Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort.

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.

Mapping visuospatial attention: the greyscales task in combination with repetitive navigated transcranial magnetic stimulation.

BACKGROUND: Visuospatial attention is executed by the frontoparietal cortical areas of the brain. Damage to these areas can result in visual neglect. We therefore aimed to assess a combination of the greyscales task and repetitive navigated transcranial magnetic stimulation (rTMS) to identify cortical regions involved in visuospatial attention processes. This pilot study was designed to evaluate an approach in a cohort of healthy volunteers, with the future aim of using this technique to map brain tumor patients before surgery. Ten healthy, right-handed subjects underwent rTMS mapping of 52 cortical spots in both hemispheres. The greyscales task was presented tachistoscopically and was time-locked to rTMS pulses. The task pictures showed pairs of horizontal rectangles shaded continuously from black at one end to white at the other, mirror-reversed. On each picture the subject was asked to report which of the two greyscales appeared darker overall. The responses were categorized into "leftward" and "rightward," depending on whether the subject had chosen the rectangle with the darker end on the left or the right. rTMS applied to cortical areas involved in visuospatial attention is supposed to affect lateral shifts in spatial bias. These shifts result in an altered performance on the greyscales task compared to the baseline performance without rTMS stimulation. RESULTS: In baseline conditions, 9/10 subjects showed classic pseudoneglect to the left. Leftward effects also occurred more often in mapping conditions. Yet, calculated rightward deviations were strikingly greater in magnitude (p < 0.0001). Overall, the right hemisphere was found to be more suggestible than the left hemisphere. Both rightward and leftward deviation scores were higher for the rTMS of this brain side (p < 0.0001). Right hemispheric distributions accord well with current models of visuospatial attention (Corbetta et al. Nat Neurosci 8(11):1603-1610, 2005). We observed leftward deviations triggered by rTMS within superior frontal and posterior parietal areas and rightward deviations within inferior frontal areas and the temporoparietal junction (TPJ). CONCLUSION: The greyscales task, in combination with rTMS, yields encouraging results in the examination of the visuospatial attention function. Future clinical implications should be evaluated.

Mapping of Arithmetic Processing by Navigated Repetitive Transcranial Magnetic Stimulation in Patients with Parietal Brain Tumors and Correlation with Postoperative Outcome.

BACKGROUND: Preserving functionality is important during neurosurgical resection of brain tumors. Specialized centers also map further brain functions apart from motor and language functions, such as arithmetic processing (AP). The mapping of AP by navigated repetitive transcranial magnetic stimulation (nrTMS) in healthy volunteers has been reported. OBJECTIVE: The present study aimed to correlate the results of mapping AP with functional patient outcomes. METHODS: We included 26 patients with parietal brain tumors. Because of preoperative impairment of AP, mapping was not possible in 8 patients (31%). We stimulated 52 cortical sites by nrTMS while patients performed a calculation task. Preoperatively and postoperatively, patients underwent a standardized number-processing and calculation test (NPCT). Tumor resection was blinded to nrTMS results, and the change in NPCT performance was correlated to resected AP-positive spots as identified by nrTMS. RESULTS: The resection of AP-positive sites correlated with a worsening of the postoperative NPCT result in 12 cases. In 3 cases, no AP-positive sites were resected and the postoperative NPCT result was similar to or better than preoperatively. Also, in 3 cases, the postoperative NPCT result was better than preoperatively, although AP-positive sites were resected. CONCLUSIONS: Despite presenting only a few cases, nrTMS might be a useful tool for preoperative mapping of AP. However, the reliability of the present results has to be evaluated in a larger series and by intraoperative mapping data.

Loss of Subcortical Language Pathways Correlates with Surgery-Related Aphasia in Patients with Brain Tumor: An Investigation via Repetitive Navigated Transcranial Magnetic Stimulation-Based Diffusion Tensor Imaging Fiber Tracking.

BACKGROUND: Within language function research, there is a shift of focus from cortical specialization to a more hodotopical view including subcortical fiber tracts in functional and oncologic considerations. Diffusion tensor imaging fiber tracking (DTI FT) is well established to visualize subcortical fiber tracts. Recently, a new technique has been developed using cortical regions mapped via repetitive navigated transcranial magnetic stimulation (rTMS) as seed regions. This study investigates if rTMS-based DTI FT for language pathways is also feasible postoperatively and whether preoperative versus postoperative fiber changes correlate with changes and severity of the patients' aphasia grades. METHODS: rTMS-based DTI FT was performed preoperatively and postoperatively in 24 patients with left hemispheric perisylvian tumors. Language pathways were analyzed individually preoperatively and postoperatively with 5 different settings of minimum fiber length and fractional anisotropy. Transient aphasia was defined as any new or worse language impairment caused by surgery that resolved within the regular 3-month follow-up interval. Because postoperative aphasia does not allow rTMS language mapping, preoperative rTMS data were used throughout. RESULTS: Patients with transient aphasia postoperatively had a significant reduction in fiber count compared with patients without deficit (321.5 ± 242.8 fibers vs. 518.0 ± 435.2 fibers; P = 0.01). Furthermore, in this patient group, the arcuate fascicle was lost postoperatively twice as often compared with patients with no deficit after surgery (52% vs. 26%; P < 0.01). CONCLUSIONS: This study shows that rTMS-based DTI FT is feasible for postoperative examination of language pathways. Moreover, changes in preoperative versus postoperative fibers correlate well with the grade of aphasia.

Non-invasive Mapping of Face Processing by Navigated Transcranial Magnetic Stimulation.

Background: Besides motor and language function, tumor resections within the frontal and parietal lobe have also been reported to cause neuropsychological impairment like prosopagnosia. Objective: Since non-navigated transcranial magnetic stimulation (TMS) has previously been used to map neuropsychological cortical function, this study aims to evaluate the feasibility and spatial discrimination of repetitive navigated TMS (rTMS) mapping for detection of face processing impairment in healthy volunteers. The study was also designed to establish this examination for preoperative mapping in brain tumor patients. Methods: Twenty healthy and purely right-handed volunteers (11 female, 9 male) underwent rTMS mapping for cortical face processing function using 5 Hz/10 pulses. Both hemispheres were investigated randomly with an interval of 2 weeks between mapping sessions. Fifty-two predetermined cortical spots of the whole hemispheres were mapped after baseline measurement. The task consisted of 80 portraits of popular persons, which had to be named while rTMS was applied. Results: In 80% of all subjects rTMS elicited naming errors in the right middle middle frontal gyrus (mMFG). Concerning anomia errors, the highest error rate (35%) was achieved in the bilateral triangular inferior frontal gyrus (trIFG). With regard to similarly or wrongly named persons, we observed 10% error rates mainly in the bilateral frontal lobes. Conclusion: It seems feasible to map the cortical face processing function and to generate face processing impairment via rTMS. The observed localizations are well in accordance with the contemporary literature, and the mapping did not interfere with rTMS-induced language impairment. The clinical usefulness of preoperative mapping has to be evaluated subsequently.

Interhemispheric connectivity revealed by diffusion tensor imaging fiber tracking derived from navigated transcranial magnetic stimulation maps as a sign of language function at risk in patients with brain tumors.

OBJECTIVE Resection of brain tumors in language-eloquent areas entails the risk of postoperative aphasia. It has been demonstrated via navigated transcranial magnetic stimulation (nTMS) that language function can partially shift to the unaffected hemisphere due to tumor-induced plasticity. Therefore, this study was designed to evaluate whether interhemispheric connectivity (IC) detected by nTMS-based diffusion tensor imaging-fiber tracking (DTI-FT) can be used to predict surgery-related aphasia in patients with brain tumors. METHODS Thirty-eight patients with left-sided perisylvian brain lesions underwent cortical language mapping of both hemispheres by nTMS prior to awake surgery. Then, nTMS-based DTI-FT was conducted with a fractional anisotropy (FA) of 0.01 and 0.2 to visualize nTMS-based IC. Receiver operating characteristics were calculated for the prediction of a postoperative (irrespective of the preoperative state) and a new surgery-related aphasia by the presence of detectable IC. RESULTS Language mapping by nTMS was possible in all patients. Seventeen patients (44.7%) suffered from surgery-related worsening of language performance (transient aphasia according to 3-month follow-up in 16 subjects [42.1%]; new permanent aphasia according to 3-month follow-up in 1 patient [2.6%]). Regarding the correlation of aphasia to nTMS-based IC, statistically significant differences were revealed for both evaluated FA values. However, better results were observed for tractography with an FA of 0.2, which led to a specificity of 93% (postoperative aphasia) and 90% (surgery-related aphasia). For postoperative aphasia, the corresponding OR was 0.1282 (95% CI 0.0143-1.1520), and for surgery-related aphasia the OR was 0.1184 (95% CI 0.0208-0.6754). CONCLUSIONS According to these results, IC detected by preoperative nTMS-based DTI-FT might be regarded as a risk factor for surgery-related aphasia, with a specificity of up to 93%. However, because the majority of enrolled patients suffered from transient aphasia postoperatively, it has to be evaluated whether this approach distinctly leads to similar results among patients with permanent language deficits. Despite this restriction, this approach might contribute to individualized patient consultation prior to tumor resection in clinical practice.