White matter hyperintensities increases with traumatic brain injury severity: associations to neuropsychological performance and fatigue.

Objective: To examine the prevalence of white matter hyperintensities (WMHs) in patients with traumatic brain injury (TBI) as compared to healthy controls, and to investigate whether there is an association between WMH lesion burden and performance on neuropsychological tests in patients with TBI.Methods: A total of 59 patients with TBI and 27 age- and gender-matched healthy controls underwent thorough neuropsychological testing and magnetic resonance imaging. The quantification of WMH lesions was performed using the fully automated Lesion Segmentation Tool.Results: WMH lesions were more common in patients with TBI than in healthy controls (p = .032), and increased with higher TBI severity (p = .025). Linear regressions showed that WMH lesions in patients with TBI were not related to performance on any neuropsychological tests (p > .05 for all). However, a negative relationship between number of WMH lesions in patients with TBI and self-assessed fatigue was found (r = - 0.33, p = .026).Conclusion: WMH lesions are more common in patients with TBI than in healthy controls, and WMH lesions burden increases with TBI severity. These lesions could not explain decreased cognitive functioning in patients with TBI but did relate to decreased self-assessment of fatigue after TBI.

Pharmaco-fMRI in Patients With Traumatic Brain Injury: A Randomized Controlled Trial With the Monoaminergic Stabilizer (-)-OSU6162.

OBJECTIVE: To examine the effects of monoaminergic stabilizer (-)-OSU6162 on brain activity, as measured by blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI), in patients in the chronic phase of traumatic brain injury suffering from fatigue. SETTING: Neurorehabilitation clinic. PARTICIPANTS: Patients with traumatic brain injury received either placebo (n = 24) or active treatment (n = 28). Healthy controls (n = 27) went through fMRI examination at one point and were used in sensitivity analysis on normalization of BOLD response. DESIGN: Randomized, double-blinded, placebo-controlled design. MAIN MEASURES: Effects on BOLD signal changes from before to after treatment during performance of a fatiguing attention task. RESULTS: The fMRI results revealed treatment effects within the right occipitotemporal cortex and the right orbitofrontal cortex. In these regions, the BOLD response was normalized relative to healthy controls at the postintervention fMRI session. No effects were seen in regions in which we previously observed activity differences between patients and healthy controls while performing this fMRI task, such as the striatum. CONCLUSION: (-)-OSU6162 treatment had influences on functional brain activity, although the normalized regional BOLD response was observed in regions that were not a priori hypothesized to be sensitive to this particular treatment, and was not accompanied by any effects on in-scanner test performance or on fatigue.

Using Functional Magnetic Resonance Imaging to Detect Chronic Fatigue in Patients With Previous Traumatic Brain Injury: Changes Linked to Altered Striato-Thalamic-Cortical Functioning.

OBJECTIVE: To investigate whether functional magnetic resonance imaging (fMRI) can be used to detect fatigue after traumatic brain injury (TBI). SETTING: Neurorehabilitation clinic. PARTICIPANTS: Patients with TBI (n = 57) and self-experienced fatigue more than 1 year postinjury, and age- and gender-matched healthy controls (n = 27). MAIN MEASURES: Self-assessment scales of fatigue, a neuropsychological test battery, and fMRI scanning during performance of a fatiguing 27-minute attention task. RESULTS: During testing within the fMRI scanner, patients showed a higher increase in self-reported fatigue than controls from before to after completing the task (P < .001). The patients also showed lower activity in several regions, including bilateral caudate, thalamus, and anterior insula (all P < .05). Furthermore, the patients failed to display decreased activation over time in regions of interest: the bilateral caudate and anterior thalamus (all P < .01). Left caudate activity correctly identified 91% of patients and 81% of controls, resulting in a positive predictive value of 91%. CONCLUSION: The results suggest that chronic fatigue after TBI is associated with altered striato-thalamic-cortical functioning. It would be of interest to study whether fMRI can be used to support the diagnosis of chronic fatigue in future studies.

The Effects of (-)-OSU6162 on Chronic Fatigue in Patients With Traumatic Brain Injury: A Randomized Controlled Trial.

OBJECTIVE: To examine the effects of the monoaminergic stabilizer (-)-OSU6162 on mental fatigue in patients with traumatic brain injury. SETTING: Single-center Neurorehabilitation Clinic. DESIGN: Randomized, double-blind, placebo-controlled trial. PARTICIPANTS: Sixty-four subjects with traumatic brain injury were randomized to treatment (n = 33) and placebo (n = 31). MAIN MEASURES: The effects of (-)-OSU6162 at a dose of 15 mg twice a day were evaluated using self-assessment scales and neuropsychological tests measuring mental fatigue. RESULTS: No difference between groups was observed on any scale at baseline. At follow-up, both groups showed significant improvement on the Fatigue Severity Scale and the Mental Fatigue Scale (both Ps < .01). Similarly, the performance of both groups increased significantly on many neuropsychological tests. However, no significant between-group difference in changes on these scales was observed before or after adjustment for confounders except for one neuropsychological test favoring the control group. Sensitivity analyses showed significantly greater changes in levels of prolactin and folic acid and heart rate (all Ps < .05) in the treatment group. The mean plasma concentration after 4 weeks of treatment was 0.14 (range, 0.01-0.32) µM, which was lower than expected. INTERPRETATION: Treatment with (-)-OSU6162 had no significant effect on mental fatigue in patients with traumatic brain injury compared with placebo.

Remote neuropsychological assessment of patients with neurological disorders and injuries-a study protocol for a cross-sectional case-control validation study.

INTRODUCTION: There are great potential benefits of being able to conduct neuropsychological assessments remotely, especially for hard-to-reach or less mobile patient groups. Such tools need to be equivalent to standard tests done in the clinic and also easy to use in a variety of clinical populations. METHODS AND ANALYSIS: This study protocol describes a cross-sectional study aimed at validating the newly developed digitalized neuropsychological test battery Mindmore Remote in patients with neurological disorders and injuries. Diagnoses comprise traumatic brain injury, stroke, Parkinson's disease, multiple sclerosis, brain tumour and epilepsy. 50 patients in each patient group will be included. In addition, 50 healthy controls will be recruited. All participants will undergo both testing with Mindmore Remote at home and traditional neuropsychological assessment face-to-face in a randomised order. The primary outcome is the association between tests from the Mindmore Remote battery and their equivalent traditional neuropsychological tests. Further, bias between methods and differences between groups will also be investigated. ETHICS AND DISSEMINATION: The study protocol has been approved by the Swedish Ethical Review Authority (2022-06230-01) and adheres to the declaration of Helsinki. All participants will be given oral and written information about the study and sign informed consent forms before entering the study. All participants are informed that they can terminate their participation in the study at any given time, without giving any explanation, and participating in the study or not will not affect their care at the clinic. Neither authors nor personnel involved in the research project are affiliated with Mindmore AB. The results from the study will be published in peer-reviewed scientific journals and presented at national and international conferences on the topic. TRIAL REGISTRATION NUMBER: NCT05819008.

Fatigue and cognitive fatigability in patients with chronic pain.

OBJECTIVES: Fatigue is common in patients with chronic pain. Still, there is a lack of studies examining objectively measurable cognitive aspects of fatigue: cognitive fatigability (CF). We aimed to investigate the presence of CF in patients with chronic pain and its relation to self-rated fatigue, attention, pain characteristics, sleep disturbance, depression, and anxiety. METHODS: Two hundred patients with chronic pain and a reference group of 36 healthy subjects underwent a comprehensive neuropsychological test battery, including measurement of CF with the Wechsler Adult Intelligence Scale-III Coding subtest, and self-assessment of trait and state fatigue. RESULTS: The patients with chronic pain did not show more CF as compared to the reference group. There was an association between CF and processing speed on a test of sustained and selective attention in the chronic pain group, while self-rated fatigue measures and pain characteristics were not associated with CF. Self-rated fatigue measures were highly correlated with self-rated pain intensity, spreading of pain, depression, anxiety, and sleep disturbance. CONCLUSIONS: The findings highlight the distinction between objective and subjective aspects of fatigue in chronic pain, and that the underlying causes of these different aspects of fatigue need to be studied further.

Cognitive and mental fatigue in chronic pain: cognitive functions, emotional aspects, biomarkers and neuronal correlates-protocol for a descriptive cross-sectional study.

INTRODUCTION: Chronic pain (CP) is one of the most frequently presenting conditions in health care and many patients with CP report mental fatigue and a decline in cognitive functioning. However, the underlying mechanisms are still unknown. METHODS AND ANALYSIS: This study protocol describes a cross-sectional study aimed at investigating the presence of self-rated mental fatigue, objectively measured cognitive fatigability and executive functions and their relation to other cognitive functions, inflammatory biomarkers and brain connectivity in patients with CP. We will control for pain-related factors such as pain intensity and secondary factors such as sleep disturbances and psychological well-being. Two hundred patients 18-50 years with CP will be recruited for a neuropsychological investigation at two outpatient study centres in Sweden. The patients are compared with 36 healthy controls. Of these, 36 patients and 36 controls will undergo blood sampling for inflammatory markers, and of these, 24 female patients and 22 female controls, between 18 and 45 years, will undergo an functional MRI investigation. Primary outcomes are cognitive fatigability, executive inhibition, imaging and inflammatory markers. Secondary outcomes include self-rated fatigue, verbal fluency and working memory. The study provides an approach to study fatigue and cognitive functions in CP with objective measurements and may demonstrate new models of fatigue and cognition in CP. ETHICS AND DISSEMINATION: The study has been approved by the Swedish Ethics Review Board (Dnr 2018/424-31; 2018/1235-32; 2018/2395-32; 2019-66148; 2022-02838-02). All patients gave written informed consent to participate in the study. The study findings will be disseminated through publications in journals within the fields of pain, neuropsychology and rehabilitation. Results will be spread at relevant national and international conferences, meetings and expert forums. The results will be shared with user organisations and their members as well as relevant policymakers. TRIAL REGISTRATION NUMBER: NCT05452915.

Sedentary behavior as a potential risk factor for depression among 70-year-olds.

BACKGROUND: Sedentary behavior has previously been associated with the risk of depression. In addition, older adults have been proven to be more sedentary and more depressed than other age groups. However, studies using objective measures of sedentary behavior and taking physical activity into account are lacking. Thus, the purpose of this population-based study was to examine how total sedentary time and length of sedentary bouts were associated with the risk of depression among 70-year-olds. METHODS: The present study used data from the Healthy Ageing Initiative (n = 3,633), an ongoing cross-sectional research project in Umeå, Sweden. Sedentary behavior was measured objectively with the ActiGraph GT3X+ accelerometer, and depression was measured with the Geriatric Depression Scale. Several covariates, including physical activity, were included in logistic regression analyses. RESULTS: Results from two hierarchical logistic regression models showed that a greater percentage of the day spent sedentary [odds ratio (OR) = 1.031, p = 0.010] and longer average length of sedentary bouts (OR = 1.116, p = 0.045) increased the risk of depression. LIMITATIONS: Limitations include of possible underrepresentation of severely depressed participants, and possible observer effects. CONCLUSIONS: The present study verified the relationship between sedentary behavior and depression and provides new information about the risks associated with increased length of sedentary bouts.  These findings may be important to consider in the development of future recommendations for the prevention of depression among older adults.

Attention in Older Adults: A Normative Study of the Integrated Visual and Auditory Continuous Performance Test for Persons Aged 70 Years.

OBJECTIVE: Our objective was to present normative data from 70-year-olds on the Integrated Visual and Auditory Continuous Performance Test (IVA), a computerized measure of attention and response control. METHOD: 640 participants (330 men and 310 women), all aged 70 years, completed the IVA, as well as the Mini-Mental State Examination and the Geriatric Depression Scale. RESULTS: Data were stratified by education and gender. Education differences were found in 11 of 22 IVA scales. Minor gender differences were found in six scales for the high-education group, and two scales for the low-education group. Comparisons of healthy participants and participants with stroke, myocardial infarction, or diabetes showed only minor differences. Correlations among IVA scales were strong (all r > .34, p < .001), and those with the widely used Mini-Mental State Examination were weaker (all r < .21, p < .05). Skewed distributions of normative data from primary IVA scales measuring response inhibition (Prudence) and inattention (Vigilance) represent a weakness of this test. CONCLUSIONS: This study provides IVA norms for 70-year-olds stratified by education and gender, increasing the usability of this instrument when testing persons near this age. The data presented here show some major differences from original IVA norms, and explanations for these differences are discussed. Explanations include the broad age-range used in the original IVA norms (66-99 years of age) and the passage of 15 years since the original norms were collected.