A randomised controlled trial investigating the causal role of the medial prefrontal cortex in mediating self-agency during speech monitoring and reality monitoring.

Self-agency is the awareness of being the agent of one's own thoughts and actions. Self-agency is essential for interacting with the outside world (reality-monitoring). The medial prefrontal cortex (mPFC) is thought to be one neural correlate of self-agency. We investigated whether mPFC activity can causally modulate self-agency on two different tasks of speech-monitoring and reality-monitoring. The experience of self-agency is thought to result from making reliable predictions about the expected outcomes of one's own actions. This self-prediction ability is necessary for the encoding and memory retrieval of one's own thoughts during reality-monitoring to enable accurate judgments of self-agency. This self-prediction ability is also necessary for speech-monitoring where speakers consistently compare auditory feedback (what we hear ourselves say) with what we expect to hear while speaking. In this study, 30 healthy participants are assigned to either 10 Hz repetitive transcranial magnetic stimulation (rTMS) to enhance mPFC excitability (N = 15) or 10 Hz rTMS targeting a distal temporoparietal site (N = 15). High-frequency rTMS to mPFC enhanced self-predictions during speech-monitoring that predicted improved self-agency judgments during reality-monitoring. This is the first study to provide robust evidence for mPFC underlying a causal role in self-agency, that results from the fundamental ability of improving self-predictions across two different tasks.

Causal role of medial superior frontal cortex on enhancing neural information flow and self-agency judgments in the self-agency network.

Self-agency is being aware of oneself as the agent of one's thoughts and actions. Self-agency is necessary for successful interactions with the outside world (reality-monitoring). Prior research has shown that the medial superior prefrontal gyri (mPFC/SFG) may represent one neural correlate underlying self-agency judgments. However, the causal relationship remains unknown. Here, we applied high-frequency 10Hz repetitive transcranial magnetic stimulation (rTMS) to modulate the excitability of the mPFC/SFG site that we have previously shown to mediate self-agency. For the first time, we delineate causal neural mechanisms, revealing precisely how rTMS modulates SFG excitability and impacts directional neural information flow in the self-agency network by implementing innovative magnetoencephalography (MEG) phase-transfer entropy (PTE) metrics, measured from pre-to-post rTMS. We found that, compared to control rTMS, enhancing SFG excitability by rTMS induced significant increases in information flow between SFG and specific cingulate and paracentral regions in the self-agency network in delta-theta, alpha, and gamma bands, which predicted improved self-agency judgments. This is the first multimodal imaging study in which we implement MEG PTE metrics of 5D imaging of space, frequency and time, to provide cutting-edge analyses of the causal neural mechanisms of how rTMS enhances SFG excitability and improves neural information flow between distinct regions in the self-agency network to potentiate improved self-agency judgments. Our findings provide a novel perspective for investigating causal neural mechanisms underlying self-agency and create a path towards developing novel neuromodulation interventions to improve self-agency that will be particularly useful for patients with psychosis who exhibit severe impairments in self-agency.

A randomised controlled trial investigating the causal role of the medial prefrontal cortex in mediating self-agency during speech monitoring and reality monitoring.

Self-agency is being aware of oneself as the agent of one's thoughts and actions. Self agency is necessary for successful interactions with the external world (reality-monitoring). The medial prefrontal cortex (mPFC) is considered to represent one neural correlate underlying self-agency. We investigated whether mPFC activity can causally modulate self-agency on two different tasks involving speech-monitoring and reality-monitoring. The experience of self-agency is thought to result from being able to reliably predict the sensory outcomes of one's own actions. This self-prediction ability is necessary for successfully encoding and recalling one's own thoughts to enable accurate self-agency judgments during reality-monitoring tasks. This self-prediction ability is also necessary during speech-monitoring tasks where speakers compare what we hear ourselves say in auditory feedback with what we predict we will hear while speaking. In this randomised-controlled study, heathy controls (HC) are assigned to either high-frequency transcranial magnetic stimulation (TMS) to enhance mPFC excitability or TMS targeting a control site. After TMS to mPFC, HC improved self-predictions during speech-monitoring tasks that predicted improved self-agency judgments during different reality-monitoring tasks. These first-in-kind findings demonstrate the mechanisms of how mPFC plays a causal role in self-agency that results from the fundamental ability of improving self-predictions across two different tasks.

Abnormal resting-state functional connectivity underlies cognitive and clinical symptoms in patients with schizophrenia.

Introduction: The cognitive and psychotic symptoms in patients with schizophrenia (SZ) are thought to result from disrupted brain network connectivity. Methods: We capitalize on the high spatiotemporal resolution of magnetoencephalography imaging (MEG) to record spontaneous neuronal activity in resting state networks in 21 SZ compared with 21 healthy controls (HC). Results: We found that SZ showed significant global disrupted functional connectivity in delta-theta (2-8 Hz), alpha (8-12 Hz), and beta (12-30 Hz) frequencies, compared to HC. Disrupted global connectivity in alpha frequencies with bilateral frontal cortices was associated with more severe clinical psychopathology (i.e., positive psychotic symptoms). Specifically, aberrant connectivity in beta frequencies between the left primary auditory cortex and cerebellum, was linked to greater hallucination severity in SZ. Disrupted connectivity in delta-theta frequencies between the medial frontal and left inferior frontal cortex was associated with impaired cognition. Discussion: The multivariate techniques employed in the present study highlight the importance of applying our source reconstruction techniques which leverage the high spatial localization abilities of MEG for estimating neural source activity using beamforming methods such as SAM (synthetic aperture morphometry) to reconstruct the source of brain activity, together with functional connectivity assessments, assayed with imaginary coherence metrics, to delineate how neurophysiological dysconnectivity in specific oscillatory frequencies between distinct regions underlie the cognitive and psychotic symptoms in SZ. The present findings employ powerful techniques in spatial and time-frequency domains to provide potential neural biomarkers underlying neuronal network dysconnectivity in SZ that will inform the development of innovations in future neuromodulation treatment development.

A Feasibility Study of a Remotely-Delivered Mindfulness-Based Training for Adolescents During the COVID-19 Pandemic.

Social distancing, home confinement, economic challenges, and COVID-19-related illness and deaths during the COVID-19 pandemic can significantly affect mental health in youth. One promising approach to reduce anxiety and depression in adolescents is the neuroscience-based mindfulness intervention Training for Awareness, Resilience, and Action (TARA). The objective of this individually randomized waitlist-controlled trial (RCT) was (1) to test the feasibility of TARA, delivered partially over Zoom, and (2) to assess changes in the emotional wellbeing in healthy adolescents between the ages of 14-18 years old during the COVID-19 pandemic. METHODS: Twenty-one healthy adolescents were randomized to the TARA intervention or to the waitlist control group in February 2020, just before the start of the pandemic. The TARA group intervention was delivered in person for the first five sessions and remotely over Zoom for the remaining seven sessions due to the pandemic. The participants' acceptability of TARA was assessed weekly using the Child Session Rating Scale (CSRS). The primary outcome was the emotional wellbeing measured using emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ) pre/post-TARA. We also explored weekly changes in TARA participants' wellbeing using the Child Outcome Rating Scale (CORS). RESULTS: The overall session rating in TARA participants improved after the switch to Zoom (Cohen's d = 1.2, p = 0.008). The results of the two-way ANOVA showed no statistically significant difference in the change of the SDQ emotional symptoms during the 12 weeks between the TARA group and waitlist-control group (timepoint × group interaction: F = 0.77, p = 0.38). The exploratory analysis using the CORS in the TARA participants showed a significant improvement in their functioning over the weeks of training. CONCLUSION: Our results support the feasibility of TARA delivered over Zoom. While our primary outcome did not provide support for the improvement of the emotional wellbeing with TARA compared to a passive control group, our exploratory analysis in the intervention group indicated an improved functioning over the weeks of TARA training. The important general positive impact of this study lies in the possibility of offering a neuroscience-based mindfulness intervention remotely to youth living in remote areas and for all youth during pandemic times.

A Domain-General Developmental "Do-GooD" Network Model of Prosocial Cognition in Adolescence: A Systematic Review.

Adolescence is a period of substantial neural and social development, and prosocial decisions are beneficial to personal well-being, the well-being of others, and the functioning of society. Advances in network neuroscience call for a systematic synthesis and reappraisal of prosocial neural correlates during adolescent development. In this systematic review, we aim to outline the progress made in this field, identify the similarities between study results, and propose a model for prosocial cognition in adolescents to young adults. A total of 25 articles were included in this review. After reviewing and synthesizing the literature, we propose a DOmain-General Developmental "Do-GooD" network model of prosocial cognition that aligns with the reviewed literature, accounts for development, and combines elements of the value-based decision-making model with distinct value contributions from the default mode network, salience network, and control network. We offer predictions to test the "Do-GooD" model and propose new future directions for studying prosocial behavior and its development during adolescence, which in turn may lead to improving education and the development of better health interventions for adolescents.

A Comprehensive Assessment of 68Ga-PSMA-11 PET in Biochemically Recurrent Prostate Cancer: Results from a Prospective Multicenter Study on 2,005 Patients.

We prospectively investigated the performance of the prostate-specific membrane antigen (PSMA) ligand 68Ga-PSMA-11 for detecting prostate adenocarcinoma in patients with elevated levels of prostate-specific antigen (PSA) after initial therapy. Methods:68Ga-PSMA-11 hybrid PET was performed on 2,005 patients at the time of biochemically recurrent prostate cancer after radical prostatectomy (RP) (50.8%), definitive radiation therapy (RT) (19.7%), or RP with postoperative RT (PORT) (29.6%). The presence of prostate cancer was assessed qualitatively (detection rate = positivity rate) and quantitatively on a per-patient and per-region basis, creating a disease burden estimate from the presence or absence of local (prostate/prostate bed), nodal (N1: pelvis), and distant metastatic (M1: distant soft tissue and bone) disease. The primary study endpoint was the positive predictive value (PPV) of 68Ga-PSMA-11 PET/CT confirmed by histopathology. Results: After RP, the scan detection rate increased significantly with rising PSA level (44.8% at PSA < 0.25%-96.2% at PSA > 10 ng/mL; P < 0.001). The detection rate significantly increased with rising PSA level in each individual region, overall disease burden, prior androgen deprivation, clinical T-stage, and Gleason grading from the RP specimen (P < 0.001). After RT, the detection rate for in-gland prostate recurrence was 64.0%, compared with 20.6% prostate bed recurrence after RP and 13.3% after PORT. PSMA-positive pelvic nodal disease was detected in 42.7% after RP, 40.8% after PORT, and 38.8% after RT. In patients with histopathologic validation, the PPV per patient was 0.82 (146/179). The SUVmax of histologically proven true-positive lesions was significantly higher than that of false-positive lesions (median, 11.0 [interquartile range, 6.3-22.2] vs. 5.1 [interquartile range, 2.2-7.4]; P < 0.001). Conclusion: We confirmed a high PPV for 68Ga-PSMA-11 PET in biochemical recurrence and the PSA level as the main predictor of scan positivity.

The Role of PSMA PET/CT and PET/MRI in the Initial Staging of Prostate Cancer.

CONTEXT: Prostate cancer (PCa) is the most common solid organ malignancy in men and is the third leading cause of cancer death. Accurate methods for the detection and staging of PCa are necessary to determine the extent of disease and inform treatment options. OBJECTIVE: To review the performance and diagnostic accuracy of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging in the initial staging of PCa and evaluate its impact on definitive therapy planning. EVIDENCE ACQUISITION: A comprehensive literature search was performed using PubMed. References from retrieved articles and recommendations from the authors were also included. EVIDENCE SYNTHESIS: PSMA PET has moderately high sensitivity and specificity for detecting intraprostatic tumors and moderately high sensitivity for detecting regional and extrapelvic metastases, compared with conventional imaging. PSMA PET can also have an important role in the presurgical detection of extraprostatic disease and can guide surgical planning. Additionally, PSMA PET has proven to be an effective tool for planning definitive radiation therapy in treatment-naïve patients. CONCLUSIONS: PSMA PET has a promising role in the initial staging of PCa and informing appropriate treatment options. Further research is necessary to evaluate the appropriate role of PSMA PET in management changes, and to understand the appropriate management of patients with metastatic disease. PATIENT SUMMARY: We reviewed the diagnostic accuracy and treatment impact of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging in the initial staging of prostate cancer (PCa). We conclude that PSMA PET is effective at imaging initial PCa and may result in the modification of treatment plans for patients.

Neural Correlates of Smartphone Dependence in Adolescents.

Increases in depressive and suicide-related symptoms among United States adolescents have been recently linked to increased use of smartphones. Understanding of the brain mechanisms that underlie the potential smartphone dependence may help develop interventions to address this important problem. In this exploratory study, we investigated the neural mechanisms underlying potential smartphone dependence in a sample of 19 adolescent volunteers who completed self-assessments of their smartphone dependence, depressive symptoms, and sleep problems. All 19 adolescents underwent diffusion MRI that allowed for assessment of white matter structural connectivity within the framework of connectomics. Based on previous literature on the neurobiology of addiction, we hypothesized a disruption of network centrality of three nodes in the mesolimbic network: Nucleus Accumbens, anterior cingulate cortex, and amygdala. Our results showed positive correlations between the node centrality of the right amygdala and self-reported smartphone dependence, between smartphone dependence and sleep problems, and between sleep problems and depressive symptoms. A higher phone dependence was observed in females compared to males. Supported by these results, we propose a model of how smartphone dependence can be linked to aberrations in brain networks, sex, sleep disturbances, and depression in adolescents.