Abnormal regional homogeneity of drug-naive obsessive-compulsive patients

To explore the possible abnormal resting-state activity in patients with obsessive-compulsive disorder (OCD), the regional homogeneity (ReHo) of 22 pairs of patients and well-matched healthy controls was calculated. Compared with controls, the patients showed higher ReHo in the left anterior cingulate cortex, but lower ReHo in the left inferior temporal gyrus. These findings supported the abnormal resting-state brain activity in drug-naive OCD patients. No significant correlations between ReHo value and four clinical characteristics were found, suggesting that abnormal ReHo might be trait-related in OCD. NeuroReport 21:786-790 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Blocking central opiate function modulates hedonic impact and anterior cingulate response to rewards and losses.

Reward processing is linked to specific neuromodulatory systems with a dopaminergic contribution to reward learning and motivational drive being well established. Neuromodulatory influences on hedonic responses to actual receipt of reward, or punishment, referred to as experienced utility are less well characterized, although a link to the endogenous opioid system is suggested. Here, in a combined functional magnetic resonance imaging-psychopharmacological investigation, we used naloxone to block central opioid function while subjects performed a gambling task associated with rewards and losses of different magnitudes, in which the mean expected value was always zero. A graded influence of naloxone on reward outcome was evident in an attenuation of pleasure ratings for larger reward outcomes, an effect mirrored in attenuation of brain activity to increasing reward magnitude in rostral anterior cingulate cortex. A more striking effect was seen for losses such that under naloxone all levels of negative outcome were rated as more unpleasant. This hedonic effect was associated with enhanced activity in anterior insula and caudal anterior cingulate cortex, areas implicated in aversive processing. Our data indicate that a central opioid system contributes to both reward and loss processing in humans and directly modulates the hedonic experience of outcomes.

Contingency awareness in human aversive conditioning involves the middle frontal gyrus.

In contrast to the wealth of data describing the neural mechanisms underlying classical conditioning, we know remarkably little about the mechanisms involved in acquisition of explicit contingency awareness. Subjects variably acquire contingency awareness in classical conditioning paradigms, in which they are able to describe the temporal relationship between a conditioned cue and its outcome. Previous studies have implicated the hippocampus and prefrontal cortex in the acquisition of explicit knowledge, although their specific roles remain unclear. We used functional magnetic resonance imaging to track the trial-by-trial acquisition of explicit knowledge in a concurrent trace and delay conditioning paradigm. We show that activity in bilateral middle frontal gyrus and parahippocampal gyrus correlates with the accuracy of explicit contingency awareness on each trial. In contrast, amygdala activation correlates with conditioned responses indexed by skin conductance responses (SCRs). These results demonstrate that brain regions known to be involved in other aspects of learning and memory also play a specific role, reflecting on each trial the acquisition and representation of contingency awareness.

迁移性安慰剂效应的多模态机制 ：从痛觉到情绪的行为、ERP和fMRI研究

Although studies on placebo effect proved the placebo expectation established by pain-alleviating treatment could significantly alleviate later pain perception, or the placebo expectation established by anxiety-reducing treatment could significantly reduce the intensity of induced negative feelings, it is still unclear whether or not the placebo effect can occur in a transferable manner. That is, we still don’t know if the placebo expectation derived from pain-alleviating can significantly reduce later negative emotional arousal or not. Experiment 1: We compared the effect of the verbal expectation (purely verbal induction and without pain-alleviating reinforcement) with the reinforced expectation (building the belief in the placebo’s ataractic efficiency on unpleasant picture processing by secret reduction of the intensity of the pain-evoking stimulus) on the negative emotion. The results showed that the expectation, which was reinforced by actual analgesia, was transferable and could produce significant placebo effect on negative emotional arousal. However, the expectation that was merely induced by verbal instruction did not have such power. Experiment 2 both examined the direct analgesic effect of the placebo on the sensory pain (how strong is the pain stimulus) and emotional pain (how disturbing is the pain stimulus) and the transferable ataractic effect of the placebo on the negative emotion (how disturbing is the emotional picture stimulus), and further proved that the placebo expectation that was established from pain-reducing reinforcement not only induced significant placebo effect on pain, but also significant placebo effect on unpleasant feeling. These results support the viewpoint that the reduction of affective pain based on the conditioning mechanism plays an important role in the placebo analgesia, but can’t explain the transferred placebo effect on visual unpleasantness. Experiment 3 continued to use the paradigm of the reinforced expectation group and recorded the EEG activities, the data showed that the transferable placebo treatment was accompanied with decreased P2 amplitude and increased N2 distributed, and significant differences between the transferable placebo condition and the control condition (i.e., P2 and N2) were observed within the first 150-300 ms, a duration brief enough to rule out the possibility that differences between the two conditions merely reflect a bias “to try to please the investigator. In Experiment 4, we selected the placebo responders in the pre-experiment and let them to go through the formal fMRI scan. The results found that the transferable placebo treatment reduced the negative emotional response, emotion-responsive regions such as the amygdala, insula, anterior cingulate cortex and the thalamus showed an attenuated activation. And in the placebo condition, there was an enhanced activation in the subcollosal gyrus, which may be involved in emotional regulation. In conclusion, the transferable placebo treatment induced the reliable placebo effect on the behavior, EEG activity and bold signal, and we attempted to discuss the pychophysiological mechanism based on the positive expectancy.

Imagery and retrieval of auditory and visual information: neural correlates of successful and unsuccessful performance.

Remembering past events - or episodic retrieval - consists of several components. There is evidence that mental imagery plays an important role in retrieval and that the brain regions supporting imagery overlap with those supporting retrieval. An open issue is to what extent these regions support successful vs. unsuccessful imagery and retrieval processes. Previous studies that examined regional overlap between imagery and retrieval used uncontrolled memory conditions, such as autobiographical memory tasks, that cannot distinguish between successful and unsuccessful retrieval. A second issue is that fMRI studies that compared imagery and retrieval have used modality-aspecific cues that are likely to activate auditory and visual processing regions simultaneously. Thus, it is not clear to what extent identified brain regions support modality-specific or modality-independent imagery and retrieval processes. In the current fMRI study, we addressed this issue by comparing imagery to retrieval under controlled memory conditions in both auditory and visual modalities. We also obtained subjective measures of imagery quality allowing us to dissociate regions contributing to successful vs. unsuccessful imagery. Results indicated that auditory and visual regions contribute both to imagery and retrieval in a modality-specific fashion. In addition, we identified four sets of brain regions with distinct patterns of activity that contributed to imagery and retrieval in a modality-independent fashion. The first set of regions, including hippocampus, posterior cingulate cortex, medial prefrontal cortex and angular gyrus, showed a pattern common to imagery/retrieval and consistent with successful performance regardless of task. The second set of regions, including dorsal precuneus, anterior cingulate and dorsolateral prefrontal cortex, also showed a pattern common to imagery and retrieval, but consistent with unsuccessful performance during both tasks. Third, left ventrolateral prefrontal cortex showed an interaction between task and performance and was associated with successful imagery but unsuccessful retrieval. Finally, the fourth set of regions, including ventral precuneus, midcingulate cortex and supramarginal gyrus, showed the opposite interaction, supporting unsuccessful imagery, but successful retrieval performance. Results are discussed in relation to reconstructive, attentional, semantic memory, and working memory processes. This is the first study to separate the neural correlates of successful and unsuccessful performance for both imagery and retrieval and for both auditory and visual modalities.

Co-activation of the amygdala, hippocampus and inferior frontal gyrus during autobiographical memory retrieval.

Functional MRI was used to investigate the role of medial temporal lobe and inferior frontal lobe regions in autobiographical recall. Prior to scanning, participants generated cue words for 50 autobiographical memories and rated their phenomenological properties using our autobiographical memory questionnaire (AMQ). During scanning, the cue words were presented and participants pressed a button when they retrieved the associated memory. The autobiographical retrieval task was interleaved in an event-related design with a semantic retrieval task (category generation). Region-of-interest analyses showed greater activation of the amygdala, hippocampus, and right inferior frontal gyrus during autobiographical retrieval relative to semantic retrieval. In addition, the left inferior frontal gyrus showed a more prolonged duration of activation in the semantic retrieval condition. A targeted correlational analysis revealed pronounced functional connectivity among the amygdala, hippocampus, and right inferior frontal gyrus during autobiographical retrieval but not during semantic retrieval. These results support theories of autobiographical memory that hypothesize co-activation of frontotemporal areas during recollection of episodes from the personal past.

Changes in fos expression in the rat brain after unilateral lesions of the anterior thalamic nuclei

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.

An fMRI study of Joint Attention Experience

Although much is now known about eye movement detection, little is known about the higher cognitive processes involved in joint attention. We developed video stimuli which when watched, engender an experience of joint attention in the observer. This allowed us to compare an experience of joint attention to nonjoint attention within an fMRI scanning environment. Joint attention was associated with activity in the ventromedial frontal cortex, the left superior frontal gyrus (BA10), cingulate cortex, and caudate nuclei. The ventromedial frontal cortex has been consistently shown to be activated during mental state attribution tasks. BA10 may serve a cognitive integration function, which in this case seems to utilize a perception–action matching process. The activation we identified in BA10 overlaps with a location of increased grey matter density that we recently found to be associated with autistic spectrum disorder. This study therefore constitutes evidence that the neural substrate of joint attention also serves a mentalizing function. The developmental failure of this substrate in the left anterior frontal lobe may be important in the etiology of autistic spectrum disorder.

Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation

Background. Many studies have separately reported abnormalities of frontal and temporal lobe structures in schizophrenia, but little is known of structural fronto-temporal associations in this condition. We investigated whether male patients with chronic schizophrenia would show abnormal patterns of correlation between regional brain volumes.

Methods. Structural magnetic resonance images of the brain in 42 patients were compared with 43 matched unaffected controls. We explored the pattern of association between regional brain volumes by correlational analyses, and non-parametrically tested for significance of between-group differences by randomization.

Results. The schizophrenics demonstrated significant volume deficits in several brain regions (left temporal lobe and hippocampus, right dorsolateral prefrontal cortex), and significant volume increases in the ventricular system (third ventricle and left temporal horn of the lateral ventricle). Controls demonstrated large positive correlations (r > 0.4) between prefrontal and temporal lobe regions. By contrast, inter-regional correlations significantly reduced in schizophrenics included those between prefrontal, anterior cingulate and temporal regions, and between posterior cingulate and hippocampus (P < 0.05). The most salient abnormality in patients was a dissociation between prefrontal and superior temporal gyrus volumes (P < 0.01).

Conclusions. These results support the existence of a relative 'fronto-temporal dissociation' in schizophrenia which we suggest may be due to lack of mutually trophic influences during frontal and temporal lobe development.

Cognitive performance is related to cortical grey matter volumes in early stages of schizophrenia: A population-based study of first-episode psychosis

Background: Neuropsychological deficits have been reported in association with first-episode psychosis (FEP). Reductions in grey matter (GM) volumes have been documented in FEP subjects compared to healthy controls. However, the possible inter-relationship between the findings of those two lines of research has been scarcely investigated.

Objective: To investigate the relationship between neuropsychological deficits and GM volume abnormalities in a population-based sample of FEP patients compared to healthy controls from the same geographical area.

Methods: FEP patients (n = 88) and control subjects (n = 86) were evaluated by neuropsychological assessment (Controlled Oral Word Association Test, forward and backward digit span tests) and magnetic resonance imaging using voxel-based morphometry.

Results: Single-group analyses showed that prefrontal and temporo-parietal GM volumes correlated significantly (p < 0.05, corrected) with cognitive performance in FEP patients. A similar pattern of direct correlations between neocortical GM volumes and cognitive impairment was seen in the schizophrenia subgroup (n = 48). In the control group, cognitive performance was directly correlated with GM volume in the right dorsal anterior cingulate cortex and inversely correlated with parahippocampal gyral volumes bilaterally. Interaction analyses with "group status" as a predictor variable showed significantly greater positive correlation within the left inferior prefrontal cortex (BA46) in the FEP group relative to controls, and significantly greater negative correlation within the left parahippocampal gyrus in the control group relative to FEP patients.

Conclusion: Our results indicate that cognitive deficits are directly related to brain volume abnormalities in frontal and temporo-parietal cortices in FEP subjects, most specifically in inferior portions of the dorsolateral prefrontal cortex. (C) 2009 Elsevier B.V. All rights reserved.

Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: Relevance to schizophrenia.

A series of studies in schizophrenic patients report a decrease of glutathione (GSH) in prefrontal cortex (PFC) and cerebrospinal fluid, a decrease in mRNA levels for two GSH synthesizing enzymes and a deficit in parvalbumin (PV) expression in a subclass of GABA neurons in PFC. GSH is an important redox regulator, and its deficit could be responsible for cortical anomalies, particularly in regions rich in dopamine innervation. We tested in an animal model if redox imbalance (GSH deficit and excess extracellular dopamine) during postnatal development would affect PV-expressing neurons. Three populations of interneurons immunolabeled for calcium-binding proteins were analyzed quantitatively in 16-day-old rat brain sections. Treated rats showed specific reduction in parvalbumin immunoreactivity in the anterior cingulate cortex, but not for calbindin and calretinin. These results provide experimental evidence for the critical role of redox regulation in cortical development and validate this animal model used in schizophrenia research.

Quantitative analysis of postnatal neurogenesis and neuron number in the macaque monkey dentate gyrus

The dentate gyrus is one of only two regions of the mammalian brain where substantial neurogenesis occurs postnatally. However, detailed quantitative information about the postnatal structural maturation of the primate dentate gyrus is meager. We performed design-based, stereological studies of neuron number and size, and volume of the dentate gyrus layers in rhesus macaque monkeys (Macaca mulatta) of different postnatal ages. We found that about 40% of the total number of granule cells observed in mature 5-10-year-old macaque monkeys are added to the granule cell layer postnatally; 25% of these neurons are added within the first three postnatal months. Accordingly, cell proliferation and neurogenesis within the dentate gyrus peak within the first 3 months after birth and remain at an intermediate level between 3 months and at least 1 year of age. Although granule cell bodies undergo their largest increase in size during the first year of life, cell size and the volume of the three layers of the dentate gyrus (i.e. the molecular, granule cell and polymorphic layers) continue to increase beyond 1 year of age. Moreover, the different layers of the dentate gyrus exhibit distinct volumetric changes during postnatal development. Finally, we observe significant levels of cell proliferation, neurogenesis and cell death in the context of an overall stable number of granule cells in mature 5-10-year-old monkeys. These data identify an extended developmental period during which neurogenesis might be modulated to significantly impact the structure and function of the dentate gyrus in adulthood.