Randomized double-blind placebo-controlled trial of the effects of oral trehalose in spinocerebellar ataxia type 3: An interim analysis.

INTRODUCTION: Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease characterized by increasingly worsening ataxia and non-ataxia features, negatively impacting patients' quality of life. This study was designed to test formally evaluate whether oral trehalose was effective in SCA3 patients. METHODS: In this double-blind, randomized controlled trial, SCA3 patients received either 100 g oral trehalose or 30 g maltose to improve ataxia severity over six months. We also measured other clinical (non-ataxia), patient-reported (quality of life, motivations), and safety endpoints. An unscheduled interim analysis was conducted using two-way ANOVAs to analyze the interaction between time (baseline, 3-months, 6-months) and intervention (Trehalose vs. Placebo). RESULTS: Fifteen participants (Trehalose = 7 vs. Placebo = 8) completed the study at the time of interim analysis. There was no interaction effect on the ataxia severity, and available data suggested an estimated sample size of 132 (66 per arm) SCA3 patients required to demonstrate changes in a 6-month trial. There were significant interaction effects for executive function (ƞ2 = 0.28-0.43). Safety data indicated that 100 g oral trehalose was well-tolerated. CONCLUSION: We performed an unplanned interim analysis due to a slow recruitment rate. The new estimated sample size was deemed unfeasible, leading to premature termination of the clinical trial. In this small, current sample of SCA3 patients, 100 g oral trehalose did not differentially impact on ataxia severity compared to placebo. Interestingly, our findings may suggest an improvement in executive function. Future efforts will require a large multi-country, multi-center study to investigate the potential effect of trehalose.

Hybrid Treatment Planning for Chest Wall Irradiation Utilizing Three-Dimensional Conformal Radiotherapy (3DCRT), Intensity-Modulated Radiation Therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT): A Systematic Review.

Novel hybrid approaches for chest wall irradiation show promising outcomes regarding target coverage and sparing organs at risk (OARs). In this systematic review, we compared hybrid volumetric modulated arc therapy (H-VMAT) or hybrid intensity-modulated radiotherapy (H-IMRT) techniques with non-hybrid techniques, such as three-dimensional conformal radiation therapy (3DCRT), field-in-field (FIF), intensity-modulated arc therapy (IMRT), and volumetric modulated arc therapy (VMAT), for breast cancer patients with mastectomy. Our focus was the plan quality and dose distribution to the OARs. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, we performed a systematic review and quality appraisal of primary studies evaluating hybrid therapy to the chest wall and the OARs. An extensive online search of PubMed and Scopus databases was conducted using appropriate keywords. The dose to the OARs (lung, heart, and contralateral breast), planning target volume (PTV), homogeneity index (HI), and conformity index (CI) were extracted. The data were then tabulated and compared for the outcomes between modalities among the studies. Nine studies that met the search criteria were selected to evaluate the PTV coverage and dosimetric results of hybrid and non-hybrid techniques. In terms of 95% PTV coverage, among nine reviewed studies, the largest difference between the two techniques was between VMAT (47.6 Gy) and H-VMAT (48.4 Gy); for the conformity index, the largest difference was noted between 3DCRT (0.58) and H-VMAT (0.79). In both cases, differences were statistically significant (P < 0.005). Two studies showed dose homogeneity improvement within the treatment target in H-VMAT (0.15 and 0.07) compared with 3DCRT (0.41 and 0.12), with a P value of <0.001. Two studies did not report on the homogeneity index, and three others observed no statistical difference. Regarding OARs, in the comparison of H-VMAT and VMAT, the largest significant change was in the volume receiving 5 Gy (V5Gy) of the ipsilateral lung and the V10Gy of the contralateral lung. For the ipsilateral lung, V5Gy was 90.7% with VMAT versus 51.45% with H-VMAT. For the contralateral lung, V10Gy was 54.9% with VMAT versus 50.5% with H-VMAT. In six studies, the mean dose of the contralateral breast was lower in hybrid techniques than in single modalities: VMAT (4.2%, 6.0%, 1.9%, 7.1%, 4.57%) versus H-VMAT (1.4%, 3.4%, 1.8%, 3.5%, 2.34%) and IMRT (9.1%) versus H-IMRT (4.69%). Although most studies did not report on monitor units and treatment time, those that included them showed that hybrids had lower monitor units and shorter treatment times. Hybrid techniques in radiotherapy, such as combining two modalities, can indeed facilitate lower doses to OARs for patients with a high risk of toxicities. Prospective clinical studies are needed to determine the outcomes of breast cancer treated with hybrid techniques.

Toxicity profile of patients treated with proton and carbon-ion therapy for primary nasopharyngeal carcinoma: A systematic review and meta-analysis.

BACKGROUND: Proton and carbon-ion therapy may spare normal tissues in regions with many critical structures surrounding the target volume. As toxicity outcome data are emerging, we aimed to synthesize the published data for the toxicity outcomes of proton or carbon-ion therapy (together known as particle beam therapy [PBT]) for primary nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: We searched PubMed and Scopus electronic databases to identify original studies reporting toxicity outcomes following PBT of primary NPC. Quality assessment was performed using NIH's Quality Assessment Tool. Reports were extracted for information on demographics, main results, and clinical and dose factors correlates. Meta-analysis was performed using the random-effects model. RESULTS: Twelve studies were selected (six using mixed particle-photon beams, five performed comparisons to photon-based therapy). The pooled event rates for acute grade ≥2 toxicities mucositis, dermatitis, xerostomia weight loss are 46% (95% confidence interval [95% CI]-29%-64%, I2 = 87%), 47% (95% CI-28%-67%, I2 = 87%), 16% (95% CI-9%-29%, I2 = 76%), and 36% (95% CI-27%-47%, I2 = 45%), respectively. Only one late endpoint (xerostomia grade ≥2) has sufficient data for analysis with pooled event rate of 9% (95% CI-3%-29%, I2 = 77%), lower than intensity-modulated radiotherapy 27% (95% CI-10%-54%, I2 = 95%). For most endpoints with significant differences between the PBT and photon-based therapies, PBT resulted in better outcomes. In two studies where dose distribution was studied, doses to the organs at risk were independent risk factors for toxicities. CONCLUSION: PBT may reduce the risk of acute toxicities for patients treated for primary NPC, likely due to dose reduction to critical structures. The pooled event rate for toxicities derived in this study can be a guide for patient counseling.

Brain volumetric changes in menopausal women and its association with cognitive function: a structured review.

The menopausal transition has been proposed to put women at risk for undesirable neurological symptoms, including cognitive decline. Previous studies suggest that alterations in the hormonal milieu modulate brain structures associated with cognitive function. This structured review provides an overview of the relevant studies that have utilized MRI to report volumetric differences in the brain following menopause, and its correlations with the evaluated cognitive functions. We performed an electronic literature search using Medline (Ovid) and Scopus to identify studies that assessed the influence of menopause on brain structure with MRI. Fourteen studies met the inclusion criteria. Brain volumetric differences have been reported most frequently in the frontal and temporal cortices as well as the hippocampus. These regions are important for higher cognitive tasks and memory. Additionally, the deficit in verbal and visuospatial memory in postmenopausal women has been associated with smaller regional brain volumes. Nevertheless, the limited number of eligible studies and cross-sectional study designs warrant further research to draw more robust conclusions.

The Association Between Depth of the Olfactory Sulcus, Age, Gender and Olfactory Function: An MRI-based Investigation in More Than 1000 Participants.

OBJECTIVE: The present study aimed to investigate the relationship between olfactory sulcus (OS) depth and olfactory function considering age and gender and to provide normative data on OS depth in a population with normal olfactory function. MATERIALS AND METHODS: OS depth was obtained using T1 magnetic resonance imaging scans. Participants (mean age ± sd = 57 ± 16 years, ranging from 20 to 80 years) were screened for olfactory function using the Sniffin' Sticks Screening 12 test. They were divided into an olfactory dysfunction group (n = 604) and a normosmia group (n = 493). Participants also completed questionnaires measuring depression, anxiety and quality of life. RESULTS: The right OS was deeper than the left side in all age groups. On the left side, women had deeper OS compared with men, exhibiting a higher degree of symmetry in left and right OS depth in women. Variance of olfactory function was largely determined by age, OS depth explained only minor portions of this variance. Normative data for minimum OS depth was 7.55 mm on the left and 8.78 mm on the right for participants aged between 18 and 35 years (n = 144), 6.47 mm on the left and 6.99 mm on the right for those aged 36-55 years (n = 120), and 5.28 mm on the left and 6.19 mm on the right for participants older than 55 years (n = 222). CONCLUSION: Considering the limited resolution of the presently used T1 weighted MR scans and the nature of the olfactory screening test, OS depth explained only minor portions of the variance of olfactory function, which was largely determined by age. Age-related normative data of OS depth are presented as a reference for future work.

Magnetic Resonance Imaging and Its Clinical Correlation in Spinocerebellar Ataxia Type 3: A Systematic Review.

Background: Spinocerebellar ataxia type 3 (SCA3) is a complex cerebrocerebellar disease primarily characterized by ataxia symptoms alongside motor and cognitive impairments. The heterogeneous clinical presentation of SCA3 necessitates correlations between magnetic resonance imaging (MRI) and clinical findings in reflecting progressive disease changes. At present, an attempt to systematically examine the brain-behavior relationship in SCA3, specifically, the correlation between MRI and clinical findings, is lacking. Objective: We investigated the association strength between MRI abnormality and each clinical symptom to understand the brain-behavior relationship in SCA3. Methods: We conducted a systematic review on Medline and Scopus to review studies evaluating the brain MRI profile of SCA3 using structural MRI (volumetric, voxel-based morphometry, surface analysis), magnetic resonance spectroscopy, and diffusion tensor imaging, including their correlations with clinical outcomes. Results: Of 1,767 articles identified, 29 articles met the eligibility criteria. According to the National Institutes of Health quality assessment tool for case-control studies, all articles were of excellent quality. This systematic review found that SCA3 neuropathology contributes to widespread brain degeneration, affecting the cerebellum and brainstem. The disease gradually impedes the cerebral cortex and basal ganglia in the late stages of SCA3. Most findings reported moderate correlations (r = 0.30-0.49) between MRI features in several regions and clinical findings. Regardless of the MRI techniques, most studies focused on the brainstem and cerebellum. Conclusions: Clinical findings suggest that rather than individual brain regions, the connectivity between different brain regions in distributed networks (i.e., cerebellar-cerebral network) may be responsible for motor and neurocognitive function in SCA3. This review highlights the importance of evaluating the progressive changes of the cerebellar-cerebral networks in SCA3 patients, specifically the functional connectivity. Given the relative lack of knowledge about functional connectivity on SCA3, future studies should investigate possible functional connectivity abnormalities in SCA3 using fMRI.

Cognitive Decline following Radiotherapy of Head and Neck Cancer: Systematic Review and Meta-Analysis of MRI Correlates.

Radiotherapy for head and neck cancers exposes small parts of the brain to radiation, resulting in radiation-induced changes in cerebral tissue. In this review, we determine the correlation between cognitive deterioration in patients with head and neck cancer after radiotherapy and magnetic resonance imaging (MRI) changes. Systematic searches were performed in PubMed, Scopus, and Cochrane databases in February 2021. Studies of head and neck cancer patients treated with radiotherapy and periodical cognitive and MRI assessments were included. Meta-analysis was performed to analyse the correlation of Montreal Cognitive Assessment (MoCA) scores to MRI structural and functional changes. Seven studies with a total of 404 subjects (irradiated head and neck patients, n = 344; healthy control, n = 60) were included. Most studies showed the significance of MRI in detecting microstructural and functional changes in association with neurocognitive function. The changes were seen in various brain areas, predominantly the temporal region, which also shows dose dependency (6/7 studies). An effect size (r = 0.43, p < 0.001) was reported on the correlation of MoCA scores to MRI structural and functional changes with significant correlations shown among patients treated with head and neck radiotherapy. However, the effect size appears modest.

Heterogeneity in brain functional changes of cognitive processing in ADHD across age: A systematic review of task-based fMRI studies.

This review aims to establish the cognitive processing of patients with attention-deficit hyperactive disorder (ADHD) across age. Functional magnetic resonance imaging (fMRI) studies on children and adult populations were conducted, thus delineating deficits that could have been maintained and ameliorated across age. This allowed for the examination of the correlation between patterns of brain activation and the corresponding development of functional heterogeneity in ADHD. A systematic literature search of fMRI studies on ADHD was conducted using the PubMed and Scopus electronic databases based on PRISMA guidelines. References and citations were verified in Scopus database. The present study has identified 14 studies on children, 16 studies on adults, and one study on both populations of ADHD consisting of 1371 participants. Functional heterogeneity is present in ADHD across age, which can manifest either as different brain activation patterns, intra-subject variability, or both. This is shown in the increased role of the frontal regions and the specialized network in adults with ADHD from inefficient non-specific activation in childhood. Functional heterogeneity may manifest when delayed maturation is insufficient to normalize frontal lobe functions.

Effects of white noise on word recall performance and brain activity in healthy adolescents with normal and low auditory working memory.

The present study examined the impact of white noise on word recall performance and brain activity in 40 healthy adolescents, split in two groups (normal and low) depending on their auditory working memory capacity (AWMC). Using functional magnetic resonance imaging, participants performed a backward recall task under four different signal-to-noise ratio (SNR) conditions: 15, 10, 5, and 0-dB SNR. Behaviorally, normal AWMC individuals scored significantly higher than low AWMC individuals across noise levels. Whole-brain analyses showed brain activation not to be statistically different between groups across noise levels. In the normal group, a significant positive relationship was found between performance and number of activated voxels in the right superior frontal gyrus. In the low group, significant positive correlations were found between performance and number of activated voxels in left superior frontal gyrus, left inferior frontal gyrus, and left anterior cingulate cortex. These findings suggest that the strategic structure involved in the enhancement of AWM performance may differ in normal and low AWMC individuals.

Hemispheric Lateralization of Auditory Working Memory Regions During Stochastic Resonance: An fMRI Study.

BACKGROUND: The auditory and prefrontal cortex supports auditory working memory processing. Many neuroimaging studies have shown hemispheric lateralization of auditory working memory brain regions in the presence of background noise, but few studies have focused on the lateralization of these regions during stochastic resonance. PURPOSE: To investigate the effects of stochastic resonance on lateralization of auditory working memory regions, and also to examine the brain-behavior relationship during stochastic resonance. STUDY TYPE: Cross-sectional. POPULATION/SUBJECTS: Forty healthy young adults (18-24 years old). FIELD STRENGTH/SEQUENCE: 3.0T, T1 , and T2 *-weighted imaging. ASSESSMENT: The auditory working memory performance was assessed using a backward recall task. Functional magnetic resonance imaging (fMRI) was used to measure brain activity during task performance. Functional MRI data were analyzed using SPM12 and WFU PickAtlas. STATISTICAL TESTS: One-way independent analyses of variance (ANOVA) were conducted on the behavioral and functional data to examine the main effect of noise level on performance (P < 0.01) and brain activity (P < 0.0042). Hemispheric lateralization was determined by calculating the laterality index. A paired samples t-test was performed to compare brain activity between hemispheres (P < 0.05). Pearson's correlation analysis and simple linear regression (P < 0.0042) were used to examine the relationship between brain activity and behavioral performance. RESULTS: Performance was significantly enhanced during the 50 and 55 dB sound pressure level (SPL) conditions via the stochastic resonance mechanism [F(1,195) = 49.17, P < 0.001]. Activity of the right superior frontal gyrus in the 55 dB SPL condition was significantly positively correlated with performance (R2 = 0.681, P < 0.001). DATA CONCLUSION: Our findings demonstrate changes in the lateralization of auditory working memory regions during stochastic resonance and suggest that the right superior frontal gyrus may be a strategic structure involved in the enhancement of auditory working memory performance. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2020;51:1821-1828.

Low intensity white noise improves performance in auditory working memory task: An fMRI study.

Research suggests that white noise may facilitate auditory working memory performance via stochastic resonance. Stochastic resonance is quantified by plotting cognitive performance as a function of noise intensity. The plot would appear as an inverted U-curve, that is, a moderate noise is beneficial for performance whereas too low and too much noise attenuates performance. However, knowledge about the optimal signal-to-noise ratio (SNR) needed for stochastic resonance to occur in the brain, particularly in the neural network of auditory working memory, is limited and demand further investigation. In the present study, we extended previous works on the impact of white noise on auditory working memory performance by including multiple background noise levels to map out the inverted U-curve for the stochastic resonance. Using functional magnetic resonance imaging (fMRI), twenty healthy young adults performed a word-based backward recall span task under four signal-to-noise ratio conditions: 15, 10, 5, and 0-dB SNR. Group results show significant behavioral improvement and increased activation in frontal cortices, primary auditory cortices, and anterior cingulate cortex in all noise conditions, except at 0-dB SNR, which decreases activation and performance. When plotted as a function of signal-to-noise ratio, behavioral and fMRI data exhibited a noise-benefit inverted U-shaped curve. Additionally, a significant positive correlation was found between the activity of the right superior frontal gyrus (SFG) and performance in 5-dB SNR. The predicted phenomenon of SR on auditory working memory performance is confirmed. Findings from this study suggest that the optimal signal-to-noise ratio to enhance auditory working memory performance is within 10 to 5-dB SNR and that the right SFG may be a strategic structure involved in enhancement of auditory working memory performance.

Early and Late Shift of Brain Laterality in STG, HG, and Cerebellum with Normal Aging during a Short-Term Memory Task.

Evidence suggests that cognitive performance deteriorates in noisy backgrounds and the problems are more pronounced in older people due to brain deficits and changes. The present study used functional MRI (fMRI) to investigate the neural correlates of this phenomenon during short-term memory using a forward repeat task performed in quiet (STMQ) and in noise: 5-dB SNR (STMN) on four groups of participants of different ages. The performance of short-term memory tasks was measured behaviourally. No significant difference was found across age groups in STMQ. However, older adults (50-65 year olds) performed relatively poorly on the STMN. fMRI results on the laterality index indicate changes in hemispheric laterality in the superior temporal gyrus (STG), Heschl's gyrus (HG), and cerebellum, and a leftward asymmetry in younger participants which changes to a more rightward asymmetry in older participants. The results also indicate that the onset of the laterality shift varies from one brain region to another. STG and HG show a late shift while the cerebellum shows an earlier shift. The results also reveal that noise influences this shifting. Finally, the results support the hypothesis that functional networks that underlie STG, HG, and cerebellum undergo reorganization to compensate for the neural deficit/cognitive decline.