Pharmacological treatment of depression in patients with brain tumors.

Patients with brain tumors suffer from intense psychosocial distress. Although the prevalence of depressive symptoms in patients with brain tumors is high, the pharmacological antidepressant treatment of those patients is not well defined and results from clinical trials are largely missing. In this review, we describe the current standard of evidence and clinical guidelines for the pharmacological treatment of depression in brain tumor patients. We present specific side effects and interactions that should guide treatment decisions. Furthermore, we provide evidence for the diagnosis, screening and risk factors for depression in brain tumor patients and we elaborate on potential antineoplastic effects of antidepressant drugs and ongoing clinical trials. Antidepressant drugs should not be withheld from patients with brain tumors. Future clinical trials should explore the effectiveness and side effects of antidepressants in this specific patient population.

[Rational treatment of depressive syndromes in brain tumor patients]. / Rationale Behandlung depressiver Syndrome bei Hirntumorpatienten.

BACKGROUND: Brain tumors represent a disease that causes both physical and psychological distress for those affected. The pharmacological treatment of depressive symptoms in particular has not been sufficiently researched in these patients. Depression can severely affect the quality of life and has an impact on the course of the disease. OBJECTIVE: The aim of this work is to describe the diagnosis and treatment of depressive symptoms in brain tumor patients. MATERIAL AND METHODS: For this work a comprehensive literature search was conducted to identify relevant studies addressing the topic of depressive symptoms in brain tumors. The included studies were critically appraised to ensure their quality and relevance. RESULTS: The review of the literature revealed that depressive symptoms are a common complication in brain tumor patients. It was found that there are no studies to date on the efficacy of antidepressant medications in brain tumor patients. DISCUSSION: The results of this work highlight the need to pay increased attention to mental health in brain tumor patients. It is important that healthcare professionals identify depression in these patients at an early stage and provide appropriate interventions to improve their quality of life. Future research should focus on further exploring the mechanisms behind the association between brain tumors and depression in order to develop targeted and effective intervention options.

Association of antidepressant drug use with outcome of patients with glioblastoma.

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT-IV trials to explore the relation of antidepressant drug use with progression-free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma.

Targeted therapies in patients with newly diagnosed glioblastoma-A systematic meta-analysis of randomized clinical trials.

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n = 3941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR = 0.98 [95% confidence interval (CI) 0.86-1.11, P = .7731]). By comparison, targeted therapy showed a benefit for PFS (HR = 0.83 [95% CI 0.74-0.94, P = .0037]), especially for patients with an unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, P = .0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR = 0.70 [95% CI 0.61-0.80, P = .0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared to standard care. However, no improvement in OS was observed with any of the targeted agents.

Neurological autoimmune diseases following vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): A follow-up study.

BACKGROUND AND PURPOSE: Population-based studies suggest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may trigger neurological autoimmunity including immune-mediated thrombotic thrombocytopenia. Long-term characterization of cases is warranted to facilitate patient care and inform vaccine-hesitant individuals. METHODS: In this single-center prospective case study with a median follow-up of 387 days long-term clinical, laboratory and imaging characteristics of patients with neurological autoimmunity diagnosed in temporal association (≤6 weeks) with SARS-CoV-2 vaccinations are reported. RESULTS: Follow-up data were available for 20 cases (central nervous system demyelinating diseases n = 8, inflammatory peripheral neuropathies n = 4, vaccine-induced immune thrombotic thrombocytopenia n = 3, myositis n = 2, myasthenia n = 1, limbic encephalitis n = 1, giant cell arteritis n = 1). Following therapy, the overall disability level improved (median modified Rankin Scale at diagnosis 3 vs. 1 at follow-up). The condition of two patients worsened despite immunosuppressants possibly related to their autoimmune diagnoses (limbic encephalitis n = 1, giant cell arteritis n = 1). At 12 months' follow-up, 12 patients achieved complete clinical remissions with partial responses in five and stable disease in one case. Correspondingly, autoimmune antibodies were non-detectable or titers had significantly lowered in all, and repeat imaging revealed radiological responses in most cases. Under vigilant monitoring 15 patients from our cohort underwent additional SARS-CoV-2 vaccinations (BNT162b2 n = 12, mRNA-1273 n = 3). Most patients (n = 11) received different vaccines than prior to diagnosis of neurological autoimmunity. Except for one short-lasting relapse, which responded well to steroids, re-vaccinations were well tolerated. CONCLUSIONS: In this study long-term characteristics of neurological autoimmunity encountered after SARS-CoV-2 vaccinations are defined. Outcome was favorable in most cases. Re-vaccinations were well tolerated and should be considered on an individual risk/benefit analysis.

Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells.

Glioblastomas are highly malignant brain tumors that derive from brain-tumor-initiating cells (BTICs) and can be subdivided into several molecular subtypes. Metformin is an antidiabetic drug currently under investigation as a potential antineoplastic agent. The effects of metformin on glucose metabolism have been extensively studied, but there are only few data on amino acid metabolism. We investigated the basic amino acid profiles of proneural and mesenchymal BTICs to explore a potential distinct utilization and biosynthesis in these subgroups. We further measured extracellular amino acid concentrations of different BTICs at baseline and after treatment with metformin. Effects of metformin on apoptosis and autophagy were determined using Western Blot, annexin V/7-AAD FACS-analyses and a vector containing the human LC3B gene fused to green fluorescent protein. The effects of metformin on BTICs were challenged in an orthotopic BTIC model. The investigated proneural BTICs showed increased activity of the serine and glycine pathway, whereas mesenchymal BTICs in our study preferably metabolized aspartate and glutamate. Metformin treatment led to increased autophagy and strong inhibition of carbon flux from glucose to amino acids in all subtypes. However, oral treatment with metformin at tolerable doses did not significantly inhibit tumor growth in vivo. In conclusion, we found distinct amino acid profiles of proneural and mesenchymal BTICs, and inhibitory effects of metformin on BTICs in vitro. However, further studies are warranted to better understand potential resistance mechanisms against metformin in vivo.

Neurological autoimmune diseases following vaccinations against SARS-CoV-2: a case series.

BACKGROUND AND PURPOSE: Population-based studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may trigger immune-mediated thrombotic thrombocytopenia (VITT) raising concerns for other autoimmune responses. The aim was to characterize neurological autoimmunity after SARS-CoV-2 vaccinations. METHODS: In this single-centre prospective case study patients with neurological autoimmunity in temporal association (≤6 weeks) with SARS-CoV-2 vaccinations and without other triggers are reported. Clinical, laboratory and imaging data were collected with a median follow-up of 49 days. RESULTS: In the study period 232,603 inhabitants from the main catchment area of our hospital (Rhein-Neckar-Kreis, county) received SARS-CoV-2 vaccinations. Twenty-one cases (new onset n = 17, flares n = 4) diagnosed a median of 11 days (range 3-23) following SARS-CoV-2 vaccinations (BNT162b2 n = 12, ChAdOx1 n = 8, mRNA-1273 n = 1) were identified. Cases included VITT with cerebral venous sinus thrombosis (n = 3), central nervous system demyelinating diseases (n = 8), inflammatory peripheral neuropathies (n = 4), myositis (n = 3), myasthenia (n = 1), limbic encephalitis (n = 1) and giant cell arteritis (n = 1). Patients were predominantly female (ratio 3.2:1) and the median age at diagnosis was 50 years (range 22-86). Therapy included administration of steroids (n = 15), intravenous immunoglobulins in patients with Guillain-Barré syndrome or VITT (n = 4), plasma exchange in cases unresponsive to steroids (n = 3) and anticoagulation in VITT. Outcomes were favourable with partial and complete remissions achieved in 71% and 24%, respectively. Two patients received their second vaccination without further aggravation of autoimmune symptoms under low-dose immunosuppressants. CONCLUSIONS: In this study various neurological autoimmune disorders encountered following SARS-CoV-2 vaccinations are characterized. Given the assumed low incidence and mostly favourable outcome of autoimmune responses, the benefits of vaccinations outweigh the comparatively small risks.

Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin.

Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. BTICs of different subtypes were challenged with oxidative phosphorylation (OXPHOS) inhibition with metformin to assess the differential effects of metabolic intervention on key resistance features. Whereas mesenchymal BTICs varied according to their invasiveness, they were in general more glycolytic and less responsive to metformin. Proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathway, and responded better to metformin. Targeting glycolysis may be a promising approach to inhibit tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors.

Diagnostic biomarkers from proteomic characterization of cerebrospinal fluid in patients with brain malignancies.

Recent technological advances in molecular diagnostics through liquid biopsies hold the promise to repetitively monitor tumor evolution and treatment response of brain malignancies without the need of invasive surgical tissue accrual. Here, we implemented a mass spectrometry-based protein analysis pipeline which identified hundreds of proteins in 251 cerebrospinal fluid (CSF) samples from patients with four types of brain malignancies (glioblastoma, lymphoma, brain metastasis, and leptomeningeal disease [LMD]) and from healthy individuals with a focus on glioblastoma in a retrospective and confirmatory prospective observational study. CSF proteome deregulation via disruption of the blood brain barrier appeared to be largely conserved across brain tumor entities. CSF analysis of glioblastoma patients identified two proteomic clusters that correlated with tumor size and patient survival. By integrating CSF data with proteomic analyses of matching glioblastoma tumor tissue and primary glioblastoma cells, we identified potential CSF biomarkers for glioblastoma, in particular chitinase-3-like protein 1 (CHI3L1) and glial fibrillary acidic protein (GFAP). Key findings were validated in a prospective cohort consisting of 35 glioma patients. Finally, in LMD patients who frequently undergo repeated CSF work-up, we explored our proteomic pipeline as a mean to profile consecutive CSF samples. Therefore, proteomic analysis of CSF in brain malignancies has the potential to reveal biomarkers for diagnosis and therapy monitoring.

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis.

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.

Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study.

BACKGROUND: Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). METHODS: Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. RESULTS: 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. CONCLUSIONS: This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Use of metformin and survival of patients with high-grade glioma.

High-grade glioma (HGG) is associated with poor prognosis. Drug repurposing evolves as new modality to improve standard therapy. The antidiabetic drug metformin has been found to inhibit glioma cell growth in vitro and in vivo. The aim of the present retrospective cohort study was to evaluate the survival of patients with HGG with or without treatment with metformin, based on a large cohort of a cancer registry. The analysis included 1,093 patients with HGG diagnosed between 1998 and 2013 from the population-based clinical cancer registry Regensburg (Germany), which covers 2.1 Mio inhabitants and 98% of all cancer diagnoses. We performed multivariable adjusted Cox-regression analyses. Hazard Ratios (HRs) with 95% Confidence Intervals (CIs) for overall survival (OS) and progression-free survival (PFS) of patients with HGG with or without treatment with metformin were obtained. Use of metformin was associated with a significantly better overall and progression-free survival of patients with WHO grade III glioma (HR for OS = 0.30; 95% CI = 0.11-0.81, HR for PFS = 0.29; 95% CI = 0.11-0.78), while there were no significant relations with OS (HR = 0.83; 95% CI = 0.57-1.20) or PFS (HR = 0.85; 95% CI = 0.59-1.22) in patients with WHO grade IV glioma. In conclusion, use of metformin is associated with better overall and progression-free survival of patients with WHO grade III. Possible underlying mechanisms include the higher prevalence of IDH mutations in WHO grade III glioma, which might sensitize to the metabolic drug metformin.

Drug Repurposing of Metabolic Agents in Malignant Glioma.

Gliomas are highly invasive brain tumors with short patient survival. One major pathogenic factor is aberrant tumor metabolism, which may be targeted with different specific and unspecific agents. Drug repurposing is of increasing interest in glioma research. Drugs interfering with the patient's metabolism may also influence glioma metabolism. In this review, we outline definitions and methods for drug repurposing. Furthermore, we give insights into important candidates for a metabolic drug repurposing, namely metformin, statins, non-steroidal anti-inflammatory drugs, disulfiram and lonidamine. Advantages and pitfalls of drug repurposing will finally be discussed.

Combined Modulation of Tumor Metabolism by Metformin and Diclofenac in Glioma.

Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathways did not sufficiently explain synergistic effects. However, we observed that metformin inhibited cellular oxygen consumption and increased extracellular lactate levels, indicating glycolytic rescue mechanisms. Combined treatment inhibited metformin-induced lactate increase. The combination of metformin and diclofenac may represent a promising new strategy in the treatment of glioblastoma. Combined treatment may reduce the effective doses of the single agents and prevent metabolic rescue mechanisms. Further studies are needed in order to determine possible side effects in humans.

Early postoperative tumor progression predicts clinical outcome in glioblastoma-implication for clinical trials.

Molecular markers define the diagnosis of glioblastoma in the new WHO classification of 2016, challenging neuro-oncology centers to provide timely treatment initiation. The aim of this study was to determine whether a time delay to treatment initiation was accompanied by signs of early tumor progression in an MRI before the start of radiotherapy, and, if so, whether this influences the survival of glioblastoma patients. Images from 61 patients with early post-surgery MRI and a second MRI just before the start of radiotherapy were examined retrospectively for signs of early tumor progression. Survival information was analyzed using the Kaplan-Meier method, and a Cox multivariate analysis was performed to identify independent variables for survival prediction. 59 percent of patients showed signs of early tumor progression after a mean time of 24.1 days from the early post-surgery MRI to the start of radiotherapy. Compared to the group without signs of early tumor progression, which had a mean time of 23.3 days (p = 0.685, Student's t test), progression free survival was reduced from 320 to 185 days (HR 2.3; CI 95% 1.3-4.0; p = 0.0042, log-rank test) and overall survival from 778 to 329 days (HR 2.9; CI 95% 1.6-5.1; p = 0.0005). A multivariate Cox regression analysis revealed that the Karnofsky performance score, O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, and signs of early tumor progression are prognostic markers of overall survival. Early tumor progression at the start of radiotherapy is associated with a worse prognosis for glioblastoma patients. A standardized baseline MRI might allow for better patient stratification.

Use of cardiac glycosides and risk of glioma.

Cardiac glycosides induce apoptotic effects on glioma cells, but whether cardiac glycosides protect against risk for glioma is unknown. We therefore explored the relation between glycoside use and glioma risk using a large and validated database. We performed a case-control analysis using the Clinical Practice Research Datalink involving 2005 glioma cases diagnosed between 1995 and 2012 that were individually matched to 20,050 controls on age, gender, general practice, and number of years of active history in the database. Conditional logistic regression analysis was used to evaluate the association between cardiac glycosides and the risk of glioma adjusting for body mass index and smoking. We also examined use of common heart failure and arrhythmia medications to differentiate between a specific glycoside effect and a generic effect of treatment for congestive heart failure or arrhythmia. Cardiac glycoside use was inversely related to glioma incidence. After adjustment for congestive heart failure, arrhythmia, diabetes, and common medications used to treat those conditions, the OR of glioma was 0.47 (95% CI 0.27-0.81, Bonferroni-corrected p value = 0.024) for use versus non-use of cardiac glycosides, based on 17 exposed cases. In contrast, no associations were noted for other medications used to treat congestive heart failure or arrhythmias. The OR of glioma in people with congestive heart failure was 0.65 (95% CI 0.40-1.04), and for arrhythmia it was 1.01 (95% CI 0.78-1.31). These data indicate that cardiac glycoside use is independently associated with reduced glioma risk.

Statin use and risk of glioma: population-based case-control analysis.

Statins have been reported to decrease the incidence of cancer, but the risk of glioma among statin users has been investigated in only two prior observational studies, both of them suggesting a modest protective effect of statins. We conducted a matched case-control study using data from the UK-based Clinical Practice Research Datalink to analyse use of statins among 2469 cases with glioma and 24,690 controls. We performed conditional logistic regression analysis to calculate relative risks, estimated as odds ratios (ORs) with 95 % confidence intervals (CIs) adjusting for multiple confounding factors. As compared with non-use of statins, use of statins was not associated with risk of glioma (OR for ≥90 prescriptions=0.75; 95 % CI 0.48-1.17). Our findings do not support previous sparse evidence of a possible inverse association between statin use and glioma risk.

Heartbeat evoked potentials and autonomic arousal during dissociative seizures: insights from electrophysiology and neuroimaging.

Introduction: Dissociative seizures often occur in the context of dysregulated affective arousal and entail dissociative symptoms such as a disintegration of bodily awareness. However, the interplay between affective arousal and changes in interoceptive processing at the onset of dissociative seizures is not well understood. Methods: Using retrospective routine data obtained from video-electroencephalography telemetry in a university hospital epilepsy monitoring unit, we investigate ictal changes in cardiac indices of autonomic arousal and heartbeat evoked potentials (HEPs) in 24 patients with dissociative seizures. Results: Results show autonomic arousal during seizures with increased heart rate and a shift towards sympathetic activity. Compared with baseline, ictal HEP amplitudes over central and right prefrontal electrodes (F8, Fz) were significantly less pronounced during seizures, suggesting diminished cortical representation of interoceptive information. Significant correlations between heart rate variability measures and HEPs were observed at baseline, with more sympathetic and less parasympathetic activity related to less pronounced HEPs. Interestingly, these relationships weakened during seizures, suggesting a disintegration of autonomic arousal and interoceptive processing during dissociative seizures. In a subgroup of 16 patients, MRI-based cortical thickness analysis found a correlation with HEP amplitudes in the left somatosensory association cortex. Conclusions: These findings possibly represent an electrophysiological hint of how autonomic arousal could negatively impact bodily awareness in dissociative seizures, and how these processes might be related to underlying brain structure.