Inhibitory interneurons in Alzheimer's disease.

Alzheimer's disease is currently the most common neurodegenerative disorder, characterized by distinct cognitive and sensory deficits. The underlying pathogenetic mechanisms, however, still remain elusive. How the molecular and morphological changes associated with Alzheimer's disease affect information processing in neuronal circuits and translate into cognitive dysfunction is unclear. Inhibitory interneurons have recently emerged as one of the earliest and important culprits in mediating dysfunction of neuronal circuits in neurodegeneration. Amyloid-beta and tau protein have been both linked to interneuron dysfunction, and likely play an important, albeit unknown, role in mediating changes in the overall activity of neuronal circuits. Resolving the role of inhibitory interneurons in neurodegeneration-specific changes in neuronal activity is crucial for understanding the impact of Alzheimer's disease on brain function and even for possible identification of effective treatments and diagnostic techniques (Ref. 63).

Unmasking Latent Inhibitory Connections in Human Cortex to Reveal Dormant Cortical Memories.

Balance of cortical excitation and inhibition (EI) is thought to be disrupted in several neuropsychiatric conditions, yet it is not clear how it is maintained in the healthy human brain. When EI balance is disturbed during learning and memory in animal models, it can be restabilized via formation of inhibitory replicas of newly formed excitatory connections. Here we assess evidence for such selective inhibitory rebalancing in humans. Using fMRI repetition suppression we measure newly formed cortical associations in the human brain. We show that expression of these associations reduces over time despite persistence in behavior, consistent with inhibitory rebalancing. To test this, we modulated excitation/inhibition balance with transcranial direct current stimulation (tDCS). Using ultra-high-field (7T) MRI and spectroscopy, we show that reducing GABA allows cortical associations to be re-expressed. This suggests that in humans associative memories are stored in balanced excitatory-inhibitory ensembles that lie dormant unless latent inhibitory connections are unmasked.

Inhibitory synaptic plasticity: spike timing-dependence and putative network function.

While the plasticity of excitatory synaptic connections in the brain has been widely studied, the plasticity of inhibitory connections is much less understood. Here, we present recent experimental and theoretical findings concerning the rules of spike timing-dependent inhibitory plasticity and their putative network function. This is a summary of a workshop at the COSYNE conference 2012.

Inhibitory plasticity balances excitation and inhibition in sensory pathways and memory networks.

Cortical neurons receive balanced excitatory and inhibitory synaptic currents. Such a balance could be established and maintained in an experience-dependent manner by synaptic plasticity at inhibitory synapses. We show that this mechanism provides an explanation for the sparse firing patterns observed in response to natural stimuli and fits well with a recently observed interaction of excitatory and inhibitory receptive field plasticity. The introduction of inhibitory plasticity in suitable recurrent networks provides a homeostatic mechanism that leads to asynchronous irregular network states. Further, it can accommodate synaptic memories with activity patterns that become indiscernible from the background state but can be reactivated by external stimuli. Our results suggest an essential role of inhibitory plasticity in the formation and maintenance of functional cortical circuitry.

Social psychological determinants of the use of performance-enhancing drugs by gym users.

The aim of this study is to identify the social psychological determinants of the use of performance-enhancing drugs by gym users who practice bodybuilding, fitness, powerlifting or combat sports. In this questionnaire-based study, 144 respondents answered questions on their actual use and intention to use such drugs and also on their background characteristics and beliefs, such as their attitudes, social influences and self-efficacy. While all social psychological determinants correlated with intention to use these drugs, the most important predictors were personal norms, beliefs about performance outcomes and the perceived behavior of others. Non-users held more restrictive norms about using performance-enhancing drugs, were less optimistic about the performance-enhancing outcomes and believed that fewer significant others used performance-enhancing drugs than users and ex-users. The results of this study indicate that users attribute advantages to performance-enhancing drugs and are inclined to overlook the risks of using them. Preventive interventions should focus on influencing personal norms and social processes.

Gating deficits in model networks: a path to schizophrenia?

Gating deficits and hallucinatory sensations are prominent symptoms of schizophrenia. Comparing these abnormalities with the failure modes of network models is an interesting way to explore how they arise. We present a network model that can both propagate and gate signals. The model exhibits effects reminiscent of clinically observed pathologies when the balance between excitation and inhibition that it requires is not properly maintained.

The development and validation of a handicap questionnaire for children with a chronic illness.

INTRODUCTION: This paper describes the development and initial psychometric evaluation of the Handicap Scale for Children (HSC). This questionnaire is based on the London Handicap Scale (LHS), a valid and reliable utility instrument for measuring social participation in adults. METHODS: A multidisciplinary research group was involved in developing the HSC. The questionnaire was tested in 114 children with a chronic disease and 239 healthy children in the 8-18 age range. Relating the Health Utility Index Mark 3 (HUI3) attributes to corresponding HSC scores tested the assumption that a negative health status would lead to participation problems. RESULTS: Questionnaire development resulted in a five-dimension questionnaire: mobility, physical independence, daily activities, social integration and orientation. Each dimension included one item with a six-point response scale. A higher score indicates greater handicap. Feasibility testing with 10 children showed that none of the children experienced difficulties in filling in the questionnaire. Conceptual validity, measured by correlations between the dimensions of the HSC and HUI3, was satisfactory. As expected, moderate correlation coefficients between predefined pairs of HUI and HSC attributes were found; other correlation coefficients were low. Criterion validity was also satisfactory, as shown by large differences between the healthy and the chronically ill group and by several criteria within the chronically ill group. CONCLUSION: Based on this initial evaluation, the questionnaire seems feasible and valid for use with children in the age range 8-18 years.

A cardiac-specific health-related quality of life module for young adults with congenital heart disease: development and validation.

This study represents the development and validation of a cardiac-specific module of the generic health-related quality of life (HRQoL) instrument, the TAAQOL (TNO/AZL Adult Quality Of Life), for young adults with congenital heart disease (CHD). Items were selected based on literature, an explorative previous study in CHD patients, interviews with patients, and the advice of experts. The newly developed Congenital Heart Disease-TNO/AZL Adult Quality of Life (CHD-TAAQOL) was tested in 156 patients with mild or complex CHD and consisted of three hypothesised subject scales: 'Symptoms' (9 items), 'Impact Cardiac Surveillance' (7 items), and 'Worries' (10 items). Cronbach's alpha for the three scales were 0.77, 0.78, and 0.82, respectively. Scale structure was confirmed by Principal Component Analysis, corrected item-scale and interscale correlations. Overall, 55% of reported health status problems were associated with negative emotions, which is an argument for assessing HRQoL as a concept distinct from health status. Convergent validity with validated generic instruments (TAAQOL and Short Form-36, SF-36) showed satisfactory coefficients. Discriminant validity was proven by significantly higher scores for mild CHD patients compared with those with complex CHD. In conclusion, the CHD-TAAQOL module together with the generic TAAQOL can be used to assess group differences for cardiac-specific HRQoL in young adults with CHD. Testing psychometric properties of the CHD-TAAQOL shows satisfactory results. However, to detect changes in HRQoL over time, further research is needed.

Detecting psychosocial problems among 5-6-year-old children in preventive Child Health Care: the validity of a short questionnaire used in an assessment procedure for detecting psychosocial problems among children.

BACKGROUND: An extended re-assessment of the psychometric properties of the LSPPK, an instrument aimed at identifying children with emotional and behavioural problems. METHODS: Data came from a national sample in The Netherlands of parents of 1248 children (aged 5-6 years) interviewed by child health professionals (CHP). Data were obtained regarding psychosocial problems, treatment status and scores on the LSPPK (Parent and CHP Index), and on the Child Behavior Checklist (CBCL). The scale structure, reliability, criterion and content validity and added value of the LSPPK were assessed using the CBCL and treatment status as criteria. RESULTS: The scale structure corresponded with that found originally; the LSPPK improved the prediction of problems according to the CBCL, compared to predictions using readily available risk indicators alone. Reliability varied between 0.55 and 0.69. For the LSPPK Parent Index, sensitivity varied between 0.42 and 0.50. For the CHP Index sensitivity varied between 0.60 and 0.96, but specificity varied between 0.76 and 0.79. Both indices were very sensitive for attention and social problems, but less so for other problems. CONCLUSION: The LSPPK Parent Index cannot distinguish sufficiently between children with or without serious problems. Either too many children with problems remain unnoticed or too many children without problems are labelled as a case. The LSPPK CHP Index, reflecting the CHP's interpretation of the Parent Index after interviewing the parents does not compensate adequately for the weaknesses of the Parent Index. Better assessment procedures and strategies need to be developed.

Health related quality of life and health status in adult survivors with previously operated complex congenital heart disease.

OBJECTIVE: To examine the impact of previously operated complex congenital heart disease on health related quality of life and subjective health status and to determine the relation between these parameters and physical status. DESIGN: Cross sectional; information on medical follow up was sought retrospectively. SETTING: Patients were randomly selected from the archives of the paediatric cardiology department, Leiden University Medical Centre, Leiden, The Netherlands, and approached irrespective of current cardiac care or hospital of follow up. PATIENTS: Seventy eight patients with previously operated complex congenital heart disease (now aged 18-32 years) were compared with the general population. MAIN OUTCOME MEASURES: Health related quality of life was determined with a specifically developed questionnaire (Netherlands Organisation for Applied Scientific Research Academic Medical Centre (TNO-AZL) adult quality of life (TAAQOL)) and subjective health status was assessed with the 36 item short form health survey (SF-36). Physical status was determined with the objective physical index, Somerville index, and New York Heart Association functional class. RESULTS: Health related quality of life of the patients was significantly worse than that of the general population in the dimensions gross motor functioning and vitality (p < 0.01). Correlations between health related quality of life and physical status were poor. Patients had significantly worse subjective health status than the general population in the dimensions physical functioning, role functioning physical, vitality, and general health perceptions (p < 0.01). Correlations between subjective health status and physical indices were weak. CONCLUSION: Adult survivors with previously operated complex congenital heart disease experienced limitations only in the physical dimensions of health related quality of life and subjective health status. Objectively measured medical variables were only weakly related to health related quality of life. These results indicate that, when evaluating health related quality of life, dedicated questionnaires such as the TAAQOL should be used.

Performance of the EuroQol in children with imperforate anus.

OBJECTIVE: To investigate the feasibility and validity of a proxy version of the EuroQol in children treated for imperforate anus. METHODS: Patients included were between 1 and 51 years of age. Instruments included were the EuroQol, the TACQOL and a disease specific questionnaire, the Langemeijer Stool Questionnaire. Patients older than 15 years filled in all questionnaires themselves, in the age groups 5-10 and 11-15 a parent administered the questionnaires. Feasibility was judged on the number of missing values. In search of validity, EuroQol scores were compared with the prevalence of disease symptoms (convergent validity) and with the TACQOL (construct validity). RESULTS: The number of missings was not related to age. The disease specific questionnaire correlated significantly with the EQvas from 11 years on and with the EQ-5Dindex from 5 years on. The mean correlation between contextual similar domains of the EuroQol and the TACQOL was -0.55. The correlation between different domains was -0.32. CONCLUSION: The results support the idea that the use of a proxy version of the EuroQol is feasible and valid. The convergent validity of the EQvas was supported from 11 years on. The EQ-5D showed good construct and convergent validity from 5 years on.

Development and psychometric evaluation of the TAPQOL: a health-related quality of life instrument for 1-5-year-old children.

The 43-item TNO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire was developed to meet the need for a reliable and valid instrument for measuring parent's perceptions of health-related quality of life (HRQoL) in preschool children. HRQoL was defined as health status in 12 domains weighted by the impact of the health status problems on well-being. The aim of this study was to evaluate the psychometric performance of the TAPQOL. A sample of 121 parents of preterm children completed the TAPQOL questionnaire (response rate 88%) as well as 362 parents of children from the general population (response rate 60%). On the base of Cronbach's alpha, item-rest correlation, and principal component analysis, the TAPQOL scales were constructed from the data for the preterm children sample. The psychometric performance of these scales was evaluated for both the preterm children sample and the general population sample. Cronbach's alpha ranged from 0.66 to 0.88 for the preterm children sample and from 0.43 to 0.84 for the general population sample. The unidimensionality of the separate scales was confirmed by principal component analysis for both the preterm children sample and the general population sample. Spearman's correlation coefficients between scales were, on average, low. T-tests showed that the very preterm children, the children with chronic diseases, the less healthy and the less happy children had lower mean scores on the TAPQOL scales than healthy children, indicating a worse quality of life. This study shows that the TAPQOL is a reliable and valid parent's perception of HRQoL in preschool children. More research is needed to evaluate the psychometric performance of the TAPQOL in different clinical populations.

[Quality of life in children with sickle cell disease in Amsterdam area]. / Kwaliteit van leven bij kinderen met sikkelcelziekte in de regio Amsterdam.

OBJECTIVE: To determine the differences in quality of life between children with sickle cell disease and healthy immigrant children. DESIGN: Descriptive, comparative. METHOD: The quality of life of children with sickle cell disease between 5 and 15 years old being treated in the Emma Children's Hospital AMC in Amsterdam, the Netherlands, was assessed by using a questionnaire for parents (TNO-AZL Children's Quality of Life Questionnaire (TACQOL) parent form) if the child was between 5 and 11 years old and a questionnaire for children (TACQOL child form) if the child was between 8 and 15 years old. The study period was April-October 1998. The questionnaires were completed by 45 (parents of) patients. The results were compared with a healthy reference group of immigrant children. Statistical analysis was performed using the Student t-Test. RESULTS: Children with sickle cell disease as well as their parents scored significantly lower on the items general physical, motor and independent daily functioning and on occurrence of negative emotions. No significance was observed for the items cognitive functioning and school performance nor for social functioning or occurrence of positive emotions. CONCLUSION: In children, sickle cell disease leads to compromised physical and possibly also psychological wellbeing, as well as the experience of decreased independence in daily functioning, but not to compromised cognitive or social aspects of the quality of life.

Quality of life in children with sickle cell disease in Amsterdam area

OBJECTIVE: To determine the differences in quality of life between children with sickle cell disease and healthy immigrant children. DESIGN: Descriptive, comparative. METHOD: The quality of life of children with sickle cell disease between 5 and 15 years old being treated in the Emma Children's Hospital AMC in Amsterdam, the Netherlands, was assessed by using a questionnaire for parents (TNO-AZL Children's Quality of Life Questionnaire (TACQOL) parent form) if the child was between 8 and 15 years old. The study period was April-October 1998. The questionnaires were completed by 45 (parents of) patients. The results were compared with a healthy reference group of immigrant children. Statistical analysis was performed using the Student t-Test. RESULTS: Children with sickle cell disease as well as their parents scored signifcantly lower on the items general physical, motor and independent daily functioning and on occurrence of negative emotions. No significance was observed for the items cognitive functioning and school performance nor for social functioning or occurrence of positive emotions. CONCLUSIONS: In children, sickle cell disease leads to compromised physical and possibly also psychological wellbeing, as well as the experience of decreased independence in daily functioning, but not to compromised cognitive or social aspects of the quality of life. (AU)

AIDS-related knowledge, attitudes, and behavior: a comparison of Dutch students and dropouts.

School dropouts are considered an important target group for AIDS prevention. They are expected to be less knowledgeable about AIDS and to show a higher degree of risky behavior as compared with their school-attending peers. Several small-scale studies among specific groups of dropouts seem to confirm such expectations. However, due to differences in methodology, it is often difficult to compare the results of such studies with findings for youths who have not dropped out of school. The present study sought to remedy this by examining AIDS-related knowledge, attitudes, and behavior among comparable samples of Dutch secondary school students and dropouts (excluding homeless and drug-addicted adolescents). The two groups were compared with regard to knowledge about AIDS prevention, attitude toward condom use, intention to use condoms, sexual history, and condom use. Contrary to expectations, few differences were found. It was concluded that, in most respects, dropouts are similar to those who have remained in school.

The proxy problem: child report versus parent report in health-related quality of life research.

This study evaluates the agreement between child and parent reports on children's health-related quality of life (HRQoL) in a representative sample of 1,105 Dutch children (age 8-11 years old). Both children and their parents completed a 56 item questionnaire (TACQOL). The questionnaire contains seven eight-item scales: physical complaints, motor functioning, autonomy, cognitive functioning, social functioning, positive emotions and negative emotions. The Pearson correlations between the child and parent reports were between 0.44 and 0.61 (p < 0.001). The intraclass correlations were between 0.39 and 0.62. On average, the children reported a significantly lower HRQoL than their parents on the physical complaints, motor functioning, autonomy, cognitive functioning and positive emotions scales (paired t-test: p < 0.05). Agreement on all of the scales was related to the magnitude of the HRQoL scores and to some background variables (gender, age, temporary illness and visiting a physician). According to multitrait-multimethod analyses, both the child and parent reports proved to be valid.

Measuring health-related quality of life in children: the development of the TACQOL parent form.

Health-related quality of life (HRQoL), conceptualized as patients' own evaluations of their health status, is an important criterion in evaluation health and health care and in the treatment of individual patients. Until now, few systematic attempts have been made to develop instruments to assess the HRQoL of children using such a conceptualization. This article describes the conceptualization and results of a study aiming to develop such an instrument for children aged 6-15 years using their parents as a proxy. The feasibility and psychometric performance of the instrument were evaluated in a study of 77 patients of the paediatric out-patient clinic of Leiden University Hospital. For each of the a priori-defined domains, a parent form scale could be constructed with satisfactory reliability and moderate correlations with the other scales. Only some of the parents indicating health status problems also signalled negative reactions to these problems. This is, in our view, a strong argument for the distinction between health status and quality of life (QoL). The correlation coefficients between the parent form and a children's questionnaire were low. Overall, the psychometric performance of the TACQOL parent form looks promising, which suggests that this instrument--with some modifications--can indeed be used to assess group differences in HRQoL in children. The results, however, should be replicated in larger samples, currently under study. The relation between parents' proxy reports on the HRQoL of their children and children's self-reports needs further investigation.

Psychological responses to the needle-free Medi-Jector or the multidose Disetronic injection pen in human growth hormone therapy.

The aim of the study was to test the hypothesis that daily administration of growth hormone using the Medi-Jector results in fewer adverse psychological responses than needle injection with a multidose injection pen. The Medi-Jector is a needle-free injection device that can deliver growth hormone subcutaneously through jet injection. The group studied consisted of 18 children aged 10 y or over who were participating in a study of the bioequivalence and bioequipotence of the administration of growth hormone through jet injection or needle injection. Previously, all subjects had received growth hormone therapy with commercially available multidose injection pens. The study was designed as a prospective, randomized, two-period cross-over trial. A questionnaire was used to assess psychological responses such as non-compliance, opinion on ease of preparation, affective responses to administration and local side-effects, as well as overall preference. In addition, the subjects kept a diary during the study. The subjects found the Medi-Jector less offputting (p < 0.01), less painful with respect to both frequency (p < 0.04) and intensity (p < 0.01) and less unpleasant (p < 0.05) than a multidose injection pen with a 28G needle (p < 0.01). No difference in compliance was detected. Most subjects preferred the Medi-Jector for future use (p < 0.05). The mean score on a 1-10 point scale (10 is excellent) was 7.9 (SD 1.4) for the Medi-Jector and 6.8 (SD 2.3) for the multidose injection pen (p < 0.08). The prevalence of visible bruises each day was higher (p < 0.01) with the Medi-Jector (2.5, SD 2.1) than with the multidose injection pen (0.7, SD 1.1), but children showed indifferent affective responses to bruising. Thirteen out of 18 subjects decided to continue therapy with the Medi-Jector (p < 0.06). It is concluded that use of the Medi-Jector in growth hormone therapy tends to lead to fewer adverse psychological responses than a multidose injection pen with 28G needles.