Cerebral intraparenchymal hemorrhage due to electrode implantation (CIPHEI) is a rare but serious complication of deep brain stimulation (DBS) surgery. This study retrospectively investigated a large single-center cohort of DBS implantations to calculate the frequency of CIPHEI and identify patient- and procedure-related risk factors for CIPHEI and their potential interactions. We analyzed all DBS implantations between January 2013 and December 2021 in a generalized linear model for binomial responses using bias reduction to account for sparse sampling of CIPHEIs. As potential risk factors, we considered age, gender, history of arterial hypertension, level of invasivity, types of micro/macroelectrodes, and implanted DBS electrodes. If available, postoperative coagulation and platelet function were exploratorily assessed in CIPHEI patients. We identified 17 CIPHEI cases across 839 electrode implantations in 435 included procedures in 418 patients (3.9%). Exploration and cross-validation analyses revealed that the three-way interaction of older age (above 60 years), high invasivity (i.e., use of combined micro/macroelectrodes), and implantation of directional DBS electrodes accounted for 82.4% of the CIPHEI cases. Acquired platelet dysfunction was present only in one CIPHEI case. The findings at our center suggested implantation of directional DBS electrodes as a new potential risk factor, while known risks of older age and high invasivity were confirmed. However, CIPHEI risk is not driven by the three factors alone but by their combined presence. The contributions of the three factors to CIPHEI are hence not independent, suggesting that potentially modifiable procedural risks should be carefully evaluated when planning DBS surgery in patients at risk.

Studies at 3T have shown that T1 relaxometry enables characterization of brain tissues at the single‐subject level by comparing individual physical properties to a normative atlas. In this work, an atlas of normative T1 values at 7T is introduced with 0.6 mm isotropic resolution and its clinical potential is explored in comparison to 3T.

Background: Intracranial recordings with stereoelectroencephalography (SEEG) aims at defining the epileptogenic zone in patients with pharmacoresistant epilepsy. Currently used techniques for depth electrode implantation include stereotactic frame-based and navigated frameless applications, both either conventional or robotassisted. Safety and diagnostic effectiveness depend on accuracy of implantation.Objective: To evaluate the planning experience, accuracy of stereotactic electrode placement as well as accuracy predictors with the use of latest generation planning software.Methods: Retrospective study of 15 consecutive patients who received depth electrodes using the Leksell stereotactic frame, after planning with Elements (Brainlab, Munich, Germany). For each electrode, we calculated the entry point error (EPE) as lateral deviation and target point error (TPE) both as lateral deviation and distance to tip. Multivariate regression analysis and computation of 95% confidence intervals using the bootstrap method were applied for statistical analysis and evaluation of accuracy predictors.Results: The mean EPE, lateral deviation at TP and distance to tip at TP were 0.6 +/- 0.5 mm, 1.1 +/- 0.7 mm and 1.5 +/- 0.8 mm respectively. Order of implantation (1-6 vs. >6) is predictor for distance to tip at TP and length of electrode predictor for the lateral deviation at TP. Localization of electrode generally did not correlate to error, but insular electrodes were significantly less accurate than lobar ones. Conclusion: Combination of frame-based stereotaxy with latest generation planning software may offer a better planning and implantation experience. Accuracy predictors should be analyzed and be considered for the improvement of accuracy and safety of SEEG implantation methods.

Importance The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. Objective Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. Design, setting, and participants Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. Interventions N.A. Main outcomes and measures Cohen’s kappa, accuracy, and F1-score to assess model performance. Results Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. Conclusions and relevance Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

Objectives Alexander disease (AD) is a rare disorder of the CNS. Diagnosis is based on clinical symptoms, typical MRI findings, and mutations in the glial fibrillary acid protein (GFAP) gene. In this case study, we describe a new mutation (p.L58P) in GFAP that caused a phenotype of adult-onset AD (AOAD). Methods In our outpatient clinic, a patient presented with cerebellar and bulbar symptoms after brain concussion. We used MRI and performed next-generation exome sequencing (NGS) to find mutations in GFAP to diagnose AD. The mutation was then transfected into HeLa cell lines to prove its pathogenicity. Results The brain MRI finding showed typical AD alterations. The NGS found a heterozygous variant of unknown significance in GFAP (c.173T>C; p.L58P). After transfecting HeLa cell lines with this mutation, we showed that GFAP-L58P formed pathogenic clusters of cytoplasmic aggregates. Discussion We have found a new mutation that causes AOAD. We recommend that AOAD is included in the diagnostic workup in adult patients with gait ataxia and cerebellar and bulbar symptoms in association with a traumatic head injury.

We report on 189 patients who were evaluated for APS. Final diagnoses included 77 cases of PSP, 32 patients with MSA and 11 patients with CBS. 35 patients were diagnosed or confirmed with iPD, while in 26 cases a differentiation between iPD and APS could not be definitely made.

Background: Focally increased spinal cord motion at the level of cervical spinal stenosis has been revealed by phase-contrast MRI (PC-MRI). Objective: To investigate spinal cord motion among patients suffering of degenerative cervical myelopathy (DCM) across the entire cervical spine applying automated segmentation and standardized PC-MRI post-processing protocols. Methods: Prospective, matched-pair controlled trial on 29 patients with stenosis at C5/C6. MRI-protocol covering all cervical segments: 3D T2-SPACE, prospectively ECG-triggered sagittal PC-MRI. Segmentation by trained 3D hierarchical deep convolutional neural network and data processing were conducted via in-house software pipeline. Parameters per segment: maximum velocity, peak-to-peak (PTP)-amplitude, total displacement, PTPamplitudeHB (PTP-amplitude per duration of heartbeat), and, for characterization of intraindividual alterations, the PTP-amplitude index between the cervical segments C3/C4-C7/T1 and C2/C3. Results: Spinal cord motion was increased at C4/C5, C5/C6 and C6/C7 among patients (all parameters, p < 0.001-0.025). The PTP-amplitude index revealed an increase from C3/C4 to C4/C5 (p = 0.002), C4/C5 to C5/C6 (p = 0.037) and a decrease from C5/C6 to C6/C7 and C6/C7 to C7/T1 (p < 0.001, each). This implied an upbuilding stretch on spinal cord tissue cranial and a mechanical compression caudal of the stenotic level. Furthermore, significant far range effects across the entire cervical spinal cord were observed (e.g. PTPamplitude C2/C3 vs. C6/C7, p = 0.026) in contrast to controls (p = 1.00). Conclusion: This study revealed the nature and extends of mechanical stress on the entire cervical spinal cord tissue due to focal stenosis. These pathophysiological alterations of spinal cord motion can be expected to be clinically relevant.

Design Prospective diagnostic study. Objectives Primary imaging-based diagnosis of spinal cord tumor-suspected lesions is often challenging. The identification of the definite entity is crucial for dedicated treatment and therefore reduction of morbidity. The aim of this trial was to investigate specific quantitative signal patterns to differentiate unclear intramedullary tumor-suspected lesions based on diffusion tensor imaging (DTI). Setting Medical Center - University of Freiburg, Germany. Methods Forty patients with an unclear tumor-suspected lesion of the spinal cord prospectively underwent DTI. Primary diagnosis was determined by histological or clinical work-up or remained indeterminate with follow-up. DTI metrics (FA/ADC) were evaluated at the central lesion area, lesion margin, edema, and normal spinal cord and compared between different diagnostic groups (ependymomas, other spinal cord tumors, inflammations). Results Mean DTI metrics for all spinal cord tumors ( n = 18) showed significantly reduced FA and increased ADC values compared to inflammatory lesions ( n = 8) at the lesion margin ( p < 0.001, p = 0.001) and reduced FA at the central lesion area ( p < 0.001). There were no significant differences comparing the neoplastic subgroups of ependymomas ( n = 10) and other spinal cord tumors ( n = 8), but remaining differences for both compared to the inflammation subgroup. We found significant higher ADC ( p = 0.040) and a trend to decreased FA ( p = 0.081) for ependymomas compared to inflammations at the edema. Conclusion Even if distinct differentiation of ependymomas from other spinal cord neoplasms was not possible based on quantitative DTI metrics, FA and ADC were feasible to separate inflammatory lesions. This may avoid unnecessary surgery in patients with unclear intramedullary tumor-suspected lesions.

We present anatomy-based symptom-lesion mapping to assess the association between lesions of tracts in the extreme capsule and aphasia. The study cohort consisted of 123 patients with acute left-hemispheric stroke without a lesion of language-related cortical areas of the Stanford atlas of functional regions of interest. On templates generated through global fibre tractography, lesions of the extreme capsule and of the arcuate fascicle were quantified and correlated with the occurrence of aphasia (n = 18) as defined by the Token Test. More than 15% damage of the slice plane through the extreme capsule was a strong independent predictor of aphasia in stroke patients, odds ratio 16.37, 95% confidence interval: 3.11-86.16, P< 0.01. In contrast, stroke lesions of >15% in the arcuate fascicle were not associated with aphasia. Our results support the relevance of a ventral pathway in the language network running through the extreme capsule.

As magnetic resonance imaging (MRI) signs of normal pressure hydrocephalus (NPH) may precede clinical symptoms we sought to evaluate an algorithm that automatically detects this pattern. A support vector machine (SVM) was trained in 30 NPH patients treated with ventriculoperitoneal shunts and 30 healthy controls. For comparison, four neuroradiologists visually assessed sagittal MPRAGE images and graded them as no NPH pattern, possible NPH pattern, or definite NPH pattern. Human accuracy to visually detect a NPH was between 0.85 and 0.97. Interobserver agreement was substantial (κ = 0.656). Accuracy of the SVM algorithm was 0.93 and AUROC 0.99. Among 272 prespecified regions, gray matter and CSF volumes of both caudate, the right parietal operculum, the left basal forebrain, and the 4th ventricle showed the highest discriminative power to separate a NPH and a no NPH pattern. A NPH pattern can be reliably detected using a support vector machine (SVM). Its role in the work-up of asymptomatic patients or neurodegenerative disease has to be evaluated.

The brain hemispheres can be divided into an upper dorsal and a lower ventral system. Each system consists of distinct cortical regions connected via long association tracts. The tracts cross the central sulcus or the limen insulae to connect the frontal lobe with the posterior brain. The dorsal stream is associated with sensorimotor mapping. The ventral stream serves structural analysis and semantics in different domains, as visual, acoustic or space processing. How does the prefrontal cortex, regarded as the platform for the highest level of integration, incorporate information from these different domains? In the current view, the ventral pathway consists of several separate tracts, related to different modalities. Originally the assumption was that the ventral path is a continuum, covering all modalities. The latter would imply a very different anatomical basis for cognitive and clinical models of processing. To further define the ventral connections, we used cutting-edge in vivo global tractography on highresolution diffusion tensor imaging (DTI) data from 100 normal subjects from the human connectome project and ex vivo preparation of fiber bundles in the extreme capsule of 8 humans using the Klingler technique. Our data showed that ventral stream tracts, traversing through the extreme capsule, form a continuous band of fibers that fan out anteriorly to the prefrontal cortex, and posteriorly to temporal, occipital and parietal cortical regions. Introduction of additional volumes of interest in temporal and occipital lobes differentiated between the inferior fronto-occipital fascicle (IFOF) and uncinate fascicle (UF). Unequivocally, in both experiments, in all subjects a connection between the inferior frontal and middle-to-posterior temporal cortical region, otherwise known as the temporo-frontal extreme capsule fascicle (ECF) from nonhuman primate brain-tracing experiments was identified. In the human brain, this tract connects the language domains of "Broca's area " and "Wernicke's area ". The differentiation in the three tracts, IFOF, UF and ECF seems arbitrary, all three pass through the extreme capsule. Our data show that the ventral pathway represents a continuum. The three tracts merge seamlessly and streamlines showed considerable overlap in their anterior and posterior course. Terminal maps identified prefrontal cortex in the frontal lobe and association cortex in temporal, occipital and parietal lobes as streamline endings. This anatomical substrate potentially facilitates the prefrontal cortex to integrate information across different domains and modalities.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson’s disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

Background and PurposeWith improved life expectancy, preventing neurocognitive decline after cerebral radiotherapy is gaining more importance. Hippocampal damage has been considered the main culprit for cognitive deficits following conventional whole-brain radiation therapy (WBRT). Here, we aimed to determine to which extent hippocampus-avoidance WBRT (HA-WBRT) can prevent hippocampal atrophy compared to conventional WBRT.Methods and MaterialsThirty-five HA-WBRT and 48 WBRT patients were retrospectively selected, comprising a total of 544 contrast-enhanced T1-weighted magnetic resonance imaging studies, longitudinally acquired within 24 months before and 48 months after radiotherapy. HA-WBRT patients were treated analogously to the ongoing HIPPORAD-trial (DRKS00004598) protocol with 30 Gy in 12 fractions and dose to 98% of the hippocampus ≤ 9 Gy and to 2% ≤ 17 Gy. WBRT was mainly performed with 35 Gy in 14 fractions or 30 Gy in 10 fractions. Anatomical images were segmented and the hippocampal volume was quantified using the Computational Anatomy Toolbox (CAT), including neuroradiological expert review of the segmentations.ResultsAfter statistically controlling for confounding variables such as age, gender, and total intracranial volume, hippocampal atrophy was found after both WBRT and HA-WBRT (p < 10−6). However, hippocampal decline across time following HA-WBRT was approximately three times lower than following conventional WBRT (p < 10−6), with an average atrophy of 3.1% versus 8.5% in the first 2 years after radiation therapy, respectively.ConclusionHA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize hippocampal atrophy compared to conventional WBRT.

The concepts of brain reserve and cognitive reserve were recently suggested as valuable predictors of stroke outcome. To test this hypothesis, we used age, years of education and lesion size as clinically feasible coarse proxies of brain reserve, cognitive reserve, and the extent of stroke pathology correspondingly. Linear and logistic regression models were used to predict cognitive outcome (Montreal Cognitive Assessment) and stroke-induced impairment and disability (NIH Stroke Scale; modified Rankin Score) in a sample of 104 chronic stroke patients carefully controlled for potential confounds. Results revealed 46% of explained variance for cognitive outcome (p < 0.001) and yielded a significant three-way interaction: Larger lesions did not lead to cognitive impairment in younger patients with higher education, but did so in younger patients with lower education. Conversely, even small lesions led to poor cognitive outcome in older patients with lower education, but didn’t in older patients with higher education. We observed comparable three-way interactions for clinical scores of stroke-induced impairment and disability both in the acute and chronic stroke phase. In line with the hypothesis, years of education conjointly with age moderated effects of lesion on stroke outcome. This non-additive effect of cognitive reserve suggests its post-stroke protective impact on stroke outcome.

BackgroundThe current study was aimed at investigating the feasibility of hippocampus‐avoidance whole‐brain radiation therapy with a simultaneous integrated boost (HA‐WBRT+SIB) for metastases and at assessing tumor control in comparison with conventional whole‐brain radiation therapy (WBRT) in patients with multiple brain metastases.MethodsBetween August 2012 and December 2016, 66 patients were treated within a monocentric feasibility trial with HA‐WBRT+SIB: hippocampus‐avoidance WBRT (30 Gy in 12 fractions, dose to 98% of the hippocampal volume ≤ 9 Gy) and a simultaneous integrated boost (51 or 42 Gy in 12 fractions) for metastases/resection cavities. Intracranial tumor control, hippocampal failure, and survival were subsequently compared with a retrospective cohort treated with WBRT via propensity score matching analysis.ResultsAfter 1:1 propensity score matching, there were 62 HA‐WBRT+SIB patients and 62 WBRT patients. Local tumor control (LTC) of existing metastases was significantly higher after HA‐WBRT+SIB (98% vs 82% at 1 year; P = .007), whereas distant intracranial tumor control was significantly higher after WBRT (82% vs 69% at 1 year; P = .016); this corresponded to higher biologically effective doses. Intracranial progression‐free survival (PFS; 13.5 vs 6.4 months; P = .03) and overall survival (9.9 vs 6.2 months; P = .001) were significantly better in the HA‐WBRT+SIB cohort. Four patients (6.5%) developed hippocampal metastases after hippocampus avoidance. The neurologic death rate after HA‐WBRT+SIB was 27.4%.ConclusionsHA‐WBRT+SIB can be an efficient therapeutic option for patients with multiple brain metastases and is associated with improved LTC of existing metastases, higher intracranial PFS, a reduction of the neurologic death rate, and an acceptable risk of radiation necrosis. The therapy has the potential to prevent neurocognitive adverse effects, which will be further evaluated in the multicenter, phase 2 HIPPORAD trial.

Background Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). Methods This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter. Discussion This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases. Trial registration The HIPPORAD trial is registered with the German Clinical Trials Registry ( DRKS00004598 , registered 2 June 2016).

According to the German S3 guideline dementia every patient with a dementia disorder should have a MRI. The goal is not only to uncover treatable conditions but also to detect region-specific atrophy pattern which are characteristic of primary dementia disorders such as Alzheimer's disease, fronto-temporal lobar degeneration and others. Diagnostic accuracy can be improved by Voxel- and Region-based volumetric analysis of the individual brain compared to age-matched controls.Neurodegenerative Erkrankungen nehmen in einer älter werdenden Gesellschaft stark zu. Bei klinischem Verdacht lassen sich diese Erkrankungen häufig anhand krankheitsspezifischer Atrophiemuster diagnostizieren. Die Erkennung wird erleichtert, wenn der Datensatz des Patienten mit einer Gruppe „alters- und geschlechtsgematchter“ Kontrollen verglichen und Voxel bzw. Regionen, die sich unterscheiden, hervorgehoben werden.