Linking connectivity of deep brain stimulation of nucleus accumbens area with clinical depression improvements: a retrospective longitudinal case series.

Treatment-resistant depression is a severe form of major depressive disorder and deep brain stimulation is currently an investigational treatment. The stimulation's therapeutic effect may be explained through the functional and structural connectivities between the stimulated area and other brain regions, or to depression-associated networks. In this longitudinal, retrospective study, four female patients with treatment-resistant depression were implanted for stimulation in the nucleus accumbens area at our center. We analyzed the structural and functional connectivity of the stimulation area: the structural connectivity was investigated with probabilistic tractography; the functional connectivity was estimated by combining patient-specific stimulation volumes and a normative functional connectome. These structural and functional connectivity profiles were then related to four clinical outcome scores. At 1-year follow-up, the remission rate was 66%. We observed a consistent structural connectivity to Brodmann area 25 in the patient with the longest remission phase. The functional connectivity analysis resulted in patient-specific R-maps describing brain areas significantly correlated with symptom improvement in this patient, notably the prefrontal cortex. But the connectivity analysis was mixed across patients, calling for confirmation in a larger cohort and over longer time periods.

The Common Neural Mechanism of Somatic Symptoms of Depression and Anxiety Disorders: A Resting-State Functional Magnetic Resonance Imaging Study.

INTRODUCTION: Somatic symptoms often occur as a manifestation of depression and anxiety. The subgenual anterior cingulate cortex (sgACC) has been shown to be closely related to both depression and anxiety and plays an important role in somatic symptoms. However, little is known regarding whether the abnormal function of the sgACC contributes to the common somatic symptoms of depression and anxiety. METHODS: Resting-state functional connectivity (RSFC) analysis based on the seed of the sgACC was investigated in 23 major depressive disorder (MDD) patients with somatic symptoms, 20 generalized anxiety disorder (GAD) patients with somatic symptoms, and 22 demographically matched healthy controls (HCs). The severity of depression, anxiety, and somatic symptoms was assessed using the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), and the 15-item somatic symptom severity scale from the Patient Health Questionnaire (PHQ-15), respectively. An analysis of covariance analysis (ANCOVA) was conducted to determine RSFC alterations among GAD, MDD, and HC groups with age, gender, and head motion as covariates. Correlation analyses were conducted between the RSFC of the sgACC and PHQ-15. RESULTS: The significantly different RSFC of right sgACC among the three groups was found in right STG, left cerebellum, and right postcentral. Post hoc analysis indicated that both MDD and GAD patients showed a decreased RSFC between the right sgACC and right STG than HCs, and both were negatively correlated with the PHQ-15 scores. CONCLUSION: The abnormally decreased RSFC of the sgACC and STG may be the underlying common mechanisms of depression and anxiety combined with somatic symptoms.

Investigating neural circuits of emotion regulation to distinguish euthymic patients with bipolar disorder and major depressive disorder.

BACKGROUND: Up to 40% of patients with bipolar disorder (BD) are initially diagnosed as having major depressive disorder (MDD), and emotional lability is a key aspect of both sets of mood disorders. However, it remains unknown whether differences in the regulation of emotions through cognitive reappraisal may serve to distinguish BD and MDD. Therefore, we examined this question in euthymic BD and MDD patients. METHODS: Thirty-eight euthymic BD, 33 euthymic MDD and 37 healthy control (HC) participants, matched for age, gender and depression severity, engaged in an emotion regulation (ER) cognitive reappraisal task during an fMRI scan were examined. Participants either reappraised (Think condition) or passively watched negative (Watch condition) or neutral (Neutral condition) pictures and rated their affect. Activation and connectivity analyses were used to examine group differences in reappraisal (Think vs Watch) and reactivity (Watch vs Neutral) conditions in ER-specific neural circuits. RESULTS: Irrespective of group, participants rated most negatively the images during the Watch condition relative to Think and Neutral conditions, and more negatively to Think relative to Neutral. Notably, BD participants exhibited reduced subgenual anterior cingulate activation (sgACC) relative to MDD during reappraisal, but exhibited greater sgACC activation relative to MDD during reactivity, whereas MDD participants elicited greater activation in right amygdala relative to BD during reactivity. We found no group differences in task-related connectivity. CONCLUSIONS: Euthymic BD and MDD patients engage differential brain regions to process and regulate emotional information. These differences could serve to distinguish the clinical groups and provide novel insights into the underlying pathophysiology of BD.

The role of the subgenual anterior cingulate cortex in dorsomedial prefrontal-amygdala neural circuitry during positive-social emotion regulation.

Positive-social emotions mediate one's cognitive performance, mood, well-being, and social bonds, and represent a critical variable within therapeutic settings. It has been shown that the upregulation of positive emotions in social situations is associated with increased top-down signals that stem from the prefrontal cortices (PFC) which modulate bottom-up emotional responses in the amygdala. However, it remains unclear if positive-social emotion upregulation of the amygdala occurs directly through the dorsomedial PFC (dmPFC) or indirectly linking the bilateral amygdala with the dmPFC via the subgenual anterior cingulate cortex (sgACC), an area which typically serves as a gatekeeper between cognitive and emotion networks. We performed functional MRI (fMRI) experiments with and without effortful positive-social emotion upregulation to demonstrate the functional architecture of a network involving the amygdala, the dmPFC, and the sgACC. We found that effortful positive-social emotion upregulation was associated with an increase in top-down connectivity from the dmPFC on the amygdala via both direct and indirect connections with the sgACC. Conversely, we found that emotion processes without effortful regulation increased network modulation by the sgACC and amygdala. We also found that more anxious individuals with a greater tendency to suppress emotions and intrusive thoughts, were likely to display decreased amygdala, dmPFC, and sgACC activity and stronger connectivity strength from the sgACC onto the left amygdala during effortful emotion upregulation. Analyzed brain network suggests a more general role of the sgACC in cognitive control and sheds light on neurobiological informed treatment interventions.

Regional brain volume reductions in major depressive disorder and bipolar disorder: An analysis by voxel-based morphometry.

OBJECTIVES: The present study investigated the usefulness of evaluating the existence of volume reduction in brain regions using voxel-based morphometry (VBM) to dissociate major depressive disorder (MDD) from bipolar disorder (BD). METHODS/DESIGN: This study enrolled 92 individuals with MDD, 32 individuals with BD, and 43 healthy controls (HCs). We focused on gray matter volume (GMV) of the subgenual anterior cingulate cortex (sgACC), subcallosal area (SCA), and hippocampus. The degree of volume reduction in these brain regions was calculated as the z score, and the differences of z scores in these regions were investigated among the MDD, BD, and HC groups. We then performed a receiver operating characteristic curve analysis to dissociate the individuals with MDD and BD from the HCs based on the z scores in the GMV of these brain regions. RESULTS: While there were no significant differences in the z scores of the hippocampus among the three groups, the z score of the sgACC was significantly higher in the MDD group than in the BD and HC groups, and the SCA z score was significantly higher in the MDD and BD groups than in the HC group. CONCLUSIONS: Our findings suggest that VBM evaluation of GMV reduction in the sgACC may be useful as an objective adjunctive tool to distinguish between MDD and BD.

Neurocomputational mechanisms of prosocial learning and links to empathy.

Reinforcement learning theory powerfully characterizes how we learn to benefit ourselves. In this theory, prediction errors-the difference between a predicted and actual outcome of a choice-drive learning. However, we do not operate in a social vacuum. To behave prosocially we must learn the consequences of our actions for other people. Empathy, the ability to vicariously experience and understand the affect of others, is hypothesized to be a critical facilitator of prosocial behaviors, but the link between empathy and prosocial behavior is still unclear. During functional magnetic resonance imaging (fMRI) participants chose between different stimuli that were probabilistically associated with rewards for themselves (self), another person (prosocial), or no one (control). Using computational modeling, we show that people can learn to obtain rewards for others but do so more slowly than when learning to obtain rewards for themselves. fMRI revealed that activity in a posterior portion of the subgenual anterior cingulate cortex/basal forebrain (sgACC) drives learning only when we are acting in a prosocial context and signals a prosocial prediction error conforming to classical principles of reinforcement learning theory. However, there is also substantial variability in the neural and behavioral efficiency of prosocial learning, which is predicted by trait empathy. More empathic people learn more quickly when benefitting others, and their sgACC response is the most selective for prosocial learning. We thus reveal a computational mechanism driving prosocial learning in humans. This framework could provide insights into atypical prosocial behavior in those with disorders of social cognition.

A novel concurrent TMS-fMRI method to reveal propagation patterns of prefrontal magnetic brain stimulation.

Major depressive disorder (MDD) is a severe mental disorder associated with high morbidity and mortality rates, which remains difficult to treat, as both resistance and recurrence rates are high. Repetitive transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) provides a safe and effective treatment for selected patients with treatment-resistant MDD. Little is known about the mechanisms of action of TMS provided to the left DLPFC in MDD and we can currently not predict who will respond to this type of treatment, precluding effective patient selection. In order to shed some light on the mechanism of action, we applied single pulse TMS to the left DLPFC in 10 healthy participants using a unique TMS-fMRI set-up, in which we could record the direct effects of TMS. Stimulation of the DLPFC triggered activity in a number of connected brain regions, including the subgenual anterior cingulate cortex (sgACC) in four out of nine participants. The sgACC is of particular interest, because normalization of activity in this region has been associated with relief of depressive symptoms in MDD patients. This is the first direct evidence that TMS pulses delivered to the DLPFC can propagate to the sgACC. The propagation of TMS-induced activity from the DLPFC to sgACC may be an accurate biomarker for rTMS efficacy. Further research is required to determine whether this method can contribute to the selection of patients with treatment resistant MDD who will respond to rTMS treatment.

Anodal frontal tDCS for chronic cluster headache treatment: a proof-of-concept trial targeting the anterior cingulate cortex and searching for nociceptive correlates.

BACKGROUND: Percutaneous occipital nerve stimulation (ONS) is effective in refractory chronic cluster headache (rCCH) patients. Responders to ONS differ from non-responders by greater glucose metabolism in subgenual anterior cingulate cortex (sgACC). We reasoned that transcranial direct current stimulation (tDCS), a non-invasive approach, might be able to activate this area and thus improve rCCH patients. Our objective was to explore in a pilot trial the therapeutic potential of tDCS (anode at Fz, cathode over C7) and its possible effects on pain perception, frontal executive functions and mood in rCCH patients. METHODS: Thirty-one patients were asked to apply daily 20-min sessions of 2 mA tDCS for 4 or 8 weeks after a 1-month baseline. CH attacks were monitored with paper diaries. The primary outcome measure was change in weekly attacks between baseline and the last week of tDCS. Twenty-three patients were available for a modified ITT analysis, 21 for per-protocol analysis. We also explored treatment-related changes in thermal pain thresholds and nociceptive blink reflexes (nBR), frontal lobe function and mood scales. RESULTS: In the per-protocol analysis there was a mean 35% decrease of attack frequency (p = 0.0001) with 41% of patients having a ≥ 50% decrease. Attack duration and intensity were also significantly reduced. After 8 weeks (n = 10), the 50% responder rate was 45%, but at follow-up 2 weeks after tDCS (n = 16) mean attack frequency had returned to baseline levels. The treatment effect was significant in patients with high baseline thermal pain thresholds in the forehead (n = 12), but not in those with low thresholds (n = 9). The Frontal Assessment Battery score increased after tDCS (p = 0.01), while there was no change in depression scores or nBR. CONCLUSION: tDCS with a Fz-C7 montage may have a preventive effect in rCCH patients, especially those with low pain sensitivity, suggesting that a sham-controlled trial in cluster headache is worthwhile. Whether the therapeutic effect is due to activation of the sgACC that can in theory be reached by the electrical field, or of other prefrontal cortical areas remains to be determined.

Reduced global functional connectivity of the medial prefrontal cortex in major depressive disorder.

BACKGROUND: Major depressive disorder is a disabling neuropsychiatric condition that is associated with disrupted functional connectivity across brain networks. The precise nature of altered connectivity, however, remains incompletely understood. The current study was designed to examine the coherence of large-scale connectivity in depression using a recently developed technique termed global brain connectivity. METHODS: A total of 82 subjects, including medication-free patients with major depression (n = 57) and healthy volunteers (n = 25) underwent functional magnetic resonance imaging with resting data acquisition for functional connectivity analysis. Global brain connectivity was computed as the mean of each voxel's time series correlation with every other voxel and compared between study groups. Relationships between global connectivity and depressive symptom severity measured using the Montgomery-Åsberg Depression Rating Scale were examined by means of linear correlation. RESULTS: Relative to the healthy group, patients with depression evidenced reduced global connectivity bilaterally within multiple regions of medial and lateral prefrontal cortex. The largest between-group difference was observed within the right subgenual anterior cingulate cortex, extending into ventromedial prefrontal cortex bilaterally (Hedges' g = -1.48, P < 0.000001). Within the depressed group, patients with the lowest connectivity evidenced the highest symptom severity within ventromedial prefrontal cortex (r = -0.47, P = 0.0005). CONCLUSIONS: Patients with major depressive evidenced abnormal large-scale functional coherence in the brain that was centered within the subgenual cingulate cortex, and medial prefrontal cortex more broadly. These data extend prior studies of connectivity in depression and demonstrate that functional disconnection of the medial prefrontal cortex is a key pathological feature of the disorder. Hum Brain Mapp 37:3214-3223, 2016. © 2016 Wiley Periodicals, Inc.

Influence of age of onset on limbic and paralimbic structures in depression.

AIM: Major depressive disorder (MDD) onset during childhood/adolescence is associated with a greater illness burden and distinct clinical profile. However, limited research exists on the effect of age of MDD onset on volumetric abnormalities in para/limbic structures during adulthood. METHODS: Subgenual anterior cingulate cortex (sgACC), hippocampus and caudate nucleus volumes were measured by manual tracing in depressed individuals (n = 45) and healthy controls (HC; n = 19). Volumetric comparisons were carried out between HC and MDD patients divided into those with pediatric (≤ 18 years; n = 17) and adult onset (≥ 19 years; n = 28). RESULTS: The adult MDD-onset group had smaller sgACC volumes than the pediatric-onset and HC groups (age, sex controlled). No differences in caudate and hippocampus volumes existed. sgACC and hippocampal volumes were inversely correlated with depression severity. CONCLUSIONS: Surprisingly, pediatric MDD-onset was not associated with more pronounced sgACC, hippocampus and caudate volume reductions. Nevertheless, age of illness onset appears to be a meaningful dimension of study in efforts to understand the neurobiological heterogeneity of MDD.

Effect of Low-Intensity Transcranial Focused Ultrasound Stimulation in Patients With Major Depressive Disorder: A Randomized, Double-Blind, Sham-Controlled Clinical Trial.

OBJECTIVE: Low-intensity transcranial focused ultrasound (tFUS) has emerged as a promising non-invasive brain stimulation modality with high spatial selectivity and the ability to reach deep brain areas. The present study aimed to investigate the safety and effectiveness of low-intensity tFUS in treating major depressive disorder. METHODS: Participants were recruited in an outpatient clinic and randomly assigned to either the verum tFUS or sham stimulation group. The intervention group received six sessions of tFUS stimulation to the left dorsolateral prefrontal cortex over two weeks. Neuropsychological assessments were conducted before and after the sessions. Resting-state functional magnetic resonance imaging (rsfMRI) was also performed to evaluate changes in functional connectivity (FC). The primary outcome measure was the change in depressive symptoms, assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The tFUS stimulation sessions were well tolerated without any undesirable side effects. The analysis revealed a significant main effect of session sequence on the MADRS scores and significant interactions between the session sequences and groups. The rsfMRI analysis showed a higher FC correlation between the right superior part of the subgenual anterior cingulate cortex (sgACC) and several other brain regions in the verum group compared with the sham group. CONCLUSION: Our results reveal that tFUS stimulation clinically improved MADRS scores with network-level modulation of a sgACC subregion. This randomized, sham-controlled clinical trial, the first study of its kind, demonstrated the safety and probable efficacy of tFUS stimulation for the treatment of depression.

Functional Connectivity Mapping for rTMS Target Selection in Depression.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cortex (sgACC) functional connectivity to individualize treatment targets. However, the efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site's functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression. METHODS: The reliability and accuracy of estimating sgACC functional connectivity were validated with data from individuals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations between sgACC-StimFC and clinical improvement using standardized assessments and to evaluate sources of heterogeneity. RESULTS: An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=-0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=-0.49). CONCLUSIONS: Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration-related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ∼3% of the variance in outcomes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true-albeit small-effect and highlight opportunities for incorporating additional functional connectivity measures to generate models of rTMS response with enhanced predictive power.

Treatment with the second-generation antipsychotic quetiapine is associated with increased subgenual ACC activation during reward processing in major depressive disorder.

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.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS).

OBJECTIVE: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. METHODS: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. RESULTS: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. CONCLUSION: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials.

Target selection for deep brain stimulation in treatment resistant schizophrenia.

The use of deep brain stimulation (DBS) in treatment resistant patients with schizophrenia is of considerable current interest, but where to site the electrodes is challenging. This article reviews rationales for electrode placement in schizophrenia based on evidence for localized brain abnormality in the disorder and the targets that have been proposed and employed to date. The nucleus accumbens and the subgenual anterior cingulate cortex are of interest on the grounds that they are sites of potential pathologically increased brain activity in schizophrenia and so susceptible to the local inhibitory effects of DBS; both sites have been employed in trials of DBS in schizophrenia. Based on other lines of reasoning, the ventral tegmental area, the substantia nigra pars reticulata and the habenula have also been proposed and in some cases employed. The dorsolateral prefrontal cortex has not been suggested, probably reflecting evidence that it is underactive rather than overactive in schizophrenia. The hippocampus is also of theoretical interest but there is no clear functional imaging evidence that it shows overactivity in schizophrenia. On current evidence, the nucleus accumbens may represent the strongest candidate for DBS electrode placement in schizophrenia, with the substantia nigra pars reticulata also showing promise in a single case report; the ventral tegmental area is also of potential interest, though it remains untried.

Childhood Threat Is Associated With Lower Resting-State Connectivity Within a Central Visceral Network.

Childhood adversity is associated with altered or dysregulated stress reactivity; these altered patterns of physiological functioning persist into adulthood. Evidence from both preclinical animal models and human neuroimaging studies indicates that early life experience differentially influences stressor-evoked activity within central visceral neural circuits proximally involved in the control of stress responses, including the subgenual anterior cingulate cortex (sgACC), paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST) and amygdala. However, the relationship between childhood adversity and the resting-state connectivity of this central visceral network remains unclear. To this end, we examined relationships between childhood threat and childhood socioeconomic deprivation, the resting-state connectivity between our regions of interest (ROIs), and affective symptom severity and diagnoses. We recruited a transdiagnostic sample of young adult males and females (n = 100; mean age = 27.28, SD = 3.99; 59 females) with a full distribution of maltreatment history and symptom severity across multiple affective disorders. Resting-state data were acquired using a 7.2-min functional magnetic resonance imaging (fMRI) sequence; noted ROIs were applied as masks to determine ROI-to-ROI connectivity. Threat was determined by measures of childhood traumatic events and abuse. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education level). Covarying for age, race and sex, greater childhood threat was significantly associated with lower BNST-PVN, amygdala-sgACC and PVN-sgACC connectivity. No significant relationships were found between SED and resting-state connectivity. BNST-PVN connectivity was associated with the number of lifetime affective diagnoses. Exposure to threat during early development may entrain altered patterns of resting-state connectivity between these stress-related ROIs in ways that contribute to dysregulated neural and physiological responses to stress and subsequent affective psychopathology.

Alteration of grey matter volume is associated with pain and quality of life in children with sickle cell disease.

Pain is the most common symptom experienced by patients with sickle cell disease (SCD) and is associated with poor quality of life. We investigated the association between grey matter volume (GMV) and the frequency of pain crises in the preceding 12 months and SCD-specific quality of life (QOL) assessed by the PedsQLTM SCD module in 38 pediatric patients with SCD. Using voxel-based morphometry methodology, high-resolution T1 structural scans were preprocessed using SPM and further analyzed in SPSS. The whole brain multiple regression analysis identified that perigenual anterior cingulate cortex (ACC) GMV was negatively associated with the frequency of pain crises (r = -0.656, P = 0.003). A two-group t-test analysis showed that the subgroup having pain crisis/crises in the past year also showed significantly lower GMV at left supratemporal gyrus than the group without any pain crisis (p=0.024). The further 21 pain-related regions of interest (ROI) analyses identified a negative correlation between pregenual ACC (r = -0.551, P = 0.001), subgenual ACC (r = -0.540, P = 0.001) and the frequency of pain crises. Additionally, the subgroup with poorer QOL displayed significantly reduced GMV in the parahippocampus (left: P = 0.047; right: P = 0.024). The correlations between the cerebral structural alterations and the accentuated pain experience and QOL suggests a possible role of central mechanisms in SCD pain.

Testing a Developmental Model of Positive Parenting, Amygdala-Subgenual Anterior Cingulate Cortex Connectivity, and Depressive Symptoms in Adolescents Before and During the COVID-19 Pandemic.

Background: Neurobiological measures may inform our understanding of individual differences in adolescents' general risk for and resilience to depressive symptoms, including during the COVID-19 pandemic. We tested a developmental model linking variation in amygdala-subgenual anterior cingulate cortex (sgACC) resting-state connectivity to perceived parenting experiences earlier in adolescence, to concurrent depressive symptoms before the pandemic, and to subsequent 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 T2, and 12-19 years during the pandemic at T3). We assessed positive parenting (warm and supportive) (T1), depressive symptoms (T1 to T3), and functional connectivity between the sgACC and basolateral (BLA) and centromedial amygdala (T1 and T2). We modeled associations among earlier positive parenting, amygdala-sgACC connectivity, and depressive symptoms before and during the pandemic. Results: Less positive parenting at T1 was associated prospectively with stronger BLA-sgACC connectivity at T2 (ß = -0.22) 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 the pandemic (r = 0.21) and during the pandemic (ß = 0.19; independent of the effect of pre-pandemic symptoms). Conclusions: Adolescents who experience less positive parenting may develop a pattern of BLA-sgACC connectivity that increases their risk for mental health problems. BLA-sgACC connectivity may be associated with depressive symptoms in general, including during periods of heightened risk for adolescents, such as the pandemic.

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.

Personalized prediction of transcranial magnetic stimulation clinical response in patients with treatment-refractory depression using neuroimaging biomarkers and machine learning.

BACKGROUND: Functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and subgenual cingulate (sgACC) may serve as a biomarker for transcranial magnetic stimulation (rTMS) treatment response. The first aim was to establish whether this finding is veridical or artifactually induced by the pre-processing method. Furthermore, alternative biomarkers were identified and the clinical utility for personalized medicine was examined. METHODS: Resting-state fMRI data were collected in medication-refractory depressed patients (n = 70, 16 males) before undergoing neuronavigated left DLPFC rTMS. Seed-based analyses were performed with and without global signal regression pre-processing to identify biomarkers of short-term and long-term treatment response. Receiver Operating Characteristic curve and supervised machine learning analyses were applied to assess the clinical utility of these biomarkers for the classification of categorical rTMS response. RESULTS: Regardless of the pre-processing method, DLPFC-sgACC connectivity was not associated with treatment outcome. Instead, poorer connectivity between the sgACC and three clusters (peak locations: frontal pole, superior parietal lobule, occipital cortex) and DLPFC-central opercular cortex were observed in long-term nonresponders. The identified connections could serve as acceptable to excellent markers. Combining the features using supervised machine learning reached accuracy rates of 95.35% (CI=82.94-100.00) and 88.89% (CI=63.96-100.00) in the cross-validation and test dataset, respectively. LIMITATIONS: The sample size was moderate, and features for machine learning were based on group differences. CONCLUSIONS: Long-term nonresponders showed greater disrupted connectivity in regions involving the central executive network. Our findings may aid the development of personalized medicine for medication-refractory depression.