Abstract
Background
Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health ...priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD.
Methods
In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS cTBS to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS iTBS to the left DLPFC) delivered 5 days a week for 4–6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals.
Discussion
Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD.
Trial registration
The trial is registered on
https://clinicaltrials.gov/ct2/home
(#NCT04142996).
It has been shown in recent studies that it is possible to detect changes in the main excitatory neurotransmitter, glutamate, upon functional activation with visual and motor paradigms using a 7 T ...MRI and functional magnetic resonance spectroscopy. A cognitive task would be desirable for this technique because it could then be used to examine psychiatric disorders that have cognitive deficiencies. The aim of the work presented here was to use functional magnetic resonance spectroscopy with a 7 T MRI to show that increases in glutamate can be observed within the anterior cingulate cortex using the Stroop Task as the activation paradigm in healthy controls. Significant glutamate increases (0.24±0.09 µmol/g, P<0.025), comparable with what has been reported in the studies of the occipital cortex and motor cortex, were observed when the participants (n=7) performed the task, followed by a trend toward returning to baseline in the post-task recovery period (-0.23±0.13 µmol/g). This method would be ideal for the study of neuropsychiatric disorders that have been shown to have abnormal resting glutamate levels and cognitive deficiencies in the anterior cingulate cortex, such as schizophrenia. This exploratory study is the first to demonstrate functional magnetic resonance spectroscopy in the anterior cingulate with a cognitive task using a 7 T MRI.
Abstract Introduction Sleep disturbances are commonly observed in individuals with depression, and are associated with severity of depression, treatment outcomes, and risk of relapse. Repetitive ...transcranial magnetic stimulation, including newer optimized theta-burst stimulation (TBS) protocols, is recognized as a safe and effective intervention for treatment-resistant depression (TRD). Presently, little is known about the impact of TBS treatments on sleep in individuals with depression. We examined changes in subjective sleep and depression in individuals with TRD receiving daily TBS treatments, and the relationship between changes in these symptom domains. Methods 50 participants (50% female, mean age 46.82 years) with TRD received four or six weeks of daily TBS treatments targeting the left or bilateral dorsolateral prefrontal cortex while participating in a randomized, double-blind clinical trial. Sleep disturbances and depression severity were measured at baseline, session 20 and session 30 using the Leeds Sleep Evaluation Questionnaire and 17-item Hamilton Rating Scale for Depression (HRSD-17), respectively. Linear mixed models examined whether scores changed significantly throughout treatment. Spearman’s correlations investigated whether changes in depression and sleep were associated. Results HRSD-17 scores improved significantly from baseline to weeks 4 and 6 (p< 0.001). We also observed significant improvements in quality of sleep (QOS), ease of awakening from sleep (AFS), and behaviour following wakefulness (BFW) after 4 and 6 weeks of TBS (p< 0.001). After 4 weeks of TBS, improvements in HRSD-17 significantly correlated with BFW scores (p= 0.008). After 6 weeks of TBS, improvements in HRSD-17 scores significantly correlated with improvements in both AFS and BFW scores (p< 0.005). Conclusion Participants reported improvements in depression, sleep quality, ease of waking, and daytime alertness following TBS. Furthermore, improvements in several aspects of sleep and depression were correlated. These findings suggest that TBS may be an effective intervention for individuals experiencing comorbid depression and sleep disturbances. This also strengthens the view that sleep enhancement may contribute to better mental health outcomes. Support (if any) Support was provided by the Royal’s Institute of Mental Health Research’s Emerging Research Innovators in Mental Health award, the Fonds de Recherche en Santé – Québec Research Scholar Junior 1 grant (grant number 297133), and an anonymous donation.
Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to ...antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.
To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.
The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.
In total, 45 1H-MRS studies contributed data.
Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.
Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).
In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean SD age, 30.3 10.4 years) and 1197 healthy volunteers (mean SD age, 27.5 8.8 years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.
Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major ...depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls.
Functional magnetic resonance imaging at 7.0 Tesla was undertaken among Schizophrenia participants (Sz), and clinical (major mood disorder; MDD) and healthy controls (HC), during performance of the ...Stoop task. Stroop conditions included congruent and incongruent word color items, color-only items, and word-only items. Previous modeling results extended to this most widely used selective-attention task. All groups executed item-encoding operations (subprocesses of the item encoding process) at the same rate (performance accuracy being similarly high throughout), thus displaying like processing capacity; Sz participants, however, employed more subprocesses for item completions than did the MDD participants, who in turn used more subprocesses than the HC group. The reduced efficiency in deploying cognitive-workload capacity among the Sz participants was paralleled by more diffuse neuroconnectivity (Blood-Oxygen-Level-Dependent co-activation) with the anterior cingulate cortex (ACC) (Broadman Area 32), spreading away from this encoding-intensive region; and by less evidence of network dissociation across Stroop conditions. Estimates of cognitive work done to accomplish item completion were greater for the Sz participants, as were estimates of entropy in both the modeled trial-latency distribution, and its associated neuro-circuitry. Findings are held to be symptom and assessment significant, and to have potential implications for clinical intervention.
An ongoing prospective study is acquiring preoperative imaging data for men with prostate cancer (PCa) using the molecular imaging agent
F-DCFPyL targeted against prostate-specific membrane antigen ...(PSMA). To date, six men (of a planned accrual of 24) with clinically localized, biopsy-proven PCa have undergone preoperative
F-DCFPyL positron emission tomography (PET) imaging and multiparametric magnetic resonance imaging acquired using a hybrid PET/MRI system. Lesions identified by
F-DCFPyL uptake on PET/MRI were characterized in terms of maximum standardized uptake value (SUV
) and volume using a boundary threshold of 40% SUV
. Following surgery, all prostatectomy specimens were processed using a whole-mount technique for accurate deformable co-registration and correlation with PCa foci defined on digitized pathology images. Well-defined intraprostatic dominant lesions were identified by
F-DCFPyL PET/MRI (mean SUV
11.4±8.25; mean volume 2.2±2.4cm
) in all six men. Co-registered digitized whole-mount pathology for the first case revealed that intense
F-DCFPyL uptake (SUV
27±1.1cm
) and multiparametric MRI changes (Prostate Imaging Reporting and Data System score of 4) were highly correlated with a 0.5-cm
dominant (largest) lesion with Gleason pattern 4 PCa in the right mid peripheral zone. A smaller focus (0.01cm
) of lower-grade PCa (Gleason pattern 3) had much lower uptake (SUV 2.7). These early prospective data show that dominant intraprostatic lesions could be identified in all six men using
F-DCFPyL as an imaging probe. Trial accrual will continue to quantify in terms of spatial concordance the ability of
F-DCFPyL to identify the location and characterize the grade of intraprostatic cancer foci in clinically localized PCa. PATIENT SUMMARY: Positron emission tomography using a novel probe called
F-DCFPyL directed against the prostate-specific membrane antigen protein was able to identify locations of prostate cancer in the prostate glands of men undergoing imaging before surgery. In the future, such imaging may allow better targeting of treatment to the portion of the prostate containing the most aggressive components of cancer rather than treating the whole prostate in a uniform fashion.
Purpose:
Optical coherence tomography (OCT) is useful in diagnosing and monitoring retinal pathology such as age-related macular degeneration, diabetic macular edema (DME), central serous ...chorioretinopathy, and epiretinal membrane, among others. This study compared the ability of horizontal (H) 25-, 13-, and 7-cut macular OCT vs 24-, 12-, and 6-cut radial (R) macular OCT in identifying various macular pathology.
Methods:
This was a prospective study of 161 established patients evaluated at Wilford Hall Eye Center Retina Clinic between September and October of 2019. Pathology included age-related macular degeneration, central serous chorioretinopathy, DME, and epiretinal membrane, among others. Patients obtained 25-, 13-, and 7-cut H raster OCT as well as 24-, 12-, and 6-cut R OCT. Primary outcomes were sensitivity in detecting macular fluid and each macular abnormality.
Results:
The 24-cut radial (R24) OCT equally or out-performed the H25 (horizontal 25-cut OCT) in detecting macular fluid across all pathological groups. Generally, a higher number of cuts correlated with better detection of fluid. In detecting any macular abnormalities, H25, R24, and R12 had 100% sensitivity. R6 OCT had near 100% sensitivity across all groups, except for DME (95%). Overall, R OCT had better sensitivity (0.960) than H OCT (0.907) in detecting macular pathology.
Conclusions:
R outperformed H macular OCT in detecting fluid and other abnormalities. Clinically, both scanning patterns can be used by ophthalmologists in diagnosis and management of commonly encountered macular diseases. Technicians may be able to use a variety of these scans to screen for pathology prior to physician evaluation.
This mixed methods study examines the correlation between a student’s self-perception of math ability and subsequent math achievement in a public, rural middle school in Kentucky. The question asked ...is: "Is there a significant correlation between student self-efficacy and subsequent math achievement in the middle grades?" In addition, this study is also designed to answer the following sub-questions: "Is the relationship significant between student self-efficacy and subsequent math achievement when only considering self-efficacy and future performance?" and "Is there a significant relationship between student self-efficacy and future performance when past performance is considered?" The secondary question asked is: "How do teachers foster student self-efficacy in mathematics classrooms?" Using the NWEA MAP Assessment to examine math performance and the Patterns of Adaptive Learning Scales (PALS) to examine student self-efficacy, it was determined a significant relationship did not exist between the two variables. Thus, it is more important to use past performance to increase student success.
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