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Endothelial dysfunction represents a potential pathomechanism of neurological post-COVID-19 syndrome (PCS). A recent study demonstrated reduced cerebrovascular reactivity (CVR) in patients with PCS. The aim of this pilot study was to prospectively assess CVR in patients with PCS using breath-hold functional MRI (bh-fMRI). Fourteen patients with neurological PCS and leading symptoms of fatigue/memory issues/concentration disorder (PCSfmc), 11 patients with PCS and leading symptoms of myopathy/neuropathy (PCSmn), and 17 healthy controls underwent bh-fMRI. Signal change and time to peak (TTP) were assessed globally and in seven regions of interest and compared between the subgroups using one-way ANCOVA adjusting for age, time since infection, Fazekas score, and sex. No significant differences were observed. In PCS patients, the global CVR exhibited a slight, non-significant tendency to be lower compared to healthy controls (PCSfmc: 0.78 ± 0.11%, PCSmn: 0.84 ± 0.10% and 0.87 ± 0.07%). There was a non-significant trend towards lower global TTP values in the PCS subgroups than in the control group (PCSfmc: 26.41 ± 1.39 s, PCSmn: 26.32 ± 1.36 s versus 29.52 ± 0.93 s). Endothelial dysfunction does not seem to be the sole pathomechanism of neurological symptoms in PCS. Further studies in larger cohorts are required.

Background: Perianal rhabdomyosarcoma ((P)RMS) are rare and have a poor prognosis. Data in young children are limited and local therapy is not well defined. Combined brachytherapy and surgery is routinely being used for RMS at other sites in children as it provides good oncologic outcomes and allows for organ-sparing surgery. The objective of this study was to evaluate this combination treatment for local tumor control and organ-sparing surgery in young children with (P)RMS. Methods: A retrospective review of the medical records of all children who underwent surgery and brachytherapy for (P)RMS at our institution since 2009 was conducted. Results: Surgery for (P)RMS was performed in 6 patients at a median age of 19 months (range 8–50). Embryonal RMS was diagnosed in 4 patients and alveolar RMS in 2 patients, of which 1 patient had FOXO1 fusion-positive RMS. All patients underwent postoperative high-dose rate (HDR) brachytherapy. Organ-preserving surgery was achieved in 5 of 6 patients (83 %). In 1 patient, the entire sphincter was infiltrated, making organ-preserving resection impossible. 5 of 6 patients (83 %) exhibited an event-free and overall survival at a median follow-up of 26 months (range 8–107). One patient died due to locoregional recurrence. Complications were urethral leakage in 1 patient followed by urethral stenosis and delayed wound healing and vaginal stenosis in another patient. No patient reported fecal incontinence. Conclusions: Combined treatment with surgery and HDR brachytherapy is feasible in very young children with (P)RMS and leads to a favorable oncologic outcome. Preliminary data show a good functional preservation.

Abstract Introduction In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. Methods ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing–Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing–Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. Perspective Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)—ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034

Abstract Differential diagnosis between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) using cerebrospinal fluid (CSF) biomarkers is challenging. A recent study suggested that the addition of Aβ38 and Aβ43 to a standard AD biomarker panel (Aβ40, Aβ42, t‐tau, p‐tau) to improve the differential diagnosis. We tested this hypothesis in an independent German cohort of CAA and AD patients and controls using the same analytical techniques. We found excellent discrimination between AD and controls and between CAA and controls, but not between AD and CAA. Adding Aβ38 and Aβ43 to the panel did not improve the discrimination between AD and CAA.

In neuroimaging, there is no equivalent alternative to magnetic resonance imaging (MRI). However, image acquisitions are generally time-consuming, which may limit utilization in some cases, e.g., in patients who cannot remain motionless for long or suffer from claustrophobia, or in the event of extensive waiting times. For multiple sclerosis (MS) patients, MRI plays a major role in drug therapy decision-making. The purpose of this study was to evaluate whether an ultrafast, T2-weighted (T2w), deep learning-enhanced (DL), echo-planar-imaging-based (EPI) fluid-attenuated inversion recovery (FLAIR) sequence (FLAIRUF) that has targeted neurological emergencies so far might even be an option to detect MS lesions of the brain compared to conventional FLAIR sequences. Therefore, 17 MS patients were enrolled prospectively in this exploratory study. Standard MRI protocols and ultrafast acquisitions were conducted at 3 tesla (T), including three-dimensional (3D)-FLAIR, turbo/fast spin-echo (TSE)-FLAIR, and FLAIRUF. Inflammatory lesions were grouped by size and location. Lesion conspicuity and image quality were rated on an ordinal five-point Likert scale, and lesion detection rates were calculated. Statistical analyses were performed to compare results. Altogether, 568 different lesions were found. Data indicated no significant differences in lesion detection (sensitivity and positive predictive value [PPV]) between FLAIRUF and axially reconstructed 3D-FLAIR (lesion size ≥3 mm × ≥2 mm) and no differences in sensitivity between FLAIRUF and TSE-FLAIR (lesion size ≥3 mm total). Lesion conspicuity in FLAIRUF was similar in all brain regions except for superior conspicuity in the occipital lobe and inferior conspicuity in the central brain regions. Further findings include location-dependent limitations of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) as well as artifacts such as spatial distortions in FLAIRUF. In conclusion, FLAIRUF could potentially be an expedient alternative to conventional methods for brain imaging in MS patients since the acquisition can be performed in a fraction of time while maintaining good image quality.

The ongoing controversies about the neural basis of tinnitus, whether linked with central neural gain or not, may hamper efforts to develop therapies. We asked to what extent measurable audiometric characteristics of tinnitus without (T) or with co-occurrence of hyperacusis (TH) are distinguishable on the level of cortical responses. To accomplish this, electroencephalography (EEG) and concurrent functional near-infrared spectroscopy (fNIRS) were measured while patients performed an attentionally demanding auditory discrimination task using stimuli within the individual tinnitus frequency (fTin) and a reference frequency (fRef). Resting-state-fMRI-based functional connectivity (rs-fMRI-bfc) in ascending auditory nuclei (AAN), the primary auditory cortex (AC-I), and four other regions relevant for directing attention or regulating distress in temporal, parietal, and prefrontal cortex was compiled and compared to EEG and concurrent fNIRS activity in the same brain areas. We observed no group differences in pure-tone audiometry (PTA) between 10 and 16 kHz. However, the PTA threshold around the tinnitus pitch was positively correlated with the self-rated tinnitus loudness and also correlated with distress in T-groups, while TH experienced their tinnitus loudness at minimal loudness levels already with maximal suffering scores. The T-group exhibited prolonged auditory brain stem (ABR) wave I latency and reduced ABR wave V amplitudes (indicating reduced neural synchrony in the brainstem), which were associated with lower rs-fMRI-bfc between AAN and the AC-I, as observed in previous studies. In T-subjects, these features were linked with elevated spontaneous and reduced evoked gamma oscillations and with reduced deoxygenated hemoglobin (deoxy-Hb) concentrations in response to stimulation with lower frequencies in temporal cortex (Brodmann area (BA) 41, 42, 22), implying less synchronous auditory responses during active auditory discrimination of reference frequencies. In contrast, in the TH-group gamma oscillations and hemodynamic responses in temporoparietal regions were reversed during active discrimination of tinnitus frequencies. Our findings suggest that T and TH differ in auditory discrimination and memory-dependent directed attention during active discrimination at either tinnitus or reference frequencies, offering a test paradigm that may allow for more precise sub-classification of tinnitus and future improved treatment approaches.

Abstract Image templates are a common tool for neuroscience research. Often, they are used for spatial normalization of magnetic resonance imaging (MRI) data, which is a necessary procedure for analyzing brain morphology and function via voxel-based analysis. This allows the researcher to reduce individual shape differences across images and make inferences across multiple subjects. Many templates have a small field-of-view typically focussed on the brain, limiting the use for applications requiring detailed information about other extra-cranial structures in the head and neck area. However, there are several applications where such information is important, for example source reconstruction of electroencephalography (EEG) and/or magnetoencephalography (MEG). We have constructed a new template based on 225 T1w and FLAIR images with a big field-of-view that can serve both as target for across subject spatial normalization as well as a basis to build high-resolution head models. This template is based on and iteratively re-registered to the MNI152 space to provide maximal compatibility with the most commonly used brain MRI template.

Abstract Background Noncoding RNAs such as microRNAs (miRNAs) have attracted attention as biological pathway regulators, which differ from chromosomal translocations and gene point mutations. Their involvement in the molecular mechanisms underlying light chain (AL) amyloidosis pathogenesis is yet to be elucidated. Aims To decipher specific miRNA expression profile in AL‐amyloidosis and to examine how miRNAs are involved in AL pathogenesis. Methods The expression profile of miRNAs and mRNA from bone marrow (BM)‐derived CD138+ cells were determined using the NanoString nCounter assay and RNA‐Seq, respectively. The effect of aberrantly expressed miRNAs on potential molecular targets was analyzed by qRT‐PCR, Western blot, Mito‐potential assay, and Annexin‐PI staining. Results Genes which were significantly differentially expressed between AL‐amyloidosis and MM, were found to be involved in cell growth and apoptotic mechanisms. Specifically, BCL2L1, MCL1, and BCL2 were upregulated in AL‐amyloidosis compared with MM and controls. The levels of miR‐181a‐5p and miR‐9‐5p, which regulate the above‐mentioned genes, were lower in BM samples from AL‐amyloidosis compared with controls, providing a mechanism for BCL2 family gene upregulation. When miR‐9‐5p and miR‐181a‐5p were overexpressed in ALMC1 cells, BCL2L1, MCL1, and BCL2 were downregulated and induced apoptosis. Treatment of ALMC‐1 cells with venetoclax, (BCL‐2 inhibitor), resulted in the upregulation of those miRNAs, the downregulation of BCL2, MCL1, and BCL2L1 mRNA and protein levels, and subsequent apoptosis. Conclusion Our findings suggest that miR‐9‐5p and miR‐181a‐5p act as tumor‐suppressors whose downregulation induces anti‐apoptotic mechanisms underlying the pathogenesis of AL‐amyloidosis. The study highlights the post‐transcriptional regulation in AL‐amyloidosis and provides pathogenetic evidence for the potential use of BCL‐2 inhibitors in this disease.

Abstract Objectives Metachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre‐symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation. Methods We retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated. Results We included 104 brain MRIs from patients with late‐infantile (n = 43), early‐juvenile (n = 24), late‐juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late‐infantile patients, 94% of the symptomatic early‐juvenile patients and 100% of the symptomatic late‐juvenile and adult patients. Symptomatic early‐juvenile, late‐juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early‐symptomatic late‐infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs. Interpretation Patients with late‐infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of ‘delayed myelination’, even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis.

Abstract Usage of MR imaging biomarkers is limited to experts. Automatic quantitative reports provide access for clinicians to data analysis. Automated data analysis was tested for usability in a small cohort of patients with hereditary spastic paraplegia type 4 (SPG4). We analyzed 3T MRI 3D-T1 datasets of n = 25 SPG4 patients and matched healthy controls using a commercial segmentation tool (AIRAscore structure 2.0.1) and standard VBM. In SPG4 total brain volume was reduced by 27.6 percentiles (p = 0.001) caused mainly by white matter loss (− 30.8th, p

Abstract Lewy-body pathology with aggregation of abnormal conformations of the protein alpha-synuclein (α-Syn) represent the histopathological hallmarks of Parkinson’s disease (PD). Genetic prototypes such as PD due to mutations in the alpha-synuclein gene (SNCA) offer the opportunity to evaluate α-Syn-related profiles in patient-derived biomaterial. We identified a family with a SNCA triplication and assessed the index patient for CSF α-Syn seeding capacity and levels of total α-Syn along with other neurodegenerative CSF markers (Aβ1-42, total-Tau, phospho-Tau, NFL). As no published CSF data in patients with SNCA triplication are available, we descriptively compared his CSF profiles to those of sporadic PD patients and PD patients with GBA mutations as these are also specifically associated with prominent α-Syn pathology. Additionally, skin biopsies with staining for phospho-α-Syn were done. To assess cerebral glucose metabolism and brain atrophy combined positron emission tomography and magnetic resonance imaging ([18F]FDG-PET/MRI) was performed. Age at onset was 24 years and motor impairment was accompanied by prominent non-motor symptoms with early development of dementia, depression, REM sleep behavior disorder, hyposmia, and dysautonomia. Correspondingly, PET-MRI showed hypometabolism and atrophy in frontal, temporoparietal and occipital regions. CSF levels of total α-Syn were threefold higher and RT-QuIC showed remarkable α-Syn seeding activity in all kinetic categories in the SNCATriplication patient compared to patients with GBA mutations. Our results are consistent with findings that not only mutant forms but also overexpression of the wild-type α-Syn protein lead to PD and PD dementia and show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC as a specific in vivo biomarker of α-Syn brain pathology.

Abstract Background Hypoglycemia in patients with diabetes mellitus, particularly type 1 can mimic acute ischemic stroke by causing focal neurological deficits. In acute ischemic stroke, the interpretation of emergency imaging including computed tomography with angiography and perfusion is crucial to guide revascularizing therapy including intravenous thrombolysis. However, different metabolic abnormalities and stroke mimics can cause focal hypoperfusion. Methods We describe two type 1 diabetes patients presenting with acute focal neurological deficits and hypoglycemia, who underwent multimodal computed tomography and follow-up imaging. Case presentation Patient 1, a 20-year-old man presented with aphasia and interstitial glucose level of 54 mg/dl. Patient 2, a 77-year-old man presented with aphasia, mild right-sided brachiofacial paresis and interstitial glucose level of 83 mg/dl. On brain imaging, no acute infarct signs were noted. Yet, both had focal left hemispheric cerebral hypoperfusion without large-vessel occlusion or stenosis. Due to persistent symptoms after normalization of blood glucose and despite a perfusion imaging pattern that was interpretated as non-typical for ischemia, both patients underwent thrombolysis without any complications. Conclusion Computed tomography perfusion might help to discriminate hypoglycemia with focal neurological signs from acute stroke, but further evidence is needed.

Abstract Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Heterozygous carriers of disease‐causing variants and individuals harbouring pseudodeficiency alleles in the ARSA gene exhibit reduced ARSA activity. In the context of these genotypes, low ARSA activity has been suggested to lead to an atypical form of MLD or other neurological abnormalities, but data are limited. The aim of our study was to analyse the impact of low ARSA activity in two subjects who are heterozygous for the ARSA pseudodeficiency allele and a disease‐causing variant. Biochemical testing included ARSA activity measurements and urinary sulfatide analysis. Biochemical data of a large cohort of MLD patients, heterozygotes, pseudodeficient individuals and healthy controls were analysed. MRI was performed at 3T using T1‐ and T2‐weighted sequences and MR spectroscopy. We present two long‐term follow‐ups who are heterozygous for the ARSA pseudodeficiency allele and a disease‐causing variant in the ARSA gene in cis. The two related index cases exhibit markedly reduced ARSA activity compared to controls and heterozygous carriers. The neurological evaluation and MRI do not reveal any abnormalities. Our data underline that extremely low enzyme activity due to a pseudodeficiency allele and a disease‐causing variant in the ARSA gene even in cis does not lead to clinical symptoms or pre‐symptomatic MRI changes suspicious for MLD. The review of literature corroborates that any association of low ARSA activity with disease features remains questionable. It seems important to combine the measurement of ARSA activity with elevated sulfatide as well as genetic testing, as done in current newborn screening approaches. Heterozygosity for metachromatic leukodystrophy and an arylsulfatase A pseudodeficiency allele does not cause neurological or neuropsychiatric features.

Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission.We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p

Background and purpose: Metachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to demyelination and subsequently to a progressive decline in cognitive and motor function. It affects mainly white matter where changes during the course of the disease can be visualized on T2-weighted MRI as hyperintense areas. Associated changes in brain metabolism can be quantified by MR spectroscopy (MRS) and may give complementary information as biomarkers for disease characterisation and progression. Our study aimed to further investigate the correlation of MRS with clinical parameters for motor and cognitive function by using a model free MRS analysis approach that would be precise and straightforward to implement. Materials and methods: 53 MRS datasets derived from 29 patients (10 late-infantile, 19 juvenile) and 12 controls were acquired using a semi-LASER CSI sequence covering a slice through the centrum semiovale above the corpus callosum. We defined four regions of interest in the white matter (frontal white matter [FWM] and the cortico-spinal tract [CST] area, each left and right) and one in cortical grey matter. Spectra were analysed using a model and fitting free approach by calculating the definite integral of 10 intervals which were distributed along the whole spectrum. These 10 intervals were orientated towards the main peaks of the metabolites N-acetylaspartate (NAA), creatine, myo-inositol, choline, glutamine/glutamate and aspartate to approximately attribute changes in the intervals to corresponding metabolites. Their ratios to the main creatine peak integral were correlated with clinical parameters assessing motor and cognitive abilities. Furthermore, in a post-hoc analysis, NAA levels of a subset of 21 MR datasets were correlated to NAA levels in urine measured by 1H (proton) nuclear magnetic resonance (NMR) spectroscopy.The applied interval integration method was validated in the control cohort against the standard approach, using spectral profile templates of known metabolites (LCModel). Both methods showed good agreement, with coefficients of variance being slightly lower for our approach compared to the related LCModel results. Moreover, the new approach was able to extract information out of the frequency range around the main peaks of aspartate and glutamine where LCModel showed only few usable values for the respective metabolites. Results: MLD spectra clearly differed from controls. The most pronounced differences were found in white matter (much less in grey matter), with larger values corresponding to main peaks of myo-inositol, choline and aspartate, and smaller values associated with NAA and glutamine. Late-infantile patients had more severe changes compared to later-onset patients, especially in intervals corresponding to NAA, aspartate, myo-inositol, choline and glutamine.There was a high correlation of several intervals in the corticospinal tract region with motor function (with the most relevant interval corresponding to NAA peak with a correlation coefficient of −0.75; p

Abstract Background Atypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated. Methods The clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions. Results Data from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth. Conclusions The model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients’ stratification for dose escalation.

Abstract Tinnitus is attributed to partial sensory deafferentation resulting in a central maladaptive neuroplasticity. Unfortunately, the agent of deafferentation is usually unknown or irreversible. In patients with unilateral vestibular schwannoma (VS), however, the auditory nerve is affected by a benign tumor. Hence, removal of the tumor can cease the tinnitus. In turn, sustaining complaints after surgery indicate cortical neuroplasticity. The present study is a cross sectional study which aims to track cortical structural changes by surface-based morphometry in 46 VS patients with sustained (i.e. centralized) or ceased (i.e. peripheral) tinnitus after surgery. A volumetric analysis of cortical and subcortical gray matter (GM) anatomy was performed on preoperative high-resolution MRI and related to the presence of hearing impairment, pre- and/or postoperative tinnitus. Patients with sustained (i.e. chronic) tinnitus showed an increased GM volume of the bilateral caudate nucleus, the contralateral superior colliculus, the middle frontal and middle temporal gyrus, the fusiform gyrus as well as the ipsilateral pars orbitalis when compared to those patients in whom tinnitus ceased postoperatively. Chronic tinnitus in VS patients is associated with characteristic structural changes in frontal, temporal and subcortical areas. Notably, a significant GM change of the caudate nucleus was detected providing further support for the striatal gaiting model of tinnitus.

Generative adversarial networks (GANs) can synthesize high-contrast MRI from lower-contrast input. Targeted translation of parenchymal lesions in multiple sclerosis (MS), as well as visualization of model confidence further augment their utility, provided that the GAN generalizes reliably across different scanners. We here investigate the generalizability of a refined GAN for synthesizing high-contrast double inversion recovery (DIR) images and propose the use of uncertainty maps to further enhance its clinical utility and trustworthiness. A GAN was trained to synthesize DIR from input fluid-attenuated inversion recovery (FLAIR) and T1w of 50 MS patients (training data). In another 50 patients (test data), two blinded readers (R1 and R2) independently quantified lesions in synthetic DIR (synthDIR), acquired DIR (trueDIR) and FLAIR. Of the 50 test patients, 20 were acquired on the same scanner as training data (internal data), while 30 were scanned at different scanners with heterogeneous field strengths and protocols (external data). Lesion-to-Background ratios (LBR) for MS-lesions vs. normal appearing white matter, as well as image quality parameters were calculated. Uncertainty maps were generated to visualize model confidence. Significantly more MS-specific lesions were found in synthDIR compared to FLAIR (R1: 26.7 ± 2.6 vs. 22.5 ± 2.2 p < 0.0001; R2: 22.8 ± 2.2 vs. 19.9 ± 2.0, p = 0.0005). While trueDIR remained superior to synthDIR in R1 [28.6 ± 2.9 vs. 26.7 ± 2.6 (p = 0.0021)], both sequences showed comparable lesion conspicuity in R2 [23.3 ± 2.4 vs. 22.8 ± 2.2 (p = 0.98)]. Importantly, improvements in lesion counts were similar in internal and external data. Measurements of LBR confirmed that lesion-focused GAN training significantly improved lesion conspicuity. The use of uncertainty maps furthermore helped discriminate between MS lesions and artifacts. In conclusion, this multicentric study confirms the external validity of a lesion-focused Deep-Learning tool aimed at MS imaging. When implemented, uncertainty maps are promising to increase the trustworthiness of synthetic MRI.

ObjectiveThe role of resection in progressive glioblastoma (GBM) to prolong survival is still controversial. The aim of this study was to determine 1) the predictors of post-progression survival (PPS) in progressive GBM and 2) which subgroups of patients would benefit from recurrent resection.MethodsWe have conducted a retrospective bicentric cohort study on isocitrate dehydrogenase (IDH) wild-type GBM treated in our hospitals between 2006 and 2015. Kaplan-Maier analyses and univariable and multivariable Cox regressions were performed to identify predictors and their influence on PPS.ResultsOf 589 patients with progressive IDH wild-type GBM, 355 patients were included in analyses. Median PPS of all patients was 9 months (95% CI 8.0-10.0), with complete resection 12 months (95% CI 9.7-14.3, n=81), incomplete resection 11 months (95% CI 8.9-13.1, n=70) and without resection 7 months (95% CI 06-08, n=204). Multivariable Cox regression demonstrated a benefit for PPS with complete (HR 0.67, CI 0.49-0.90) and incomplete resection (HR 0.73, 95% CI 0.51-1.04) and confirmed methylation of the O6-methylguanine-DNA-methyltransferase (MGMT) gene promoter, lower age at diagnosis, absence of deep brain and multilocular localization, higher Karnofsky Performance Status (KPS) and recurrent therapies to be associated with longer PPS. In contrast, traditional eloquence and duration of progression-free survival had no effect on PPS. Subgroup analyses showed that all subgroups of confirmed predictors benefited from resection, except for patients in poor condition with a KPS

BackgroundTo evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers in patients with probable cerebral amyloid angiopathy (CAA) according to the modified Boston criteria in a retrospective multicentric cohort.MethodsBeta-amyloid 1-40 (Aβ40), beta-amyloid 1-42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau181) were measured in 31 patients with probable CAA, 28 patients with Alzheimer’s disease (AD), and 30 controls. Receiver-operating characteristics (ROC) analyses were performed for the measured parameters as well as the Aβ42/40 ratio to estimate diagnostic parameters. A meta-analysis of all amenable published studies was conducted.ResultsIn our data Aβ42/40 (AUC 0.88) discriminated best between CAA and controls while Aβ40 did not perform well (AUC 0.63). Differentiating between CAA and AD, p-tau181 (AUC 0.75) discriminated best in this study while Aβ40 (AUC 0.58) and Aβ42 (AUC 0.54) provided no discrimination. In the meta-analysis, Aβ42/40 (AUC 0.90) showed the best discrimination between CAA and controls followed by t-tau (AUC 0.79), Aβ40 (AUC 0.76), and p-tau181 (AUC 0.71). P-tau181 (AUC 0.76), Aβ40 (AUC 0.73), and t-tau (AUC 0.71) differentiated comparably between AD and CAA while Aβ42 (AUC 0.54) did not. In agreement with studies examining AD biomarkers, Aβ42/40 discriminated excellently between AD and controls (AUC 0.92–0.96) in this study as well as the meta-analysis.ConclusionThe analyzed parameters differentiate between controls and CAA with clinically useful accuracy (AUC > ∼0.85) but not between CAA and AD. Since there is a neuropathological, clinical and diagnostic continuum between CAA and AD, other diagnostic markers, e.g., novel CSF biomarkers or other parameters might be more successful.

The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase 1–mutated (IDH1-mutated) tumor entities affirmed the role of metabolism in cancer. However, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology, and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA-Seq. We discovered comparison-specific metabolites and pathways modulated by IDH1 (IDH1 mutation status cohort) and tumor entity. The Longitudinal investigation cohort provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan-Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces potentially novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies, aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so-far–unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.

Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood.The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (n = 125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias (HSP; n = 40), a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups.After sDTI measurement at C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established.In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTFA (p

IntroductionDelirium is recognized as a severe complication of coronavirus-disease-2019 (COVID-19). COVID-19-associated delirium has been linked to worse patient outcomes and is considered to be of multifactorial origin. Here we sought to evaluate the incidence and risk factors of delirium in hospitalized COVID-19 patients, along with its impact on clinical outcome.MethodsConsecutive adult COVID-19 patients admitted to a tertiary academic referral hospital between March 1st and December 31st, 2020 were included. Potential risk factors for delirium were evaluated, including: age, gender, disease severity (as per the highest WHO grading reached during admission), laboratory parameters for infection and renal function (as per their most extreme values), and presence of comorbidities. To assess the relative strength of risk factors for predicting the occurrence of delirium, we performed a random-forest survival analysis.Results347 patients with positive COVID-19 PCR test and median age 68.2 [IQR 55.5, 80.5] years were included. Of those, 79 patients (22.8%) developed delirium, 81 (23.3%) were transferred to ICU, 58 (16.7%) died. 163 (73.8%) patients were discharged home, 13 (5.9%) to another hospital, 32 (14.5%) to nursing homes, 13 (5.9%) to rehabilitation with an overall median admission-to-discharge time of 53 [IQR 14, 195] days. The strongest predictors for the occurrence of delirium were blood urea nitrogen (minimal depth value (MD): 3.33), age (MD: 3.75), disease severity (as captured by WHO grading; MD: 3.93), leukocyte count (MD: 4.22), the presence of a neurodegenerative history (MD: 4.43), ferritin (MD: 4.46) and creatinine (MD: 4.59) levels.ConclusionThe risk of delirium in COVID-19 can be stratified based on COVID-19 disease severity and-similar to delirium associated with other respiratory infections-the factors advanced age, neurodegenerative disease history, and presence of elevated infection and renal-retention parameters. Screening for these risk factors may facilitate early identification of patients at high-risk for COVID-19-associated delirium.

ObjectiveThe exact role of the extent of resection or residual tumor volume on overall survival in glioblastoma patients is still controversial. Our aim was to create a statistical model showing the association between resection extent/residual tumor volume and overall survival and to provide a nomogram that can assess the survival benefit of individual patients and serve as a reference for non-randomized studies.MethodsIn this retrospective multicenter cohort study, we used the non-parametric Cox regression and the parametric log-logistic accelerated failure time model in patients with glioblastoma. On 303 patients (training set), we developed a model to evaluate the effect of the extent of resection/residual tumor volume on overall survival and created a score to estimate individual overall survival. The stability of the model was validated by 20-fold cross-validation and predictive accuracy by an external cohort of 253 patients (validation set).ResultsWe found a continuous relationship between extent of resection or residual tumor volume and overall survival. Our final accelerated failure time model (pseudo R2 = 0.423; C-index = 0.749) included residual tumor volume, age, O6-methylguanine-DNA-methyltransferase methylation, therapy modality, resectability, and ventricular wall infiltration as independent predictors of overall survival. Based on these factors, we developed a nomogram for assessing the survival of individual patients that showed a median absolute predictive error of 2.78 (mean: 1.83) months, an improvement of about 40% compared with the most promising established models.ConclusionsA continuous relationship between residual tumor volume and overall survival supports the concept of maximum safe resection. Due to the low absolute predictive error and the consideration of uneven distributions of covariates, this model is suitable for clinical decision making and helps to evaluate the results of non-randomized studies.

Abstract Background As optic nerve sheath meningiomas (ONSM) are rare, there are no prospective studies. Our retrospective analysis focusses on a cohort of patients with uniform disease characteristics all treated with the same radiotherapy regimen. We describe treatment decision making, radiotherapy planning and detailed neuro-ophthalmological outcome of the patients. Methods 26 patients with unilateral ONSM extending only to the orbit and the optic canal were evaluated for neuro-ophthalmological outcome. Radiation treatment was planned in a simultaneous integrated boost approach to gross tumor volume (GTV) + 2 mm / 5 mm to 54 Gy / 51 Gy in 1.8 Gy / 1.7 Gy fractions. Follow-up was done by specialized neuro-ophthalmologists. Visual acuity and visual field defects were evaluated after therapy as well as during follow-up. Results Interdisciplinary treatment decision for patients with ONSM follows a rather complex decision tree. Radiation treatment planning (equivalent uniform dose (EUD), maximum dose to the optic nerve) improved with experience over time. With this patient selection visual acuity as well as visual field improved significantly at first follow-up after treatment. For visual acuity this also applied to patients with severe defects before treatment. Long term evaluation showed 16 patients with improved visual function, 6 were stable, in 4 patients visual function declined. Interdisciplinary case discussion rated the visual decline as radiation-associated in two patients. Conclusions With stringent patient selection radiotherapy for unilateral primary ONSM to 51 Gy / 54 Gy is safe and leads to significantly improved visual function. Interdisciplinary treatment decision and experience of the radiation oncology team play a major role.

Abstract Background Various prognostic factors have been suggested in meningioma patients including WHO grading, brain invasion and bone involvement, for instance. Brain invasion was included as an independent criterion in the recent WHO classification. However, assessability of brain or bone involvement is often limited or varies between histopathologic, operative and imaging reports. Objective of our study was to investigate prognostic values including brain and bone involvement according to different clinical approaches. Methods A cohort of 111 patients was treated with primary, adjuvant or salvage irradiation between 2008 and 2017 using intensity-modulated radiotherapy. Positron-emission tomography (PET) was available for treatment planning in 81% of patients. Clinical data were extracted from the medical reports. Brain and bone involvement were stratified separately according to histopathologic, operative and imaging reports as well as judged in synopsis. Results WHO grade I tumours, lower estimated proliferation index, primary versus recurrence treatment and localization (i.e. skull base, optic nerve sheath) were beneficial prognostic factors for local control. Judgement of brain and bone invasion partly differed between diagnostic modalities. In synopsis, brain or bone invasion did not show a significant influence on local control rates. Conclusions Several previously described prognostic factors could be reproduced. However, partly divergent histopathological, surgical and image-based judgements could be found in regard to brain and bone invasion and all methods imply limitations. Therefore, we suggest a particular, complemental synopsis judgement. In synopsis, brain or bone involvement did not coherently impair local control in our irradiated patients. This might be explained by elaborate radiation techniques and PET-based treatment planning.

Background and Purpose: It is believed that stroke occurring due to posterior circulation large vessel occlusion (PCLVO) and that occurring due to anterior circulation large vessel occlusion (ACLVO) differ in terms of their pathophysiology and the outcome of their acute management in relation to endovascular mechanical thrombectomy (MT). Limited sample size and few randomized controlled trials (RCTs) with respect to PCLVO make the safety and efficacy of MT, which has been confirmed in ACLVO, difficult to assess in the posterior circulation. We therefore conducted a meta-analysis to study to which extent MT in PCLVO differs from ACLVO.Materials and Methods: We searched the databases PubMed, Cochrane, and EMBASE for studies published between 2010 and January 2021, with information on risk factors, safety, and efficacy outcomes of MT in PCLVO vs. ACLVO and conducted a systematic review and meta-analysis; we compared baseline characteristics, reperfusion treatment profiles [including rates of intravenous thrombolysis (IVT) and onset-to-IVT and onset-to-groin puncture times], recanalization success [Thrombolysis In Cerebral Infarction scale (TICI) 2b/3], symptomatic intracranial hemorrhage (sICH), and favorable functional outcome [modified Rankin Score (mRS) 0–2] and mortality at 90 days.Results: Sixteen studies with MT PCLVO (1,172 patients) and ACLVO (7,726 patients) were obtained from the search. The pooled estimates showed higher baseline National Institutes of Health Stroke Scale (NIHSS) score (SMD 0.32, 95% CI 0.15–0.48) in the PCLVO group. PCLVO patients received less often IVT (OR 0.65, 95% CI 0.53–0.79). Onset-to-IVT time (SMD 0.86, 95% CI 0.45–1.26) and onset-to-groin puncture time (SMD 0.59, 95% CI 0.33–0.85) were longer in the PCLVO group. The likelihood of obtaining successful recanalization and favorable functional outcome at 90 days was comparable between the two groups. PCLVO was, however, associated with less sICH (OR 0.56, 95% CI 0.37–0.85) but higher mortality (OR 1.92, 95% CI 1.46–2.53).Conclusions: This meta-analysis indicates that MT in PCLVO may be comparably efficient in obtaining successful recanalization and 90 day favorable functional outcome just as in ACLVO. Less sICH in MT-treated PCLVO patients might be the result of the lower IVT rate in this group. Higher baseline NIHSS and longer onset-to-IVT and onset-to-groin puncture times may have contributed to a higher 90 day mortality in PCLVO patients.

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with (“lesional”) and without (“non-lesional”) radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68–75%) compared to models to lateralize the side of TLE (56–73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67–75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68–76%) than models that stratified non-lesional patients (53–62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.

Background: Studies have previously shown evidence for presymptomatic cortical atrophy in genetic FTD. Whilst initial investigations have also identified early deep grey matter volume loss, little is known about the extent of subcortical involvement, particularly within subregions, and how this differs between genetic groups. Methods: 480 mutation carriers from the Genetic FTD Initiative (GENFI) were included (198 GRN, 202 C9orf72, 80 MAPT), together with 298 non-carrier cognitively normal controls. Cortical and subcortical volumes of interest were generated using automated parcellation methods on volumetric 3 T T1-weighted MRI scans. Mutation carriers were divided into three disease stages based on their global CDR® plus NACC FTLD score: asymptomatic (0), possibly or mildly symptomatic (0.5) and fully symptomatic (1 or more). Results: In all three groups, subcortical involvement was seen at the CDR 0.5 stage prior to phenoconversion, whereas in the C9orf72 and MAPT mutation carriers there was also involvement at the CDR 0 stage. In the C9orf72 expansion carriers the earliest volume changes were in thalamic subnuclei (particularly pulvinar and lateral geniculate, 9–10%) cerebellum (lobules VIIa-Crus II and VIIIb, 2–3%), hippocampus (particularly presubiculum and CA1, 2–3%), amygdala (all subregions, 2–6%) and hypothalamus (superior tuberal region, 1%). In MAPT mutation carriers changes were seen at CDR 0 in the hippocampus (subiculum, presubiculum and tail, 3–4%) and amygdala (accessory basal and superficial nuclei, 2–4%). GRN mutation carriers showed subcortical differences at CDR 0.5 in the presubiculum of the hippocampus (8%). Conclusions: C9orf72 expansion carriers show the earliest and most widespread changes including the thalamus, basal ganglia and medial temporal lobe. By investigating individual subregions, changes can also be seen at CDR 0 in MAPT mutation carriers within the limbic system. Our results suggest that subcortical brain volumes may be used as markers of neurodegeneration even prior to the onset of prodromal symptoms.

Abstract Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been suggested as a treatment to reduce accumulation of thymidine and deoxyuridine. However, all studies so far have failed to measure the toxic metabolites in cerebrospinal fluid (CSF), which is the crucial compartment for CNS damage. Our study is the first prospective, longitudinal investigation, exploiting detailed serial testing of predefined clinical and molecular outcome parameters (including serial CSF assessments) in a 29-year-old MNGIE patient undergoing 1 year of extensive HMD. We demonstrate that HMD only transiently restores increased serum and urine levels of thymidine and deoxyuridine, but fails to reduce CSF levels of the toxic metabolites and is ineffective to influence neurological function. These findings have direct important implications for clinical practice: They prevent a burdensome, long-term invasive, but ultimately probably ineffective procedure in future MNGIE patients.

An amendment to this paper has been published and can be accessed via the original article.

Background Intravenous thrombolysis (IVT) in wake‐up stroke (WUS) or stroke with unknown onset (SUO) has been recently proven to be safe and effective using advanced neuroimaging (magnetic resonance imaging or computerized tomography‐perfusion) for patient selection. However, in most of the thrombolyzing centers advanced neuroimaging is not instantly available. We hypothesize that pragmatic non‐contrast computed tomography‐based IVT in WUS/SUO may be feasible and safe. Methods and Results TRUST‐CT (Thrombolysis in Stroke With Unknown Onset Based on Non‐Contrast Computerized Tomography) is an international multicenter registry‐based study. WUS/SUO patients undergoing non‐contrast computed tomography‐based IVT with National Institute of Health Stroke Scale ≥4 and initial Alberta Stroke Program Early Computerized Tomography score ≥7 were included and compared with propensity score matched non‐thrombolyzed WUS/SUO controls. Primary end point was the incidence of symptomatic intracranial hemorrhage; secondary end points included 24‐hour National Institute of Health Stroke Scale improvement of ≥4 and modified Rankin Scale at 90 days. One hundred and seventeen WUS/SUO patients treated with non‐contrast computed tomography‐based IVT were included. As compared with 112 controls, the median admission National Institute of Health Stroke Scale was 10 and the median Alberta Stroke Program Early Computerized Tomography score was 10 in both groups. Four (3.4%) IVT patients and one control patient (0.9%) suffered symptomatic intracranial hemorrhage (adjusted odds ratio 7.9, 95% CI 0.65–96, P=0.1). A decrease of ≥4 National Institute of Health Stroke Scale points was observed in 67 (57.3%) of IVT patients as compared with 25 (22.3%) in controls (adjusted odds ratio 5.8, CI 3.0–11.2, P

Object: There is an increasing interest in preoperative diffusion tensor imaging-based fiber tracking (DTI-FT) to preserve function during surgeries in motor eloquent brain regions. However, DTI tractography is challenged by inherent presumptions during particular tracking steps [e.g., deterministic vs. probabilistic DTI, fractional anisotropy (FA) and fiber length (FL) thresholding] and the missing “ground truth” information. In the present study, we intended to establish an objective, neurophysiology-driven approach for parameter selection during DTI-FT of the corticospinal tract integrating both imaging and neurophysiological information.Methods: In ten patients with lesions in eloquent motor areas, preoperative navigated transcranial magnetic stimulation (nTMS) was performed, followed by individual deterministic DTI-FT from a grid of cortical seed points. We investigated over 300 combinations of FA and FL thresholds and applied subsequently a multidimensional mathematical modeling of this empirical data. Optimal DTI parameters were determined by the relationship between DTI-FT (i.e., number of fibers, NoF) and nTMS (i.e., amplitudes of motor-evoked potentials) results. Finally, neurophysiological DTI parameters and the resulting tractography were compared to the current standard approaches of deterministic DTI fiber tracking with a 75% and 50% FA and a FL threshold of 110 mm as well as with intraoperative direct cortical and subcortical stimulation.Results: There was a good goodness-of-fit for the mathematical model (r2 = 0.68 ± 0 13; range: 0.59–0.97; n = 8) except of two cases. Neurophysiology-driven parameter selection showed a high correlation between DTI-FT and nTMS results (r = 0.73 ± 0.16; range: 0.38–0.93). In comparison to the standard approach, the mathematically calculated thresholds resulted in a higher NoF in 75% of patients. In 50% of patients this approach helped to clarify the exact tract location or to detect additional functional tracts, which were not identified by the standard approach. This was confirmed by direct cortical or subcortical stimulation.Conclusion: The present study evaluates a novel user-independent method to extract objective DTI-FT parameters that were completely based on neurophysiological data. The findings suggest that this method may improve the specificity and sensitivity of DTI-FT and thereby overcome the disadvantages of current approaches.