Sex-Specific Abnormalities and Treatment-Related Plasticity of Subgenual Anterior Cingulate Cortex Functional Connectivity in Chronic Pain

The subgenual anterior cingulate cortex (sgACC) is a key node of the descending antinociceptive system with sex differences in its functional connectivity (FC). We previously reported that, in a male-prevalent chronic pain condition, sgACC FC is abnormal in women but not in men. This raises the possibility that, within a sex, sgACC FC may be either protective or represent a vulnerability to develop a sex-dominant chronic pain condition. The aim of this study was to characterize sgACC FC in a female-dominant chronic pain condition, carpal tunnel syndrome (CTS), to investigate whether sgACC abnormalities are a common feature in women with chronic pain or unique to individuals with pain conditions that are more prevalent in the opposite sex. We used fMRI to determine the resting state FC of the sgACC in healthy controls (HCs, n = 25, 18 women; 7 men) and people with CTS before (n = 25, 18 women; 7 men) and after (n = 17, 13 women; 4 men) successful surgical treatment. We found reduced sgACC FC with the medial pre-frontal cortex (mPFC) and temporal lobe in CTS compared with HCs. The group-level sgACC-mPFC FC abnormality was driven by men with CTS, while women with CTS did not have sgACC FC abnormalities compared with healthy women. We also found that age and sex influenced sgACC FC in both CTS and HCs, with women showing greater FC with bilateral frontal poles and men showing greater FC with the parietal operculum. After surgery, there was reduced sgACC FC with the orbitofrontal cortex, striatum, and premotor areas and increased FC with the posterior insula and precuneus compared with pre-op scans. Abnormally reduced sgACC-mPFC FC in men but not women with a female-prevalent chronic pain condition suggests pain-related sgACC abnormalities may not be specific to women but rather to individuals who develop chronic pain conditions that are more dominant in the opposite sex. Our data suggest the sgACC plays a role in chronic pain in a sex-specific manner, and its communication with other regions of the dynamic pain connectome undergoes plasticity following pain-relieving treatment, supporting it as a potential therapeutic target for neuromodulation in chronic pain.

Oxytocin modulates neurocomputational mechanisms underlying prosocial reinforcement learning

Humans often act in the best interests of others. However, how we learn which actions result in good outcomes for other people and the neurochemical systems that support this "prosocial learning" remain poorly understood. Using computational models of reinforcement learning, functional magnetic resonance imaging and dynamic causal modelling, we examined how different doses of intranasal oxytocin, a neuropeptide linked to social cognition, impact how people learn to benefit others (prosocial learning) and whether this influence could be dissociated from how we learn to benefit ourselves (self-oriented learning). We show that a low dose of oxytocin prevented decreases in prosocial performance over time, despite no impact on self-oriented learning. Critically, oxytocin produced dose-dependent changes in the encoding of prediction errors (PE) in the midbrain-subgenual anterior cingulate cortex (sgACC) pathway specifically during prosocial learning. Our findings reveal a new role of oxytocin in prosocial learning by modulating computations of PEs in the midbrain-sgACC pathway.

Testing a Developmental Model of Parental Warmth, Amygdala–Subgenual Anterior Cingulate Cortex Connectivity, and Depressive Symptoms in Adolescents During the COVID-19 Pandemic

Background: Neurobiological measures may serve as predictive markers of risk for and resilience to depressive symptoms during the COVID-19 pandemic. We tested a developmental model linking variation in amygdala–subgenual anterior cingulate cortex (sgACC) resting-state connectivity both to earlier experiences in the family environment and to subsequent vulnerability to depressive symptoms during the pandemic.Methods: We used data from a longitudinal study that included three waves (N=214 adolescents; ages 9-15 years at Time 1 (T1), 11-17 years at Time 2 (T2), and 12-19 years during the pandemic at Time 3 [T3]). We assessed parental warmth (T1), depressive symptoms (T1 to T3), and functional connectivity between the sgACC and basolateral (BLA) and centromedial amygdala (CMA) (T1 and T2). We modeled associations among early parental warmth, amygdala–sgACC connectivity, and depressive symptoms before and during the pandemic.Results: Less parental warmth was associated prospectively with stronger BLA–sgACC connectivity approximately two years later (=-.23, p=.021) over and above the effect of BLA–sgACC connectivity at T1. Stronger BLA–sgACC connectivity, in turn, was associated with heightened depressive symptoms, both before (r=.21, p=.031) and during the pandemic (=.22, p=.031; independent of the effect of pre-pandemic symptoms). Conclusion: Adolescents who experience less parental warmth may develop a pattern of BLA–sgACC connectivity that increases their risk for mental health problems during the pandemic. BLA–sgACC connectivity in early to middle adolescence may be a predictive marker of risk for depressive symptoms in general and specifically during periods of heightened stress.

Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals cross-diagnostic and diagnosis-specific RNA expression changes in major psychiatric disorders

Despite strong evidence of heritability and growing discovery of genetic markers for major mental illness, little is known about how gene expression in the brain differs across psychiatric diagnoses, or how known genetic risk factors shape these differences. Here we investigate expressed genes and gene transcripts in postmortem subgenual anterior cingulate cortex (sgACC), a key component of limbic circuits linked to mental illness. RNA obtained postmortem from 200 donors diagnosed with bipolar disorder, schizophrenia, major depression, or no psychiatric disorder was deeply sequenced to quantify expression of over 85,000 gene transcripts, many of which were rare. Case–control comparisons detected modest expression differences that were correlated across disorders. Case–case comparisons revealed greater expression differences, with some transcripts showing opposing patterns of expression between diagnostic groups, relative to controls. The ~250 rare transcripts that were differentially-expressed in one or more disorder groups were enriched for genes involved in synapse formation, cell junctions, and heterotrimeric G-protein complexes. Common genetic variants were associated with transcript expression (eQTL) or relative abundance of alternatively spliced transcripts (sQTL). Common genetic variants previously associated with disease risk were especially enriched for sQTLs, which together accounted for disproportionate fractions of diagnosis-specific heritability. Genetic risk factors that shape the brain transcriptome may contribute to diagnostic differences between broad classes of mental illness.

Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.

Alterations in the Excitatory and Inhibitory Coupling in Migraine: A Magnetic Resonance Study

Background: There is evidence suggesting that an imbalance between the levels of the excitatory neurotransmitter, glutamate, and inhibitory neurotransmitter, gamma aminobutyric acid (GABA), leads to migraine attacks; however, the pathophysiology and specific diagnostic markers remain unknown. Methods: Twenty-one migraine patients (18 female, 3 male, mean age=40.63 14.23years) and 11 healthy controls (9 female, 2 male, mean age=39.78 15.31 years) were included in this study. We used 1H-MRS at 3 Tesla with voxels-of-interest located in the bilateral thalamus and subgenual anterior cingulate cortex (SG ACC) to quantify the GABA and GLX (glutamate-glutamine complex) concentrations measured via the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence in migraineurs and healthy controls. Result: Statistical analyses revealed significantly decreased GLX/NAA (N-acetylaspartate) in the right thalamus of migraine patients compared to healthy controls. However, we found no group differences in GABA levels in the SG ACC and bilateral thalamus.Conclusion: The right thalamus may be involved in the pain modulation process of migraineurs through changes in the GLX levels. Decreased GLX levels within the right thalamus might be associated with the disruption of "excitation-inhibition" homeostasis in migraine.Trial registration: ClinicalTrials.gov, NCT02580968. Registered 30 October 2015, https://clinicaltrials.gov/ct2/show/study/NCT02580968