Ventral striatal signal changes represent missed opportunities and predict future choice.

Realizing one has missed an opportunity can influence decision behavior in the future, such that a large missed opportunity leads to more risk taking in the next round. To investigate the neuronal mechanism of this phenomenon we used functional magnetic resonance imaging (fMRI) in combination with a sequential decision task in which the magnitude of possible gains linearly increased, but at the same time the gain probability decreased. After subjects decided to stop a trial and to collect the gains, not only the chosen option (actual outcome), but also the alternative option (maximum possible gain in this round) was revealed. Our data show that a missed chance influenced volunteers' decision behavior: volunteers took more risk after rounds in which they had missed a large opportunity. This was paralleled by signal changes in a lateral area of the ventral striatum that scaled with the difference between what could have been gained and what was actually gained in this round. In addition, after gains signal changes in dopaminoceptive structures including the midbrain and ventral striatum together with the insula predicted individual choice behavior in the subsequent round. Thus, our data provide a neural mechanism for how missed opportunities influence future decisions.

The effect of opioid receptor blockade on the neural processing of thermal stimuli.

The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent) signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.

Activation of the opioidergic descending pain control system underlies placebo analgesia.

Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

Blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans.

The endogenous opioid system is involved in fear learning in rodents, as opioid agonists attenuate and opioid antagonists facilitate the acquisition of conditioned fear. It has been suggested that an opioidergic signal, which is engaged through conditioning and acts inhibitory on unconditioned stimulus input, is the source of these effects. To clarify whether blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans, and to elucidate the neural underpinnings of such an effect, we used functional magnetic resonance imaging in combination with behavioral recordings and a double-blind pharmacological intervention. All subjects underwent the same classical fear-conditioning paradigm, but subjects in the experimental group received the opioid antagonist naloxone before and during the experiment, in contrast to subjects in the control group, who received saline. Blocking endogenous opioid neurotransmission with naloxone led to more sustained responses to the unconditioned stimulus across trials, evident in both behavioral and blood oxygen level-dependent responses in pain responsive cortical regions. This effect was likely caused by naloxone blocking conditioned responses in a pain-inhibitory circuit involving opioid-rich areas such as the rostral anterior cingulate cortex, amygdala, and periaqueductal gray. Most importantly, naloxone enhanced the acquisition of fear on the behavioral level and changed the activation profile of the amygdala: whereas the control group showed rapidly decaying conditioned responses across trials, the naloxone group showed sustained conditioned responses in the amygdala. Together, these results demonstrate that in humans the endogenous opioid system has an inhibitory role in the acquisition of fear.

Subregions of the ventral striatum show preferential coding of reward magnitude and probability.

As shown in non-human primate and human fMRI studies the probability and magnitude of anticipated rewards modulate activity in the mesolimbic dopaminergic system. Importantly, non-human primate data have revealed that single dopaminergic neurons code for both probability and magnitude of expected reward, suggesting an identical system. Using a guessing task that allowed the independent assessment of the factors probability and magnitude we were able to assess the impact of reward probability and magnitude in ventral striatal subregions in a large sample (n=98). We observed more anterior and lateral peak activation foci in the ventral striatum for reward probability and a more posterior and medial activation peak for reward magnitude, suggesting a functional segregation at the mesoscopic level. Importantly, this functional bias observed for the group average was also tested in each individual subject, allowing for proper random effects inference for the spatial dissociation. Taken together, our data point toward a functional dissociation of neuronal assemblies suggesting that certain populations of neurons are more sensitive to expected reward probability and other populations are more sensitive to reward magnitude.

Gene-gene interaction associated with neural reward sensitivity.

Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.

Dissociable systems for gain- and loss-related value predictions and errors of prediction in the human brain.

Midbrain dopaminergic neurons projecting to the ventral striatum code for reward magnitude and probability during reward anticipation and then indicate the difference between actual and predicted outcome. It has been questioned whether such a common system for the prediction and evaluation of reward exists in humans. Using functional magnetic resonance imaging and a guessing task in two large cohorts, we are able to confirm ventral striatal responses coding both reward probability and magnitude during anticipation, permitting the local computation of expected value (EV). However, the ventral striatum only represented the gain-related part of EV (EV+). At reward delivery, the same area shows a reward probability and magnitude-dependent prediction error signal, best modeled as the difference between actual outcome and EV+. In contrast, loss-related expected value (EV-) and the associated prediction error was represented in the amygdala. Thus, the ventral striatum and the amygdala distinctively process the value of a prediction and subsequently compute a prediction error for gains and losses, respectively. Therefore, a homeostatic balance of both systems might be important for generating adequate expectations under uncertainty. Prevalence of either part might render expectations more positive or negative, which could contribute to the pathophysiology of mood disorders like major depression.

Nogo CAA 3'UTR Insertion polymorphism is not associated with Schizophrenia nor with bipolar disorder.

The Nogo gene maps to 2p14-p13, a region consistently associated with schizophrenia and bipolar disorder. The association of a polymorphism in Nogo was previously investigated by two groups, with divergent results. In this report, using an alternative approach, we evaluated this same polymorphism in 725 individuals, including patients with schizophrenia, bipolar disorder, normal controls and non-human primate samples. Our results indicate that the polymorphism is not associated with any of these diseases, but has a remarkably biased distribution in ethnic groups. Genotyping of primate samples, suggest that this polymorphism is a recent event in human speciation.

Reduced phospholipid breakdown in Alzheimer's brains: a 31P spectroscopy study.

BACKGROUND: Abnormalities of membrane phospholipid metabolism have been described in Alzheimer's disease (AD). We investigated, with the aid of (31)P magnetic resonance spectroscopy, the in vivo intracerebral availability of phosphomonoesters (PME) and phosphodiesters (PDE) in patients with AD. METHODS: Eighteen outpatients with mild or moderate probable AD and 16 nondemented elderly volunteers were assessed with the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) and its cognitive subscale of the CAMDEX schedule (CAMCOG). Scans were performed on a 1.5 T magnetic resonance imager addressing a 40-cm(3) voxel in the left prefrontal cortex. Main outcome measures were mean relative peak areas of PME and PDE, which provide an estimate of membrane phospholipid metabolism. RESULTS: PME resonance and the PME/PDE ratio were increased in AD patients as compared to controls (p<0.05). PME was negatively correlated with global cognitive performance as shown by the Mini-Mental State Examination (r(s)=-0.36, p=0.05) and CAMCOG scores (r(s)=-0.49, p=0.007), as well as with discrete neuropsychological functions, namely, memory (r(s)=-0.53, p=0.004), visual perception (r(s)=-0.54, p=0.003), orientation (r(s)=-0.36, p=0.05), and abstract thinking (r(s)=-0.48, p=0.01). CONCLUSIONS: We provide evidence of reduced membrane phospholipid breakdown in the prefrontal cortex of mild and moderately demented AD patients. These abnormalities correlate with neuropsychological deficits that are characteristic of AD.

Widespread electrical cortical dysfunction in schizophrenia.

The purpose of this study was to compare slow cortical electrical activity between healthy and schizophrenic individuals using 123-channel EEG and current density reconstruction (CDR). Twenty-nine healthy subjects and 14 drug-free patients performed three visual paired-associate tasks (verbal, pictorial and spatial). We modeled the generators of the slow potentials (SPs) at their peak amplitude by Lp-norm minimization using individual MRIs to model the volume conductor and source. Activity in each architectonic area of Brodmann was scored with respect to individual maximum current by a percentile method. Resulting scores by cortical area were analyzed by multivariate analysis of variance (MANOVA) with planned comparisons, to search for differences among levels. Results showed a multifocal pattern of current density foci comprising the SP generators, including frontal and posterior cortices in all subjects. A few cortical areas, not exclusively frontal, were observed to significantly differ between groups. Moreover, changes in patients' frontal activity were not exclusively to lower scores or 'hipofrontality': overall effects (all tasks collapsed) included increased electrical activity in right area 10, left 38 and 47 bilaterally, and decreased activity in right area 6 and left areas 39, 21 and 19. A few additional areas showed significantly altered activity only in particular tasks. We conclude that the present method, by preserving individual anatomical and functional information, indicates bidirectional patterns of altered electrical activity in specific cortical association areas in schizophrenia, which are not compatible with the exclusive 'hipofrontality' hypothesis. Our results agree with the hypothesis of schizophrenia as a syndrome resulting from abnormalities in multiple encephalic foci.

Increased phospholipase A2 activity in schizophrenia with absent response to niacin.

An absent response to the niacin skin test has been reported to occur in about 80% of schizophrenic patients, as compared to 20% of healthy individuals. Niacin provokes redness in skin caused by a capillary vasodilatation mediated by prostaglandins. The metabolism of prostaglandins is regulated by the enzyme phospholipase A2 (PLA2). Several studies have reported increased PLA2 activity in schizophrenia. In this study we investigated the relationship between niacin response and PLA2 activity in 38 drug-free schizophrenic patients and in 28 healthy controls. Twenty-two of these patients were reevaluated after 8 weeks under treatment with new generation antipsychotic drugs. Niacin response was absent in 23% of the schizophrenic patients and in 14% in controls (n.s.). PLA2 activity was higher in schizophrenics than in controls (344+/-115 vs. 290+/-71 pmol/ml/min; p=0.03). Patients with absent response to niacin had the highest PLA2 activity as compared to those with positive response (426+/-155 vs. 319+/-111; p=0.02). After 8 weeks on antipsychotic treatment, PLA2 activity was reduced (355+/-115 before, 267+/-39 after, p=0.001) and 4 out of 13 patients with absent response to niacin converted to positive. The reduction of PLA2 activity in these patients was higher than in patients who remained with absent response (36% vs. 23%). Our data support the findings that absent response to niacin is more frequent in schizophrenic than in healthy individuals although the magnitude of the difference was smaller than that reported in the literature. The relationship between absent response to niacin in schizophrenia and increased PLA2 activity suggests further that the skin test may be useful to easily identify a subgroup of patients with a disordered phospholipid metabolism.

31P-spectroscopy of frontal lobe in schizophrenia: alterations in phospholipid and high-energy phosphate metabolism.

Studies using 31P-magnetic resonance spectroscopy (MRS) reported on abnormalities in frontal lobe metabolism in schizophrenia. The most consistent findings were a reduction in the resonances of phosphomonoesters (PME) and/or increased phosphodiesters (PDE), which are, respectively, the precursors and the metabolites of membrane phospholipids, thus suggesting an accelerated phospholipid metabolism in the disease. Other studies reported increased high-energy phosphates (ATP-adenosine triphosphate and PCr-phosphocreatine) in schizophrenia, reflecting decreased use of energy in the frontal lobe. We investigated 53 schizophrenic patients (DSM-IV) and 35 healthy controls. Eighteen from these patients were drug nai;ve and the remaining 35 were drug-free for an average of 6 months. Phospholipid metabolism and high-energy phosphates were assessed in the left frontal lobe using 31P-MRS. Psychopathological evaluation was done with the Brief Psychiatric Rating Scale (BPRS) and the Negative Symptoms Rating Scale (NSRS). Neuropsychological evaluation was performed with the Wisconsin Card Sorting Test (WCST), Stroop Test and Wechsler Adult Intelligence Scale. Drug-nai;ve patients showed reduced PDE in the left frontal lobe compared to controls and to previously medicated patients (p<0.05). No differences among the three groups were found regarding the other spectroscopy parameters. In healthy controls, but not in schizophrenics, a negative (and probably physiological) correlation was found between PME and PDE (p<0.01). In schizophrenic patients, ATP was correlated with negative symptoms and with neuropsychological impairment (p<0.01). The lack of a correlation between PME and PDE, as well as the reduction of PDE in schizophrenia, suggest a disrupted phospholipid metabolism in the disease, albeit on a contrary direction of that reported in literature. The relationships of ATP with negative symptoms and neuropsychological deficit suggest an alteration of energetic demand in the frontal lobe of schizophrenic patients, which is in line with the hypofrontality hypothesis of the disease.

Tratamento do transtorno de panico com inibidores seletivos da recaptura de serotonina / Panic disorder treatment with selective serotonin reuptake inhibitors

Os principais inibidores seletivos da recaptura de serotonina disponiveis para o tratamento do transtorno do panico sao fluvoxamina, fluoxetina, paroxetina, sertralina e o citalopram...

Espectroscopia de fosforo-31 por ressonancia magnetica / 31Phosphorus magnetic resonance spectroscopy

A espectroscopia de fosforo por ressonancia magnetica permite avaliar o metabolismo neuronal "in vivo". Os autores descrevem esse instrumento de pesquisa e discutem a sua aplicacao em pesquisa de doencas neuropsiquiatricas.

Estabilidade intra-individual dos parametros obtidos pela espectroscopia de fosforo do encefalo / Intraindividual stability of 31phosphorus magnetic resonance spectroscopy parameters

A espectroscopia por ressonancia magnetica de 31fosforo permite avaliar o metabolismo neuronal in vivo. O presente estudo tem o objetivo de verificar a estabilidade intra-individual dos parametros da espectroscopia por ressonancia magnetica de 31fosforo. Foram avaliadas dois exames realizados em um mesmo voluntario com um intervalo de quinze dias para cada voluntario. Concluimos que existe estabilidade intra-individual dos resultados...