Pilot trial testing the effects of exercise on chemotherapy-induced peripheral neurotoxicity (CIPN) and the interoceptive brain system.

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a prevalent, dose-limiting, tough-to-treat toxicity involving numbness, tingling, and pain in the extremities with enigmatic pathophysiology. This randomized controlled pilot study explored the feasibility and preliminary efficacy of exercise during chemotherapy on CIPN and the role of the interoceptive brain system, which processes bodily sensations. METHODS: Nineteen patients (65 ± 11 years old, 52% women; cancer type: breast, gastrointestinal, multiple myeloma) starting neurotoxic chemotherapy were randomized to 12 weeks of exercise (home-based, individually tailored, moderate intensity, progressive walking, and resistance training) or active control (nutrition education). At pre-, mid-, and post-intervention, we assessed CIPN symptoms (primary clinical outcome: CIPN-20), CIPN signs (tactile sensitivity using monofilaments), and physical function (leg strength). At pre- and post-intervention, we used task-free ("resting") fMRI to assess functional connectivity in the interoceptive brain system, involving the salience and default mode networks. RESULTS: The study was feasible (74-89% complete data across measures) and acceptable (95% retention). We observed moderate/large beneficial effects of exercise on CIPN symptoms (CIPN-20, 0-100 scale: - 7.9 ± 5.7, effect size [ES] = - 0.9 at mid-intervention; - 4.8 ± 7.3, ES = - 0.5 at post-intervention), CIPN signs (ES = - 1.0 and - 0.1), and physical function (ES = 0.4 and 0.3). Patients with worse CIPN after neurotoxic chemotherapy had lower functional connectivity within the default mode network (R2 = 40-60%) and higher functional connectivity within the salience network (R2 = 20-40%). Exercise tended to increase hypoconnectivity and decrease hyperconnectivity seen in CIPN (R2 = 12%). CONCLUSION: Exercise during neurotoxic chemotherapy is feasible and may attenuate CIPN symptoms and signs, perhaps via changes in interoceptive brain circuitry. Future work should test for replication with larger samples. TRIAL REGISTRATION: Registered Jan 2017 on ClinicalTrials.gov as NCT03021174.

Symptom Clusters Seen in Adult COVID-19 Recovery Clinic Care Seekers.

BACKGROUND: COVID-19 symptom reports describe varying levels of disease severity with differing periods of recovery and symptom trajectories. Thus, there are a multitude of disease and symptom characteristics clinicians must navigate and interpret to guide care. OBJECTIVE: To find natural groups of patients with similar constellations of post-acute sequelae of COVID-19 (PASC) symptoms. DESIGN: Cohort SETTING: Outpatient COVID-19 recovery clinic with patient referrals from 160 primary care clinics serving 36 counties in Texas. PATIENTS: Adult patients seeking COVID-19 recovery clinic care between November 15, 2020, and July 31, 2021, with laboratory-confirmed mild (not hospitalized), moderate (hospitalized), or severe (hospitalized with critical care) COVID-19. MAIN MEASURES: Demographics, COVID illness onset, and duration of persistent PASC symptoms via semi-structured medical assessments. KEY RESULTS: Four hundred forty-one patients (mean age 51.5 years; 295 [66.9%] women; 99 [22%] Hispanic, and 170 [38.5%] non-White, racial minority) met inclusion criteria. Using a k-medoids algorithm, we found that PASC symptoms cluster into two distinct groups: neuropsychiatric (N = 186) (e.g., subjective cognitive dysfunction) and pulmonary (N = 255) (e.g., dyspnea, cough). The neuropsychiatric cluster had significantly higher incidences of otolaryngologic (X2 = 14.3, p < 0.001), gastrointestinal (X2 = 6.90, p = 0.009), neurologic (X2 = 441, p < 0.001), and psychiatric sequelae (X2 = 40.6, p < 0.001) with more female (X2 = 5.44, p = 0.020) and younger age (t = 2.39, p = 0.017) patients experiencing longer durations of PASC symptoms before seeking care (t = 2.44, p = 0.015). Patients in the pulmonary cluster were more often hospitalized for COVID-19 (X2 = 3.98, p = 0.046) and had significantly higher comorbidity burden (U = 20800, p = 0.019) and pulmonary sequelae (X2 = 13.2, p < 0.001). CONCLUSIONS: Health services clinic data from a large integrated health system offers insights into the post-COVID symptoms associated with care seeking for sequelae that are not adequately managed by usual care pathways (self-management and primary care clinic visits). These findings can inform machine learning algorithms, primary care management, and selection of patients for earlier COVID-19 recovery referral. TRIAL REGISTRATION: N/A.

Cisheteronormativity and its influence on the psychosocial experience of LGBTQ+ people with cancer: A qualitative systematic review.

OBJECTIVE: Cisheteronormativity refers to the relationship of heterosexual and cisgender privilege stemming from patriarchy. Although studies have shown that cisheteronormativity can impact health outcomes for lesbian, gay, bisexual, transgender, queer and other sexual, gender diverse, and gender nonconforming (LGBTQ+) people, the specific impact on cancer care has not been described. We synthesized the qualitative evidence on how cisheteronormativity impacts the psychosocial experience of LGBTQ+ people with cancer. METHODS: We conducted a historic search in the CINAHL, LGBT+ Health, PsycInfo, and PubMed databases. Qualitative studies that described the psychosocial experience of LGBTQ+ people with cancer were included. After appraising the quality of the publications, 11 articles were included. Then, we conducted inductive nominal coding, taxonomic analysis, and thematic synthesis. RESULTS: Two main themes emerged, (1) Cisheteronormativity as a social determinant of health, and (2) Cancer, sexual orientation, and gender: Associations and introjections. The themes comprise four categories and 13 subcategories that describe the impact of cisheteronormativity on the cancer experience of LGBTQ+ people. CONCLUSION: Cisheteronormativity within the healthcare system impacts the psychosocial experience of LGBTQ+ people with cancer. Understanding how these gender biases, norms, and social expectations impact the cancer experience is necessary to transform social norms and promote health equity.

Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults.

Answer questions and earn CME/CNE Over the past few decades, a body of research has emerged confirming what many adult patients with noncentral nervous system cancer have long reported-that cancer and its treatment are frequently associated with cancer-related cognitive impairment (CRCI). The severity of CRCI varies, and symptoms can emerge early or late in the disease course. Nonetheless, CRCI is typically mild to moderate in nature and primarily involves the domains of memory, attention, executive functioning, and processing speed. Animal models and novel neuroimaging techniques have begun to unravel the pathophysiologic mechanisms underlying CRCI, including the role of inflammatory cascades, direct neurotoxic effects, damage to progenitor cells, white matter abnormalities, and reduced functional connectivity, among others. Given the paucity of research on CRCI with other cancer populations, this review synthesizes the current literature with a deliberate focus on CRCI within the context of breast cancer. A hypothetical case-study approach is used to illustrate how CRCI often presents clinically and how current science can inform practice. While the literature regarding intervention for CRCI is nascent, behavioral and pharmacologic approaches are discussed.

Health Promotion, Functional Abilities, and Quality of Life Before and During COVID-19 in People With Multiple Sclerosis.

BACKGROUND: Because multiple sclerosis (MS) is an autoimmune disease and many individuals with MS take disease-modifying drugs that suppress immune response, serious concerns have been expressed about the potential effect of COVID-19 on those with this chronic condition. OBJECTIVES: The purpose of this research was to utilize the most recent 5 years of data from an ongoing longitudinal study of health promotion and quality of life (QoL) among people with long-standing MS to investigate changes across time in functional limitations, health promotion, and health-related QoL. METHODS: Participants are mailed an annual survey to complete about their health promotion, depressive symptoms, health status, social support, MS-related functional limitations, and QoL. Differences across time were analyzed with repeated measures of analysis of variances and planned contrasts. RESULTS: In 2021, the 141 participants had a mean age of 69 years and had been diagnosed with MS for 34 years, on average. Most had attended college, were married/partnered women, and reported adequate economic resources. Thirty-seven percent reported they were in poor to fair health. Physical activity and health responsibility scores decreased significantly during 2020-2021 compared with 2017-2019. Significant changes in depressive symptoms, social support, and functional limitation scores followed a different pattern, with the largest changes occurring between 2018 and 2019. QoL and other health promotion scores did not change significantly across time. DISCUSSION: The relatively small changes in health indicators revealed here suggest that older people with long-standing MS may have generally been able to maintain their health promotion, functional abilities, and QoL from before to during the COVID-19 pandemic. However, nurses and other providers should support them to resume their physical activity and regular provider contact as COVID-19 restrictions are eased. The patterns observed here demonstrate the importance of examining changes across an extended period, rather than simply looking at 1 year before and 1 year after a major event, such as COVID-19. These findings can help nurses understand how to help their patients with chronic health conditions maximize their health as they move forward.

Correlates of mental health problems among students in Texas alternative high schools and school-level efforts to address mental health.

Students in alternative high schools (AHSs) are an understudied population who experience disproportionate levels of risk factors that contribute to mental health problems. Using logistic regression, we explored associations between mental health problems and risk and protective factors among students in Texas AHSs (n = 515; mean age 17.1 years; 51% female, 78% youth of color, 64% eligible for free/reduced lunch). Principals (n = 14) and lead health educators (n = 14) reported on school-level efforts to address mental health. Students reported, on average, 1.55 of 4 mental health problems in the past year. Logistic regression indicated that greater number of adverse childhood experiences, lower self-esteem, female gender, and sleep disruption (getting <8 h of sleep per night) were common contributors to symptoms of depression, anxiety, suicidal ideation, and PTSD with models showing medium-to-large effects (AUC: 0.73-0.81). We assessed school-level efforts to address mental health using descriptive statistics. At the school level, most (>50%) principals reported having policies and services to support student mental health, with the exception of having mental health/social services staff represented on school health councils (36%) and having Gay-Straight Alliances (21%). Most lead health educators (86%) reported educating AHS students about mental health, and many (57%) reported receiving professional development in mental health. Future research with a larger number of schools is needed to analyze whether school policies are statistically associated with student-level mental health outcomes. Such multi-level research can inform policies and practices for AHS student mental health.

Headache outcomes of a sleep behavioral intervention in breast cancer survivors: Secondary analysis of a randomized clinical trial.

BACKGROUND: Breast cancer survivors often have persisting headache. In a secondary analysis of the Brief Behavioral Therapy for Cancer-Related Insomnia (BBT-CI) clinical trial (ClinicalTrials.gov identifier NCT02165839), the authors examined the effects of BBT-CI on headache outcomes in patients with breast cancer. METHODS: Patients with breast cancer who were receiving chemotherapy were randomly assigned to receive either the BBT-CI intervention or the Healthy EAting Education Learning for healthy sleep (HEAL) control intervention, and both were delivered over 6 weeks by trained staff. Headache outcomes and heart rate variability (HRV) were measured at baseline, 6 weeks, 6 months, and 12 months. Mixed-effects models were used to examine longitudinal headache outcomes in the groups according to the intention to treat. Principal component analysis and agglomerative hierarchical clustering were conducted to reduce 16 variables for data-driven phenotyping. RESULTS: Patients in the BBT-CI arm (n = 73) exhibited a significant reduction in headache burden over time (P = .02; effect size [Cohen d] = 0.43), whereas the reduction was not significant among those in the HEAL arm (n = 66). The first principal component was positively loaded by headache, sleep, fatigue, and nausea/vomiting and was negatively loaded by cognitive, physical, and emotional functioning. Agglomerative hierarchical clustering revealed 3 natural clusters. Cluster I (n = 58) featured the highest burden of headache, insomnia, and nausea/vomiting; cluster II (n = 50) featured the lowest HRV despite a low burden of headache and insomnia; and cluster III (n = 31) showed an inverse relation between HRV and headache-insomnia, signifying autonomic dysfunction. CONCLUSIONS: BBT-CI is efficacious in reducing headache burden in breast cancer survivors. Patient phenotyping demonstrates a headache type featuring sleep disturbance, nausea/vomiting, and low physical functioning-revealing similarities to migraine. LAY SUMMARY: Breast cancer survivors often have persisting headache symptoms. In patients with cancer, treatment of chronic headache disorders using daily medications may be challenging because of drug interactions with chemotherapy and other cancer therapies as well as patients' reluctance to add more drugs to their medicine list. Headache and sleep disorders are closely related to each other. This study demonstrates that a sleep behavioral therapy reduced headache burden in breast cancer survivors. In addition, the majority of headache sufferers had a headache type with similarities to migraine-featuring sleep disturbance, nausea/vomiting, and low physical functioning.

Neurocognitive Impairment After Hematopoietic Stem Cell Transplant for Hematologic Malignancies: Phenotype and Mechanisms.

Hematopoietic stem cell transplant (HSCT) plays a central role in the treatment of hematologic cancers. With the increasing survival of patients after HSCT, survivorship issues experienced by this population have become an important outcome. Cognitive impairment is an established sequela of HSCT, with studies to date establishing its presence, associated risk factors, and clinical phenotype. There are multiple potential contributors to cognitive impairment after HSCT. Efforts are ongoing to further characterize its clinical phenotype, associated biomarkers, and biologic underpinnings. A fundamental knowledge of post-HSCT cognitive impairment is of value for all clinicians who interface with this population, and further academic efforts are needed to more fully understand the impact of this cancer treatment on brain health. IMPLICATIONS FOR PRACTICE: As survival outcomes after hematopoietic stem cell transplant (HSCT) improve, an awareness of the post-treatment challenges faced by this population has become central to its care. HSCT can have a sustained and broad impact on brain health, causing cognitive dysfunction, fatigue, disturbed mood, and sleep. In affected patients, autonomy, return to work, relationships, and quality of life may all be affected. A fundamental fluency in this area is important for clinicians interfacing with HSCT survivors, facilitating the identification and management of cognitive dysfunction and concurrent symptom clusters, and stimulating interest in these sequelae as areas for future clinical research.

Predicting Patient Reported Outcomes of Cognitive Function Using Connectome-Based Predictive Modeling in Breast Cancer.

Being able to predict who will likely experience cancer related cognitive impairment (CRCI) could enhance patient care and potentially reduce economic and human costs associated with this adverse event. We aimed to determine if post-treatment patient reported CRCI could also be predicted from baseline resting state fMRI in patients with breast cancer. 76 newly diagnosed patients (n = 42 planned for chemotherapy; n = 34 not planned for chemotherapy) and 50 healthy female controls were assessed at 3 times points [T1 (prior to treatment); T2 (1 month post chemotherapy); T3 (1 year after T2)], and at yoked intervals for controls. Data collection included self-reported executive dysfunction, memory function, and psychological distress and resting state fMRI data converted to connectome matrices for each participant. Statistical analyses included linear mixed modeling, independent t tests, and connectome-based predictive modeling (CPM). Executive dysfunction increased over time in the chemotherapy group and was stable in the other two groups (p < 0.001). Memory function decreased over time in both patient groups compared to controls (p < 0.001). CPM models successfully predicted executive dysfunction and memory function scores (r > 0.31, p < 0.002). Support vector regression with a radial basis function (SVR RBF) showed the highest performance for executive dysfunction and memory function (r = 0.68; r = 0.44, p's < 0.001). Baseline neuroimaging may be useful for predicting patient reported cognitive outcomes which could assist in identifying patients in need of surveillance and/or early intervention for treatment-related cognitive effects.

Neurocognitive dysfunction in adult cerebellar medulloblastoma.

OBJECTIVE: Impaired neurocognitive function (NCF) is a well-established consequence of pediatric medulloblastoma (MB) and its treatments. However, the frequency and features of neurocognitive dysfunction in adult-onset MB patients are largely unknown. METHODS: Adult patients (≥ 18 years) with MB who had received formal neurocognitive evaluation (N = 27) were identified. Demographic, medical, and treatment histories were extracted from the medical record. Lesion properties on MRI were analyzed and used to evaluate lesion-symptom mapping further. Demographically adjusted z-scores were calculated for each neurocognitive test and used to assess impairment frequency. Regression analyses were conducted to identify clinical and paraclinical factors associated with impaired NCF. RESULTS: Mean age of the patient sample was 33 years (SD = 11) at the time of MB diagnosis. Prior therapy included surgical resection (89%), radiation (70%), and chemotherapy (26%). A significant proportion of patients were impaired on tests of verbal learning and memory (32%), executive function (29%), and naming (18%). Age, education, lesion size, time from surgery, and number of chemotherapy cycles had the greatest contribution to test performance in random-forest regression models. CONCLUSION: This study identifies frequent impairment of NCF in adult patients with MB, particularly in the domains of learning and memory and executive function. Neurocognitive impairment is influenced by patients' demographic, disease, and treatment history. Further study is warranted to characterize the clinical impact of adult MB more fully.

Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy.

Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-ß-cyclodextrin (HPßCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general.

Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial.

PURPOSE: Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms. METHODS: Cancer patients (N = 355, 56 ± 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0-10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness. RESULTS: Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076). CONCLUSIONS: Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients. TRIAL REGISTRATION: Clinical Trials.gov , # NCT00924651, http://www.clinicaltrials.gov .

The effect of IDH1 mutation on the structural connectome in malignant astrocytoma.

Mutation of the IDH1 gene is associated with differences in malignant astrocytoma growth characteristics that impact phenotypic severity, including cognitive impairment. We previously demonstrated greater cognitive impairment in patients with IDH1 wild type tumor compared to those with IDH1 mutant, and therefore we hypothesized that brain network organization would be lower in patients with wild type tumors. Volumetric, T1-weighted MRI scans were obtained retrospectively from 35 patients with IDH1 mutant and 32 patients with wild type malignant astrocytoma (mean age = 45 ± 14 years) and used to extract individual level, gray matter connectomes. Graph theoretical analysis was then applied to measure efficiency and other connectome properties for each patient. Cognitive performance was categorized as impaired or not and random forest classification was used to explore factors associated with cognitive impairment. Patients with wild type tumor demonstrated significantly lower network efficiency in several medial frontal, posterior parietal and subcortical regions (p < 0.05, corrected for multiple comparisons). Patients with wild type tumor also demonstrated significantly higher incidence of cognitive impairment (p = 0.03). Random forest analysis indicated that network efficiency was inversely, though nonlinearly associated with cognitive impairment in both groups (p < 0.0001). Cognitive reserve appeared to mediate this relationship in patients with mutant tumor suggesting greater neuroplasticity and/or benefit from neuroprotective factors. Tumor volume was the greatest contributor to cognitive impairment in patients with wild type tumor, supporting our hypothesis that greater lesion momentum between grades may cause more disconnection of core neurocircuitry and consequently lower efficiency of information processing.

Task-based neurofeedback training: A novel approach toward training executive functions.

Cognitive training is an emergent approach to improve cognitive functions in various neurodevelopmental and neurodegenerative diseases. However, current training programs can be relatively lengthy, making adherence potentially difficult for patients with cognitive difficulties. Previous studies suggest that providing individuals with real-time feedback about the level of brain activity (neurofeedback) can potentially help them learn to control the activation of specific brain regions. In the present study, we developed a novel task-based neurofeedback training paradigm that benefits from the effects of neurofeedback in parallel with computerized training. We focused on executive function training given its core involvement in various developmental and neurodegenerative diseases. Near-infrared spectroscopy (NIRS) was employed for providing neurofeedback by measuring changes in oxygenated hemoglobin in the prefrontal cortex. Of the twenty healthy adult participants, ten received real neurofeedback (NFB) on prefrontal activity during cognitive training, and ten were presented with sham feedback (SHAM). Compared with SHAM, the NFB group showed significantly improved executive function performance including measures of working memory after four sessions of training (100min total). The NFB group also showed significantly reduced training-related brain activity in the executive function network including right middle frontal and inferior frontal regions compared with SHAM. Our data suggest that providing neurofeedback along with cognitive training can enhance executive function after a relatively short period of training. Similar designs could potentially be used for patient populations with known neuropathology, potentially helping them to boost/recover the activity in the affected brain regions.

The impact of executive function on response to cognitive behavioral therapy in late-life depression.

OBJECTIVE: Late-life depression (LLD) is a common and debilitating condition among older adults. Cognitive behavioral therapy (CBT) has strong empirical support for the treatment of depression in all ages, including in LLD. In teaching patients to identify, monitor, and challenge negative patterns in their thinking, CBT for LLD relies heavily on cognitive processes and, in particular, executive functioning, such as planning, sequencing, organizing, and selectively inhibiting information. It may be that the effectiveness of CBT lies in its ability to train these cognitive areas. METHODS: Participants with LLD completed a comprehensive neuropsychological battery before enrolling in CBT. The current study examined the relationship between neuropsychological function prior to treatment and response to CBT. RESULTS: When using three baseline measures of executive functioning that quantify set shifting, cognitive flexibility, and response inhibition to predict treatment response, only baseline Wisconsin Card Sort Task performance was associated with a significant drop in depression symptoms after CBT. Specifically, worse performance on the Wisconsin Card Sort Task was associated with better treatment response. CONCLUSIONS: These results suggest that CBT, which teaches cognitive techniques for improving psychiatric symptoms, may be especially beneficial in LLD if relative weaknesses in specific areas of executive functioning are present.

Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls.

Breast cancer (BC) chemotherapy is associated with cognitive changes including persistent deficits in some individuals. We tested the accuracy of default mode network (DMN) resting state functional connectivity patterns in discriminating chemotherapy treated (C+) from non-chemotherapy (C-) treated BC survivors and healthy controls (HC). We also examined the relationship between DMN connectivity patterns and cognitive function. Multivariate pattern analysis was used to classify 30 C+, 27 C-, and 24 HC, which showed significant accuracy for discriminating C+ from C- (91.23%, P < 0.0001) and C+ from HC (90.74%, P < 0.0001). The C- group did not differ significantly from HC (47.06%, P = 0.60). Lower subjective memory function was correlated (P < 0.002) with greater hyperplane distance (distance from the linear decision function that optimally separates the groups). Disrupted DMN connectivity may help explain long-term cognitive difficulties following BC chemotherapy.

Estimating individual contribution from group-based structural correlation networks.

Coordinated variations in brain morphology (e.g., cortical thickness) across individuals have been widely used to infer large-scale population brain networks. These structural correlation networks (SCNs) have been shown to reflect synchronized maturational changes in connected brain regions. Further, evidence suggests that SCNs, to some extent, reflect both anatomical and functional connectivity and hence provide a complementary measure of brain connectivity in addition to diffusion weighted networks and resting-state functional networks. Although widely used to study between-group differences in network properties, SCNs are inferred only at the group-level using brain morphology data from a set of participants, thereby not providing any knowledge regarding how the observed differences in SCNs are associated with individual behavioral, cognitive and disorder states. In the present study, we introduce two novel distance-based approaches to extract information regarding individual differences from the group-level SCNs. We applied the proposed approaches to a moderately large dataset (n=100) consisting of individuals with fragile X syndrome (FXS; n=50) and age-matched typically developing individuals (TD; n=50). We tested the stability of proposed approaches using permutation analysis. Lastly, to test the efficacy of our method, individual contributions extracted from the group-level SCNs were examined for associations with intelligence scores and genetic data. The extracted individual contributions were stable and were significantly related to both genetic and intelligence estimates, in both typically developing individuals and participants with FXS. We anticipate that the approaches developed in this work could be used as a putative biomarker for altered connectivity in individuals with neurodevelopmental disorders.

FMRI activation during executive function predicts response to cognitive behavioral therapy in older, depressed adults.

OBJECTIVES: To test our hypothesis that pre-treatment executive function and brain regional activation during executive function would discriminate between responders and non-responders to cognitive behavioral therapy (CBT) in elderly depressed outpatients. DESIGN: Clinical cohort study. SETTING: University-affiliated hospital. PARTICIPANTS: Sixty outpatients (age 59 years and older) completed 12 weeks of CBT between July 2010 and December 2011. Forty-four completed fMRI procedures. MEASUREMENTS: The main outcome consisted of a conversion from a clinical diagnosis (Mini-International Neuropsychiatric Interview) of depression to no clinical diagnosis of depression or a significant improvement in diagnostic criteria. Brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting task (WCST) was the primary predictor variable. RESULTS: 67% of patients had a positive response to CBT. Decreased activation in the left inferior frontal triangle and right superior frontal gyrus as well as increased activity in the right middle frontal gyrus and left superior frontal gyrus predicted a positive response to CBT. Demographic and neurocognitive measures of WCST performance were not significant predictors of a positive CBT outcome, whereas the measure of WCST-induced activity in the prefrontal cortex was a significant predictor. CONCLUSIONS: These data are among the first to suggest that measures of prefrontal brain activation during executive functioning predict response to CBT in older adults. Further exploration of the specific underlying processes that these prefrontal cortical regions are engaging that contributes to better CBT outcomes is warranted in larger, randomized studies.

Multivariate pattern analysis of FMRI in breast cancer survivors and healthy women.

Advances in breast cancer (BC) treatments have resulted in significantly improved survival rates. However, BC chemotherapy is often associated with several side effects including cognitive dysfunction. We applied multivariate pattern analysis (MVPA) to functional magnetic resonance imaging (fMRI) to find a brain connectivity pattern that accurately and automatically distinguishes chemotherapy-treated (C+) from non-chemotherapy treated (C-) BC females and healthy female controls (HC). Twenty-seven C+, 29 C-, and 30 HC underwent fMRI during an executive-prefrontal task (Go/Nogo). The pattern of functional connectivity associated with this task discriminated with significant accuracy between C+ and HC groups (72%, p = .006) and between C+ and C- groups (71%, p = .012). However, the accuracy of discrimination between C- and HC was not significant (51%, p = .46). Compared with HC, behavioral performance of the C+ and C- groups during the task was intact. However, the C+ group demonstrated altered functional connectivity in the right frontoparietal and left supplementary motor area networks compared to HC, and in the right middle frontal and left superior frontal gyri networks, compared to C-. Our results provide further evidence that executive function performance may be preserved in some chemotherapy-treated BC survivors through recruitment of additional neural connections.

Altered resting state functional connectivity in young survivors of acute lymphoblastic leukemia.

BACKGROUND: Chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL) has been associated with long-term cognitive impairments in some patients. However, the neurobiologic mechanisms underlying these impairments, particularly in young survivors, are not well understood. This study aimed to examine intrinsic functional brain connectivity in pediatric ALL and its relationship with cognitive status. PROCEDURE: We obtained resting state functional magnetic resonance imaging (rsfMRI) and cognitive testing data from 15 ALL survivors age 8-15 years and 14 matched healthy children. The ALL group had a history of intrathecal chemotherapy treatment but were off-therapy for at least 6 months at the time of enrollment. We used seed-based analyses to compare intrinsic functional brain network connectivity between the groups. We also explored correlations between connectivity and cognitive performance, demographic, medical, and treatment variables. RESULTS: We demonstrated significantly reduced connectivity between bilateral hippocampus, left inferior occipital, left lingual gyrus, bilateral calcarine sulcus, and right amygdala in the ALL group compared to controls. The ALL group also showed regions of functional hyperconnectivity including right lingual gyrus, precuneus, bilateral superior occipital lobe, and right inferior occipital lobe. Functional hypoconnectivity was associated with reduced cognitive function as well as younger age at diagnosis in the ALL group. CONCLUSIONS: This is the first study to demonstrate that intrinsic functional brain connectivity is disrupted in pediatric ALL following chemotherapy treatment. These results help explain cognitive dysfunction even when objective test performance is seemingly normal. Children diagnosed at a younger age may show increased vulnerability to altered functional brain connectivity.