A voxel-based diffusion tensor imaging study in unipolar and bipolar depression.

OBJECTIVE: 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. METHODS: Using diffusion tensor imaging (DTI) we employed a voxel-based analysis approach to examine fractional anisotropy (FA) in 86 patients experiencing an acute major depressive episode according to DSM-IV (N=39 BD, mean age 39.2 years; N=43 UD, mean age 39.0 years), and 42 healthy controls (HC, mean age 36.1 years). The groups did not differ in sex, age or total education time. FA was investigated in white matter (FA >.2) and hypothesis-driven anatomically defined tracts (region-of-interest [ROI] analysis). Additionally, an exploratory gray matter FA analysis was performed. RESULTS: White matter analysis showed decreased FA in the right corticospinal tract in UD vs HC and in the right corticospinal tract/superior longitudinal fascicle in BD vs HC and also in BD vs UD. ROI analysis revealed decreased FA in BD vs UD in the corpus callosum and in the cingulum. Gray matter exploratory analysis revealed decreased FA in the left middle frontal gyrus and in the right inferior frontal gyrus in UD vs HC, and in the left superior medial gyrus in BD vs HC. CONCLUSION: This is one of very few studies directly showing differences in FA between BD and UD. Gray matter FA changes in prefrontal areas might be precursors for future prefrontal gray matter abnormalities in these disorders.

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.

BACKGROUND: 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. OBJECTIVE: To detect microstructural cerebellar tissue alterations in early MS patients with a "normal appearing" cerebellum using diffusion tensor imaging (DTI). METHODS: A total of 68 patients with relapsing-remitting MS (RRMS) and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). RESULTS: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS (N=23, median age 30 years, median Expanded Disability Status Scale =1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. CONCLUSION: "Normal appearing" cerebellar white matter can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage.

TCD-Profiling Using AVERAGE. A New Technique to Evaluate Transcranial Doppler Ultrasound Flow Spectra of Subjects with Cerebral Small Vessel Disease.

BACKGROUND: 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. METHODS: We developed a technique to generate normalized and averaged flow spectra during middle cerebral artery Doppler ultrasound examinations. Second, acceleration curves were calculated, and the absolute amount of the maximum positive and negative acceleration was calculated. Findings were termed 'TCD-profiling coefficient' (TPC). Validation study: we applied this noninvasive method to 5 young adults for reproducibility. Degenerative microangiopathy study: we also tested this new technique in 30 elderly subjects: 15 free of symptoms but with MRI-verified presence of cerebral SVD, and 15 healthy controls. SVD severity was graded according to a predefined score. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) study: TPC values of 10 CADASIL patients were compared with those of 10 healthy controls. Pulse wave analysis and local measurements of carotid stiffness were also performed. CADASIL patients were tested for cognitive impairment with the Montreal Cognitive Assessment scale. White matter and basal ganglia lesions in their cerebral MRI were evaluated according to the Wahlund score. RESULTS: Validation study: the technique delivered reproducible results. Degenerative microangiopathy study: patients with SVD had significantly larger TPCs compared with controls (SVD: 2,132; IQR 1,960-2,343%/s vs. CONTROLS: 1,935; IQR 1,782-2,050%/s, p = 0.01). TPC values of subjects with SVD significantly correlated with SVD severity scores (R = 0.58, n = 15, p < 0.05). CADASIL study: TPC values of CADASIL patients were significantly higher than values of the controls (CADASIL: 2,504; IQR 2,308-2,930%/s vs. controls 2,084; 1,839-2,241%/s, p = 0.008), and also significantly higher than the TPC values of the patients with SVD from the degenerative microangiopathy study (p = 0.007). CADASIL patients had significantly worse cognitive test results than healthy controls. CONCLUSION: TCD-profiling detects impairment of the cerebral microcirculatory state. The suitability of the TCD-profiling for the evaluation of cerebral microangiopathy was confirmed.

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.

Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study.

BACKGROUND: 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. METHODS: We employed a force transducer based quantitative-motor system (Q-Motor) to objectively assess tongue function in 33 patients with MS. The variability of tongue force output (TFV) and the mean applied tongue force (TF) were measured during an isometric tongue protrusion task. Twenty-three age and gender matched healthy volunteers served as controls. Correlation analyses of motor performance in MS patients with individual disease burden as expressed by the Expanded Disability Status Scale (EDSS) and with microstructural brain damage as measured by the fractional anisotropy (FA) on Diffusion Tensor Imaging were performed. RESULTS: MS patients showed significantly increased TFV and decreased TF compared to controls (p < 0.02). TFV but not TF was correlated with the EDSS (p < 0.04). TFV was inversely correlated with FA in the bilateral posterior limb of the internal capsule expanding to the brain stem (p < 0.001), a region critical to tongue function. TF showed a weaker, positive and unilateral correlation with FA in the same region (p < 0.001). CONCLUSIONS: Changes in TFV were more robust and correlated better with disease phenotype and FA changes than TF. TFV might serve as an objective and non-invasive outcome measure to augment the quantitative assessment of motor dysfunction in MS.

Assessment of immune functions and MRI disease activity in relapsing-remitting multiple sclerosis patients switching from natalizumab to fingolimod (ToFingo-Successor).

BACKGROUND: 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. METHODS/DESIGN: This is an exploratory, open-label, monocentric, investigator-initiated clinical trial. Fifteen RRMS patients under stable treatment with natalizumab will receive one last natalizumab infusion followed by a wash-out period of 8 weeks before fingolimod treatment initiation for a period of 24 weeks. Disease activity under natalizumab and during switching will be closely monitored by assessment of relapse rate and disease severity as well as high-frequent high-resolution magnetic resonance imaging including quantitative diffusion tensor imaging. Immunological assays include longitudinal assessment of adhesion molecule expression, functional evaluation of the migratory capacity of immune cells in an in-vitro model of the blood-brain-barrier, and the quality of cellular antiviral immune responses. DISCUSSION: Our trial represents the first detailed and longitudinal functional analysis of key immunological parameters in the process of switching from natalizumab and fingolimod, especially with regard to potential additive effects of both drugs on trafficking and immune surveillance. Moreover, our study will generate valuable information about even subtle disease exacerbations as consequence of natalizumab cessation, which will help to understand whether a switching protocol containing a wash-out period of 8 weeks before fingolimod treatment is appropriate in terms of disease stability.

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.

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.

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.

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.

Early microstructural white matter changes in patients with HIV: a diffusion tensor imaging study.

BACKGROUND: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV). METHODS: We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests. RESULTS: Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients (HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV-MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV-associated neurocognitive disorder showed widespread FA-reduction. CONCLUSION: These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather than a reactive origin of depression in HIV-patients.

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.

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.

BACKGROUND AND OBJECTIVES: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). METHODS: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. RESULTS: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. DISCUSSION: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

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.

BACKGROUND AND PURPOSE: Language training success in chronic aphasia remains only moderate. Electric brain stimulation may be a viable way to enhance treatment efficacy. METHODS: In a randomized, double-blind, sham-controlled crossover trial, we assessed if anodal transcranial direct current stimulation compared to cathodal transcranial direct current stimulation and sham stimulation over the right temporo-parietal cortex would improve the success of short-term high-frequency anomia training. Twelve chronic poststroke aphasia patients were studied. Naming outcome was assessed after training and 2 weeks later. RESULTS: All training conditions led to a significant increase in naming ability, which was retained for at least 2 weeks after the end of the training. Application of anodal transcranial direct current stimulation significantly enhanced the overall training effect compared to sham stimulation. Baseline naming ability significantly predicted anodal transcranial direct current stimulation effects. CONCLUSIONS: Anodal transcranial direct current stimulation applied over the nonlanguage dominant hemisphere can enhance language training outcome in chronic aphasia. Clinical Trial Registration- URL: www.clinicaltrials.gov/. Unique identifier: NCT00822068.

Microstructural and volumetric abnormalities of the putamen in juvenile myoclonic epilepsy.

PURPOSE: 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). METHODS: We performed DTI and MRI for 10 patients with JME and 59 age-matched neurologically healthy volunteers. Evaluation of microstructural damage was investigated using calculation of mean fractional anisotropy (FA) values in a priori regions of interest (ROIs) for the putamen, frontal lobe, and a thalamocortical region, after application of an improved eddy current correction method and a new statistical parametric mapping (SPM)-compatible toolbox incorporating intensive multicontrast FA image registration. Stereologic analysis on MRI was performed to estimate macroscopic volume of the putamen in both cerebral hemispheres for all subjects. KEY FINDINGS: Relative to controls, patients had significantly reduced FA in the frontal lobe (p = 0.01) and thalamocortical fiber WM (p < 0.001). In contrast, putamen FA was bilaterally increased (p = 0.01) and correlated with decreasing putamen volume (r(2) = -0.63, p = 0.004) in patients only. Putamen FA correlated negatively with onset of JME (total: r(2) = -0.50, p = 0.01), duration of JME (r(2) = 0.52, p = 0.01), and thalamocortical fiber FA (r(2) = -0.47, p = 0.01). SIGNIFICANCE: This is the first evidence of combined microstructural and macrostructural putamen abnormalities in patients with JME, with early age of onset and a longer duration of epilepsy being significant predictors for greater architectural alterations. These findings are consistent with studies indicating neurophysiologic abnormalities of frontostriatal networks in patients with JME, and may contribute to explain the frequent presentation of executive dysfunction in these patients. Confirmation and further exploration of the increase in putamen FA in patients with JME is required in larger samples.

Extremely low-energy ARPES of quantum well states in cubic-GaN/AlN and GaAs/AlGaAs heterostructures.

Quantum well (QW) heterostructures have been extensively used for the realization of a wide range of optical and electronic devices. Exploiting their potential for further improvement and development requires a fundamental understanding of their electronic structure. So far, the most commonly used experimental techniques for this purpose have been all-optical spectroscopy methods that, however, are generally averaging in momentum space. Additional information can be gained by angle-resolved photoelectron spectroscopy (ARPES), which measures the electronic structure with momentum resolution. Here we report on the use of extremely low-energy ARPES (photon energy ~ 7 eV) to increase depth sensitivity and access buried QW states, located at 3 nm and 6 nm below the surface of cubic-GaN/AlN and GaAs/AlGaAs heterostructures, respectively. We find that the QW states in cubic-GaN/AlN can indeed be observed, but not their energy dispersion, because of the high surface roughness. The GaAs/AlGaAs QW states, on the other hand, are buried too deep to be detected by extremely low-energy ARPES. Since the sample surface is much flatter, the ARPES spectra of the GaAs/AlGaAs show distinct features in momentum space, which can be reconducted to the band structure of the topmost surface layer of the QW structure. Our results provide important information about the samples' properties required to perform extremely low-energy ARPES experiments on electronic states buried in semiconductor heterostructures.

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.

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.