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Selected abstracts of my recent neuroscience related publications listet in PubMed:
A voxel-based diffusion tensor imaging study in unipolar and bipolar depression
The absence of neurobiological diagnostic markers of bipolar disorder (BD) leads to its frequent misdiagnosis as unipolar depression (UD). We investigated if changes in fractional anisotropy (FA) could help to differentiate BD from UD in the state of depression.
Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration
To report on a novel neuronal target antigen in 3 patients with autoimmune cerebellar degeneration.
Early silent microstructural degeneration and atrophy of the thalamocortical network in multiple sclerosis
Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing-remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesions-as frequently claimed-or is the atrophy stronger correlated to "silent" (nonlesional) microstructural thalamic alterations? One-hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3 T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic volume (RTV) and thalamic FA were significantly reduced in patients with CIS and RRMS relative to healthy controls. Both measures were also correlated. The age, gender, WM lesion load, thalamic FA, and gray matter volume-corrected RTV were reduced even in the absence of thalamic and extensive white matter lesions-also in patients with short disease duration (≤24 months). A voxel-based correlation analysis revealed that the RTV reduction had a significant effect on local WM FA-in areas next to the thalamus and basal ganglia. These WM alterations could not be explained by WM lesions, which had a differing spatial distribution. Early thalamic atrophy is mainly driven by silent microstructural thalamic alterations. Lesions do not disclose the early damage of thalamocortical circuits, which seem to be much more affected in CIS and RRMS than expected. Thalamocortical damage can be detected by DTI in normal appearing brain tissue. Hum Brain Mapp 37:1866-1879, 2016. © 2016 Wiley Periodicals, Inc.
Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration
Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction.
Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study
Deterioration of fine motor control of the tongue is common in Multiple Sclerosis (MS) and has a major impact on quality of life. However, the underlying neuronal substrate is largely unknown. Here, we aimed to explore the association of tongue motor dysfunction in MS patients with overall clinical disability and structural brain damage.
Recovery of thalamic microstructural damage after Shiga toxin 2-associated hemolytic-uremic syndrome
The underlying pathophysiology of neurological complications in patients with hemolytic-uremic syndrome (HUS) remains unclear. It was recently attributed to a direct cytotoxic effect of Shiga toxin 2 (Stx2) in the thalamus. Conventional MRI of patients with Stx2-caused HUS revealed - despite severe neurological symptoms - only mild alterations if any, mostly in the thalamus. Against this background, we questioned: Does diffusion tensor imaging (DTI) capture the thalamic damage better than conventional MRI? Are neurological symptoms and disease course better reflected by thalamic alterations as detected by DTI? Are other brain regions also affected?
Early and Degressive Putamen Atrophy in Multiple Sclerosis
Putamen atrophy and its long-term progress during disease course were recently shown in patients with multiple sclerosis (MS). Here we investigated retrospectively the time point of atrophy onset in patients with relapsing-remitting MS (RRMS). 68 patients with RRMS and 26 healthy controls (HC) were admitted to 3T MRI in a cross-sectional study. We quantitatively analyzed the putamen volume of individual patients in relation to disease duration by correcting for age and intracranial volume (ICV). Patient's relative putamen volume (RPV), expressed in percent of ICV, was significantly reduced compared to HC. Based on the correlation between RPV and age, we computed the age-corrected RPV deviation (ΔRPV) from HC. Patients showed significantly negative ΔRPV. Interestingly, the age-corrected ΔRPV depended logarithmically on disease duration: Directly after first symptom manifestation, patients already showed a reduced RPV followed by a further degressive volumetric decline. This means that atrophy progression was stronger in the first than in later years of disease. Putamen atrophy starts directly after initial symptom manifestation or even years before, and progresses in a degressive manner. Due to its important role in neurological functions, early detection of putamen atrophy seems necessary. High-resolution structural MRI allows monitoring of disease course.
Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor)
In light of the increased risk of progressive multifocal encephalopathy (PML) development under long-term treatment with the monoclonal antibody natalizumab which is approved for treatment of active relapsing remitting multiple sclerosis (RRMS), there is a clear need for alternative treatment options with comparable efficacy and reduced PML risk. One such option is fingolimod, a functional sphingosin-1-receptor antagonist that has been approved as first oral drug for treatment of active RRMS. However, the optimal switching design in terms of prevention of disease reoccurrence is still unknown. Moreover, potential additive effects of both drugs on immune functions, especially with regard to migration, have not yet been evaluated.
A human post-mortem brain model for the standardization of multi-centre MRI studies
Multi-centre MRI studies of the brain are essential for enrolling large and diverse patient cohorts, as required for the investigation of heterogeneous neurological and psychiatric diseases. However, the multi-site comparison of standard MRI data sets that are weighted with respect to tissue parameters such as the relaxation times (T1, T2) and proton density (PD) may be problematic, as signal intensities and image contrasts depend on site-specific details such as the sequences used, imaging parameters, and sensitivity profiles of the radiofrequency (RF) coils. Water or gel phantoms are frequently used for long-term and/or inter-site quality assessment. However, these phantoms hardly mimic the structure, shape, size or tissue distribution of the human brain. The goals of this study were: (1) to validate the long-term stability of a human post-mortem brain phantom, performing quantitative mapping of T1, T2, and PD, and the magnetization transfer ratio (MTR) over a period of 18months; (2) to acquire and analyse data for this phantom and the brain of a healthy control (HC) in a multi-centre study for MRI protocol standardization in four centres, while conducting a voxel-wise as well as whole brain grey (GM) and white matter (WM) tissue volume comparison. MTR, T2, and the quotient of PD in WM and GM were stable in the post-mortem brain with no significant changes. T1 was found to decrease from 267/236ms (GM/WM) to 234/216ms between 5 and 17weeks post embedment, stabilizing during an 18-month period following the first scan at about 215/190ms. The volumetric measures, based on T1-weighted MP-RAGE images obtained at all participating centres, revealed inter- and intra-centre variations in the evaluated GM and WM volumes that displayed similar trends in both the post-mortem brain as well as the HC. At a confidence level of 95%, brain regions such as the brainstem, deep GM structures as well as boundaries between GM and WM tissues were found to be less reproducible than other brain regions in all participating centres. The results demonstrate that a post-mortem brain phantom may be used as a reliable tool for multi-centre MR studies.
Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure
In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.
Volume transition analysis: a new approach to resolve reclassification of brain tissue in repeated MRI scans
Variability in brain tissue volumes derived from magnetic resonance images is attributable to various sources. In quantitative comparisons it is therefore crucial to distinguish between biologically and methodically conditioned variance and to take spatial accordance into account.
Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease
In Alzheimer's disease, the contribution of inflammation is still controversially discussed. The aim of this study was to identify a particular immune profile in the peripheral blood (PB) and cerebrospinal fluid (CSF) in patients with mild Alzheimer's disease (mAD) and mild cognitive impairment (MCI) and its potential functional relevance and association with neurodegeneration. A total of 88 patients with cognitive decline (54 mAD, 19 MCI, and 15 other dementias) were included in this study and compared with a group of younger (mean age, 31.3 years) and older (mean age, 68.9 years) healthy volunteers. Patients underwent detailed neurologic and neuropsychological examination, magnetic resonance imaging including voxel-based morphometry of gray matter, voxel-based diffusion tensor imaging, and white matter lesion volumetry, and PB and CSF analysis including multiparameter flow cytometry. Multiparameter flow cytometry revealed that proportions of activated HLA-DR positive CD4(+) and CD8(+) T-cells were slightly and significantly increased in the PB of MCI and mAD patients, respectively, when compared with healthy elderly controls but not in patients with other dementias. Although only a slight enhancement of the proportion of activated CD4(+) T-cells was observed in the CSF of both MCI and mAD patients, the proportion of activated CD8(+) T-cells was significantly increased in the CSF of mAD patients when compared with healthy elderly individuals. A slight increase in the proportion of activated CD8(+) T-cells was also observed in the intrathecal compartment of MCI patients. Activation of cytotoxic CD8(+) T-cells was considerably related to AD-typical neuropsychological deficits. Voxel-based regression analysis revealed a significant correlation between CD8(+) T-cell activation and microstructural tissue damage within parahippocampal areas as assessed by diffusion tensor imaging. Taken together, peripheral and intrathecal CD8(+) T-cell activation in mAD was significantly different from other dementias, suggesting a specific adaptive immune response. Lymphocyte activation seems to have a clinical impact because levels of activated CD8(+) T-cells were correlated with clinical and structural markers of AD pathology.
In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: relation to histopathology
A particularly popular automated magnetic resonance imaging (MRI) hippocampal subfield mapping technique is the one described by Van Leemput et al. (2009: Hippocampus 19:549-557) that is currently distributed with FreeSurfer software. This method assesses the probabilistic locations of subfields based on a priori knowledge of subfield topology determined from high-field MRI. Many studies have applied this technique to conventionally acquired T1-weighted MRI data. In the present study, we investigated the relationship between this technique applied to conventional T1-weighted MRI data acquired at 3 T and postsurgical hippocampal histology in patients with medically intractable mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Patients with mTLE (n = 82) exhibited significant volume loss of ipsilateral CA1, CA2-3, CA4-dentate gyrus (DG), subiculum, and fimbria relative to controls (n = 81). Histopathological analysis indicated that the most significant neuronal loss was observed in CA1, then CA4 and CA3, and more subtle neuronal loss in CA2, consistent with classical HS. Neuronal density of CA1 significantly correlated with MRI-determined volume of CA1, and increasingly so with CA2-3 and CA4-DG. Patients with increased HS based on histopathology had greater volume loss of the ipsilateral hippocampal regions on MRI. We conclude by suggesting that whilst time efficient and fully reproducible when applied to conventional single acquisition sequences, the use of the automated subfield technique described here may necessitate the application to multiacquisition high-resolution MR sequences for accurate delineation of hippocampal subfields.
Executive performance is related to regional gray matter volume in healthy older individuals
Individual differences in executive functioning and brain morphology are considerable. In this study, we investigated their interrelation in a large sample of healthy older individuals. Digit span, trail-making, and Stroop tasks were used to assess different executive subfunctions in 367 nondemented community-dwelling individuals (50-81 years). Task performance was analyzed relative to brain structure using voxel-based morphometry, corrected for age and sex. Improved task performance was associated with increased local gray matter volume in task-specific patterns that showed partial, but not complete overlap with known task-specific functional imaging patterns. While all three tasks showed associations with prefrontal gray matter volume as expected for executive functioning, the strongest overlap between the three tasks was found in insular cortex, suggesting that it has a previously underestimated role for executive functions. The association between the insular cortex and executive functioning was corroborated using stereological region-of-interest measurement of insular volume in a subgroup of 93 subjects. Quantitatively, the volume of the single most strongly related region explained 2.4 ± 1.1% of the variance in executive performance over and above the variance explained by age, which amounted to 7.4 ± 4.1%. The age-independent peak associations between executive performance and gray matter described here occurred in regions that were also strongly affected by age-related gray matter atrophy, consistent with the hypothesis that age-related regional brain volume loss and age-related cognitive changes are linked.
Voxel-based statistical analysis of fractional anisotropy and mean diffusivity in patients with unilateral temporal lobe epilepsy of unknown cause
To determine regional alterations of fractional anisotropy (FA) and mean diffusivity (MD) in patients with magnetic resonance imaging (MRI)-negative temporal lobe epilepsy with unknown cause (TLEu) using diffusion tensor imaging (DTI) and voxel-based statistics (VBS).
Cortical plasticity is preserved in nondemented older individuals with severe ischemic small vessel disease
Ischemic small vessel disease (SVD) is a common finding on routine scans in older people, but cognitive sequelae vary considerably. To improve understanding of mechanisms underlying decline or preservation of cognitive function in this condition, we assessed cognition and cortical plasticity in 20 elderly subjects with severe SVD and 20 age-matched controls without SVD, as rated on conventional MRI. Cognitive status was determined with a neuropsychological test battery, cortical plasticity induced with a paired associative stimulation protocol. Microstructural white matter changes were further analyzed for fractional anisotrophy using diffusion tensor imaging. We found that cortical plasticity as well as memory functions were preserved in severe SVD, while executive functions showed trendwise or significant decreases. Within the SVD group, lower white matter integrity in parahippocampal regions and posterior parts of the corpus callosum was associated with larger cortical plasticity, an association not seen for prefrontal white matter tracts. Enhanced cortical plasticity in subjects with lower white matter integrity in memory-relevant areas might thus indicate a compensatory mechanism to counteract memory decline in severe SVD.
Grasping multiple sclerosis: do quantitative motor assessments provide a link between structure and function?
Motor disability in MS is commonly assessed by the Expanded Disability Status Scale (EDSS). Categorical rating scales are limited by subjective error and inter-rater variability. Therefore, objective and quantitative measures of motor disability may be useful to supplement the EDSS in the setting of clinical trials. It was previously shown that grip-force-variability (GFV) is increased in MS. We hypothesized that GFV may be an objective measure of motor disability in MS. To investigate whether the increase in GFV in MS is correlated to the clinical disability as assessed by the EDSS and to microstructural changes in the brain as assessed by diffusion tensor imaging, GFV was recorded in a grasping and lifting task in 27 MS patients and 23 controls using a grip-device equipped with a force transducer. The EDSS was assessed by neurologists experienced in MS. Patients underwent diffusion tensor imaging at 3T to assess the fractional anisotropy (FA) of the cerebral white matter as a measure of microstructural brain integrity. GFV was increased in MS and correlated to changes in the FA of white matter in the vicinity of the somatosensory and visual cortex. GFV also correlated with the EDSS. GFV may be a useful objective measure of motor dysfunction in MS linked to disability and structural changes in the brain. Our data suggests that GFV should be further explored as an objective measure of motor dysfunction in MS. It could supplement the EDSS, e.g., in proof of concept studies.
A brief review of Susac syndrome
Susac syndrome was named after J.O. Susac who first described the syndrome in 1979. It is characterized by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. It mainly occurs in young women. This underdiagnosed disease needs to be considered in the differential diagnosis of a broad variety of disorders. In Susac syndrome, autoimmune processes leading to damage and inflammation-related occlusion of the microvessels in brain, retina, and inner ear are thought to play a causal role. The diagnosis is based primarily on the clinical presentation, the documentation of branch retinal artery occlusion by fluorescence angiography, and characteristic findings on cerebral MRI, that help in distinguishing Susac syndrome from other inflammatory entities, like multiple sclerosis. Antiendothelial cell antibodies could be detected in some patients. Patients are successfully treated with immunosuppression, however, the best regimen still needs to be defined. As a result of the rarity of the disease, controlled therapeutic trials are missing so far. In this review, we want to demonstrate the clinical features, natural history, treatment, and clinical course of Susac syndrome, illustrated by a typical case history.
Volume estimation of the thalamus using freesurfer and stereology: consistency between methods
Freely available automated MR image analysis techniques are being increasingly used to investigate neuroanatomical abnormalities in patients with neurological disorders. It is important to assess the specificity and validity of automated measurements of structure volumes with respect to reliable manual methods that rely on human anatomical expertise. The thalamus is widely investigated in many neurological and neuropsychiatric disorders using MRI, but thalamic volumes are notoriously difficult to quantify given the poor between-tissue contrast at the thalamic gray-white matter interface. In the present study we investigated the reliability of automatically determined thalamic volume measurements obtained using FreeSurfer software with respect to a manual stereological technique on 3D T1-weighted MR images obtained from a 3 T MR system. Further to demonstrating impressive consistency between stereological and FreeSurfer volume estimates of the thalamus in healthy subjects and neurological patients, we demonstrate that the extent of agreeability between stereology and FreeSurfer is equal to the agreeability between two human anatomists estimating thalamic volume using stereological methods. Using patients with juvenile myoclonic epilepsy as a model for thalamic atrophy, we also show that both automated and manual methods provide very similar ratios of thalamic volume loss in patients. This work promotes the use of FreeSurfer for reliable estimation of global volume in healthy and diseased thalami.
Progression of microstructural putamen alterations in a case of symptomatic recurrent seizures using diffusion tensor imaging
Microstructural alterations of the putamen were recently reported in patients with partial and generalized epilepsy disorders. However, it is unknown whether these alterations pre-exist or are secondary to recurrent seizures. Here we investigated the progression of putamen fractional anisotropy (FA) alterations in a case of recurrent psychomotor seizures using longitudinal diffusion tensor imaging (DTI) shortly before (DTI-1) and after a psychomotor seizure (DTI-2). We obtained FA values of a hypothesis-guided putamen region-of-interest (ROI) and seven exploratory ROIs. FA values from both DTIs were compared with reference values from 19 controls. Relative to controls, the patient's putamen FA was increased at DTI-1 (13% left putamen, 7% right putamen), an effect that was exacerbated at DTI-2 (24% left putamen (p<0.05), 20% right putamen). In the exploratory ROIs we found FA reductions in the corticospinal tract, temporal lobe, and occipital lobe (p<0.05) relative to controls at DTI-1 and DTI-2. In contrast to the putamen, all exploratory ROIs showed no relevant FA change between DTI-1 and DTI-2. These results suggest that recurrent seizures may lead to progressive microstructural putamen alterations.
Methodological aspects of functional transcranial Doppler sonography and recommendations for simultaneous EEG recording
The neurovascular coupling describes a vasoregulative principle of the brain that adapts local cerebral blood flow in accordance with the underlying neuronal activity. It is the basis of modern indirect brain imaging techniques. Because of its wide availability and high tolerability the functional transcranial Doppler has been often used to assess brain function in clinical conditions. In the present paper we will give an overview of the current understanding of the coupling, explain basic principles of the Doppler technique and summarize relevant findings of functional Doppler tests in the different vascular territories of the brain. Finally, the concept of a combined functional electroencephalogram and transcranial Doppler technique will be outlined, which allows simultaneous investigation of the neuronal and vascular responses of neurovascular coupling.
Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study
Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV).
Variability and asymmetry of the sulcal contours defining Broca's area homologue in the chimpanzee brain
There has been recent motivation to search for neuroanatomical asymmetries in nonhuman primates in order to provide comparative information on how the human brain is structurally organized to support specific cognitive capabilities, such as language functions. We took the opportunity to study Broca's area homologue in a novel sample of 80 preserved postmortem chimpanzee (Pan troglodytes) cerebral hemispheres. Consistent with the only prior study documenting the morphology of Broca's area homologue in the chimpanzee (Sherwood et al.  Anat Rec 271:276–285), we report great interindividual variation in the structure and connections of the sulci investigated, most notably a left-sided bias in the bifurcation of the inferior precentral sulcus, an anatomical feature that occurs much more frequently in chimpanzees relative to humans. Consistent with our recent neuroimaging report (Keller et al. [2009b] J Neurosci 29:14607–14616), no population-based interhemispheric asymmetries of sulcal length existed that could be considered markers of the size of Broca's area homologue. With strict anatomical guidelines, we report that the diagonal sulcus was present in 25% left and 20% right chimpanzee hemispheres studied, which is substantially less that the general prevalence in humans. Through the presentation of schematic drawings, photographs, morphological recordings and sulcal length metrics, our data illustrate the interindividual variability of Broca's area homologue in the chimpanzee and support the notion of no macroscopic asymmetry of this important homologous language brain region in one of the closest evolutionary ancestor to modern humans.
Enhanced rapid-onset cortical plasticity in CADASIL as a possible mechanism of preserved cognition
Ischemic small vessel disease (SVD) may lead to cognitive impairment, but cognitive deficits with a given burden of SVD vary significantly. The underlying mechanisms of impaired or preserved cognition are unknown. Here, we investigated the impact of ischemic SVD on rapid-onset cortical plasticity, as induced with a paired-associative stimulation protocol. To exclude concomitant effects of aging, we examined 12 middle-aged patients (48.3 ± 8.3 years) with cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) who suffered from severe ischemic SVD and a group of 12 age-matched controls (49.9 ± 8.3 years). Cognitive status, motor performance and learning, and motor cortex excitability in response to cathodal transcranial direct current stimulation (ctDCS) were assessed. White matter integrity was analyzed by conventional magnetic resonance imaging and diffusion tensor imaging. We found that cognitive and motor functions were largely preserved in CADASIL patients, while rapid-onset cortical plasticity was significantly higher in the CADASIL group compared with controls (repeated measures analysis of variance [group × time] interaction: P = 0.03). This finding was even more pronounced in patients with higher white matter lesion load. ctDCS revealed no evidence of cortical dysplasticity. We conclude that increased rapid-onset cortical plasticity may contribute to largely preserved cognitive and motor function despite extensive ischemic SVD.
[Susac syndrome: an interdisciplinary challenge]
Susac syndrome, named after John Susac, the first to describe this condition, is characterized by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. Although certainly a rare disease, Susac syndrome needs to be considered in the differential diagnosis of a broad variety of diseases. The pathogenesis is not yet clear. Autoimmune processes leading to damage and inflammation-related occlusion of the microvessels in brain, retina, and inner ear are thought to play a causal role. The diagnosis is based primarily on the clinical presentation, the documentation of branch retinal artery occlusion by fluorescence angiography, and characteristic findings on cerebral MRI. Usually, immunosuppressive therapy is required, though controlled therapy trials are missing so far. The intention of this review article is to raise awareness of this disease among neurologists, psychiatrists, ophthalmologists, and ENT specialists as a high number of unreported cases probably exists. Accordingly, the focus is on the clinical presentation and the diagnostic approach.
Microstructural and volumetric abnormalities of the putamen in juvenile myoclonic epilepsy
Patients with juvenile myoclonic epilepsy (JME) show evidence of microstructural white matter (WM) damage of thalamocortical fiber tracts and changes of blood oxygen level dependent (BOLD) signal in a striatothalamocortical network. The objective of the present study was to investigate microstructural and volumetric alterations of the putamen in patients with JME using diffusion tensor imaging (DTI) and conventional magnetic resonance imaging (MRI).
Can the language-dominant hemisphere be predicted by brain anatomy?
It has long been suspected that cortical interhemispheric asymmetries may underlie hemispheric language dominance (HLD). To test this hypothesis, we determined interhemispheric asymmetries using stereology and MRI of three cortical regions hypothesized to be related to HLD (Broca's area, planum temporale, and insula) in healthy adults in whom HLD was determined using functional transcranial Doppler sonography and functional MRI (15 left HLD, 10 right HLD). We observed no relationship between volume asymmetry of the gyral correlates of Broca's area or planum temporale and HLD. However, we observed a robust relationship between volume asymmetry of the insula and HLD (p = .008), which predicted unilateral HLD in 88% individuals (86.7% left HDL and 90% right HLD). There was also a subtle but significant positive correlation between the extent of HLD and insula volume asymmetry (p = .02), indicating that a larger insula predicted functional lateralization to the same hemispheric side for the majority of subjects. We found no visual evidence of basic anatomical markers of HLD other than that the termination of the right posterior sylvian fissure was more likely to be vertical than horizontal in right HLD subjects (p = .02). Predicting HLD by virtue of gross brain anatomy is complicated by interindividual variability in sulcal contours, and the possibility remains that morphological and cytoarchitectural organization of the classical language regions may underlie HLD when analyses are not constrained by the natural limits imposed by measurement of gyral volume. Although the anatomical correlates of HLD will most likely be found to include complex intra- and interhemispheric connections, there is the possibility that such connectivity may correlate with gray matter morphology. We suggest that the potential significance of insular morphology should be considered in future studies addressing the anatomical correlates of human language lateralization.
Short-term anomia training and electrical brain stimulation
Language training success in chronic aphasia remains only moderate. Electric brain stimulation may be a viable way to enhance treatment efficacy.
Pain is associated with regional grey matter reduction in the general population
Regional decreases in grey matter volume as detected by magnetic resonance imaging-based volumetry have been reported in several clinical chronic pain cohorts. Here, we used voxel-based morphometry in a nonclinical cohort to investigate whether grey matter alterations also occur in older individuals (aged 40-85 years) from the general population. Based on self-report of pain, we identified 31 pain-free controls, 45 subjects with ongoing pain (low back pain, headache, or lower extremity joint pain) who had at least moderate pain on more than 3 days/month, and 29 individuals with past pain (stopped for >12 months). Relative to controls, the ongoing pain group showed regional grey matter volume decreases, predominantly in cingulate, prefrontal, and motor/premotor regions. No grey matter volume decreases were found in the group with pain that had stopped for >12 months. These results show that pain-related grey matter volume decreases are present in individuals from the general population. The lack of morphometric anomalies in subjects with past pain supports recent evidence suggesting that pain-related grey matter changes are reversible after cessation of pain.
G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial
The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.
Triad of visual, auditory and corticospinal tract lesions: a new syndrome in a patient with HIV infection
A case of a rapidly progressive degeneration of the visual, auditory and corticospinal tract in a patient with a HIV infection is presented.
Neuroimaging in Susac's syndrome: focus on DTI
Susac's syndrome is an underdiagnosed disease that is thought to occur mainly in young women. It is characterized by the triad of hearing loss, branch retinal artery occlusions, and encephalopathy with predominantly cognitive and psychiatric symptoms. Treatment consists of immunosuppressive therapy. Focal ischemic lesions in the central portion of the corpus callosum detectable by conventional MRI ("snowballs") are a typical feature of Susac's syndrome. The appearance of these lesions is not, however, correlated with the type and severity of the neuropsychological deficits.
Correcting eddy current and motion effects by affine whole-brain registrations: evaluation of three-dimensional distortions and comparison with slicewise correction
Eddy-current (EC) and motion effects in diffusion-tensor imaging (DTI) bias the estimation of quantitative diffusion indices, such as the fractional anisotropy. Both effects can be retrospectively corrected by registering the strongly distorted diffusion-weighted images to less-distorted T2-weighted images acquired without diffusion weighting. Two different affine spatial transformations are usually employed for this correction: slicewise and whole-brain transformations. However, a relation between estimated transformation parameters and EC distortions has not been established yet for the latter approach. In this study, a novel diffusion-gradient-direction-independent estimation of the EC field is proposed based solely on affine whole-brain registration parameters. Using this model, it is demonstrated that a more distinct evaluation of the whole-brain EC effects is possible if the through-plane distortion was considered in addition to the well-known in-plane distortions. Moreover, a comparison of different whole-brain registrations relative to a slicewise approach is performed, in terms of the relative tensor error. Our findings suggest that for appropriate intersubject comparison of DTI data, a whole-brain registration containing nine affine parameters provides comparable performance (between 0 and 3%) to slicewise methods and can be performed in a fraction of the time.
Integrity of the hippocampus and surrounding white matter is correlated with language training success in aphasia
Aphasia after middle cerebral artery (MCA) stroke shows highly variable degrees of recovery. One possible explanation may be offered by the variability of the occlusion location. Branches from the proximal portion of the MCA often supply the mesial temporal lobe including parts of the hippocampus, a structure known to be involved in language learning. Therefore, we assessed whether language recovery in chronic aphasia is dependent on the proximity of the MCA infarct and correlated with the integrity of the hippocampus and its surrounding white matter. Language reacquisition capability was determined after 2weeks of intensive language therapy and 8months after treatment in ten chronic aphasia patients. Proximity of MCA occlusion relative to the internal carotid artery was determined by magnetic resonance imaging (MRI) based on the most proximal anatomical region infarcted. Structural damage to the hippocampus was assessed by MRI-based volumetry, regional microstructural integrity of hippocampus adjacent white matter by fractional anisotropy. Language learning success for trained materials was correlated with the proximity of MCA occlusion, microstructural integrity of the left hippocampus and its surrounding white matter, but not with lesion size, overall microstructural brain integrity and a control region outside of the MCA territory. No correlations were found for untrained language materials, underlining the specificity of our results for training-induced recovery. Our results suggest that intensive language therapy success in chronic aphasia after MCA stroke is critically dependent on damage to the hippocampus and its surrounding structures.
Specific pattern of early white-matter changes in pure hereditary spastic paraplegia
Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. Most MR studies on HSP include very heterogeneous samples of patients, and findings were inconsistent. Here, we examined six patients with pure HSP and SPG4 mutations by clinical evaluation, detailed neuropsychological testing, and neuroimaging analyses, including conventional MRI, diffusion tensor imaging (DTI), and brain volumetry. Differences of voxel-wise statistics and ROI-based analysis of DTI data between patients and 32 healthy volunteers were evaluated. Although conventional MRI and brain volumetry were normal, DTI revealed widespread disturbance of white matter (WM) integrity (P < 0.001), mainly affecting the corticospinal tract. With longer disease duration, frontal regions were also involved. The WM changes were also present in subclinical subjects harbouring the pathogenic mutation. These subtle WM abnormalities have functional relevance because they correlated with clinical symptoms. Thus, early alterations of nerve fibres, which can be detected by DTI, might serve as a biological marker in HSP, in particular with respect to future longitudinal studies.
Structural correlates of functional language dominance: a voxel-based morphometry study
The goal of this study was to explore the structural correlates of functional language dominance by directly comparing the brain morphology of healthy subjects with left- and right-hemisphere language dominance.
A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects
Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult-onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss-of-function of the paraplegin-AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7-HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP.
Serum C-reactive protein is linked to cerebral microstructural integrity and cognitive function
C-reactive protein is a marker of inflammation and vascular disease. It also seems to be associated with an increased risk of dementia. To better understand potential underlying mechanisms, we assessed microstructural brain integrity and cognitive performance relative to serum levels of high-sensitivity C-reactive protein (hs-CRP).
Individual white matter fractional anisotropy analysis on patients with MRI negative partial epilepsy
Conventional structural MRI fails to identify a cerebral lesion in 25% of patients with cryptogenic partial epilepsy (CPE). Diffusion tensor imaging is an MRI technique sensitive to microstructural abnormalities of cerebral white matter (WM) by quantification of fractional anisotropy (FA). The objectives of the present study were to identify focal FA abnormalities in patients with CPE who were deemed MRI negative during routine presurgical evaluation.
Imaging short- and long-term training success in chronic aphasia
To date, functional imaging studies of treatment-induced recovery from chronic aphasia only assessed short-term treatment effects after intensive language training. In the present study, we show with functional magnetic resonance imaging (fMRI), that different brain regions may be involved in immediate versus long-term success of intensive language training in chronic post-stroke aphasia patients.
Excessive Daytime Sleepiness Is a Common Symptom in Fabry Disease
Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O(2) desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%), and the prevalence of chronic fatigue (48%). EDS was independently associated with the physical component summary of the SF-36 data (corrected R(2) = -0.323, p < 0.001). EDS and age explained a quarter of variance in mental component summary (corrected R(2) = -0.253, p < 0.001). We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD.
Diffusion tensor imaging in a case of Kearns-Sayre syndrome: striking brainstem involvement as a possible cause of oculomotor symptoms
Kearns-Sayre syndrome (KSS) is a rare autosomal dominant mitochondrial disorder affecting the central nervous system. Progressive external ophthalmoplegia is an early and characteristic clinical symptom of the disease. We describe a 22-year-old female patient with a typical KSS including early and severe external ophthalmoplegia. Conventional MRI and diffusion tensor imaging (DTI) was performed to investigate the early involvement of the central nervous system (CNS). DTI revealed substantial white matter alterations that were primarily confined to the brainstem. These early DTI changes support the hypothesis that regional affection of the brainstem may play a role in the pathogenesis of the early oculomotor symptoms. DTI might be helpful to detect an early involvement of the CNS in KSS.
Gelastic seizures: A case of lateral frontal lobe epilepsy and review of the literature
We describe a 40-year-old patient with gelastic seizures triggered by hand movement. Despite nonlesional magnetic resonance imaging (MRI), electroencephalography (EEG), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI) are concordant with seizure onset in the right frontocentral area. Seizure semiology and EEG recordings imply involvement of mesial frontal structures remote from seizure initiation site. We reviewed all published cases on gelastic seizures of frontal lobe origin to find characteristic features. For further investigation of the phenomenon of movement-induced seizures, fMRI was performed using a finger tapping paradigm. Interictal fMRI revealed widespread activation of right motor cortex during finger tapping on either side outreaching the anatomical representation of the left finger. In line with this finding DTI revealed fiber track impairment in the right frontocentral region, supporting the hypothesis of a focal derangement. This case highlights the importance of complementary functional investigations in MRI-negative epilepsies.
Pattern and progression of white-matter changes in a case of posterior cortical atrophy using diffusion tensor imaging
The progression of white-matter changes in a case of posterior cortical atrophy (PCA) was examined over a period of 15 months using diffusion tensor imaging (DTI) and the association with neuropsychological variables was studied.
Nerve fiber impairment of anterior thalamocortical circuitry in juvenile myoclonic epilepsy
Juvenile myoclonic epilepsy (JME) is a syndrome of idiopathic generalized epilepsy (IGE) without structural brain abnormalities detectable by MRI or CT.
Transient lesion in the splenium related to antiepileptic drug: case report and new pathophysiological insights
Transient focal lesions in the splenium of the corpus callosum (SCC) have been associated with antiepileptic drug (AED) treatment. However, the aetiology is widely unknown. We describe a transient SCC lesion in an epilepsy patient after abrupt AED reduction. Whole head high-field diffusion tensor imaging (DTI) including fully automated quantitative fractional anisotropy (FA) analysis was used to get insight into the pathophysiology of transient SCC lesions. Our results demonstrate that a reversible loss of directional fibre organisation in the splenium, likely due to intramyelinic oedema, is the morphological correlate of transient SCC lesions. We conclude that DTI provides a highly sensitive and quantitative tool to detect subtle and transient loss of fibre integrity associated with AED treatment.
Diffusion tensor imaging demonstrates fiber impairment in Susac syndrome
Anterior cingulate reflects susceptibility to framing during attractiveness evaluation
Human cognitive decisions can be strongly susceptible to the manner in which options are presented ('framing effect'). Here we investigated the neural basis of response adjustments induced by changing frames during intuitive decisions. Evidence exists that the anterior cingulate cortex plays a general role in behavioral adjustments. We hypothesized, therefore, that the anterior cingulate cortex is also involved in the 'framing effect'. Our hypothesis was tested by using a binary attractiveness judgment task ('liking' versus 'nonliking') during functional magnetic resonance imaging. We found that the framing-related anterior cingulate cortex activity predicted how strongly susceptible an individual was to a biased response. Our results support the hypothesis that paralimbic processes are crucial for predicting an individual's susceptibility to framing.
Diffusion-tensor imaging at 3 T: detection of white matter alterations in neurological patients on the basis of normal values
Fractional anisotropy (FA) is a powerful measure to study the integrity of the cerebral white matter in vivo. However, because clinical FA assessments are frequently based on single slice evaluations, intra- and interindividual comparisons are highly dependent on image alignment. We attempted to develop an observer-independent, fully automated technique for quantitative FA assessment.
The association between scalp hair-whorl direction, handedness and hemispheric language dominance: is there a common genetic basis of lateralization?
The hemispheres of the human brain are functionally asymmetric. The left hemisphere tends to be dominant for language and superior in the control of manual dexterity. The mechanisms underlying these asymmetries are not known. Genetic as well as environmental factors are discussed. Recently, atypical anticlockwise hair-whorl direction has been related to an increased probability for non-right-handedness and atypical hemispheric language dominance. These findings are fascinating and important since hair-whorl direction is a structural marker of lateralization and could provide a readily observable anatomical clue to functional brain lateralization. Based on data on handedness and hair-whorl direction, Amar Klar proposed a genetic model ("random-recessive model") in that a single gene with two alleles controls both handedness and hair-whorl orientation (Klar, A.J.S., 2003. Human handedness and scalp hair-whorl direction develop from a common genetic mechanism. Genetics 165, 269-276). The present study was designed to further investigate the relationship between scalp hair-whorl direction with handedness and hemispheric language dominance. 1212 subjects were investigated for scalp hair-whorl direction and handedness. Additionally, we determined hemispheric language dominance (as assessed by a word generation task) in a subgroup of 212 subjects using functional transcranial Doppler sonography (fTCD). As for the single attributes - hair-whorl direction, handedness, and language dominance - we reproduced previously published results. However, we found no association between hair-whorl direction and either language dominance or handedness. These results strongly argue against a common genetic basis of handedness or language lateralization with scalp hair-whorl direction. Inspection of hair patterns will not help us to determine language dominance.
Interhemispheric dissociation of language regions in a healthy subject
Transcranial magnetic stimulation--a sandwich coil design for a better sham
To improve the quality of TMS studies by developing a new sham condition.
Evidence for a neural correlate of a framing effect: bias-specific activity in the ventromedial prefrontal cortex during credibility judgments
Neural processes within the medial prefrontal cortex play a crucial role in assessing and integrating emotional and other implicit information during decision-making. Phylogenetically, it was important for the individual to assess the relevance of all kinds of environmental stimuli in order to adapt behavior in a flexible manner. Consequently, we can in principle not exclude that environmental information covertly influences the evaluation of actually decision relevant facts ("framing effect").
Atypical hemispheric dominance for attention: functional MRI topography
The right hemisphere is predominantly involved in tasks associated with spatial attention. However, left hemispheric dominance for spatial attention can be found in healthy individuals, and both spatial attention and language can be lateralized to the same hemisphere. Little is known about the underlying regional distribution of neural activation in these 'atypical' individuals. Previously a large number of healthy subjects were screened for hemispheric dominance of visuospatial attention and language, using functional Doppler ultrasonography. From this group, subjects were chosen who were 'atypical' for hemispheric dominance of visuospatial attention and language, and their pattern of brain activation was studied with functional magnetic resonance imaging during a task probing spatial attention. Right-handed subjects with the 'typical' pattern of brain organization served as control subjects. It was found that subjects with an inverted lateralization of language and spatial attention (language right, attention left) recruited left-hemispheric areas in the attention task, homotopic to those recruited by control subjects in the right hemisphere. Subjects with lateralization of both language and attention to the right hemisphere activated an attentional network in the right hemisphere that was comparable to control subjects. The present findings suggest that not the hemispheric side, but the intrahemispheric pattern of activation is the distinct feature for the neural processes underlying language and attention.
Scalp position and efficacy of transcranial magnetic stimulation
To assess the impact of the scalp site on the biological effects of TMS.
Hippocampus activity differentiates good from poor learners of a novel lexicon
Language proficiency is a key to academic and workplace success for native and non-native speakers. It is largely unknown, however, why some people pick up languages more easily than others. We used event-related functional magnetic resonance imaging (e-fMRI) to elucidate which brain regions are modulated during the acquisition of a novel lexicon and which of these learning-related activity changes correlated with general semantic language knowledge. Fourteen healthy young subjects learned a novel vocabulary of 45 concrete nouns via an associative learning principle over the course of five blocks during e-fMRI. As a control condition, subjects took part in a structurally identical "No-Learning" condition lacking any learning principle. Overall, increasing vocabulary proficiency was associated with (intercorrelated) modulations of activity within the left hippocampus and the left fusiform gyrus, regions involved in the binding and integration of multimodal stimuli, and with an increasing activation of the left inferior parietal cortex, the presumed neural store of phonological associations. None of these activity changes were observed during the control condition. Furthermore, subjects who showed less suppression of hippocampal activity over learning blocks scored higher on semantic knowledge in their native language and learned the novel vocabulary more efficiently. Our findings indicate that (a) the successful acquisition of a new lexicon depends on correlated amplitude changes between the left hippocampus and neocortical regions and (b) learning-related hippocampus activity is a stable marker of individual differences in the ability to acquire and master vocabularies.
Nonlinear responses within the medial prefrontal cortex reveal when specific implicit information influences economic decision making
The authors used functional magnetic resonance imaging (fMRI) to investigate how individual economic decisions are influenced by implicit memory contributions.
Crossed cerebro-cerebellar language dominance
In addition to its traditional role in motor control, the cerebellum has been implicated in various cognitive and linguistic functions. Lesion, anatomic, and functional imaging studies indicate a link between left frontal language regions and the right cerebellum. To probe the specificity of this circuit, we examined the association between language-related lateralized activation of the frontal cortex with lateralized activation of the cerebellum. Functional magnetic resonance imaging (fMRI) was carried out during letter-cued word generation in 14 healthy subjects: 7 subjects displayed typical left-hemisphere and 7 subjects displayed atypical right-hemisphere language dominance. We found activation of the cerebellar hemisphere contralateral to the language-dominant cerebral hemisphere in each subject. The cerebellar activation was confined to the lateral posterior cerebellar hemisphere (lobule VI, VII B, Cr I, Cr II). This study demonstrates that crossed cerebral and cerebellar language dominance is a typical characteristic of brain organization. The functional significance of the reported activations can now be tested in patients with lesions of the lateral posterior cerebellum.
Language lateralization in young children assessed by functional transcranial Doppler sonography
Compared to adults, children show superior recovery of language function after damage to the dominant brain hemisphere. Possible explanations are that children have different patterns of language representation or display different patterns of reorganization. Information about language lateralization in children could provide insights into the repair mechanisms of the young brain. While functional magnetic resonance imaging (fMRI) is usually difficult to perform in children younger than 5 years, functional transcranial Doppler sonography (fTCD) is nonfrightening and readily applicable in young and very young children. However, for serial examinations, sufficient validity and reliability are required. To this end, we designed a picture-description language task (PDLT) for fTCD examinations in children, compared the outcome to established protocols and determined the 1 month retest-reliability of the measurement in 16 children aged 2-9 years. The dependent variable was the task-related hemispheric perfusion difference based on averaged relative cerebral blood flow velocity (CBFV) increases in the middle cerebral arteries. This picture-description language lateralization index was compared to language lateralization by a phonetic word generation task (PWGT) in adults revealing good intermethod validity (r=0.70; P
Determining the hemispheric dominance of spatial attention: a comparison between fTCD and fMRI
Human brain mapping allows the systematic assessment of interindividual differences in functional brain anatomy. Functional transcranial Doppler sonography (fTCD) is an imaging tool that allows for fast and mobile assessment of hemispheric lateralization of task-related brain activation. It is ideal to screen large cohorts of subjects. The goal of the present study was to investigate whether fTCD and functional magnetic resonance imaging (fMRI) determine hemispheric lateralization of brain activation related to visuospatial attention concordantly. Used together, fMRI and fTCD may then open up a wide range of potential applications in neuroscience. Fifteen subjects were examined both with fTCD and fMRI while they judged accuracy of line bisections (Landmark task). For fTCD, the maximal mean difference in stimulus-related relative cerebral blood flow velocity changes in the left and right middle cerebral arteries was assessed as the lateralization index LI(fTCD). For fMRI, two approaches were used to determine hemispheric dominance. First, we measured brain activity as the extent of the activated region, i.e., the number of activated voxels above a statistical threshold. Second, we calculated the magnitude of the fMRI signal change between the activation and the control task within a region of interest. Results of fTCD and fMRI were concordant in every single case. Therefore, scanning large cohorts with fTCD for hemispheric dominance during Landmark task will provide results consistent with fMRI. FMRI can then be used for in depth assessment of the specific patterns of activation.
A method for the automated assessment of temporal characteristics of functional hemispheric lateralization by transcranial Doppler sonography
Transcranial Doppler sonography (TCD) can guide and complement investigations based on functional magnetic resonance and positron emission tomography imaging by providing continuous information on cerebral perfusion changes correlated to cerebral activation. So far, however, the role of functional TCD has been limited by a lack of sensitivity.
The investigation of functional brain lateralization by transcranial Doppler sonography
Functional transcranial Doppler sonography (fTCD) adds to the techniques of functional imaging. fTCD measures cerebral perfusion changes related to neural activation in a way comparable to functional magnetic resonance tomography. fTCD contends itself with comparison of averaged, event-related blood flow velocity changes within the territories of two cerebral arteries, for example the left versus the right middle cerebral artery. It can thus serve to evaluate the functional lateralization of higher cognitive functions like hemispheric language dominance (HLD). We present typical applications of fTCD by summarizing studies employing the technique. Then, the physical and physiological underpinnings of fTCD are reviewed. After a brief description of a prototype paradigm for assessing HLD, a detailed outline of the fTCD data analysis is presented. Caveats for fTCD, like other functional imaging techniques, are that the validity of results depends on adequate control of the task parameters, particularly cooperation and reference conditions. We complete the review with examinations of the reliability and validity of the fTCD technique. We conclude that fTCD can be employed to substitute the invasive amobarbital procedure to determine language lateralization in individual patients before undergoing brain surgery. Because of its easy applicability, robustness and mobility, fTCD can also be used to examine many subjects (including children) to obtain representative data on the variability of lateralization of higher cognitive functions, or to scan for atypical patterns of lateralization.
Task repetition can affect functional magnetic resonance imaging-based measures of language lateralization and lead to pseudoincreases in bilaterality
Repeated functional magnetic resonance imaging (fMRI) during learning and recovery can inform us about functional reorganization in the brain. We examined how, in the absence of reorganization, simple task repetition affects measures of fMRI activation. We studied fMRI activation over 10 consecutive sessions of silent word generation in a healthy subject. Additionally, we performed functional transcranial Doppler sonography (fTCD) to learn about the temporal pattern of corresponding changes in cerebral blood flow velocity (CBFV) and pulsatility. With repetition, word generation-associated increases in heart rate diminished steadily. Task repetition also led to a net increase in CBFV bilaterally and to a bilateral increase in the number of activated voxels on fMRI. As a result, whereas the absolute interhemispheric difference of activated voxels remained constant, there was a decrease in the standard fMRI index for language lateralization [LIfMRI = 100 (activated voxels in left hemisphere - voxels in right)/(voxels in left + voxels in right)]. Thus task repetition can lead to changes in task-related autonomic drive and an augmentation of bihemispheric blood flow. This can mimic increasing bilaterality of brain activation.
Changes of cerebrovascular response to visual stimulation in migraineurs after repetitive sessions of somatosensory stimulation (acupuncture): a pilot study
To evaluate the effect of repetitive somatosensory stimulation (acupuncture) on cerebrovascular response in migraineurs by functional transcranial Doppler.
Different modes of manual acupuncture stimulation differentially modulate cerebral blood flow velocity, arterial blood pressure and heart rate in human subjects
The psychophysiological effect of different modes of manual acupuncture stimulation was investigated in 12 healthy, right handed, male subjects (mean age 29). The cerebral blood flow velocity (CBFV) in both middle cerebral arteries, arterial blood pressure (BP), heart rate (HR) and the perceived intensity of the stimulation were monitored while an acupuncture needle in the right dorsal thenar muscle (point Hegu, Li 4) was repetitively rotated with either high frequency (4-8 Hz) and low amplitude (hf-la) or low frequency (1-2 Hz) and high amplitude (lf-ha). Response patterns induced by hf-la and 1f-ha [corrected] stimulation differed significantly (P < 0.05) as tested by Student's t-test: (1), 1f-ha [corrected] stimulation was perceived as more intense and induced a more marked right hemispheric CBFV increase; (2), while hf-la stimulation lead to a slight decrease of BP and HR, lf-ha stimulation induced an initial pressor response (increase of BP, decrease of HR) and a more marked long term decrease of BP. Data indicate that the mode of manual acupuncture stimulation has a differential effect on the perceived stimulation intensity, the cerebral activation and the cardiovascular reflex response.
Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study
Depending on individual lesion location and extent, reorganization of the human motor system has been observed with a high interindividual variability. In addition, variability of forces exerted, of motor effort, and of movement strategies complicates the interpretation of functional imaging studies. We hypothesize that a general pattern of reorganization can be identified if a homogeneous patient population is chosen and experimental conditions are controlled. Patients with amyotrophic lateral sclerosis (ALS) and healthy volunteers were trained to perform a simple finger flexion task with 10% of each individual's maximum grip force with constant movement amplitude and frequency. The activation pattern in ALS patients was distinctly different to that in healthy controls: In ALS patients, motor cortex activation was located more anteriorly, encompassing the premotor gyrus. The cluster volume within the supplementary motor area (SMA) was higher and shifted toward the pre-SMA. Contralateral inferior area 6 and bilateral parietal area 40 revealed higher cluster volumes. Our results demonstrate a general pattern of functional changes after motor neuron degeneration. They support the concept of a structurally parallel and functionally specialized organization of voluntary motor control. Degeneration of the first and second motor neurons leads to enhanced recruitment of motor areas usually involved in initiation and planning of movement. Partial compensation between functionally related motor areas seems to be a strategy to optimize performance if the most efficient pathway is unavailable.
Language and spatial attention can lateralize to the same hemisphere in healthy humans
Disorders of language classically occur after left brain lesions, and disorders of spatial attention after right brain lesions. It is unclear whether the hemispheric dissociation of functions is a fixed pattern of brain organization.
Behavioural relevance of atypical language lateralization in healthy subjects
In most humans, language is lateralized to the left side of the brain. It has been speculated that this hemispheric specialization is a prerequisite for the full realization of linguistic potential. Using standardized questionnaires and performance measures, we attempted to determine if there are behavioural correlates of atypical, i.e. right-hemispheric and bilateral, language lateralization. The side and degree of language lateralization were determined by measuring the hemispheric perfusion differences by functional transcranial Doppler ultrasonography during a word generation task in healthy volunteers. Subjects with left (n = 264), bilateral (n = 31) or right (n = 31) hemisphere language representation did not differ significantly with respect to mastery of foreign languages, academic achievement, artistic talents, verbal fluency or (as assessed in a representative subgroup) in intelligence or speed of linguistic processing. These findings suggest that atypical hemispheric specialization for language, i.e. right-hemisphere or bilateral specialization, is not associated with major impairments of linguistic faculties in otherwise healthy subjects.
Altered cerebrovascular response pattern in interictal migraine during visual stimulation
A dysbalance of the cerebrovascular response during functional activation of the brain has been postulated as a factor in the pathophysiology of migraine. To determine the dynamic pattern of the cerebrovascular response in migraineurs compared with a control group, changes of the cerebral perfusion during cerebral activation were studied with high temporal resolution by functional transcranial Doppler sonography (fTCD). The cerebral blood flow velocity (CBFV) in the right posterior cerebral artery (PCA) and the left middle cerebral artery (MCA) was measured simultaneously during visual stimulation in 19 interictal migraineurs and in 19 age- and sex-matched control subjects. Data were analysed with a previously validated technique based on automated stimulus-related averaging of the CBFV. The MCA migraineurs exhibited a steady increase of CBFV during the stimulation, while normal subjects showed a habituation of the CBFV response. The lack of habituation in migraineurs was significantly (P < or = 0.05) more pronounced across patients with a high attack frequency (> or = 4 per month) compared with migraineurs with a low attack frequency (< 4 per month). In the PCA, compared with normal subjects, migraineurs showed significantly (P < or = 0.05) stronger CBFV changes at the beginning and after the end of stimulation, with a slower decline to baseline. Data are in accordance with electrophysiological findings in migraineurs. It is assumed that a lack of habituation of the cerebrovascular response in migraineurs might contribute to a disturbance of the metabolic homeostasis of the brain that might induce migraine attacks.
Handedness and hemispheric language dominance in healthy humans
In most people the left hemisphere of the brain is dominant for language. Because of the increased incidence of atypical right-hemispheric language in left-handed neurological patients, a systematic association between handedness and dominance has long been suspected. To clarify the relationship between handedness and language dominance in healthy subjects, we measured lateralization directly by functional transcranial Doppler sonography in 326 healthy individuals using a word-generation task. The incidence of right-hemisphere language dominance was found to increase linearly with the degree of left-handedness, from 4% in strong right-handers (handedness = 100) to 15% in ambidextrous individuals and 27% in strong left-handers (handedness = -100). The relationship could be approximated by the formula: f1.gif" BORDER="0">. These results clearly demonstrate that the relationship between handedness and language dominance is not an artefact of cerebral pathology but a natural phenomenon.
Assessment of hemispheric language lateralization: a comparison between fMRI and fTCD
The cerebral blood flow velocity (CBFV) in the basal arteries during a word-generation task was assessed by functional transcranial Doppler ultrasonography (fTCD) and by functional magnetic resonance imaging (fMRI). The study investigates how event-related CBFV modulations in the middle cerebral artery (MCA) relate to regional cerebral blood flow (rCBF) changes. Both fMRI and fTCD were used in 13 subjects (7 men, 6 women, aged 21 to 44 years). The maximum difference of relative CBFV changes between the left and right MCA during the word-generation task was used as the language laterality index (LIfTCD). For the fMRI examination during the nearly identical language task, the corresponding index was defined by LIfMRI = 100(N(L) - N(R))/(N(L) + N(R)), where N(L) and N(R) refer to the numbers of voxels activated in the left and right hemisphere, respectively. The evoked CBFV changes expressed by LIfTCD and the corresponding laterality index, LIfMRI, estimated by fMRI showed a close linear relation (regression analysis: r = 0.95, p < 0.0001). The results of this study demonstrate that language-related velocity changes in the MCAs relate to rCBF increases in a linear fashion. Since the laterality indices assessed by fMRI and fTCD are in such close agreement both techniques can therefore be used in a complementary way.
Language lateralization in healthy right-handers
Our knowledge about the variability of cerebral language lateralization is derived from studies of patients with brain lesions and thus possible secondary reorganization of cerebral functions. In healthy right-handed subjects 'atypical', i.e. right hemisphere language dominance, has generally been assumed to be exceedingly rare. To test this assumption we measured language lateralization in 188 healthy subjects with moderate and strong right-handedness (59% females) by a new non-invasive, quantitative technique previously validated by direct comparison with the intracarotid amobarbital procedure. During a word generation task the averaged hemispheric perfusion differences within the territories of the middle cerebral arteries were determined. (i) The natural distribution of language lateralization was found to occur along a bimodal continuum. (ii) Lateralization was equivalent in men and women. (iii) Right hemisphere dominance was found in 7.5% of subjects. These findings indicate that atypical language dominance in healthy right-handed subjects of either sex is considerably more common than previously suspected.
Determination of cognitive hemispheric lateralization by "functional" transcranial Doppler cross-validated by functional MRI
Cortical tuning: a function of anticipated stimulus intensity
We investigated the activation of the brain during anticipation of tactile stimuli by continuous cerebral blood flow velocity (CBFV) monitoring with bilateral transcranial Doppler sonography. A forced choice paradigm was performed where a first group of subjects (n=16) was expecting suprathreshold and a second group (n=19) was anticipating threshold tactile stimuli to the index finger after a cueing tone. During the anticipation of suprathreshold stimuli the CBFV always exhibited a significantly stronger increase in the right hemisphere than in the left, even when stimuli were anticipated at the right index finger. Conversely when stimuli at perception threshold were expected, the respective contralateral hemisphere showed a significantly stronger perfusion increase. These data show that preparatory activation of the brain during stimulus anticipation is dependant on the expected stimulus intensity.
Cerebral hemodynamic response to generalized spike-wave discharges
Data in the literature concerning metabolic demand during generalized spike-wave activity (gSW) are conflicting. We investigated instantaneous changes in cerebral blood flow velocities (CBFV) in both middle cerebral arteries (MCAs) by transcranial Doppler sonography (TCD) during gSW paroxysms recorded by scalp EEG.
Reproducibility of functional transcranial Doppler sonography in determining hemispheric language lateralization
Since functional transcranial Doppler ultrasonography (fTCD) allows convenient and fully automated quantification of language lateralization, it seems ideal for longitudinal studies of perfusion changes during deterioration as well as recovery of language functions. However, during serial examinations, the technical, stochastic, and physiological variabilities of cerebral blood flow velocities (CBFV) have to be considered. Therefore, before fTCD is accepted as a tool for evaluation of changes in lateralization in the diseased state, its reliability in healthy subjects needs to be determined.
Cerebral hemodynamics during electrically induced seizures
Electroconvulsive therapy (ECT) is an appropriate clinical model to investigate blood flow during seizures. In this study cerebral blood flow velocity (CBFV) was measured during 40 ECTs in 10 patients by means of transcranial Doppler sonography. EEG was recorded continuously. Under general anesthesia, the pre-convulsive blood flow velocity (Vmean) decreased significantly. After ECT, we measured a dramatic increase in Vmean which was significantly greater in the left MCA than in the right MCA. After termination of seizures, flow velocities returned to baseline levels. The striking increase in cerebral blood flow velocity reflects excessive cerebral metabolism during convulsive neuronal activation. The left hemisphere seems to be more sensitive to electrical stimuli as was indicated by its predominant augmentation of CBFVs.
Noninvasive determination of language lateralization by functional transcranial Doppler sonography: a comparison with the Wada test
Functional transcranial Doppler ultrasonography (fTCD) can assess event-related changes in cerebral blood flow velocities and, by comparison between sides, can provide a measure of hemispheric perfusional lateralization. It is easily applicable, insensitive to movement artifacts, and can be used in patients with less than perfect cooperation. In the present study we investigated the validity of fTCD in determining the hemispheric dominance for language by direct comparison of fTCD with intracarotid amobarbital anesthesia (Wada test).
Regional cerebral blood flow increases during preparation for and processing of sensory stimuli
Preparing for and processing of sensory stimuli are energy-requiring processes. We attempted to assess the relative contributions of these processes to increases in regional cerebral perfusion. Nineteen healthy right-handed subjects were examined while they were engaged in detecting tactile stimuli to the index finger 5 s after a cueing tone. Cerebral blood flow velocity (CBFV) modulations in the middle cerebral arteries (MCAs) were continuously measured by bilateral simultaneous transcranial Doppler ultrasonography. Tactile stimuli well above threshold per se did not produce a significant, relative CBFV increase in the contralateral MCA. However, when subjects were expecting a threshold tactile stimulus, there was a significant regional increase in CBFV in the hemisphere contralateral to the attended index finger for approximately 15 s, starting within the first seconds after the cueing. This increase was present even before the tactile stimulus was applied and also in sessions when the stimulus was omitted. We conclude that preparation of the cortex causes a stronger regional cerebral blood flow increase than the processing of the tactile stimulus itself.
AVERAGE: a Windows program for automated analysis of event related cerebral blood flow
Functional transcranial Doppler sonography (fTCD) is used to measure changes in brain perfusion during different states of brain activity by evaluating flow velocities within the major brain arteries. We developed a computer program called AVERAGE which can be used with various TCD devices and allows for subtle quantitative off-line analysis of Doppler flow signals. AVERAGE supports data transformation, heart beat analysis, noise reduction, trigger signal and marker modification, artifact analysis and artifact rejection, as well as data reduction. Perfusion differences and their time course within two different arteries can be analyzed by parametric and non parametric statistical methods. This is important, for instance, in studies on hemispherical dominance during mental task processing. Each data processing step is supported by graphical output. If investigated bilaterally with interhemispheric analysis even minimal activations can reliably be detected and quantified with a sensitivity known from positron emission tomography approaches.
Persistent unihemispheric perceptual impairments in humans following focal seizures
Perception has been linked to a highly coordinated activation of cortical regions whose functional organization and performance is subject to plastic changes. We tested whether chronic repetitive disturbances of the brain by focal epileptic activity have a long-standing detrimental effect on the perceptual performance in the affected hemisphere. Nine patients were examined who had a history of complex partial seizures but no structural cerebral damage on magnetic resonance imaging and no evidence of ongoing epileptic activity on scalp electroencephalography and who had clinically been without seizures for at least 3 days. The side of primary epileptic involvement was determined by seizure semiology (n = 2), focal electroencephalographic slowing (n = 3) or focal abnormality during single photon emission topography (SPECT) (n = 4). The computer controlled psychometric assessment of the somesthetic frequency discrimination revealed that the perception in the hand corresponding to the affected hemisphere was impaired relative to the contralateral hand (P < 0.01), and to the performance of a group of normal controls (P < 0.01). We conclude that mechanisms related to focal epileptic activity can result in regional perceptual decrements even when there is no clinical or surface-electroencephalographic evidence of epileptic discharges. This in turn suggests that somatosensory testing may be of help in localizing, or at least lateralizing an epileptic focus.
Successive activation of both cerebral hemispheres during cued word generation
Most humans have a left hemispheric dominance for language. However, during diagnostic language testing there also is activation of the right hemisphere, which is probably related to attention. To investigate further the role of attention during language production we monitored cerebral blood flow velocities in the middle cerebral arteries by continuous bilateral transcranial Doppler ultrasonography (TCD) in nine right-handed subjects. During cued word generation, a successive activation of the right hemisphere in the preparatory phase, and of the left hemisphere during word searching was demonstrated. These findings indicate that attentional processes precede verbal activation and that the two procedures can be separated by comparative blood flow velocity measurement.
TCD-Profiling Using AVERAGE. A New Technique to Evaluate Transcranial Doppler Ultrasound Flow Spectra of Subjects with Cerebral Small Vessel Disease
There is an unmet need for screening methods to detect and quantify cerebral small vessel disease (SVD). Transcranial Doppler ultrasound (TCD) flow spectra of the larger intracranial arteries probably contain relevant information about the microcirculation. However, it has not yet been possible to exploit this information as a valuable biomarker.
Non-lesional cerebellar damage in patients with clinically isolated syndrome: DTI measures predict conversion into clinically definite multiple sclerosis
Today, no specific test for the diagnosis of multiple sclerosis (MS) is available due to the lack of characteristic symptoms at beginning. This circumstance also complicates estimation of disease progression. Recent findings provided evidence for early, non-lesional cerebellar damage in patients with (clinically definite) relapsing-remitting MS.
Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis
White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant.
FDG μPET Fails to Detect a Disease-Specific Phenotype in Rats Transgenic for Huntington's Disease – A 15 Months Follow-up Study
FDG-PET detects hypometabolism in premanifest and symptomatic Huntington's disease (HD). A cross-sectional study suggested that whole-brain FDG-PET is capable to detect a phenotype in transgenic (tg) HD rats. Recently, a longitudinal follow-up study showed no FDG-PET changes in tgHD rats. Both studies applied small sample sizes and analysis was limited to whole-brain or striatum.
Early detection of widespread progressive brain injury after cardiac arrest: a single case DTI and post-mortem histology study
We tested the hypothesis in sense of a proof of principle that white matter (WM) degeneration after cardiopulmonary arrest (CPA) can be assessed much earlier by diffusion tensor imaging (DTI) than by conventional MRI.
DTI detects water diffusion abnormalities in the thalamus that correlate with an extremity pain episode in a patient with multiple sclerosis
Various types of multiple sclerosis (MS) related pain have been discussed. One concept is that deafferentation secondary to lesions in the spino-thalamo-cortical network can cause central pain. However, this hypothesis is somehow limited by a lack of a robust association between pain episodes and sites of lesion location.
Brainstem involvement as a cause of central sleep apnea: pattern of microstructural cerebral damage in patients with cerebral microangiopathy
The exact underlying pathomechanism of central sleep apnea with Cheyne-Stokes respiration (CSA-CSR) is still unclear. Recent studies have demonstrated an association between cerebral white matter changes and CSA. A dysfunction of central respiratory control centers in the brainstem was suggested by some authors. Novel MR-imaging analysis tools now allow far more subtle assessment of microstructural cerebral changes. The aim of this study was to investigate whether and what severity of subtle structural cerebral changes could lead to CSA-CSR, and whether there is a specific pattern of neurodegenerative changes that cause CSR. Therefore, we examined patients with Fabry disease (FD), an inherited, lysosomal storage disease. White matter lesions are early and frequent findings in FD. Thus, FD can serve as a "model disease" of cerebral microangiopathy to study in more detail the impact of cerebral lesions on central sleep apnea.
Concomitant fractional anisotropy and volumetric abnormalities in temporal lobe epilepsy: cross-sectional evidence for progressive neurologic injury
In patients with temporal lobe epilepsy and associated hippocampal sclerosis (TLEhs) there are brain abnormalities extending beyond the presumed epileptogenic zone as revealed separately in conventional magnetic resonance imaging (MRI) and MR diffusion tensor imaging (DTI) studies. However, little is known about the relation between macroscopic atrophy (revealed by volumetric MRI) and microstructural degeneration (inferred by DTI).
The influence of spatial registration on detection of cerebral asymmetries using voxel-based statistics of fractional anisotropy images and TBSS
The sensitivity of diffusion tensor imaging (DTI) for detecting microstructural white matter alterations has motivated the application of voxel-based statistics (VBS) to fractional anisotropy (FA) images (FA-VBS). However, detected group differences may depend on the spatial registration method used. The objective of this study was to investigate the influence of spatial registration on detecting cerebral asymmetries in FA-VBS analyses with reference to data obtained using Tract-Based Spatial Statistics (TBSS). In the first part of this study we performed FA-VBS analyses using three single-contrast and one multi-contrast registration: (i) whole-brain registration based on T2 contrast, (ii) whole-brain registration based on FA contrast, (iii) individual-hemisphere registration based on FA contrast, and (iv) a combination of (i) and (iii). We then compared the FA-VBS results with those obtained from TBSS. We found that the FA-VBS results depended strongly on the employed registration approach, with the best correspondence between FA-VBS and TBSS results when approach (iv), the "multi-contrast individual-hemisphere" method was employed. In the second part of the study, we investigated the spatial distribution of residual misregistration for each registration approach and the effect on FA-VBS results. For the FA-VBS analyses using the three single-contrast registration methods, we identified FA asymmetries that were (a) located in regions prone to misregistrations, (b) not detected by TBSS, and (c) specific to the applied registration approach. These asymmetries were considered candidates for apparent FA asymmetries due to systematic misregistrations associated with the FA-VBS approach. Finally, we demonstrated that the "multi-contrast individual-hemisphere" approach showed the least residual spatial misregistrations and thus might be most appropriate for cerebral FA-VBS analyses.
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