Cortical Midline Regions Research Articles

Context matters: Anterior and posterior cortical midline responses to sad movie scenes

Narrative movies can create powerful emotional responses. While recent research has advanced the understanding of neural networks involved in immersive movie viewing, their modulation within a movie’s dynamic context remains inconclusive. In this study, 24 healthy participants passively watched sad scene climaxes taken from 24 romantic comedies, while brain activity was measured using functional magnetic resonance (fMRI). To study effects of context, the sad scene climaxes were presented with either coherent scene context, replaced non-coherent context or without context. In a second viewing, the same clips were rated continuously for sadness. The ratings varied over time with peaks of experienced sadness within the assumed climax intervals. Activations in anterior and posterior cortical midline regions increased if presented with both coherent and replaced context, while activation in the temporal gyri decreased. This difference was more pronounced for the coherent context condition. Psycho-Physiological interactions (PPI) analyses showed a context-dependent coupling of midline regions with occipital visual and sub-cortical reward regions. Our results demonstrate the pivotal role of midline structures and their interaction with perceptual and reward areas in processing contextually embedded socio-emotional information in movies.

Distinct neural substrates of affective and cognitive theory of mind impairment in semantic dementia

ABSTRACTUsing structural MRI, we investigated the brain substrates of both affective and cognitive theory of mind (ToM) in 19 patients with semantic dementia. We also ran intrinsic connectivity analyses to identify the networks to which the substrates belong and whether they are functionally disturbed in semantic dementia. In line with previous studies, we observed a ToM impairment in patients with semantic dementia even when semantic memory was regressed out. Our results also highlighted different neural bases according to the nature (affective or cognitive) of the representations being inferred. The affective ToM deficit was associated with atrophy in the amygdala, suggesting the involvement of emotion-processing deficits in this impairment. By contrast, cognitive ToM performances were correlated with the volume of medial prefrontal and parietal regions, as well as the right frontal operculum. Intrinsic connectivity analyses revealed decreased functional connectivity, mainly between midline cortical regions and temporal regions. They also showed that left medial temporal regions were functionally isolated, a further possible hindrance to normal social cognitive functioning in semantic dementia. Overall, this study addressed for the first time the neuroanatomical substrates of both cognitive and affective ToM disruption in semantic dementia, highlighting disturbed connectivity within the networks that sustain these abilities.

Oxytocin blurs the self-other distinction during trait judgments and reduces medial prefrontal cortex responses.

The neuropeptide oxytocin (OXT) may act either to increase or blur the distinction between self and other and thereby promote either more selfish or altruistic behaviors. To attempt to distinguish between these two possibilities we performed a double-blind, between-subject, placebo-controlled design study to investigate the effect of intranasal OXT on self and other (mother, classmate, or stranger) trait judgments in conjunction with functional magnetic resonance imaging. Results showed that OXT reduced response times for making both self and other judgments, but also reduced the accuracy of their subsequent recall, thereby abolishing the normal self-bias observed in this task. OXT also abolished the positive correlation between response and self-esteem scale scores seen in the PLC group, suggesting that its effects were strongest in individuals with higher levels of self-esteem. A whole-brain functional magnetic resonance imaging analysis revealed that OXT also reduced responses during both self and other trait judgments in the dorsal (dmPFC) and ventral (vmPFC) medial prefrontal cortex. A subsequent region of interest analysis revealed that behavioral performance and self-esteem scale scores were associated with dmPFC activation and its functional connectivity with the anterior cingulate and between the vmPFC and posterior cingulate. Thus overall, while OXT may improve speed of decision making in self -vs. other trait judgments it also blunts the normal bias towards remembering self-attributes and reduces mPFC responses and connectivity with other cortical midline regions involved in self-processing. This is consistent with the view that OXT can reduce self-centered behavior. Hum Brain Mapp 37:2512-2527, 2016. © 2016 Wiley Periodicals, Inc.

Sharing self-related information is associated with intrinsic functional connectivity of cortical midline brain regions.

Human beings are social animals and they vary in the degree to which they share information about themselves with others. Although brain networks involved in self-related cognition have been identified, especially via the use of resting-state experiments, the neural circuitry underlying individual differences in the sharing of self-related information is currently unknown. Therefore, we investigated the intrinsic functional organization of the brain with respect to participants’ degree of self-related information sharing using resting state functional magnetic resonance imaging and self-reported social media use. We conducted seed-based correlation analyses in cortical midline regions previously shown in meta-analyses to be involved in self-referential cognition: the medial prefrontal cortex (MPFC), central precuneus (CP), and caudal anterior cingulate cortex (CACC). We examined whether and how functional connectivity between these regions and the rest of the brain was associated with participants’ degree of self-related information sharing. Analyses revealed associations between the MPFC and right dorsolateral prefrontal cortex (DLPFC), as well as the CP with the right DLPFC, the left lateral orbitofrontal cortex and left anterior temporal pole. These findings extend our present knowledge of functional brain connectivity, specifically demonstrating how the brain’s intrinsic functional organization relates to individual differences in the sharing of self-related information.

Neural correlates of self-perceptions in adolescents with major depressive disorder

Alteration in self-perception is a salient feature in major depression. Hyperactivity of anterior cortical midline regions has been implicated in this phenomenon in depressed adults. Here, we extend this work to depressed adolescents during a developmental time when neuronal circuitry underlying the sense of self matures by using task-based functional magnetic resonance imaging (fMRI) and connectivity analyses. Twenty-three depressed adolescents and 18 healthy controls (HC) viewed positive and negative trait words in a scanner and judged whether each word described them (‘self’ condition) or was a good trait to have (‘general’ condition). Self-perception scores were based on participants’ endorsements of positive and negative traits during the fMRI task. Depressed adolescents exhibited more negative self-perceptions than HC. Both groups activated cortical midline regions in response to self-judgments compared to general-judgments. However, depressed adolescents recruited the posterior cingulate cortex/precuneus more for positive self-judgments. Additionally, local connectivity of the dorsal medial prefrontal cortex was reduced during self-reflection in depressed adolescents. Our findings highlight differences in self-referential processing network function between depressed and healthy adolescents and support the need for further investigation of brain mechanisms associated with the self, as they may be paramount to understanding the etiology and development of major depressive disorder.

Immunity factor contributes to altered brain functional networks in individuals at risk for Alzheimer’s disease: Neuroimaging-genetic evidence

Clusterin (CLU) is recognized as a secreted protein that is related to the processes of inflammation and immunity in the pathogenesis of Alzheimer’s disease (AD). The effects of the risk variant of the C allele at the rs11136000 locus of the CLU gene are associated with variations in the brain structure and function. However, the relationship of the CLU-C allele to architectural disruptions in resting-state networks in amnestic mild cognitive impairment (aMCI) subjects (i.e., individuals with elevated risk of AD) remains relatively unknown. Using resting-state functional magnetic resonance imaging and an imaging genetic approach, this study investigated whether individual brain functional networks, i.e., the default mode network (DMN) and the task-positive network, were modulated by the CLU-C allele (rs11136000) in 50 elderly participants, including 26 aMCI subjects and 24 healthy controls. CLU-by-aMCI interactions were associated with the information-bridging regions between resting-state networks rather than with the DMN itself, especially in cortical midline regions. Interestingly, the complex communications between resting-state networks were enhanced in aMCI subjects with the CLU rs11136000 CC genotype and were modulated by the degree of memory impairment, suggesting a reconstructed balance of the resting-state networks in these individuals with an elevated risk of AD. The neuroimaging-genetic evidence indicates that immunity factors may contribute to alterations in brain functional networks in aMCI. These findings add to the evidence that the CLU gene may represent a potential therapeutic target for slowing disease progression in AD.

Functional connectivity of brain regions for self- and other-evaluation in children, adolescents and adults with autism.

Developing strong ties between oneself and others lays the foundation for developing social competence. Neuroimaging studies have consistently identified specific cortical midline regions activated during evaluative judgments about the self and others. Individuals with autism spectrum disorder (ASD) process self-relevant information differently from their peers, both behaviorally and at the neural level. We compared resting-state functional connectivity (rsFC) of regions involved in self-referential (e.g. medial prefrontal cortex; mPFC) and other-referential (e.g. posterior cingulate cortex; PCC) processing between neurotypical individuals and individuals with ASD in three age cohorts using regions of interest (ROIs) identified through an activation likelihood estimation meta-analysis. Typically developing children demonstrated greater connectivity within the midline self- and other-referential networks compared with age-matched children with ASD. No group differences in rsFC of mPFC or PCC emerged between typically developing adolescents and adolescents with ASD. Neurotypical adults exhibited stronger rsFC of the PCC with orbitofrontal cortex compared with adults with ASD. Developmental differences in functional connectivity between areas underlying self- and other-referential thought may explain altered developmental trajectories in the understanding of self and others in individuals with ASD.

Dysfunctional Patterns of Gamma-Band Activity in Response to Human Faces Compared to Non-Facial Stimuli in Patients with Schizophrenia

ObjectiveHealthy individuals show stronger gamma-band activities (GBAs) for socially relevant stimuli (human faces) than for non-relevant ones. This study aimed to examine whether this gamma-band preference occurs in patients with schizophrenia.MethodsEEG was recorded for 24 patients with schizophrenia and 23 healthy controls while they viewed pictures of human faces, chairs, and nature scenes. The spectral powers of high-beta (20–30 Hz) and gamma (30–80 Hz) frequencies were analyzed along 3 midline cortical regions, and phase synchronization was calculated.ResultsCompared to the response to non-facial stimuli, higher event related deactivation to facial stimuli was observed for the high-beta frequency across groups. For the gamma frequency, early-stage GBA was increased and late-stage GBA was decreased for all 3 stimuli in patients with schizophrenia compared to healthy controls. Preferential GBA patterns (100–200 and 200–300 ms) were found in healthy controls, but not in patients with schizophrenia. Significant correlation existed between negative symptoms and GBA in the frontal region for chair and scene stimuli. There was no significant intergroup difference in phase synchronization pattern.ConclusionOur results suggest that patients with schizophrenia have deficits in the preferential pattern of GBA for human faces and the deficits in the preferential pattern were mainly influenced by over-response to socially non-relevant stimuli.

The Ups and Downs of 3,4-Methylenedioxymethamphetamine: Linking Subjective Effects to Spontaneous Brain Function

Psychoactive drugs, especially drugs with so-called psyche-delic properties, exert profound effects on sensory perception,cognition, and emotion by modulating target neurotransmittersystems. The compound 3,4-methylenedioxymethampheta-mine (MDMA) exerts stimulant and psychedelic effects throughits actions on dopamine, norepinephrine, and serotonin(5-hydroxytryptamine, [5-HT]) transporters, by inhibiting theirreuptake and stimulating their release. In addition to producingeuphoria and positive mood, MDMA appears to produceunique “prosocial” or “empathogenic” feelings. These effectsdistinguish MDMA from other stimulant and hallucinogenicdrugs and are believed to be driven by its greater action at the5-HT transporter. In humans, our understanding of thesesubjective and interoceptive effects has relied mainly onreports from users and a few controlled laboratory studies.A fundamental question—where and how MDMA and otherpsychedelic drugs exert their effects in the human brain—remains largely unanswered.In this issue of Biological Psychiatry, Carhart-Harris et al.(1)address this knowledge gap by employing two modes offunctional magnetic resonance imaging (fMRI), arterial spinlabeling to measure cerebral blood flow (CBF) and resting-state functional connectivity (RSFC) to measure region-to-region coupling of spontaneous activity after a single dose ofMDMA or placebo in a double-blind, balanced-order design inhealthy experienced users. Behaviorally, MDMA induced“intense” and positive mood effects. For RSFC analyses, theauthors used a seed-based approach to examine brain con-nectivity with the ventromedial prefrontal cortex (PFC), hippo-campus, and amygdala as representative paralimbic/limbicnodes of socioemotional functioning. The CBF in the medialtemporal lobe, thalamus, inferior visual cortex, and somato-sensory cortex was decreased by MDMA. It also increasedRSFC between amygdala and hippocampus and decreasedRSFC between midline cortical regions, medial PFC, andmedial temporal lobe. It decreased RSFC between ventrome-dial PFC and posterior cingulate cortex and between medialPFC and hippocampus. These neural effects of MDMA wererelated to self-reports: subjective intensity of drug effects wascorrelated with a reduction in hippocampus and amygdalaCBF, and drug intensity and positive mood were correlated attrend level with RSFC within the ventromedial PFC, hippo-campus, and amygdala network.By examining MDMA effects on brain function in relation toits behavioral effects, this study takes an important step,adding valuable mechanistic insight into where in the brainMDMA exerts its potent psychoactive effects. This studycritically begins to provide a brain-based framework (perfusionand connectivity) to help explain the unique prosocial orempathogenic effects of MDMA. The findings may help us tounderstand its appeal in nonmedical contexts as well as itspotential use as an adjunct to psychotherapy. The studyhighlights some scientific challenges for pharmacoimagingstudies more generally and points to important and muchneeded avenues for future research. We note some key issuesin methods and interpretation and future directions raised byCarhart-Harris et al. First, how can we relate the mood andneural (fMRI) effects of drugs to their underlying neurochemicalmechanisms of action? Second, can we advance our under-standing of the neural targets of drug action by comparingMDMA with the psychedelic, prosocial, and mood-elevatingeffects of other psychoactive drugs? Third, how do the acuteeffects of drugs on mood and brain function relate to theireffects on sensory, cognitive, emotional, and social function?Task-dependent and task-independent (i.e., resting state)fMRI scans provide important data about regional and circuit-wide CBF and functional activation and connectivity. However,fMRI provides no direct information about the neurochemicalmechanisms that underlie these changes. Carhart-Harris et al.use existing knowledge of the predominant pharmacologicmechanism of action of MDMA on 5-HT transporters, regionaldistribution of 5-HT receptor systems in the brain, and priorevidence of serotoninergic effects on brain function andsubjective effects to attribute the CBF and RSFC brainchanges by MDMA to 5-HT actions. However, MDMA alsodirectly and indirectly acts on other monoamines, which couldcontribute to the observed effects. Novel approaches areneeded to link brain function changes to modulation ofspecific neurotransmitters to identify the receptor and mole-cular mechanisms that underlie the effects of a drug. Thisissue applies broadly to pharmacologic challenge studies thatuse fMRI techniques to investigate brain and behavior. Studiesincorporating in vivo and dynamic measures of endogenouslevels or release of neurotransmitters at the synapse (e.g.,positron emission tomography with arterial spin labeling orRSFC fMRI (2)) will address these knowledge gaps as tech-nological and conceptual advances in this emerging area tiethe magnetic resonance imaging–based measures to specificneurotransmitter function.On a related note, advances in neuroimaging analysespermit the study of drug effects on brain function at thenetwork, rather than regional, level (3). These new approaches

Effects of ketamine on cognition–emotion interaction in the brain

Cognition–emotion interaction in the brain can be investigated by incorporating stimuli with emotional content into cognitive tasks. Emotional stimuli in the context of a working memory (WM) task yield increased activation in WM-related lateral prefrontal regions, whereas cognitive effort enhances deactivation in emotion-related cortical midline regions. N-methyl-d-aspartate glutamate receptors (NMDA-Rs) are critically involved in WM, and NMDA-R antagonists, such as ketamine, accordingly affect WM but also have a profound impact on emotional processing, as underscored by the rapid reduction of depressive symptoms after administration of a single dose of ketamine. The effect of ketamine on both cognitive and emotional processing therefore makes it a useful tool to further explore cognition–emotion interaction in the brain. Twenty-three healthy subjects were administered ketamine to investigate whether its effects on WM performance and brain reactivity depend on emotional content or emotional valence of stimuli. Furthermore, we aimed at investigating how ketamine affects the integration of emotion and WM processes in emotion-related cortical midline regions and WM-related lateral prefrontal regions. Results show that ketamine modulates cognition–emotion interaction in the brain by inducing lateralized and valence-specific effects in emotion-related cortical midline regions, WM-related lateral prefrontal regions and insula. In emotion-related cortical midline regions ketamine abolishes enhancement of deactivation normally observed during cognitive effort, while in the right DLPFC and the left insula the previously described pattern of increased activation due to emotional content is abrogated exclusively for negative stimuli. Our data therefore shows a specific effect of ketamine on cognition–emotion interaction in the brain and indicates that its effect on amelioration of negative biases in MDD patients might be related to less interference of cognitive processing by negative emotional content.

Large-Scale Network Dysfunction in Major Depressive Disorder: A Meta-analysis of Resting-State Functional Connectivity.

Major depressive disorder (MDD) has been linked to imbalanced communication among large-scale brain networks, as reflected by abnormal resting-state functional connectivity (rsFC). However, given variable methods and results across studies, identifying consistent patterns of network dysfunction in MDD has been elusive. To investigate network dysfunction in MDD through a meta-analysis of rsFC studies. Seed-based voxelwise rsFC studies comparing individuals with MDD with healthy controls (published before June 30, 2014) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE) and authors contacted for additional data. Twenty-seven seed-based voxel-wise rsFC data sets from 25 publications (556 individuals with MDD and 518 healthy controls) were included in the meta-analysis. Coordinates of seed regions of interest and between-group effects were extracted. Seeds were categorized into seed-networks by their location within a priori functional networks. Multilevel kernel density analysis of between-group effects identified brain systems in which MDD was associated with hyperconnectivity (increased positive or reduced negative connectivity) or hypoconnectivity (increased negative or reduced positive connectivity) with each seed-network. Major depressive disorder was characterized by hypoconnectivity within the frontoparietal network, a set of regions involved in cognitive control of attention and emotion regulation, and hypoconnectivity between frontoparietal systems and parietal regions of the dorsal attention network involved in attending to the external environment. Major depressive disorder was also associated with hyperconnectivity within the default network, a network believed to support internally oriented and self-referential thought, and hyperconnectivity between frontoparietal control systems and regions of the default network. Finally, the MDD groups exhibited hypoconnectivity between neural systems involved in processing emotion or salience and midline cortical regions that may mediate top-down regulation of such functions. Reduced connectivity within frontoparietal control systems and imbalanced connectivity between control systems and networks involved in internal or external attention may reflect depressive biases toward internal thoughts at the cost of engaging with the external world. Meanwhile, altered connectivity between neural systems involved in cognitive control and those that support salience or emotion processing may relate to deficits regulating mood. These findings provide an empirical foundation for a neurocognitive model in which network dysfunction underlies core cognitive and affective abnormalities in depression.

Default mode network dissociation in depressive and anxiety states.

The resting state brain networks, particularly the Default Mode Network (DMN), have been found to be altered in several psychopathological conditions such as depression and anxiety. In this study we hypothesized that cortical areas of the DMN, particularly the anterior regions--medial prefrontal cortex and anterior cingulate cortex--would show an increased functional connectivity associated with both anxiety and depression. Twenty-four healthy participants were assessed using Hamilton Depression and Anxiety Rating Scales and completed a resting-state functional magnetic resonance imaging scan. Multiple regression was performed in order to identify which areas of the DMN were associated with anxiety and depression scores. We found that the functional connectivity of the anterior portions of DMN, involved in self-referential and emotional processes, was positively correlated with anxiety and depression scores, whereas posterior areas of the DMN, involved in episodic memory and perceptual processing were negatively correlated with anxiety and depression scores. The dissociation between anterior and posterior cortical midline regions, raises the possibility of a functional specialization within the DMN in terms of self-referential tasks and contributes to the understanding of the cognitive and affective alterations in depressive and anxiety states.

Are Auditory Hallucinations Related to the Brain's Resting State Activity? A 'Neurophenomenal Resting State Hypothesis'.

While several hypotheses about the neural mechanisms underlying auditory verbal hallucinations (AVH) have been suggested, the exact role of the recently highlighted intrinsic resting state activity of the brain remains unclear. Based on recent findings, we therefore developed what we call the 'resting state hypotheses' of AVH. Our hypothesis suggest that AVH may be traced back to abnormally elevated resting state activity in auditory cortex itself, abnormal modulation of the auditory cortex by anterior cortical midline regions as part of the default-mode network, and neural confusion between auditory cortical resting state changes and stimulus-induced activity. We discuss evidence in favour of our 'resting state hypothesis' and show its correspondence with phenomenal, i.e., subjective-experiential features as explored in phenomenological accounts. Therefore I speak of a 'neurophenomenal resting state hypothesis' of auditory hallucinations in schizophrenia.

Neural and genetic markers of vulnerability to post-traumatic stress symptoms among survivors of the World Trade Center attacks.

Although recent research has begun to describe the neural and genetic processes underlying variability in responses to trauma, less is known about how these processes interact. We addressed this issue by using functional magnetic resonance imaging to examine the relationship between posttraumatic stress symptomatology (PTSS), a common genetic polymorphism of the serotonin transporter [5-HTT (5-hydroxy tryptamine)] gene and neural activity in response to viewing images associated with the 9/11 terrorist attack among a rare sample of high-exposure 9/11 survivors (n = 17). Participants varied in whether they carried a copy of the short allele in the promoter region of the 5-HTT gene. During scanning, participants viewed images of the 9/11 attack, non-9/11 negative and neutral images. Three key findings are reported. First, carriers of the short allele displayed higher levels of PTSS. Second, both PTSS and the presence of the short allele correlated negatively with activity in a network of cortical midline regions (e.g. the retrosplenal and more posterior cingulate cortices (PCCs)) implicated in episodic memories and self-reflection when viewing 9/11 vs non-9/11 negative control images. Finally, exploratory analyses indicated that PCC activity mediated the relationship between genotype and PTSS. These results highlight the role of PCC in distress following trauma.

Functional connectivity and neuronal variability of resting state activity in bipolar disorder--reduction and decoupling in anterior cortical midline structures.

The cortical midline structures seem to be involved in the modulation of different resting state networks, such as the default mode network (DMN) and salience network (SN). Alterations in these systems, in particular in the perigenual anterior cingulate cortex (PACC), seem to play a central role in bipolar disorder (BD). However, the exact role of the PACC, and its functional connections to other midline regions (within and outside DMN) still remains unclear in BD. We investigated functional connectivity (FC), standard deviation (SD, as a measure of neuronal variability) and their correlation in bipolar patients (n = 40) versus healthy controls (n = 40), in the PACC and in its connections in different frequency bands (standard: 0.01-0.10 Hz; Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz). Finally, we studied the correlations between FC alterations and clinical-neuropsychological parameters and we explored whether subgroups of patients in different phases of the illness present different patterns of FC abnormalities. We found in BD decreased FC (especially in Slow-5) from the PACC to other regions located predominantly in the posterior DMN (such as the posterior cingulate cortex (PCC) and inferior temporal gyrus) and in the SN (such as the supragenual anterior cingulate cortex and ventrolateral prefrontal cortex). Second, we found in BD a decoupling between PACC-based FC and variability in the various target regions (without alteration in variability itself). Finally, in our subgroups explorative analysis, we found a decrease in FC between the PACC and supragenual ACC (in depressive phase) and between the PACC and PCC (in manic phase). These findings suggest that in BD the communication, that is, information transfer, between the different cortical midline regions within the cingulate gyrus does not seem to work properly. This may result in dysbalance between different resting state networks like the DMN and SN. A deficit in the anterior DMN-SN connectivity could lead to an abnormal shifting toward the DMN, while a deficit in the anterior DMN-posterior DMN connectivity could lead to an abnormal shifting toward the SN, resulting in excessive focusing on internal contents and reduced transition from idea to action or in excessive focusing on external contents and increased transition from idea to action, respectively, which could represent central dimensions of depression and mania. If confirmed, they could represent diagnostic markers in BD.

Altered temporal variance and neural synchronization of spontaneous brain activity in anesthesia.

Recent studies at the cellular and regional levels have pointed out the multifaceted importance of neural synchronization and temporal variance of neural activity. For example, neural synchronization and temporal variance has been shown by us to be altered in patients in the vegetative state (VS). This finding nonetheless leaves open the question of whether these abnormalities are specific to VS or rather more generally related to the absence of consciousness. The aim of our study was to investigate the changes of inter- and intra-regional neural synchronization and temporal variance of resting state activity in anesthetic-induced unconsciousness state. Applying an intra-subject design, we compared resting state activity in functional magnetic resonance imaging (fMRI) between awake versus anesthetized states in the same subjects. Replicating previous studies, we observed reduced functional connectivity within the default mode network (DMN) and thalamocortical network in the anesthetized state. Importantly, intra-regional synchronization as measured by regional homogeneity (ReHo) and temporal variance as measured by standard deviation (SD) of the BOLD signal were significantly reduced in especially the cortical midline regions, while increased in the lateral cortical areas in the anesthetized state. We further found significant frequency-dependent effects of SD in the thalamus, which showed abnormally high SD in Slow-5 (0.01-0.027 Hz) in the anesthetized state. Our results show for the first time of altered temporal variance of resting state activity in anesthesia. Combined with our findings in the vegetative state, these findings suggest a close relationship between temporal variance, neural synchronization and consciousness.

Poster #S39 ENDOGENOUS TESTOSTERONE LEVELS ARE ASSOCIATED WITH NEURAL ACTIVITY IN MEN WITH SCHIZOPHRENIA DURING A FACIAL EMOTION PROCESSING TASK

Alteration in self-perception is a salient feature in major depression. Hyperactivity of anterior cortical midline regions has been implicated in this phenomenon in depressed adults. Here, we extend this work to depressed adolescents during a developmental time when neuronal circuitry underlying the sense of self matures by using task-based functional magnetic resonance imaging (fMRI) and connectivity analyses. Twenty-three depressed adolescents and 18 healthy controls (HC) viewed positive and negative trait words in a scanner and judged whether each word described them (‘self’ condition) or was a good trait to have (‘general’ condition). Self-perception scores were based on participants’ endorsements of positive and negative traits during the fMRI task. Depressed adolescents exhibited more negative self-perceptions than HC. Both groups activated cortical midline regions in response to self-judgments compared to general-judgments. However, depressed adolescents recruited the posterior cingulate cortex/precuneus more for positive self-judgments. Additionally, local connectivity of the dorsal medial prefrontal cortex was reduced during self-reflection in depressed adolescents. Our findings highlight differences in self-referential processing network function between depressed and healthy adolescents and support the need for further investigation of brain mechanisms associated with the self, as they may be paramount to understanding the etiology and development of major depressive disorder.

Activation of the medial prefrontal and posterior cingulate cortex during encoding of negative material predicts symptom worsening in major depression

Considerable research indicates that depressed individuals have better memory for negative material than do nondepressed individuals, and that this bias is associated with differential patterns of neural activation. It is not known, however, whether these aberrant activation patterns predict illness course. Using functional neuroimaging, we examined whether change in depressive symptoms is predicted by baseline patterns of neural activation that underlie negative memory biases in major depressive disorder. Depressed participants viewed negative and neutral pictures during functional MRI at baseline and completed an incidental memory task for these pictures 1 week later. Depression severity was assessed by administering the Beck Depression Inventory both at baseline (Time 1) and at Time 2, an average of 18 months later. Contrast maps of activation for subsequently remembered negative versus subsequently remembered neutral pictures were regressed against change in Beck Depression Inventory scores between Time 1 and Time 2, controlling for initial symptom severity. Results from this analysis revealed no associations between memory sensitivity for negative stimuli and symptom change. In contrast, whole brain analyses revealed significant positive associations between within-subject changes in depressive symptoms and baseline neural activation to successfully recalled negative pictures in the posterior cingulate cortex and medial prefrontal cortex. These findings indicate that neural activation in cortical midline regions is a better predictor of long-term symptomatic outcome than is memory sensitivity for negative material.

BOLD signal and functional connectivity associated with loving kindness meditation.

Loving kindness is a form of meditation involving directed well-wishing, typically supported by the silent repetition of phrases such as “may all beings be happy,” to foster a feeling of selfless love. Here we used functional magnetic resonance imaging to assess the neural substrate of loving kindness meditation in experienced meditators and novices. We first assessed group differences in blood oxygen level-dependent (BOLD) signal during loving kindness meditation. We next used a relatively novel approach, the intrinsic connectivity distribution of functional connectivity, to identify regions that differ in intrinsic connectivity between groups, and then used a data-driven approach to seed-based connectivity analysis to identify which connections differ between groups. Our findings suggest group differences in brain regions involved in self-related processing and mind wandering, emotional processing, inner speech, and memory. Meditators showed overall reduced BOLD signal and intrinsic connectivity during loving kindness as compared to novices, more specifically in the posterior cingulate cortex/precuneus (PCC/PCu), a finding that is consistent with our prior work and other recent neuroimaging studies of meditation. Furthermore, meditators showed greater functional connectivity during loving kindness between the PCC/PCu and the left inferior frontal gyrus, whereas novices showed greater functional connectivity during loving kindness between the PCC/PCu and other cortical midline regions of the default mode network, the bilateral posterior insula lobe, and the bilateral parahippocampus/hippocampus. These novel findings suggest that loving kindness meditation involves a present-centered, selfless focus for meditators as compared to novices.

The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level–Dependent Resting State Functional Connectivity

BackgroundThe compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals. MethodsIn a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level–dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week. ResultsMarked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects. ConclusionsThe MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug’s characteristic subjective effects arise from its modulation of spontaneous brain activity.