptor bindings, dopamine transporter binding, and endogenous dopamine synthesis rate, PET scans were performed on healthy men after intravenous injection of [(11)C]SCH23390, [(11)C]raclopride, [(11)C]FLB457, [(11)C]PE2I, or L-[beta-(11)C]DOPA. All PET images were anatomically standardized using SPM2, and a database was built for each radiotracer. Gray matter images were segmented and extracted from all anatomically standardized magnetic resonance images using SPM2, and they were used for partial volume correction. These databases allow the comparison of regional distributions of striatal and extrastriatal dopamine D(1) and D(2) receptors, dopamine transporter, and endogenous dopamine synthesis capability. These distributions were in good agreement with those from human postmortem studies. This database can be used in various researches to understand the physiology of dopaminergic functions in the living human brain. This database could also be used to investigate regional abnormalities of dopaminergic neurotransmission in neuropsychiatric disorders.