The roles of the orbitofrontal cortex via the habenula in non-reward and depression,and in the responses of serotonin and dopamine neurons

Cortical regions such as the orbitofrontal cortex involved in reward and in non-reward and which are implicated in depression, and the amygdala, are connected to the habenula via the striatum and pallidum, and via subcortical limbic structures. The habenula in turn projects to the raphe nuclei, the source of the serotonin-containing neurons that project to the forebrain. It is proposed that this provides a route for cortical signals related to reward, and to not obtaining expected rewards, to influence the serotonin-containing neuronal system that is influenced by many antidepressant treatments. This helps to provide a more circuit-based understanding of the brain mechanisms related to depression, and how some treatments influence this system. The habenula also projects via the rostromedial tegmental nucleus to the dopamine-containing neurons, and this, it is proposed, provides a route for reward prediction error signals and other reward- and punishment-related signals of cortical and striatal origin to influence the dopamine system.     

The orbitofrontal cortex and its role in the assignment of behavioural significance

Converging evidence suggests a specific role for the orbitofrontal cortex (OFC) in processing of reinforcer value and stimulus hedonicity. However, in a recent study posterior parts of the OFC were also activated in the absence of physical reward or positive reinforcement, namely when affectively neutral stimuli were perceived as salient and required an immediate adjustment of behaviour. This suggests that the OFC may be similarly responsive to different types of behaviourally significant events irrespective of their affective valence or the associated response demands. The present functional neuroimaging study aimed at testing this hypothesis. By systematically varying the exact nature of the behavioural significance of experimental stimuli we were able to directly compare neural responses to significant events that signalled the chance to gain a monetary reward for correct performance with brain activation related to salient, but affectively neutral events that occurred unexpectedly and required a rapid adjustment of behaviour towards these events. The observed commonalities in orbitofrontal activation for different types of significant events, which occurred independent of the hedonic value or the actual response requirements, confirmed the hypothesis that the OFC may be more generally involved in evaluating the behavioural relevance of salient environmental stimuli and is not restricted to the processing of reward and positive incentive value. Our findings thus further underscore the putative role of the OFC in the prioritisation of attentional selection and behavioural control.     

Common and distinct networks underlying reward valence and processing stages: a meta-analysis of functional neuroimaging studies

To better understand the reward circuitry in human brain, we conducted activation likelihood estimation (ALE) and parametric voxel-based meta-analyses (PVM) on 142 neuroimaging studies that examined brain activation in reward-related tasks in healthy adults. We observed several core brain areas that participated in reward-related decision making, including the nucleus accumbens (NAcc), caudate, putamen, thalamus, orbitofrontal cortex (OFC), bilateral anterior insula, anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC), as well as cognitive control regions in the inferior parietal lobule and prefrontal cortex (PFC). The NAcc was commonly activated by both positive and negative rewards across various stages of reward processing (e.g., anticipation, outcome, and evaluation). In addition, the medial OFC and PCC preferentially responded to positive rewards, whereas the ACC, bilateral anterior insula, and lateral PFC selectively responded to negative rewards. Reward anticipation activated the ACC, bilateral anterior insula, and brain stem, whereas reward outcome more significantly activated the NAcc, medial OFC, and amygdala. Neurobiological theories of reward-related decision making should therefore take distributed and interrelated representations of reward valuation and valence assessment into account.     

Dissociable roles of the medial prefrontal cortex, the anterior cingulate cortex, and the hippocampus in behavioural flexibility revealed by serial reversal of three-choice discrimination in rats

Contributions of different limbic cortical areas to mediation of behavioural flexibility were examined using repeated acquisition of three-choice discrimination in operant chambers. Rats were trained on a series of positional discrimination tasks with three levers, where position of the correct lever remained the same within a task but shifted across tasks. Ibotenic acid lesions of the medial prefrontal cortex impaired acquisition of each discrimination task by increasing errors specifically in the early phase of each task. These errors were characterised by perseveration to the previously correct lever. By contrast, lesions of the anterior cingulate cortex resulted in the impairment of discrimination in general without inducing perseveration; the impairment was instead characterised by disruption of general error-correction processes. Hippocampal lesions severely impaired learning by increasing perseverative tendencies that were present throughout the learning stages in each task. These results extend our understanding of the contributions of the different nodes of the limbic cortico-striatal circuit to different aspects of behavioural flexibility.     

Gray matter reduction associated with emotion regulation in female outpatients with major depressive disorder: A voxel-based morphometry study

Objective

Though emotion dysregulation is the key feature in major depressive disorder, and structural changes in brain areas of depressed patients have been found, it is unknown how these regional volume alterations correlate with the ability to regulate emotion in the depressed population.

Method

We examined the gray matter concentration (GMC) and volume (GMV) in 17 depressed patients and 17 healthy volunteers using a voxel-based morphometry (VBM) study. Images were acquired using a 1.5 T MRI scanner, and were spatially normalized and segmented. Statistical comparisons were performed using the general linear model. The identified volumetric alterations in the depressed participants were correlated with their performance on an emotion regulation task that involved reduction of positive or negative emotions to emotional pictures that were selected according to their individual ratings.

Results

The depressed participants showed specific difficulty in regulating negative emotion, though not positive emotion, which was associated with reduced GMV and concentration in the anterior cingulate cortex (ACC) and the inferior orbitofrontal cortex (OFC). Decreased GMC in the superior temporal cortex was also found in people with major depressive disorder.

Conclusions

Abnormal structures in the ACC and OFC and the dysregulation of negative emotion may relate to the pathology of major depressive disorder.     

Neural correlates of thought suppression

The present report used functional magnetic resonance imaging (fMRI) to examine the neural correlates of thought suppression. Subjects were imaged while alternately (i) attempting to suppress a particular thought, (ii) attempting to suppress all thoughts, or (iii) thinking freely about any thought. Suppression of a particular thought, when compared to the free-thought control condition, revealed greater activation in the anterior cingulate. When the task of suppressing all conscious thoughts was compared to free-thought, a more distributed network of brain regions, including the anterior cingulate and the insula, was activated. These findings are consistent with previous research on cognitive control and may provide potential insights into psychological disorders involving recurring, intrusive thoughts.     

Glutamate System Genes Associated with Ventral Prefrontal and Thalamic Volume in Pediatric Obsessive-Compulsive Disorder

This pilot study was undertaken to determine if there was a significant association between specific glutamate system genes and regional volumes of interest implicated in the pathogenesis of obsessive-compulsive disorder (OCD). Volumetric magnetic resonance imaging (MRI) and genotyping of seven polymorphisms in two genes, glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and solute linked carrier, family 1, member 1 (SLC1A1) were conducted in 31 psychotropic-naïve pediatric OCD patients. The rs1805476 variant of GRIN2B was associated with left but not right orbital frontal cortex (OFC) (p?=?0.04) and right but not left anterior cingulate cortex (ACC) volume (p?=?0.02). The SLC1A1 rs3056 variant was associated with increased total (p?=?0.01), left (p?=?0.02) and right (p?=?0.02) thalamic volume. These results suggest that GRIN2B and SLC1A1 may be associated with regional volumetric alterations in OFC, ACC, and thalamus in children with OCD.     

Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study

In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion HCl reduces overall cigarette craving levels in nicotine dependent subjects, we performed a preliminary study of smokers to determine if bupropion HCl treatment attenuates cue-induced cigarette craving and associated brain metabolic activation. Thirty-seven, otherwise healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion HCl) underwent two ¹⁸F-fluorodeoxyglucose positron emission tomography scanning sessions in randomized order—one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores on the Urge to Smoke (UTS) Scale and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion HCl diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion HCl, including its enhancement of catecholaminergic neurotransmission.     

Cognitive dissonance induction in everyday life: An fMRI study

This functional magnetic resonance imaging (fMRI) study explored the neural substrates of cognitive dissonance during dissonance “induction.” A novel task was developed based on the results of a separate item selection study (n = 125). Items were designed to generate dissonance by prompting participants to reflect on everyday personal experiences that were inconsistent with values they had expressed support for. One experimental condition (dissonance) and three control conditions (justification, consonance, and non-self-related inconsistency) were used for comparison. Items of all four types were presented to each participant (n = 14) in a randomized design. The fMRI analysis used a whole-brain approach focusing on the moments dissonance was induced. Results showed that in comparison with the control conditions the dissonance experience led to higher levels of activation in several brain regions. Specifically dissonance was associated with increased neural activation in key brain regions including the anterior cingulate cortex (ACC), anterior insula, inferior frontal gyrus, and precuneus. This supports current perspectives that emphasize the role of anterior cingulate and insula in dissonance processing. Less extensive activation in the prefrontal cortex than in some previous studies is consistent with this study’s emphasis on dissonance induction, rather than reduction. This article also contains a short review and comparison with other fMRI studies of cognitive dissonance.     

Effects of prefrontal theta-burst stimulation on brain function in treatment-resistant depression: A randomized sham-controlled neuroimaging study

Background

Theta-burst transcranial magnetic stimulation (TBS) can quickly modulate brain activity and can be used to treat treatment-resistant depression (TRD). Whole-brain analytical research has revealed that left high-frequency PFC rTMS modulates brain activity in anterior cingulate cortex (ACC) and the fronto-cingulo-temporal circuit. We aimed to investigate whether the prefrontal TBS's antidepressant mechanisms involve these regions.

Selective reduction of Von Economo neuron number in agenesis of the corpus callosum

Von Economo neurons (VENs) are large spindle-shaped neurons localized to anterior cingulate cortex (ACC) and fronto-insular cortex (FI). VENs appear late in development in humans, are a recent phylogenetic specialization, and are selectively destroyed in frontotemporal dementia, a disease which profoundly disrupts social functioning and self-awareness. Agenesis of the corpus callosum (AgCC) is a congenital disorder that can have significant effects on social and emotional behaviors, including alexithymia, difficulty intuiting the emotional states of others, and deficits in self- and social-awareness that can impair humor, comprehension of non-literal or affective language, and social judgment. To test the hypothesis that VEN number is selectively reduced in AgCC, we used stereology to obtain unbiased estimates of total neuron number and VEN number in postmortem brain specimens of four normal adult controls, two adults with isolated callosal dysgenesis, and one adult whose corpus callosum and ACC were severely atrophied due to a non-fatal cerebral arterial infarction. The partial agenesis case had approximately half as many VENs as did the four normal controls, both in ACC and FI. In the complete agenesis case the VENs were almost entirely absent. The percentage of neurons in FI that are VENs was reduced in callosal agenesis, but was actually slightly above normal in the stroke patient. These results indicate that the VEN population is selectively reduced in AgCC, but that the VENs do not depend on having an intact corpus callosum. We conclude that in agenesis of the corpus callosum the reduction in the number of VENs is not the direct result of the failure of this structure to develop, but may instead be another consequence of the genetic disruption that caused the agenesis. The reduction of the VEN population could help to explain some of the social and emotional deficits that are seen in this disorder.     

Developmental changes in the reward positivity: An electrophysiological trajectory of reward processing

Children and adolescents learn to regulate their behavior by utilizing feedback from the environment but exactly how this ability develops remains unclear. To investigate this question, we recorded the event-related brain potential (ERP) from children (8–13 years), adolescents (14–17 years) and young adults (18–23 years) while they navigated a “virtual maze” in pursuit of monetary rewards. The amplitude of the reward positivity, an ERP component elicited by feedback stimuli, was evaluated for each age group. A current theory suggests the reward positivity is produced by the impact of reinforcement learning signals carried by the midbrain dopamine system on anterior cingulate cortex, which utilizes the signals to learn and execute extended behaviors. We found that the three groups produced a reward positivity of comparable size despite relatively longer ERP component latencies for the children, suggesting that the reward processing system reaches maturity early in development. We propose that early development of the midbrain dopamine system facilitates the development of extended goal-directed behaviors in anterior cingulate cortex.     

Alterations of brain activity in fibromyalgia patients

Fibromyalgia is a chronic pain syndrome, characterized by widespread musculoskeletal pain with diffuse tenderness at multiple tender points. Despite intense investigations, the pathophysiology of fibromyalgia remains elusive. Evidence shows that it could be due to changes in either the peripheral or central nervous system (CNS). For the CNS changes, alterations in the high brain area of fibromyalgia patients have been investigated but the definite mechanisms are still unclear. Magnetic Resonance Imaging (MRI) and Functional Magnetic Resonance (fMRI) have been used to gather evidence regarding the changes of brain morphologies and activities in fibromyalgia patients. Nevertheless, due to few studies, limited knowledge for alterations in brain activities in fibromyalgia is currently available. In this review, the changes in brain activity in various brain areas obtained from reports in fibromyalgia patients are comprehensively summarized. Changes of the grey matter in multiple regions such as the superior temporal gyrus, posterior thalamus, amygdala, basal ganglia, cerebellum, cingulate cortex, SII, caudate and putamen from the MRI as well as the increase of brain activities in the cerebellum, prefrontal cortex, anterior cingulate cortex, thalamus, somatosensory cortex, insula in fMRI studies are presented and discussed. Moreover, evidence from pharmacological interventions offering benefits for fibromyalgia patients by reducing brain activity is presented. Because of limited knowledge regarding the roles of brain activity alterations in fibromyalgia, this summarized review will encourage more future studies to elucidate the underlying mechanisms involved in the brains of these patients.     

Neural correlates of experienced moral emotion: An fMRI investigation of emotion in response to prejudice feedback

Guilt, shame, and embarrassment are quintessential moral emotions with important regulatory functions for the individual and society. Moral emotions are, however, difficult to study with neuroimaging methods because their elicitation is more intricate than that of basic emotions. Here, using functional MRI (fMRI), we employed a novel social prejudice paradigm to examine specific brain regions associated with real-time moral emotion, focusing on guilt and related moral-negative emotions. The paradigm induced intense moral-negative emotion (primarily guilt) in 22 low-prejudice individuals through preprogrammed feedback indicating implicit prejudice against Black and disabled people. fMRI data indicated that this experience of moral-negative emotion was associated with increased activity in anterior paralimbic structures, including the anterior cingulate cortex (ACC) and anterior insula, in addition to areas associated with mentalizing, including the dorsomedial prefrontal cortex, posterior cingulate cortex, and precuneus. Of significance was prominent conflict-related activity in the supragenual ACC, which is consistent with theories proposing an association between acute guilt and behavioral inhibition. Finally, a significant negative association between self-reported guilt and neural activity in the pregenual ACC suggested a role of self-regulatory processes in response to moral-negative affect. These findings are consistent with the multifaceted self-regulatory functions of moral-negative emotions in social behavior.     

Response conflict and frontocingulate dysfunction in unmedicated participants with major depression

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.     

Empathy examined through the neural mechanisms involved in imagining how I feel versus how you feel pain

Perspective-taking is a stepping stone to human empathy. When empathizing with another individual, one can imagine how the other perceives the situation and feels as a result. To what extent does imagining the other differs from imagining oneself in similar painful situations? In this functional magnetic resonance imaging experiment, participants were shown pictures of people with their hands or feet in painful or non-painful situations and instructed to imagine and rate the level of pain perceived from different perspectives. Both the Self's and the Other's perspectives were associated with activation in the neural network involved in pain processing, including the parietal operculum, anterior cingulate cortex (ACC; BA32) and anterior insula. However, the Self-perspective yielded higher pain ratings and involved the pain matrix more extensively in the secondary somatosensory cortex, the ACC (BA 24a'/24b'), and the insula proper. Adopting the perspective of the Other was associated with specific increase in the posterior cingulate/precuneus and the right temporo-parietal junction. These results show the similarities between Self- and Other-pain representation, but most interestingly they also highlight some distinctiveness between these two representations, which is a crucial aspect of human empathy. It may be what allows us to distinguish empathic responses to others versus our own personal distress. These findings are consistent with the view that empathy does not involve a complete Self-Other merging.     

Prefrontal changes in the glutamate-glutamine cycle and neuronal/glial glutamate transporters in depression with and without suicide

There are indications for changes in glutamate metabolism in relation to depression or suicide. The glutamate-glutamine cycle and neuronal/glial glutamate transporters mediate the uptake of the glutamate and glutamine. The expression of various components of the glutamate-glutamine cycle and the neuronal/glial glutamate transporters was determined by qPCR in postmortem prefrontal cortex. The anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC) were selected from young MDD patients who had committed suicide (MDD-S; n = 17), from MDD patients who died of non-suicide related causes (MDD-NS; n = 7) and from matched control subjects (n = 12). We also compared elderly depressed patients who had not committed suicide (n = 14) with matched control subjects (n = 22). We found that neuronal located components (EAAT3, EAAT4, ASCT1, SNAT1, SNAT2) of the glutamate-glutamine cycle were increased in the ACC while the astroglia located components (EAAT1, EAAT2, GLUL) were decreased in the DLPFC of MDD-S patients. In contrast, most of the components in the cycle were increased in the DLPFC of MDD-NS patients. In conclusion, the glutamate-glutamine cycle - and thus glutamine transmission - is differentially affected in depressed suicide patients and depressed non-suicide patients in an area specific way.     

Beauty in a smile: the role of medial orbitofrontal cortex in facial attractiveness

The attractiveness of a face is a highly salient social signal, influencing mate choice and other social judgements. In this study, we used event-related functional magnetic resonance imaging (fMRI) to investigate brain regions that respond to attractive faces which manifested either a neutral or mildly happy face expression. Attractive faces produced activation of medial orbitofrontal cortex (OFC), a region involved in representing stimulus-reward value. Responses in this region were further enhanced by a smiling facial expression, suggesting that the reward value of an attractive face as indexed by medial OFC activity is modulated by a perceiver directed smile.