Brain energy consumption induced by electrical stimulation increases systemic glucose tolerance i... more Brain energy consumption induced by electrical stimulation increases systemic glucose tolerance in normal weight men. In obesity, fundamental reductions in brain energy levels, gray matter density, and cortical metabolism, as well as chronically impaired glucose tolerance suggest that disturbed neuroenergetic regulation may be involved in the development of overweight and obesity. Here, we induced neuronal excitation by anodal direct current stimulation (tDCS) versus sham, examined cerebral energy consumption with ³¹phosphorus magnetic resonance spectroscopy, and determined systemic glucose uptake by euglycemic-hyperinsulinemic glucose clamp in 15 normal weight and 15 obese participants. We demonstrate blunted brain energy consumption and impaired systemic glucose uptake in obese compared with normal weight volunteers, indicating neuroenergetic dysregulation in obese humans. Broadening our understanding of reduced multifocal gray matter volumes in obesity, our findings show that red...
To determine clinical features and to identify changes in brain structure and function in compoun... more To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers.
Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapy... more Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age-and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndromerelated morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.
Background: Mutations in the PINK1 gene can cause Parkinson's disease and are frequently associat... more Background: Mutations in the PINK1 gene can cause Parkinson's disease and are frequently associated with psychiatric symptoms that might even precede motor signs.
Abnormal repeat length has been associated with an earlier age of onset and more severe disease p... more Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17).
Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequi... more Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear. To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W). Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating. University of Lübeck. Twenty family members. The PINK1 genotype and PD status of all family members. The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers. Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.
Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report ... more Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreich's ataxia database registry. Within the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreich's ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and…
Degenerative Neurological and Neuromuscular Disease, 2015
This review focuses on clinical diagnosis and both pharmacological and nonpharmacological therape... more This review focuses on clinical diagnosis and both pharmacological and nonpharmacological therapeutic options in early stages of the autosomal dominant inherited neurodegenerative Huntington's disease (HD). The available literature has been reviewed for motor, cognitive, and psychiatric alterations, which are the three major symptom domains of this devastating progressive disease. From a clinical point of view, one has to be aware that the HD phenotype can vary highly across individuals and during the course of the disease. Also, symptoms in juvenile HD can differ substantially from those with adult-onset of HD. Although there is no cure of HD and management is limited, motor and psychiatric symptoms often respond to pharmacotherapy, and nonpharmacological approaches as well as supportive care are essential. International treatment recommendations based on study results, critical statements, and expert opinions have been included. This review is restricted to symptomatic and supportive approaches since all attempts to establish a cure for the disease or modifying therapies have failed so far.
The current dominant view of the visual system is marked by the functional and anatomical dissoci... more The current dominant view of the visual system is marked by the functional and anatomical dissociation between a ventral stream specialised for perception and a dorsal stream specialised for action. The "double-dissociation" between visual agnosia (VA), a deficit of visual recognition, and optic ataxia (OA), a deficit of visuo-manual guidance, considered as consecutive to ventral and dorsal damage, respectively, has provided the main argument for this dichotomic view. In the first part of this paper, we show that the currently available empirical data do not suffice to support a double-dissociation between OA and VA. In the second part, we review evidence coming from human neuropsychology and monkey data, which cast further doubts on the validity of a simple double-dissociation between perception and action because they argue for a far more complex organisation with multiple parallel visual-to-motor connections: 1. A dorso-dorsal pathway (involving the most dorsal part of the parietal and pre-motor cortices): for immediate visuo-motor control-with OA as typical disturbance. The latest research about OA is reviewed, showing how these patients exhibit deficits restricted to the most direct and fast visuo-motor transformations. We also propose that mild mirror ataxia, consisting of misreaching errors when the controlesional hand is guided to a visual goal though a mirror, could correspond to OA with an isolated "hand effect". 2. A ventral stream-prefrontal pathway (connections from the ventral visual stream to pre-frontal areas, by-passing the parietal areas): for "mediate" control (involving spatial or temporal transpositions . Mediate responses as direct evidence for intention: Neuropsychology of Not to-, Not now-and Not there-tasks. In S. Johnson (Ed.), Cognitive Neuroscience perspectives on the problem of intentional action (pp. 67-105). MIT Press.])-with VA as typical disturbance. Preserved visuo-manual guidance in patients with VA is restricted to immediate goal-directed guidance, they exhibit deficits for delayed or pantomimed actions. 3. A ventro-dorsal pathway (involving the more ventral part of the parietal lobe and the pre-motor and pre-frontal areas): for complex planning and programming relying on high representational levels with a more bilateral organisation or an hemispheric lateralisation-with mirror apraxia, limb apraxia and spatial neglect as representatives. Mirror apraxia is a deficit that affects both hands after unilateral inferior parietal lesion with the patients reaching systematically and repeatedly toward the virtual image in the mirror. Limb apraxia is localized on a more advanced conceptual level of object-related actions and results from deficient integrative, computational and "working memory" capacities of the left inferior parietal lobule. A component of spatial working memory has recently been revealed also in spatial neglect consecutive to lesion involving the network of the right inferior parietal lobule and the right frontal areas. We conclude by pointing to the differential temporal constraints and integrative capabilities of these parallel visuo-motor pathways as keys to interpret the neuropsychological deficits.
Background: Force of contraction (FOC) frequency-dependently increases in multicellular muscle st... more Background: Force of contraction (FOC) frequency-dependently increases in multicellular muscle strip preparations of human nonfailing myocardium, whereas FOC declines in human failing myocardium with increasing stimulation frequency. We investigated whether these characteristics can be observed in single isolated myocytes. Methods and Results: Isolated multicellular muscle strip preparations and single isolated cardiomyocytes of failing (heart transplants, dilative cardiomyopathy; n ϭ 11) and nonfailing (donor hearts; n ϭ 11) human hearts were studied. The changes in contraction amplitude (cell shortening in micrometers) at increasing frequency of stimulation (0.5-2 Hz) were continuously recorded with a 1-dimensional high-speed camera that detected the cell edges and measured their distance during contraction. The increase in stimulation frequency was associated with a significant decrease in FOC (2 v 0.5 Hz; 68% basal) and a decrease in cell shortening of human left ventricular cardiomyocytes from failing hearts (2 v 0.5 Hz; 65% basal). In contrast, in human nonfailing myocardium, contraction increased at increasing stimulation frequencies (2 v 0.5 Hz; FOC, 180% basal; cell shortening, 129% basal). Conclusions: The negative force-frequency relationship measured in multicellular preparations of failing human myocardium results from alterations at the single cell level.
The effect of stereotactic thalamotomy was assessed with preand postoperative functional magnetic... more The effect of stereotactic thalamotomy was assessed with preand postoperative functional magnetic resonance imaging (fMRI) under motor stimulation. A patient with unilateral essential tremor (ET) of the left arm underwent stereotactically guided thalamotomy of the right ventral intermediate thalamic nucleus (VIM). FMRI was done directly before and after surgery on a 1.5-Tesla scanner. The stimulation paradigm was maintainance of the affected arm in an extended position and hand clenching being performed in a block design manner. Statistical analysis was done with Brain Voyager 2000. After thalamotomy the tremor diminished completely. As a difference between the pre-and postoperative fMRI, a significant activation was found in the VIM contralateral to the activation site, adjacent to the inferior olivary nucleus contralateral to the activation site and in the dorsal cingulum. In conclusion, fMRI can detect the functional effect of thalamotomy for tremor treatment. Direct postoperative fMRI provides a sufficient method for estimating the effect of thalamotomy immediately after intervention. The importance of the intermediate thalamic nucleus and the olivary nucleus in tremor generation is supported by our findings.
To the best of our knowledge, this is the first case of these aberrant reversible SSEP abnormalit... more To the best of our knowledge, this is the first case of these aberrant reversible SSEP abnormalities in a case of Hashimoto encephalopathy.
Brain energy consumption induced by electrical stimulation increases systemic glucose tolerance i... more Brain energy consumption induced by electrical stimulation increases systemic glucose tolerance in normal weight men. In obesity, fundamental reductions in brain energy levels, gray matter density, and cortical metabolism, as well as chronically impaired glucose tolerance suggest that disturbed neuroenergetic regulation may be involved in the development of overweight and obesity. Here, we induced neuronal excitation by anodal direct current stimulation (tDCS) versus sham, examined cerebral energy consumption with ³¹phosphorus magnetic resonance spectroscopy, and determined systemic glucose uptake by euglycemic-hyperinsulinemic glucose clamp in 15 normal weight and 15 obese participants. We demonstrate blunted brain energy consumption and impaired systemic glucose uptake in obese compared with normal weight volunteers, indicating neuroenergetic dysregulation in obese humans. Broadening our understanding of reduced multifocal gray matter volumes in obesity, our findings show that red...
To determine clinical features and to identify changes in brain structure and function in compoun... more To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers.
Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapy... more Spinocerebellar ataxia 17 (SCA17) is a rare genetic disorder characterized by cerebellar, extrapyramidal, pyramidal as well as psychiatric signs. The pathoanatomical basis of this disorder is still not well known. A total of 12 patients and 12 age-and sex-matched controls were examined by in vivo MRI voxel-based morphometry (VBM). Besides general patterns of disease-related brain atrophy, characteristic syndromerelated morphological changes in SCA17 patients were studied. In comparison with normal controls, SCA17 patients showed a pattern of degeneration of the grey matter centred around mesial cerebellar structures, occipito-parietal structures, the anterior putamen bilaterally, the thalamus and other parts of the motor network, reflecting the cerebellar, pyramidal and extrapyramidal signs. A correlation analysis revealed a clear association between the clinical cerebellar, extrapyramidal and psychiatric scores and degeneration in specific areas. Two degeneration patterns were found as follows: regarding motor dysfunction, atrophy of the grey matter involved mainly the cerebellum and other motor networks, in particular the basal ganglia. In contrast, correlations with psychiatric scores revealed grey matter degeneration patterns in the frontal and temporal lobe, the cuneus and cingulum. Most interestingly, there was a highly significant correlation between the clinical Mini-Mental State Examination scores and atrophy of the nucleus accumbens, probably accounting for the leading psychiatric signs.
Background: Mutations in the PINK1 gene can cause Parkinson's disease and are frequently associat... more Background: Mutations in the PINK1 gene can cause Parkinson's disease and are frequently associated with psychiatric symptoms that might even precede motor signs.
Abnormal repeat length has been associated with an earlier age of onset and more severe disease p... more Abnormal repeat length has been associated with an earlier age of onset and more severe disease progression in the rare neurodegenerative disorder spinocerebellar ataxia 17 (SCA17).
Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequi... more Although homozygous mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been unequivocally associated with early-onset Parkinson disease (PD), the role of single heterozygous PINK1 mutations is less clear. To investigate the role of homozygous and heterozygous PINK1 mutations in a large German pedigree (family W). Mutation analysis of PINK1 and results of standardized neurological and motor examination by 3 independent movement disorder specialists, including blinded video rating. University of Lübeck. Twenty family members. The PINK1 genotype and PD status of all family members. The index patient of family W carried a homozygous nonsense mutation (c.1366C>T; p.Q456X) and presented with a phenotype closely resembling idiopathic PD but with an onset at 39 years of age. The family included a total of 4 affected homozygous members (age, 60-71 years; age at onset, 39-61 years), 6 members with slight or mild signs of PD (affected) and a heterozygous mutation (age, 31-49 years), and 5 unaffected heterozygous mutation carriers (age, 34-44 years). Although none of the heterozygous affected family members was aware of their signs (asymptomatic), the clinical findings were unequivocal and predominantly or exclusively present on their dominant right-hand side, eg, unilaterally reduced or absent arm swing and unilateral rigidity. The heterozygous members were all considerably younger than the affected homozygous mutation carriers. Heterozygous PINK1 mutations may predispose to PD, as was previously suggested by the presence of dopamine hypometabolism in asymptomatic mutation carriers. Long-term follow-up of our large family W provides an excellent opportunity to further evaluate the role of single heterozygous PINK1 mutations later in life, which will have major implications on genetic counseling.
Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report ... more Friedreich's ataxia is a rare autosomal recessive neurodegenerative disorder. Here we report cross-sectional baseline data to establish the biological and clinical characteristics for a prospective, international, European Friedreich's ataxia database registry. Within the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) framework, we assessed a cohort of patients with genetically confirmed Friedreich's ataxia. The primary outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) and…
Degenerative Neurological and Neuromuscular Disease, 2015
This review focuses on clinical diagnosis and both pharmacological and nonpharmacological therape... more This review focuses on clinical diagnosis and both pharmacological and nonpharmacological therapeutic options in early stages of the autosomal dominant inherited neurodegenerative Huntington's disease (HD). The available literature has been reviewed for motor, cognitive, and psychiatric alterations, which are the three major symptom domains of this devastating progressive disease. From a clinical point of view, one has to be aware that the HD phenotype can vary highly across individuals and during the course of the disease. Also, symptoms in juvenile HD can differ substantially from those with adult-onset of HD. Although there is no cure of HD and management is limited, motor and psychiatric symptoms often respond to pharmacotherapy, and nonpharmacological approaches as well as supportive care are essential. International treatment recommendations based on study results, critical statements, and expert opinions have been included. This review is restricted to symptomatic and supportive approaches since all attempts to establish a cure for the disease or modifying therapies have failed so far.
The current dominant view of the visual system is marked by the functional and anatomical dissoci... more The current dominant view of the visual system is marked by the functional and anatomical dissociation between a ventral stream specialised for perception and a dorsal stream specialised for action. The "double-dissociation" between visual agnosia (VA), a deficit of visual recognition, and optic ataxia (OA), a deficit of visuo-manual guidance, considered as consecutive to ventral and dorsal damage, respectively, has provided the main argument for this dichotomic view. In the first part of this paper, we show that the currently available empirical data do not suffice to support a double-dissociation between OA and VA. In the second part, we review evidence coming from human neuropsychology and monkey data, which cast further doubts on the validity of a simple double-dissociation between perception and action because they argue for a far more complex organisation with multiple parallel visual-to-motor connections: 1. A dorso-dorsal pathway (involving the most dorsal part of the parietal and pre-motor cortices): for immediate visuo-motor control-with OA as typical disturbance. The latest research about OA is reviewed, showing how these patients exhibit deficits restricted to the most direct and fast visuo-motor transformations. We also propose that mild mirror ataxia, consisting of misreaching errors when the controlesional hand is guided to a visual goal though a mirror, could correspond to OA with an isolated "hand effect". 2. A ventral stream-prefrontal pathway (connections from the ventral visual stream to pre-frontal areas, by-passing the parietal areas): for "mediate" control (involving spatial or temporal transpositions . Mediate responses as direct evidence for intention: Neuropsychology of Not to-, Not now-and Not there-tasks. In S. Johnson (Ed.), Cognitive Neuroscience perspectives on the problem of intentional action (pp. 67-105). MIT Press.])-with VA as typical disturbance. Preserved visuo-manual guidance in patients with VA is restricted to immediate goal-directed guidance, they exhibit deficits for delayed or pantomimed actions. 3. A ventro-dorsal pathway (involving the more ventral part of the parietal lobe and the pre-motor and pre-frontal areas): for complex planning and programming relying on high representational levels with a more bilateral organisation or an hemispheric lateralisation-with mirror apraxia, limb apraxia and spatial neglect as representatives. Mirror apraxia is a deficit that affects both hands after unilateral inferior parietal lesion with the patients reaching systematically and repeatedly toward the virtual image in the mirror. Limb apraxia is localized on a more advanced conceptual level of object-related actions and results from deficient integrative, computational and "working memory" capacities of the left inferior parietal lobule. A component of spatial working memory has recently been revealed also in spatial neglect consecutive to lesion involving the network of the right inferior parietal lobule and the right frontal areas. We conclude by pointing to the differential temporal constraints and integrative capabilities of these parallel visuo-motor pathways as keys to interpret the neuropsychological deficits.
Background: Force of contraction (FOC) frequency-dependently increases in multicellular muscle st... more Background: Force of contraction (FOC) frequency-dependently increases in multicellular muscle strip preparations of human nonfailing myocardium, whereas FOC declines in human failing myocardium with increasing stimulation frequency. We investigated whether these characteristics can be observed in single isolated myocytes. Methods and Results: Isolated multicellular muscle strip preparations and single isolated cardiomyocytes of failing (heart transplants, dilative cardiomyopathy; n ϭ 11) and nonfailing (donor hearts; n ϭ 11) human hearts were studied. The changes in contraction amplitude (cell shortening in micrometers) at increasing frequency of stimulation (0.5-2 Hz) were continuously recorded with a 1-dimensional high-speed camera that detected the cell edges and measured their distance during contraction. The increase in stimulation frequency was associated with a significant decrease in FOC (2 v 0.5 Hz; 68% basal) and a decrease in cell shortening of human left ventricular cardiomyocytes from failing hearts (2 v 0.5 Hz; 65% basal). In contrast, in human nonfailing myocardium, contraction increased at increasing stimulation frequencies (2 v 0.5 Hz; FOC, 180% basal; cell shortening, 129% basal). Conclusions: The negative force-frequency relationship measured in multicellular preparations of failing human myocardium results from alterations at the single cell level.
The effect of stereotactic thalamotomy was assessed with preand postoperative functional magnetic... more The effect of stereotactic thalamotomy was assessed with preand postoperative functional magnetic resonance imaging (fMRI) under motor stimulation. A patient with unilateral essential tremor (ET) of the left arm underwent stereotactically guided thalamotomy of the right ventral intermediate thalamic nucleus (VIM). FMRI was done directly before and after surgery on a 1.5-Tesla scanner. The stimulation paradigm was maintainance of the affected arm in an extended position and hand clenching being performed in a block design manner. Statistical analysis was done with Brain Voyager 2000. After thalamotomy the tremor diminished completely. As a difference between the pre-and postoperative fMRI, a significant activation was found in the VIM contralateral to the activation site, adjacent to the inferior olivary nucleus contralateral to the activation site and in the dorsal cingulum. In conclusion, fMRI can detect the functional effect of thalamotomy for tremor treatment. Direct postoperative fMRI provides a sufficient method for estimating the effect of thalamotomy immediately after intervention. The importance of the intermediate thalamic nucleus and the olivary nucleus in tremor generation is supported by our findings.
To the best of our knowledge, this is the first case of these aberrant reversible SSEP abnormalit... more To the best of our knowledge, this is the first case of these aberrant reversible SSEP abnormalities in a case of Hashimoto encephalopathy.
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