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Participants | depressive disorder, DSM-5, Affective Disorders | MOS | The trial was advertised through pediatricians, social media platforms, and study flyers posted at specialty clinics at the University of California Los Angeles (UCLA) Semel Institute, Los Angeles, CA; the University of Colorado Anschutz Medical Campus in Aurora, CO; and the Stanford University Department of Psychiatry, Stanford, CA, USA. We enrolled youth who met the following criteria: (1) age between 9 and 17 years, 11 mos.; (2) met DSM-5 criteria for otherwise specified BD (OSBD) or major depressive disorder, based on the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime interview for DSM-IV [A child psychiatrist conducted a separate evaluation to provide a second opinion on whether the proband met the study’s eligibility criteria. Probands who consented and were deemed study-eligible were offered medication management with this or another study-affiliated psychiatrist, who based treatment recommendations on medication guidelines developed for this population [ | PMC10324335 |
Random Assignment to Psychosocial Interventions | Once eligible, children and families were randomly assigned to FFT-HR or enhanced usual care (EC) using a dynamic allocation procedure [ | PMC10324335 | ||
Interview-based Clinical Outcome Assessments | depression, hypo/mania, syndromal | RECURRENCES | Independent evaluators who were unaware of treatment assignments conducted interviews with the youth and at least one parent at the time of randomization (covering the 4 prior months), every 4 months in year 1, and then every 6 months for up to 4 years (median follow-up of 98 weeks, range 0-255 weeks). To quantify the severity and polarity of symptoms at each follow-up interview, evaluators administered the YMRS (hypo/mania) and CDRS-R (depression) interviews covering the prior 1- and 2-week intervals, respectively. Next, evaluators rated each week of the preceding 4- or 6-month interval using the Adolescent Longitudinal Interval Follow-up Evaluation (A-LIFE) Psychiatric Status Ratings (PSRs) [PSR data were used to define the time to recovery from pretreatment symptoms (all PSR scales ≤ 2 (mildly symptomatic) for ≥ 8 consecutive weeks) and among those who recovered during follow-up, time to new mood episodes or recurrences (≥ 2 weeks with PSR depression ratings of 4 (syndromal, moderate severity) or higher, or ≥ 1 week PSR hypo/mania ratings of 5 (syndromal) or higher). Interrater reliabilities for weekly depression and hypo/mania PSRs were 0.88-0.99 (intraclass rs) across raters at three sites. | PMC10324335 |
Self-report Assessments | Ideation | To expand our understanding of the symptom and functional impact of psychosocial interventions, high-risk probands completed a battery of questionnaires at intake and at each 4-6 months follow-up: the 15-item Suicidal Ideation Questionnaire, Junior Version [ | PMC10324335 | |
Statistical Analyses: Comparisons of Treatment Groups for Symptomatic Outcomes | depression, hypo/mania | Details of the statistical modeling are described elsewhere [Using repeated measures mixed-effect models, we examined the main and interactive effects of treatment (FFT-HR versus EC) and study assessment visit (every 4 months in year 1 and every 6 months thereafter) as predictors of depression or hypo/mania (mean weekly PSR) severity scores. In mediational analyses, we examined changes in family functioning as measured by the child’s reports on the Conflict Behavior Questionnaire (CBQ) and the Social Adjustment Scale-Self Report as mediators of the association between treatment condition and PSR scores from baseline to post-treatment and end of follow-up. To model mediation effects, PSR scores at follow-up were regressed on treatment group and youth’s CBQ or Social Adjustment Scale scores from the prior 4-6 month assessment interval, with random intercepts and slopes fitted within-subject. Indirect effects were estimated and bootstrapped with 1000 iterations to test the effects of the treatment group on PSR scores | PMC10324335 | |
Neuroimaging Hypotheses and Protocol | mood instability | CORTEX | We examined changes in neural functioning from before to after 4 months of psychosocial treatment using functional magnetic resonance imaging (fMRI). Youth were scanned only if they did not have MRI contraindications (Broadly, we hypothesized that intrinsic networks and neural network function subserving emotional control and problem-solving would be enhanced by FFT-HR compared to EC. Specifically, during rest, we hypothesized that FFT-HR would increase cortico-limbic connectivity to a greater extent than EC and that treatment-related changes in connectivity would correlate with pre- to post-treatment improvements in symptom severity. During emotion processing, we hypothesized that youth in FFT-HR would show greater reductions in amygdala activation and greater increases in DLPFC and ventrolateral prefrontal cortex (VLPFC) activation compared to those in EC. Further, we hypothesized that decreases in amygdala activation and increases in DLPFC activation would be associated with symptom improvement over the pre- to post-treatment interval. During problem solving, we hypothesized that changes in corticolimbic activation would correspond with changes in mood instability, which is frequently reported by parents and probands when the latter are challenged with daily complex executive functioning tasks, such as addressing conflicts within the family. | PMC10324335 |
Neuroimaging Analyses | depression | Resting-state functional connectivity analyses aimed to examine changes in task-free correlational networks from pre- to post-treatment. We examined (a) default mode networks known for self-control and rumination during depression and (b) salience networks responsible for emotional expression. Group independent component analysis after automatic detection and removal of motion-related artifacts [Second, emotion processing was evaluated using an implicit emotion perception task, in which subjects viewed photographs of young adult faces with happy, fearful, or calm expressions. Subjects were instructed to press a button to indicate the gender of each face, intending for the neural processing of emotion to be implicit. This task has been shown to reliably activate the amygdala in healthy youth and adults [Finally, the youth engaged in a novel problem-solving task that involved viewing both family-oriented problems ( | PMC10324335 | |
RESULTS | PMC10324335 | |||
Clinical Outcomes | hypo/mania, Depressive, bipolar I or II disorders, depressive symptoms | The sample characteristics are described in Table The FFT-HR and EC groups were matched in treatment duration (4 months) but not in the number of sessions (12 There was no evidence that the treatment delayed or prevented the onset of bipolar I or II disorders, which was observed in 18 of the 113 cases (15.9%) with at least one follow-up assessment. Depressive symptoms were far more common during follow-up than symptoms of hypo/mania, with about half (50.8%) of the sample experiencing a course characterized by persistent depressive symptoms, 16.5% experiencing an ongoing, moderately symptomatic course, and one-third (32.5%) experiencing a significantly improving course over time [ | PMC10324335 | |
Psychosocial Variables in the Pathway from Treatment to Symptomatic Outcomes | What psychosocial factors might explain the effects of FFT-HR on the symptomatic course of youth with high-risk phenotypes? In a recent article [We observed a similar pattern in a separate analysis [ | PMC10324335 | ||
Neuroimaging Results | What neural factors might explain the effects of FFT-HR (compared to EC) on the symptomatic course of youth with high-risk phenotypes? Out of 72 participants (out of a possible 83 at UCLA and Stanford) who received neuroimaging scans at baseline, 40 were scanned again after the 4-month interventions; usable resting state data were available for 34 (Fig. Table | PMC10324335 | ||
Neuroimaging, I: Changes in the Resting State | Depression | Examining interactions between the treatment group (FFT-HR, n=17 Adjusting for age, sex, and scanner site, post-minus pre-treatment changes in anterior DMN connectivity were significantly correlated with post-minus pre-treatment changes in Children’s Depression Rating Scale scores in the FFT-HR group (r= -0.71 p=0.006) but not in the EC group (r= -0.07; p=0.82; Fisher’s | PMC10324335 | |
Neuroimaging, II: Treatment-related Changes in Emotion Perception Using the Facial Expression Task | Twenty youth in FFT-HR and 20 in EC were included in the whole brain voxel-wise analysis of pre- to post-treatment neural changes during face emotion processing [ | PMC10324335 | ||
Neuroimaging, III: Changes in Neural Activity During a Problem-solving Task | mood instability | Analyses of neural activation during the problem-solving task were conducted with 16 subjects in the FFT-HR group and 20 in the EC group with useable data for this task. At the pre-treatment scan, results from a whole brain voxel-wise analysis, with family-wise error correction for multiple comparisons at the cluster level, showed that imagining and solving family problems were associated with enhanced activity in medial frontal, lateral frontal, and cingulate cortices, regions that play a key role in processes of introspection, emotion regulation, and conflict resolution. In a whole brain voxel-wise analysis comparing pre- to post-treatment changes in activation while participants viewed statements of family problems, the FFT-HR group, but not the EC group, showed treatment-related increases in activation in bilateral caudate/thalamus (Max Z = 3.92, Notably, these results were associated with viewing and solving family problems but not viewing or solving non-familial problems. Covarying for age or sites balanced with medication exposures did not change these results. Thus, observed neural changes were specific to salient family-related stimuli and corresponded with improvements in mood instability. | PMC10324335 | |
DISCUSSION | ideation, ideation/behavior, mood instability, rigidity, depressive, hypo/mania, depressive symptoms, depression, Depression | CORTEX | In this article, we have presented clinical, psychosocial, and neuroimaging results from one of the first randomized trials of a psychosocial intervention in the early stages of BD. Following phenomenological research on offspring of parents with BD [Our results suggest that in high-risk youth, a brief family psychoeducational therapy is effective in reducing the likelihood of new depressive episodes and suicidal ideation or behaviors over an average of 2 years after a period of mood symptoms. We identified possible psychosocial and neural mediating mechanisms of these treatment effects. First, the youth’s view of family functioning, such as whether the mother/child relationship is characterized by high or low conflict, is an important mediator of whether children show improvements in depressive symptoms or suicidal ideation/behavior in FFT-HR compared to EC. Whether it is critical to work directly with the family to achieve these changes in youth’s perceptions or whether such changes can emerge from individual cognitive restructuring or acceptance-based interventions deserves investigation.The neuroimaging results have implications for understanding brain mechanisms in high-risk youth at rest while processing emotions and while attempting to regulate emotions during problem-solving, as well as the ways in which these functions change with psychosocial intervention. Resting-state findings indicate that compared to EC, FFT-HR was associated with stronger connectivity between the VLPFC and aDMN, possibly indicating enhanced self-awareness, illness awareness, and emotion regulation. Stronger connectivity was associated with improvements in mood lability on the parent-rated CALS. FFT-HR was also associated with increased anterior DMN connectivity, which was correlated with pre- to post-treatment improvements in Children’s Depression Rating Scale scores. DMN connectivity, in concert with enhanced prefrontal connectivity, may reflect adaptive changes in neural networks indicative of “neural reserve” or the capacity to tolerate brain insults [Changes in neural networks in youth at risk for BD are observable at rest prior to symptom onset, as demonstrated by previous findings that VLPFC-caudate dysconnectivity correlates with family chaos and amygdala-fusiform dysconnectivity correlates with family rigidity in healthy offspring of parents with BD, compared to offspring of healthy parents or offspring of parents with depression [We observed that during the emotion processing task, DLPFC activation increased from pre- to post-treatment in the FFT-HR group but not in the EC group. These increases were also correlated with improvement in depressive symptoms, while pre/post decreases in amygdala/hippocampal activation were correlated with improvement in hypo/mania symptoms. In the family situations problem-solving task, activation in the medial frontal cortex increased from pre- to post-treatment in the FFT-HR group more than in the EC group, and was correlated with improvements in mood instability. Thus, across tasks, psychosocial treatment was associated with the enhancement of emotion regulation circuitry, although the specific location within the frontal cortex differed based on task design and demands.Our findings indicate changes during treatment in corticolimbic networks that promote emotion regulation, self-reflection, and awareness. These changes correlate with improvements in symptoms and behavior, and they occur to a greater extent in FFT-HR than in standard psychoeducation. Together, these neuroimaging findings across rest and task-based fMRI suggest that the change mechanisms of FFT-HR and EC may be separable, with FFT-HR having a greater association with executive regulatory control through the prefrontal cortex, commensurate with the teaching of communication and problem-solving skills in FFT-HR that promote these functions. | PMC10324335 |
Study Limitations | primary and comorbid | First, the sample sizes for the neuroimaging analyses were modest. Nonetheless, we found robust and consistent results across resting and task-based fMRI after correcting for multiple comparisons and adjusting for neuroimaging site, age, and sex. Second, high-risk youth were clinically heterogeneous, and were on a variety of medication regimens, with random assignment stratified on whether the participant was taking a mood stabilizing or antipsychotic agent or neither. HR youth had primary and comorbid diagnoses that are typical of bipolar offspring samples, who are frequently treated with a combination of psychosocial and pharmacological interventions. The treatment groups were not significantly different in distributions of diagnoses or medication exposure at baseline or follow-up, and univariate analyses did not find that primary diagnosis or medication class predicted treatment-related differences in the neuroimaging results.Third, the EC condition was matched to the FFT-HR condition in duration (4 months) but not in the number of sessions (12 Finally, we could not disentangle the specific components of FFT-HR that map onto changes in psychosocial or neural variables. Within-person changes resulting from psychoeducation ( | PMC10324335 | |
CONCLUSION | ideation, manic, ’s mood swings, bipolar illness, mania, depressive, hypomania, depression | DISORDER | What have we learned about high-risk states in BD? First, working with families of high-risk youth on their understanding of the child’s mood swings and their ability to communicate and solve problems may be associated with a more favorable trajectory of mood symptoms and reductions in suicidal ideation and behavior. The effects of family intervention in the high-risk period appear to be more consistently focused on depression than on hypomania or mania, possibly reflecting the dominant polarity of symptoms early in the course of the disorder [FFT-HR appears to enhance neural circuits that underlie emotion regulation, such as activity in prefrontal and executive control regions critical for adaptive self-regulation, especially in the context of the significant and known family environmental disturbances associated with bipolar illness [We were unable to show that FFT-HR is effective in preventing the onset of syndromal BD I or II. Although FFT-HR had preventative effects on depressive episodes, the incidence of conversions to bipolar I or II, and more generally of new onset manic episodes, was relatively low (16%) over the short period of follow-up (average 2 years). Studies in which high-risk youth are followed over longer periods may demonstrate the preventative effects of family or other psychosocial interventions. Other approaches to early intervention that emphasize skill-building, such as dialectical behavior therapy [ | PMC10324335 |
ACKNOWLEDGEMENTS | The authors wish to thank the teams of diagnostic assessors, treating psychiatrists and psychologists, research assistants, and methodology consultants who provided assistance to this study. | PMC10324335 | ||
LIST OF ABBREVIATIONS | Specified Bipolar Disorder, bipolar disorder | ANTERIOR, CORTEX | Anterior Default Mode NetworkBipolar DisorderChildren’s Affective Lability ScaleConflict Behavior QuestionnaireDorsolateral Prefrontal CortexEnhanced CareFamily-Focused Therapy for High-Risk YouthOther Specified Bipolar Disorder (formerly bipolar disorder, not otherwise specified)Psychiatric Status Ratings from Adolescent Longitudinal Interval Follow-up EvaluationVentrolateral Prefrontal Cortex | PMC10324335 |
ETHICS APPROVAL AND CONSENT TO PARTICIPATE | The study was conducted in accordance with the Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects. The study was approved by the Medical Institutional Review Boards of the University of California, Los Angeles Semel Institute, University of Colorado Anschutz Medical Campus, and Stanford University. All participating family members and children signed approved informed consent or assent documents before participating in the study. | PMC10324335 | ||
HUMAN AND ANIMAL RIGHTS | No animals/humans were used for studies that are the basis of this research. | PMC10324335 | ||
CONSENT FOR PUBLICATION | Not applicable. | PMC10324335 | ||
AVAILABILITY OF DATA AND MATERIALS | Not applicable. | PMC10324335 | ||
FUNDING | Financial support for this study was provided by US National Institute of Mental Health (NIMH) grants R01-MH093676, R01-MH093666, R34-MH117200, and R01-MH123575. The funding sources had no role in the design or conduct of the study; the collection, management, analysis and interpretation of data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. | PMC10324335 | ||
CONFLICT OF INTEREST | Johnson and Johnson, Alkermes, and Neumora | BRAIN | Dr. Miklowitz receives research support from the National Institute of Mental Health (NIMH), the Danny Alberts Foundation, Attias Family Foundation, Carl and Roberta Deutsch Foundation, Kayne Family Foundation, AIM for Youth Metal Health, and Max Gray Fund; and book royalties from Guilford Press and John Wiley and Sons. Dr. Weintraub reports research support from NIMH and AIM for Youth Mental Health. Dr. Walshaw receives research support from Bluebird Biotech and Second Sight. Dr. Schneck receives research support from the NIMH and the Ryan White Foundation. Dr. Chang is a consultant for Sunovion, Abbvie, and COMPASS Pathways. He is also on the speakers’ bureau for Sunovion. Mr. Merranko reports no biomedical financial interests or potential conflicts of interest. Dr. Garrett receives research support from the Baptist Health Foundation of San Antonio, the Texas Child Mental Health Care Consortium, and the Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center San Antonio. Dr. Singh has received research support from Stanford’s Maternal Child Health Research Institute and Stanford’s Department of Psychiatry and Behavioral Sciences, NIMH, National Institute of Aging, Patient Centered Outcomes Research Institute, Johnson and Johnson, and the Brain and Behavior Research Foundation. She is on the advisory board for Sunovion and Skyland Trail, and is a consultant for Johnson and Johnson, Alkermes, and Neumora. She has previously consulted for X, moonshot factory, Alphabet Inc. and Limbix Health. She receives honoraria from the American Academy of Child and Adolescent Psychiatry and royalties from the American Psychiatric Association Publishing and Thrive Global. | PMC10324335 |
Subject terms | cardiometabolic diseases, metabolic syndrome, fasting blood glucose | METABOLIC SYNDROME | Low-education women, a substantially older population, are subject to increased risks of metabolic syndrome and consequent cardiometabolic diseases; early detection and effective management were urgently needed. Ninety-nine women with metabolic syndrome, age 61 and education ≤ 6 years, from four community units were randomly assigned to either a self-management intervention (n = 51) or a control arm (n = 48). The intervention consisted of five dimensions, physical activity and diet modifications (daily exercise classes and two nutrition courses), goal setting, coaching and peer support, problem-solving, and self-monitoring. The control arm received an education leaflet. Assessments were performed at baseline, six months, and 18 months. Compared with the control, the intervention participants improved the overall rate of meeting the recommended servings for six health foods, including vegetables, dairy products, and nuts (except whole grains, fruits, and protein); the rate of meeting regular leisure-time physical activity; and criteria biomarkers—waist circumference, fasting blood glucose, high-density lipoprotein cholesterol (except blood pressure and triglycerides); as well as body weight and body mass index; consequently decreased the number of risk factors and rate of metabolic syndrome. In conclusion, the multidimensional self-management intervention improved physical activity, healthy eating, and metabolic syndrome risks among low-education women with metabolic syndrome. | PMC10293226 |
Introduction | cardiometabolic diseases like heart disease, stroke, impaired fasting blood glucose, abdominal obesity, MetS, Metabolic syndrome | CARDIOVASCULAR DISEASE, STROKE, ELEVATED TRIGLYCERIDES, METABOLIC SYNDROME, HIGH BLOOD PRESSURE, METABOLIC SYNDROME | Metabolic syndrome (MetS), a condition caused by the presence of a cluster of risk factors—abdominal obesity (large waist circumference) and two or more other risks, elevated triglycerides, high blood pressure, impaired fasting blood glucose, or low high-density lipoprotein cholesterol (HDL-C), increases the chance of developing cardiometabolic diseases like heart disease, stroke, and diabetesFor management of metabolic syndrome, lifestyle behavior modification is essential, that is to eat healthy foods—whole grains, fruits, vegetables, lean meats, skinless poultry, non-fried fish, and low-fat or fat-free dairy products; limit unhealthy foods—processed foods, saturated and trans fats, red meat, sodium, and added sugars; become physically active—moderate-vigorous physical activity at least 30 min a day, and most day of the week; and lose weightThe effectiveness of self-management interventions for improving healthy lifestyle behaviors and associated health outcomes have been studied among patients with cardiovascular diseaseAn effective self-management intervention should be holistic with diverse approaches | PMC10293226 |
Aims and hypotheses | METABOLIC SYNDROME | This study aimed to examine the efficacy of a multidimensional self-management intervention on low-education women with metabolic syndrome. We hypothesized that the intervention would improve individual-level health-promotion behaviors—physical activity and healthy diet, and metabolic syndrome and its related biomarkers during and after the intervention period compared with the attention control arm. | PMC10293226 | |
Methods | PMC10293226 | |||
Design | metabolic syndrome | METABOLIC SYNDROME, RECRUITMENT | This study was an 18-month two-arm parallel cluster randomized controlled trial with a 1:1 allocation ratio. Recruitment period was from September to October 2017 and follow-up period was from November 2017 to April 2019. The intervention arm received a self-management program, while the attention-control arm received a health education leaflet about metabolic syndrome care. Three assessments were performed—at baseline, six months, and 18 months. Blinding the study participants, investigators, volunteers, and outcomes assessors (except the technicians who did the blood analysis) was not possible because they knew what type of treatment was being received or delivered to engage in that treatment. | PMC10293226 |
Participants and setting | cognitive impairment, abdominal adiposity, dementia, hearing and visual acuity difficulties | METABOLIC SYNDROME | Potential participants were recruited from four conveniently chosen communities in northern Taiwan. With an estimated median distance of 8.35 km (range 7.2–9.7 km), contamination, spill-over of intervention effects to the control, was considered minimal as communications or acquaintance between the intervention and control arm were unlikely. Having abdominal adiposity (waist circumference ≥ 80 cm in Chinese females or body mass index (BMI)> 30 kg/mInclusion criteria were (1) adult women with age ≥ 50 years, (2) low education, defined as having less than 6 years of education or being primary school graduates, (3) presence of metabolic syndrome, (4) community-dwelling, and (5) no hearing and visual acuity difficulties. Unconscious or individuals with cognitive impairment or dementia were excluded.Using the statistical power analysis of G*Power 3.1.7 software | PMC10293226 |
Recruitment and randomization | metabolic syndrome | METABOLIC SYNDROME | One-hundred and sixty women were screened initially, 55 without metabolic syndrome were excluded, two declined. The four community units with 103 women were randomly assigned to either the intervention or control arm by drawing lots enclosed in sealed opaque envelopes. Each arm consisted of two community units. Two participants were lost in each arm during the follow-up because of moving or loss of contact. Ninety-nine participants, 51 in the intervention arm and 48 in the control arm, completed the study. The retention rate was 96.2% for the intervention arm and 96.0% for the control arm. The principal investigator, enrolled and assigned participants in random order to study arms. We received no complaints of related discomfort or injuries from the participants. The study design flowchart is shown in Fig. Study design flowchart. | PMC10293226 |
The self-management program | The intervention consisted of five dimensions—lifestyle modification, goal setting, coaching and peer support, problem-solving, and self-monitoring. | PMC10293226 | ||
Lifestyle modification | We applied three of the five World Health Organization’s Key Actions for Health Promotion | PMC10293226 | ||
Providing supportive environments and accessible resources | We worked with the intervention community managers to identify vicinity sites, such as community-based activity centers, for administering exercise classes, nutrition courses, and related physical and clinical assessments. | PMC10293226 | ||
Providing simple exercise skills and group course | We offered daytime community health volunteer-supervised aerobic exercise classes for 40 min a day, 5 days a week, throughout the 18-month intervention. Exercise specialists designed the exercises, which composed of three parts—warm-up, main activity (aerobics), and cool down (stretching). Additional supervised 40-min and 5 days a week nighttime walking session were offered. | PMC10293226 | ||
Providing nutrition courses and simple healthy meal plans | To implement the dietary guidelines | PMC10293226 | ||
Goal setting | The goal was to engage in moderate to vigorous exercise 30 min or more per day, five days or more per week, and to adhere to the 2018 Taiwan’s Daily Food Guide | PMC10293226 | ||
Coaching and peer support | metabolic syndrome | METABOLIC SYNDROME | One nurse investigator, one trained community health volunteer, and 6–7 participants formed a peer support group. Each group took a 12-hour course provided by the research team and the metabolic syndrome experts to learn about exercise, healthy diet, behavior change, communication skills, and methods of physical measurements (body weight, height, waist circumference, and blood pressure). To empower participants to meet the goal, the peers (nurses and community health volunteers) set the same goal, provided education, and shared experience to encourage participants by phone calls or LINE messages once weekly during the first six months and once monthly thereafter. | PMC10293226 |
Problem-solving | The most common problem encountered was the concern of the safety commuting to exercise sites on rainy days. The community health volunteers and the participants conferred to reach feasible alternatives, such as following the exercise videos shown on YouTube or digital video discs. | PMC10293226 | ||
Self-monitoring | fasting blood glucose | The intervention participants were encouraged to visit nearby support sites monthly to monitor their body weight, body mass index, waist circumference, blood pressure, and fasting blood glucose. To monitor and reinforce healthy activities, each participant kept a health passport containing personal measurements recorded by the community health volunteers, and weekly exercise and dietary logs entered by crossing a checklist to allow for the low literacy of participants. | PMC10293226 | |
Data collection | To obtain accurate and quality data from low- or no-literacy participants, trained investigators used fact-to-face interviews to ensure complete cooperative responses, capture verbal and non-verbal cues, and control interactions. There were neither missing data in demographic characteristics, medical history, lifestyle behaviors nor biomarker assessments at baseline and follow-up. | PMC10293226 | ||
Participant characteristics | DISEASES | Participant characteristics included demographic data—age, employment, education, and marital status; medical history—diseases and medicine use; smoking and drinking. | PMC10293226 | |
Biomarkers of metabolic syndrome | We followed the World Health Organization’s Physical Measurements Guideline | PMC10293226 | ||
Leisure-time physical activity | Leisure-time physical activity (LTPA) was assessed using two questions modified from studies of Gionet and Godin | PMC10293226 | ||
Healthy diet behaviors | Participants were asked six questions based on Daily Food Guide of the Taiwan Health Promotion Administration, Ministry of Health and Welfare | PMC10293226 | ||
Data analysis | METABOLIC SYNDROME | We used the Statistical Package for Social Sciences (SPSS) software version 27.0 (International Business Machines Corporation, Armonk, NY, USA). All statistical tests were two-sided with 0.05 levels of statistical significance (α). Descriptive analysis included means, standard deviations, and frequency distribution (percentages) for the demographic, lifestyle behaviors, and biomarkers of metabolic syndrome. A number of the baseline intervention and control arm continuous variables failed the Shapiro–Wilk test of normality. The Chi-square test for dichotomous variables and the Mann–Whitney U test for continuous and ordinal variables examined baseline differences between the intervention and control arms. Generalized estimating equations (GEE) compared rates of change between the intervention and control arms from baseline to the six- and 18-month assessments.The effect size was obtained by pooling estimates across both pretest and posttest standard deviations for weighting the differences of the pre-post-means to account for intervention’s influence on the standard deviation. Additionally, a bias correction was appliedEffect size for frequency data was computed based on Binomial Effect Size Display | PMC10293226 | |
Ethics approval and consent to participate | We followed the declaration of Helsinki. The ethical committee of a medical center in Taiwan approved this study on February 15, 2017 (No. 201602059A3). All participants were assured that their anonymity and confidentiality would be preserved and that they could withdraw from the study at any time and for any reason. Signed informed consent was obtained from each participant before enrollment into the study. | PMC10293226 | ||
Results | PMC10293226 | |||
Effects of the self-management intervention | Table | PMC10293226 | ||
Acknowledgements | The authors thank all the participating subjects, the community managers, and the community health volunteers. Special acknowledgment is extended to Miss Kuan-Ying Kao, the study’s research assistant. | PMC10293226 | ||
Author contributions | S.H.C., Y.Y.C., and W.J.J. designed and conducted the study. S.H.C. and Y.Y.C. analyzed and interpreted the data and prepared the first draft. W.J.J. produced figures and tables. J.P.M.W. analyzed and interpreted the data and substantially revised the manuscript. All authors critically reviewed and approved the revised manuscripts. | PMC10293226 | ||
Funding | This study was supported by the Ministry of Science and Technology (MOST 107-2314-B-255-006, MOST 109-2314-B-255-002, and MOST 110-2314-B-255-007) and Chang Gung University of Science and Technology (ZRRPF3L0011 and ZRRPF3M0051), Taiwan. The funding source did not involve any parts of the study, including its design, execution, analyses, interpretation of the data, or decision to submit results. | PMC10293226 | ||
Data availability | The datasets generated and analyzed in the current study are not publicly available due to the identity information contained in the data. Deleting this information can obtain them from the corresponding author upon reasonable request. | PMC10293226 | ||
Competing interests | The authors declare no competing interests. | PMC10293226 | ||
References | PMC10293226 | |||
Subject terms | BRAIN | Brain dopamine may regulate the ability to maintain and manipulate sequential information online. However, the precise role of dopamine remains unclear. This pharmacological fMRI study examined whether and how the dopamine D2/3 receptor agonist pramipexole modulates fronto-subthalamic or fronto-striatal pathways during sequential working memory. This study used a double-blind, randomized crossover design. Twenty-two healthy male volunteers completed a digit ordering task during fMRI scanning after receiving a single oral dose of 0.5-mg pramipexole or placebo. The pramipexole effects on task performance, regional activity, activity pattern similarity, and functional connectivity were analyzed. Pramipexole impaired task performance, leading to less accurate and slower responses in the digit ordering task. Also, it downregulated the maintenance-related subthalamic and dorsolateral prefrontal activity, increasing reaction times for maintaining sequences. In contrast, pramipexole upregulated the manipulation-related subthalamic and dorsolateral prefrontal activity, increasing reaction time costs for manipulating sequences. In addition, it altered the dorsolateral prefrontal activity pattern similarity and fronto-subthalamic functional connectivity. Finally, pramipexole reduced maintenance-related striatal activity, which did not affect the behavior. This study confirms the role of the fronto-subthalamic pathway in sequential working memory. Furthermore, it shows that D2 transmission can regulate sequential working memory by modulating the fronto-subthalamic pathway. | PMC10066371 | |
Introduction | CORTEX, BRAIN | Brain dopamine is known to regulate visuospatial working memory [In visuospatial working memory, the dual-state theory of prefrontal dopamine function [Distinct roles of D1 We have put forward a fronto-basal ganglia model for sequential working memory [We hypothesize that activation of D2/3 receptors regulates sequential working memory by modulating the fronto-subthalamic hyperdirect or fronto-striatal indirect pathway. D2 receptors are abundant in the striatum and also found in the subthalamic nucleus (STN) and frontal cortex [ | PMC10066371 | |
Materials and methods | The study was approved by the ethics committee of the University of Lübeck following the Declaration of Helsinki. All participants signed written informed consent before participating in this study. | PMC10066371 | ||
Participants | excessive head motion (mean total displacement, neurological or psychiatric disease | We only recruited male volunteers to avoid problems that could arise with unknown pregnancies in female volunteers. Twenty-six healthy men participated (mean age 26.0 ± 4.1 years, range 20–38 years). They were right-handed and had normal or corrected-to-normal vision. None of them had a history of neurological or psychiatric disease. All of them were free of medication. Four participants were excluded because of excessive head motion (mean total displacement >1.5 mm, | PMC10066371 | |
Study design | nausea | This study had a double-blind, randomized crossover design. Participants received pramipexole and placebo in separate sessions at least seven days apart (mean interval 40.4 ± 34.2 days). At each session, they received 10-mg domperidone in a non-blind fashion to antagonize nausea and other potential side effects induced by pramipexole [ | PMC10066371 | |
Digit ordering task | All participants conducted the digit ordering task during fMRI scanning (Fig. | PMC10066371 | ||
Analysis of task performance | We controlled behavioral data quality by monitoring premature (reaction time, RT, shorter than 0.1 s) and inattentive responses (RT longer than 3 SDs above the individual mean). Participants made no premature response and very few inattentive responses (pramipexole: 1.1%, placebo: 1.5%). The inattentive responses were excluded from further analysis.First, we detected the pramipexole effects on accuracy and RT using ANOVAs with two factors ( | PMC10066371 | ||
Acquisition of MRI and fMRI data | BRAIN | Brain imaging data were acquired on a Siemens Magnetom Skyra 3 T MRI scanner with a 64-channel head coil. Structural T1-weighted images used a magnetization-prepared rapid gradient-echo sequence (208 sequential sagittal slices, repetition time 2300 ms, echo time 2.43 ms, inversion time 1100 ms, flip angle 8°, field of view 240 × 240 mmFunctional T2*-weighted images used a simultaneous multi-slice echo-planar imaging sequence with acceleration factor 4 (56 interleaved axial slices, repetition time 1000 ms, echo time 30 ms, flip angle 60°, field of view 204 × 204 mmField map images used a gradient echo sequence (46 axial slices, repetition time 489 ms, short echo time 4.92 ms, long echo time 7.38 ms, flip angle 60°, field of view 204 × 204 mm | PMC10066371 | |
Preprocessing and analysis of fMRI data | REGRESSION | fMRI data were processed using SPM12 (v7771, We controlled fMRI data quality by monitoring the scan-to-scan total displacement (mean total displacement <1.5 mm) [First, we replicated the manipulation-related regional activation. The general linear model convolved a design matrix with a canonical hemodynamic response function at the subject level. The design matrix included correct and incorrect ordered and random trials as separate regressors. Each trial was time-locked to its onset. The total displacement was included as a nuisance regressor. Classical parameter estimation was applied with a one-lag autoregressive model. The manipulation-related activation was defined as correct random Second, we detected pramipexole effects on regional activity in fronto-subthalamic and fronto-striatal pathways. The left dlPFC and left striatal regions were derived from a meta-analysis of 1091 fMRI studies on working memory (NeuroSynth) [Third, we explored relationships between behavior and fronto-subthalamic and fronto-striatal pathways. We examined whether the pramipexole-induced RT change (ordered trials) correlated with the maintenance-related regional activity change in the dlPFC, STN, or striatum (stepwise regression in the IBM SPSS, Fourth, we detected pramipexole effects on prefrontal activity pattern similarity. Beta values of ordered and random trials (i.e., model-based estimates of fMRI signals without time dimension) were extracted from dlPFC voxels and sorted spatially according to MNI coordinates. Pearson correlation coefficients were computed between the betas of ordered trials and those of random trials, normalized using Fisher’s transformation, and entered into a paired Finally, we detected pramipexole effects on fronto-subthalamic functional connectivity. Raw fMRI signals were extracted from the left dlPFC and left STN regions and demeaned. Pearson correlation coefficients were computed between the dlPFC and STN signals, normalized using Fisher’s transformation, and entered into a paired | PMC10066371 | |
Results | PMC10066371 | |||
Pramipexole impaired task performance | sleepiness | Pramipexole impaired digit ordering task performance (Fig. The pramipexole effect on RT persisted across serial positions and experimental blocks (Fig. The pramipexole effect on RT was unlikely due to sleepiness or other side effects of the drug. Participants responded equally fast in an independent decision-making task under pramipexole | PMC10066371 | |
Relationships between task performance and fronto-subthalamic pathway | Figure | PMC10066371 | ||
Pramipexole reduced prefrontal activity pattern similarity | Figure | PMC10066371 | ||
Pramipexole enhanced fronto-subthalamic functional connectivity | Pramipexole enhanced the functional connectivity between the left dlPFC and left STN (paired | PMC10066371 | ||
Discussion | PD | BRAIN | Brain dopamine may regulate sequential working memory. Dopamine deficiency in PD leads to difficulties in diverse sequencing tasks that rely on the persistent maintenance and flexible manipulation of sequential information [A single oral dose of the D2/3 receptor agonist pramipexole led to less accurate and slower responses in the digit ordering task. Also, it downregulated the dlPFC, STN, and striatal regional activity for maintaining sequences (ordered trials). In contrast, pramipexole upregulated the dlPFC and STN regional activity for manipulating sequences (random | PMC10066371 |
Fronto-basal ganglia loops and sequential working memory | In the fronto-basal ganglia model for sequential working memory [This study confirmed the role of the fronto-subthalamic pathway in sequential working memory. The relationship between D2-receptor modulated STN activity and sequential working memory is non-linear: both insufficient and excessive STN activity impairs sequential working memory [ | PMC10066371 | ||
Non-linear relationships between STN and sequential working memory. | The non-linear relationship is presented as a quadratic function for simplicity. Other non-linear functions are possible [ | PMC10066371 | ||
D2/3 transmission in the fronto-subthalamic pathway | CORTEX | A novel finding is that D2 receptor activation can downregulate the maintenance-related STN and dlPFC activity and dlPFC activity pattern similarity but upregulate the manipulation-related STN and dlPFC activity and fronto-subthalamic functional connectivity. Although the STN and frontal cortex have a much lower density of D2 receptors than the striatum [Mechanisms underlying the observed maintenance-related activity downregulation and manipulation-related activity upregulation remain unclear. For the prefrontal cortex, the maintenance-related activity change may result from decreased regional cerebral blood flow. Black et al. [Futhermore, D2 transmission can modulate membrane resonance of STN neurons and high-voltage spindles (HVSs) in the fronto-basal ganglia loops. Yang et al. [ | PMC10066371 | |
D2 transmission and sequential working memory | sleepiness, behavioral deficits | A second novel finding is that D2 receptor activation can negatively affect sequential working memory. Pramipexole can impair sequence maintenance by inhibiting maintenance-related STN activity and impair sequence manipulation by enhancing manipulation-related STN activity. Another possibility is that pramipexole slowed down information processing in general, although sleepiness and other side effects of pramipexole have been minimized. Additionally, despite no direct correlation, pramipexole-induced dlPFC activity pattern similarity or fronto-subthalamic functional connectivity change might produce behavioral deficits.This finding is not entirely consistent with previous pharmacological studies and dopaminergic models of visuospatial working memory. For example, the D2 receptor agonist bromocriptine and the partial agonist aripiprazole can increase the dlPFC activity for maintaining visual objects or spatial locations [The inconsistency between our observation and previous studies is not unexpected. The cognitive and neural mechanisms that encode and retrieve sequential information may differ from those that encode and retrieve visuospatial information. For example, Ranganath and colleagues found that frontal theta power was enhanced for maintaining serial positions over visual features of the same item in healthy adults [ | PMC10066371 | |
D2 transmission in the fronto-striatal pathway | PD | A third finding is that D2 receptor activation can downregulate the striatal activity for maintaining (but not manipulating) sequences. This finding is compatible with our previous results. First, the striatum is hypo-activated in PD patients medicated with D2/3 receptor agonists and levodopa [D2 receptors are abundant in the striatum [The role of striatal D2 transmission might differ in sequential | PMC10066371 | |
Limitations | A major limitation is that female volunteers were excluded, and women might respond differently to pramipexole during sequential working memory. As there are concerns about giving pramipexole to women of childbearing age [ | PMC10066371 | ||
Conclusions | This study shows that D2 receptor activation could modulate the fronto-subthalamic pathway during sequential working memory. The D2/3 receptor agonist pramipexole downregulated the maintenance-related STN and dlPFC activity, increasing reaction times for maintaining sequences. In contrast, pramipexole upregulated the manipulation-related STN and dlPFC activity, increasing reaction time costs for manipulating sequences. In addition, pramipexole altered the dlPFC activity pattern similarity and fronto-subthalamic functional connectivity. It also reduced maintenance-related striatal activity, which did not affect the behavior. This study confirmed the role of the fronto-subthalamic pathway in sequential working memory. Furthermore, it shows that both insufficient and excessive STN activity can impair sequential working memory. Our finding does not fit neatly with existing dopaminergic models of working memory and therefore suggests the need for more work in this area. | PMC10066371 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41386-022-01494-z. | PMC10066371 | ||
Author contributions | MH, NB | NB, TFM, and ZY designed the study. MH, EM, and AK collected the data. ZY analyzed the data. ZY and TFM wrote the original draft of the manuscript. MH, EM, AK, and NB reviewed and edited the manuscript. All authors approved the submitted version. | PMC10066371 | |
Funding | This work was supported by the German Research Foundation (MU 1311/20-1) and the National Natural Science Foundation of China (31961133025) and the Innovation of Science and Technology 2030 (2021ZD0203600). | PMC10066371 | ||
Competing interests | The authors declare no competing interests. | PMC10066371 | ||
References | PMC10066371 | |||
1. Introduction | NSSI, Non-suicidal self-injury, death | Background: Non-suicidal self-injury (NSSI) is a common mental health problem, with a 19% lifetime prevalence in Australian adolescents and 12% in adults. Though rates of professional help-seeking for NSSI are low, disclosure to family and friends is more common, providing opportunities for them to encourage professional support. Mental Health First AidNon-suicidal self-injury (NSSI) refers to injuries intentionally inflicted upon oneself that are not intended to result in death and are not culturally sanctioned [The most common reasons for NSSI cited by adolescents and adults are to distract or seek relief from distressing thoughts, feelings, problems, or bad memories [Help-seeking rates in people who engage in NSSI are low, with less than 50% seeking emotional support for this behaviour, and only 16% report seeking medical treatment [Conversely, responses to NSSI involving dismissive, trivialising, or stigmatising attitudes were associated with withdrawal from further help-seeking, increased frequency of NSSI, and increased suicide attempts [Although family and friends are most likely to notice signs of NSSI and receive NSSI disclosures [MHFA courses have consistently been shown to increase the mental health literacy of first aiders, reduce stigmatising attitudes towards mental health problems, and improve first aiders’ confidence in responding to mental health problems and crises [ | PMC9963380 | |
2. Materials and Methods | PMC9963380 | |||
2.1. Intervention | The Why people engage in NSSI;How to talk to someone about their NSSI;How to help the person stay safe;How to connect someone to appropriate professional help;How to assess for suicidal thoughts and behaviours. | PMC9963380 | ||
2.2. Procedures | A member of the research team contacted instructors who were delivering the Course attendees were invited to complete three surveys: one before the course (pre-course; completed on paper or online via the survey software Survey Monkey [ | PMC9963380 | ||
2.3. Measures | NSSI | In the pre-course survey, participants were asked to provide demographic information, outline any personal and professional experience with NSSI, indicate whether they had participated in any previous training related to mental health or NSSI, and the reason for attending the course. These questions were adapted from a previous evaluation on the | PMC9963380 | |
2.3.1. Knowledge about NSSI | NSSI | At each time point, participants were presented with 16 true or false questions about NSSI that were based on the course content. They were asked to respond with “Disagree”, “Agree”, or “Don’t know” (the latter was coded as an incorrect response). Knowledge scores were calculated as the percentage of correct answers (possible range: 0–100), and mastery of knowledge was set at 80%, consistent with previous evaluations [ | PMC9963380 | |
2.3.2. Stigmatising Attitudes and Social Distance | NSSI, bruising | HEAT, SCRATCHES | At each time point, participants were presented with a vignette that depicted Alicia, an 18-year-old girl who is described as “your niece”, showing warning signs for NSSI, such as “bruising and scratches on her arms and legs” and “wearing her winter clothes in spite of the heat” (see | PMC9963380 |
2.3.3. Confidence in Intended Helping in Response to the Alicia Vignette | Participants were asked how confident they were in their ability to help Alicia on a 5-point Likert scale from “Not at all confident” (a score of 1) to “Extremely confident” (a score of 5). | PMC9963380 | ||
2.3.4. Quality of Intended Helping Behaviours in Response to the Alicia Vignette | At each time point, participants were asked to rate how likely they would be to take 18 actions to support Alicia using a 5-point Likert scale from “Very unlikely” (a score of 1) to “Very likely” (a score of 5). Ten actions contrary to the course teachings and underlying guidelines [ | PMC9963380 | ||
2.3.5. Confidence in and Quality of Actual Helping Behaviours | NSSI, non-suicidal self-injury | In the pre-course and six-month follow-up surveys, participants were asked: “In the past 6 months, have you had contact with someone who you thought might be engaging in non-suicidal self-injury?” Those who answered “Yes” were asked how many people they assisted. They were then asked to provide the age range, gender, and type of relationship (e.g., family member or work colleague) of the person they had the most contact with.Participants were asked to select which, if any, of 20 possible actions they took to support the person they knew. These actions were the same as those assessing intended helping actions, plus two additional items (“I did not do anything” and “I did something else”). Participants who selected “I did something else” were asked to specify what they did in a free-text box. They were then asked how confident they were in their ability to help the person on a 5-point Likert scale from “Not at all confident” (a score of 1) to “Extremely confident” (a score of 5).Participants who reported helping a person engaging in NSSI were asked two open-ended questions with free-text response options: “What were the effects on the person of what you did?” and “What did the person do as a result of your help?” Participants who reported that they did not offer help were asked “Are there any particular reasons that you did not try to help?” and were prompted to specify these reasons in a free-text box.As with intended helping behaviour, separate scales were created for recommended and non-recommended actual helping behaviours. Concordance was calculated by summing the number of selected actions that were consistent with the guidelines and course curriculum separately for recommended and non-recommended actions. A cut-off score for mastery was set at 80% of concordant actions for both scales. This translates to a score of 7 or more of the 8 recommended actions and 8 or more of the 10 non-recommended actions. The agreement coefficient, determined from the subset of participants that responded to these items, was 0.82 for recommended actions (n = 85) and 0.83 for non-recommended actions (n = 84) [ | PMC9963380 | |
2.3.6. Course Satisfaction | In the post-course survey, participants were asked to provide information about course satisfaction, including how new, understandable, and relevant the information in the course was; how well it was presented; and how much they liked the course materials. A 5-point Likert scale was used for each question. Participants were also asked to specify what aspects of the course they found most helpful and what could be improved using a free-text response. | PMC9963380 | ||
2.4. Statistical Analysis | REGRESSION | Data were analysed using linear and logistic mixed models. Mixed models retain all available data and provide an intention-to-treat estimate of change under the assumption of missingness at random. Models included a fixed effect of time and a random effect of participants to adjust for the correlation of responses within participants over time. Logistic regression was used to explore predictors of missingness at six-month follow-up, using participant demographics and pre-course outcomes as potential predictors of attrition. Age was associated with missingness at follow-up (The stigma variable was highly skewed; therefore, a linear model was deemed inappropriate. For this outcome, mean scores were dichotomised based on scoring 1 (the lowest possible score) or scoring greater than 1 (indicating some stigma). A mixed-effect logistic regression model was used to calculate the odds of scoring 1 on stigma (low stigma) after the course. Effect sizes were calculated and interpreted using Cohen’s d and Cohen’s criteria for small, medium, and large effects, where the difference between means was divided by their pooled standard deviation [Course satisfaction data were analysed using means and standard deviations. Content analysis was used to determine prominent themes in the free-text responses [ | PMC9963380 | |
3. Results | PMC9963380 | |||
3.1. Participant Demographics | Between 2018 and 2021, 153 course attendees from 15 courses were approached to participate in the evaluation and 147 (96.1%) consented to participate. Of the 147 participants, 137 (93.2%) provided at least some data at the post-course survey and 72 (49%) provided at least some data at six-month follow-up. Missingness at follow-up was associated with age of the participant, where, for each additional 10 years of age, the odds of completing the follow-up survey increased 30% (Participant characteristics are shown in | PMC9963380 | ||
3.2. Knowledge about NSSI | NSSI | Mean knowledge about NSSI at pre-course was moderate (see | PMC9963380 | |
3.3. Social Distance | Mean social distance scores were low at pre-course (m = 1.90, SD = 0.70; see | PMC9963380 | ||
3.4. Stigma | Stigmatising attitudes at pre-course were low (m = 1.67, SD = 0.55) and decreased at post-course and follow-up (see | PMC9963380 |
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