Subcallosal Anterior Cingulate Cortex Research Articles

Comparative basolateral amygdala connectomics reveals dissociable single-neuron projection patterns to frontal cortex in macaques and mice

Basolateral amygdala (BLA) is a key hub for affect in the brain,1,2,3 and dysfunction within this area contributes to a host of psychiatric disorders.4,5 BLA is extensively and reciprocally interconnected with frontal cortex,6,7,8,9 and some aspects of its function are evolutionarily conserved across rodents, anthropoid primates, and humans.10 Neuron density in BLA is substantially lower in primates compared to murine rodents,11 and frontal cortex (FC) is dramatically expanded in primates, particularly the more anterior granular and dysgranular areas.12,13,14 Yet, how these anatomical differences influence the projection patterns of single BLA neurons to frontal cortex across rodents and primates is unknown. Using a barcoded connectomic approach, we assessed the single BLA neuron connections to frontal cortex in mice and macaques. We found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single BLA neuron projections to nucleus accumbens were similarly organized in mice and macaques, BLA-FC connections differed substantially. Notably, BLA connections to subcallosal anterior cingulate cortex (scACC) in macaques were least likely to branch to other medial frontal cortex areas compared to perigenual ACC (pgACC). This pattern of connections was reversed in the mouse homologues of these areas, infralimbic and prelimbic cortex (IL and PL), mirroring functional differences between rodents and non-human primates. Taken together, these results indicate that BLA connections to FC are not linearly scaled from mice to macaques and instead the organization of single-neuron BLA connections is distinct between these species.

Temporally specific patterns of neural activity in interconnected corticolimbic structures during reward anticipation

Functional neuroimaging studies indicate that interconnected parts of the subcallosal anterior cingulate cortex (ACC), striatum, and amygdala play a fundamental role in affect in health and disease. Yet, although the patterns of neural activity engaged in the striatum and amygdala during affective processing are well established, especially during reward anticipation, less is known about subcallosal ACC. Here, we recorded neural activity in non-human primate subcallosal ACC and compared this with interconnected parts of the basolateral amygdala and rostromedial striatum while macaque monkeys performed reward-based tasks. Applying multiple analysis approaches, we found that neurons in subcallosal ACC and rostromedial striatum preferentially signal anticipated reward using short bursts of activity that form temporally specific patterns. By contrast, the basolateral amygdala uses a mixture of both temporally specific and more sustained patterns of activity to signal anticipated reward. Thus, dynamic patterns of neural activity across populations of neurons are engaged in affect, especially in subcallosal ACC.

Chemogenetics identifies separate area 25 brain circuits involved in anhedonia and anxiety in marmosets.

Poor outcomes are common in individuals with anxiety and depression, and the brain circuits underlying symptoms and treatment responses remain elusive. To elucidate these neural circuits, experimental studies must specifically manipulate them, which is only possible in animals. Here, we used a chemogenetics strategy involving engineered designer receptors exclusively activated by designer drugs (DREADDs) to activate a region of the marmoset brain that is dysfunctional in human patients with major depressive disorder, called the subcallosal anterior cingulate cortex area 25 (scACC-25). Using this DREADDs system, we identified separate scACC-25 neural circuits that underlie specific components of anhedonia and anxiety in marmosets. Activation of the neural pathway connecting the scACC-25 to the nucleus accumbens (NAc) caused blunting of anticipatory arousal (a form of anhedonia) in marmosets in response to a reward-associated conditioned stimulus in an appetitive Pavlovian discrimination test. Separately, activation of the circuit between the scACC-25 and the amygdala increased a measure of anxiety (the threat response score) when marmosets were presented with an uncertain threat (human intruder test). Using the anhedonia data, we then showed that the fast-acting antidepressant ketamine when infused into the NAc of marmosets prevented anhedonia after scACC-25 activation for more than 1 week. These neurobiological findings provide targets that could contribute to the development of new treatment strategies.

Activation of Primate Subcallosal Cingulate Cortex Alters the Balance of Affective Tone From Positivity to Negativity

The loss of pleasure, commonly called anhedonia, is a major symptom of depression and appears particularly resilient to traditional antidepressants. Such treatment-resistant patients do respond more favourably, however, to ketamine, one of the recently discovered rapidly acting anti-depressants, as well as deep brain stimulation targeting the subcallosal anterior cingulate cortex (scACC). Indeed, the development of the latter as a treatment strategy arose from the findings that activity within the scACC is positively correlated with depression and reductions in its activity correlate with anti-depressant efficacy.

Face processing of social cognition in patients with first episode psychosis: Its deficits and association with the right subcallosal anterior cingulate cortex

The clinical importance of social cognition is well acknowledged in patients with psychosis, in particular those with first episode psychosis (FEP). Nevertheless, its brain substrates and circuitries remain elusive, lacking precise analysis between multimodal brain characteristics and behavioral sub-dimensions within social cognition. In the present study, we examined face processing of social cognition in 71 FEP patients and 77 healthy controls (HCs). We looked for a possible correlation between face processing and multimodal MRI characteristics such as resting-state functional connectivity (rsFC) and brain volume. We observed worse recognition accuracy, longer recognition response time, and longer memory response time in FEP patients when compared with HCs. Of these, memory response time was selectively correlated with specific rsFCs, which included the right subcallosal sub-region of BA24 in the ACC (scACC), only in FEP patients. The volume of this region was also correlated with memory response time in FEP patients. The scACC is functionally and structurally important in FEP-associated abnormalities of face processing measures in social cognition.

The association of neuropsychiatric symptoms with regional brain volumes from patients in a tertiary multi-disciplinary memory clinic.

To examine the interaction between structural brain volume measures derived from a clinical magnetic resonance imaging (MRI) and occurrence of neuropsychiatric symptoms (NPS) in outpatient memory clinic patients. Clinical and neuroimaging data were collected from the medical records of outpatient memory clinic patients who were seen by neurologists, geriatric neuropsychiatrists, and geriatricians. MRI scan acquisition was carried out on a 3 T Siemens Verio scanner at Johns Hopkins Bayview Medical Center. Image analyses used an automated multi-label atlas fusion method with a geriatric atlas inventory to generate 193 anatomical regions from which volumes were measured. Regions of interest were generated a priori based on previous literature review of NPS in dementia. Regional volumes for agitation, apathy, and delusions were carried forward in a linear regression analysis. Seventy-two patients had clinical and usable neuroimaging data that were analyzed and grouped by Mini-Mental State Exam (MMSE). Neuropsychiatric Inventory Questionnaire (NPI-Q) agitation was inversely associated with rostral anterior cingulate cortex (ACC) bilaterally and left subcallosal ACC volumes in the moderate severity group. Delusions were positively associated with left ACC volumes in both severe and mild groups but inversely associated with the right dorsolateral prefrontal cortex (DLPFC) in the moderate subgroup. Agitation, apathy, and delusions are associated with volumes of a priori selected brain regions using clinical data and clinically acquired MRI scans. The ACC is an anatomic region common to these symptoms, particularly agitation and delusions, which closely mirror the findings of research-quality studies and suggest its importance as a behavioral hub.

Analysis of the presence or absence of atrophy of the subgenual and subcallosal cingulate cortices using voxel-based morphometry on MRI is useful to select prescriptions for patients with depressive symptoms.

ObjectiveWe objectively evaluated the presence or absence of atrophy of the subgenual anterior cingulate cortex (sgACC) and the subcallosal anterior cingulate cortex (scACC), using new voxel-based morphometry (VBM) software employing Statistical Parametric Mapping software v8 and diffeomorphic anatomic registration through an exponentiated lie algebra. We prepared a database covering young-mature adulthood and investigated the clinical usefulness of the evaluation.Subjects and methodsOne hundred seven patients with major depressive disorder (MDD), 74 patients with bipolar disorder (BD), and 240 healthy control subjects underwent 1.5T magnetic resonance imaging scanning. Using new VBM software and databases covering young-mature adults and the elderly, target volumes of interest were set in the sgACC and scACC, four indicators (severity, extent, ratio, and whole-brain extent) were determined, and the presence or absence of atrophy of the sgACC and scACC was evaluated on the basis of the indicators. In addition, the relationships between the presence or absence of atrophy of the sgACC and scACC and performance of diagnosing MDD and BD and therapeutic drugs were investigated.ResultsIt was clarified that the disease is likely to be MDD when atrophy is detected in the sgACC, and likely to be BD when no atrophy is detected in the sgACC but is detected in the scACC. Regarding the relationship with therapeutic drugs, it was clarified that, when atrophy is detected in both the sgACC and the scACC, concomitant administration of mood stabilizers and atypical antipsychotics acting as dopamine-system stabilizers is necessary in many cases.ConclusionVBM on magnetic resonance imaging enabled automatic analysis of atrophy in the sgACC and scACC, and findings obtained by this procedure are useful not only for differentiation of MDD and BD patients but also for selection of prescriptions.

Alterations in brain connectivity in three sub-regions of the anterior cingulate cortex in heroin-dependent individuals: Evidence from resting state fMRI

Previous studies that utilized task-based approaches have demonstrated that the chronic use of heroin is associated with altered activity of the anterior cingulate cortex (ACC). However, few studies have focused on examining the variation in resting-state functional connectivity in heroin-dependent individuals, which might help further understanding the mechanisms underlying heroin addiction. Due to the structural and functional heterogeneity of the ACC, we systematically mapped the resting-state functional connectivity patterns of three sub-regions of the ACC in heroin-dependent individuals, wondered whether the partition of three sub-regions of the ACC is feasible in heroin-dependent individuals, and identified how heroin affected the correlated activities among three sub-regions of the ACC using resting-state functional magnetic resonance imaging (fMRI). In the present study, fMRI data were acquired from 21 heroin-dependent individuals (Her group) and 15 non-addicted controls (CN group). Compared to controls, there were reduced functional connectivities in the dorsal ACC (dACC) and rostral ACC (rACC) networks with different areas of the dorsal striatum (the caudate and the putamen) in the Her group. Meanwhile, there exhibited an inverted alteration of pattern for orbital frontal cortex (OFC) and superior frontal gyrus (SFG) in the functional connectivity network with the dACC and subcallosal ACC (sACC), and a different alteration of the cerebellum and the amygdala in the functional connectivity network with the rACC and the sACC. In addition, we also found reduced connectivities between dACC and rACC, as well as reduced connectivities between sACC and dACC. Our findings of variations of functional connectivities in three sub-regions of ACC in Her group implied that these sub-regions of the ACC together with other key brain areas (such as dorsal striatum, OFC, SFG, cerebellum, amygdale, etc.) might potentially play independent and/or overlapping roles in heroin addiction, which might indicate the potential direction of future research.

Resting state functional MRI connectivity predicts hypothalamus-pituitary-axis status in healthy males

Homeostasis of the human stress response system is critically maintained by a hierarchical system of neural and endocrine elements for which intact negative feedback is important to prevent maladaptation towards stress. Such feedback is efficiently probed by the established combined dexamethasone-suppression/corticotropin-releasing hormone stimulation (dex/CRH) test. Here we investigate which suprahypothalamic networks might modulate the response assessed by this neuroendocrine test. Combined resting state fMRI (rs-fMRI)/EEG was acquired in 20 healthy male volunteers along with dex/CRH profiles obtained on a different day outside the scanner. Seed-based network analysis and inter-seed cross correlation analysis for selected atlas-based limbic, paralimbic and medial prefrontal cortex seeds were correlated with stimulated cortisol and adrenocorticotropin hormone (ACTH) concentrations. Lower connectivity between a left hippocampus-based network and the right hippocampus significantly predicted stimulated cortisol concentration (R(2)=0.70, corrected pcluster=0.001). Six further significantly negative correlations were detected mainly in the left anterior cingulate cortex (ACC) and the medial prefrontal cortex (mPFC). The strongest positive correlation with stimulated hormone concentration was detected for the left subcallosal ACC (ACTH, R(2)=0.57, corrected pcluster=0.009). Inter-seed connectivity mainly pointed to hippocampal/amygdala interactions as correlates of the dex/CRH response. In conclusion, resting state functional connectivity patterns of limbic, particularly hippocampal, as well as cingulate and medial prefrontal areas can explain some of the variance of the dex/CRH test in healthy subjects. Functional connectivity analysis can be considered useful to study supra-hypothalamic control systems of the HPA axis.

Cortico-limbic morphology separates tinnitus from tinnitus distress

Tinnitus is a common auditory disorder characterized by a chronic ringing or buzzing “in the ear.”Despite the auditory-perceptual nature of this disorder, a growing number of studies have reported neuroanatomical differences in tinnitus patients outside the auditory-perceptual system. Some have used this evidence to characterize chronic tinnitus as dysregulation of the auditory system, either resulting from inefficient inhibitory control or through the formation of aversive associations with tinnitus. It remains unclear, however, whether these “non-auditory” anatomical markers of tinnitus are related to the tinnitus signal itself, or merely to negative emotional reactions to tinnitus (i.e., tinnitus distress). In the current study, we used anatomical MRI to identify neural markers of tinnitus, and measured their relationship to a variety of tinnitus characteristics and other factors often linked to tinnitus, such as hearing loss, depression, anxiety, and noise sensitivity. In a new cohort of participants, we confirmed that people with chronic tinnitus exhibit reduced gray matter in ventromedial prefrontal cortex (vmPFC) compared to controls matched for age and hearing loss. This effect was driven by reduced cortical surface area, and was not related to tinnitus distress, symptoms of depression or anxiety, noise sensitivity, or other factors. Instead, tinnitus distress was positively correlated with cortical thickness in the anterior insula in tinnitus patients, while symptoms of anxiety and depression were negatively correlated with cortical thickness in subcallosal anterior cingulate cortex (scACC) across all groups. Tinnitus patients also exhibited increased gyrification of dorsomedial prefrontal cortex (dmPFC), which was more severe in those patients with constant (vs. intermittent) tinnitus awareness. Our data suggest that the neural systems associated with chronic tinnitus are different from those involved in aversive or distressed reactions to tinnitus.

The Use of Alcohol as a Moderator for Tinnitus-Related Distress

Tinnitus is an auditory phantom percept with a tone, hissing, or buzzing sound in the absence of any objective physical sound source. Persons with tinnitus engage in a number of health behaviors to manage tinnitus. This can go from prescription medication, masking devices, behavioral training techniques to cortical implants. Potentially less adaptive methods of coping with tinnitus, such as the use of alcohol, are poorly studied. The purpose of this study was to further explore the neurobiological mechanism of tinnitus improvement by the use of alcohol. We observed differences in the alpha, beta and gamma frequency band when comparing resting-state EEG before and after alcohol intake. More precisely increased synchronized alpha1 activity was found in the posterior cingulate cortex and decreased synchronized alpha2 activity was demonstrated in orbitofrontal cortex, ventrolateral prefrontal cortex and subcallosal anterior cingulate cortex after alcohol intake. Increased synchronized activity was found in a region between the pregenual and dorsal anterior cingulate cortex and the left insula for beta and decreased activity in the precuneus after alcohol intake. For the gamma frequency band decreased synchronized activity in the precuneus and the posterior cingulate cortex was demonstrated after alcohol intake. Region of interest analyses in auditory cortices and parahippocampal area revealed however no differences in the different frequency bands before and after alcohol consumption.

The neural correlates of tinnitus-related distress

Tinnitus is an auditory phantom percept with a tone, hissing, or buzzing sound in the absence of any objective physical sound source. About 6% to 25% of the affected people report interference with their lives as tinnitus causes a considerable amount of distress. However, the underlying neurophysiological mechanism for the development of tinnitus-related distress remains not well understood. Hence we focus on the cortical and subcortical source differences in resting-state EEG between tinnitus patients with different grades of distress using continuous scalp EEG recordings and Low Resolution Electromagnetic Tomography (LORETA). Results show more synchronized alpha activity in the tinnitus patients with a serious amount of distress with peaks localized to various emotion-related areas. These areas include subcallosal anterior cingulate cortex, the insula, parahippocampal area and amygdala. In addition, less alpha synchronized activity was found in the posterior cingulate cortex, precuneus and DLPFC. A comparison between the tinnitus group with distress and the Nova Tech EEG (NTE) normative database demonstrated increased synchronized alpha and beta activity and less synchronized delta and theta activity in the dorsal anterior cingulate cortex in tinnitus patients with distress. It is interesting that the areas found show some overlap with the emotional component of the pain matrix and the distress related areas in asthmatic dyspnea. Unpleasantness of pain activates the anterior cingulate and prefrontal cortices, amygdala, and insula. As such, it might be that distress is related to alpha and beta activity in the dorsal anterior cingulate cortex, the amount of distress perceived to an alpha network consisting of the amygdala-anterior cingulate cortex-insula–parahippocampal area.

Distinct neural mechanisms of risk and ambiguity: A meta-analysis of decision-making

Converging evidence from human and animal studies suggests that decision-making relies upon a distributed neural network based in the frontal lobes. In particular, models of decision-making emphasize the involvement of orbitofrontal cortices (OFC) and the medial wall. While decision-making has been studied broadly as a class of executive function, recent models have suggested the differentiation between risky and ambiguous decision-making. Given recent emphasis on the role of OFC in affectively laden “hot” executive function and dorsolateral prefrontal cortex (DLPFC) in more purely cognitive “cool” executive function, we hypothesize that the neural substrates of decision-making may differ depending on the nature of the decision required. To test this hypothesis, we used recently developed meta-analytic techniques to examine the existent functional neuroimaging literature. An initial meta-analysis of decision-making, both risky and ambiguous, found significantly elevated probabilities of activation in frontal and parietal regions, thalamus, and caudate. Ambiguous decision-making was associated with activity in DLPFC, regions of dorsal and subcallosal anterior cingulate cortex (ACC), and parietal cortex. Risky decision-making was associated with activity in OFC, rostral portions of the ACC, and parietal cortex. Direct statistical comparisons revealed significant differences between risky and ambiguous decision-making in frontal regions, including OFC, DLPFC, and ACC, that were consistent with study hypotheses. These findings provide evidence for the dissociation of neural circuits underlying risky and ambiguous decision-making, reflecting differential involvement of affective “hot” and cognitive “cool” processes.

Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition

Background Choosing between actions associated with uncertain rewards and punishments is mediated by neural circuitry encompassing the orbitofrontal cortex, anterior cingulate cortex (ACC), and striatum; however, the precise conditions under which these different components are activated during decision-making cognition remain uncertain. Methods Fourteen healthy volunteers completed an event-based functional magnetic resonance imaging protocol to investigate blood-oxygenation-level-dependent (BOLD) responses during independently modeled phases of choice cognition. In the “decision phase,” participants decided which of two simultaneous visually presented gambles they wished to play for monetary reward. The gambles differed in their magnitude of gains, magnitude of losses, and the probabilities with which these outcomes were delivered. In the “outcome phase,” the result of each choice was indicated on the visual display. Results In the decision phase, choices involving large gains were associated with increased BOLD responses in the pregenual ACC, paracingulate, and right posterior orbitolateral cortex compared with choices involving small gains. In the outcome phase, good outcomes were associated with increased BOLD responses in the posterior orbitomedial cortex, subcallosal ACC, and ventral striatum compared with negative outcomes. There was only limited overlap between reward-related activity in ACC and orbitofrontal cortex during the decision and outcome phases. Conclusions Neural activity within the medial and lateral orbitofrontal cortex, pregenual ACC, and striatum mediate distinct representations of reward-related information that are deployed at different stages during a decision-making episode.

Changes in regional cerebral blood flow abnormalities in late-life depression following response to electroconvulsive therapy.

The impact of electroconvulsive therapy (ECT) on the regional cerebral blood flow (rCBF) abnormalities in late-life depression is still unknown and the clinical significance of these findings in late-life depression has not been fully discussed. Using single photon emission computed tomography (SPECT) with 99mTc-hexamethylpropylene amine oxime (99mTc-HMPAO), we examined the changes of rCBF patterns in nine late-life patients with major depressive episodes before and following response to ECT compared with nine age- and sex-matched healthy volunteers. Statistical comparisons were made on both region-of-interest (ROI) and voxel-by-voxel bases. In ROI-based analyses, a mean rCBF was significantly decreased in the patients before ECT compared with the control, significantly increased (normalized) in the patients 2 weeks after ECT compared with that before ECT, and still increased in the patients 12 weeks after ECT compared with that before ECT. In voxel-by-voxel analyses, a significant rCBF reduction was found in the bilateral pre- and subcallosal anterior cingulate cortex, the bilateral caudal orbitofrontal cortex, the right insular cortex and the right posterior middle frontal gyrus in patients before ECT compared with the control, and similar rCBF patterns were shown at 2 weeks and 12 weeks after ECT. We propose the hypothesis that a mean rCBF reduction may have a state-related property while persistent anterior paralimbic hypoperfusion may have a trait-like property, which relates to the relapse vulnerability as well as a tendency toward medication failure and illness chronicity in late-life depression.

Functional connectivity of the anterior cingulate cortex within the human frontal lobe: a brain-mapping meta-analysis.

A database of positron-emission-tomography studies published between January 1993 and November 1996 was created to address several questions regarding the function and connectivity of the human anterior cingulate cortex (ACC). Using this database, we have previously reported on the relationship between behavioural variables and the probability of blood-flow response in distinct subdivisions of the ACC. The goal of the current analysis was to discover which areas of the frontal cortex show increased blood-flow co-occurring consistently with increased blood-flow in the ACC. Analyses of the frequency distributions of peaks in the ACC and the remaining frontal cortex (FC) yielded several important findings. First, FC peaks in the precentral gyrus, superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, medial frontal gyrus and orbitomedial frontal gyri were more frequent in subtractions that also yielded a peak in the ACC than in those that did not yield an ACC peak. Second, regional differences in the frequency distribution of these FC peaks were observed when the ACC peaks were subdivided into the rostral versus caudal ACC and supracallosal versus subcallosal ACC. Peaks in the precentral gyrus and in the vicinity of the supplementary motor area were more prevalent in subtractions with co-occurring peaks in the caudal than with the rostral ACC. Peaks in the middle frontal gyrus were more frequent in subtractions with co-occurring peaks in the paralimbic part of the supracallosal ACC, relative to the subcallosal or limbic supracallosal ACC. These observations are consistent with known differences in the anatomic connectivity in these cortical regions, as defined in non-human primates. Further analyses of the influence of behavioural variables on the relationships between the ACC and other regions of the frontal cortex suggested that this type of meta-analysis may provide testable hypotheses about functional and effective connectivity within the human frontal lobe.

Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies.

We reviewed 107 blood flow activation studies carried out with positron emission tomography and published between January 1993 and November 1996. These studies had reported their findings as peaks of significant difference in cerebral blood-flow (CBF) between two scans/tasks and had located the peaks in standardized stereotaxic space. We coded each task along several dimensions, including the type and rate of input and output, the types of cognitive processes, and the relative difficulty of tasks within a study. Based on this coding, a difference score (A-B) was calculated for each subtraction. Subsequently, the frequency distributions of the difference scores for subtractions yielding a peak in the anterior cingulate region (cingulate peak) were compared with those distributions obtained from subtractions without a cingulate peak (no cingulate-peak). The cingulate peak subtractions (n = 158) differed from the no cingulate peak subtractions (n = 229) in terms of difficulty level (p = 0.001) and the presence of a remote memory component (p = 0.01). Regional differences in the frequency distribution of certain task parameters, such as difficulty level, recent memory and the use of the hand for responding, were also observed when peaks found in the anterior cingulate cortex (ACC) were further classified as located in the rostral vs caudal ACC, supracallosal vs subcallosal ACC, and limbic vs paralimbic parts of the supracallosal ACC. We conclude that task difficulty plays a major role in modulating blood-flow response in the ACC, possibly interacting with other parameters such as the nature of the response and memory demands.