Rumination-Focused Cognitive Behavioral Therapy Reduces Rumination and Targeted Cross-network Connectivity in Youth With a History of Depression: Replication in a Preregistered Randomized Clinical Trial.

Background: Rumination-focused cognitive behavioral therapy (RF-CBT) is designed to reduce depressive rumination or the habitual tendency to dwell on experiences in a repetitive, negative, passive, and global manner. RF-CBT uses functional analysis, experiential exercises, and repeated practice to identify and change the ruminative habit. This preregistered randomized clinical trial (NCT03859297, R61) is a preregistered replication of initial work. We hypothesized a concurrent reduction of both self-reported rumination and cross-network connectivity between the left posterior cingulate cortex and right inferior frontal and inferior temporal gyri. Methods: Seventy-six youths with a history of depression and elevated rumination were randomized to 10 to 14 sessions of RF-CBT (n = 39; 34 completers) or treatment as usual (n = 37; 28 completers). Intent-to-treat analyses assessed pre-post change in rumination response scale and in functional connectivity assessed using two 5 minute, 12 second runs of resting-state functional magnetic resonance imaging. Results: We replicated previous findings: a significant reduction in rumination response scale and a reduction in left posterior cingulate cortex to right inferior frontal gyrus/inferior temporal gyrus connectivity in participants who received RF-CBT compared with those who received treatment as usual. Reductions were large (z change = 0.84; 0.73, respectively [ps < .05]). Conclusions: This adolescent clinical trial further demonstrates that depressive rumination is a brain-based mechanism that is modifiable via RF-CBT. Here, we replicated that RF-CBT reduces cross-network connectivity, a possible mechanism by which rumination becomes less frequent, intense, and automatic. This National Institute of Mental Health-funded fast-fail study continues to the R33 phase during which treatment-specific effects of RF-CBT will be compared with relaxation therapy.

Rumination Induction Task in fMRI: Test-Retest Reliability in Youth and Potential Mechanisms of Change with Intervention.

Background: Rumination is a transdiagnostic problem that is common in major depressive disorder (MDD). Rumination Focused Cognitive Behavioral Therapy (RF-CBT) explicitly targets the ruminative habit. This study examined changes in brain activation during a rumination induction task in adolescents with remitted MDD following RF-CBT. We also evaluated the reliability of the rumination task among adolescents who received treatment as usual (TAU). Method: Fifty-five adolescents ages 14-17 completed a self-relevant rumination induction fMRI task and were then randomized to either RF-CBT (n = 30) or TAU (n = 25). Participants completed the task a second time either following 10-14 sessions of RF-CBT or the equivalent time delay for the TAU group. We assessed activation change in the RF-CBT group using paired-samples t-tests and reliability by calculating intraclass correlation coefficients (ICCs) of five rumination-related ROIs during each of three blocks for the TAU and RF-CBT groups separately (Rumination Instruction, Rumination Prompt, and Distraction). Results: Following treatment, participants in the RF-CBT group demonstrated an increase in activation of the left precuneus during Rumination Instruction and the left angular and superior temporal gyri during Rumination Prompt ( p < .01). The TAU group demonstrated fair to excellent reliability ( M = .52, range = .27-.86) across most ROIs and task blocks. In contrast, the RF-CBT group demonstrated poor reliability across most ROIs and task blocks ( M = .21, range = -.19-.69). Conclusion: RF-CBT appears to lead to rumination-related brain change. We demonstrated that the rumination induction task has fair to excellent reliability among individuals who do not receive an intervention that explicitly targets the ruminative habit, whereas reliability of this task is largely poor in the context of RF-CBT. This has meaningful implications in longitudinal and intervention studies, particularly when conceptualizing it as an important target for intervention. It also suggests one of many possible mechanisms for why fMRI test-retest reliability can be low that appears unrelated to the methodology itself.

Durable effects of deep brain ultrasonic neuromodulation on major depression: a case report.

BACKGROUND: Severe forms of depression have been linked to hyperactivity of the subcallosal cingulate cortex. The ability to stimulate the subcallosal cingulate cortex or associated circuits noninvasively and directly would maximize the number of patients who could receive treatment. To this end, we have developed an ultrasound-based device for effective noninvasive modulation of deep brain circuits. Here we describe an application of this tool to an individual with treatment-resistant depression. CASE PRESENTATION: A 30-year-old Caucasian woman with severe treatment-resistant non-psychotic depression was recruited into a clinical study approved by the Institutional Review Board of the University of Utah. The patient had a history of electroconvulsive therapy with full remission but without sustained benefit. Magnetic resonance imaging was used to coregister the ultrasound device to the subject's brain anatomy and to evaluate neural responses to stimulation. Brief, 30-millisecond pulses of low-intensity ultrasound delivered into the subcallosal cingulate cortex target every 4 seconds caused a robust decrease in functional magnetic resonance imaging blood-oxygen-level-dependent activity within the target. Following repeated stimulation of three anterior cingulate targets, the patient's depressive symptoms resolved within 24 hours of the stimulation. The patient remained in remission for at least 44 days afterwards. CONCLUSIONS: This case illustrates the potential for ultrasonic neuromodulation to precisely engage deep neural circuits and to trigger a durable therapeutic reset of those circuits. Trial registration ClinicalTrials.gov, NCT05301036. Registered 29 March 2022, https://clinicaltrials.gov/ct2/show/NCT05301036.

Propofol for treatment resistant depression: A randomized controlled trial.

Background: Anesthetic agents including ketamine and nitrous oxide have shown antidepressant properties when appropriately dosed. Our recent open-label trial of propofol, an intravenous anesthetic known to elicit transient positive mood effects, suggested that it may also produce robust and durable antidepressant effects when administered at a high dose that elicits an electroencephalographic (EEG) burst-suppression state. Here we report findings from a randomized controlled trial ( NCT03684447 ) that compared two doses of propofol. We hypothesized greater improvement with a high dose that evoked burst suppression versus a low dose that did not. Methods: Participants with moderate-to-severe, treatment-resistant depression were randomized to a series of 6 treatments at low versus high dose (n=12 per group). Propofol infusions were guided by real-time processed frontal EEG to achieve predetermined pharmacodynamic criteria. The primary and secondary depression outcome measures were the 24-item Hamilton Depression Rating Scale (HDRS-24) and the Patient Health Questionnaire (PHQ-9), respectively. Secondary scales measured suicidal ideation, anxiety, functional impairment, and quality of life. Results: Treatments were well tolerated and blinding procedures were effective. The mean [95%-CI] change in HDRS-24 score was -5.3 [-10.3, -0.2] for the low-dose group and -9.3 [-12.9, -5.6] for the high-dose group (17% versus 33% reduction). The between-group effect size (standardized mean difference) was -0.56 [-1.39, 0.28]. The group difference was not statistically significant (p=0.24, linear model). The mean change in PHQ-9 score was -2.0 [-3.9, -0.1] for the low dose and -4.8 [-7.7, -2.0] for the high dose. The between-group effect size was -0.73 [-1.59, 0.14] (p=0.09). Secondary outcomes favored the high dose (effect sizes magnitudes 0.1 - 0.9) but did not generally reach statistical significance (p>0.05). Conclusions: The medium-sized effects observed between doses in this small, controlled, clinical trial suggest that propofol may have dose-dependent antidepressant effects. The findings also provide guidance for subsequent trials. A larger sample size and additional treatments in series are likely to enhance the ability to detect dose-dependent effects. Future work is warranted to investigate potential antidepressant mechanisms and dose optimization.

Reduced connectivity of the cognitive control neural network at rest in young adults who had their first drink of alcohol prior to age 18.

The cognitive control network (CCN) is an important network responsible for performing and modulating executive functions. In adolescents, alcohol use has been associated with weaker cognitive control, higher reward sensitivity, and later-in-life alcohol problems. Given that the CCN continues to develop into young adulthood, it is important to understand relations between early alcohol use, the CCN, and reward networks. Participants included individuals 18-23 years without alcohol use disorder. Based upon self-reported age of first alcoholic drink, participants were split into two groups: Early (onset) Drinkers (first drink < age 18, N = 52) and Late (onset) Drinkers (first drink > age 18, N = 44). All participants underwent an 8-minute resting-state fMRI scan. Seed regions of interest included the anterior dorsolateral prefrontal cortex (DLPFC), amygdala, and ventral striatum. Early Drinkers demonstrated significant reduced connectivity of CCN regions, including bilateral anterior DLPFC, compared to Late Drinkers. There were no significant differences between Early and Late Drinkers in connectivity between reward and CCN regions. These results suggest that individuals who begin drinking alcohol earlier in life may have alterations in the development of the CCN; however, longitudinal research is necessary to determine whether lower connectivity precedes or follows early alcohol use, and any other relevant factors.

Self-Injury in Adolescence Is Associated with Greater Behavioral Risk Avoidance, Not Risk-Taking.

Strategies to link impulsivity and self-injurious behaviors (SIBs) show highly variable results, and may differ depending on the impulsivity measure used. To better understand this lack of consistency, we investigated correlations between self-report and behavioral impulsivity, inhibitory control, SIBs, and rumination. We included participants aged 13-17 years with either current or remitted psychopathology who have (n = 31) and who do not have (n = 14) a history of SIBs. Participants completed self-report measures of impulsivity, the Rumination Responsiveness Scale (RRS), and two behavioral measures of impulsivity: the Balloon Analogue Risk Task (BART) and Parametric Go/No-Go (PGNG). Lifetime SIBs were positively associated with self-reported impulsivity, specifically positive and negative urgency. However, individuals with greater lifetime SIBs demonstrated greater risk aversion (lower impulsivity) as measured by the BART, whereas there was no relation between lifetime SIBs and PGNG performance. There was no relation between rumination and behavioral impulsivity, although greater rumination was associated with higher negative urgency. Future research examining the role of SIBs in the context of active versus remitted psychopathology is warranted. Because most adolescents were remitted from major depressive disorder at the time of study, follow-up studies can determine if lower risk-taking may aid individuals with more prior SIBs to achieve and maintain a remitted state.

Stent selection among patients with chronic kidney disease: Results from the NCDR CathPCI Registry.

OBJECTIVES: This study sought to define contemporary rates of drug eluting stent (DES) usage in patients with chronic kidney disease (CKD). BACKGROUND: Among patients with CKD undergoing percutaneous coronary interventions (PCIs), outcomes are superior for those who receive DES compared to those who receive bare metal stents (BMSs). However, perceived barriers may limit the use of DES in this population. METHODS: All adult PCI cases from the NCDR CathPCI Registry involving coronary stent placement between July 1, 2009 and December 31, 2015 were analyzed. The rate of DES usage was then compared among four groups, stratified by CKD stage (I/II, III, IV, and V). Subgroup analysis was conducted based on PCI status and indication. Cases were linked to Medicare claims data to assess 1-year mortality. RESULTS: A total of 3,650,333 PCI cases met criteria for analysis. DES usage significantly declined as renal function worsened (83.0%, 79.9%, 75.6%, and 75.6%, respectively, in the four CKD stages; p < .001). DES usage was universally lower across the four groups in the setting of ST-Elevation Myocardial Infarction (STEMI) (70.6%, 66.5%, 58.7%, 58.0%; p < .001) and higher in the setting of elective PCI (87.6%, 84.9%, 82.3%, 77.9%; p < .0001). DES was associated with improved 1-year survival, and usage increased over time across each group. CONCLUSIONS: DESs are underutilized in patients with advanced renal dysfunction. Although DES usage has increased over time, variation still exists between patients with normal renal function and those with CKD.

Aquaporin-4 square array assembly: opposing actions of M1 and M23 isoforms.

Osmotic homeostasis in the brain involves movement of water through aquaporin-4 (AQP4) membrane channels. Perivascular astrocyte end-feet contain distinctive orthogonal lattices (square arrays) assembled from 4- to 6-nm intramembrane particles (IMPs) corresponding to individual AQP4 tetramers. Two isoforms of AQP4 result from translation initiation at methionine residues M1 and M23, but no functional differences are known. In this study, Chinese hamster ovary cells were transfected with M1, M23, or M1+M23 isoforms, and AQP4 expression was confirmed by immunoblotting, immunocytochemistry, and immunogold labeling. Square array organization was examined by freeze-fracture electron microscopy. In astrocyte end-feet, >90% of 4- to 6-nm IMPs were found in square arrays, with 65% in arrays of 13-30 IMPs. In cells transfected with M23, 95% of 4- to 6-nm IMPs were in large assemblies (rafts), 85% of which contained >100 IMPs. However, in M1 cells, >95% of 4- to 6-nm IMPs were present as singlets, with <5% in incipient arrays of 2-12 IMPs. In M1+M23 cells, 4- to 6-nm IMPs were in arrays of intermediate sizes, resembling square arrays in astrocytes. Structural cross-bridges of 1 x 2 nm linked >90% of IMPs in M23 arrays ( approximately 1,000 cross-bridges per microm2) but were rarely seen in M1 cells. These studies show that M23 and M1 isoforms have opposing effects on intramembrane organization of AQP4: M23 forms large square arrays with abundant cross-bridges; M1 restricts square array assembly.

Aquaglyceroporin AQP9: solute permeation and metabolic control of expression in liver.

Aquaglyceroporins form the subset of the aquaporin water channel family that is permeable to glycerol and certain small, uncharged solutes. AQP9 has unusually broad solute permeability and is expressed in hepatocyte plasma membranes. Proteoliposomes reconstituted with expressed, purified rat AQP9 protein were compared with simple liposomes for solute permeability. At pH 7.5, AQP9 proteoliposomes exhibited Hg(2+)-inhibitable glycerol and urea permeabilities that were increased 63-fold and 90-fold over background. beta-Hydroxybutyrate permeability was not increased above background, and osmotic water permeability was only minimally elevated. During starvation, the liver takes up glycerol for gluconeogenesis. Expression of AQP9 in liver was induced up to 20-fold in rats fasted for 24-96 h, and the AQP9 level gradually declined after refeeding. No changes in liver AQP9 levels were observed in rats fed ketogenic diets or high-protein diets, but AQP9 levels were elevated in livers of rats made diabetic by streptozotocin injection. When blood glucose levels of the diabetic rats were restored to normal by insulin treatments, the AQP9 levels returned to baseline. Confocal immunofluorescence revealed AQP9 immunostaining on the sinusoidal surfaces of hepatocyte plates throughout the livers of control rats. Denser immunostaining was observed in the same distribution in livers of fasted and streptozotocin-treated rats. We conclude that AQP9 serves as membrane channel in hepatocytes for glycerol and urea at physiological pH, but not for beta-hydroxybutyrate. In addition, levels of AQP9 expression fluctuate depending on the nutritional status of the subject and the circulating insulin levels.