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Functional Connectivity of the Anterior Cingulate Cortex in Depression and in Health
Abstract
The first voxel-level resting-state functional connectivity (FC) neuroimaging analysis of depression of the anterior cingulate cortex (ACC) showed in 282 patients with major depressive disorder compared with 254 controls, some higher, and some lower FCs. However, in 125 unmedicated patients, primarily increases of FC were found: of the subcallosal anterior cingulate with the lateral orbitofrontal cortex, of the pregenual/supracallosal anterior cingulate with the medial orbitofrontal cortex, and of parts of the anterior cingulate with the inferior frontal gyrus, superior parietal lobule, and with early cortical visual areas. In the 157 medicated patients, these and other FCs were lower than in the unmedicated group. Parcellation was performed based on the FC of individual ACC voxels in healthy controls. A pregenual subdivision had high FC with medial orbitofrontal cortex areas, and a supracallosal subdivision had high FC with lateral orbitofrontal cortex and inferior frontal gyrus. The high FC in depression between the lateral orbitofrontal cortex and the subcallosal parts of the ACC provides a mechanism for more non-reward information transmission to the ACC, contributing to depression. The high FC between the medial orbitofrontal cortex and supracallosal ACC in depression may also contribute to depressive symptoms.
... Widespread dysfunction throughout the limbic system and neocortex is associated with depression severity (Drysdale et al., 2017;Fingelkurts & Fingelkurts, 2015;Kaiser et al., 2015;Rolls et al., 2019). The brain regions comprising the limbic system, including the amygdala, ventral striatum, and anterior cingulate cortex (ACC), show altered functional connectivity compared to controls (Drysdale et al., 2017;Rolls et al., 2019). ...
... Widespread dysfunction throughout the limbic system and neocortex is associated with depression severity (Drysdale et al., 2017;Fingelkurts & Fingelkurts, 2015;Kaiser et al., 2015;Rolls et al., 2019). The brain regions comprising the limbic system, including the amygdala, ventral striatum, and anterior cingulate cortex (ACC), show altered functional connectivity compared to controls (Drysdale et al., 2017;Rolls et al., 2019). Patients with MDD often have hyperconnectivity within the default mode network and hypoconnectivity within the frontoparietal dorsal attention network (Kaiser synchronization (Pang & Robinson, 2018). ...
Understanding the neural basis of major depressive disorder (MDD) is vital to guiding neuromodulatory treatments. The available evidence supports the hypothesis that MDD is fundamentally a disease of cortical disinhibition, where breakdowns of inhibitory neural systems lead to diminished emotion regulation and intrusive ruminations. Recent research also points towards network changes in the brain, especially within the prefrontal cortex (PFC), as primary sources of MDD etiology. However, due to limitations in spatiotemporal resolution and clinical opportunities for intracranial recordings, this hypothesis has not been directly tested. We recorded intracranial EEG from the dorsolateral (dlPFC), orbitofrontal (OFC), and anterior cingulate cortices (ACC) in neurosurgical patients with MDD. We measured daily fluctuations in self-reported depression severity alongside directed connectivity between these PFC subregions. We focused primarily on delta oscillations (1-3 Hz), which have been linked to GABAergic inhibitory control and intracortical communication. Depression symptoms worsened when connectivity within the left vs. right PFC became imbalanced. In the left hemisphere, all directed connectivity towards the ACC, from the dlPFC and OFC, was positively correlated with depression severity. In the right hemisphere, directed connectivity between the OFC and dlPFC increased with depression severity as well. This is the first evidence that delta oscillations flowing between prefrontal subregions transiently increase intensity when people are experiencing more negative mood. These findings support the overarching hypothesis that MDD worsens with prefrontal disinhibition.
... Mean beta values were used as dependent variables and severity of symptoms as measured by BDI-II and BAI-scores as independent variables. Additionally, because an effect of pharmacotherapy on RFSC has commonly been found (Rolls et al., 2019), we performed an independent-sample t-test within the patient group, testing for a difference in RSFC values between medication groups. Bonferroni correction was used to correct for multiple comparisons. ...
... Medication was not found to have a significant effect on the results. However, there are findings that antidepressant medication influences RSFCs (Rolls et al., 2019), and in our study, the effect of medication may not have been detected because only 25% of patients were unmedicated at the time of the study. Thus, future studies should focus on antidepressant-free patients. ...
The brain's default mode network (DMN) and the executive control network (ECN) switch engagement are influenced by the ventral attention network (VAN). Alterations in resting‐state functional connectivity (RSFC) within this so‐called triple network have been demonstrated in patients with major depressive disorder (MDD) or anxiety disorders (ADs). This study investigated alterations in the RSFC in patients with comorbid MDD and ADs to better understand the pathophysiology of this prevalent group of patients. Sixty‐eight participants (52.9% male, mean age 35.3 years), consisting of 25 patients with comorbid MDD and ADs (MDD + AD), 20 patients with MDD only (MDD) and 23 healthy controls (HCs) were investigated clinically and with 3T resting‐state fMRI. RSFC utilizing a seed‐based approach within the three networks belonging to the triple network was compared between the groups. Compared with HC, MDD + AD showed significantly reduced RSFC between the ECN and the VAN, the DMN and the VAN and within the ECN. No differences could be found for the MDD group compared with both other groups. Furthermore, symptom severity and medication status did not affect RSFC values. The results of this study show a distinct set of alterations of RSFC for patients with comorbid MDD and AD compared with HCs. This set of dysfunctions might be related to less adequate switching between the DMN and the ECN as well as poorer functioning of the ECN. This might contribute to additional difficulties in engaging and utilizing consciously controlled emotional regulation strategies.
... Following up this theory, it was found in a largescale resting-state functional connectivity (rsFC) study that there is higher connectivity of the lateral OFC with the precuneus and language-related regions in depression, and lower connectivity of the medial OFC with medial temporal lobe memory-related brain regions in depression [65]. That was followed up in a number of further investigations which showed that only the higher functional connectivity of the lateral OFC (but not the lower functional connectivity of the medial OFC) in MDD could be ameliorated by antidepressant drugs such as SSRIs [66][67][68][69][70][71]. A further investigation showed increased sensitivity to non-reward (not winning in a monetary incentive delay (MID) task) of the lateral OFC related to symptoms of depression such as negative feelings, and low sensitivity to the reward of winning in the medial OFC [33]. ...
... Given that the medial OFC is involved in representations of reward/pleasant stimuli and the lateral OFC of punishment/ unpleasant/non-reward stimuli [32,33] (Section "Introduction to the orbitofrontal cortex (OFC) and depression"), this is evidence that supports the attractor theory of depression [64], with depressed people having fewer happy memories and anhedonia related to the medial OFC, and more ruminating sad thoughts associated with the increased connectivity of the lateral OFC [65]. A series of further rsFC studies with a large sample size and crossvalidation by replication with other patient samples further confirmed that MDD patients had decreased functional connectivity between the medial OFC (involved in emotion), and amygdala and fusiform gyrus, as well as increased connectivity between the lateral OFC and brain areas that include the posterior cingulate cortex (involved in memory), subcallosal ACC, languagerelated inferior frontal gyrus regions, and self-related precuneus [66,67,[69][70][71] (see summary Fig. 5 for more details). Those discoveries of decreased FCs in medial OFC and increased FCs in lateral OFC in MDD provide a framework for understanding depression in the context of brain systems involved in emotion [5,64,112]. ...
We describe evidence for dissociable roles of the medial and lateral orbitofrontal cortex (OFC) in major depressive disorder (MDD) from structure, functional activation, functional connectivity, metabolism, and neurochemical systems. The reward-related medial orbitofrontal cortex has lower connectivity and less reward sensitivity in MDD associated with anhedonia symptoms; and the non-reward related lateral OFC has higher functional connectivity and more sensitivity to non-reward/aversive stimuli in MDD associated with negative bias symptoms. Importantly, we propose that conventional antidepressants act to normalize the hyperactive lateral (but not medial) OFC to reduce negative bias in MDD; while other treatments are needed to operate on the medial OFC to reduce anhedonia, with emerging evidence suggesting that ketamine may act in this way. The orbitofrontal cortex is the key cortical region in emotion and reward, and the current review presents much new evidence about the different ways that the medial and lateral OFC are involved in MDD.
... Mean beta values were used as dependent variables and severity of symptoms as measured by BDI-II and BAI-scores as independent variables. Additionally, since an effect of pharmacotherapy on RFSC has commonly been found (Rolls et al., 2019), we performed an independent-sample-t-test within the patient group, testing for a difference in RSFC-values between medication groups. Bonferroni-correction was used to correct for multiple comparisons. ...
... Medication was not found to have a significant effect on the results. However, there are findings that antidepressant medication influences RSFCs (Rolls et al., 2019) and in our study the effect of medication may not have been detected since only 25 % of patients were unmedicated at the time of the study. Thus, future studies should focus on antidepressant-free patients ...
The brain‘s default mode network (DMN) and the executive control network (ECN) switch engagement influenced by the ventral attention network (VAN). Alterations in resting-state functional connectivity (RSFC) within this so-called triple network have been demonstrated in patients with major depressive disorder (MDD) or anxiety disorders (AD). This study investigated alterations in the RSFC in patients with comorbid MDD and ADs to better understand the pathophysiology of this prevalent group of patients. Sixty-eight participants (52.9 % male, mean age 35.25 years), consisting of 25 patients with comorbid MDD and ADs (MDD+AD), 20 patients with MDD only (MDD-AD) and 23 healthy controls (HC) were investigated clinically and with 3T resting-state fMRI. RSFC utilizing a seed-based approach within the three networks belonging to the triple network was compared between the groups. Compared to HC, MDD+AD showed significantly reduced RSFC between the ECN and the VAN, the DMN and the VAN and within the ECN. No differences could be found for the MDD group compared to both other groups. Furthermore, symptom severity and medication status did not affect RSFC values. The results of this study show a distinct set of alterations of RSFC for patients with comorbid MDD and AD compared to healthy controls. This set of dysfunctions might be related to less adequate switching between the DMN and the ECN as well as poorer functioning of the ECN. This might contribute to additional difficulties engaging and utilizing consciously controlled emotional regulation strategies.
... Neuroimaging studies point to the anterior cingulate cortex (ACC), a region involved in emotions, information processing, and regulation, which serves a vital role in the pathophysiology of depression (3,4). Previously published studies ubiquitously found that abnormalities of gray matter volume (5)(6)(7)(8)(9)(10)(11), white matter volume (12,13), and functional activity (14)(15)(16)(17) of the ACC could be responsible for depression in MDD patients. In addition, accumulating evidence from previous studies indicated that the alterations in the structural and functional activity of ACC have emerged as a promising predictor of the effectiveness of depression treatment. ...
... Previous evidence based on FC has suggested that MDD patients have extensively aberrant FC between the ACC and multiple areas of the brain (9,14,17). The structure and function of the ACC, however, are considered to be heterogeneous and can generally be divided into five subregions associated with distinct functions (33)(34)(35). ...
Objectives
Childhood trauma (CT) is a known risk factor for major depressive disorder (MDD), but the mechanisms linking CT and MDD remain unknown. The purpose of this study was to examine the influence of CT and depression diagnosis on the subregions of the anterior cingulate cortex (ACC) in MDD patients.
Methods
The functional connectivity (FC) of ACC subregions was evaluated in 60 first-episode, drug-naïve MDD patients (40 with moderate-to-severe and 20 with no or low CT), and 78 healthy controls (HC) (19 with moderate-to-severe and 59 with no or low CT). The correlations between the anomalous FC of ACC subregions and the severity of depressive symptoms and CT were investigated.
Results
Individuals with moderate-to severe CT exhibited increased FC between the caudal ACC and the middle frontal gyrus (MFG) than individuals with no or low CT, regardless of MDD diagnosis. MDD patients showed lower FC between the dorsal ACC and the superior frontal gyrus (SFG) and MFG. They also showed lower FC between the subgenual/perigenual ACC and the middle temporal gyrus (MTG) and angular gyrus (ANG) than the HCs, regardless of CT severity. The FC between the left caudal ACC and the left MFG mediated the correlation between the Childhood Trauma Questionnaire (CTQ) total score and HAMD-cognitive factor score in MDD patients.
Conclusion
Functional changes of caudal ACC mediated the correlation between CT and MDD. These findings contribute to our understanding of the neuroimaging mechanisms of CT in MDD.
... These findings are consistent with our research results. The anterior cingulate cortex (ACC) has been identified as an important brain region involved in depression (Rolls et al., 2019;Wu et al., 2022). Due to its location, the ACC is interconnected with both the remaining limbic system structures and the Fig. 2. Results of SBM analyses using two-sample t-tests between the NSSI and HC groups (p < 0.05, cluster-level FWE correction) revealed significant differences in brain regions. ...
Background
Non-suicidal self-injury (NSSI) involves repetitive self-harm without suicidal intent and is common among adolescents, often linked to major depressive disorder (MDD). NSSI can lead to physical harm, cognitive impairments, interpersonal issues, violent behavior, and increased risks of psychological disorders and suicide attempts later in life.
Methods
Voxel-based morphometry (VBM) and surface-based morphometry (SBM) were performed on 44 NSSI patients and 44 healthy controls (HCs). Differences in GMV, CT, and cortical complexity were compared using the two-sample t-tests and correlated with neuropsychological scales.
Results
NSSI patients exhibited significant GMV atrophy in multiple regions, including the left insula, left anterior cingulate cortex, left putamen, left middle frontal gyrus, and right superior frontal gyrus showing increased GMV in the cerebellum posterior lobe. NSSI patients had increased CT in multiple left hemisphere regions and decreased CT in the right middle frontal gyrus. Additionally, they exhibited reduced cortical complexity, including decreased SD in the right frontal gyrus, and lower GI in the left insula. There were no significant differences between the two groups in terms of fractal dimension (FD). NSSI patients showed negative correlation between the CT of the right middle frontal gyrus and the anger dimension of the BPAQ, as well as the SD of the right superior frontal gyrus and the hostility dimension of the BPAQ.
Conclusion
NSSI patients have significant structural changes in the insular cortex, prefrontal cortex, precentral and postcentral gyrus, temporal lobe, putamen, and anterior cingulate cortex, offering a morphological perspective on the pathophysiology of NSSI in MDD.
... In conclusion, our analysis suggests that reduced perfusion of the CMA and increased rs-FC between the CMA and the SMA are associated with psychomotor retardation in patients with MDD. This finding is highly plausible, given the integrative role of the ACC for emotion processing and action planning and the frequently reported alterations of structure and function of the ACC in patients with depression [7,58,59]. Furthermore, the CMA has a critical role within the motor circuit. Bracht). ...
Psychomotor retardation, characterized by slowing of speech, thoughts, and a decrease of movements, is frequent in patients with major depressive disorder (MDD). However, its neurobiological correlates are still poorly understood. This study aimed to explore if cerebral blood flow (CBF) and resting state functional connectivity (rs-FC) of the motor network are altered in patients with MDD and if these changes are associated with psychomotor retardation. Thirty-six right-handed patients with depression and 19 right-handed healthy controls (HC) that did not differ regarding age and sex underwent arterial spin labelling (ASL) and resting-state functional MRI (rs-fMRI) scans. Psychomotor retardation was assessed with the motoric items of the core assessment of psychomotor change (CORE) questionnaire. Patients with MDD had more pronounced psychomotor retardation scores than HC. Patients with MDD had reduced CBF in bilateral cingulate motor area (CMA) and increased resting-state functional connectivity (rs-FC) between the cluster in the CMA and a cluster localized in bilateral supplementary motor areas (SMA). Furthermore, increased rs-FC between the CMA and the left SMA was associated with more pronounced psychomotor retardation. Our results suggest that reduced perfusion of the CMA and increased rs-FC between the CMA and the SMA are associated with psychomotor retardation in patients with depression.
... Research indicates that the ACC is implicated in emotion regulation and modulates reward and non-reward mechanisms in depression (54). The rostral anterior cingulate cortex (rACC), a critical component of the ACC located anterior to the corpus callosum, serves as a hub within the default mode network (55). ...
Background
Depression is a chronic psychiatric condition that places significant burdens on individuals, families, and societies. The rapid evolution of non-invasive brain stimulation techniques has facilitated the extensive clinical use of Transcranial Magnetic Stimulation (TMS) for depression treatment. In light of the substantial recent increase in related research, this study aims to employ bibliometric methods to systematically review the global research status and trends of TMS in depression, providing a reference and guiding future studies in this field.
Methods
We retrieved literature on TMS and depression published between 1999 and 2023 from the Science Citation Index Expanded (SCIE) and Social Science Citation Index (SSCI) databases within the Web of Science Core Collection (WoSCC). Bibliometric analysis was performed using VOSviewer and CiteSpace software to analyze data on countries, institutions, authors, journals, keywords, citations, and to generate visual maps.
Results
A total of 5,046 publications were extracted covering the period from 1999 to 2023 in the field of TMS and depression. The publication output exhibited an overall exponential growth trend. These articles were published across 804 different journals, BRAIN STIMULATION is the platform that receives the most articles in this area. The literature involved contributions from over 16,000 authors affiliated with 4,573 institutions across 77 countries. The United States contributed the largest number of publications, with the University of Toronto and Daskalakis ZJ leading as the most prolific institution and author, respectively. Keywords such as “Default Mode Network,” “Functional Connectivity,” and “Theta Burst” have recently garnered significant attention. Research in this field primarily focuses on TMS stimulation patterns, their therapeutic efficacy and safety, brain region and network mechanisms under combined brain imaging technologies, and the modulation effects of TMS on brain-derived neurotrophic factor (BDNF) and neurotransmitter levels.
Conclusion
In recent years, TMS therapy has demonstrated extensive potential applications and significant implications for the treatment of depression. Research in the field of TMS for depression has achieved notable progress. Particularly, the development of novel TMS stimulation patterns and the integration of TMS therapy with multimodal techniques and machine learning algorithms for precision treatment and investigation of brain network mechanisms have emerged as current research hotspots.
... Crucially, extensive research highlights the importance of the ACC in representing reward information and monitoring rewarding outcomes, as well as in facilitating learning and enabling strategic adjustments [35][36][37][38][39] . Moreover, altered activity in the ACC and regions connected to it has been associated with depression [40][41][42][43][44][45][46] . ...
The rewards that we get from our choices and actions can have a major influence on our future behavior. Understanding how reward biasing of behavior is implemented in the brain is important for many reasons, including the fact that diminution in reward biasing is a hallmark of clinical depression. We hypothesized that reward biasing is mediated by the anterior cingulate cortex (ACC), a cortical hub region associated with the integration of reward and executive control and with the etiology of depression. To test this hypothesis, we recorded neural activity during a biased judgment task in patients undergoing intracranial monitoring for either epilepsy or major depressive disorder. We found that beta (12–30 Hz) oscillations in the ACC predicted both associated reward and the size of the choice bias, and also tracked reward receipt, thereby predicting bias on future trials. We found reduced magnitude of bias in depressed patients, in whom the beta-specific effects were correspondingly reduced. Our findings suggest that ACC beta oscillations may orchestrate the learning of reward information to guide adaptive choice, and, more broadly, suggest a potential biomarker for anhedonia and point to future development of interventions to enhance reward impact for therapeutic benefit.
... In a study by Hall et al. (20), whole-brain analysis revealed lower activation levels in the right insula of adolescents with depression compared to the HC group. The ACC has been shown to be a critical brain region involved in depression (21)(22)(23). In this study, we observed a reduction in the FC between the ACC and the precuneus, indicating potential disruptions in the neural pathways related to emotional processing in adolescent depression. ...
Objective
Among adolescents with depression, the occurrence of non-suicidal self-injury (NSSI) behavior is prevalent, constituting a high-risk factor for suicide. However, there has been limited research on the neuroimaging mechanisms underlying adolescent depression and NSSI behavior, and the potential association between the two remains unclear. Therefore, this study aims to investigate the alterations in functional connectivity (FC) of the regions in the prefrontal cortex with the whole brain, and elucidates the relationship between these alterations and NSSI behavior in adolescents with depression.
Methods
A total of 68 participants were included in this study, including 35 adolescents with depression and 33 healthy controls. All participants underwent assessments using the 17-item Hamilton Depression Rating Scale (17-HAMD) and the Ottawa Self-Harm Inventory. In addition, functional magnetic resonance imaging (fMRI) data of the participants’ brains were collected. Subsequently, the FCs of the regions in the prefrontal cortex with the whole brain was calculated. The FCs showing significant differences were then subjected to correlation analyses with 17-HAMD scores and NSSI behavior scores.
Result
Compared to the healthy control group, the adolescent depression group exhibited decreased FCs in several regions, including the right frontal eye field, left dorsolateral prefrontal cortex, right orbitofrontal cortex, left insula and right anterior cingulate coetex. The 17-HAMD score was positively correlated with the frequency of NSSI behavior within 1 year (rs = 0.461, p = 0.005). The FC between the right anterior cingulate cortex and the right precuneus showed a negative correlation with the 17-HAMD scores (rs = −0.401, p = 0.023). Additionally, the FC between the right orbitofrontal cortex and the right insula, demonstrated a negative correlation with the frequency of NSSI behavior within 1 year (rs = −0.438, p = 0.012, respectively).
Conclusion
Adolescents with depression showed decreased FCs of the prefrontal cortex with multiple brain regions, and some of these FCs were associated with the NSSI frequency within 1 year. This study provided neuroimaging evidence for the neurophysiological mechanisms underlying adolescent depression and its comorbidity with NSSI behavior.
... A study revealed lower NOS protein levels in the brain tissue of patients with MDD who died by suicide compared to the normal control group [23]. Additionally, lower levels of NOS1 mRNA have been observed in the anterior cingulate cortex of patients with MDD [24,25]. Thus, HTR2A and NOS1 genes may play a crucial role in determining whether individuals with MDD may attempt suicide. ...
Background
Both genetic and environmental factors play crucial roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items remains unknown. This study aims to explore the interactions between the genetic variants of the serotonin 2 A receptor ( HTR2A ) and the nitric oxide synthase 1 ( NOS1 ) and environmental factors in patients who experience MDD and SA.
Methods
A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic data and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-environment interactions.
Results
Four tagSNPs (rs17068986, rs3125, rs527590, and rs7959232) exhibited significant differences between the three groups. However, these differences were not significant between the MDD-SA and MDD-NSA groups after Bonferroni correction. A logistic regression analysis revealed that negative life events (OR = 1.495, 95%CI: 1.071–2.087, P = 0.018), self-guilt (OR = 2.263, 95%CI: 1.515–3.379, P < 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264–4.013, P = 0.006) were all independently associated with SA in patients with MDD. Furthermore, GMDR analysis indicated a significant interaction between HTR2A rs3125 and negative life events. Negative life events in conjunction with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD when compared to the absence of negative life events in conjunction with the CC genotype (OR = 2.547, 95% CI: 1.264–5.131, P = 0.009).
Conclusion
Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The observed interaction likely modulates the risk of MDD and SA, shedding light on the pathogenesis of SA in patients with MDD.
... At the local level, the presence of affective dysregulation was associated with a decreased segregation and integration ability of the IFG in the information processing across brain networks. The IFG has been shown to be involved in depression by means of functional (70)(71)(72)(73)(74)(75)(76) and structural connectivity studies (76-79). In particular, alterations of the right IFG structural connectivity were revealed by DTI in late-life depression in subjects both cognitively normal (76) and suffering from memory de cits (78, 79). ...
Background: The frequent presentation of Alzheimer’s disease (AD) with neuropsychiatric symptoms (NPS) in the context of normal or minimally-impaired cognitive function led to the concept of Mild Behavioral Impairment (MBI). While MBI's impact on subsequent cognitive decline is recognized, its association with brain network changes in biologically-defined AD remains unexplored.
Methods: We investigated correlations between structural covariance networks and MBI-C checklist sub-scores in 33 biologically-defined AD patients (ranging from Mild Cognitive Impairment to early dementia). Network properties were assessed through graph theory analysis. The subjects were all characterized as amyloid-positive, whether assessed through cerebrospinal fluid (CSF) analysis or amyloid positron emission tomography (PET) scans.
Results: Affective dysregulation correlated with decreased segregation and integration in the right inferior frontal gyrus (IFG). Impulse dyscontrol and social inappropriateness correlated positively with centrality and efficiency in the right posterior cingulum cortex (PCC). Global network properties showed a preserved small-world organization.
Conclusions: This study reveals associations between MBI subdomains and structural brain network alterations in biologically-confirmed AD. Our data suggest that the IFG's involvement is crucial for mood dysregulation in AD, while PCC could be involved in compensatory mechanisms in respect to social cognition and impulse control. In conclusion, our findings provide further evidence that network changes in specific brain regions may be related to NPS across the AD spectrum and underscore the significance of biomarker-based neuroimaging for precise differential diagnosis of MBI.
... A lower FA in the cingulum might be associated with dysfunctions in connectivity patterns (44) due to either a reduction (45) or a demyelination (46) of axonal fibers. Moreover, abnormal connectivity in cingulate cortices determines an altered activation in frontal regions (47,48), which correlated with the severity of MDD (49,50). The specific effects of antidepressant medications on cingulate cortices might be explained by structural modifications within axonal fibers related to proliferation and branching processes (51). ...
Major Depressive Disorder (MDD) is a severe psychiatric disorder characterized by selective impairments in mood regulation, cognition and behavior. Although it is well-known that antidepressants can effectively treat moderate to severe depression, the biochemical effects of these medications on white matter (WM) integrity are still unclear. Therefore, the aim of the study is to review the main scientific evidence on the differences in WM integrity in responders and non-responders to antidepressant medications. A record search was performed on three datasets (PubMed, Scopus and Web of Science) and ten records matched our inclusion criteria. Overall, the reviewed studies highlighted a good efficacy of antidepressants in MDD treatment. Furthermore, there were differences in WM integrity between responders and non-responders, mainly localized in cingulate cortices, hippocampus and corpus callosum, where the former group showed higher fractional anisotropy and lower axial diffusivity values. Modifications in WM integrity might be partially explained by branching and proliferation as well as neurogenesis of axonal fibers mediated by antidepressants, which in turn may have positively affected brain metabolism and increase the quantity of the serotonergic neurotransmitter within synaptic clefts. However, the reviewed studies suffer from some limitations, including the heterogeneity in treatment duration, antidepressant administration, medical posology, and psychiatric comorbidities. Therefore, future studies are needed to reduce confounding effects of antidepressant medications and to adopt longitudinal and multimodal approaches in order to better characterize the differences in WM integrity between responders and non-responders.
... We observed the same pattern of relationship in both ACC ROIs. Studies of the functional connectivity of subregions of the ACC have suggested that the more rostral portion may be associated with autonomic function via its connections with the insula and orbitofrontal cortices, while the more dorsal component of the ACC, via connections with lateral prefrontal regions, may be associated with cognitive control and error monitoring (Matthews et al., 2004;Margulies et al., 2007;Rolls et al., 2019). Both cognitive control and autonomic processes are likely engaged during the emotional regulate condition of this task, and alterations in these functions are associated with poor emotional regulation in internalizing disorders. ...
Anxiety and depression co-occur; the neural substrates of shared and unique components of these symptoms are not understood. Given emotional alterations in internalizing disorders, we hypothesized that function of regions associated with emotion processing/regulation, including the anterior cingulate cortex (ACC), amygdala and fusiform gyrus (FG), would differentiate these symptoms. Forty-three adults with depression completed an emotional functional magnetic resonance imaging task and the Hamilton Depression and Anxiety Scales. We transformed these scales to examine two orthogonal components, one representing internalizing symptom severity and the other the type of internalizing symptoms (anxiety vs depression). We extracted blood oxygen level dependent signal from FG subregions, ACC, and amygdala and performed generalized psychophysiological interaction analyses to assess relationships between symptoms and brain function. Type of internalizing symptoms was associated with FG3-FG1 coupling (F = 8.14, P = 0.007). More coupling was associated with a higher concentration of depression, demonstrating that intra-fusiform coupling is differentially associated with internalizing symptom type (anxiety vs depression). We found an interaction between task condition and internalizing symptoms and dorsal (F = 4.51, P = 0.014) and rostral ACC activity (F = 4.27, P = 0.012). Post hoc comparisons revealed that less activity was associated with greater symptom severity during emotional regulation. Functional coupling differences during emotional processing are associated with depressive relative to anxiety symptoms and internalizing symptom severity. These findings could inform future treatments for depression.
... Furthermore, MDD subjects who died by suicide show increased QUIN-positive cells in the subgenual ACC and anteriormid cingulate cortex [31]. Evidence has shown that structural and functional damage to the ACC is core to the features of MDD [32,33]. Abnormal connectivity of the ACC in MDD has also been linked with the peripheral kynurenine pathway [34]. ...
Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD ( n = 44) and matched nonpsychiatric controls ( n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.
... The NOS protein level was lower in the brain tissue of patients with MDD who died by suicide than in the normal control group [17]. Lower levels of NOS1 mRNA have been observed in the anterior cingulate cortex (ACC) of patients with MDD [18,19]. Therefore, HTR2A and NOS1 genes may play an important role in determining whether individuals with MDD may attempt suicide. ...
Background: Both genetic and environmental factors play important roles in the development of major depressive disorder (MDD) and suicide attempts (SA). However, the interaction between both items has yet to be identified. This study, aims to explore the interactions between the genetic variants of serotonin 2A receptor (HTR2A) and the nitric oxide synthase 1 (NOS1) and environmental factors in patients who experience MDD and SA.
Methods: A total of 334 patients with MDD and a history of SA (MDD-SA) were recruited alongside 518 patients with MDD with no history of SA (MDD-NSA), and 716 healthy controls (HC). The demographic information and clinical characteristics were collected. Sequenom mass spectrometry was used to detect eight tag-single nucleotide polymorphisms (tagSNPs) in HTR2A (rs1328683, rs17068986, and rs3125) and NOS1 (rs1123425, rs2682826, rs3741476, rs527590, and rs7959232). Generalized multifactor dimensionality reduction (GMDR) was used to analyze gene -environment interactions.
Results: Among the three groups, significant differences were found in four tagSNPs (rs17068986, rs3125, rs527590 and rs7959232), but these differences not found to be significant between MDD-SA and MDD-NSA after Bonferroni correction. Logistic regression analysis showed that negative life events (OR = 1.495, 95%CI: 1.071-2.087, P = 0.018), self-guilt (OR =2.263, 95%CI: 1.515-3.379, P< 0.001), and negative cognition (OR = 2.252, 95%CI: 1.264-4.013, P = 0.006) were all independently associated with SA in patients with MDD. GMDR analysis indicated that the interaction between HTR2A rs3125 and negative life events was significant. Negative life events in association with the HTR2A rs3125 CG + GG genotype were associated with a higher SA risk in patients with MDD, compared with the condition of no-negative life events in association with the CC genotype (OR = 2.547, 95% CI: 1.264-5.131, P = 0.009).
Conclusion: Several risk factors and a potential interaction between HTR2A rs3125 and negative life events were identified in patients with SA and MDD. The interaction may modulate the risk of MDD and SA, and this finding provides evidence of the pathogenesis of SA in patients with MDD.
... With seven cortical ROIs and 14 subcortical ROIs, we verified over 90% of the anatomical connections identified in published tract-tracing studies in non-human mammals using functional connectivity in humans. Our current 7 Tesla findings revealed reciprocal connectivity between sgACC/pACC and dmIns/dpIns regions previously unreported in 3 Tesla functional connectivity studies of the ACC (72)(73)(74)(75)(76) and the insula (77)(78)(79)(80). The improvement in sgACC connectivity, in particular, was expected at 7 Tesla, as this region is part of the medial/orbital surface that is typically susceptible to low SNR, partial volume effects and physiological aliasing; in the current study, these effects were mitigated by higher resolution image acquisition at 7 Tesla, minimal smoothing, and more precise nuisance regression using signals from individual ventricles. ...
The brain continuously anticipates the energetic needs of the body and prepares to meet those needs before they arise, called allostasis. In support of allostasis, the brain continually models the sensory state of the body, called interoception. We replicated and extended a large-scale system supporting allostasis and interoception in the human brain using ultra-high precision 7 Tesla functional magnetic resonance imaging (fMRI) (N = 90), improving the precision of subgenual and pregenual anterior cingulate topography combined with extensive brainstem nuclei mapping. We observed over 90% of the anatomical connections published in tract-tracing studies in non-human animals. The system also included regions of dense intrinsic connectivity broadly throughout the system, some of which were identified previously as part of the backbone of neural communication across the brain. These results strengthen previous evidence for a whole-brain system supporting the modeling and regulation of the internal milieu of the body.
... Indeed, neuroimaging data in humans have revealed the crucial role of different cingulate subregions as major hubs anchoring multiple large-scale brain networks, such as default mode (dorsal posterior cingulate cortex), salience (dorsal anterior cingulate cortex), executive control (anterior middle cingulate cortex), and visceromotor (subgenual anterior cingulate cortex) networks 15,16,[19][20][21][22][23][24][25] . Furthermore, extensive clinical neuroimaging research has exposed the cingulate cortex as a core brain region preferentially affected in various neuropsychiatric conditions [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] , but with the exact location and nature of cingulate abnormalities varying across disorders. Collectively, these previous findings in basic and clinical neuroscience have highlighted the substantial heterogeneity of the cingulate cortex in multiple dimensions including anatomy, function, connectivity, and involvement in networks and diseases. ...
Heterogeneity of the cingulate cortex is evident in multiple dimensions including anatomy, function, connectivity, and involvement in networks and diseases. Using the recently developed functional connectivity gradient approach and resting-state functional MRI data, we found three functional connectivity gradients that captured distinct dimensions of cingulate hierarchical organization. The principal gradient exhibited a radiating organization with transitions from the middle toward both anterior and posterior parts of the cingulate cortex and was related to canonical functional networks and corresponding behavioral domains. The second gradient showed an anterior–posterior axis across the cingulate cortex and had prominent geometric distance dependence. The third gradient displayed a marked differentiation of subgenual and caudal middle with other parts of the cingulate cortex and was associated with cortical morphology. Aside from providing an updated framework for understanding the multifaceted nature of cingulate heterogeneity, the observed hierarchical organization of the cingulate cortex may constitute a novel research agenda with potential applications in basic and clinical neuroscience.
... The insula, especially the anterior insula, has reciprocal connections with limbic regions ( Ghaziri et al., 2017 ), which has been implicated in the integration of emotional, cognitive, and motivational functions and reported significant in bvFTD ( Day et al., 2013 ;Namkung et al., 2017 ). The anterior cingulate gyrus is a principal hub in the salience network and is in a significant connection region of the Papez circuit, which modulates motivation, goal-directed behaviors, social decisionmaking, and emotional regulation ( Apps et al., 2016 ;Lockwood and Wittmann, 2018 ;Rolls et al., 2019 ). The orbital frontal gyrus is altered in various neuropsychiatric diseases, such as autistic spectrum disorders, and connects with the insula and the anterior cingulate cortex to regulate emotional experiences and executive functions ( Schmitz et al., 2006 ). ...
Background
Abnormalities of neurodegenerative disease are not only involved in individual brain regions but also characterized by the alterations of a balance of connectomes. Graph theory is a novel approach to examine the balance of connectomes. However, the clinical relevance of white matter connectome changes in behavioral variant of frontotemporal dementia (bvFTD) is not well understood.
Methods
In this study, we used DTI image data from 24 patients with bvFTD and 28 normal controls to exploratory investigate the clinical relevance of white matter topological alterations.
Results
The topological organization was disrupted in patients with bvFTD both globally and locally, some of which were correlated with the severity of behavior symptoms reflected as frontal behavior inventory (FBI), clinical statuses including the mini‐mental state examination (MMSE) and frontotemporal lobar degeneration‐clinical dementia rating scale (FTLD‐CDR). Notably, the nodal parameters of the lost hub regions including bilateral dorsolateral superior frontal gyrus, right orbital inferior frontal gyrus, left insula and left anterior cingulate gyrus were associated with the severity of cognitive and behavioral symptoms.
Conclusion
Topological measures would be a potential marker to explore the disease severity, mapping the large‐scale structural connectome of the brain will help to understand emergent cognitive behaviors in the disease condition of bvFTD.
... Therefore, ACC-SPL hyperconnectivity may explain the common cognitive symptoms in both disorders-dysfunctional perception, hypoprosexia, and pseudodementia. Rolls et al. have found the same increase in the ACC/SPL connectivity in patients with unipolar depression in comparison to HC, as well as increased rsFC between the ACC and the orbitofrontal cortex, middle and inferior frontal gyri, temporal cortical areas, etc. [48]. ...
Background: This study aimed to explore possible differences of the whole-brain functional connectivity of the anterior cingulate cortex (ACC) and anterior insula (AI), in a sample of depressed patients with major depressive disorder (MDD), bipolar disorder (BD) and healthy controls (HC). Methods: A hundred and three subjects (nMDD = 35, nBD = 25, and nHC = 43) between the ages of eighteen and sixty-five years old underwent functional magnetic resonance imaging. The CONN Toolbox was used to process and analyze the functional connectivity of the ACC and AI. Results: The comparison between the patients (MDD/BD) and HC yielded increased resting-state functional connectivity (rsFC) between the ACC and the motor and somatosensory cortices (SSC), superior parietal lobule (SPL), precuneus, and lateral occipital cortex, which was driven by the BD group. In addition, hyperconnectivity between the right AI and the motor and SSC was found in BD, as compared to HC. In MDD, as compared to HC, hyperconnectivity between ACC and SPL and the lateral occipital cortex was found, with no statistical rsFC differences for the AI seed. Compared to BD, the MDD group showed ACC–cerebellum hyperconnectivity and a trend for increased rsFC between the right AI and the bilateral superior frontal cortex. Conclusions: Considering the observed hyperconnectivity between the ACC/somatosensory cortex in the patient group, we suggest depression may be related to an impairment of the sensory-discriminative function of the SSC, which results in the phenomenological signature of mental pain in both MDD and BD. These findings suggest that future research should investigate this particular network with respect to motor functions and executive control, as a potential differential diagnostic biomarker for MDD and BD.
... The cingulate cortex has been proposed to predict AD progression (Lee et al., 2020). Neuropsychiatric symptoms of depression and AD have also been associated with the cingulate and orbitalfrontal cortex (Rolls, 2019b;Rolls et al., 2019;Chen et al., 2021). The orbitalfrontal cortex is also thought to play a role in motivated decision making (Zimmermann et al., 2017). ...
Introduction: 7,8-dihydroxyflavone (7,8-DHF) is a low molecular weight compound that can cross the blood brain barrier and has been implicated in numerous functions and behaviours. It is thought to have neuroprotective capability and has been shown to alleviate symptoms in a wide range of diseases. Methods: 7,8-DHF was administered systemically to wildtype mice during Morris water maze training. Long-term spatial memory was assessed 28 days later. Ex-vivo T2-weighted (T2w) imaging was undertaken on a subset of these mice to assess brain-wide changes in volume. Results: We found that systemic 7,8-DHF administration during the training period enhanced spatial memory 28 days later. Volumetric changes were observed in numerous brain regions associated with a broad range of functions including cognition, sensory, and motor processing. Discussion: Our findings give the first whole brain overview of long-term anatomical changes following 7,8-DHF administration providing valuable information for assessing and understanding the widespread effects this drug has been shown to have in behaviour and disease.
... Nevertheless, prior studies in MDD have implicated structural and functional disturbances and have identified other putative brain-based predictors for treatment response. Structural and functional disturbances in the anterior cingulate cortex (Drevets et al., 2008;Koolschijn et al., 2009;Li et al., 2022;Rolls et al., 2019;van Tol et al., 2010), inferior frontal gyrus (Bora et al., 2012;Coryell et al., 2005;Hastings et al., 2004;Koolschijn et al., 2009), orbitofrontal cortex (Drevets, 2007;Rolls, 2019;Rolls et al., 2020;Scheuerecker et al., 2010), and superior temporal gyrus (Kambe et al., 2018;Liu et al., 2018;Ramezani et al., 2014;Takahashi et al., 2010) have been implicated in the etiology of MDD (Bora et al., 2012;Peterson et al., 2009). Prior structural MRI studies in MDD have reported that larger posterior hippocampal volumes (MacQueen et al., 2008), greater gray matter volumes of the anterior and posterior cingulate cortex (Costafreda et al., 2009), and early thickening of the rostral anterior cingulate cortex (Bartlett et al., 2018) predict treatment response for antidepressant medications. ...
The anatomical changes that antidepressant medications induce in the brain and through which they exert their therapeutic effects remain largely unknown. We randomized 61 patients with Persistent Depressive Disorder (PDD) to receive either desvenlafaxine or placebo in a 12-week trial and acquired anatomical MRI scans in 42 of those patients at baseline before randomization and immediately at the end of the trial. We also acquired MRIs once in 39 age- and sex-matched healthy controls. We assessed whether the serotonin-norepinephrine reuptake inhibitor, desvenlafaxine, differentially changed cortical thickness during the trial compared with placebo. Patients relative to controls at baseline had thinner cortices across the brain. Although baseline thickness was not associated with symptom severity, thicker baseline cortices predicted greater reduction in symptom severity in those treated with desvenlafaxine but not placebo. We did not detect significant treatment-by-time effects on cortical thickness. These findings suggest that baseline thickness may serve as predictive biomarkers for treatment response to desvenlafaxine. The absence of treatment-by-time effects may be attributable either to use of insufficient desvenlafaxine dosing, a lack of desvenlafaxine efficacy in treating PDD, or the short trial duration.
... Recent studies have identified disruptions in functional connectivity (FC) in specific brain networks in MDD (Brakowski et al., 2017;Rolls et al., 2018). Several brain networks were revealed to mediate depressive symptoms, including the default mode network (DMN) and salience brain network (Guo et al., 2014;Manoliu et al., 2013). ...
It remains challenging to identify depression accurately due to its biological heterogeneity. As people suffering from depression are associated with functional brain network alterations, we investigated subtypes of patients with first-episode drug-naive (FEDN) depression based on brain network characteristics. This study included data from 91 FEDN patients and 91 matched healthy individuals obtained from the International Big-Data Center for Depression Research. Twenty large-scale functional connectivity networks were computed using group information guided independent component analysis. A multivariate unsupervised normative modeling method was used to identify subtypes of FEDN and their associated networks, focusing on individual-level variability among the patients for quantifying deviations of their brain networks from the normative range. Two patient subtypes were identified with distinctive abnormal functional network patterns, consisting of 10 informative connectivity networks, including the default mode network and frontoparietal network. 16% of patients belonged to subtype I with larger extreme deviations from the normal range and shorter illness duration, while 84% belonged to subtype II with weaker extreme deviations and longer illness duration. Moreover, the structural changes in subtype II patients were more complex than the subtype I patients. Compared with healthy controls, both increased and decreased gray matter (GM) abnormalities were identified in widely distributed brain regions in subtype II patients. In contrast, most abnormalities were decreased GM in subtype I. The informative functional network connectivity patterns gleaned from the imaging data can facilitate the accurate identification of FEDN-MDD subtypes and their associated neurobiological heterogeneity.
... Thus, even the same brain region may exhibit distinct alterations across different frequency of interests. For instance, a very recent study involving individuals with MDD demonstrated frequency-dependent decreases in degree centrality in the anterior cingulate cortex in the HF band of 0.175-0.25 Hz (Ries et al., 2019), which is opposite to low frequency findings Rolls et al., 2019). Hence, these HF signals cannot be simply treated as artifacts due to nonneural noise. ...
Background:
Functional connectome studies have revealed widespread connectivity alterations in major depressive disorder (MDD). However, the low frequency bandpass filtering (0.01-0.08 Hz or 0.01-0.1 Hz) in most studies have impeded our understanding on whether and how these alterations are affected by frequency of interest.
Methods:
Here, we performed frequency-resolved (0.01-0.06 Hz, 0.06-0.16 Hz and 0.16-0.24 Hz) connectome analyses using a large-sample resting-state functional MRI dataset of 1002 MDD patients and 924 healthy controls from seven independent centers.
Results:
We reported significant frequency-dependent connectome alterations in MDD in left inferior parietal, inferior temporal, precentral, and fusiform cortices and bilateral precuneus. These frequency-dependent connectome alterations are mainly derived by abnormalities of medium- and long-distance connections and are brain network-dependent. Moreover, the connectome alteration of left precuneus in high frequency band (0.16-0.24 Hz) is significantly associated with illness duration.
Limitations:
Multisite harmonization model only removed linear site effects. Neurobiological underpinning of alterations in higher frequency (0.16-0.24 Hz) should be further examined by combining fMRI data with respiration, heartbeat and blood flow recordings in future studies.
Conclusions:
These results highlight the frequency-dependency of connectome alterations in MDD and the benefit of examining connectome alteration in MDD under a wider frequency band.
... The insula, especially the anterior insula, has reciprocal connections with limbic regions ( Ghaziri et al., 2017 ), which has been implicated in the integration of emotional, cognitive, and motivational functions and reported significant in bvFTD ( Day et al., 2013 ;Namkung et al., 2017 ). The anterior cingulate gyrus is a principal hub in the salience network and is in a significant connection region of the Papez circuit, which modulates motivation, goal-directed behaviors, social decisionmaking, and emotional regulation ( Apps et al., 2016 ;Lockwood and Wittmann, 2018 ;Rolls et al., 2019 ). The orbital frontal gyrus is altered in various neuropsychiatric diseases, such as autistic spectrum disorders, and connects with the insula and the anterior cingulate cortex to regulate emotional experiences and executive functions ( Schmitz et al., 2006 ). ...
Graph theory is a novel approach used to examine the balance of brain connectomes. However, the clinical relevance of white matter (WM) connectome changes in the behavioral variant of frontotemporal dementia (bvFTD) is not well understood. We aimed to investigate the clinical relevance of WM topological alterations in bvFTD. Thirty patients with probable bvFTD and 30 healthy controls underwent diffusion tensor imaging, structural MRI, and neuropsychological assessment. White matter connectivity between 90 brain regions was calculated and the graph approach was applied to capture the individual characteristics of anatomical network. voxel-based morphometry and tract-base spatial statistics were used to present the gray matter atrophy and disrupted white matter integrity. The topological organization was disrupted in patients with bvFTD both globally and locally. Compared to controls, bvFTD data showed a different pattern of hub region distributions. Notably, the nodal efficiency of the right orbital superior frontal gyrus was associated with apathy and disinhibition. Topological measures may be potential image markers for early diagnosis and monitoring disease severity of bvFTD.
... Fourth, we cannot obtain treatment information and other clinical information, which may alter brain activities [85]. It should be validated in a larger sample size and more comprehensive population in the future. ...
Background
Subclinical anxiety, depressive and somatic symptoms appear closely related. However, it remains unclear whether somatic symptoms mediate the association between subclinical anxiety and depressive symptoms and what the underlying neuroimaging mechanisms are for the mediating effect.
Methods
Data of healthy participants ( n = 466) and participants in remission of major depressive disorder ( n = 53) were obtained from the Human Connectome Project. The Achenbach Adult Self-Report was adopted to assess anxiety, depressive and somatic symptoms. All participants completed four runs of resting-state functional magnetic resonance imaging. Mediation analyses were utilized to explore the interactions among these symptoms and their neuroimaging mechanisms.
Results
Somatic symptoms partially mediated the association between subclinical anxiety and depressive symptoms in healthy participants (anxiety→somatic→depression: effect: 0.2785, Boot 95% CI: 0.0958–0.3729; depression→somatic→anxiety: effect: 0.0753, Boot 95% CI: 0.0232–0.1314) and participants in remission of MDD (anxiety→somatic→depression: effect: 0.2948, Boot 95% CI: 0.0357–0.7382; depression→somatic→anxiety: effect: 0.0984, Boot 95% CI: 0.0007–0.2438). Resting-state functional connectivity (FC) between the right medial superior frontal gyrus and the left thalamus and somatic symptoms as chain mediators partially mediated the effect of subclinical depressive symptoms on subclinical anxiety symptoms in healthy participants (effect: 0.0020, Boot 95% CI: 0.0003–0.0043). The mean strength of common FCs of subclinical depressive and somatic symptoms, somatic symptoms, and the mean strength of common FCs of subclinical anxiety and somatic symptoms as chain mediators partially mediated the effect of subclinical depressive symptoms on subclinical anxiety symptoms in remission of MDD (effect: 0.0437, Boot 95% CI: 0.0024–0.1190). These common FCs mainly involved the insula, precentral gyri, postcentral gyri and cingulate gyri. Furthermore, FC between the triangular part of the left inferior frontal gyrus and the left postcentral gyrus was positively associated with subclinical anxiety, depressive and somatic symptoms in remission of MDD (FDR-corrected p < 0.01).
Conclusions
Somatic symptoms partially mediate the interaction between subclinical anxiety and depressive symptoms. FCs involving the right medial superior frontal gyrus, left thalamus, triangular part of left inferior frontal gyrus, bilateral insula, precentral gyri, postcentral gyri and cingulate gyri maybe underlie the mediating effect of somatic symptoms.
... The anterior cingulate cortex (ACC) is central to neuroanatomical models of depressive disorders, including subthreshold depression. Morphological studies including meta-analyses show reduced volumes and thickness of the ACC in depression [7,23,51,58], and a large body of research employing resting-state functional magnetic resonance imaging (rsfMRI) has specifically implicated the rostral portion of the ACC in emotion control and reward processing (e.g., [9,14,50]. Ventromedial prefrontal regions such as the ACC are considered part of the default mode network (DMN), a network of interconnected structures, divided into the ventral medial prefrontal cortex (PFC), the dorsal medial prefrontal cortex; the posterior cingulate cortex and adjacent precuneus, and the lateral parietal cortex, that are suppressed during tasks that require external attention and active during relatively passive states [8,48]. Depression is characterized by altered resting-state functional connectivity (rsFC) within the DMN and from the DMN to the dorsolateral prefrontal cortex [21], portions of which are considered part of the DMN in updated models [8,36]. ...
Subthreshold depressive symptoms are highly prevalent among older adults and are associated with numerous health risks including cognitive decline and decreased physical health. One brain region central to neuroanatomical models of depressive disorders is the anterior cingulate cortex (ACC). The rostral portion of the ACC—comprised of the pregenual ACC and subgenual ACC—is implicated in emotion control and reward processing. The goal of the current study was to examine how functional connectivity in subregions of the rostral ACC relate to depressive symptoms, measured by the Beck Depression Inventory-Second Edition, in an ethnically diverse sample of 28 community-dwelling older adults. Based on meta-analyses of previous studies in primarily young adults with clinical depression, we hypothesized that greater depressive symptoms would be associated with primarily increased resting-state functional connectivity from both the subgenual ACC and pregenual ACC to default mode network regions and the dorsolateral PFC. We instead found that higher depressive symptoms were associated with lower functional connectivity of the ACC to the dorsolateral PFC and regions within the default mode network, including from the subgenual ACC to the dorsolateral PFC and anterior cingulate and from the pregenual ACC to the middle cingulate gyrus. This preliminary study highlights brain alterations at subthreshold levels of depressive symptoms in older adults, which could serve as targets for interventions.
... Interestingly, the anterior cingulate cortex (ACC), part of the autonomic forebrain loop, functioning as a relay hub and transmitting various input signals after evaluating requirements from other regions to guide adaptive behaviors, is particularly sensitive to cytokines (158,159). Notably, both depression and CD are inflammation-related disorders and dysfunction of the ACC was reported in depression and CD (160,161). Further, a recent study from Xu group found that patients with CD who were in the active phase exhibited higher amplitude of low frequency fluctuation (ALFF) in the left ACC and a positive correlation between mWavelet-ALFF values of the ACC and Hospital Anxiety and Depression Scale-depression scores in CD patients (162). These suggest that ACC may serve as an intersection in the brain, which senses gut inflammation and responses inappropriately, increasing risk of depression. ...
Depression is a worldwide disease causing severe disability, morbidity, and mortality. Despite abundant studies, the precise mechanisms underlying the pathophysiology of depression remain elusive. Recently, cumulate research suggests that a disturbance of microbiota-gut-brain axis may play a vital role in the etiology of depression while correcting this disturbance could alleviate depression symptoms. The vagus nerve, linking brain and gut through its afferent and efferent branches, is a critical route in the bidirectional communication of this axis. Directly or indirectly, the vagus afferent fibers can sense and relay gut microbiota signals to the brain and induce brain disorders including depression. Also, brain changes in response to stress may result in gut hyperpermeability and inflammation mediating by the vagal efferents, which may be detrimental to depression. Notably, vagus nerve stimulation owns an anti-inflammatory effect and was proved for depression treatment. Nevertheless, depression was accompanied by a low vagal tone, which may derive from response to stress and contribute to pathogenesis of depression. In this review, we aim to explore the role of the vagus nerve in depression from the perspective of the microbiota-gut-brain axis, highlighting the relationship among the vagal tone, the gut hyperpermeability, inflammation, and depression.
... Recently, an increasing number of studies have reported that the cingulate cortex is widely related to the development of depression. For example, increased anterior cingulate-inferior frontal gyrus connectivity has been reported by Rolls et al. (2019). Zhu et al. (2022) reported that the posterior cingulate showed higher resting-state functional connectivity with the right middle frontal gyrus (MFG) and the left middle temporal gyrus (MTG) in depressive patients. ...
Psoriasis is a chronic, autoimmune disorder that is related to mental health disorders such as depression. However, few studies have focused on the features of brain activity in psoriasis patients with depression (PPD) and the association between brain activity and disease severity. A total of 29 PPD and 24 healthy controls were involved in this study, and all participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning. The psoriasis area and severity index (PASI) and the self-rating depression scale (SDS) were used to measure clinical symptoms. Compared with HCs, PPD patients showed increased fractional amplitude of low-frequency fluctuation (fALFF) in the Frontal_Mid_L and increased functional connectivity (FC) between the hypothalamus-R and the Cingulum_Mid_R. Correlation analysis suggested a positive correlation between PASI and SDS scores in PPD, while the fALFF and FC values were negatively correlated with their SDS and PASI scores. These brain regions may be associated with the development of depressive symptoms and disease severity in psoriasis patients.
... There is considerable evidence that ACA is involved in emotion. Stimulation in the subcallosal ACA has been widely used to treat depression (Rolls et al., 2019). In addition, it was suggested that ACA had features predictive of treatment outcome in depression (Pantazatos et al., 2020). ...
Chronic sleep deprivation (SD) is a common problem for humans and can lead to many deleterious effects, including depression, anxiety, stroke, permanent cognitive deficits, stress, and other physiological diseases. It is vital to acquire information about the relevant neural activities at the whole-brain level to systematically explore the mechanisms of brain dysfunction related to SD. Expression of the immediate-early gene (IEG) Fos in the mouse brain has been widely used as a functional marker of brain activity in the field of neuroscience. However, most previous studies only analyzed the change of c-Fos in several specific brain regions using traditional research methods or in short-term SD model. Here, we applied c-Fos mapping through the fluorescence micro-optical sectioning tomography (fMOST) technique and AAV-PHP.eB to comprehensive analysis the state of cumulative activation across the whole brain in a mouse model of chronic SD. The chronic rapid eyes movement (REM) SD model was induced by moving mice to a separate holding area filled with water. The experimental period lasted for 6 h per day. The results showed that after 14 days of SD, the mice displayed anxiety behaviors in open field test and elevated plus maze test, and displayed depression-like behaviors in tail suspension test and the sucrose preference test. The c-Fos + cells were detected in a maximum of 230 brain regions. SD-induced stress model evoked c-Fos expression in several brain regions compared to the control group. In particular, the isocortex-cerebral cortex plate area, including the retrosplenial, anterior cingulate, agranular insular, gustatory, and parasubiculum, appear to be the most sensitive regions after chronic REM SD.
... In turn, pain relief is accompanied by recovery from atrophy of ACC volume, and restoration of its' functional connectivity with brain regions of antinociceptive circuits [48][49][50][51]. The ACC is considered as a critical hub for multi-dimensional modulation of nociceptive information, including pain sensation, negative affect (anxiodepressive consequences of chronic pain), and cognitive control [52][53][54][55]. Thus, ACC hypo-gyrification may be not related to either pain processing or comorbid mood (depression and anxiety) deficits of FM. ...
Background
Although neuroanatomical studies correlated to fibromyalgia (FM) are gaining increasing interest, the cortical morphology of patients are largely unknown, and data on cortical gyrification are scarce. The objective of the present study is to assess the cortical morphology in female patients with FM compared with healthy controls (HC) using surface-based morphometry (SBM) analysis of magnetic resonance imaging (MRI).
Methods
T1-MRIs and clinical data of 20 FM patients and 20 HC subjects were obtained from a public databset via OpenNeuro. For each subject, surface parameters including cortical thickness, local gyrification index (LGI), sulcal depth, and fractal dimensionality were estimated using SBM analysis. These data were compared between two groups controlled by age. The correlations between regional SBM parameters showing group differences and clinical profiles were analyzed.
Results
Compared with HC subjects, FM patients showed reduced cortical thickness in right primary motor cortex, lower LGI in right rostral anterior cingulate and higher sulcal depth in right precuneus (p < 0.05 cluster level family- wise error corrected). In FM patients, correlation analysis showed that the cortical thickness in right primary motor cortex were inversely correlated with scores of pain catastrophizing scale (r = -0.498, p = 0.030) and pain self-perception scale (r = -0.527, p = 0.020), and disease duration (r = -0.488, p = 0.034), respectively.
Conclusions
Our findings provide evidence of neuroanatomical aberrations in FM patients, which may provide insight into the neuropathology of FM.
This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment. Conventional repetitive transcranial magnetic stimulation faces challenges due to the intricacies of brain anatomy and patient variability. Neuronavigation offers innovative solutions by integrating neuroimaging with three-dimensional localization to pinpoint brain regions and refine therapeutic targeting. This systematic review of recent literature underscores the enhanced efficacy of neuronavigation in improving treatment outcomes for these disorders. This editorial highlights the pivotal role of neuronavigation in advancing psychiatric care.
Background
This study aimed to evaluate a novel rTMS protocol for treatment-resistant depression (TRD), using an EEG 10–20 system guided dual-target accelerated approach of right lateral orbitofrontal cortex (lOFC) inhibition followed by left dorsolateral prefrontal cortex (dlPFC) excitation, along with comparing 20 Hz dlPFC accelerated TMS v. sham.
Methods
Seventy five patients participated in this trial consisting of 20 sessions over 5 consecutive days comparing dual-site (cTBS of right lOFC followed sequentially by 20 Hz rTMS of left dlPFC), active control (sham right lOFC followed by 20 Hz rTMS of left dlPFC) and sham control (sham for both targets). Resting-state fMRI was acquired prior to and following treatment.
Results
Hamilton Rating Scale for Depression (HRSD-24) scores were similarly significantly improved at 4 weeks in both the Dual and Single group relative to Sham. Planned comparisons immediately after treatment highlighted greater HRSD-24 clinical responders (Dual: 47.8% v. Single:18.2% v. Sham:4.3%, χ 2 = 13.0, p = 0.002) and in PHQ-9 scores by day 5 in the Dual relative to Sham group. We further showed that accelerated 20 Hz stimulation targeting the left dlPFC (active control) is significantly better than sham at 4 weeks. Dual stimulation decreased lOFC-subcallosal cingulate functional connectivity. Greater baseline lOFC-thalamic connectivity predicted better therapeutic response, while decreased lOFC-thalamic connectivity correlated with better response.
Conclusions
Our novel accelerated dual TMS protocol shows rapid clinically relevant antidepressant efficacy which may be related to state-modulation. This study has implications for community-based accessible TMS without neuronavigation and rapid onset targeting suicidal ideation and accelerated discharge from hospital.
The functional neuropeptide S receptor 1 (NPSR1) gene A/T variant (rs324981) is associated with fear processing. We investigated the impact of NPSR1 genotype on fear processing and on symptom reduction following treatment in individuals with spider phobia. A replication approach was applied [discovery sample: Münster (MS) nMS = 104; replication sample Würzburg (WZ) nWZ = 81]. Participants were genotyped for NPSR1 rs324981 [T-allele carriers (risk) versus AA homozygotes (no-risk)]. A sustained and phasic fear paradigm was applied during functional magnetic resonance imaging. A one-session virtual reality exposure treatment was conducted. Change of symptom severity from pre to post treatment and within session fear reduction were assessed. T-allele carriers in the discovery sample displayed lower anterior cingulate cortex (ACC) activation compared to AA homozygotes independent of condition. For sustained fear, this effect was replicated within a small cluster and medium effect size. No association with symptom reduction was found. Within-session fear reduction was negatively associated with ACC activation in T-allele carriers in the discovery sample. NPSR1 rs324981 genotype might be associated with fear processing in the ACC in spider phobia. Interpretation as potential risk-increasing function of the NPSR1 rs324981 T-allele via impaired top-down control of limbic structures remains speculative. Potential association with symptom reduction warrants further research.
A computational neuroscience approach to the symptoms, mechanisms of, and treatments for schizophrenia and depression is described. The approach is based on a stochastic neurodynamical framework in which the stability of attractor networks in the brain is analyzed. The stability is influenced by statistical fluctuations in populations of neurons caused by the neuronal spiking time randomness for a given mean firing rate. The stability of the high firing rate attractor state which implements effects such as short-term memory and attention is increased if the firing rates are sufficiently high to dominate the spiking-related noise. The stability of the low, spontaneous, firing rate state in the absence of input must also be maintained, and GABA-mediated inhibition is important for this. The approach aims towards producing a neurally based mechanistic model that can account for the phenomenology of disorders as experienced by patients, such as schizophrenia, depression, and obsessive-compulsive disorder.
In schizophrenia, the approach suggests that a reduction of the firing rates of cortical neurons, caused for example by reduced NMDA receptor function or reduced spines on neurons, present in schizophrenia, can lead to instability of the high firing rate attractor states that normally implement short-term memory and attention in the prefrontal cortex, contributing to the cognitive symptoms of schizophrenia. Reduced NMDA receptor function in the orbitofrontal cortex by reducing firing rates may produce negative symptoms, by reducing reward, motivation, and emotion. Reduced functional connectivity between some brain regions increases the temporal variability of the functional connectivity, which is likely to contribute to reduced stability and more loosely associative thoughts. Further, the forward projections have decreased functional connectivity relative to the back projections in schizophrenia, and this is suggested to reduce the effects on external bottom-up inputs from the world relative to internal top-down thought processes. Reduced cortical inhibition caused by a reduction of GABA neurotransmission, present in schizophrenia in for example the temporal lobes, can lead to instability of the spontaneous firing states of cortical networks, leading to a noise-induced jump to a high firing rate attractor state even in the absence of external inputs, contributing to the positive symptoms of schizophrenia.
For depression, the theory is that there is an attractor system in the lateral orbitofrontal cortex that is sensitive to not obtaining expected rewards, which can lead to sadness and depression, and that this system is over-responsive and over-connected in depression. The lateral orbitofrontal cortex has increased functional connectivity with the precuneus and posterior cingulate cortex in depression, which are involved in the sense of self and autobiographical memories, and this may account for the low self-esteem in depression. The lateral orbitofrontal cortex also has increased functional connectivity in depression with the angular gyrus, a brain area related to language, and this may be related to rumination in depression. The reward-related medial orbitofrontal cortex has reduced connectivity with temporal lobe memory systems in depression and reduced sensitivity to rewards, and these may contribute to fewer happy memories, and anhedonia, in depression.
Objective:
To assess whether anterior cingulate cortex (ACC) abnormalities contribute to suicide risk in major depressive disorder and bipolar disorder, the investigators compared resting-state functional connectivity (rsFC) of ACC subdivisions between individuals with major depressive or bipolar disorder with and without a lifetime history of suicidal behavior.
Methods:
Forty-two inpatients with and 26 inpatients without a history of suicidal behavior (SB+ and SB-, respectively) associated with major depressive or bipolar disorder and 40 healthy control (HC) participants underwent rsFC neuroimaging. RsFC of the subgenual, perigenual, rostral, dorsal, and caudal subdivisions of the ACC was calculated. Possible confounders, such as psychosis and severity of depression, were controlled for, seed-to-voxel and post hoc region of interest (ROI)-to-ROI analyses were performed, and the accuracy of rsFC in classifying suicidal behavior was studied.
Results:
Compared with individuals in the SB- and HC groups, patients in the SB+ group had higher rsFC between the left rostral and right dorsal ACC seeds and visual cortex clusters. Conversely, rsFC between the left rostral and right dorsal ACC seeds and cingulate and frontal clusters was lower in the SB+ group than in the HC group. Left rostral ACC to left Brodmann's area 18 connectivity showed up to 75% discriminative accuracy in distinguishing SB+ from SB- patients.
Conclusions:
A history of suicidal behavior among individuals with major depressive disorder or bipolar disorder was associated with altered rsFC of the rostral and caudal ACC, regions involved in conflict detection and error monitoring. Replication of these findings is needed to further explore the involvement of the ACC in the neurobiology of suicidal behavior and suicidal ideation.
Previous research revealed various aspects of resting-state EEG for depression and insomnia. However, the EEG characteristics of depressed subjects with insomnia are rarely studied, especially EEG microstates that capture the dynamic activities of the large-scale brain network. To fill these research gaps, the present study collected resting-state EEG data from 32 subclinical depression subjects with insomnia (SDI), 31 subclinical depression subjects without insomnia (SD), and 32 healthy controls (HCs). Four topographic maps were generated from clean EEG data after clustering and rearrangement. Temporal characteristics were obtained for statistical analysis, including cross-group variance analysis (ANOVA) and intra-group correlation analysis. In our study, the global clustering of all individuals in the EEG microstate analysis revealed the four previously discovered categories of microstates (A, B, C, and D). The occurrence of microstate B was lower in SDI than in SD and HC subjects. The correlation analysis showed that the total Pittsburgh Sleep Quality Index (PSQI) score negatively correlated with the occurrence of microstate C in SDI (r = − 0.415, p < 0.05). Conversely, there was a positive correlation between Self-rating Depression Scale (SDS) scores and the duration of microstate C in SD (r = 0.359, p < 0.05). These results indicate that microstates reflect altered large-scale brain network dynamics in subclinical populations. Abnormalities in the visual network corresponding to microstate B are an electrophysiological characteristic of subclinical individuals with symptoms of depressive insomnia. Further investigation is needed for microstate changes related to high arousal and emotional problems in people suffering from depression and insomnia.
Background:
The second-generation antipsychotic (SGA) quetiapine is an essential option for antidepressant augmentation therapy in major depressive disorder (MDD), yet neurobiological mechanisms behind its antidepressant properties remain unclear. As SGAs interfere with activity in reward-related brain areas, including the anterior cingulate cortex (ACC) - a key brain region in antidepressant interventions, this study examined whether quetiapine treatment affects ACC activity during reward processing in MDD patients.
Methods:
Using the ACC as region of interest, an independent t-test comparing reward-related BOLD response of 51 quetiapine-taking and 51 antipsychotic-free MDD patients was conducted. Monetary reward outcome feedback was measured in a card-guessing paradigm using pseudorandom blocks. Participants were matched for age, sex, and depression severity and analyses were controlled for confounding variables, including total antidepressant medication load, illness chronicity and acute depression severity. Potential dosage effects were examined in a 3 × 1 ANOVA. Differences in ACC-related functional connectivity were assessed in psycho-physiological interaction (PPI) analyses.
Results:
Left subgenual ACC activity was significantly higher in the quetiapine group compared to antipsychotic-free participants and dependent on high-dose quetiapine intake. Results remained significant after controlling for confounding variables. The PPI analysis did not yield significant group differences in ACC-related functional connectivity.
Limitations:
Causal interpretation is limited due to cross-sectional findings.
Conclusion:
Elevated subgenual ACC activity to rewarding stimuli may represent a neurobiological marker and potential key interface of quetiapine's antidepressant effects in MDD. These results underline ACC activity during reward processing as an investigative avenue for future research and therapeutic interventions to improve MDD treatment outcomes.
Background: Previous research has revealed various aspects of resting-state EEG for depression and insomnia. However, the EEG characteristics of depressed patients with co-morbid insomniac are rarely studied, especially EEG microstates that capture the dynamic activities of the large-scale brain network.
Methods:To fill the research gaps, this study collected resting-state EEG data from 32 sub-clinical depressions with co-morbid insomnia (CI), 31 comorbid-free depressions (CFD), and 32 healthy controls (HC). Four topographic maps were generated from clean EEG data after clustering and rearrangement. Temporal characteristics were obtained for statistical analysis, including cross-group variance analysis (ANOVA) and intra-group correlation analysis.
Results: The global clustering of all individuals in the EEG microstate analysis revealed the four previously discovered categories of microstates (A, B, C, and D). The occurrence of microstate B was found to be lower in CI than in CFD. The correlation analysis showed that the total PSQI score was negatively correlated with the occurrence of microstate C in CI (r=-0.354, p<.05). Conversely, there was a positive correlation between SDS scores and the duration of microstate C in CFD (r=0.359, p<.05).
Conclusion: The spatiotemporal dynamics of the brain network can vary due to abnormalities in the visual network corresponding to microstate B in patients with depression and insomnia.. Further investigation is needed for microstate change can be related to high arousal and emotional problems in people suffering from depression and insomnia. Microstates may therefore become crucial neurobiological predictors to forecast the likelihood of future cases of depression and insomnia.
Background
Anterior cingulate cortex (ACC) plays an essential role in the pathophysiology of major depressive disorder (MDD) and its treatment. However, it's still unclear whether the effects of disease and antidepressant treatment on ACC perform diversely in neural mechanisms.
Methods
Fifty-nine MDD patients completed resting-state fMRI scanning twice at baseline and after 12-week selective serotonin reuptake inhibitor (SSRI) treatment, respectively in acute state and remission state. Fifty-nine demographically matched healthy controls were enrolled. Using fractional amplitude of low-frequency fluctuation (fALFF) in ACC as features, we performed multi-voxel pattern analysis over pretreatment MDD patients vs health control (HC), and over pretreatment MDD patients vs posttreatment MDD patients.
Results
Discriminative regions in ACC for MDD impairment and changes after antidepressants were obtained. The intersection set and difference set were calculated to form ACC subregions of recovered, unrecovered and compensative, respectively. The recovered ACC subregion mainly distributed in rostral ACC (80 %) and the other two subregions had nearly equal distribution over dorsal ACC and rostral ACC. Furthermore, only the compensative subregion had significant changed functional connectivity with cingulo-opercular control network (CON) after antidepressant treatment.
Limitations
The number of subjects was relatively small. The results need to be validated with larger sample sizes and multisite data.
Conclusions
This finding suggested that the local function of ACC was partly recovered on regulating emotion after antidepressant by detecting the common subregional targets of depression impairment and antidepressive effect. Besides, changed fALFF in the compensative ACC subregion and its connectivity with CON may partly compensate for the cognition deficits.
Depression alleviation following treatment with repetitive transcranial magnetic stimulation (rTMS) tends to be more effective when TMS is targeted to cortical areas with high resting state functional connectivity (rsFC) with the subgenual anterior cingulate cortex (sgACC). However, it has not yet been confirmed that rsFC-guided TMS coil placement leads to TMS modulation of the sgACC. For each participant (N=115, 34 depressed patients), a peak rsFC cortical hotspot for the sgACC and control targets were prospectively identified. Single pulses of TMS interleaved with fMRI readouts were then administered to these targets and established significant downstream fMRI BOLD responses in the sgACC. We then marked an association between TMS-evoked BOLD responses in the sgACC and rsFC between the stimulation site and sgACC. This effect was qualified by a difference between healthy and patient participants: only in depressed patients, positively connected sites of stimulation led to the strongest evoked responses in the sgACC. Our results highlight rsFC-based targeting as a viable strategy to causally modulate sgACC subcortical targets and further suggest that cortical sites with high positive rsFC to the sgACC might represent an alternative target for the treatment of depression.
Background
Previous studies have shown major depressive disorder (MDD) is associated with altered neuro-metabolites in the anterior cingulate cortex (ACC). However, the regional metabolic heterogeneity in the ACC in individuals with MDD remains unclear.
Methods
We recruited 59 first-episode, treatment-naive young adults with MDD and 50 healthy controls who underwent multi-voxel ¹H-MRS scanning at 3 T (Tesla) with voxels placed in the ACC, which was divided into two subregions, pregenual ACC (pACC) and anterior midcingulate cortex (aMCC). Between and within-subjects metabolite concentration variations were analyzed with SPSS.
Results
Compared with control subjects, patients with MDD exhibited higher glutamate (Glu) and glutamine (Gln) levels in the pACC and higher myo-inositol (MI) level in the aMCC. We observed higher Glu and Gln levels and lower N-acetyl-aspartate (NAA) level in the pACC than those in the aMCC in both MDD and healthy control (HC) groups. More importantly, the metabolite concentration gradients of Glu, Gln and NAA were more pronounced in MDD patients relative to HCs. In the MDD group, the MI level in the aMCC positively correlated with the age of onset.
Limitations
The use of the relative concentration of metabolites constitutes a key study limitation.
Conclusions
We observed inconsistent alterations and distribution of neuro-metabolites concentration in the pACC and aMCC, revealing regional metabolic heterogeneity of ACC in first-episode, treatment-naive young individuals with MDD. These results provided new evidence for abnormal neuro-metabolites of ACC in the pathophysiology of MDD and suggested that pACC and aMCC might play different roles in MDD.
Dynamic functional network connectivity (dFNC) could capture temporal features of spontaneous brain activity during MRI scanning, and it might be a powerful tool to examine functional brain network alters in major depressive disorder (MDD). Therefore, this study investigated the changes in temporal properties of dFNC of first-episode, drug-naïve patients with MDD. A total of 48 first-episode, drug-naïve MDD patients and 46 age- and gender-matched healthy controls were recruited in this study. Sliding windows were implied to construct dFNC. We assessed the relationships between altered dFNC temporal properties and depressive symptoms. Receiver operating characteristic (ROC) curve analyses were used to examine the diagnostic performance of these altered temporal properties. The results showed that patients with MDD have more occurrences and spent more time in a weak connection state, but with fewer occurrences and shorter dwell time in a strong connection state. Importantly, the fractional time and mean dwell time of state 2 was negatively correlated with Hamilton Depression Rating Scale (HDRS) scores. ROC curve analysis demonstrated that these temporal properties have great identified power including the fractional time and mean dwell time in state 2, and the AUC is 0.872, 0.837, respectively. The AUC of the combination of fractional time and mean dwell time in state 2 with age, gender is 0.881. Our results indicated the temporal properties of dFNC are altered in first-episode, drug-naïve patients with MDD, and these changes' properties could serve as a potential biomarker in MDD.
Importance
Depression is associated with poor sleep quality. Understanding the neural connectivity that underlies both conditions and mediates the association between them is likely to lead to better-directed treatments for depression and associated sleep problems.
Objective
To identify the brain areas that mediate the association of depressive symptoms with poor sleep quality and advance understanding of the differences in brain connectivity in depression.
Design, Setting, and Participants
This study collected data from participants in the Human Connectome Project using the Adult Self-report of Depressive Problems portion of the Achenbach Adult Self-Report for Ages 18-59, a survey of self-reported sleep quality, and resting-state functional magnetic resonance imaging. Cross-validation of the sleep findings was conducted in 8718 participants from the UK Biobank.
Main Outcomes and Measures
Correlations between functional connectivity, scores on the Adult Self-Report of Depressive Problems, and sleep quality.
Results
A total of 1017 participants from the Human Connectome Project (of whom 546 [53.7%] were female; age range, 22 to 35 years) drawn from a general population in the United States were included. The Depressive Problems score was positively correlated with poor sleep quality (r = 0.371; P < .001). A total of 162 functional connectivity links involving areas associated with sleep, such as the precuneus, anterior cingulate cortex, and the lateral orbitofrontal cortex, were identified. Of these links, 39 were also associated with the Depressive Problems scores. The brain areas with increased functional connectivity associated with both sleep and Depressive Problems scores included the lateral orbitofrontal cortex, dorsolateral prefrontal cortex, anterior and posterior cingulate cortices, insula, parahippocampal gyrus, hippocampus, amygdala, temporal cortex, and precuneus. A mediation analysis showed that these functional connectivities underlie the association of the Depressive Problems score with poor sleep quality (β = 0.0139; P < .001).
Conclusions and Relevance
The implication of these findings is that the increased functional connectivity between these brain regions provides a neural basis for the association between depression and poor sleep quality. An important finding was that the Depressive Problems scores in this general population were correlated with functional connectivities between areas, including the lateral orbitofrontal cortex, cingulate cortex, precuneus, angular gyrus, and temporal cortex. The findings have implications for the treatment of depression and poor sleep quality.
To analyze the functioning of the posterior cingulate cortex (PCC) in depression, we performed the first fully voxel-level resting state functional-connectivity neuroimaging analysis of depression of the PCC, with 336 patients with major depressive disorder and 350 controls. Voxels in the PCC had significantly increased functional connectivity with the lateral orbitofrontal cortex, a region implicated in non-reward and which is thereby implicated in depression. In patients receiving medication, the functional connectivity between the lateral orbitofrontal cortex and PCC was decreased back towards that in the controls. In the 350 controls, it was shown that the PCC has high functional connectivity with the parahippocampal regions which are involved in memory. The findings support the theory that the non-reward system in the lateral orbitofrontal cortex has increased effects on memory systems, which contribute to the rumination about sad memories and events in depression. These new findings provide evidence that a key target to ameliorate depression is the lateral orbitofrontal cortex.
The orbital and medial prefrontal cortex (OMPFC) has been implicated in decision-making, reward and emotion processing, and psychopathology, such as depression and obsessive–compulsive disorder. Human and monkey anatomical studies indicate the presence of various cortical subdivisions and suggest that these are organized in two extended networks, a medial and an orbital one. Attempts have been made to replicate these neuroanatomical findings in vivo using MRI techniques for imaging connectivity. These revealed several consistencies, but also many inconsistencies between reported results. Here, we use fMRI resting-state functional connectivity (FC) and data-driven modularity optimization to parcellate the OMPFC to investigate replicability of in vivo parcellation more systematically. By collecting two resting-state data sets per participant, we were able to quantify the reliability of the observed modules and their boundaries. Results show that there was significantly more than chance overlap in modules and their boundaries at the level of individual data sets. Moreover, some of these consistent boundaries significantly co-localized across participants. Hierarchical clustering showed that the whole-brain FC profiles of the OMPFC subregions separate them in two networks, a medial and orbital one, which overlap with the organization proposed by Barbas and Pandya (J Comp Neurol 286:353–375, 1989) and Ongür and Price (Cereb Cortex 10:206–219, 2000). We conclude that in vivo resting-state FC can delineate reliable and neuroanatomically plausible subdivisions that agree with established cytoarchitectonic trends and connectivity patterns, while other subdivisions do not show the same consistency across data sets and studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s00429-017-1378-2) contains supplementary material, which is available to authorized users.
Background: Deep brain stimulation (DBS) is a neurosurgical intervention with demonstrated effectiveness for treatment resistant depression (TRD), but longitudinal studies on the stability of cognitive parameters following treatment are limited. The objectives of this study are to (i) identify baseline cognitive predictors of treatment response to subcallosal cingulate gyrus (SCG) DBS for unipolar TRD and (ii) compare neurocognitive performance prior to and 12 months after DBS implantation.
Methods: Twenty unipolar TRD patients received SCG DBS for 12 months. A standardized neuropsychological battery was used to assess a range of neurocognitive abilities at baseline and after 12 months. Severity of depression was evaluated using the 17 item Hamilton Rating Scale for Depression.
Results: Finger Tap-Dominant Hand Test and total number of errors made on the Wisconsin Card Sorting Test predicted classification of patients as treatment responders or non-responders, and were independent of improvement in mood. Change in verbal fluency was the only neuropsychological test that correlated with change in mood from baseline to the follow up period. None of the neuropsychological measures displayed deterioration in cognitive functioning from baseline to repeat testing at 12 months.
Limitations: This was an open label study with a small sample size which limits predictive analysis. Practice effects of the neuropsychological testing could explain the improvement from baseline to follow up on some tasks. Replication using a larger sample of subjects who received neuropsychological testing before and at least 12 months after DBS surgery is required.
Conclusion: These preliminary results (i) suggest that psychomotor speed may be a useful baseline predictor of response to SCG DBS treatment and (ii) support previous suggestions that SCG DBS has no deleterious effects on cognition.
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Cheng, Rolls et al. report the first whole-brain voxel-level functional connectivity study in depression. Medial orbitofrontal cortex reward areas show decreased functional connectivity with parahippocampal memory systems, while the lateral orbitofrontal cortex non-reward system displays increased functional connectivity with the precuneus, angular gyrus, and temporal visual cortex.
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Cheng, Rolls et al. report the first whole-brain voxel-level functional connectivity study in depression. Medial orbitofrontal cortex reward areas show decreased functional connectivity with parahippocampal memory systems, while the lateral orbitofrontal cortex non-reward system displays increased functional connectivity with the precuneus, angular gyrus, and temporal visual cortex.
Unlabelled:
The functional organization of human medial frontal cortex (MFC) is a subject of intense study. Using fMRI, the MFC has been associated with diverse psychological processes, including motor function, cognitive control, affect, and social cognition. However, there have been few large-scale efforts to comprehensively map specific psychological functions to subregions of medial frontal anatomy. Here we applied a meta-analytic data-driven approach to nearly 10,000 fMRI studies to identify putatively separable regions of MFC and determine which psychological states preferentially recruit their activation. We identified regions at several spatial scales on the basis of meta-analytic coactivation, revealing three broad functional zones along a rostrocaudal axis composed of 2-4 smaller subregions each. Multivariate classification analyses aimed at identifying the psychological functions most strongly predictive of activity in each region revealed a tripartite division within MFC, with each zone displaying a relatively distinct functional signature. The posterior zone was associated preferentially with motor function, the middle zone with cognitive control, pain, and affect, and the anterior with reward, social processing, and episodic memory. Within each zone, the more fine-grained subregions showed distinct, but subtler, variations in psychological function. These results provide hypotheses about the functional organization of medial prefrontal cortex that can be tested explicitly in future studies.
Significance statement:
Activation of medial frontal cortex in fMRI studies is associated with a wide range of psychological states ranging from cognitive control to pain. However, this high rate of activation makes it challenging to determine how these various processes are topologically organized across medial frontal anatomy. We conducted a meta-analysis across nearly 10,000 studies to comprehensively map psychological states to discrete subregions in medial frontal cortex using relatively unbiased data-driven methods. This approach revealed three distinct zones that differed substantially in function, each of which were further subdivided into 2-4 smaller subregions that showed additional functional variation. Each individual region was recruited by multiple psychological states, suggesting subregions of medial frontal cortex are functionally heterogeneous.
Unlabelled:
The laryngeal motor cortex (LMC) is essential for the production of learned vocal behaviors because bilateral damage to this area renders humans unable to speak but has no apparent effect on innate vocalizations such as human laughing and crying or monkey calls. Several hypotheses have been put forward attempting to explain the evolutionary changes from monkeys to humans that potentially led to enhanced LMC functionality for finer motor control of speech production. These views, however, remain limited to the position of the larynx area within the motor cortex, as well as its connections with the phonatory brainstem regions responsible for the direct control of laryngeal muscles. Using probabilistic diffusion tractography in healthy humans and rhesus monkeys, we show that, whereas the LMC structural network is largely comparable in both species, the LMC establishes nearly 7-fold stronger connectivity with the somatosensory and inferior parietal cortices in humans than in macaques. These findings suggest that important "hard-wired" components of the human LMC network controlling the laryngeal component of speech motor output evolved from an already existing, similar network in nonhuman primates. However, the evolution of enhanced LMC-parietal connections likely allowed for more complex synchrony of higher-order sensorimotor coordination, proprioceptive and tactile feedback, and modulation of learned voice for speech production.
Significance statement:
The role of the primary motor cortex in the formation of a comprehensive network controlling speech and language has been long underestimated and poorly studied. Here, we provide comparative and quantitative evidence for the significance of this region in the control of a highly learned and uniquely human behavior: speech production. From the viewpoint of structural network organization, we discuss potential evolutionary advances of enhanced temporoparietal cortical connections with the laryngeal motor cortex in humans compared with nonhuman primates that may have contributed to the development of finer vocal motor control necessary for speech production.
Major depression disease (MDD) is associated with the dysfunction of multinode brain networks. However, converging evidence implicates the reciprocal interaction between midline limbic regions (typified by the ventral anterior cingulate cortex, vACC) and the dorso-lateral prefrontal cortex (dlPFC), reflecting interactions between emotions and cognition. Furthermore, growing evidence suggests a role for abnormal glutamate metabolism in the vACC, while serotonergic treatments (selective serotonin reuptake inhibitor, SSRI) effective for many patients implicate the serotonin system. Currently, no mechanistic framework describes how network dynamics, glutamate, and serotonin interact to explain MDD symptoms and treatments. Here, we built a biophysical computational model of 2 areas (vACC and dlPFC) that can switch between emotional and cognitive processing. MDD networks were simulated by slowing glutamate decay in vACC and demonstrated sustained vACC activation. This hyperactivity was not suppressed by concurrent dlPFC activation and interfered with expected dlPFC responses to cognitive signals, mimicking cognitive dysfunction seen in MDD. Simulation of clinical treatments (SSRI or deep brain stimulation) counteracted this aberrant vACC activity. Theta and beta/gamma oscillations correlated with network function, representing markers of switch-like operation in the network. The model shows how glutamate dysregulation can cause aberrant brain dynamics, respond to treatments, and be reflected in EEG rhythms as biomarkers of MDD.
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.
The authors' goal was to compare regional brain volumes in depressed elderly subjects with those of nondepressed elderly subjects by using voxel-based morphometry.
They used statistical parametric mapping to analyze magnetic resonance imaging scans from 30 depressed patients 59 to 78 years old and 47 nondepressed comparison subjects 55 to 81 years old.
Depressed patients had smaller right hippocampal volume than comparison subjects. The volume of the hippocampal-entorhinal cortex was inversely associated with the number of years since the first lifetime episode of depression.
These data provide further evidence of structural brain abnormalities in geriatric depression, particularly in patients with a longer course of illness.
Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD.
Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC.
We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group.
Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.
Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.Molecular Psychiatry advance online publication, 18 June 2013; doi:10.1038/mp.2013.78.
Importance
Currently, fewer than 40% of patients treated for major depressive disorder achieve remission with initial treatment. Identification of a biological marker that might improve these odds could have significant health and economic impact.Objective
To identify a candidate neuroimaging “treatment-specific biomarker” that predicts differential outcome to either medication or psychotherapy.Design
Brain glucose metabolism was measured with positron emission tomography prior to treatment randomization to either escitalopram oxalate or cognitive behavior therapy for 12 weeks. Patients who did not remit on completion of their phase 1 treatment were offered enrollment in phase 2 comprising an additional 12 weeks of treatment with combination escitalopram and cognitive behavior therapy.Setting
Mood and anxiety disorders research program at an academic medical center.Participants
Men and women aged 18 to 60 years with currently untreated major depressive disorder.Intervention
Randomized assignment to 12 weeks of treatment with either escitalopram oxalate (10-20 mg/d) or 16 sessions of manual-based cognitive behavior therapy.Main Outcome and Measure
Remission, defined as a 17-item Hamilton Depression Rating Scale score of 7 or less at both weeks 10 and 12, as assessed by raters blinded to treatment.Results
Positive and negative predictors of remission were identified with a 2-way analysis of variance treatment (escitalopram or cognitive behavior therapy) × outcome (remission or nonresponse) interaction. Of 65 protocol completers, 38 patients with clear outcomes and usable positron emission tomography scans were included in the primary analysis: 12 remitters to cognitive behavior therapy, 11 remitters to escitalopram, 9 nonresponders to cognitive behavior therapy, and 6 nonresponders to escitalopram. Six limbic and cortical regions were identified, with the right anterior insula showing the most robust discriminant properties across groups (effect size = 1.43). Insula hypometabolism (relative to whole-brain mean) was associated with remission to cognitive behavior therapy and poor response to escitalopram, while insula hypermetabolism was associated with remission to escitalopram and poor response to cognitive behavior therapy.Conclusions and Relevance
If verified with prospective testing, the insula metabolism-based treatment-specific biomarker defined in this study provides the first objective marker, to our knowledge, to guide initial treatment selection for depression.Trial Registration
Registered at clinicaltrials.gov (NCT00367341)
Neurophysiological evidence for invariant representations of objects and faces in the primate inferior temporal visual cortex is described. Then a computational approach to how invariant representations are formed in the brain is described that builds on the neurophysiology. A feature hierarchy model in which invariant representations can be built by self-organizing learning based on the temporal and spatial statistics of the visual input produced by objects as they transform in the world is described. VisNet can use temporal continuity in an associative synaptic learning rule with a short-term memory trace, and/or it can use spatial continuity in continuous spatial transformation learning which does not require a temporal trace. The model of visual processing in the ventral cortical stream can build representations of objects that are invariant with respect to translation, view, size, and also lighting. The model has been extended to provide an account of invariant representations in the dorsal visual system of the global motion produced by objects such as looming, rotation, and object-based movement. The model has been extended to incorporate top-down feedback connections to model the control of attention by biased competition in, for example, spatial and object search tasks. The approach has also been extended to account for how the visual system can select single objects in complex visual scenes, and how multiple objects can be represented in a scene. The approach has also been extended to provide, with an additional layer, for the development of representations of spatial scenes of the type found in the hippocampus.
This review begins with a brief historical overview of attempts in the first half of the 20th century to discern brain systems that underlie emotion and emotional behavior. These early studies identified the amygdala, hippocampus, and other parts of what was termed the 'limbic' system as central parts of the emotional brain. Detailed connectional data on this system began to be obtained in the 1970s and 1980s, as more effective neuroanatomical techniques based on axonal transport became available. In the last 15 years these methods have been applied extensively to the limbic system and prefrontal cortex of monkeys, and much more specific circuits have been defined. In particular, a system has been described that links the medial prefrontal cortex and a few related cortical areas to the amygdala, the ventral striatum and pallidum, the medial thalamus, the hypothalamus, and the periaqueductal gray and other parts of the brainstem. A large body of human data from functional and structural imaging, as well as analysis of lesions and histological material indicates that this system is centrally involved in mood disorders.
Longitudinal neuroimaging investigations of antidepressant treatment offer the opportunity to identify potential baseline biomarkers associated with poor outcome.
To explore the neural correlates of nonresponse to cognitive behavioural therapy (CBT) or venlafaxine (VEN), we compared pretreatment (18)F-fluoro-2-deoxy-d-glucose positron emission tomography scans of participants with major depressive disorder responding to either 16 weeks of CBT (n = 7) or VEN treatment (n = 9) with treatment nonresponders (n = 8).
Nonresponders to CBT or VEN, in contrast to responders, exhibited pretreatment hypermetabolism at the interface of the pregenual and subgenual cingulate cortices.
Limitations of our study include the small sample sizes and the absence of both arterial sampling to determine absolute glucose metabolism and high-resolution structural magnetic resonance imaging coregistration for region-of-interest analyses.
Our current findings are consistent with those reported in previous studies of relative hyperactivity in the ventral anterior cingulate cortex in treatment-resistant populations.
In the past 15 years parts of the cingulate cortex have been activated in thousands of neuroimaging studies and it has become a primary site of interest in structural and functional analyses of many neurological and psychiatric diseases. There are now more then 20 times the number of annual publications that analyse this region than there were 30 years ago. There are many diseases that have an early and direct impact on the cingulate cortex, including, chronic pain and stress syndromes, depression, obsessive-compulsive and attention-deficit/hyperactivity disorders, and neurodegenerative diseases such as schizophrenia, mild cognitive impairment, dementia with Lewy bodies, and Alzheimer’s disease. This major new text brings together cutting-edge information on the human cingulate cortex and its diseases as written by the leading authorities, and synthesizes these with other approaches-including neurophysiology and neuroanatomy in experimental animals; mainly in monkeys. The book considers cingulate infrastructure in terms of its cytology, receptor binding and circuitry, including functions such as emotion and autonomic and skeletomotor regulation, pain processing and chronic stress syndromes, cognition, and visuospatial orientation. Cingulate Neurobiology and Disease is a major publication in neuroscience, one that will have a major influence on research for years to come.
In the past 15 years parts of the cingulate cortex have been activated in thousands of neuroimaging studies and it has become a primary site of interest in structural and functional analyses of many neurological and psychiatric diseases. There are now more then 20 times the number of annual publications that analyse this region than there were 30 years ago. There are many diseases that have an early and direct impact on the cingulate cortex, including, chronic pain and stress syndromes, depression, obsessive-compulsive and attention-deficit/hyperactivity disorders, and neurodegenerative diseases such as schizophrenia, mild cognitive impairment, dementia with Lewy bodies, and Alzheimer’s disease. This major new text brings together cutting-edge information on the human cingulate cortex and its diseases as written by the leading authorities, and synthesizes these with other approaches-including neurophysiology and neuroanatomy in experimental animals; mainly in monkeys. The book considers cingulate infrastructure in terms of its cytology, receptor binding and circuitry, including functions such as emotion and autonomic and skeletomotor regulation, pain processing and chronic stress syndromes, cognition, and visuospatial orientation. Cingulate Neurobiology and Disease is a major publication in neuroscience, one that will have a major influence on research for years to come.
The orbitofrontal cortex represents the reward or affective value of primary reinforcers including taste, touch, texture, and face expression. It learns to associate other stimuli with these to produce representations of the expected reward value for visual, auditory, and abstract stimuli including monetary reward value. The orbitofrontal cortex thus plays a key role in emotion, by representing the reward value of the goals for action. The learning process is stimulus-reinforcer association learning. Negative reward prediction error neurons are related to this affective learning. Activations in the orbitofrontal cortex correlate with the subjective emotional experience of affective stimuli, and damage to the orbitofrontal cortex impairs emotion-related learning, emotional behaviour, and subjective affective state. Top-down attention to affect modulates orbitofrontal cortex representations, and attention to intensity modulates representations in earlier cortical areas that represent the physical properties of stimuli. Top-down word-level cognitive inputs can bias affective representations in the orbitofrontal cortex, providing a mechanism for cognition to influence emotion. Whereas the orbitofrontal cortex provides a representation of reward or affective value on a continuous scale, areas beyond the orbitofrontal cortex such as the medial prefrontal cortex area 10 are involved in binary decision-making when a choice must be made. For this decision-making, the orbitofrontal cortex provides a representation of the value of each specific reward on the same scale, with no conversion to a common currency. Increased activity in a lateral orbitofrontal cortex non-reward area provides a new attractor-related approach to understanding and treating depression. Consistent with the theory, the lateral orbitofrontal cortex has increased functional connectivity in depression, and the medial orbitofrontal cortex, involved in reward, has decreased functional connectivity in depression.
To analyze the involvement of different brain regions in behavioral inhibition and impulsiveness, differences in activation were investigated in fMRI data from a response inhibition task, the stop-signal task, in 1709 participants. First, areas activated more in stop-success (SS) than stop-failure (SF) included the lateral orbitofrontal cortex (OFC) extending into the inferior frontal gyrus (ventrolateral prefrontal cortex, BA 47/12), and the dorsolateral prefrontal cortex (DLPFC). Second, the anterior cingulate and anterior insula (AI) were activated more on failure trials, specifically in SF versus SS. The interaction between brain region and SS versus SF activations was significant (P = 5.6 * 10(-8) ). The results provide new evidence from this "big data" investigation consistent with the hypotheses that the lateral OFC is involved in the stop-related processing that inhibits the action; that the DLPFC is involved in attentional processes that influence task performance; and that the AI and anterior cingulate are involved in emotional processes when failure occurs. The investigation thus emphasizes the role of the human lateral OFC BA 47/12 in changing behavior, and inhibiting behavior when necessary. A very similar area in BA47/12 is involved in changing behavior when an expected reward is not obtained, and has been shown to have high functional connectivity in depression. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.
Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography 'connectome blueprint' to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.Molecular Psychiatry advance online publication, 11 April 2017; doi:10.1038/mp.2017.59.
Objective:
The purpose of this article was to inform the first-line treatment choice between cognitive-behavioral therapy (CBT) or an antidepressant medication for treatment-naive adults with major depressive disorder by defining a neuroimaging biomarker that differentially identifies the outcomes of remission and treatment failure to these interventions.
Method:
Functional MRI resting-state functional connectivity analyses using a bilateral subcallosal cingulate cortex (SCC) seed was applied to 122 patients from the Prediction of Remission to Individual and Combined Treatments (PReDICT) study who completed 12 weeks of randomized treatment with CBT or antidepressant medication. Of the 122 participants, 58 achieved remission (Hamilton Depression Rating Scale [HAM-D] score ≤7 at weeks 10 and 12), and 24 had treatment failure (<30% decrease from baseline in HAM-D score). A 2×2 analysis of variance using voxel-wise subsampling permutation tests compared the interaction of treatment and outcome. Receiver operating characteristic curves constructed using brain connectivity measures were used to determine possible classification rates for differential treatment outcomes.
Results:
The resting-state functional connectivity of the following three regions with the SCC was differentially associated with outcomes of remission and treatment failure to CBT and antidepressant medication and survived application of the subsample permutation tests: the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and the left ventromedial prefrontal cortex. Using the summed SCC functional connectivity scores for these three regions, overall classification rates of 72%-78% for remission and 75%-89% for treatment failure was demonstrated. Positive summed functional connectivity was associated with remission with CBT and treatment failure with medication, whereas negative summed functional connectivity scores were associated with remission to medication and treatment failure with CBT.
Conclusions:
Imaging-based depression subtypes defined using resting-state functional connectivity differentially identified an individual's probability of remission or treatment failure with first-line treatment options for major depression. This biomarker should be explored in future research through prospective testing and as a component of multivariate treatment prediction models.
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.
Despite the common conception of the dorsal premotor cortex (PMd) as a single brain region, its diverse connectivity profiles and behavioral heterogeneity argue for a differentiated organization of the PMd. A previous study revealed that the right PMd is characterized by a rostro-caudal and a ventro-dorsal distinction dividing it into five subregions: rostral, central, caudal, ventral and dorsal. The present study assessed whether a similar organization is present in the left hemisphere, by capitalizing on a multimodal data-driven approach combining connectivity-based parcellation (CBP) based on meta-analytic modeling, resting-state functional connectivity, and probabilistic diffusion tractography. The resulting PMd modules were then characterized based on multimodal functional connectivity and a quantitative analysis of associated behavioral functions. Analyzing the clusters consistent across all modalities revealed an organization of the left PMd that mirrored its right counterpart to a large degree. Again, caudal, central and rostral modules reflected a cognitive-motor gradient and a premotor eye-field was found in the ventral part of the left PMd. In addition, a distinct module linked to abstract cognitive functions was observed in the rostro-ventral left PMd across all CBP modalities, implying greater differentiation of higher cognitive functions for the left than the right PMd.