Androgen deprivation increases frontopolar cortical thickness in prostate cancer patients: an effect of early neurodegeneration?

Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT leads to altered testosterone levels that may affect brain morphology as well as cognition. Considering the reliability of cortical thickness (CT) as a marker of cognitive and brain changes, e.g., in Alzheimer's disease, we assessed the impacts of ADT on CT and working memory. Thirty men with non-metastatic prostate cancer receiving ADT and 32 patients not receiving ADT (controls or CON), matched in age and years of education, participated in N-back task and quality-of-life (QoL) assessments as well as brain imaging at baseline and prospectively at 6 months. Imaging data were processed with published routines to estimate CT and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. ADT and CON did not differ in N-back performance or QoL across time points. Relative to CON, patients receiving ADT showed significantly higher frontopolar cortex (FPC) CT at 6-month follow-up vs. baseline. Follow-up vs. baseline FPC CT change correlated negatively with changes in 2-back correct response rate and in testosterone levels across all participants. In mediation analysis, FPC CT change mediated the association between testosterone level change and 2-back accuracy rate change. Increases in FPC CT following 6 months of ADT may reflect early neurodegenerative changes in response to androgen deprivation. While no significant impact on working memory or QoL was observed over 6 months, further research of longer duration of treatment is warranted to unravel the full spectrum of cognitive and neural consequences of ADT in prostate cancer patients.

Effects of androgen deprivation on white matter integrity and processing speed in prostate cancer patients.

Studies have associated chemotherapy-elicited changes in cognitive function with impaired white matter integrity in cancer patients. Androgen deprivation therapy (ADT) may lead to cognitive deficits in prostate cancer patients; however, whether ADT influences white matter integrity has never been investigated. In a prospective study, 15 men with non-metastatic prostate cancer receiving ADT and 15 not receiving ADT (controls or CON), comparable in age and years of education, participated in N-back task, flankers' task, and quality-of-life (QoL) assessments. All participants underwent diffusion tensor imaging of the brain at baseline and at 6 months. Imaging data were processed with published routines. The results of a paired t-test of 6-month follow-up vs. baseline were evaluated at a corrected threshold for the whole brain each in ADT and CON. ADT patients showed significantly worse 1-back accuracy during follow-up, but the two groups did not differ in 2-back accuracy, 1- or 2-back reaction time (RT), flankers' task RT or QoL across time points. In ADT, significantly reduced fractional anisotropy (FA) was noted in the corpus callosum, forceps minor/anterior thalamic radiation, superior and posterior corona radiata. The differences in FA correlated significantly with changes in 2-back and flankers' task RT. No significant FA changes were noted during follow-up in CON. Six-month ADT affects white matter integrity, and the deficits were associated with slower processing speed. These findings add to the literature supporting the deleterious effects of androgen deprivation on the brain and cognition in prostate cancer patients.

Brief Report: Implementation of a Universal Prescreening Protocol to Increase Recruitment to Lung Cancer Studies at a Veterans Affairs Cancer Center.

Introduction: The oncology clinical trial recruitment process is time, labor, and resource intensive, and poor accrual rates are common. We describe the VA Connecticut Cancer Center experience of implementing a standardized, universal prescreening protocol and its impact on thoracic oncology research recruitment. Methods: Research coordinators prescreened potentially eligible patients with confirmed or suspected cancer from multiple clinical sources and entered relevant patient and research study information into a centralized electronic database. The database provided real-time lists of potential studies for each patient. This enabled the research team to alert the patient's oncologist in advance of clinic visits and to prepare documents needed for enrollment. Clinicians could ensure sufficient time and attention in clinic to the informed consent process, therefore maximizing enrollment opportunities. Patients were also monitored on waitlists for future studies. Results: From March 2017 to December 2020, a total of 1518 patients with lung nodules and suspected or confirmed lung cancers were prescreened. Of these, 379 patients were enrolled to a study, 103 patients declined participation, and 639 were monitored for future studies. Our prescreening protocol identified all new patients with lung cancer who were ultimately added to the cancer registry. We found a substantial increase in study enrollment after prescreening implementation. Conclusions: Universal prescreening was associated with improved patient enrollment to thoracic oncology studies. The protocol was integral in our VA becoming the top accruing VA site for National Cancer Institute's National Clinical Trials Network studies for 2019 to 2021.

Hypothalamic connectivities predict individual differences in ADT-elicited changes in working memory and quality of life in prostate cancer patients.

Androgen deprivation therapy (ADT) has been associated with adverse effects on cognition. However, we currently lack understanding of the neurobiology and prognostic markers of these effects. Given that ADT acts via the hypothalamus-pituitary-gonadal axis, we assessed whether baseline hypothalamic resting state functional connectivity (rsFC) could predict changes in working memory and quality of life in prostate cancer patients following androgen deprivation. In a prospective observational study, 28 men with non-metastatic prostate cancer receiving ADT and 38 patients not receiving ADT (controls), matched in age, years of education and Montreal Cognitive Assessment score, participated in brain imaging at baseline, and N-back task and quality-of-life (QoL) assessments at baseline and at 6 months follow-up. Imaging data were processed with published routines and evaluated at a corrected threshold. ADT and control groups did not differ in N-back performance or QoL across time points. In ADT, the changes in 0-back correct response rate (follow-up-baseline) were correlated with baseline hypothalamus-precentral gyrus rsFC; the changes in 1-back correct response rate and reaction time were each correlated with hypothalamus-middle frontal gyrus and superior parietal lobule rsFC. The changes in physical well-being subscore of QoL were correlated with baseline hypothalamus-anterior cingulate and cuneus rsFC. The hypothalamus rsFCs predicted N-back and QoL change with an area under the receiver operating characteristic curve of 0.93 and 0.73, respectively. Baseline hypothalamus-frontoparietal and salience network rsFC's predict inter-subject variations in the changes in working-memory and QoL following 6 months of ADT. Whether and how hypothalamic rsFCs may predict the cognitive and QoL effects with longer-term ADT remain to be investigated.

The effects of androgen deprivation on working memory and quality of life in prostate cancer patients: The roles of hypothalamic connectivity.

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT alters testosterone levels via its action on the hypothalamus-pituitary-gonadal axis and may influence hypothalamic functions. Given the wide regional connectivity of the hypothalamus and its role in regulating cognition and behavior, we assessed the effects of ADT on hypothalamic resting state functional connectivity (rsFC) and their cognitive and clinical correlates. METHODS: In a prospective observational study, 22 men with nonmetastatic prostate cancer receiving ADT and 28 patients not receiving ADT (controls), matched in age, years of education, and Montreal Cognitive Assessment score, participated in N-back task and quality of life (QoL) assessments and brain imaging at baseline and at 6 months. Imaging data were processed with published routines and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. RESULTS: ADT and control groups did not differ in N-back performance or QoL across time points. Relative to controls, patients receiving ADT showed significantly higher hypothalamus-right mid-cingulate cortex (MCC) and precentral gyrus (PCG) rsFC during follow-up versus baseline. Further, the changes in MCC and PCG rsFC were correlated positively with the change in QoL score and 0-back correct response rate, respectively, in patients with undergoing ADT. CONCLUSION: Six-month ADT affects hypothalamic functional connectivity with brain regions critical to cognitive motor and affective functions. Elevated hypothalamic MCC and PCG connectivity likely serve to functionally compensate for the effects of ADT and sustain attention and overall QoL. The longer-term effects of ADT remain to be investigated.

Impact of Hematology Electronic Consultations on Utilization of Referrals and Patient Outcomes in an Integrated Health Care System.

INTRODUCTION: Electronic consultations (e-consults) may be a valuable tool in the current era of increased demand for hematologists. Despite the increasing use of e-consults in hematology, their optimal utilization and impact on patient outcomes and workload are largely unknown. METHODS: In this retrospective cohort study, we studied the hematology consult experience at Veterans Affairs Connecticut from 2006 to 2018. We included 7,664 hematology consults (3,240 e-consults and 4,424 face-to-face [FTF] consults) requested by 1,089 unique clinicians. RESULTS: We found that e-consults were rapidly adopted and used equally among physicians of different degrees of experience. The number of FTF consults did not decrease after the introduction of e-consult services. E-consults were preferentially used for milder laboratory abnormalities that had been less likely to result in a consult before their availability. Referring clinicians used e-consults preferentially for periprocedural management, anemia, leukopenia, and anticoagulation questions. Eighty-three percent of e-consults were resolved without needing an FTF visit in the year after the consult. Consults for pancytopenia, gammopathy, leukocytosis, and for patients with known malignancy were less likely to be resolved by e-consult. Among patients who were diagnosed with a new hematologic malignancy after their consult, having an e-consult before an FTF visit did not adversely affect survival. CONCLUSION: In summary, e-consults safely expanded delivery of hematology services in our health care system but increased total consult volume. We report novel data on what types of consults may be best suited to the electronic modality, the impact of e-consults on workload, and their optimal use and implementation.

Androgen Deprivation Therapy and Cognitive Function in Prostate Cancer.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is widely used in prostate cancer. Interest in assessing how ADT impacts cognition is growing. RECENT FINDINGS: Studies in animals and humans suggest that androgens may affect cognitive function. However, extant studies utilizing common neurocognitive tests have not consistently demonstrated ADT-induced cognitive impairment. Retrospective analyses investigating the association between ADT and risk of dementia in large electronic patient databases have also produced conflicting results. There is only limited data on ADT-induced changes in the brain as detected by functional imaging. It remains unclear whether cognitive deficits can occur in a patient undergoing ADT. Commonly used neurocognitive tests may not be optimal for detection of more subtle but clinically relevant cognitive impairment. While large electronic patient databases are attractive sources of information, their heterogeneity, complexity, and potential reporting biases can be a challenge. Better tools are needed to assess the cognitive impact of ADT prospectively.

Cortical thickness reduction in combat exposed U.S. veterans with and without PTSD.

We investigated the extent of cortical thinning in U.S. Veterans exposed to combat who varied in the severity of their posttraumatic stress disorder (PTSD) symptoms. In addition, we explored the neural correlates of PTSD symptom dimensions and the interactive effects of combat exposure and PTSD upon cortical thickness. Sixty-nine combat exposed Veterans completed high-resolution magnetic resonance imaging (MRI) scans to estimate cortical thickness. The Clinician Administered PTSD Scale (CAPS) and Combat Exposure Scale (CES) assessments were completed to measure current PTSD and historical combat severity, respectively. PTSD symptom dimensions (numbing, avoidance, reexperiencing, anxious arousal, and dysphoric arousal) were studied. Vertex-wise whole cerebrum analyses were conducted. We found widespread negative correlations between CAPS severity and cortical thickness, particularly within the prefrontal cortex. This prefrontal correlation remained significant after controlling for depression severity, medication status, and other potential confounds. PTSD dimensions, except anxious arousal, negatively correlated with cortical thickness in various unique brain regions. CES negatively correlated with cortical thickness in the left lateral prefrontal, regardless of PTSD diagnosis. A significant interaction between CES and PTSD diagnosis was found, such that CES negatively correlated with cortical thickness in the non-PTSD, but not in the PTSD, participants. The results underscore the severity of cortical thinning in U.S. Veterans suffering from high level of PTSD symptoms, as well as in Veterans with no PTSD diagnosis but severe combat exposure. The latter finding raises considerable concerns about a concealed injury potentially related to combat exposure in the post-9/11 era.

Real-Time fMRI Neurofeedback with War Veterans with Chronic PTSD: A Feasibility Study.

Many patients with post-traumatic stress disorder (PTSD), especially war veterans, do not respond to available treatments. Here, we describe a novel neurofeedback (NF) intervention using real-time functional magnetic resonance imaging for treating and studying PTSD. The intervention involves training participants to control amygdala activity after exposure to personalized trauma scripts. Three combat veterans with chronic PTSD participated in this feasibility study. All three participants tolerated well the NF training. Moreover, two participants, despite the chronicity of their symptoms, showed clinically meaningful improvements, while one participant showed a smaller symptom reduction. Examination of changes in resting-state functional connectivity patterns revealed a normalization of brain connectivity consistent with clinical improvement. These preliminary results support feasibility of this novel intervention for PTSD and indicate that larger, well-controlled studies of efficacy are warranted.

An examination of the roles of trauma exposure and posttraumatic stress disorder on emotion regulation strategies of Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn veterans.

Theories of posttraumatic stress disorder (PTSD) implicate emotional processes, including difficulties utilizing adaptive emotion regulation strategies, as critical to the etiology and maintenance of PTSD. Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn (OIF/OEF/OND) veterans report high levels of combat exposure and PTSD. We aimed to extend findings suggesting that emotion regulation difficulties are a function of PTSD, rather than combat trauma exposure or common comorbidities, to OIF/OEF/OND veterans, in order to inform models of PTSD risk and recovery that can be applied to returning veterans. We tested differences in emotion regulation, measured with the Difficulties in Emotion Regulation Scale and Emotion Regulation Questionnaire, among trauma-exposed veterans with (n = 24) or without PTSD (n = 22) and healthy civilian comparison participants (n = 27) using multivariate analyses of covariance, adjusting for major depressive disorder, anxiety disorders, and demographic variables (age, sex, and ethnicity). Veterans with PTSD reported more use of expressive suppression and more difficulties with emotion regulation than veterans without PTSD and healthy comparison participants. Groups did not differ on cognitive reappraisal. Findings suggest the key role of PTSD above and beyond trauma exposure, depression, and anxiety in specific aspects of emotion dysregulation among OIF/OEF/OND veterans. Interventions that help veterans expand and diversify their emotion regulation skills may serve as helpful adjunctive treatments for PTSD among OIF/OEF/OND veterans.

POSTTRAUMATIC STRESS SYMPTOMS AND AVERSION TO AMBIGUOUS LOSSES IN COMBAT VETERANS.

BACKGROUND: Psychiatric symptoms typically cut across traditional diagnostic categories. In order to devise individually tailored treatments, there is a need to identify the basic mechanisms that underlie these symptoms. Behavioral economics provides a framework for studying these mechanisms at the behavioral level. Here, we utilized this framework to examine a widely ignored aspect of trauma-related symptomatology-individual uncertainty attitudes-in combat veterans with and without posttraumatic stress disorder (PTSD). METHODS: Fifty-seven combat veterans, including 30 with PTSD and 27 without PTSD, completed a risk and ambiguity decision-making task that characterizes individual uncertainty attitudes, distinguishing between attitudes toward uncertain outcomes with known ("risk") and unknown ("ambiguity") probabilities, and between attitudes toward uncertain gains and uncertain losses. Participants' choices were used to estimate risk and ambiguity attitudes in the gain and loss domains. RESULTS: Veterans with PTSD were more averse to ambiguity, but not risk, compared to veterans without PTSD, when making choices between possible losses, but not gains. The degree of aversion was associated with anxious arousal (e.g., hypervigilance) symptoms, as well as with the degree of combat exposure. Moreover, ambiguity attitudes fully mediated the association between combat exposure and anxious arousal symptoms. CONCLUSIONS: These results provide a foundation for prospective studies of the causal association between ambiguity attitudes and trauma-related symptoms, as well as etiologic studies of the neural underpinnings of these behavioral outcomes. More generally, these results demonstrate the potential of neuroeconomic and behavioral economic techniques for devising objective and incentive-compatible diagnostic tools, and investigating the etiology of psychiatric disorders.

Neuropsychological Functioning in Veterans with Posttraumatic Stress Disorder: Associations with Performance Validity, Comorbidities, and Functional Outcomes.

OBJECTIVES: Numerous studies have shown that individuals with posttraumatic stress disorder (PTSD) display reduced performances on neuropsychological tests, although most prior research has not adequately accounted for comorbidities or performance validity concerns that are common in this population and could partially account for the observed neurocognitive findings. Moreover, few studies have examined the functional implications of neuropsychological results in PTSD. METHODS: We examined neuropsychological functioning in 44 veterans with PTSD and 40 veteran trauma comparison (TC) participants with combat exposure and no PTSD. RESULTS: After excluding four veterans with PTSD for performance validity concerns, multivariate analyses of variance by neurocognitive domain revealed significantly worse performance by the PTSD group in the domains of speed of information processing (p=.035) and executive functions (p=.017), but no group differences in attention/working memory, verbal/language functioning, visuoconstruction, or episodic memory. Group differences by PTSD status were still present after covarying for depression, a history of head injuries, and substance use disorders. Executive functioning performance was associated with poorer self-reported occupational functioning and physical health-related quality of life, while speed of information processing performance was associated with poorer physical health-related quality of life. DISCUSSION: These results are generally consistent with a fronto-limbic conceptualization of PTSD-associated neuropsychological dysfunction and show that cognitive functioning may be associated with critical functional outcomes. Taken together, results suggest that consideration of neurocognitive functioning may enhance the clinical management of individuals with PTSD.

Correlates of VA mental health treatment utilization among OEF/OIF/OND veterans: Resilience, stigma, social support, personality, and beliefs about treatment.

Veterans of Operations Iraqi Freedom/Enduring Freedom/New Dawn (OEF/OIF/OND) tend not to engage in mental health care. Identifying modifiable factors related to mental health service utilization could facilitate development of interventions to increase utilization. The current study examined the relationship between mental health care utilization and measures of PTSD symptoms, resilience, stigma, beliefs about mental health care, perceived barriers to mental health care, posttraumatic growth and meaning, social support, and personality factors in a sample of 100 OEF/OIF/OND veterans with PTSD symptoms referred to VA mental health care. Participants who received psychotherapy and pharmacotherapy (PP) scored higher on measures of PTSD symptoms, stigma, and adaptive beliefs about mental health treatment, and lower on measures of resilience, postdeployment social support, emotional stability, and conscientiousness, than participants who received no treatment (NT). Participants who received psychotherapy only (PT) scored higher on a measure of PTSD symptoms than NT participants. PT participants scored higher on an emotional stability measure and lower on measures of PTSD symptoms and stigma than PP participants. Multinomial logistic regression including all variables significantly related to treatment utilization indicated that PTSD symptoms and adaptive beliefs about psychotherapy and pharmacotherapy were higher in the PT and PP groups than in the NT group, and concerns about discrimination were higher in the PP group than the NT group. Interventions targeting beliefs about mental health care could increase mental health treatment utilization among OEF/OIF/OND veterans. Concerns about stigma may affect the utilization process differently at different decision points. (PsycINFO Database Record

"I'm Coming Home, Tell the World I'm Coming Home". The Long Homecoming and Mental Health Treatment of Iraq and Afghanistan War Veterans.

This study explored the journey of American armed forces personnel from their decision to join the service, through their service in an active military conflict and how these factors may be associated with potential resistance for mental healthcare. The data came from qualitative interviews with 46 OIF/OEF/OND active-duty military, reservists, and discharged veterans of the average age of 25 years, who presented for a new episode of mental health treatment to a large Veterans Affairs Hospital (VAH) in Northeastern United States in 2011-2012. Qualitative analysis of veterans' perceptions revealed several major themes describing how a mental health diagnosis would negatively impact both their sense of identity and pragmatic career-building goals: enlisting as a career-building avenue, 'noble superhero' identity, escaping from hardship, and mental illness as a career-killer. Findings suggest that factors making young veterans resist mental healthcare may be reduced by partnering VAH psychiatrists with career counselors, and by enhancing military leadership's awareness and understanding about how to support soldiers with emotional and mental health needs, with a goal to eliminating stigma.