Introduction:Anhedonic depression is a subtype of depression characterized by deficits in reward processing. This subtype of depression is associated with higher suicide risk and longer depressive episodes, underscoring the importance of effective treatments. Anhedonia has also been found to correlate with alterations in activity in several subcortical regions, including the caudate head and nucleus accumbens. Low intensity focused ultrasound pulsation (LIFUP) is an emerging technology that enables non-invasive stimulation of these subcortical regions, which were previously only accessible with surgically-implanted electrodes. Methods:This double-blinded, sham-controlled study aims to investigate the effects of LIFUP to the left caudate head and right nucleus accumbens in participants with anhedonic depression. Participants in this protocol will undergo three sessions of LIFUP over the span of 5-9 days. To investigate LIFUP-related changes, this 7-week protocol collects continuous digital phenotyping data, an array of self-report measures of depression, anhedonia, and other psychopathology, and magnetic resonance imaging (MRI) before and after the LIFUP intervention. Primary self-report outcome measures include Ecological Momentary Assessment, the Positive Valence Systems Scale, and the Patient Health Questionnaire. Primary imaging measures include magnetic resonance spectroscopy and functional MRI during reward-based tasks and at rest. Digital phenotyping data is collected with an Apple Watch and participants' personal iPhones throughout the study, and includes information about sleep, heart rate, and physical activity. Discussion:This study is the first to investigate the effects of LIFUP to the caudate head or nucleus accumbens in depressed subjects. Furthermore, the data collected for this protocol covers a wide array of potentially affected modalities. As a result, this protocol will help to elucidate potential impacts of LIFUP in individuals with anhedonic depression.

Objective This study aimed to examine the potential of experiencing aesthetic chills to enhance reward learning in individuals with elevated depressive symptoms, specifically anhedonia, by investigating the effect of chills on participants' ability to modulate behavior as a function of rewards. Methods A total of 103 participants with elevated depressive symptoms took part in the experiment. Among them, 59 participants had depressive symptoms (BDI ≥ 20), with 26 classified as “High Anhedonic” (HA) and 33 as “Low Anhedonic” (LA). Additionally, 39 participants without elevated depressive symptoms (BDI < 20 and SHAPs <32) were included as the control group. We utilized ChillsDB, an open-source database of validated audiovisual stimuli known to elicit chills in the US population. Results Anhedonic participants who experienced chills demonstrated a significant increase in response bias (p = .004) towards rewards compared to those who did not experience chills. Highlighting specificity, no significant difference in reward bias was observed among LA participants. Conclusions These findings suggest that the experience of chills has the potential to impact reward learning in anhedonic individuals, aligning with the known neurobiology of this phenomenon. These results highlight the potential of aesthetic chills as a novel approach to elicit and enhance positive affect in depressed populations.

Background: The Probabilistic Reward Task (PRT) is a signal detection task that assesses reward learning. In laboratory versions of the task, individuals with current or past major depressive disorder (MDD) were characterized by reduced response bias towards a more frequently rewarded stimuli, compared to controls. Our main goal was to develop and validate a novel online version of the PRT, and, in exploratory analyses, evaluate whether lifetime history of depression was associated with blunted reward learning. Methods: 429 participants recruited via CloudResearch completed questionnaires assessing psychiatric history and an online PRT featuring visually appealing stimuli. 108 participants reported either current or past diagnosis of MDD (lifetime MDD group), and were compared to 321 without lifetime MDD. Results: Participants showed overall increase in response bias, validating the online PRT. Females with lifetime MDD (N = 43), compared to females without prior history of MDD (N = 173), exhibited blunted response bias towards the more frequently rewarded stimulus (i.e., reduced reward learning). Limitations: Participants did not undergo a structured clinical interview, thus we cannot confirm whether they met full diagnostic criteria for depression. Conclusions: The online PRT yielded similar psychometric properties as laboratory versions of the task. In exploratory analyses, females with lifetime MDD showed a lower propensity to modulate behavior as a function of rewards, which might contribute to heightened vulnerability for developing MDD in females. Future studies should consider social, cultural, and neurobiological factors contributing to sex differences in reward responsiveness and how factors may relate to disease prognosis and treatment outcomes.

BACKGROUND: Neurocognitive factors including aberrant reward learning, blunted GABA (gamma-aminobutyric acid), and potentiated stress sensitivity have been linked to anhedonia, a hallmark depressive symptom, possibly in a sex-dependent manner. However, previous research has not investigated the putative associations among these factors or the extent to which they represent trait- or state-based vulnerabilities for depression. METHODS: Young adults with current major depressive disorder (MDD) (n = 44), remitted MDD (n = 42), and healthy control participants (HCs) (n = 44), stratified by sex assigned at birth, underwent magnetic resonance spectroscopy to assess macromolecular contaminated GABA (GABA+) and then a reward learning task before and after acute stress. We assessed changes in reward learning after stress and associations with GABA+. RESULTS: Results revealed blunted baseline reward learning in participants with remitted MDD versus participants with current MDD and HCs but, surprisingly, no differences between participants with current MDD and HCs. Reward learning was reduced following acute stress regardless of depressive history. GABA+ in the rostral anterior cingulate cortex, but not the dorsolateral prefrontal cortex, was associated with reduced baseline reward learning only in female participants. GABA+ did not predict stress-related changes in reward learning. CONCLUSIONS: To our knowledge, this is the first study to investigate associations among GABA, reward learning, and stress reactivity in current versus past depression. Hypothesized depression-related differences in reward learning did not emerge, precluding claims about state versus trait vulnerabilities. However, our finding that blunted GABA was associated with greater reward learning in female participants provides novel insights into sexselective associations between the frontal GABAergic inhibitory system and reward processing.

Perceived control is strongly related to mental health and well-being. Specifically, lack of perceived control has been associated with learned helplessness and stress-related disorders, such as depression and anxiety. However, it is unknown whether brain activation to control and its protective effect against stress can predict changes in quality of life. To address this gap, we examined the neural underpinning of controllability in healthy females (N = 40) performing the Value of Control task in an functional magnetic resonance imaging scanner. Quality of life and perceived stress were assessed at baseline and 6-month follow-up. Increased brain activation for control was found within the putamen, insula, thalamus, mid-cingulate, dorsolateral prefrontal cortex, motor cortex, and cerebellum. In contrast, increased brain activation for lack of control was found within the posterior cingulate and prefrontal cortices. In an exploratory analysis, an elastic-net algorithm was used to identify brain predictors of quality of life 6 months later. The right putamen's activation to control was selected as the best prospective predictor of improvement in life enjoyment and satisfaction and this association was mediated by changes in perceived stress. Our findings suggest that neural responsiveness to control may have utility as a potential marker of quality of life and resilience to adversity.

Elevated resting heart rate (RHR) and reduced heart rate variability (HRV) are signs of autonomic nervous system dysfunction identified in schizophrenia (SCZ). This dysfunction has been found to manifest prior to the onset of the clinical diagnosis. Yet whether such autonomic dysfunction is associated with vulnerability to schizophrenia remains unknown. This case-control study included recent onset SCZ patients (n = 35) and healthy controls (HC) (n = 33). Patients were scored for self-disorders (SD's) using the EASE manual and all participants underwent a 5-minute resting state electrocardiogram (ECG) recording. Patients were included from outpatient clinics in Denmark. The main measures comprised EASE total scores (SDs), RHR (beats per minute) and three standard HRV measures usually included in testing autonomic nervous system dysfunction: root mean squared of successive differences (RMSSD), standard deviation of normal-to-normal interval (SDNN) and high-frequency/ low frequency ratio (HF/LF). Pearson correlations and linear regression models adjusted for age, sex and medication were used in the SCZ group. The main finding was a positive moderate association between SDs and RHR (r = 0.463; p = 0.005) and a negative association between SDs and HRV (RMSSD) (r = -0.440; p = 0.008) in the SCZ group. Linear regression models found SDs to explain 22 % of the variance of RHR and 19 % in RMSSD. SDs correlated with LF/HF (r = 0.434; p = 0.009), but non-significantly with SDNN. The study provides evidence of an intriguing link between SDs as a susceptibility trait for schizophrenia spectrum disorders and altered cardiac autonomic functioning.

Increasingly, research is highlighting the implications of exposure to unpredictable environments during childhood (i.e., “childhood unpredictability”) on outcomes in adulthood. Converging evidence from preclinical and clinical studies has implicated childhood unpredictability in disrupted reward processing and anhedonia. From the stress generation literature, altered social support has emerged as a possible mechanism by which this effect may occur. In the current study, our goal was to understand whether the pathway from childhood unpredictability to anhedonia occurs through reduced perceptions of social support. Toward this end, we recruited an online community sample of adults in the US (N = 242) to complete surveys assessing childhood unpredictability, depressive symptoms, anhedonia, and social support, as well as a novel online version of the Probabilistic Reward Task. We found that childhood unpredictability was associated with increased depressive symptoms and anhedonia (but not objective measure of anhedonia), and reduced perceptions of social support in adulthood. Mediation analyses revealed a significant indirect effect of perceived social support on the association between childhood unpredictability and anhedonia, controlling for age, sex, and non-anhedonic depressive symptoms. Unexpectedly, measures of reward responsiveness from the behavioral task were not related to childhood unpredictability. The current findings replicate previous reports linking childhood unpredictability and self-reported anhedonia, and extend them to incorporate the potential mediating pathway of reduced social support. Implications for treatment for anhedonia are discussed.

BackgroundUnderstanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated (1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC), and (2) how such effects related to gene expression and receptor maps.MethodsAcross 115 participants (37 controls, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with the anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABA-A receptor distribution maps derived from positron emission tomography.ResultsResults revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen and amygdala with regions from the ventral attention/salience network, frontoparietal network and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1, OPRK1, SST, GABRA3, GABRA5), similar to previous genetic MDD studies.ConclusionsAcute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes previously associated with imaging abnormalities in MDD and are rich in μ− and κ− opioid receptors. These findings point to overlapping circuitry underling stress response, reward, and MDD.

Background. Childhood sexual abuse (CSA) and emotional maltreatment are salient risk factors for the development of major depressive disorder (MDD) in women. However, the type- and timing-specific effects of emotional maltreatment experienced during adolescence on future depressive symptomatology in women with CSA have not been explored. The goal of this study was to fill this gap. Methods. In total, 203 women (ages 20-32) with current depressive symptoms and CSA (MDD/CSA), remitted depressive symptoms and CSA (rMDD/CSA), and current depressive symptoms without CSA (MDD/no CSA) were recruited from the community and completed self-report measures. Depressive symptoms were assessed using the Beck Depression Inventory (BDI-II) and a detailed maltreatment history was collected using the Maltreatment and Abuse Chronology of Exposure (MACE). Differences in maltreatment exposure characteristics, including multiplicity and severity of maltreatment, as well as the chronologies of emotional maltreatment subtypes were compared among groups. A random forest machine-learning algorithm was utilized to assess the impact of exposure to emotional maltreatment subtypes at specific ages on current depressive symptoms. Results. MDD/CSA women reported greater prevalence and severity of emotional maltreatment relative to rMDD/CSA and MDD/no CSA women [F (2,196) = 9.33, p < 0.001], specifically from ages 12 to 18. The strongest predictor of current depressive symptoms was parental verbal abuse at age 18 for both MDD/CSA women (variable importance [VI] = 1.08, p = 0.006) and MDD/no CSA women (VI = 0.68, p = 0.004). Conclusions. Targeting emotional maltreatment during late adolescence might prove beneficial for future intervention efforts for MDD following CSA.

Objective: Preclinical work suggests that excess glucocorticoids and reduced cortical gamma-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). Methods: Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (gamma-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. Results: Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. Conclusions: Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled pilot study, we tested the effects of one infusion of ketamine (0.5 mg/kg, n = 10) or the psychoactive comparator drug midazolam (0.04 mg/kg, n = 12) in adults with BPD. Infusions were well tolerated in both groups. Dissociative symptoms during infusion were more intense with ketamine than midazolam (t(12.3) = 3.61, p = 0.01), but they resolved by 40 min after infusion in both groups. Post-infusion adverse events were at the expected low levels in both groups. For our primary outcome measure of suicidal ideation and our secondary outcome measure of depression, we found numerical reduction but not significant group or group x timepoint difference (p > 0.05). For our secondary outcome measures of anxiety and BPD symptoms, we did not observe group or group x timepoint differences. There was a group x timepoint effect for socio-occupational functioning (F(1,20.12) = 5.16, p = 0.03, at Day 14, ketamine group showed more improvement than midazolam group). An exploratory analysis revealed that improvement in socio-occupational functioning was correlated with improvement in depression in the ketamine group (r(8) = 0.65, p = 0.04) but not midazolam group (r(9) = 0.41, p = 0.216). This pilot study provides the first randomized controlled evidence of the effects of antidepressant-dosed ketamine in people with BPD. Our results provide reason for optimism that antidepressant-dosed ketamine will be well-tolerated in larger studies and may provide clinical benefit for mood symptoms and related impairments in people with BPD.

Increase in stress-related disorders in women begins post-puberty and persists throughout the lifespan. To characterize sex differences in stress response in early adulthood, we used functional magnetic resonance imaging while participants underwent a stress task in conjunction with serum cortisol levels and questionnaires assessing anxiety and mood. Forty-two healthy subjects aged 18-25 years participated (21M, 21F). Interaction of stress and sex in brain activation and connectivity were examined. Results demonstrated significant sex differences in brain activity with women exhibiting increased activation in regions that inhibit arousal compared to men during the stress paradigm. Women had increased connectivity among stress circuitry regions and default mode network, whereas men had increased connectivity between stress and cognitive control regions. In a subset of subjects (13F, 17M), we obtained gamma-aminobutyric acid (GABA) magnetic resonance spectroscopy in rostral anterior cingulate cortex (rostral ACC) and dorsolateral prefrotal cortex (dlPFC) and conducted exploratory analyses to relate GABA measurements with sex differences in brain activation and connectivity. Prefrontal GABA levels were negatively associated with inferior temporal gyrus activation in men and women and with ventromedial prefrontal cortex activation in men. Despite sex differences in neural response, we found similar subjective ratings of anxiety and mood, cortisol levels, and GABA levels between sexes, suggesting sex differences in brain activity result in similar behavioral responses among the sexes. These results help establish sex differences in healthy brain activity from which we can better understand sex differences underlying stress-associated illnesses.

Understanding the neurobiological effects of stress is critical to address the etiology of major depressive disorder (MDD). During acute stress, the salience network is thought to play a key role in allocating resources, yet more evidence is needed to understand stress circuitry. Here, across healthy participants and individuals with current or past MDD, we investigated (1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC), and (2) how such effects related to gene expression.

Research to identify effective treatments for psychopathology has benefited immensely from focus on biomarker identification. Despite the high prevalence of Borderline Personality Disorder (BPD) (1-5%), identification of biomarkers has lagged behind the field for this population. Even less data is available on potential gender differences in biomarkers for BPD. We reviewed the state of the field with focus on EEG markers of BPD pathology and recovery.

Borderline personality disorder (BPD) is highly stigmatized. Although person-first labels are now used for most mental illnesses (e.g., a person with schizophrenia) rather than premodified noun labels (e.g., "he is a schizophrenic"), it is still common to hear people referred to as "borderlines." In a series of two experimental studies, we examined how diagnostic labels influence negative attitudes about BPD. In Study 1, we presented vignettes with no diagnostic label, a person-first label, or a premodified noun label and compared BPD vignettes to schizophrenia vignettes. In Study 2, we again examined the influence of diagnostic label on attitudes about BPD and manipulated the gender depicted in the BPD vignettes. In Study 1, negative attitudes related to anger and blame were greater for BPD than schizophrenia. Diagnosis and label construction did not interact. In Study 2, we found little evidence of gender effects, except that male 4 characters with BPD were considered more dangerous and evoked more fear, while female characters were viewed with greater pity. Gender and label construction did not interact. Although we expected that attitudes would be most negative in the premodified noun label condition and least negative in the person-first condition, this was not the case. In both Studies 1 and 2, the condition with no diagnostic label produced the greatest negative attitudes in some but not all stigma domains, while person-first and premodified noun labels did not differ. Results suggest that in some contexts, diagnostic labels reduce negative attitudes about BPD regardless of their specific construction.

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex–striatum–anterior cingulate cortex (vmPFC–Str–ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal–Insula–Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females.

Borderline personality disorder (BPD) is associated with deficits in neuropsychological measures such as memory, cognitive flexibility, and learning. Mixed findings suggest that deficits may be specific to particular aspects of learning. This is the first study to examine Kamin blocking in a BPD sample. A sample of 51 female subjects (N = 24 control, N = 27 BPD) were recruited. Participants completed a learning task in three phases: a first acquisition phase to learn cue-outcome associations, a second pairing phase to set up blocked cues, and a third testing phase to measure the extent of blocking and to test reversal learning. Participants indicated choice and certainty at each trial, and received feedback immediately after each trial. In phase one, mean correctness but not learning rate was less in BPD than control. Participants with BPD were also less certain about their responses, which correlated positively with correctness – this correlation was not found for control subjects. Kamin blocking, maintenance of previous learning, and reversal learning did not differ between groups. These results cohere with the idea that learning deficits in BPD are in specific domains, including the novel finding that Kamin blocking is preserved in BPD. The significant correlation between certainty and correctness in BPD may hint at mechanisms underlying the maintenance of low mood.

Background Symptoms of borderline personality disorder (BPD) and post-traumatic stress disorder (PTSD) commonly co-occur. Recent evidence supports the concomitant treatment of BPD and PTSD. Methods This study uses a longitudinal cross-lagged panel model to examine BPD and PTSD symptom response in a sample of 110 women undergoing residential treatment for BPD. The naturalistic treatment primarily followed a dialectical-behavior therapy protocol, with individualized integration of other major evidence-based treatments (EBTs) for BPD, including mentalization-based treatment, good psychiatric management, and transference-focused psychotherapy. Results A residentially-based integration of treatment approaches resulted in significant reductions in BPD (d = 0.71) and PTSD (d = 0.75) symptoms. Moreover, changes in BPD symptoms prospectively predicted changes in PTSD symptoms (constrained path b = 1.73), but the reverse was not true (constrained path b = 0.05). Conclusions A naturalistic integration of EBTs for BPD may benefit both BPD and PTSD symptoms even in the absence of PTSD-oriented intervention. Additionally, the attenuation of BPD symptoms may have positive impact on PTSD symptoms.