What's the use of worrying? Its function and its dysfunction

OBJECTIVE: To provide an overview of theory and research regarding the phenomenology and function of worry. METHOD: A systematic literature search focusing on conceptualizations of worry as a cognitive activity and worry research over the last 20 years was conducted. RESULTS: Worry can be both functional and dysfunctional. Disruption to daily functioning, perceived uncontrollability, pervasiveness and extensive coverage of worry themes (including "remote" events and the presence of meta-worry), all have specificity to more severe and dysfunctional worry. CONCLUSIONS: Research investigating both the relationship between worry and anxiety and the attributes of severe worriers, has brought attention to its role in fostering emotional disturbance and has clarified factors relevant to treatment.     

α-Synuclein in synaptic function and dysfunction

α-Synuclein is a neuronal protein that is enriched in presynaptic terminals. Under physiological conditions, it binds to synaptic vesicle membranes and functions in neurotransmitter release, although the molecular details remain unclear, and it is controversial whether α-synuclein inhibits or facilitates neurotransmitter release. Pathologically, in synucleinopathies including Parkinson’s disease (PD), α-synuclein forms aggregates that recruit monomeric α-synuclein and spread throughout the brain, which triggers neuronal dysfunction at molecular, cellular, and organ levels. Here, we present an overview of the effects of α-synuclein on SNARE-complex assembly, neurotransmitter release, and synaptic vesicle pool homeostasis, and discuss how the observed divergent effects of α-synuclein on neurotransmitter release can be reconciled. We also discuss how gain-of-function versus loss-of-function of α-synuclein may contribute to pathogenesis in synucleinopathies.     

The blood–brain barrier and immune function and dysfunction

The blood–brain barrier (BBB) is the monocellular interface that divides the peripheral circulation from direct contact with the central nervous system (CNS). This interface consists of several parallel barriers that include most notably the capillary bed of the CNS and the choroid plexus. These barriers at one level create the dichotomy between the circulating factors of the immune system and the components of the CNS only to regulate interactions between the immune and central nervous systems at other levels. The BBB is thus an integral part of the neuroimmune axis. Here, we will consider four aspects of BBB–neuroimmune interactions: BBB disruption as mediated by LPS and cytokines, cytokine transport across the BBB, immune cell trafficking, and effects of lipopolysaccharide (LPS) on various functions of the BBB.     

Use of the Multiple Errands Test – Simplified Version in the assessment of suboptimal effort

Most measures of suboptimal effort focus on short-term learning; fewer studies have considered non-memory feigned cognitive impairment. This study investigated the utility of the Multiple Errands Test – Simplified Version (MET-SV) in the detection of feigned executive functioning impairment. Performance of simulating malingerers (N?=?47) was compared to acquired brain injury (N?=?46) and neurologically healthy control groups (N?=?50). Although simulating malingerers were successful at feigning a realistic level of impairment compared to the brain injury group, there were significant differences regarding pattern of performance. A logistic regression model successfully classified 84% of simulating malingerers and 74.5% of brain injured individuals. Receiver Operating Characteristic (ROC) analysis supported the discriminatory power of the model. The current study is unique in yielding some understanding of the real-life observation of suspected malingerers compared to individuals with genuine cognitive difficulties. Results suggest the MET-SV can contribute to the clinical assessment of individuals suspected of suboptimal effort in the domain of executive functioning. Further research is needed to establish whether the MET-SV can be reliably used in medico-legal settings.     

Validity and reliability of the Behavior Problems Inventory,the Aberrant Behavior Checklist,and the Repetitive Behavior Scale – Revised among infants and toddlers at risk for intellectual or developmental disabilities: A multi-method assessment approach

Reliable and valid assessment of aberrant behaviors is essential in empirically verifying prevention and intervention for individuals with intellectual or developmental disabilities (IDD). Few instruments exist which assess behavior problems in infants. The current longitudinal study examined the performance of three behavior-rating scales for individuals with IDD that have been proven psychometrically sound in older populations: the Aberrant Behavior Checklist (ABC), the Behavior Problems Inventory (BPI-01), and the Repetitive Behavior Scale – Revised (RBS-R). Data were analyzed for 180 between six and 36 months old children at risk for IDD. Internal consistency (Cronbach's α) across the subscales of the three instruments was variable. Test–retest reliability of the three BPI-01 subscales ranged from .68 to .77 for frequency ratings and from .65 to .80 for severity ratings (intraclass correlation coefficients). Using a multitrait–multimethod matrix approach high levels of convergent and discriminant validity across the three instruments was found. As anticipated, there was considerable overlap in the information produced by the three instruments; however, each behavior-rating instrument also contributed unique information. Our findings support using all three scales in conjunction if possible.     

SMART – Recognising the value of existing practice and introducing recent developments: leaving no stone unturned in the assessment and treatment of the PDOC patient

ABSTRACT

Over the last 25 years there have been a number of papers highlighting the issues of high rates of misdiagnosis in prolonged disorders of consciousness (PDOC) (Andrews, K., Murphy, L., Munday, R., & Littlewood, C. (1996). Misdiagnosis of the vegetative state: Retrospective study in a rehabilitation unit. BMJ, 313(7048), 13–16; Childs, N. L., Mercer, W. N., & Childs, H. W. (1993). Accuracy of diagnosis of persistent vegetative state. Neurology, 43(8), 1465–1467). Surprisingly, these rates still remain at the same level despite defined criteria for diagnosis (Schnakers, C., Vanhaudenhuyse, A., Giacino, J., Ventura, M., Boly, M., Majerus, S.,…Laureys, S. (2009). Diagnostic accuracy of the vegetative and minimally conscious state: Clinical consensus versus standardized neurobehavioral assessment. BMC Neurology, 9(35), 1–5; Van Erp, W., Larvrijsen, J., Vos, P., Bor, H., Laureys, S., & Koopmans, R. (2015). The vegetative state: Prevalence, misdiagnosis and treatment limitations. JAMDA, 85, e9-85.e14. doi:10.1016/j.jamda.2014.10.014). This indicates the continued need for careful standardised assessment by skilled assessors to identify all potential meaningful responses and to establish a correct and incontrovertible diagnosis. The Sensory Modality Assessment and Rehabilitation Technique (SMART) is one of three assessments identified for the assessment of PDOC in the Royal College of Physician guidelines (Royal College of Physicians, 2013). The RCP guidelines and recent publications have highlighted and substantiated the value of some of the existing practices and unique features of the SMART. In recognition of the need to keep SMART current, SMART Version 3 is being developed and will be launched shortly. The interim SMART developments will be introduced in this paper and applied to practice through the illustration of a case study. Evidence suggests that SMART is a current and invaluable tool for the clinical and medico-legal assessment and treatment of the PDOC patient.     

Structure and function of the blood–brain barrier

Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood–brain barrier (BBB), blood–CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood–CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.     

Thyroid function, Alzheimer's disease and postoperative cognitive dysfunction: a tale of dangerous liaisons?

Hypothyroidism and hyperthyroidism are commonly present conditions in adults, leading to neurological symptoms, affecting the central and peripheral nervous system, and to neurocognitive impairment. Several studies investigated a possible association between Alzheimer's disease (AD) and thyroid dysfunctions. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Moreover, thyroid hormones negatively regulate expression of the amyloid-beta protein precursor (AbetaPP), which plays a key role in the development of AD. A condition, the so called euthyroid sick syndrome (ESS), characterized by reduced serum T_{3} and T_{4} concentrations without increased serum thyroid stimulation hormone secretion, occurs within hours after major surgery. After surgery, elderly patients often exhibit a transient, reversible state of cognitive alterations. Delirium occurs in 10-26% of general medical patients over 65, and it is associated with a significant increase in morbidity and mortality. Modifications in thyroid hormone functioning may take place as a consequence of psycho-physical stress caused by surgery, and probably as a consequence of reduced conversion of T4 into T3 by the liver engaged in metabolizing anesthetic drugs. Therefore, modifications of thyroid hormones post-surgery, might play a role in the pathogenesis of postoperative cognitive dysfunction.     

Expression and function of the inhibitory Fcγ-receptor in CIDP

The inhibitory Fc-gamma receptor (FcγR) IIB, expressed on myeloid and B cells, has a critical role in the balance of tolerance and auto-immunity, and is required for the anti-inflammatory activity of intravenous immunoglobulin (IVIg) in various murine disease models. We found that treatment-na?ve patients with chronic inflammatory demyelinating polyneuropathy (CIDP) showed an impaired expression of FcγIIB levels on na?ve B cells, and failed to upregulate or to maintain upregulation of FcγIIB, as B cells progressed from the na?ve to the memory compartment. The impaired expression of FcγRIIB was, at least partially, restored by clinically effective IVIg treatment. It remains to be determined whether FcγRIIB expression is a candidate for pre-treatment assessment and might thus be used as a prognostic marker of treatment response to IVIg. Nonetheless, our data suggest that new strategies specifically targeting FcγRIIB expression might have therapeutic merit in CIDP.     

Use of the frontal assessment battery in evaluating executive dysfunction in patients with Huntington’s disease

The frontal assessment battery (FAB) is a bedside cognitive scale designed to measure executive functions. Huntington’s disease (HD) is a neurodegenerative disorder characterized by motor, behavioral, and cognitive dysfunction. The aim of this study was to check the validity of the FAB for the evaluation of cognitive impairment in patients with HD. Forty-one patients diagnosed with HD and 53 healthy controls matched by education, sex and age were evaluated with a validated Brazilian version of the UHDRS, the VFT, the SDMT, the SIT, the MMSE, and the FAB. The diagnosis of HD was made by DNA analysis. FAB scores were lower in patients than in the controls (p < 0.001) and had significant correlations with the VFT (r = 0.79; p < 0.05), the SDMT (r = 0.80; p < 0.05), the SIT (r = 0.72; p < 0.05), the MMSE (r = 0.83; p < 0.05), the FCS (r = 0.79; p < 0.05) and the motor section of the UHDRS (r = −0.80; p < 0.05). The FAB differentiated between HD patients in the initial and later stages of the disease. The one-year longitudinal evaluation revealed a global trend toward a worsening in the second score of the FAB. The results demonstrate that the FAB presents good internal consistency and also convergent and discriminative validity; therefore it is a useful scale to assess executive functions and to evaluate cognitive impairment in patients with HD.     

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the development and function of the blood–brain barrier

Prenatal exposure to environmental chemicals such as dioxins is known to have adverse effects on the developing central nervous system (CNS) in mammals. Because the fetal blood–brain barrier (BBB) is immature, dioxins are thought to exert their toxic effects on the CNS by crossing the BBB and acting on neural cells directly. However, little is known whether dioxins alter the BBB. In this study, to investigate the effects of dioxins on BBB function, we exposed an in vitro BBB system comprising rat endothelial cells, astrocytes, and pericytes to the toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) either before or after BBB formation. We assessed BBB permeability and the function of tight junctions by measuring transendothelial electric resistance (TEER) values following exposure. Subsequently, total RNA and proteins were obtained from the cells for analysis. TEER values following TCDD exposure before but not after BBB formation were lower than those of the control group. We also observed that the expression of the tight junction proteins ZO-1 and claudin-5 was suppressed following TCDD exposure. To examine the cause of this reduction in protein levels, we performed a real-time quantitative polymerase chain reaction assay and observed low expression of the glial cell line-derived neurotrophic factor (GDNF) mRNA in the exposed groups. Moreover, to rescue the effects of TCDD, we applied extrinsic GDNF with TCDD. The several disruptions caused by TCDD were rescued by the GDNF addition. Our findings suggest that exposure to TCDD during BBB formation disrupts and impairs BBB function in part by the suppression of GDNF action, which may contribute to the adverse effects of TCDD on the fetal CNS.     

Magnetic resonance imaging assessment of cardiac dysfunction in δ-sarcoglycan null mice

Delta-sarcoglycan (δ-sarcoglycan) null, Scgd^−/−, mice develop cardiac and skeletal muscle histopathological alterations similar to those in humans with limb-girdle muscular dystrophy. The objective of this study was to assess the feasibility of using MRI to investigate cardiac dysfunction in Scgd^−/− mice. Cardiac MRI of 8 month old Scgd^−/− and wild type (WT) mice was performed. Compared to WT, Scgd^−/− mice had significantly lower LV ejection fraction (44 ± 5% vs. 66 ± 4%, p = 0.014), lower RV ejection fraction (25 ± 2% vs. 51 ± 3%, p < 0.001) lower myocardial circumferential strain, (15.0 ± 0.3% vs. 16.9 ± 0.3%, p = 0.007) and RV dilatation (54 ± 3 μL vs. 40 ± 3 μL, p = 0.007). The regional circumferential strain also demonstrated significant temporal dyssynchrony between opposing regions of the Scgd^−/− LV. Our results demonstrate severe cardiac dysfunction in Scgd^−/− mice at 8 months. The study identifies a set of non-invasive markers that could be used to study efficacy of novel therapeutic agents in dystrophic mice.     

Prevalence and factors of verbal learning and memory dysfunction in patients with epilepsy – A single centre study

The objective of this study is to determine prevalence and factors leading to verbal learning and memory dysfunction among patients with epilepsy.A total of 211 subjects were recruited. Their verbal memory was assessed by Rey’s Auditory Verbal Learning Test (RAVLT). This test was further subdivided into four major spheres for analysis, namely the verbal learning, interference list, immediate memory and delayed memory. All data collected were analyzed using Statistical Package for Social Sciences.Among the 211 patients, 55% (n = 116) had focal seizures and the remaining 45% (n = 95) had generalized seizures. Prevalence of verbal learning and memory impairment was high at 39.97% overall, and found most commonly in patients with focal impaired awareness seizures. Verbal learning and immediate memory dysfunction were significantly lower in focal impaired awareness group compared to others. Age more than 50 years, exposure to three or more antiepileptic drugs and use of carbamazepine more than 1000 mg a day were the predictors in poor verbal memory outcome. No statistical difference was observed in the mean RAVLT scores among the gender and hand dominance groups. Between patients with and without electroencephalogram changes as well as brain magnetic resonance imaging changes, the mean RAVLT scores showed no statistically significant difference.Verbal learning and memory impairment is prevalent among the epilepsy patients. The consequences of the memory impairment can be as debilitating as the seizure control. RAVLT is a reliable and practical test in the clinical setting.     

Efficacy and safety assessment of alteplase in the treatment of stroke — gender differences

Abstract

Background:

Evidence for gender disparity in response to pharmacological thrombolysis for acute stroke treatment is inconclusive.

Objective:

To compare the effectiveness and safety of alteplase used in the treatment of male and female stroke patients.

Material and methods:

One thousand and seventy-seven patients who recently had their first-ever clinically apparent stroke (group I: 113 patients treated with intravenous alteplase and group II: 964 not treated with alteplase) were qualified. Groups I and II were divided into subgroups based on gender and were analysed based on: the age when they had a stroke, presence of key stroke risk factors (quantitatively: ≤ or >3), neurological state according to NIHSS in the first day of stroke, mortality rate, and the modified Rankin scale (mRS) at day 90 after the stroke. In group I, other determinants were additionally assessed: recent lesions as appeared on CT scans of the head in the first day of stroke and 24 hours after recombinant tissue plasminogen activator (rtPA), neurological state according to NIHSS in the second day of stroke, and the incidence of iatrogenic bleeding.

Results:

The age of the onset of stroke was older in women both in group I and group II. Apart from lipid disorders, no statistically significant differences in the distribution of other risk factors for stroke between groups I and II were found. The neurological state (according to the NIHSS scale) on the first day of the disease was significantly more severe in women both in group I and group II. In group II, the level of functioning according to the mRS scale at day 90 day after the onset of the disease was significantly more severe in women; there was no significant difference in group I. Among patients from group I, a significantly greater improvement, according to the NIHSS scale, was found in women 24 hours after rtPA administration in comparison with men. The presence of focal ischemia, responsible for the occurrence of stroke, on the CTs of the head performed 24 hours after rtPA administration, was also significantly more often found in women (in group I). No statistically significant differences in the incidence of complications after rtPA between women and men in group I were observed. In multivariate methods, we did not find any impact of factors other than gender on the outcome after stroke.

Conclusions:

The use of alteplase in women during the treatment of stroke is associated with a greater and faster improvement in their neurological state in comparison with men. Treating stroke with alteplase in women improves long-term prognosis regarding self-efficacy in everyday functioning. Finally, there are no gender-related differences regarding the safety of intravenous thrombolytic therapy.     

Finding the experts in the crowd: Validity and reliability of crowdsourced measures of children’s gradient speech contrasts

ABSTRACT

Perceptual ratings aggregated across multiple nonexpert listeners can be used to measure covert contrast in child speech. Online crowdsourcing provides access to a large pool of raters, but for practical purposes, researchers may wish to use smaller samples. The ratings obtained from these smaller samples may not maintain the high levels of validity seen in larger samples. This study aims to measure the validity and reliability of crowdsourced continuous ratings of child speech, obtained through Visual Analog Scaling, and to identify ways to improve these measurements. We first assess overall validity and interrater reliability for measurements obtained from a large set of raters. Second, we investigate two rater-level measures of quality, individual validity and intrarater reliability, and examine the relationship between them. Third, we show that these estimates may be used to establish guidelines for the inclusion of raters, thus impacting the quality of results obtained when smaller samples are used.     

Edouard Claparède and the auditory verbal learning test

This paper describes the role of the Swiss psychologist Edouard Claparède (1873-1940) in developing the Test de mémoire des mots (Test of Memory for Words), a test consisting of one free-recall trial of a 15-word list that is the antecedent of the auditory verbal learning tests (AVLT) of Rey and others. The fact that Claparède's test has survived in modified form for 80 years makes it one of the oldest mental tests in continuous use. In addition to developing the AVLT, Claparède's pioneering contributions to neuropsychology include forensic assessment of cognitive deficits and research on implicit learning in amnesia.