Connectivity Of Cingulate Cortex Research Articles

Polygenic risk for depression and resting-state functional connectivity of subgenual anterior cingulate cortex in young adults.

Genetic variants may confer risk for depression by modulating brain structure and function; evidence has underscored the key role of the subgenual anterior cingulate cortex (sgACC) in depression. We sought to examine how the resting-state functional connectivity (rsFC) of the sgACC was associated with polygenic risk for depression in a subclinical population. Following published protocols, we computed seed-based whole-brain sgACC rsFC and calculated polygenic risk scores (PRS) using data from healthy young adults from the Human Connectome Project. We performed whole-brain regression against PRS and severity of depression symptoms in a single model for all participants and by sex, controlling for age, sex, race or ethnicity, alcohol use severity, and household income. We evaluated the results at a corrected threshold. We included data for 717 healthy young adults. We found lower rsFC between the sgACC and the default mode network and frontal regions in association with PRS and lower sgACC-cerebellar rsFC in association with depression severity. We also noted differences by sex in the connectivity correlates of PRS and depression severity. In an additional set of analyses, we observed a significant correlation between PRS and somatic complaints, as well as altered sgACC-somatosensory cortical connectivity in association with the severity of somatic complaints. The current findings should be considered specific to subclinical depression and may not generalize to patients with depressive disorders. Our findings highlight the pivotal role of distinct sgACC-based networks in the genetic predisposition for depression and the manifestation of depression among young adults with subclinical depression. Distinguishing the risk from severity markers of depression may have implications in developing early and effective treatments for people at risk for depression.

Sex-related differences in amyotrophic lateral sclerosis: A 2-[18F]FDG-PET study.

We investigated sex-related brain metabolic differences in Amyotrophic Lateral Sclerosis (ALS) and healthy controls (HC). We collected two equal-sized groups of male (m-ALS) and female ALS (f-ALS) patients (n = 130 each), who underwent 2-[18F]FDG-PET at diagnosis, matched for site of onset, cognitive status and King's stage. We included 168 age-matched healthy controls, half female (f-HC) and half male (m-HC). We compared brain metabolism of males and females separately for ALS and HC, including age as covariate. A differential network analysis was performed to evaluate brain connectivity. M-ALS showed relative hypometabolism of bilateral medial frontal, parietal and occipital cortices, and left temporal cortex, compared to f-ALS. In node-wise comparison, f-ALS showed significantly higher connectivity in right middle cingulate cortex and left superior and medial frontal gyrus. In HC we did not find any sex-related differences. Sex resulted a major determinant of brain metabolism and connectivity in ALS patients.

Effects of total sleep deprivation on functional connectivity of the anterior cingulate cortex: Insights from resting-state fMRI in healthy adult males

Inadequate sleep significantly impacts an individual's health by compromising inhibitory control and self-regulation abilities. This study employed resting-state functional magnetic resonance imaging (fMRI) to assess the functional connectivity between the anterior cingulate cortex (ACC) and the whole brain in 16 healthy adult males after 36 h of total sleep deprivation. Additionally, this study investigated alterations in individuals' inhibitory control functions and physiological mechanisms following sleep deprivation. The results showed a significant increase in functional connectivity between the ACC, the left angular gyrus, and the right hippocampus following 36 h of continuous sleep deprivation. Conversely, functional connectivity was notably decreased between the ACC and the right insular cortex, right paracingulate gyrus, and bilateral putamen. Furthermore, changes in ACC functional connectivity were significantly correlated with alterations in behavioral performance in the go/no-go task after sleep deprivation. This study contributes to understanding brain network mechanisms in the anterior cingulate gyrus after sleep deprivation. It clarifies the relationship between functional connectivity changes in the anterior cingulate gyrus and inhibitory control post-sleep deprivation.

Structural and functional correlates of olfactory reward processing in behavioral variant frontotemporal dementia

The behavioral variant of frontotemporal dementia (bvFTD) includes symptoms that reflect altered pursuit of rewards, including food, alcohol, and money. Little is known, however, about how these reward changes relate to atrophy and functional connectivity within reward-related regions. The goal of this study was to examine the structural and functional correlates of valence perception for olfactory rewards in 24 patients with bvFTD. Regression analysis of resting-state brain functional connectivity indicated that more positive valence ratings of olfactory stimuli were predicted by ventral pallidum connectivity to other reward circuit regions, particularly functional connectivity between ventral pallidum and bilateral anterior cingulate cortex/ventromedial prefrontal cortex. Structural analysis showed that atrophy of the anterior cingulate cortex was also significantly associated with perceiving stimuli as more rewarding. Finally, there was a significant interaction between ventral pallidum connectivity and atrophy of the anterior cingulate cortex. More specifically, the ventral pallidum connectivity had a greater effect on the positive perception of olfactory stimuli in the setting of low anterior cingulate cortex volume. These findings indicate that atrophy and functional connectivity within reward-relevant regions exert independent and interacting effects on the perception of pleasantness in bvFTD, potentially due to changes in hedonic “liking” signals.

Neuroimaging studies of resting-state functional magnetic resonance imaging in eating disorders

Eating disorders (EDs), including anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and pica, are psychobehavioral conditions characterized by abnormal eating behaviors and an excessive preoccupation with weight and body shape. This review examines changes in brain regions and functional connectivity in ED patients over the past decade (2013–2023) using resting-state functional magnetic resonance imaging (rs-fMRI). Key findings highlight alterations in brain networks such as the default mode network (DMN), central executive network (CEN), and emotion regulation network (ERN). In individuals with AN, there is reduced functional connectivity in areas associated with facial information processing and social cognition, alongside increased connectivity in regions linked to sensory stimulation, aesthetic judgment, and social anxiety. Conversely, BED patients show diminished connectivity in the dorsal anterior cingulate cortex within the salience network and increased connectivity in the posterior cingulate cortex and medial prefrontal cortex within the DMN. These findings suggest that rs-fMRI could serve as a valuable biomarker for assessing brain function and predicting treatment outcomes in EDs, paving the way for personalized therapeutic strategies.

Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

Inhibitory gamma-aminobutyric acidergic neurons in the anterior cingulate cortex participate in the comorbidity of pain and emotion.

Pain is often comorbid with emotional disorders such as anxiety and depression. Hyperexcitability of the anterior cingulate cortex has been implicated in pain and pain-related negative emotions that arise from impairments in inhibitory gamma-aminobutyric acid neurotransmission. This review primarily aims to outline the main circuitry (including the input and output connectivity) of the anterior cingulate cortex and classification and functions of different gamma-aminobutyric acidergic neurons; it also describes the neurotransmitters/neuromodulators affecting these neurons, their intercommunication with other neurons, and their importance in mental comorbidities associated with chronic pain disorders. Improving understanding on their role in pain-related mental comorbidities may facilitate the development of more effective treatments for these conditions. However, the mechanisms that regulate gamma-aminobutyric acidergic systems remain elusive. It is also unclear as to whether the mechanisms are presynaptic or postsynaptic. Further exploration of the complexities of this system may reveal new pathways for research and drug development.

Abnormal resting-state functional connectivity of the right anterior cingulate cortex in chronic ketamine users and its correlation with cognitive impairments

BackgroundChronic ketamine use leads to cognitive impairments, however, the neural mechanisms underpinning these impairments are still unclear. AimsMany studies showed Anterior cingulate cortex (ACC)is strongly involved in cognition and drug addiction, as supported by our previous studies. The objective of this study was to assess the variations in resting-state functional connectivity (FC) changes in the right anterior cingulate cortex (ACC) of chronic ketamine users (CKUs) and their relationship with cognitive performance. MethodsThe study enrolled 28 chronic ketamine users (CKUs) and 30 healthy controls (HCs). Resting-state functional magnetic resonance imaging (fMRI) data were gathered from both groups. Cognitive functions were evaluated using the MATRICS Consensus Cognitive Battery (MCCB). ResultsCKUs demonstrated significantly poorer cognitive performance than HCs in various cognitive domains, including Visual Learning, Speed of Processing, Working Memory, and the composite score of MCCB. Group-level comparisons revealed that CKUs exhibited enhanced functional connectivity between the right ACC and the right postcentral gyrus (PCG) compared to HCs. There was a positive relationship between the connectivity of right ACC-PCG and reasoning and problem-solving score, but there was no significant association with the characteristics of ketamine use. ConclusionCKUs showed enhanced connectivity between the right ACC and the right PCG. This enhanced functional connectivity may indicate functional compensation for cognitive deficits in CKUs, especially for reasoning and problem-solving impairments in CKUs.

Local functional connectivity abnormalities in mild cognitive impairment and Alzheimer's disease: A meta-analytic investigation using minimum Bayes factor activation likelihood estimation

Functional magnetic resonance imaging research employing regional homogeneity (ReHo) analysis has uncovered aberrant local brain connectivity in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in comparison with healthy controls. However, the precise localization, extent, and possible overlap of these aberrations are still not fully understood. To bridge this gap, we applied a novel meta-analytic and Bayesian method (minimum Bayes Factor Activation Likelihood Estimation, mBF-ALE) for a systematic exploration of local functional connectivity alterations in MCI and AD brains. We extracted ReHo data via a standardized MEDLINE database search, which included 35 peer-reviewed experiments, 1,256 individuals with AD or MCI, 1,118 healthy controls, and 205 x-y-z coordinates of ReHo variation. We then separated the data into two distinct datasets: one for MCI and the other for AD. Two mBF-ALE analyses were conducted, thresholded at “very strong evidence” (mBF ≥ 150), with a minimum cluster size of 200 mm³. We also assessed the spatial consistency and sensitivity of our Bayesian results using the canonical version of the ALE algorithm. For MCI, we observed two clusters of ReHo decrease and one of ReHo increase. Decreased local connectivity was notable in the left precuneus (Brodmann area – BA 7) and left inferior temporal gyrus (BA 20), while increased connectivity was evident in the right parahippocampal gyrus (BA 36). The canonical ALE confirmed these locations, except for the inferior temporal gyrus. In AD, one cluster each of ReHo decrease and increase were found, with decreased connectivity in the right posterior cingulate cortex (BA 30 extending to BA 23) and increased connectivity in the left posterior cingulate cortex (BA 31). These locations were confirmed by the canonical ALE. The identification of these distinct functional connectivity patterns sheds new light on the complex pathophysiology of MCI and AD, offering promising directions for future neuroimaging-based interventions. Additionally, the use of a Bayesian framework for statistical thresholding enhances the robustness of neuroimaging meta-analyses, broadening its applicability to small datasets.

Cognitive and Salience Network Connectivity Changes following a Single Season of Repetitive Head Impact Exposure in High School Football.

During a season of high school football, adolescents with actively developing brains experience a considerable number of head impacts. Our aim was to determine whether repetitive head impacts in the absence of a clinically diagnosed concussion during a season of high school football produce changes in cognitive performance or functional connectivity of the salience network and its central hub, the dorsal anterior cingulate cortex. Football players were instrumented with the Head Impact Telemetry System during all practices and games, and the helmet sensor data were used to compute a risk-weighted exposure metric (RWEcp), accounting for the cumulative risk during the season. Participants underwent MRI and a cognitive battery (ImPACT) before and shortly after the football season. A control group of noncontact/limited-contact-sport athletes was formed from 2 cohorts: one from the same school and protocol and another from a separate, nearly identical study. Sixty-three football players and 34 control athletes were included in the cognitive performance analysis. Preseason, the control group scored significantly higher on the ImPACT Visual Motor (P = .04) and Reaction Time composites (P = .006). These differences increased postseason (P = .003, P < .001, respectively). Additionally, the control group had significantly higher postseason scores on the Visual Memory composite (P = .001). Compared with controls, football players showed significantly less improvement in the Verbal (P = .04) and Visual Memory composites (P = .01). A significantly greater percentage of contact athletes had lower-than-expected scores on the Verbal Memory (27% versus 6%), Visual Motor (21% versus 3%), and Reaction Time composites (24% versus 6%). Among football players, a higher RWEcp was significantly associated with greater increments in ImPACT Reaction Time (P = .03) and Total Symptom Scores postseason (P = .006). Fifty-seven football players and 13 control athletes were included in the imaging analyses. Postseason, football players showed significant decreases in interhemispheric connectivity of the dorsal anterior cingulate cortex (P = .026) and within-network connectivity of the salience network (P = .018). These decreases in dorsal anterior cingulate cortex interhemispheric connectivity and within-network connectivity of the salience network were significantly correlated with deteriorating ImPACT Total Symptom (P = .03) and Verbal Memory scores (P = .04). Head impact exposure during a single season of high school football is negatively associated with cognitive performance and brain network connectivity. Future studies should further characterize these short-term effects and examine their relationship with long-term sequelae.

Low arousal threshold is associated with altered functional connectivity of the ascending reticular activating system in patients with obstructive sleep apnea

A low arousal threshold (LAT) is a pathophysiological trait of obstructive sleep apnea (OSA) that may be associated with brainstem ascending reticular activating system-cortical functional connectivity changes. We evaluated resting-state connectivity between the brainstem nuclei and 105 cortical/subcortical regions in OSA patients with or without a LAT and healthy controls. Twenty-five patients with moderate to severe OSA with an apnea–hypopnea index between 20 and 40/hr (15 with and 10 without a LAT) and 15 age- and sex-matched controls were evaluated. Participants underwent functional magnetic resonance imaging after overnight polysomnography. Three brainstem nuclei—the locus coeruleus (LC), laterodorsal tegmental nucleus (LDTg), and ventral tegmental area (VTA)—associated with OSA in our previous study were used as seeds. Functional connectivity values of the two brainstem nuclei (LC and LDTg) significantly differed among the three groups. The connectivity of the LC with the precuneus was stronger in OSA patients than in controls regardless of the concomitant LAT. The connectivity between the LDTg and the posterior cingulate cortex was also stronger in OSA patients regardless of the LAT. Moreover, OSA patients without a LAT showed stronger LDTg-posterior cingulate cortex connectivity than those with a LAT (post hoc p = 0.013), and this connectivity strength was negatively correlated with the minimum oxygen saturation in OSA patients (r = − 0.463, p = 0.023). The LAT in OSA patients was associated with altered LDTg-posterior cingulate cortex connectivity. This result may suggested that cholinergic activity may play a role in the LAT in OSA patients.

Functional connectivity of the posterior cingulate cortex in autism spectrum disorder

The purpose of this study was to assess the functional connectivity of the posterior cingulate cortex in autism spectrum disorder (ASD). We used resting-state functional magnetic resonance imaging (rsfMRI) brain scans of adolescents diagnosed with ASD and a neurotypical control group. The Autism Brain Imaging Data Exchange (ABIDE) consortium was utilized to acquire data from the University of Michigan (145 subjects) and data from the New York University (183 subjects). The posterior cingulate cortex showed reduced connectivity with the anterior cingulate cortex for the ASD group compared to the control group. These two brain regions have previously both been linked to ASD symptomology. Specifically, the posterior cingulate cortex has been associated with behavioral control and executive functions, which appear to be responsible for the repetitive and restricted behaviors (RRB) in ASD. Our findings support previous data indicating a neurobiological basis of the disorder, and the specific functional connectivity changes involving the posterior cingulate cortex and anterior cingulate cortex may be a potential neurobiological biomarker for the observed RRBs in ASD.

Socioeconomic factors, sleep timing and duration, and amygdala resting-state functional connectivity in children.

Reduced sleep health has been consistently linked with increased negative emotion in children. While sleep characteristics have been associated with neural function in adults and adolescents, much less is known about these associations in children while considering socioeconomic context. In this study, we examined the associations among socioeconomic factors, sleep duration and timing, and resting-state functional connectivity (rsFC) of the amygdala in children. Participants were typically-developing 5- to 9-year-olds from socioeconomically diverse families (61% female; N = 94). Parents reported on children's weekday and weekend bedtimes and wake-up times, which were used to compute sleep duration and midpoint. Analyses focused on amygdala-anterior cingulate cortex (ACC) connectivity followed by amygdala-whole brain connectivity. Lower family income-to-needs ratio and parental education were significantly associated with later weekday and weekend sleep timing and shorter weekday sleep duration. Shorter weekday sleep duration was associated with decreased amygdala-ACC and amygdala-insula connectivity. Later weekend sleep midpoint was associated with decreased amygdala-paracingulate cortex and amygdala-postcentral gyrus connectivity. Socioeconomic factors were indirectly associated with connectivity in these circuits via sleep duration and timing. These results suggest that socioeconomic disadvantage may interfere with both sleep duration and timing, in turn possibly altering amygdala connectivity in emotion processing and regulation circuits in children. Effective strategies supporting family economic conditions may have benefits for sleep health and brain development in children.

Interleukin-1β moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1β. Moreover, IL-1β moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1β may moderate the relationship between MFG-related connectivity and depressive symptoms.

Functional connectivity-hemodynamic (un)coupling changes in chronic mild brain injury are associated with mental health and neurocognitive indices: a resting state fMRI study.

To examine hemodynamic and functional connectivity alterations and their association with neurocognitive and mental health indices in patients with chronic mild traumatic brain injury (mTBI). Resting-state functional MRI (rs-fMRI) and neuropsychological assessment of 37 patients with chronic mTBI were performed. Intrinsic connectivity contrast (ICC) and time-shift analysis (TSA) of the rs-fMRI data allowed the assessment of regional hemodynamic and functional connectivity disturbances and their coupling (or uncoupling). Thirty-nine healthy age- and gender-matched participants were also examined. Patients with chronic mTBI displayed hypoconnectivity in bilateral hippocampi and parahippocampal gyri and increased connectivity in parietal areas (right angular gyrus and left superior parietal lobule (SPL)). Slower perfusion (hemodynamic lag) in the left anterior hippocampus was associated with higher self-reported symptoms of depression (r = - 0.53, p = .0006) and anxiety (r = - 0.484, p = .002), while faster perfusion (hemodynamic lead) in the left SPL was associated with lower semantic fluency (r = - 0.474, p = .002). Finally, functional coupling (high connectivity and hemodynamic lead) in the right anterior cingulate cortex (ACC)) was associated with lower performance on attention and visuomotor coordination (r = - 0.50, p = .001), while dysfunctional coupling (low connectivity and hemodynamic lag) in the left ventral posterior cingulate cortex (PCC) and right SPL was associated with lower scores on immediate passage memory (r = - 0.52, p = .001; r = - 0.53, p = .0006, respectively). Uncoupling in the right extrastriate visual cortex and posterior middle temporal gyrus was negatively associated with cognitive flexibility (r = - 0.50, p = .001). Hemodynamic and functional connectivity differences, indicating neurovascular (un)coupling, may be linked to mental health and neurocognitive indices in patients with chronic mTBI.

Targeting suicidal ideation in major depressive disorder with MRI-navigated Stanford accelerated intelligent neuromodulation therapy

High suicide risk represents a serious problem in patients with major depressive disorder (MDD), yet treatment options that could safely and rapidly ameliorate suicidal ideation remain elusive. Here, we tested the feasibility and preliminary efficacy of the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) in reducing suicidal ideation in patients with MDD. Thirty-two MDD patients with moderate to severe suicidal ideation participated in the current study. Suicidal ideation and depression symptoms were assessed before and after 5 days of open-label SAINT. The neural pathways supporting rapid-acting antidepressant and suicide prevention effects were identified with dynamic causal modelling based on resting-state functional magnetic resonance imaging. We found that 5 days of SAINT effectively alleviated suicidal ideation in patients with MDD with a high response rate of 65.63%. Moreover, the response rates achieved 78.13% and 90.63% with 2 weeks and 4 weeks after SAINT, respectively. In addition, we found that the suicide prevention effects of SAINT were associated with the effective connectivity involving the insula and hippocampus, while the antidepressant effects were related to connections of the subgenual anterior cingulate cortex (sgACC). These results show that SAINT is a rapid-acting and effective way to reduce suicidal ideation. Our findings further suggest that distinct neural mechanisms may contribute to the rapid-acting effects on the relief of suicidal ideation and depression, respectively.

Brain morphofunctional changes associated with pain in children, adolescents and young adults with sickle cell disease

INTRODUCTION: Neuroimaging has been widely used to investigate the brain signature in patients with pain, but the results are heterogeneous, especially when the brain is under development, and in specific health conditions. Sickle cell disease (SCD) is often associated with chronic pain that starts in infancy, and there is a need to understand the brain of such children. OBJECTIVES: This systematic review aims to summarize the findings in the literature on brain morphofunctional changes in children, adolescents, young adults, and young adults with SCD. METHODS: Data search was performed in PubMed, LILACS, and SciELO, and results were organized to identify brain regions that showed significant structural and functional changes assessed through structural or functional MRI, or electroencephalography. RESULTS: The synthesis of five studies showed that children with SCD present decreased cerebral cortex thickness, and increased functional connectivity, mainly concentrated in the precuneus and anterior cingulate cortex, regions that make up the default mode network (DMN), and/or the pro-nociceptive network. DISCUSSION: These alterations were related to the frequency of pain and hospitalizations, and the increased connectivity in structures of the antinociceptive network is associated with a decrease in the frequency of pain crises and their consequences. CONCLUSION: Children, adolescents and young adults with SCD have decreased thickness and connectivity in the anterior cingulate cortex and precuneus.

FC33: Hilarious Gas for treatment resistant depression in older adults: is it really serious?

Nitrous oxide (N2O – also known as Hilarious Gas) has recently emerged has a potential fast-acting antidepressant, based on a number of randomized controlled trials (RCT) in young adults with treatment resistant depression (TRD). The antidepressant mechanisms of N2O are not fully understood but may include an antagonist action on NDMA receptors, similar to ketamine. N2O shows additional cerebral effects that may be particularly appropriate for TRD in older adults, including a significant cerebral vasodilatation that facilitates blood brain barrier opening and potentially limits resistance related to poor cerebrovascular functioning. Moreover, N2O may prove to be particularly well-tolerated in this potentially fragile population, notably because it is not metabolized by the kidney or liver which organs may be impaired with aging.In this talk, we will be reviewing the available data on the efficacy, safety and pathophysiology of N2O, with a specific focus on older adults. We will also present results from our group showing a significant reduction in cerebral connectivity in the anterior cingulate cortex (ACC - as measured with pre and post treatment resting state MRI) and large increase in brain tissue pulsations (as measured with Ultrasound) with a successful treatment with N2O compounds. Finally, perspectives on current studies in older adults from our group (one RCT in non-demented older adults with TRD and one RCT in neurocognitive disorders) will be discussed.Figure 1Changes in ACC connectivity after exposure to N2O compoundsFigure 1Changes Brain Tissue Pulsations as assessed with brain ultrasound during N2O exposure

Resting-State Functional Connectivity of the Anterior Cingulate Cortex Among Persons With Mood Disorders and Suicidal Behaviors.

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. 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. 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. 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.

Taking it to the extreme: The search for determinants of cognitive vulnerability and resilience in children with autosomal dominant Alzheimer’s disease

Abstract:Presenilin-1 (PSEN1) mutations predispose individuals to develop autosomal-dominant Alzheimer's disease (ADAD) in middle adulthood. While the pathogenesis of ADAD may be different from late-onset sporadic AD (e.g., differences in disease etiology, age of disease onset, etc), these conditions share many characteristics, including similar abnormalities in amyloid and tau biomarkers, brain structure and brain activity, and clinical features (Quiroz et al., 2010, Quiroz et al., 2011, Quiroz et al. 2018). Biomarker investigations of families with ADAD have already shed light on the trajectory of some AD-related brain changes, especially prior to the onset of clinical symptoms.We have been studying a Colombian kindred with a genetic form of AD caused by a single genetic mutation in the PSEN1 (E280A), which serves as a unique model for preclinical AD. Because of a well-defined age at clinical onset, and near 100% penetrance, this kindred provides important information about the time course and relationships between physiological mechanisms and cognitive changes, and in so doing, it has yielded new insights about presymptomatic AD that will enhance future prevention trials for AD, including primary prevention trials.The well-characterized clinical trajectory of these PSEN1 E280A mutation carriers allow us to examine brain function in children, more than three decades before the average age of onset of mild cognitive impairment (MCI) and dementia in this cohort (45 years for MCI, 50 years for dementia). This is giving us the unique opportunity to characterize the cognitive and behavioral profiles of children genetically determined to develop dementia in their forties, and is helping us improve our understanding of the impact of ADAD mutations in early life cognitive and brain functioning, as well as its potential impact on learning, academic performance and educational attainment. We previously studied 20 PSEN1 E280A carriers and 20 non-carriers aged 9 to 17 years from the Colombian ADAD cohort and showed that mutation-carrying children were distinguished from non-carriers by plasma biomarker findings consistent with Aß1-42 overproduction, as well as by increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (Quiroz et al 2015). More recently, we used the WISC-IV, a measure of general intellectual abilities to examine cognitive abilities in these children. We reported in 265 children with the E280A mutation and 1089 non-carriers that they did not differ on any of the WISC-IV indices. Surprisingly, male carriers performed slightly worse than female carriers on working memory (mean difference = -4.97; P = .001) (Fox-Fuller et al., 2021). Some of our ongoing work includes comprehensive examinations of social, educational and developmental histories along with functional brain networks, as markers of synaptic dysfunction in individuals with ADAD, as this is particularly relevant to understanding the impact of PSEN1 mutations on the developing brain and subsequent neurodegenerative changes seen later in life, without the confounds of aging and age-related comorbidities that often exist in late-onset sporadic AD.Disclosures: Financial: Dr. Quiroz receives a consulting fee from Biogen. Non-Financial: Dr. Quiroz is a Hispanic Neuropsychological Society Member-At-Large and serves as the INS Teleneuropsychology Special Interest Group Chair