Family-wise Error Research Articles

Brain white matter microstructural changes in chemotherapy-treated older long-term breast cancer survivors.

To assess white matter microstructural changes in older long-term breast cancer survivors 5-15 years post-chemotherapy treatment. Breast cancer survivors aged 65 years or older who underwent chemotherapy (C+) and who did not undergo chemotherapy (C-) and age- and sex-matched healthy controls (HC) were enrolled at time point 1 (TP1) and followed for 2 years for time point 2 (TP2). All participants underwent brain MRI with diffusion tensor images and neuropsychological (NP) testing with the NIH Toolbox Cognition Battery. Tract-based spatial statistics (TBSS) analysis was performed on the diffusion tensor images to assess white matter microstructural changes with the fractional anisotropy (FA) parameter. There were significant longitudinal alterations in FA within the C+ group over time. The C+ group showed diminished FA in the body and genu of corpus callosum, anterior corona radiate, and external capsule on both the whole brain and region of interest (ROI) based analyses after p < 0.05 family-wise error (FWE) correction. However, there were no significant group differences between the groups at TP1. Additionally, at TP1, a positive correlation (R = 0.58, p = 0.04) was observed between the FA value of the anterior corona radiata and the crystallized composite score in the C+ group. Brain white matter microstructural alterations may be the underlying neural correlates of cognitive changes in older breast cancer survivors who had chemotherapy treatment years ago.

Reduced Cortico-Cortical Resting-State Connectivity in Sensory Systems Related to Bodily Pain in Juvenile Fibromyalgia.

Juvenile-onset fibromyalgia (JFM) is a paradigmatic chronic pain condition for which the underlying neurobiological substrates are poorly understood. This study examined, for the first time, data-driven resting-state functional connectivity (rsFC) alterations in 37 female adolescents with JFM compared with 43 healthy female adolescents and identified associations with bodily pain. Whole-brain voxel-wise rsFC alterations were assessed using the intrinsic connectivity contrast, a measure of node centrality at each voxel, and seed-based analyses for interpretability. We studied the relationship between rsFC alterations in somatosensory systems and the location and extension of bodily pain. Adolescents with JFM had voxel-wise rsFC reductions in the paracentral lobule (PCL)/primary somatosensory cortex (S1) (T=4.89, family-wise error corrected p-value (pFWE)< 0.001) and left midcingulate cortex (T=4.67, pFWE=0.043). Post hoc analyses revealed reduced rsFC spanning major cortical sensory hubs (T > 4.4, pFWE < 0.030). Cortico-cortical rsFC reductions within PCL/S1 in JFM occurred in locations innervated by bodily areas where the pain was most frequent (F=3.15; positive false discovery rate=0.029) and predicted widespread pain (T > 4.4, pFWE < 0.045). Conversely, adolescents with JFM had increases in PCL/S1-thalamus (T=4.75, pFWE=0.046) and PCL/S1-anterior insula rsFC (T=5.13, pFWE=0.039). Reduced cortico-cortical sensory integration involving PCL/S1 and spanning the sensory systems may underly critical pain sensory features in youth with JFM. Reduced sensory integration is paralleled by augmented cross-talk between sensory and affective/salience-processing regions, potentially indicating a shift toward more affectively colored sensory experiences to the detriment of specific sensory discrimination.

Cognitive functioning and psychosomatic syndromes in a subjective tinnitus sample.

Tinnitus is the perception of a sound in the absence of any corresponding external sound source. Current research suggests a relationship among emotional, cognitive, and psychosomatic symptoms and the occurrence or maintenance of chronic tinnitus. This study aimed to detect the prevalence and role of psychosomatic conditions, as defined by the Diagnostic Criteria for Psychosomatic Research (DCPR), and cognitive functioning in a group of patients with tinnitus. Sixty-two patients with subjective tinnitus and 62 non-tinnitus controls were recruited from the Otorhinolaryngology Unit of the University of Bari. Pure-tone audiometry was performed in all tinnitus subjects, and sound level tolerance was evaluated. Additionally, tinnitus handicap (Tinnitus Handicap Inventory [THI]), psychopathological symptoms (Symptom Checklist-90, Revised [SCL-90-R]), anxiety (State-Trait Anxiety Inventory [STAI-Y1/2]), depression (Beck Depression Inventory [BDI]), cognitive impairment (Mini-Mental State Examination [MMSE]), executive functions (Frontal Assessment Battery [FAB]), and psychosomatic syndromes (DCPR) were evaluated. Parametric and non-parametric tests were used to detect cognitive and symptomatological differences between patients and controls. The predictivity of these factors for tinnitus severity was studied using multiple regression (Backward Elimination). All tests were considered significant at p < 0.05 (family wise error corrected for each comparison). 69.4% tinnitus patients met multiple DCPR criteria, compared to 32.3% of controls. Tinnitus patients exhibited elevated rates of illness denial (ꭓ2 = 9.02; p < 0.009), demoralization (ꭓ2 = 8.05; p < 0.018), somatization (ꭓ2 = 4.92; p < 0.063) and functional symptoms (ꭓ2 = 5.21; p < 0.06) scoring significantly higher on the BDI, STAI-Y1, and STAI-Y2, and SCL-90-R compared to controls. Patients with tinnitus showed lower MMSE scores, compared to controls (t = -2.282; p < 0.001). No association between tinnitus severity and global cognitive impairment emerged. Conversely, executive function deficits were associated to tinnitus severity. Among the cognitive and psychological factors, only trait anxiety, one or more psychosomatic syndromes, and somatization clusters were strongly correlated with tinnitus severity. Our findings suggest a relationship between tinnitus severity, psychological, psychosomatic symptoms, and frontal impairment. Additionally, the influence of tinnitus on cognitive functions paves the way for integrated, multidisciplinary diagnostic and treatment options for patients. Although preliminary, our findings highlight the importance of early cognitive and psychological screening to improve patients' quality of life.

Exploring structural brain changes in children with neonatal brachial plexus palsy: a voxel-based morphometry analysis

BACKGROUND: Obstetric brachial plexus palsy (OBPP) is paralysis of the upper limb resulting from nerve injury during vaginal delivery. Although current treatment approaches frequently lead to complete reinnervation of the limb, some patients show long-term motor deficits. These impairments may result from upper limb disuse that causes structural brain changes. AIM: This study aimed to compare deep gray matter volumes between children with OBPP and healthy controls. METHODS: We analyzed the structural magnetic resonance imaging results of 46 children with OBPP (n=24, mean age — 10.20, of whom 12 were girls) and healthy age-matched controls (n=22, mean age — 9.63, of whom 10 were girls) using a voxel-based morphometry technique in SPM12 package (Statistical Parametric Mapping) in MATLAB R2019b. To minimize false discoveries, we used a stringent procedure to control the family-wise error rate. RESULTS: We found volumetric brain differences between children with OBPP and healthy controls (all FWE-corrected p 0.005). Children with OBPP had significantly lower gray matter volumes in the left amygdala, bilateral hippocampus, and right entorhinal cortex. CONCLUSION: Integrating our findings with previous work, we speculate that the amygdala–hippocampus–entorhinal cortex complex might play a significant role in motor disorders.

Optimal weighted Bonferroni tests and their graphical extensions.

Regulatory guidelines mandate the strong control of the familywise error rate in confirmatory clinical trials with primary and secondary objectives. Bonferroni tests are one of the popular choices for multiple comparison procedures and are building blocks of more advanced procedures. It is usually of interest to find the optimal weighted Bonferroni split for multiple hypotheses. We consider two popular quantities as the optimization objectives, which are the disjunctive power and the conjunctive power. The former is the probability to reject at least one false hypothesis and the latter is the probability to reject all false hypotheses. We investigate the behavior of each of them as a function of different Bonferroni splits, given assumptions about the alternative hypotheses and correlations between test statistics. Under independent tests, unique optimal Bonferroni weights exist; under dependence, optimal Bonferroni weights may not be unique based on a fine grid search. In general, we propose an optimization algorithm based on constrained nonlinear optimization and multiple starting points. The proposed algorithm efficiently identifies optimal Bonferroni weights to maximize the disjunctive or conjunctive power. In addition, we apply the proposed algorithm to graphical approaches, which include many Bonferroni-based multiple comparison procedures. Utilizing the closed testing principle, we adopt a two-step approach to find optimal graphs using the disjunctive power. We also identify a class of closed test procedures that optimize the conjunctive power. We apply the proposed algorithm to a case study to illustrate the utility of optimal graphical approaches that reflect study objectives.

The effects of a psychiatric clerkship on stigmatizing attitudes toward mental disorders as held by German medical students.

According to the United Nations, access to medical care is a fundamental human right. However, there is widespread stigmatization of severe mental illnesses and this appears to seriously hamper the quality of healthcare in people with psychiatric co-morbidity. Thus, interventions that help reduce stigma among healthcare providers are urgently needed. The objective of the current study was to investigate the effects of a psychiatric clerkship on stigmatizing attitudes toward mental disorders held by medical students. Between 2018 and 2019, a total of 256 third- and fourth-year students from Marburg University Medical School (Germany) completed two surveys-one before and one after a 2 week clerkship program that was designed to prioritize direct interaction with the patients. For measuring stigma, the questionnaires contained questions about students' attitudes toward psychiatry (ATP), including the Opening Minds Scale for Healthcare Providers (OMS-HC), Community Attitudes Toward the Mentally Ill (CAMI), and measurements according to the Stereotype-Content Model (SCM). We conducted pre-vs.-post comparisons using the Wilcoxon signed rank test with continuity correction or paired t-test and employed the Spearman method for correlational analysis. We considered p < 0.05 significant and adjusted all p-values reported here using the Benjamini-Hochberg procedure to account for family-wise error. After the clerkship, a significantly reduced stigma was found, as assessed with ATP (mean p < 0.001), OMS-HC (sum and subscale "attitudes" p < 0.001; subscale "disclosure" p = 0.002), and both SCM subscales (p < 0.001). Moreover, we observed significant associations between stigma expression (e.g., OMS-HC sum) and the willingness of students to choose psychiatric residency after finishing medical school (before clerkship: p < 0.001; ρ = -0.35; change after clerkship: p = 0.004; ρ = -0.2). Our findings indicate that a psychiatric clerkship that involves students in direct interaction with patients may effectively reduce stigma. Therefore, we advocate the incorporation of components of direct interaction in medical education to combat stigma and unequal treatment, as this could improve outcomes in patients with severe mental illnesses.

Means Grouping based on Studentized Midrange

The purpose of this paper was to develop two procedures of multiple comparisons based on methods of clustering means, that is, MGM and MGR tests. The first is based on the studentized midrange distribution, and the second based on the studentized range distribution. The tests showed performance equivalent to the performance of the compared tests. Like the tests presented that were based on methods of grouping averages, the MGM and MGR tests did not control the experimentwise error rate for almost all evaluated scenarios. However, under the complete $H_1$ hypothesis, these tests showed high power, with emphasis on the MGM test. Thus, what we propose is yet another test alternative without ambiguity in its results, and not a substitution of the traditional tests already present in the literature.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement

BackgroundADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. MethodsTwenty adults (M = 11, 55%, F = 9, 45%), ages 19–52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3–5 weeks of treatment with LDX and 3–5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. ResultsImprovement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). ConclusionsThese findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD.Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.

Sequential Anomaly Detection Under Sampling Constraints

The problem of sequential anomaly detection is considered, where multiple data sources are monitored in real time and the goal is to identify the &#x201C;anomalous&#x201D; ones among them, when it is not possible to sample all sources at all times. A detection scheme in this context requires specifying not only when to stop sampling and which sources to identify as anomalous upon stopping, but also which sources to sample at each time instance until stopping. A novel formulation for this problem is proposed, in which the number of anomalous sources is not necessarily known in advance and the number of sampled sources per time instance is not necessarily fixed. Instead, an arbitrary lower bound and an arbitrary upper bound are assumed on the number of anomalous sources, and the fraction of the expected number of samples over the expected time until stopping is required to not exceed an arbitrary, user-specified level. In addition to this sampling constraint, the probabilities of at least one false alarm and at least one missed detection are controlled below user-specified tolerance levels. A general criterion is established for a policy to achieve the minimum expected time until stopping to a first-order asymptotic approximation as the two familywise error rates go to zero. Moreover, the asymptotic optimality is established of a family of policies that sample each source at each time instance with a probability that depends on past observations only through the current estimate of the subset of anomalous sources. This family includes, in particular, a novel policy that requires minimal computation under any setup of the problem.

Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B). Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p&lt;0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.

Brain MRI diffusion abnormalities associated with arteriolosclerosis pathology

AbstractBackgroundBrain arteriolosclerosis is one of the main pathologies of cerebral small vessel disease. It involves the thickening of the vessel wall and stenosis of arterioles causing lower cognitive and motor function, and higher odds of dementia. This work intends to explore the independent association of brain arteriolosclerosis with diffusion abnormalities in the white matter (WM) of community‐based older adults.MethodParticipants comprised community‐dwelling older adults (N = 175) from four studies of aging (Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core of the Rush Alzheimer’s Disease Research Center) (Fig.1A). Whole brain 3D T1w MPRAGE, T2w FLAIR, and diffusion‐weighted MRI (2×2×2mm3, b = 1,000s/mm2 for 40 diffusion gradient directions, and 6 b = 0s/mm2 volumes) data were acquired in‐vivo using 3T MRI scanners. The fractional anisotropy (FA) and trace maps were transformed to the space of the IIT Human Brain Atlas v.5.0 and projected onto the WM skeleton of the IIT atlas. Following a participant’s death, the extracted brain underwent a detailed evaluation by a neuropathologist. Assessed neuropathologies included arteriolosclerosis, Alzheimer’s pathology, LATE‐NC, gross and microscopic infarcts, atherosclerosis, and cerebral amyloid angiopathy (Fig.1B).Linear regression was used in voxels of the WM skeleton to test the association of FA or trace with the severity of arteriolosclerosis controlling for all other neuropathologies, white matter hyperintensities (WMH), demographic variables (age at scan, sex, years of education), antemortem interval to imaging, and scanner. The statistical analyses were carried out using FSL’s PALM tool with 5,000 permutations and threshold‐free cluster enhancement. The significance level was set at p&lt;0.05, after family‐wise error rate (FWER) correction for multiple testing.ResultArteriolosclerosis score was associated with lower FA (Fig.2) and higher trace (Fig.3) of the diffusion tensor throughout the brain in multiple WM regions, even in areas typically free of WMH. Other neuropathologies or the effects of WMH on diffusion characteristics had no impact on these relationships.ConclusionThe current study showed that, regardless of the impact of other neuropathologies or visible WMH, brain arteriolosclerosis in older persons is associated with diffusion abnormalities that extend throughout the WM.

Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment

AbstractBackgroundCardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.Methods647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.ResultsCBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p&lt;0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.ConclusionCerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.

Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment

AbstractBackgroundCardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.Method647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.ResultCBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p&lt;0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.ConclusionCerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.

Characterizing the effects of chemotherapy on the brain of patients with head and neck cancer using FDG PET

AbstractBackgroundChemotherapy has known adverse effects on the brain. From small (N&lt;30) studies primarily in breast cancer, we know that post‐chemotherapy brain changes can be detected with 18F ‐fluorodeoxyglucose positron emission tomography (FDG PET), but this has been relatively unexplored in other cancers, and has not been explored in patients with head and neck cancer (HNCa) (Chen, 2018). Patients with HNCa have 2‐3 times the risk of dementia after therapy compared to controls and may be particularly vulnerable given underlying lower levels of education and heavy tobacco and alcohol use (Zer, 2018). We will determine which areas of the brain are most vulnerable to the chemotherapy in HNCa with FDG PET.MethodPatients with HNCa were identified from Vanderbilt’s Cancer Registry, limited to patients with FDG PET in the last year (2021). Clinical data was mined from the electronic health record. Images were processed with well‐established SPM12 methods (Friston, 1995). A voxel‐wise ANCOVA was performed on FDG PET images before and after chemotherapy, including covariates of age, sex, ethnicity, and time between chemotherapy and follow‐up imaging using conservative family wise error of &lt;0.05 and voxel extent threshold of 10.Result68 patients with HNCa met inclusion criteria and all patients received Carboplatin‐based chemotherapy (Table 1). Compared to baseline, 17 clusters met conservative significance thresholds with decreases in glucose metabolism following treatment (Figure 1). These included large regions (46397 1.5mm3 voxels) in the frontal and temporal lobes (pFWE = &lt;0.001). Specifically, there was significantly decreased glucose metabolism in the dorsolateral prefrontal cortex (BA 9), frontoparietal cortex (BA 10), orbital frontal cortex (BA 11), medial and superior temporal gyri (BA 21, 22), dorsal (BA 24), and the subgenual (BA 25), pregenual (BA 32), and rostral (BA 33) anterior cingulate cortex post‐chemotherapy.ConclusionTo our knowledge, this is the first study to explore the effects of chemotherapy in HNCa, a population particularly vulnerable to these effects. We found that regions in the forebrain and temporal lobes are most vulnerable. Studies like these are important to establish and confirm spatial distributions of these effects which will be crucial for development of diagnostics and monitoring tools for these effects.

Microstructural differences in migraine: A diffusion-tensor imaging study.

Diffusion-tensor imaging can be applied to describe the microstructural integrity of the whole brain. As findings about microstructural alterations in migraine are inconsistent, we aimed to replicate the most frequent results and assess a relationship between migraine parameters and changes in microstructure. Diffusion-weighted MRI data of 37 migraine patients and 40 controls were collected. Two indices of diffusion of water molecules, fractional anisotropy and mean diffusivity were used in a voxel-wise analysis. Group comparisons were carried out in SPM12 using age and sex as covariates. Statistically significant results survived family-wise error correction (pFWE < 0.05). Migraine intensity, frequency, and duration were self-reported and correlated with mean fractional anisotropy and mean diffusivity values across clusters. Migraine patients showed significantly lower fractional anisotropy in occipital regions, and significantly higher fractional anisotropy in thirteen clusters across the brain. Mean diffusivity of migraine patients was significantly decreased in the cerebellum and pons, but it was not increased in any area. Correlation between migraine duration and fractional anisotropy was significantly positive in the frontal cortex and significantly negative in the superior parietal lobule. We suggest that microstructural integrity of the migraine brain is impaired in visual areas and shows duration-related alterations in regions of the default mode network.

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women.

In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women. We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-β (Aβ) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses. FSH levels were positively associated with Aβ load in frontal cortex (multivariable adjusted P≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aβ load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores. Increasing serum gonadotropin levels, especially FSH, are associated with higher Aβ load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.

Differences in Cortical Activation During Dorsiflexion and Plantarflexion in Chronic Ankle Instability: A Task-fMRI Study.

Chronic ankle instability is a common sports injury that often presents with increased plantarflexion and restricted dorsiflexion. The cumulative effect of peripheral injuries may induce neuroplasticity in the central nervous system. However, the relationship between dorsiflexion or plantarflexion and the central nervous system in patients with chronic ankle instability remains unknown. (1) Is there a difference in region and voxel (volume pixel) of cortical activation during plantarflexion and dorsiflexion between patients with chronic ankle instability and a control group with normal ankle function? (2) Is there a correlation between activation of sensorimotor-related brain regions and three clinical measurement scales of ankle function and disease severity in patients with chronic ankle instability? Between December 2020 and May 2022, we treated 400 patients who had chronic ankle instability. Ten percent (40 patients; mean ± standard deviation age 29 ± 7 years; 17 male patients) were randomly selected to participate in this study. We recruited 42 volunteers with normal ankle function (mean age 28 ± 5 years; 21 male participants) matched by age and education level. A total of 2.5% (1 of 40) of patients with bilateral chronic ankle instability and 30% (12 of 40) with left-sided chronic ankle injury did not meet our inclusion criteria and were excluded from the study. The control group underwent MRI with good image quality. Finally, 27 patients with chronic ankle instability (mean age 26 ± 5 years; 10 male patients) and 42 participants with normal ankle function were enrolled. Ankle function and disease severity were assessed using three clinical scales: the Cumberland Ankle Instability Tool, Karlsson-Peterson Ankle Function Score, and the American Orthopedic Foot and Ankle Society Score. A uniplanar and nonweightbearing ankle dorsiflexion-plantarflexion paradigm (a recognized model or pattern) was performed using a short-block design during the functional MRI scan. This experimental design included a series of on-off periods consisting of movement and a rest period. From 15° of plantarflexion to 15° of dorsiflexion, the manipulator allowed 30° of ankle rotation. The cerebral excitability patterns between patients with chronic ankle instability and controls were analyzed using t-tests. We retained voxels with p values less than 0.05 in a voxel-level family-wise error correction. Clusters with voxel numbers greater than 10 were retained. The Cohen d coefficient was used to calculate between-group effect sizes. Spearman analysis was performed to explore the correlation between activation regions and the three clinical assessment scales. In the patient group, cortical activation was greater during plantarflexion than during dorsiflexion, which was different from that in the control group. The between-group comparison showed that patients with chronic ankle instability had reduced activation in the ipsilateral precuneus (cluster size = 35 voxels [95% CI -0.23 to 0.07]; p < 0.001) during dorsiflexion, whereas during plantarflexion, chronic ankle instability caused increased activation in the ipsilateral superior temporal gyrus (cluster size = 90 voxels [95% CI -0.73 to -0.13]; p < 0.001), precuneus (cluster size = 18 voxels [95% CI -0.56 to -0.19]; p < 0.001), supplementary motor area (cluster size = 57 voxels [95% CI -0.31 to 0.00]; p < 0.001), superior frontal gyrus (cluster size = 43 voxels [95% CI -0.82 to -0.29]; p < 0.001), medial part of the superior frontal gyrus (cluster size = 39 voxels [95% CI 0.41 to 0.78]; p < 0.001), and contralateral postcentral gyrus (cluster size = 100 voxels [95% CI -0.32 to 0.02]; p < 0.001). Patients with chronic ankle instability showed a large effect size compared with controls (Cohen d > 0.8). During plantarflexion, the number of activated voxels in the supplementary motor area had a modest, positive correlation with the Karlsson-Peterson Ankle Function Score (r = 0.52; p = 0.01), and the number of activated voxels in the primary motor cortex (M1) and primary sensory cortex (S1) had a weak, positive correlation with the American Orthopedic Foot and Ankle Society Score in patients with chronic ankle instability (M1: r = 0.45; p = 0.02, S1: r = 0.49; p = 0.01). Compared with volunteers with normal ankle function, patients with chronic ankle instability had increased cortical activation during plantarflexion and decreased cortical activation during dorsiflexion. We analyzed the central neural mechanisms of chronic ankle instability in patients with sports injuries and provided a theoretical basis for the development of new central and peripheral interventions in the future. Because there was a positive correlation between the neural activity in sensorimotor-related regions during plantarflexion and clinical severity, clinicians might one day be able to help patients who have chronic ankle instability with neuromuscular rehabilitation by applying electrical stimulation to specific targets (such as S1M1 and the supplementary motor area) or by increasing activation of sensorimotor neurons through ankle movement.

Using multiple outcomes in intervention studies: improving power while controlling type I errors

Background The CONSORT guidelines for clinical trials recommend use of a single primary outcome, to guard against the raised risk of false positive findings when multiple measures are considered. It is, however, possible to include a suite of multiple outcomes in an intervention study, while controlling the familywise error rate, if the criterion for rejecting the null hypothesis specifies that N or more of the outcomes reach an agreed level of statistical significance, where N depends on the total number of outcome measures included in the study, and the correlation between them. Methods Simulations were run, using a conventional null-hypothesis significance testing approach with alpha set at .05, to explore the case when between 2 and 12 outcome measures are included to compare two groups, with average correlation between measures ranging from zero to .8, and true effect size ranging from 0 to .7. In step 1, a table is created giving the minimum N significant outcomes (MinNSig) that is required for a given set of outcome measures to control the familywise error rate at 5%. In step 2, data are simulated using MinNSig values for each set of correlated outcomes and the resulting proportion of significant results is computed for different sample sizes,correlations, and effect sizes. Results The Adjust NVar approach can achieve a more efficient trade-off between power and type I error rate than use of a single outcome when there are three or more moderately intercorrelated outcome variables. Conclusions Where it is feasible to have a suite of moderately correlated outcome measures, then this might be a more efficient approach than reliance on a single primary outcome measure in an intervention study. In effect, it builds in an internal replication to the study. This approach can also be used to evaluate published intervention studies.

Financial Toxicity in the Spanish Speaking Population

Advances in therapy have significantly improved cancer survival outcomes but with a harmful patient consequence: financial toxicity. Financial toxicity consists of a patient's many economic burdens from cancer treatment, encompassing direct healthcare costs as well as additional devastating financial consequences, such as job loss and medical bankruptcy. With rising cancer treatment costs, financial toxicity has become a problem that is increasingly impactful in both cancer treatment and survivorship, amplifying disparities, negatively impacting quality of life, treatment adherence and survival. The long-term research goal that this study will contribute to is to develop culturally appropriate and effective patient navigation resources and psychosocial support resources for interventions to increase coping and resilience to financial toxicity in high-risk populations. This study will seek to generate the early data needed to help develop the content and method of delivering strategies, tailored for an underserved, Spanish-speaking Latino population. Eligibility Participant must be 18 years of age or older at the time of study participation, able to read and speak Spanish, have diagnosis of cancer within the past 2 years or be on active treatment for their cancer; all disease sites and all stages are eligible for enrollment. We will exclude patients unable to give consent. Methods This is a prospective observational study of cancer patients and survivors, with participants to be recruited from Scripps MD Anderson Cancer Center. Participating clinics will be screened in the electronic medical record for individuals who meet above eligibility criteria. At the time of clinic visits, eligible individuals will be approached. Individuals who express that they would like to participate in the survey study will receive the study packet with the consent statement and baseline survey questions. Study participants will also be invited to participate in the OPTIONAL patient navigation portion of the study. Participants who are not active on the MyScripps patient portal will be invited to join the patient navigation portion of the study. Those elect to participate will be provided a device if they do not have their own. Participants will be given a Greenphire Clincard on which they will receive a total of $75 in three installments. Research team members will enter the item responses into the REDCap database. They will undergo a follow-up survey during a range from 4 months to 9 months from the initial survey date. Those participating in the patient navigation portion of the study will be contacted by the navigator on a monthly basis through the electronic portal or telephone. Statistics We plan to enroll N= 80 Spanish-speaking patients in the survey study. For correlation testing, we hypothesize a moderate effect size (correlation = 0.32) for the association between the primary outcome measure, the baseline measure of self-efficacy (Hope State score) and the baseline financial toxicity score (Economic Strain and Resilience in Cancer). For feasibility testing of navigation participation, feasibility will be assessed through descriptive statistics. We hypothesize that it is feasible for 50% of invited patients to participate. When the sample size is 40, a two-sided 95% confidence interval for participant completion rate will extend 0.15 from the observed proportion for an expected proportion of 0.50. Analysis The primary outcome measure is financial toxicity, measured using the ENRICh instrument at baseline. The primary predictor is the baseline Hope State score. This modeled association is of primary interest in the analysis. We will conduct descriptive and univariate/multivariate analyses on this association of primary interest, including Chi-square test, t-test. Other univariate and multivariate analyses of associations between financial toxicity and other measures obtained from survey measures, as well as clinical, demographic, socioeconomic, and care delivery variables, considered descriptive and exploratory, will be performed. Accounting for multiple comparisons will be based on stepdown procedures and familywise error rate control; we plan to control this overall error rate using the Holm-Sidak adjustment, or procedure with equitable properties.

4 Interactions of Inflammation and Psychosocial Stress on White Matter Integrity Over Time in Older Black Adults

Objective:Higher levels of inflammation are associated with risk factors for Alzheimer’s disease and related dementias (ADRD) in older Black adults including psychosocial stressors (e.g., discrimination and early life adversity) and white matter alterations. Yet, limited work has investigated these risk factors together in a longitudinal neuroimaging study, despite the well-known ADRD disparity in older Black adults. Using data from the Minority Aging Research Study and African American Clinical Core of the Rush Alzheimer’s Disease Center, we examined interactions of psychosocial stressors and change in inflammation on changes in white matter integrity as measured via diffusion tensor imaging (DTI).Participants and Methods:Older Black adults (n=102) without known dementia at baseline (age=75.8±6.1 years; 87.3% female; education=15.4±2.7 years) completed blood draws at two time points (follow-up=2.4±0.7 years), neuroimaging at two or more time points (follow-up=3.7±1.8 years), and psychosocial questionnaires at one time point coinciding with the first blood draw/neuroimaging. Blood serum was assayed using highly-sensitive multiplexed sandwich ELISA for interleukin-6, c-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-a) and a change score was calculated for each inflammatory marker (T2 - T1). The Williams Everyday Discrimination Scale quantified experiences of discrimination in all participants and a 16-item questionnaire of emotional and physical trauma from age 0-18 assessed early life adversity in a participant subset (n=63). DTI-derived tract-based spatial statistics (TBSS) slope change measures for trace of the diffusion tensor, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were calculated, with the first two scans matched in time to blood assays. Linear regression models investigated interactions of each inflammatory marker change score (separately) and either discrimination or early life adversity (separately) on trace, FA, AD, and RD slopes as individual outcomes adjusting for age, sex, education, white matter hyperintensities (total volume and voxelwise), cardiovascular risk factors, statin and analgesic medications, thyroid conditions, and depression. Statistical significance was determined at p&lt;0.05 using family wise error correction and threshold free cluster enhancement.Results:Discrimination moderated the relationship between TNF-a and AD whereby those with increasing TNF-a and higher levels of discrimination had increasing levels of AD over time in white matter tracts connecting the left and right cerebellum, the left pallidum and medulla, and the left superior frontal gyrus and left thalamus. Both discrimination and early life adversity moderated associations between CRP and AD, where increases in CRP and higher psychosocial stressors (of either type) resulted in decreasing AD over time in tracts involving cingulate, frontal, and parietal regions. Discrimination and early life adversity also moderated associations between CRP and RD, where increasing CRP combined with greater psychosocial stressors resulted in decreasing RD in right hemisphere association and projection tracts connecting frontal, parietal, central, and subcortical regions.Conclusions:TNF-a and CRP interacted with measures of psychosocial stress to associate with DTI-derived TBSS slope change measures of AD and RD in differential, and at times, paradoxical ways. Findings suggest that both risk and resilience as related to brain connectivity may be co-occurring in the presence of psychosocial stressors for older Black adults.