Positive Allosteric Modulator of GABA Lowers BOLD Responses in the Cingulate Cortex.

Knowledge about the neural underpinnings of the negative blood oxygen level dependent (BOLD) responses in functional magnetic resonance imaging (fMRI) is still limited. We hypothesized that pharmacological GABAergic modulation attenuates BOLD responses, and that blood concentrations of a positive allosteric modulator of GABA correlate inversely with BOLD responses in the cingulate cortex. We investigated whether or not pure task-related negative BOLD responses were co-localized with pharmacologically modulated BOLD responses. Twenty healthy adults received either 5 mg diazepam or placebo in a double blind, randomized design. During fMRI the subjects performed a working memory task. Results showed that BOLD responses in the cingulate cortex were inversely correlated with diazepam blood concentrations; that is, the higher the blood diazepam concentration, the lower the BOLD response. This inverse correlation was most pronounced in the pregenual anterior cingulate cortex and the anterior mid-cingulate cortex. For subjects with diazepam plasma concentration > 0.1 mg/L we observed negative BOLD responses with respect to fixation baseline. There was minor overlap between cingulate regions with task-related negative BOLD responses and regions where the BOLD responses were inversely correlated with diazepam concentration. We interpret that the inverse correlation between the BOLD response and diazepam was caused by GABA-related neural inhibition. Thus, this study supports the hypothesis that GABA attenuates BOLD responses in fMRI. The minimal overlap between task-related negative BOLD responses and responses attenuated by diazepam suggests that these responses might be caused by different mechanisms.

Functional magnetic resonance imaging of hippocampal activation during silent mantra meditation.

OBJECTIVES: The objective of the present study was to investigate whether moderately experienced meditators activate hippocampus and the prefrontal cortex during silent mantra meditation, as has been observed in earlier studies on subjects with several years of practice. METHODS: Subjects with less than 2 years of meditation practice according to the Kundalini yoga or Acem tradition were examined by functional magnetic resonance imaging during silent mantra meditation, using an on-off block design. Whole-brain as well as region-of-interest analyses were performed. RESULTS: The most significant activation was found in the bilateral hippocampus/parahippocampal formations. Other areas with significant activation were the bilateral middle cingulate cortex and the bilateral precentral cortex. No activation in the anterior cingulate cortex was found, and only small activation clusters were observed in the prefrontal cortex. CONCLUSIONS: In conclusion, the main finding in this study was the significant activation in the hippocampi, which also has been correlated with meditation in several previous studies on very experienced meditators. We propose that the hippocampus is activated already after moderate meditation practice and also during different modes of meditation, including relaxation. The role of hippocampal activity during meditation should be further clarified in future studies, especially by investigating whether the meditation-correlated hippocampal activity is related to memory consolidation.

Brain activation during compassion meditation: a case study.

OBJECTIVES: B.L. is a Tibetan Buddhist with many years of compassion meditation practice. During meditation B.L. uses a technique to generate a feeling of love and compassion while reciting a mantra. The aim of the present study was to investigate the neural correlates of compassion meditation in 1 experienced meditator. METHODS: B.L. was examined by functional magnetic resonance imaging during compassion meditation, applying a paradigm with meditation and word repetition blocks. RESULTS: The most significant finding was the activation in the left medial prefrontal cortex extending to the anterior cingulate gyrus. Other significant loci of activation were observed in the right caudate body extending to the right insula and in the left midbrain close to the hypothalamus. CONCLUSIONS: The results in this study are in concordance with the hypothesis that compassion meditation is accompanied by activation in brain areas involved with empathy as well as with happy and pleasant feelings (i.e., the left medial prefrontal cortex and the anterior cingulate gyrus).

Medical outcome in epilepsy patients of young adulthood--a 5-year follow-up study.

UNLABELLED: The appearance of new anti-epileptic drugs (AED) during the last decade has provided neurologists and their patients with a greater choice, but the proof for their superiority over traditional AEDs is sparse, especially their use in adolescence and young adulthood. We studied a group of young adults (18-27 years) with epilepsy and compared their situation in 2004 with those 5 years earlier. MATERIALS AND METHODS: The participants (n=97) answered questionnaires regarding seizure-frequency, AED, side-effects and quality-of-life. Information was also taken from medical records. RESULTS: The use of new generation AEDs increased during the 5-year study period, particularly among women. However seizure frequency had not changed significantly over time, and compared to men the effectiveness in controlling seizures was lower in women. The participants reported normal quality-of-life (QOL), which may indicate that the increase in number of AEDs to choose from actually improved the situation for these young adults with epilepsy. Frequency of seizures and cognitive side-effects of AEDs were associated with a lower QOL. CONCLUSIONS: More women than men seem to be treated with new AEDs, and that the increase in use of new AEDs does not reduce seizure frequency in young adulthood. The effectiveness in controlling seizures seems to be lower in women in the age group studied. Further studies are required to better understand how epilepsy related factors interact.

Influence of diazepam on clinically designed FMRI.

The authors investigated the effect of diazepam on clinically relevant measures from functional magnetic resonance imaging (fMRI) examinations. Twenty volunteers were scanned twice. Using a double-blind randomized study design, the volunteers received placebo on one occasion, and on the other, 5 mg of diazepam. Three functional tests were used: motor, word generation, and working memory. Images were analyzed individually for each subject and the number of activated voxels and the laterality index were calculated. No significant effects related to the drug were detected. In contrast, the motor and working memory tasks showed a significant decrease in the number of activated voxels between Sessions 1 and 2, independently of diazepam administration. These results indicate that diazepam may be administered for premedication prior to fMRI investigations.

Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation.

PURPOSE: To study pharmacokinetics of levetiracetam (LEV) during pregnancy, delivery, lactation, and in the neonatal period. METHODS: Fourteen women with epilepsy receiving LEV treatment during pregnancy and lactation contributed with 15 pregnancies to this prospective study in which LEV concentrations in plasma and breast milk were determined. Trough maternal plasma samples were collected each trimester, and at baseline after delivery. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from newborns during 2 days after delivery. LEV concentration was also determined in breast milk and in plasma collected from 11 of the mothers and their suckling infants after birth. RESULTS: The umbilical cord/maternal plasma concentration ratios ranged from 0.56-2.0 (mean 1.15, n=13). LEV plasma concentrations in the neonates declined with an estimated half-life of 18 h (n=13). The mean milk/maternal plasma concentration ratio was 1.05 (range, 0.78-1.55, n=11). The infant dose of LEV was estimated to 2.4 mg/kg/day, equivalent to 7.9% of the weight-normalized maternal dose. Plasma concentrations in breastfed were approximately 13% of the mother's plasma levels. Maternal plasma concentrations during third trimester were only 40% of baseline concentrations outside pregnancy (p<0.001, n=7) CONCLUSIONS: Our observations suggest considerable transplacental transport of LEV and fairly slow elimination in the neonate. Plasma concentrations of LEV in nursed infants are low despite an extensive transfer of LEV into breast milk. Pregnancy appears to enhance the elimination of LEV resulting in marked decline in plasma concentration, which suggests that therapeutic monitoring may be of value.

Daily life in epilepsy: patients' experiences described by emotions.

OBJECTIVE: According to the literature, emotions are closely related to health and well-being. The aim of this study was to illuminate the impact of epilepsy on daily life in young adulthood, described by the patients' emotions. METHOD: Young adults, 18-27 years of age (n=95/102), answered a questionnaire eliciting descriptions of their daily lives with epilepsy in their own words. A content analysis was performed, and the material was categorized, according to the Belief Desire Theory of Emotions. RESULTS: The patients experienced positive (confidence, hope, harmony, and forbearance); negative (anxiety, despair, fear, resignation, indignation, sadness, insecurity, and anger); and self-evaluating emotions (being valuable, being insignificant, shame, guilt, and self-doubt). Two different groups of patients could be identified: one group whose members regarded themselves as "healthy" and another group whose members regarded themselves as being ill or "handicapped". The "healthy" group was active and flexible, focusing on possibilities and planning how to handle negative emotions. The "handicapped" group was passive and resigned to the epilepsy in a negative way, afraid of being exposed. They focused on obstacles, and their negative emotions were also directed toward the self. CONCLUSION: This study pointed out the importance of paying attention to the role of emotions in the experiences and well-being of patients with epilepsy.

Psychosocial aspects of health in adolescence: the influence of gender, and general self-concept.

PURPOSE: The aim of this study was to describe age and gender differences in psychosocial aspects of health in adolescents. A further aim was to explore if self-rated behavior problems varied with the adolescents' general self-concept and sense of coherence. METHODS: Questionnaires on self-rated psychosocial aspects of health were answered by 282 (n = 282/390) randomly selected adolescents, aged 13-22 years (M 17.9/18.0). The instruments used were "I think I am (ITIA)," "Youth Self Report (YSR)," "Sense of coherence (SOC)," and "Family APGAR." Differences between males and females (cross-individual grouping) were analyzed using nonparametric tests. A cluster analysis was performed using a three-cluster solution to identify and describe profiles (person-centered grouping). RESULTS: Compared with males, adolescent females scored less favorably on self-esteem (ITIA) (p = .028), reported more behavior problems (YSR) (p = .000), and showed a lower sense of coherence (SOC) (p = .003). The differences were most evident in the age group 15-17 years. The three clusters significantly differed from each other regarding how high proportions of problems the adolescents of each profile reported. CONCLUSIONS: Compared with male adolescents, adolescent females experienced a poorer psychosocial health in somatic, depressive, and internalizing areas. The result indicated that psychological factors had a major impact on the proportions of problems that the adolescents reported.

[A national curriculum in neurology for medical education]. / Nationellt core curriculum i neurologi för läkarutbildningen.

The knowledge within medicine is growing rapidly. It has become more and more difficult to decide what knowledge that has to be taught to medical students during their University Medical Degree (MD) education and what has to be omitted from their study plans. As help for teachers and students, a core curriculum of the education defines what is of importance for all students. However, there is a risk of "curriculum overload" with too much information being put into a short time interval. To avoid this and to define what is really the "core" of a course, a national consensus decision may be useful. As an example of this approach, we here report a new joint Swedish core curriculum in neurology for medical students. Teachers responsible for neurological education at all six universities giving University MD education in Sweden have in January 2003 agreed upon the core curriculum that we present. It is our hope that this method can be useful also for other clinical specialities.

The relationship between illness severity, sociodemographic factors, general self-concept, and illness-specific attitude in Swedish adolescents with epilepsy.

PURPOSE: The aim of this study was to describe the relationship between the epilepsy condition (illness severity), sociodemographic factors, general self-concept, and illness-specific attitude in adolescents with uncomplicated epilepsy. METHODS: Adolescents, aged 13-22, fulfilling criteria registered in four Swedish hospitals, answered questionnaires (n = 149). The instruments "I think I am" and "Sense of coherence" measured the patients' general self-concept. The "Child Attitude Toward Illness Scale" measured illness-specific attitude. A summary score (index) calculated from seizure frequency, seizure type, and antiepileptic drug (AED) with side effects measured "Illness Severity". RESULTS: Illness severity was significantly related to the participants' general self-concept, as well as to their attitude toward their condition; i.e. higher illness severity scores were correlated with lower sense of coherence (SOC), poorer self-esteem, and a more negative attitude towards the epilepsy condition. Females had more severe illness according to the Illness Severity Index, with almost 80% found in the moderate and high severity groups as compared to 63% of males in the moderate/high severity groups. CONCLUSIONS: It was concluded that the severity of the epilepsy condition was related to the adolescents' general self-concept and illness-specific attitude, but further research is needed to understand the causality of the relationship. The brief assessment of illness severity, constructed and used in this study should be addressed and developed further.

Paradigm design of sensory-motor and language tests in clinical fMRI.

Functional magnetic resonance imaging (fMRI) paradigms on sensory-motor and language functions are reviewed from a clinical user's perspective. The objective was to identify special requirements regarding the design of fMRI paradigms for clinical applications. A wide range of methods for setting up fMRI examinations were found in the literature. It was concluded that there is a need for standardised procedures adapted for clinical settings. Sensory-motor activation patterns do not vary much at different hand motion tasks. Nevertheless it is one of the most important clinical tests. In contrast, the language system is much more complex. In several studies it has been observed that word production tasks are preferable in determination of language lateralisation. Broca's area is activated by most tasks, whereas sentence processing and semantic decision also involve activation in temporoparietal and frontal areas. However, combined task analysis (CTA) of several different tasks has been found to be more robust and reliable for clinical fMRI compared to separate task analysis.

Health-related quality of life in youth: a comparison between adolescents and young adults with uncomplicated epilepsy and healthy controls.

PURPOSE: To describe health-related quality of life (HRQOL) in adolescents and young adults with uncomplicated epilepsy and to compare it with a random sample of the general population. METHODS: Young people, aged 13-22 years, meeting the criteria and registered in four Swedish hospitals answered questionnaires (n = 158/193) on HRQOL together with 282 (n = 282/390) random controls living in the same areas in Sweden. The instruments used were "I think I am," "Youth Self Report," "Sense of coherence," and "Family APGAR." Data were analyzed by using factorial analysis of variance. RESULTS: Girls had a poorer HRQOL than boys. The epilepsy group reported lower competence (i.e., they were less active, had lower social competence and poorer school achievement). Both groups had an overall positive self-esteem. Differences between girls in the epilepsy and control groups were small, whereas differences among boys were more evident. Older age was related to poorer HRQOL in both groups. CONCLUSIONS: This study points out the importance of being observant of signs of stigmatization in adolescents with epilepsy.

Topiramate kinetics during delivery, lactation, and in the neonate: preliminary observations.

PURPOSE: To study the pharmacokinetics of topiramate (TPM) during delivery, lactation, and in the neonate. METHODS: TPM concentrations in plasma and breast milk were measured with fluorescence polarization immunoassay (FPIA) in five women with epilepsy treated with TPM during pregnancy and lactation. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from the newborns on three occasions (24, 48, and 72 h) after delivery. Blood and breast milk also were collected from mothers 2 weeks, and 1 and 3 months postpartum. Blood samples also were drawn from the infants during breast-feeding. Three of the mother-infant pairs were studied both at delivery and during lactation; two contributed with data from delivery only. RESULTS: The umbilical cord plasma/maternal plasma ratios were close to unity, suggesting extensive transplacental transfer of TPM. The mean milk/maternal plasma concentration ratio was 0.86 (range, 0.67-1.1) at 2-3 weeks after delivery. The milk/maternal plasma concentration ratios at sampling 1 and 3 months after delivery were similar (0.86 and 0.69, respectively). Two to 3 weeks after delivery, two of the breast-fed infants had detectable (>0.9 microM) concentrations of TPM, although below the limit of quantification (2.8 microM), and one had an undetectable concentration. CONCLUSIONS: Our limited data suggest free passage of TPM over the placenta and an extensive transfer into breast milk. Breast-fed infants had very low TPM concentrations, and no adverse effects were observed in the infants.

Distribution of multiple sclerosis in Sweden based on mortality and disability compensation statistics.

Previous studies have shown the Fennoscandian region to be a high-risk area for multiple sclerosis (MS). In order to investigate the distribution of MS in Sweden, mortality (1952-1992) and disability pensioning statistics (1971-1994) were studied. A total of 11,414 cases with a disability pension and 5,421 cases with MS on their death certificate were analysed according to county and time period and the results were compared with the mortality figures for amyotrophic lateral sclerosis (ALS) and disability pensioning statistics for Parkinson's disease. We found increasing rates of both MS mortality and disability pensioning. Disability pensioning correlated well with mortality 10 years later (r = 0.42, p = 0.04). We also found a marked geographical variation. Värmland county had the highest mortality, with 14 out of its 16 municipalities having higher rates than the national mean. Unexpectedly, we found a high correlation between mortality due to MS and ALS (r = 0.60, p = 0.002).