Occipital Nerve Stimulation in Chronic Migraine: The Relationship Between Perceived Sensory Quality, Perceived Sensory Location, and Clinical Efficacy-A Prospective, Observational, Non-Interventional Study.

INTRODUCTION: Occipital nerve stimulation (ONS) is used to treat therapy-resistant chronic migraine. Clinical use has resulted in a wide intraindividual and interindividual variation of clinical efficacy. The aim of this study was to analyze a potential relationship between sociodemographic variables, headache parameters, perceived sensory quality, perceived sensory location, as well as clinical efficacy. METHODS: Thirty-two subjects (21.9% male, mean age 45.77 years) suffering from chronic migraine refractory to other treatment and therefore treated with ONS were included in this study. We used a computer-based imaging method for mapping the ONS-induced perceived sensory location, the perceived spatial sensory field size, as well as the perceived sensory quality in a long-term course over 21 months in weekly time intervals. Additionally, the effect of ONS on the migraine headache was documented weekly by the participants using a verbal rating scale. Over the observation period, a total of 808 individual weekly data sets were recorded and a potential relationship between ONS-induced perceptions and headache parameters could be analyzed. RESULTS: We found that 48.9% of stimulation intervals were reported as effective by patients. Women displayed a significantly higher responder rate than men. The reported effectiveness did not differ depending on age, the average number of migraine days per month, the MIDAS score, or the duration of the migraine disorder prior to ONS treatment. Implantation with trial period led to significantly lower responder rates than without the trial period. The most frequently perceived sensory quality of "tingling" was found significantly more frequently in non-responders than in responders. Responders displayed significantly lower pleasantness scores for their reported perceptions than non-responders. Sensations that were spatially perceived above the line connecting the external acoustic meati with the external occipital protuberance (MOP line) led to patients reporting a positive clinical effect significantly more frequently than sensations spatially perceived below the MOP line. Spatially small fields of sensory perception were correlated with a higher responder rate than those covering broader areas. CONCLUSIONS: The ONS-induced sensory location, the size of the spatial sensory field, as well as the sensory quality are significantly correlated with the reported clinical effectiveness. The results suggest that besides surgical technique, the individual and continuous programming of the stimulation parameters is clinically relevant in increasing the therapeutic effectiveness.

The Influence of Thyroid Hormones on Brain Structure and Function in Humans.

The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action.

Single Nucleotide Polymorphisms in Thyroid Hormone Transporter Genes MCT8, MCT10 and Deiodinase DIO2 Contribute to Inter-Individual Variance of Executive Functions and Personality Traits.

Thyroid hormones are modulators of cognitive functions, and changes in hormone levels affect intelligence, memory, attention and executive function. Single nucleotide polymorphisms (SNPs) of transporter proteins MCT8, MCT10 and deiodinase 2 (DIO2) influence thyroid metabolism and could therefore contribute to inter-individual variance of cognitive functions. This study investigates the influence of these SNPs using an extensive neuropsychological test battery. 656 healthy participants aged 18-39 years were genotyped for four SNPs: MCT8 (rs5937843 and rs6647476), MCT10 (rs14399) and DIO2 (rs225014) and underwent eleven different neuropsychological tests as well as four personality questionnaires. Test results were compared between homo- and heterozygous carriers and for the X-linked MCT8 additionally between men and women. Personality questionnaires revealed that Risk Seeking was reduced in homozygous T carriers and highest in homozygous C carriers of the DIO2 SNP and that both polymorphisms of MCT8 had an additive effect on Physical Aggression in men. Neuropsychological testing indicated that MCT10 affects nonverbal reasoning abilities, DIO2 influences working memory and verbal fluency and MCT8 influences attention, alertness and planning. This pilot study suggests an influence of polymorphisms in thyroid hormone transporter genes and deiodinase on cognitive domains and personality traits.

Partial withdrawal of levothyroxine treated disease leads to brain activations and effects on performance in a working memory task: A pilot study.

Hypothyroidism is associated with memory impairments. The present study aimed to evaluate the effects of partial withdrawal of levothyroxine on working memory tasks and brain function. Fifteen subjects under long-term levothyroxine substitution as a result of complete hypothyroidism participated in the present study. Functional magnetic resonance imaging (MRI) was performed using a working memory task (n-back task) and neuropsychological tests were performed before and 52-54 days after the induction of subclinical hypothyroidism by reducing the pretest levothyroxine dosage by 30%. Reaction time of subjects under partial levothyroxine withdrawal was significantly longer and less accurate with respect to solving the working memory tasks. Functional MRI revealed significant activation changes after medication withdrawal in the cerebellum, insula, parietal, frontal, temporal and occipital lobes, lingual gyrus, and the cuneus. Partial withdrawal of levothyroxine may lead to deficits in a working memory task and to an activation of brain areas associated with working memory ability.

Experimentally induced subclinical hypothyroidism causes decreased functional connectivity of the cuneus: A resting state fMRI study.

OBJECTIVE: The aim of this study was to experimentally evaluate the effects of subclinical mild hypothyroidism on brain network connectivity as determined by resting state fMRI (rsfMRI) which serves as a proxy for global changes in brain function. METHODS: Fifteen otherwise healthy patients with complete hypothyroidism under stable, long term levothyroxine substitution volunteered for the study. They reduced their pretest levothyroxine dosage by 30% for 52-56 days. Basally and after partial levothyroxine withdrawal, rsfMRI along with a neuropsychological analysis was performed. RsfMRI was subjected to graph-theory-based analysis to investigate whole-brain intrinsic functional connectivity. RESULTS: The desired subclinical hypothyroidism was achieved in all subjects. This was associated with a significant decrease in resting-state functional connectivity specifically in the cuneus (0.05 FWE corrected at cluster level) which was mainly caused by a weaker functional connectivity to the cerebellum and regions of the default mode network, i.e. the medial prefrontal cortex, the precuneus and the bilateral angular gyri. The decrease in cuneus connectivity was correlated to the increase in TSH serum levels. A working memory task showed a slightly longer reaction time and less accuracy after partial levothyroxine withdrawal. CONCLUSION: Even short-term partial levothyroxine partial withdrawal leads to deficits in working memory tasks and to a weaker integration of the cuneus within the default mode network.

Effect of Mild Thyrotoxicosis on Performance and Brain Activations in a Working Memory Task.

AIMS: Disturbed levels of thyroid hormones are associated with neuropsychiatric disorders, including memory impairments. The aim of this study was to evaluate effects of mild induced thyrotoxicosis on working memory and its neural correlates. METHODS: Twenty-nine healthy, male subjects with normal thyroid state participated in the study. Functional MRI was acquired during a working memory task (n-back task) before and after ingesting 250 µg L-thyroxin per day for a period of eight weeks. In addition, neuropsychological tests were performed. RESULTS: In the hyperthyroid condition the subjects showed slower reaction times, but a higher accuracy in the 0-back version of the memory tasks. Fewer differences between euthyroid and hyperthyroid state were seen for the more difficult conditions of the n-back task. FMRI revealed effects of difficulty in the parahippocampal gyrus, supplementary motor area, prefrontal cortex, anterior cingulate cortex, posterior cerebellum, rolandic operculum and insula (p<0.05, FWE corrected). When comparing euthyroid and hyperthyroid condition in relation to task-induced activation, differences of activation were found in the right prefrontal cortex as well as in the right parahippocampal area. In the psychological assessment, the alerting effect in the Attention Network Task (ANT) and four out of five parameters of the auditory verbal learning test (AVLT) showed an increase from euthyroid to hyperthyroid state. CONCLUSIONS: It can be concluded that even a short-term intake of thyroid hormones leads to an activation of brain areas associated with working memory and to an improvement of accuracy of working memory tasks.

Effect of Experimental Thyrotoxicosis on Brain Gray Matter: A Voxel-Based Morphometry Study.

BACKGROUND: Hyper-as well hypothyroidism have an effect on behavior and brain function. Moreover, during development thyroid hormones influence brain structure. OBJECTIVES: This study aimed to demonstrate an effect of experimentally induced hyperthyroidism on brain gray matter in healthy adult humans. METHODS: High-resolution 3D T1-weighted images were acquired in 29 healthy young subjects prior to as well as after receiving 250 µg of T4 per day for 8 weeks. Voxel-based morphometry analysis was performed using Statistical Parametric Mapping 8 (SPM8). RESULTS: Laboratory testing confirmed the induction of hyperthyroidism. In the hyperthyroid condition, gray matter volumes were increased in the right posterior cerebellum (lobule VI) and decreased in the bilateral visual cortex and anterior cerebellum (lobules I-IV) compared to the euthyroid condition. CONCLUSIONS: Our study provides evidence that short periods of hyperthyroidism induce distinct alterations in brain structures of cerebellar regions that have been associated with sensorimotor functions as well as working memory in the literature.

Experimentally induced thyrotoxicosis leads to increased connectivity in temporal lobe structures: a resting state fMRI study.

Adult onset hyperthyroidism may impact on different cognitive domains, including attention and concentration, memory, perceptual function, language and executive function. Previous PET studies implicated changed functionality of limbic regions, the temporal and frontal lobes in hyperthyroidism, whereas it is unknown whether cognitive effects of hyperthyroidism may be due to changed brain connectivity. This study aimed to investigate the effect of experimentally induced short-term hyperthyroidism thyrotoxicosis on resting-state functional connectivity using functional magnetic resonance imaging. Twenty-nine healthy male right-handed subjects were examined twice, once prior and once after 8 weeks of oral administration of 250 µg levothyroxine per day. Resting-state fMRI was subjected to graph-theory based analysis methods to investigate whole-brain intrinsic functional connectivity. Despite a lack of subjective changes noticed by the subjects significant thyrotoxicosis was confirmed in all subjects. This induced a significant increase in resting-state functional connectivity specifically in the rostral temporal lobes (0.05 FDR corrected at the cluster level), which is caused by an increased connectivity to the cognitive control network. The increased connectivity between temporal poles and the cognitive control network shown here under experimental conditions supports an important function of thyroid hormones in the regulation of paralimbic structures.

Imaging sensory effects of occipital nerve stimulation: a new computer-based method in neuromodulation.

BACKGROUND: Within the last years, occipital nerve stimulation (ONS) has proven to be an important method in the treatment of severe therapy-resistant neurological pain disorders. The correspondence between lead placement as well as possible stimulation parameters and the resulting stimulation effects remains unclear. OBJECTIVE: The method aims to directly relate the neuromodulatory mechanisms with the clinical treatment results, to achieve insight in the mode of action of neuromodulation, to identify the most effective stimulation sets and to optimize individual treatment effects. METHODS: We describe a new computer-based imaging method for mapping the spatial, cognitive and affective sensory effects of ONS. The procedure allows a quantitative and qualitative analysis of the relationship between lead positioning, the stimulation settings as well as the sensory and clinical stimulation effects. CONCLUSION: A regular mapping of stimulation and sensory parameters allows a coordinated monitoring. The stimulation results can be reviewed and compared with regards to clinical effectiveness.

Phenotype of migraine headache and migraine aura of Richard Wagner.

BACKGROUND: The headache phenotype and neurological symptoms of the German composer Richard Wagner (1813-1883), whose music dramas count towards the most frequently performed operas across the world, are previously undocumented. METHODS: Richard Wagner's own descriptions of his headache symptoms in his original writings and letters are investigated, as well as the complete diary records of his second wife, Cosima Wagner. RESULTS: There are manifold indications that Richard Wagner suffered from a severe headache disorder, which fulfils most likely the diagnostic criteria of migraine without aura and migraine with aura of ICHD-3 beta. CONCLUSIONS: Richard Wagner's life and opus can help to better understand the burden and suffering caused by migraine with its severe effects on the individual, familial and social life, the culture and community.

Question-writing as a learning tool for students--outcomes from curricular exams.

BACKGROUND: Writing exam questions can be a valuable learning tool. We asked students to construct multiple choice questions for curricular exams in Internal Medicine. The questions for the particular exams were chosen from a pool of at least 300 student-written questions. The uncorrected pool was accessible to all students. We studied the influence of this approach on the students' learning habits and their test results. We hypothesized that creating a pool of their own questions for the exams could encourage students to discuss the learning material. METHODS: All students had to pass 4 exams in 7 fields of Internal Medicine. Three exams were comprised of 20 questions, and we applied the new method in one of these exams. The fourth exam was comprised of 30 questions, 15 of which were chosen from a students' pool. After all exams had been completed we asked the students to fill in a web-based questionnaire on their learning habits and their views on the new approach. The test-results were compared to the results of the lecturers' questions that defined high and low performing students. RESULTS: A total of 102 students completed all four exams in a row, 68 of whom filled in the questionnaire. Low performing students achieved significantly better results in the students' questions. There was no difference in the number of constructed questions between both groups of students. The new method did not promote group work significantly. However, high performing students stated a stronger wish to be rewarded by good performance. CONCLUSIONS: Creating a curricular exam by choosing questions from a pool constructed by students did not influence the learning habits significantly and favored low performing students. Since the high performing students sought to be rewarded for their efforts, we do not consider the approach applied in our study to be appropriate.