Cognitive fatigue in traumatic brain injury: a pilot study comparing state and trait fatigue.

OBJECTIVE: Cognitive fatigue is a common and disabling symptom following a traumatic brain injury (TBI). Literature on cognitive fatigue has distinguished between two types of fatigue: "state" fatigue refers to the acute experience of fatigue, whereas "trait" fatigue refers to the susceptibility to fatigue over an extended period. However, it is not clear whether state and trait fatigue are distinguishable constructs. Here, we examine the relationship between state and trait fatigue in individuals with TBI, hypothesizing that trait and state measures assess different constructs. PARTICIPANTS: Twenty-one participants with moderate-severe TBI were recruited. DESIGN: Participants underwent a cognitively fatiguing task while in an MRI scanner and completed self-report measures examining trait and state fatigue. RESULTS: No correlation was found between state and trait fatigue. However, the two measures of trait fatigue, Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS), correlated with one another; additionally only trait fatigue correlated with depression scores, consistent with the literature. CONCLUSION: These findings suggest that trait and state fatigue may not be interdependent and that it is important to carefully define the type of fatigue under consideration when assessing fatigue in individuals with TBI.

Dual Task of Fine Motor Skill and Problem Solving in Individuals With Multiple Sclerosis: A Pilot Study.

OBJECTIVES: To (1) examine and compare dual-task performance in patients with multiple sclerosis (MS) and healthy controls (HCs) using mathematical problem-solving questions that included an everyday competence component while performing an upper extremity fine motor task; and (2) examine whether difficulties in dual-task performance are associated with problems in performing an everyday internet task. DESIGN: Pilot study, mixed-design with both a within and between subjects' factor. SETTING: A nonprofit rehabilitation research institution and the community. PARTICIPANTS: Participants (N=38) included persons with MS (n=19) and HCs (n=19) who were recruited from a nonprofit rehabilitation research institution and from the community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participant were presented with 2 testing conditions: (1) solving mathematical everyday problems or placing bolts into divots (single-task condition); and (2) solving problems while putting bolts into divots (dual-task condition). Additionally, participants were required to perform a test of everyday internet competence. RESULTS: As expected, dual-task performance was significantly worse than either of the single-task tasks (ie, number of bolts into divots or correct answers, and time to answer the questions). Cognitive but not motor dual-task cost was associated with worse performance in activities of everyday internet tasks. CONCLUSIONS: Cognitive dual-task cost is significantly associated with worse performance of everyday technology. This was not observed in the motor dual-task cost. The implications of dual-task costs on everyday activity are discussed.

The relationship between outcome prediction and cognitive fatigue: A convergence of paradigms.

Cognitive fatigue is common after strenuous cognitive effort. A large body of literature has implicated a network of brain areas in fatigue, including the basal ganglia and cortical areas including ventro-medal prefrontal cortex and anterior cingulate cortex (ACC). Furthermore, the ACC has been shown to be involved in processes such as error and conflict monitoring, outcome prediction, and effort processing. Thus, the ACC appears to be one common denominator between clinical work on fatigue and research on outcome prediction and effort. In the present study, we examined whether the same region of the ACC is activated during the processing of errors and fatigue. Cognitive fatigue was induced by having subjects perform a difficult working memory task, during which they rated on-task fatigue. Activation associated with error processing was determined by using error trials on the working memory task. After localizing the region engaged in error processing, we evaluated whether there was a relationship between BOLD activation of that region and on-task fatigue scores. The results showed that as subjects became more fatigued, they responded with longer latencies and increased accuracy for the more difficult task. Moreover, the ACC areas that were activated by error processing were also associated with fatigue. These results suggest that cognitive fatigue may be related to changes in effort and reward. We speculate that as the brain detects these changes, cognitive fatigue is generated as a way for the brain to signal itself that the effort required for the task no longer merits the rewards received for performing it.

Searching for the neural basis of reserve against memory decline: intellectual enrichment linked to larger hippocampal volume in multiple sclerosis.

BACKGROUND AND PURPOSE: Active engagement in intellectually enriching activities (e.g. reading, hobbies) builds 'reserve' against memory decline in elders and persons with multiple sclerosis (MS), but the neural basis for this protective influence of enrichment is unknown. Herein the neuroanatomical basis of reserve against memory decline in MS patients is investigated. METHODS: Relapse-onset MS patients (N = 187) underwent 3.0 T magnetic resonance imaging of the brain to quantify T2 lesion volume (T2LV) and normalized volumes of total brain, total white, total grey (using SIENAX) and thalamus, caudate, putamen, pallidum, amygdala and hippocampus (using FIRST). Patients completed a survey quantifying their engagement in early life intellectual enrichment (i.e. reading, hobbies). Verbal and visuospatial episodic memory was assessed with neuropsychological tasks in a representative subsample (N = 97). RESULTS: Controlling for demographics and T2LV, intellectual enrichment was specifically linked to larger normalized hippocampal volume (r(p) = 0.213, P = 0.004), with no link to other brain volumes/structures. Moreover, greater intellectual enrichment moderated/attenuated the negative relationship between normalized total brain volume (i.e. overall cerebral atrophy) and normalized hippocampal volume (i.e. hippocampal atrophy; P = 0.001) whereby patients who engaged in more early life intellectual enrichment better maintained hippocampal volume in the face of worse overall cerebral atrophy. Finally, the link between greater intellectual enrichment and better memory was partially mediated through larger hippocampal volume. CONCLUSIONS: These findings support larger hippocampal volume as one key component of the neuroanatomical basis of reserve against memory decline in MS. These findings are consistent with previous literature on experience-dependent neuroplasticity within the hippocampus.

Altered Effective Connectivity during a Processing Speed Task in Individuals with Multiple Sclerosis.

OBJECTIVES: Processing speed impairment is the most prevalent cognitive deficit in individuals with multiple sclerosis (MS). However, the neural mechanisms associated with processing speed remain under debate. The current investigation provides a dynamic representation of the functioning of the brain network involved in processing speed by examining effective connectivity pattern during a processing speed task in healthy adults and in MS individuals with and without processing speed impairment. METHODS: Group assignment (processing speed impaired vs. intact) was based on participants' performance on the Symbol Digit Modalities test (Parmenter, Testa, Schretlen, Weinstock-Guttman, & Benedict, 2010). First, brain regions involved in the processing speed task were determined in healthy participants. Time series from these functional regions of interest of each group of participants were then subjected to the effective connectivity analysis (Independent Multiple-Sample Greedy Equivalence Search and Linear, Non-Gaussian Orientation, Fixed Structure algorithms) that showed causal influences of one region on another during task performance. RESULTS: The connectivity pattern of the processing speed impaired group was significantly different from the connectivity pattern of the processing speed intact group and of the healthy control group. Differences in the strength of common connections were also observed. CONCLUSIONS: Effective connectivity results reveal that MS individuals with processing speed impairment not only have connections that differ from healthy participants and MS individuals without processing speed impairment, but also have increased strengths of connections.

Analysis of effectiveness and safety of a three-part triage system for the access to dermatology specialist health care.

BACKGROUND: Accessibility and waiting times pose a general problem in public financed health care systems. In Italy a three-part triage system (urgent, priority and deferrable with a corresponding maximum time target before treatment of 1, 8 and 60 days respectively) to gain faster treatment for urgent and emergent cases of dermatology outpatients has been introduced. METHODS: From February 2011 to August 2013, samples of 1526 outpatient electronic medical record cases were randomly retrieved. Diagnoses with their corresponding triage codes were recorded. Urgent visits were further analysed according to the referring physician. The appropriateness of the referral was based on the published state law diagnostic guidelines. Data were statistically analysed using the 2-tailed Pearson chi-squared test or the Fisher exact test. RESULTS: Overall, 56.5% retrieved cases were deferrable, 13.1% priority and 30.4% urgent. Frequency of diagnoses differed significantly between the three groups (P < 0.05). Appropriateness of the triage level was higher for priority than for urgent referrals (P < 0.05%). An overestimation of urgency levels was noted and urgent cases were not overseen. Triage levels were best assessed by general practitioners (75% correct allocations) followed by emergency physicians (59%) and other specialists (45%) (P < 0.01%). CONCLUSION: The triage system according to clinical need is safe. Correct allocation according to urgency occurs in <75% and leaves space for improvement. General Practitioners address patient's access significantly better than other physicians, therefore are best suited to function as gatekeepers to the access of specialist care in public funded health care systems.

Melanoma incidence and Breslow tumour thickness development in the central Alpine region of South Tyrol from 1998 to 2012: a population-based study.

BACKGROUND: Cutaneous melanoma incidence is increasing worldwide, especially for in situ and thin (<1 mm) lesions, while thick (≥1 mm) lesions have been generally stable in many studies; although epidemiological data on melanoma is readily available, population-based studies, especially on mountain regions, are rare. OBJECTIVE: The aim of this study was to analyse cutaneous melanoma incidence and Breslow tumour thickness in the central Alpine mountain region of South Tyrol, northern Italy. METHODS: All newly diagnosed cutaneous in situ and invasive melanomas in the resident population from 1998 to 2012 were taken from the Pathology Unit, Bolzano Hospital and South Tyrol Cancer Registry. Incidence and Breslow tumour thickness were analyzed. Statistical analyses included Mann-Whitney and Kruskal-Wallis tests. RESULTS: A total of 784 in situ melanomas and 1663 invasive melanomas were collected. In situ melanomas showed the highest increase: European age-standardized incidence rose from 2.44 per 100,000 inhabitants in 1998-2002 to 16.01 in 2008-2012. Invasive melanoma incidence increased from 12.69 in 1998-2002, to 22.88 in 2008-2012. The incidence rise was observed in thin melanomas (from 8.39 to 16.18) and in thick melanomas (from 4.30 to 6.70). Breslow distribution revealed a median value of 0.62 mm (mean 1.34; SD 2.24; range 0.09-30.0) and did not change significantly over time (P = 0.286). Higher Breslow values were observed at advanced age (P < 0.001), among males (P = 0.017), in nodular melanomas (P < 0.001) and at higher Clark levels (P < 0.001). Significant differences were also found in urban hospitals compared to rural hospitals during the whole period (P = 0.004), but not in the last 5 years (P = 0.053). CONCLUSION: Incidence of cutaneous melanoma is increasing in South Tyrol, especially for in situ and thin lesions, but also for thick lesions; no reduction in median tumour thickness is observed. Rural areas and elevated altitudes may contribute to this effect.

Premature newborns with fatal intrauterine herpes simplex virus-1 infection: first report of twins and review of the literature.

BACKGROUND: Neonates with blistering skin diseases are dermatologic emergencies. The pathologies involved can pose diagnostic difficulties and there exists a variety of potential life-threatening differential diagnoses. OBJECTIVE: description of the first case of intrauterine acquired herpes simplex virus (HSV) 1 infection in twins. METHODS: We present the case of two premature bicordial biamniotic twins (27th week of gestation) whose intrauterine growth retardation, fetal anaemia and cardiotocography abnormalities led to a caesarean emergency delivery. RESULTS: Accurate medical history revealed a maternal febrile gingivostomatitis at the 23rd week of gestation, which was neglected by the treating gynaecologist. Respiratory distress was present at delivery and intubation was necessary in both children. The whole skin showed extensive erosions and ulcerations and the mucosa of the eyes and genitals was also involved. Intrauterine Herpes simplex virus (HSV) 1 infection was confirmed by immunohistochemistry of skin Tzanck smear (HSV 1 positive, HSV 2 negative), real-time polymerase chain reaction of both serum and skin (HSV 1 positive; HSV 2 negative) and maternal serology positive for HSV 1 IgM and IgG. Siblings were immediately treated with high-dose endovenous acyclovir. Anaemia thrombocytopenia and hepatorenal values markedly deteriorated and both developed consequential hepatorenal failure. The third day live supportive measures were terminated after parental informed consent and both siblings deceased shortly after on their mother's breast. DISCUSSION: Intrauterine HSV infection is rare and accounts only for 5% of neonatal HSV infections. Literature reports only 64 cases and 90% of those are related to HSV-2. Transplacental viral transmission is highest during the first 20 weeks of gestation and has been observed in pregnant women with disseminated HSV infection. Mortality and morbidity of intrauterine herpetic infection are extremely high. CONCLUSION: Despite transplacental HSV transmission remains a rare event, the potential devastating outcome justifies immediate adequate antiviral treatment in a pregnant woman affected by primary HSV infection.

Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant.

The first centromeric protein identified in any species was CENP-A, a divergent member of the histone H3 family that was recognised by autoantibodies from patients with scleroderma-spectrum disease. It has recently been suggested to rename this protein CenH3. Here, we argue that the original name should be maintained both because it is the basis of a long established nomenclature for centromere proteins and because it avoids confusion due to the presence of canonical histone H3 at centromeres.

Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings.

Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and 53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray matter structures (thalamus, caudate: -4.0%), or in non-memory cognitive functioning (executive functions, processing speed, working memory: changes ranged from -11% to +4%). Non-aerobic exercise resulted in relatively no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connectivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-administered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis patients.

Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

A much needed metric: Defining reliable and statistically meaningful change of the oral version Symbol Digit Modalities Test (SDMT).

BACKGROUND: The Symbol Digit Modalities Test (SDMT) has been recommended for use in clinical trials and outcome studies to monitor cognitive change. However, defining what is a meaningful change has been elusive for several years. OBJECTIVE: The present investigation aimed to develop methods for assessing individual-level statistically significant change on the SDMT - reliable change indices (RCIs) and standardized regression-based (SRB) equations. METHODS: A total of 219 healthy individuals completed the oral version SDMT at baseline, 6-month and 1-year follow-up. RESULTS: The SDMT demonstrated high reliability across all time points (r's = 0.83 to 0.86). Reliable change scores of 7, 8, and 10 points for the 6-month intervals represented statistically meaningful change at the 0.70, 0.80, and 0.90 confidence intervals, respectively. Over 1-year, a difference of 8, 10, and 12 was statistically meaningful at the 0.70, 0.80, and 0.90 confidence intervals, respectively. SRB equations are also provided taking into account additional factors found to be predictive of SDMT scores over time. CONCLUSION: Clinicians frequently denote a decline of 4 points on the SDMT as meaningful. Results in this large normative sample show that higher cut-points are needed to demonstrate statistically significant decline at the individual level. RCIs are provided for 6 month and one year assessment, which is typical in clinical practice and trials. SRB equations are also provided for use when applicable and may provide a more precise assessment of meaningful change.

Methylphenidate may improve mental fatigue in individuals with multiple sclerosis: A pilot clinical trial.

BACKGROUND: Fatigue is the most common symptom in multiple sclerosis (MS), previously attributed to dopamine imbalance. Evidence suggests that methylphenidate, a psychostimulant that increases striatal and prefrontal dopamine levels, is effective in reducing fatigue in various disorders. However, its effect on state vs. trait mental fatigue in MS is yet to be examined. METHODS: This pilot study investigates the efficacy of methylphenidate on decreasing self-reported mental fatigue in 12 individuals with MS in a double-blind, placebo-controlled, cross-over randomized clinical trial. RESULTS: Our results show that "state", but not "trait" MS-related fatigue, was reduced after 4 weeks of methylphenidate administration as compared to placebo.

An evaluation of chronic 6- and 12-month rat toxicology studies as predictors of 2-year tumor outcome.

Chronic 6- and 12-month rat toxicology studies were evaluated for their ability to predict tumor outcome in 2-year rat carcinogenicity studies for 80 pharmaceuticals from commercial and Merck databases. The data consisted of 62 (6-month) and 54 (12-month) studies, which included 30 rat carcinogens and 50 noncarcinogens in 2-year studies. The histopathology findings considered as evidence of potential preneoplasia in the chronic studies were hyperplasia, cellular hypertrophy, and atypical cellular foci. The authors hypothesized that a whole animal-based approach should be taken, wherein (1) evidence of potential preneoplasia in any tissue may serve as a sensitive predictor of tumor outcome in any tissue in the whole animal and not necessarily the same tissue and (2) the absence of evidence for potential preneoplasia in all tissues may serve as a strong negative predictor of tumor outcome in any tissue. Based on this whole animal approach, 25 of 30 rat carcinogens showed histopathologic signals in chronic toxicology studies, yielding a test sensitivity of 83%. The negative predictivity of the absence of histopathology findings in chronic toxicology studies of 50 nontumorigenic compounds was 88%. The value of the extra 6-month treatment was not apparent. The 5 false negatives (negative chronic studies but positive 2-year studies) are for marketed drugs approved for non-life-threatening conditions and associated with rat-specific mechanisms. The absence of preneoplasia in the whole animal is a reliable predictor of negative tumor outcome in 2-year rat studies, and approximately 50% rat carcinogenicity studies could be eliminated for the 80 pharmaceuticals examined, with no risk to humans and with a substantial reduction in animal usage and drug development time.

Using functional connectivity changes associated with cognitive fatigue to delineate a fatigue network.

Cognitive fatigue, or fatigue related to mental work, is a common experience. A growing body of work using functional neuroimaging has identified several regions that appear to be related to cognitive fatigue and that potentially comprise a "fatigue network". These include the striatum of the basal ganglia, the dorsolateral prefrontal cortex (DLPFC), the dorsal anterior cingulate cortex (dACC), the ventro-medial prefrontal cortex (vmPFC) and the anterior insula. However, no work has been conducted to assess whether the connectivity between these regions changes as a function of cognitive fatigue. We used a task-based functional neuroimaging paradigm to induce fatigue in 39 healthy individuals, regressed the signal associated with the task out of the data, and investigated how the functional connectivity between these regions changed as cognitive fatigue increased. We observed functional connectivity between these regions and other frontal regions largely decreased as cognitive fatigue increased while connectivity between these seeds and more posterior regions increased. Furthermore the striatum, the DLPFC, the insula and the vmPFC appeared to be central 'nodes' or hubs of the fatigue network. These findings represent the first demonstration that the functional connectivity between these areas changes as a function of cognitive fatigue.

Tired of not knowing what that fatigue score means? Normative data of the Modified Fatigue Impact Scale (MFIS).

BACKGROUND: The Modified Fatigue Impact Scale (MFIS) is one of the most common self-report measures used to assess fatigue in multiple sclerosis (MS). Despite its widespread use, there are no existing normative data for the MFIS. OBJECTIVE: The present investigation aimed to develop normative data for the MFIS in a large community sample, stratified by age, gender, and education and to compare the derived new cutoffs to an existing cutoff. METHODS: A total of 675 healthy individuals, stratified by age, gender, and education completed the MFIS. After the removal of 19 outliers, the final sample consisted of 656 individuals. Archival data of 540 individuals with MS who completed the MFIS were also included to analyze the utility of the new cutoffs. RESULTS: There were no main effects on the MFIS for gender. However, there were main effects for age and education. Specifically, younger cohorts (25-34 and 35-44) reported less physical fatigue compared to the two oldest cohorts (55-64 and 65-74). Similar effects were found for total MFIS fatigue with individuals aged 55-64 reporting greater overall fatigue than 35-44 year olds. Finally, 18-24 year olds reported significantly higher levels of cognitive fatigue compared to 35-44 and 65-74 aged cohorts. No other effects were observed for age. Individuals with higher education consistently reported less fatigue. Subsequent analyses also revealed an interaction effect for age x gender. When examining the age x gender interaction, women age 18-24 reported significantly greater levels of physical, cognitive, psychosocial, and total fatigue than their male counterparts. In contrast, men aged 65-74 reported greater physical, cognitive, and total fatigue than women their age. Comparisons of the existing cutoff of the MFIS to the new age, gender, and education specific cutoffs found either comparable or slightly higher rates of fatigue with the latter. CONCLUSION: Based on these findings, updated normative data and age, gender, and education specific cutoffs are provided. Utilization of these updated norms will result in a more accurate assessment of fatigue and will be valuable for those conducting research and/or clinical practice with individual with MS.

The neural correlates of cognitive fatigue in traumatic brain injury using functional MRI.

PRIMARY OBJECTIVE: The present study used fMRI (functional magnetic resonance imaging) to objectively assess cognitive fatigue in persons with traumatic brain injury (TBI). It was hypothesized that while performing a cognitive task, TBI participants would show increased brain activity over time, indicative of increased cerebral 'effort' which might manifest as the subjective feeling of cognitive fatigue. METHODS AND PROCEDURES: Functional MRI was used to track brain activity across time while 11 TBI patients with moderate-severe injury and 11 age-matched healthy controls (HCs) performed a modified Symbol Digit Modalities Task (mSDMT). Cognitive fatigue was operationally defined as a relative increase in cerebral activation across time compared to that seen in HCs. ROIs were derived from the Chauduri and Behan model of cognitive fatigue. MAIN OUTCOMES AND RESULTS: While performing the mSDMT, participants with a TBI showed increased activity, while HCs subsequently showed decreased activity in several regions including the middle frontal gyrus, superior parietal cortex, basal ganglia and anterior cingulate. CONCLUSIONS: Increased brain activity exhibited by participants with a TBI might represent increased cerebral effort which may be manifested as cognitive fatigue. Functional MRI appears to be a potentially useful tool for understanding the neural mechanisms associated with cognitive fatigue in TBI.