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Playing chess requires problem-solving capacities in order to search through the chess problem space in an effective manner. Chess should thus require planning abilities for calculating many moves ahead. Therefore, we asked whether chess players are better problem solvers than non-chess players in a complex planning task. We compared planning performance between chess (N=25) and non-chess players (N=25) using a standard psychometric planning task, the Tower of London (ToL) test. We also assessed fluid intelligence (Raven Test), as well as verbal and visuospatial working memory. As expected, chess players showed better planning performance than non-chess players, an effect most strongly expressed in difficult problems. On the other hand, they showed longer planning and movement execution times, especially for incorrectly solved trials. No differences in fluid intelligence and verbal/visuospatial working memory were found between both groups. These findings indicate that better performance in chess players is associated with disproportionally longer solution times, although it remains to be investigated whether motivational or strategic differences account for this result. [ABSTRACT FROM AUTHOR]

Background: State-of-the-art stroke treatment significantly reduces lesion size and stroke severity, but it remains unclear whether these therapeutic advances have diminished the burden of post-stroke cognitive impairment (PSCI)., Aims: In a cohort of patients receiving modern state-of-the-art stroke care including endovascular therapy, we assessed the frequency of PSCI and the pattern of domain-specific cognitive deficits, identified risk factors for PSCI, and determined the impact of acute PSCI on stroke outcome., Methods: In this prospective monocentric cohort study, we examined patients with first-ever anterior circulation ischemic stroke without pre-stroke cognitive decline, using a comprehensive neuropsychological assessment ⩽10 days after symptom onset. Normative data were stratified by demographic variables. We defined PSCI as at least moderate (<1.5 standard deviation) deficits in ⩾2 cognitive domains. Multivariable regression analysis was applied to define risk factors for PSCI., Results: We analyzed 329 non-aphasic patients admitted from December 2020 to July 2023 (67.2 ± 14.4 years old, 41.3% female, 13.1 ± 2.7 years of education). Although most patients had mild stroke (median National Institutes of Health Stroke Scale (NIHSS) 24 h = 1.00 (0.00; 3.00); 87.5% with NIHSS ⩽ 5), 69.3% of them presented with PSCI 2.7 ± 2.0 days post-stroke. The most severely and often affected cognitive domains were verbal learning, episodic memory, executive functions, selective attention, and constructive abilities (39.1%-51.2% of patients), whereas spatial neglect was less frequent (18.5%). The risk of PSCI was reduced with more years of education (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23-0.99) and right hemisphere lesions (OR = 0.47, 95% CI = 0.26-0.84), and increased with stroke severity (NIHSS 24 h, OR = 4.19, 95% CI = 2.72-6.45), presence of hyperlipidemia (OR = 1.93, 95% CI = 1.01-3.68), but was not influenced by age. After adjusting for stroke severity and depressive symptoms, acute PSCI was associated with poor functional outcome (modified Rankin Scale > 2, F = 13.695, p < 0.001) and worse global cognition (Montreal Cognitive Assessment (MoCA) score, F = 20.069, p < 0.001) at 3 months post-stroke., Conclusion: Despite modern stroke therapy and many strokes having mild severity, PSCI in the acute stroke phase remains frequent and associated with worse outcome. The most prevalent were learning and memory deficits. Cognitive reserve operationalized as years of education independently protects post-stroke cognition., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Given the frequency of stroke worldwide, tools for neuropsychological assessment of patients with acute stroke are needed to identify cognitive impairments, guide rehabilitation efforts and allow for a prognosis of outcome. However, requirements for assessment tools for acute cognitive deficits differ substantially from tests for chronic neuropsychological impairments and screening tools for suspected dementia. The Oxford Cognitive Screen (OCS) has been developed as a quick to administer neurocognitive screening for acute neurological patients providing information on various cognitive domains. It is available in different languages. The present study reports cut-off scores, parallel-test reliability and concurrent validity of the German version (D-OCS). Following standardized language adaptation and translation, the D-OCS was administered to 100 healthy individuals to generate cut-off scores (5th percentile). Subsequently, 88 neurological patients were assessed with both versions of the D-OCS as well as other tests to evaluate reliability and validity of the D-OCS subscales. In a further study, the D-OCS was compared to the MoCA test in 65 acute stroke patients revealing comparable sensitivity but also differences between both tools. The cut-off scores were comparable to other international versions of the OCS. Intraclass correlations were highly significant and document reliability of the D-OCS subtests. Scores on subtests correlated significantly with independent tests securing validity. Comparison with the MoCA revealed comparable sensitivity and specificity. The D-OCS is a reliable and valid assessment tool well suited for patients with acute stroke. Differences to the MoCA test are discussed., (© 2024 The Authors. Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of The British Psychological Society.)

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., Competing Interests: The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: B.E.A.S. received a research grant from Ceregate (Hamburg, Germany) and honoraria as a scientific advisor for Precisis (Heidelberg, Germany). T.S.B. has nothing to report. M.R. has nothing to report. M.B. has nothing to report. N.S. received honoraria from Abbvie (presentation), STADAPHARM (advisor), Novartis (presentation). A.R. was supported by the Berta-Ottenstein Programme for Clinician Scientists, Faculty of Medicine, University of Freiburg. K.E. has nothing to report. P.C.R. received research support from: Else Kr&ouml;ner-Fresenius Foundation (Germany) and Fraunhofer Foundation (Germany). He is a consultant for Boston Scientific (USA), Inomed (Germany), and Brainlab (Germany). H.U. received honoraria for lectures from Biogen, Eisai, Mbits, and Lilly. He is supported by the German Federal Ministry of Education and Research and is a co-editor of Clin Neuroradiol. V.A.C. received a collaborative grant from BrainLab (Munich, Germany). He serves as an advisor for Aleva (Lausanne, Switzerland), Ceregate (Hamburg, Germany), Cortec (Freiburg, Germany), and Inbrain (Barcelona, Spain). He has an ongoing IIT with Boston Scientific (USA). He has received travel support and honoraria for lectures from Boston Scientific (USA), UNEEG Medical (Munich, Germany), and Precisis (Heidelberg, Germany). C.P.K. has nothing to report.

The role hemispheric lateralization in the prefrontal cortex plays for episodic memory formation in general, and for emotionally valenced information in particular, is debated. In a randomized, double-blind, and sham-controlled design, healthy young participants (n = 254) performed 2 runs of encoding to categorize the perceptual, semantic, or emotionally valenced (positive or negative) features of words followed by a free recall and a recognition task. To resolve competing hypotheses about the contribution of each hemisphere, we modulated left or right dorsolateral prefrontal cortex (DLPFC) activity using transcranial direct current stimulation during encoding (1 mA, 20 min). With stimulation of the left DLPFC, but not the right DLPFC, encoding and free recall performance improved particularly for words that were processed semantically. In addition, enhancing left DLPFC activity increased memory formation for positive content while reducing that for negative content. In contrast, promoting right DLPFC activity increased memory formation for negative content. The left DLPFC assesses semantic properties of new memory content at encoding and thus influences how successful new episodic memories are established. Hemispheric laterlization-more active left DLPFC and less active right DLPFC-at the encoding stage shifts the formation of memory traces in favor of positively valenced content., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To evaluate a MRI postprocessing tool for the enhanced and rapid detection of focal cortical dysplasia (FCD)., Methods: MP2RAGE sequences of 40 consecutive, so far MRI-negative patients and of 32 healthy controls were morphometrically analyzed to highlight typical FCD features. The resulting morphometric maps served as input for an artificial neural network generating a FCD probability map. The FCD probability map was inversely normalized, co-registered to the MPRAGE2 sequence, and re-transferred into the PACS system. Co-registered images were scrolled through "within a minute" to determine whether a FCD was present or not., Results: Fifteen FCD, three subcortical band heterotopias (SBH), and one periventricular nodular heterotopia were identified. Of those, four FCD and one SBH were only detected by MRI postprocessing while one FCD and one focal polymicrogryia were missed, respectively. False-positive results occurred in 21 patients and 22 healthy controls. However, true positive cluster volumes were significantly larger than volumes of false-positive clusters (p < 0.001). The area under the curve of the receiver operating curve was 0.851 with a cut-off volume of 0.05 ml best indicating a FCD., Conclusion: Automated MRI postprocessing and presentation of co-registered output maps in the PACS allowed for rapid (i.e., "within a minute") identification of FCDs in our clinical setting. The presence of false-positive findings currently requires a careful comparison of postprocessing results with conventional MR images but may be reduced in the future using a neural network better adapted to MP2RAGE images., (© 2022. The Author(s).)

D 2 -like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D 2 /D 3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D 2 /D 3 dopamine receptor availability was measured using the radiotracer [ 18 F]fallypride. Caudate D 2 /D 3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D 2 /D 3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D 2 /D 3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D 2 /D 3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers., (© 2021. The Author(s).)

Objective: The detection of focal cortical dysplasia (FCD) in magnetic resonance imaging is challenging. Voxel-based morphometric analysis and automated FCD detection using an artificial neural network (ANN) integrated into the Morphometric Analysis Program (MAP18) have been shown to facilitate FCD detection. This study aimed to evaluate whether the detection of FCD can be further improved by feeding this approach with magnetization prepared two rapid acquisition gradient echoes (MP2RAGE) instead of magnetization-prepared rapid acquisition gradient echo (MPRAGE) datasets., Methods: MPRAGE and MP2RAGE datasets were acquired in a consecutive sample of 32 patients with FCD and postprocessed using MAP18. Visual analysis and, if available, histopathology served as the gold standard for assessing the sensitivity and specificity of FCD detection. Out-of-sample specificity was evaluated in a cohort of 32 healthy controls., Results: The sensitivity and specificity of FCD detection were 82.4% and 62.5% for the MPRAGE and 97.1% and 34.4% for the MP2RAGE sequences, respectively. Median volumes of true-positive voxel clusters were .16 ml for the MPRAGE and .52 ml for the MP2RAGE sequences compared to .08- and .04-ml volumes of false-positive clusters. With regard to cluster volumes, FCD detection was substantially improved for the MP2RAGE data when the estimated optimal threshold of .23 ml was applied (sensitivity = 72.9%, specificity = 83.0%). In contrast, the estimated optimal threshold of .37 ml for the MPRAGE data did not improve FCD lesion detection (sensitivity = 42.9%, specificity = 79.5%)., Significance: In this study, the sensitivity of FCD detection by morphometric analysis and an ANN integrated into MAP18 was higher for MP2RAGE than for MPRAGE sequences. Additional usage of cluster volume information helped to discriminate between true- and false-positive MP2RAGE results., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: An increasing number of neurosurgeons use display of the dentato-rubro-thalamic tract (DRT) based on diffusion weighted imaging (dMRI) as basis for their routine planning of stimulation or lesioning approaches in stereotactic tremor surgery. An evaluation of the anatomical validity of the display of the DRT with respect to modern stereotactic planning systems and across different tracking environments has not been performed., Methods: Distinct dMRI and anatomical magnetic resonance imaging (MRI) data of high and low quality from 9 subjects were used. Six subjects had repeated MRI scans and therefore entered the analysis twice. Standardized DICOM structure templates for volume of interest definition were applied in native space for all investigations. For tracking BrainLab Elements (BrainLab, Munich, Germany), two tensor deterministic tracking (FT2), MRtrix IFOD2 ( https://www.mrtrix.org ), and a global tracking (GT) approach were used to compare the display of the uncrossed (DRTu) and crossed (DRTx) fiber structure after transformation into MNI space. The resulting streamlines were investigated for congruence, reproducibility, anatomical validity, and penetration of anatomical way point structures., Results: In general, the DRTu can be depicted with good quality (as judged by waypoints). FT2 (surgical) and GT (neuroscientific) show high congruence. While GT shows partly reproducible results for DRTx, the crossed pathway cannot be reliably reconstructed with the other (iFOD2 and FT2) algorithms., Conclusion: Since a direct anatomical comparison is difficult in the individual subjects, we chose a comparison with two research tracking environments as the best possible "ground truth." FT2 is useful especially because of its manual editing possibilities of cutting erroneous fibers on the single subject level. An uncertainty of 2 mm as mean displacement of DRTu is expectable and should be respected when using this approach for surgical planning. Tractographic renditions of the DRTx on the single subject level seem to be still illusive., (© 2021. The Author(s).)

Objective: This study investigates the clinical course of recovery of apraxia after left-hemisphere stroke and the underlying neuroanatomical correlates for persisting or recovering deficits in relation to the major processing streams in the network for motor cognition., Methods: 90 patients were examined during the acute (4.74 ± 2.73 days) and chronic (14.3 ± 15.39 months) stage after left-hemisphere stroke for deficits in meaningless imitation, as well as production and conceptual errors in tool use pantomime. Lesion correlates for persisting or recovering deficits were analyzed with an extension of the non-parametric Brunner-Munzel rank-order test for multi-factorial designs (two-way repeated-measures ANOVA) using acute images., Results: Meaningless imitation and tool use production deficits persisted into the chronic stage. Conceptual errors in tool use pantomime showed an almost complete recovery. Imitation errors persisted after occipitotemporal and superior temporal lesions in the dorso-dorsal stream. Chronic pantomime production errors were related to the supramarginal gyrus, the key structure of the ventro-dorsal stream. More anterior lesions in the ventro-dorsal stream (ventral premotor cortex) were additionally associated with poor recovery of production errors in pantomime. Conceptual errors in pantomime after temporal and supramarginal gyrus lesions persisted into the chronic stage. However, they resolved completely when related to angular gyrus or insular lesions., Conclusion: The diverging courses of recovery in different apraxia tasks can be related to different mechanisms. Critical lesions to key structures of the network or entrance areas of the processing streams lead to persisting deficits in the corresponding tasks. Contrary, lesions located outside the core network but inducing a temporary network dysfunction allow good recovery e.g., of conceptual errors in pantomime. The identification of lesion correlates for different long-term recovery patterns in apraxia might also allow early clinical prediction of the course of recovery., Competing Interests: Declaration of competing interest H.U. received honoraria for lectures from Bracco, Bayer, Union Chimique Belge (UCB) pharma, Eisai, and Stryker. The other authors report no conflicts., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: With 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 Materials: Thirty-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., Results: After 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., Conclusion: HA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize hippocampal atrophy compared to conventional WBRT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Popp, Rau, Kellner, Reisert, Fennell, Rothe, Nieder, Urbach, Egger, Grosu and Kaller.)

The visualization of diffusion MRI related properties in a comprehensive way is still a challenging problem. We propose a simple visualization technique to give neuroradiologists and neurosurgeons a more direct and personalized view of relevant connectivity patterns estimated from clinically feasible diffusion MRI. The approach, named SPECTRE (Subject sPEcific brain Connectivity display in the Target REgion), is based on tract-weighted imaging, where diffusion MRI streamlines are used to aggregate information from a different MRI contrast. Instead of using native MRI contrasts, we propose to use continuous template information as the underlying contrast for aggregation. In this respect, the SPECTRE approach is complementary to normative approaches where connectivity information is warped from the group level to subject space by anatomical registration. For the purpose of demonstration, we focus the presentation of the SPECTRE approach on the visualization of connectivity patterns in the midbrain regions at the level of subthalamic nucleus due to its importance for deep brain stimulation. The proposed SPECTRE maps are investigated with respect to plausibility, robustness, and test-retest reproducibility. Clear dependencies of reliability measures with respect to the underlying tracking algorithms are observed., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

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.

Fiber tractography based on diffusion-weighted MRI provides a non-invasive characterization of the structural connectivity of the human brain at the macroscopic level. Quantification of structural connectivity strength is challenging and mainly reduced to "streamline counting" methods. These are however highly dependent on the topology of the connectome and the particular specifications for seeding and filtering, which limits their intra-subject reproducibility across repeated measurements and, in consequence, also confines their validity. Here we propose a novel method for increasing the intra-subject reproducibility of quantitative estimates of structural connectivity strength. To this end, the connectome is described by a large matrix in positional-orientational space and reduced by Principal Component Analysis to obtain the main connectivity "modes". It was found that the proposed method is quite robust to structural variability of the data., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

Purpose: Precise segmentation of brain lesions is essential for neurological research. Specifically, resection volume estimates can aid in the assessment of residual postoperative tissue, e.g. following surgery for glioma. Furthermore, behavioral lesion-symptom mapping in epilepsy relies on accurate delineation of surgical lesions. We sought to determine whether semi- and fully automatic segmentation methods can be applied to resected brain areas and which approach provides the most accurate and cost-efficient results., Methods: We compared a semi-automatic (ITK-SNAP) with a fully automatic (lesion&#95;GNB) method for segmentation of resected brain areas in terms of accuracy with manual segmentation serving as reference. Additionally, we evaluated processing times of all three methods. We used T1w, MRI-data of epilepsy patients (n = 27; 11 m; mean age 39 years, range 16-69) who underwent temporal lobe resections (17 left)., Results: The semi-automatic approach yielded superior accuracy (p < 0.001) with a median Dice similarity coefficient (mDSC) of 0.78 and a median average Hausdorff distance (maHD) of 0.44 compared with the fully automatic approach (mDSC 0.58, maHD 1.32). There was no significant difference between the median percent volume difference of the two approaches (p > 0.05). Manual segmentation required more human input (30.41 min/subject) and therefore inferring significantly higher costs than semi- (3.27 min/subject) or fully automatic approaches (labor and cost approaching zero)., Conclusion: Semi-automatic segmentation offers the most accurate results in resected brain areas with a moderate amount of human input, thus representing a viable alternative compared with manual segmentation, especially for studies with large patient cohorts.

Apraxia is frequently described after left hemisphere stroke and results from lesions to a complex network for motor cognition with dorso-dorsal, ventro-dorsal and ventral processing streams. Apraxia also occurs after right hemisphere stroke, but lesion correlates and underlying mechanisms remain to be elucidated. To clarify the role of the right hemisphere in apraxic deficits and the influence of neglect, we prospectively examined apraxia (imitation of meaningless postures and pantomime of tool use) and neglect in 138 acute right hemisphere stroke patients with first-ever ischemic stroke in the middle cerebral artery territory and identified corresponding lesion correlates using voxel-based lesion-symptom mapping. Imitation of meaningless postures was impaired as frequently as after left hemisphere stroke (38.4%) and was significantly associated with neglect. Imitation of meaningless postures was related to temporal (middle temporal gyrus, temporoparietal junction, superior temporal gyrus and sulcus), parietal (angular gyrus, parieto-occpitpial sulcus), secondary sensorimotor cortex and (peri-)insular lesions. Presence of neglect dichotomized the results: a lesion correlate for isolated imitation without neglect was found in the right parieto-occipital cortex, while imitation deficits, when co-occurring with neglect, were related to lateral occipito-temporal, superior temporal sulcus and (peri-)insular lesions. Pantomime of tool use deficits, typical for apraxia after left hemisphere lesions, were found in only 5 cases (3.6%) and only in the context of neglect, and were associated with occipital lobe, ventral and anterior temporal lobe, and inferior frontal (areas 45/47) lesions. The syndrome of apraxia after right hemisphere stroke differs from apraxia after left hemisphere stroke. Imitation deficits are found in both hemispheres after dorso-dorsal stream lesions. Neglect also leads to and explains deficits in imitation and pantomime in patients with right ventral stream lesions. Therefore, in right hemisphere lesions, apraxia can either be explained as impaired visuomotor transformation or as a result of visuospatial deficits., Competing Interests: Declaration of competing interest HU is shareholder of the Veobrain GmbH, a spin-off of the University Medical Center Freiburg and received honoraria for lectures from Bracco, Bayer, Union Chimique Belge (UCB) pharma, and Stryker. The other authors report no conflicts., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Visual neglect and extinction are two distinct visuospatial attention deficits that frequently occur after right hemisphere cerebral stroke. However, their different lesion profiles remain a matter of debate. In the left hemisphere, a domain-general dual-loop model with distinct computational abilities onto which several cognitive functions may project, has been proposed: a dorsal stream for sensori-motor mapping in time and space and a ventral stream for comprehension and representation of concepts. We wondered whether such a distinction may apply to visual extinction and neglect in left hemisphere lesions. Of 165 prospectively studied patients with acute left hemispheric ischemic stroke with a single lesion on MRI, 122 had no visuospatial attention deficit, 10 had extinction, 31 neglect and 2 had both, visual extinction and neglect. Voxel-based-lesion-symptom mapping (VLSM, FDR<.05) showed a clear anatomical dissociation. Extinction occurred after damage to the parietal cortex (anterior bank of the intraparietal sulcus, inferior parietal lobe, and supramarginal gyrus), while visual neglect occurred after damage mainly to the temporal lobe (superior and middle temporal lobe, anterior temporal pole), inferior ventral premotor cortex, frontal operculum, angular gyrus, and insula. Direct comparison of both conditions linked extinction to intraparietal sulcus and supramarginal gyrus (FDR<.05). Thus, in the left hemisphere extinction seems to be related to dorsal stream lesions, whereas neglect maps more on the ventral stream. These data cannot be generalized to the right hemisphere. However, a domain-general point-of-view may stimulate discussion on visuospatial attention processing also in the right hemisphere., Competing Interests: Declaration of Competing Interest Dr. Urbach is a shareholder of the Veobrain Gmbh, a spin-off company of the University Medical Center Freiburg, and has received honoraria for lectures from Bracco, Bayer, Union Chimique Belge (UCB) pharma, and Stryker. The other authors report no conflicts., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: In patients with temporal lobe epilepsy (TLE) with a nonlesional and nonepileptogenic hippocampus (HC), in order to preserve functionally intact brain tissue, the HC is not resected. However, some patients experience postoperative memory decline, possibly due to disruption of the extrahippocampal memory network and secondary hippocampal volume (HV) loss. The purpose of this study was to determine the extent of hippocampal atrophy ipsilateral and contralateral to the side of the surgery and its relation to memory outcomes., Methods: Hippocampal volume and verbal as well as visual memory performance were retrospectively examined in 55 patients (mean age ± standard deviation [SD] 30 ± 15 years, 25 female, 31 left) before and 5 months after surgery within the temporal lobe that spared the entire HC. HV was extracted based on prespecified templates, and resection volumes were also determined., Results: HV loss was found both ipsilateral and contralateral to the side of surgery (P < .001). Postoperative left HV loss was a significant predictor of postoperative verbal memory deterioration after left-sided surgery (P < .01). Together with the preoperative verbal memory performance, postoperative left HV explained almost 60% of the variance (P < .0001). However, right HV was not a clear predictor of visual memory performance. Larger resection volumes were associated with smaller postoperative HV, irrespective of side of surgery (left: P < .05, right: P < .01)., Significance: A disruption of the memory network by any resection within the TL, especially within the language-dominant hemisphere, may lead to HC atrophy and memory decline. These findings may further improve the counseling of patients concerning their postoperative memory outcome before TL resections sparing the entire HC., (© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

The loss and recovery of language functions are still incompletely understood. This longitudinal functional MRI study investigated the neural mechanisms underlying language recovery in patients with post-stroke aphasia putting particular emphasis on the impact of lesion site. To identify patterns of language-related activation, an auditory functional MRI sentence comprehension paradigm was administered to patients with circumscribed lesions of either left frontal (n = 17) or temporo-parietal (n = 17) cortex. Patients were examined repeatedly during the acute (≤1 week, t1), subacute (1-2 weeks, t2) and chronic phase (>6 months, t3) post-stroke; healthy age-matched control subjects (n = 17) were tested once. The separation into two patient groups with circumscribed lesions allowed for a direct comparison of the contributions of distinct lesion-dependent network components to language reorganization between both groups. We hypothesized that activation of left hemisphere spared and perilesional cortex as well as lesion-homologue cortex in the right hemisphere varies between patient groups and across time. In addition, we expected that domain-general networks serving cognitive control independently contribute to language recovery. First, we found a global network disturbance in the acute phase that is characterized by reduced functional MRI language activation including areas distant to the lesion (i.e. diaschisis) and subsequent subacute network reactivation (i.e. resolution of diaschisis). These phenomena were driven by temporo-parietal lesions. Second, we identified a lesion-independent sequential activation pattern with increased activity of perilesional cortex and bilateral domain-general networks in the subacute phase followed by reorganization of left temporal language areas in the chronic phase. Third, we observed involvement of lesion-homologue cortex only in patients with frontal but not temporo-parietal lesions. Fourth, irrespective of lesion location, language reorganization predominantly occurred in pre-existing networks showing comparable activation in healthy controls. Finally, we detected different relationships of performance and activation in language and domain-general networks demonstrating the functional relevance for language recovery. Our findings highlight that the dynamics of language reorganization clearly depend on lesion location and hence open new perspectives for neurobiologically motivated strategies of language rehabilitation, such as individually-tailored targeted application of neuro-stimulation., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The Tower of London (TOL) is probably the most often used assessment tool for planning ability in healthy and clinical samples. Various versions, including our proposed standard problem set, have proven to be feasible and reliable in adults. In contrast, reliability information for typically developing (TD) children and neurodevelopmental disorders during childhood are largely missing. Also, it would be highly desirable to attain a problem set that can be used across the whole lifespan. Therefore, here we examine reliability of our proposed standard problem set using a computerized TOL version in 178 TD children (two different samples), 49 children with high-functioning autism spectrum disorder (ASD) and 56 children with attention-deficit/hyperactivity disorder (ADHD) (age ranges of each group 6 to 13 years), and 130 young adults (age range 18 to 32 years). Greatest lower bound estimates of reliability were adequate to high in the two samples of TD children (.76 and .80) and high to very high in patients (ASD: .90; ADHD: .83). In young adults, all reliability indices were adequate to high. Moreover, a subset of four- and five-move problems exhibited sufficient performance variability and high part-whole correlations with the complete problem set in all samples. These findings demonstrate the reliability of the presented TOL problem set in both clinical and non-clinical child samples. A clinically feasible subset of four- and five-move problems is reflective of overall planning performance at all ages, hence enabling comparisons of planning ability within and between developmental samples across almost the whole lifespan.

Background: Major depression (MD) and obsessive-compulsive disorder (OCD) are psychiatric diseases with a huge impact on individual well-being. Despite optimal treatment regiments a subgroup of patients remains treatment resistant and stereotactic surgery (stereotactic lesion surgery, SLS or Deep Brain Stimulation, DBS) might be an option. Recent research has described four networks related to MD and OCD (affect, reward, cognitive control, default network) but only on a cortical and the adjacent sub-cortical level. Despite the enormous impact of comparative neuroanatomy, animal science and stereotactic approaches a holistic theory of subcortical and cortical network interactions is elusive. Because of the dominant hierarchical rank of the neocortex, corticofugal approaches have been used to identify connections in subcortical anatomy without anatomical priors and in part confusing results. We here propose a different corticopetal approach by identifying subcortical networks and search for neocortical convergences thereby following the principle of phylogenetic and ontogenetic network development., Material and Methods: This work used a diffusion tensor imaging data from a normative cohort (Human Connectome Project, HCP; n = 200) to describe eight subcortical fiber projection pathways (PPs) from subthalamic nucleus (STN), substantia nigra (SNR), red nucleus (RN), ventral tegmental area (VTA), ventrolateral thalamus (VLT) and mediodorsal thalamus (MDT) in a normative space (MNI). Subcortical and cortical convergences were described including an assignment of the specific pathways to MD/OCD-related networks. Volumes of activated tissue for different stereotactic stimulation sites and procedures were simulated to understand the role of the distinct networks, with respect to symptoms and treatment of OCD and MD., Results: The detailed course of eight subcortical PPs (stnPP, snrPP, rnPP, vlATR, vlATRc, mdATR, mdATRc, vtaPP/slMFB) were described together with their subcortical and cortical convergences. The anterior limb of the internal capsule can be subdivided with respect to network occurrences in ventral-dorsal and medio-lateral gradients. Simulation of stereotactic procedures for OCD and MD showed dominant involvement of mdATR/mdATRc (affect network) and vtaPP/slMFB (reward network)., Discussion: Corticofugal search strategies for the evaluation of stereotactic approaches without anatomical priors often lead to confusing results which do not allow for a clear assignment of a procedure to an involved network. According to our simulation of stereotactic procedures in the treatment of OCD and MD, most of the target regions directly involve the reward (and affect) networks, while side-effects can in part be explained with a co-modulation of the control network., Conclusion: The here proposed corticopetal approach of a hierarchical description of 8 subcortical PPs with subcortical and cortical convergences represents a new systematics of networks found in all different evolutionary and distinct parts of the human brain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Hemodynamic alterations of extracranial veins are considered an etiologic factor in multiple sclerosis (MS). However, ultrasound and MRI studies could not confirm a pathophysiological link. Because of technical challenges using standard diagnostics, information about the involvement of superficial intracranial veins in proximity to the affected brain in MS is scarce., Purpose: To comprehensively investigate the hemodynamics of intracranial veins and of the venous outflow tract in MS patients and controls., Study Type: Prospective., Population: Twenty-eight patients with relapsing-remitting MS (EDSS1.9 ± 1.1; range 0-3) and 41 healthy controls., Field Strength/sequence: 3T/2D phase-contrast and time-resolved 4D flow MRI, extra- and transcranial sonography., Assessment: Hemodynamics within the superficial and deep intracranial venous system and outflow tract including the internal, basal, and great cerebral vein, straight, superior sagittal, and transverse sinuses, internal jugular and vertebral veins. Sonography adhered to the chronic cerebrospinal venous insufficiency (CCSVI) criteria., Statistical Tests: Multivariate repeated measure analysis of variance, Student's two-sample t-test, chi-square, Fisher's exact test; separate analysis of the entire cohort and 32 age- and sex-matched participants., Results: Multi- and univariate main effects of the factor group (MS patient vs. control) and its interactions with the factor vessel position (lower flow within dorsal superior sagittal sinus in MS, 3 ± 1 ml/s vs. 3.8 ± 1 ml/s; P < 0.05) in the uncontrolled cohort were attributable to age-related differences. Age- and sex-matched pairs showed a different velocity gradient in a single segment within the deep cerebral veins (great cerebral vein, vena cerebri magna [VCM] 7.6 ± 1.7 cm/s; straight sinus [StS] 10.5 ± 2.2 cm/s vs. volunteers: VCM 9.2 ± 2.3 cm/s; StS 10.2 ± 2.3 cm/s; P = 0.01), reaching comparable velocities instantaneously downstream. Sonography was not statistically different between groups., Data Conclusion: Consistent with previous studies focusing on extracranial hemodynamics, our comprehensive analysis of intracerebral venous blood flow did not reveal relevant differences between MS patients and controls. Level of Evidence 1. Technical Efficacy Stage 3. J. Magn. Reson. Imaging 2020;51:205-217., (© 2019 International Society for Magnetic Resonance in Medicine.)

Measuring the strength of directed functional interactions between brain regions is fundamental to understand neural networks. Functional near-infrared spectroscopy (fNIRS) is a suitable method to map directed interactions between brain regions but is based on the neurovascular coupling. It, thus, relies on vasomotor reactivity and is potentially biased by non-neural physiological noise. To investigate the impact of physiological noise on fNIRS-based estimates of directed functional connectivity within the rostro-caudal hierarchical organization of the prefrontal cortex (PFC), we systematically assessed the effects of pathological perturbations of vasomotor reactivity and of externally triggered arterial blood pressure (aBP) fluctuations. Fifteen patients with unilateral stenosis of the internal carotid artery (ICA) underwent multi-channel fNIRS during rest and during metronomic breathing, inducing aBP oscillations at 0.1 Hz. Comparisons between the healthy and pathological hemispheres served as quasi-experimental manipulation of the neurovascular system's capability for vasomotor reactivity. Comparisons between rest and breathing served as experimental manipulation of two different levels of physiological noise that were expected to differ between healthy and pathological hemispheres. In the hemisphere affected by ICA stenosis, the rostro-caudal hierarchical organization of the PFC was compromised reflecting the pathological effect on the vascular and neural level. Breathing-induced aBP oscillations biased the magnitude of directed interactions in the PFC, but could be adjusted using either the aBP time series (intra-individual approach) or the aBP-induced fNIRS signal variance (inter-individual approach). Multi-channel fNIRS, hence, provides a sound basis for analyses of directed functional connectivity as potential bias due to physiological noise can be effectively controlled for.

Behavioral deficits after stroke like apraxia can be related to structural lesions and to a functional state of the underlying network - three factors, reciprocally influencing each other. Combining lesion data, behavioral performance and passive functional activation of the network-of-interest, this study aims to disentangle those mutual influences and to identify 1) activation patterns associated with the presence or absence of acute apraxia in tool-associated actions and 2) the specific impact of lesion location on those activation patterns. Brain activity of 48 patients (63.31 ± 13.68 years, 35 male) was assessed in a fMRI paradigm with observation of tool-related actions during the acute phase after first-ever left-hemispheric stroke (4.83 ± 2.04 days). Behavioral assessment of apraxia in tool-related tasks was obtained independently. Brain activation was compared between patients versus healthy controls and between patient with versus without apraxia. Interaction effects of lesion location (frontal vs parietal) and behavioral performance (apraxia vs no apraxia) were assessed in a 2 × 2 factorial design. Action observation activated the ventro-dorsal parts of the network for cognitive motor function; activation was globally downregulated after stroke. Apraxic compared to non-apraxic patients showed relatively increased activity in bilateral posterior middle temporal gyrus and middle frontal gyrus/superior frontal sulcus. Altered activation occurred in regions for tool-related cognition, corroborating known functions of the ventro-dorsal and ventral streams for praxis, and comprised domain-general areas, functionally related to cognitive control. The interaction analyses revealed different levels of activation in the left anterior middle temporal gyrus in the ventral stream in apraxic patients with frontal compared to parietal lesions, suggesting a modulation of network activation in relation to behavioral performance and lesion location as separate factors. By detecting apraxia-specific activation patterns modulated by lesion location, this study underlines the necessity to combine structural lesion information, behavioral parameters and functional activation to comprehensively examine cognitive functions in acute stroke patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Inhibition is not a unitary construct, as different inhibition-related functions have been disentangled. The present single-case study compares performance of a patient with bilateral lesions in the inferior frontal gyrus (IFG) and anterior insula to healthy age-matched controls in different inhibition-related tasks. Particular focus was on the resolution of proactive interference that is supposed to rely on bilateral IFG and anterior insula. Two working memory tasks previously proven sensitive to deficits in proactive interference (recent-probes, n-back) and two tasks measuring behavioral inhibition (verb generation task, Stroop task) were administered. Against expectations, the patient did not show any deficits in measures of proactive interference. However, compared to controls, she demonstrated considerably reduced performance in both measures of behavioral inhibition, thus resulting in a classical dissociation between proactive interference and behavioral inhibition. Although performance improved during the chronic phase post stroke, the overall pattern of a classical dissociation between proactive interference and behavioral inhibition remained stable across time. Taken together, the present data support the role of the IFG in inhibition-related functions, but a direct relationship between lesions in the IFG and difficulties in resolution of proactive interference could not be corroborated., (Copyright © 2019. Published by Elsevier Ltd.)

Objective: Although post-stroke cognitive deficit can significantly limit patient independence and social re-integration, clinical routine predictors for this condition are lacking. 'Cognitive reserve' limits the detrimental effects of slowly developing neurodegeneration. We aimed to determine whether comparable effects also exist in acute stroke. Using 'years of education' as a proxy, we investigated whether cognitive reserve beneficially influences cognitive performance and disability after stroke, whilst controlling for age and lesion size as measure of stroke pathology., Methods: Within the first week of ischemic right hemisphere stroke, 36 patients were assessed for alertness, working memory, executive functions, spatial neglect, global cognition and motor deficit at 4.9 ± 2.1 days post-stroke, in addition to routine clinical tests (NIH Stroke Scale, modified Rankin Scale on admission < 24 h post-stroke and at discharge 9.5 ± 4.7 days post-stroke). The impact of education was assessed using partial correlation analysis adjusted for lesion size, age, and the time interval between stroke and assessment. To validate our results, we compared groups with similar age and lesion load, but different education levels., Results: In the acute stroke phase, years of education predicted both severity of education independent (alertness) and education dependent (working memory, executive functions, global cognition) cognitive deficits and disability (modified Rankin Scale). Spatial neglect seemed to be independent., Interpretation: Proxies of cognitive reserve should be considered in stroke research as early as in the acute stroke phase. Cognitive reserve contributes to inter-individual variability in the initial severity of cognitive deficits and disability in acute stroke, and may suggest individualised rehabilitation strategies.

Background: Creativity is the use of original ideas to accomplish something innovative. Previous research supports the notion that creativity is facilitated by an activation of the right and/or a deactivation of the left prefrontal cortex. In contrast, recent brain imaging studies suggest that creativity improves with left frontal activation., Objective: The present study was designed to further elucidate the neural basis of and ways to modulate creativity, based on the modulation of prefrontal cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS)., Methods: Ninety healthy University students performed three tasks on major aspects of creativity: conceptual expansion (Alternate Uses Task, AUT), associative thinking (Compound Remote Associate Task, CRA), and set shifting ability (Wisconsin Card Sorting Task, WCST). Simultaneously, they received cathodal stimulation of the left and anodal stimulation of the right inferior frontal gyrus (IFG), the reverse protocol, or sham stimulation., Results: The main pattern of results was a superior performance with bilateral left cathodal/right anodal stimulation, and an inferior performance in the reversed protocol compared to sham stimulation. As a potential underlying physiological mechanism, resting state EEG beta power, indicative of enhanced cortical activity, in the right frontal area increased with anodal stimulation and was associated with better performance., Conclusion: The findings provide new insights into ways of modulating creativity, whereby a deactivation of the left and an activation of the right prefrontal cortex with tDCS is associated with increased creativity. Potential future applications might include tDCS for patients with mental disorders and for healthy individuals in creative professions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Major depression is a frequent and severe disorder, with a combination of psycho- and pharmacotherapy most patients can be treated. However, ~20% of all patients suffering from major depressive disorder remain treatment resistant; a subgroup might be treated with deep brain stimulation (DBS). We present two trials of DBS to the superolateral medial forebrain bundle (slMFB DBS; FORESEE I and II). The goal was to identify informed features that allow to predict treatment response. Data from N = 24 patients were analyzed. Preoperative imaging including anatomical sequences (T1 and T2) and diffusion tensor imaging (DTI) magnetic resonance imaging sequences were used together with postoperative helical CT scans (for DBS electrode position). Pathway activation modeling (PAM) as well as preoperative structural imaging and morphometry was used to understand the response behavior of patients (MADRS). A left fronto-polar and partly orbitofrontal region was identified that showed increased volume in preoperative anatomical scans. Further statistical analysis shows that the volume of this "HUB-region" is predictive for later MADRS response from DBS. The HUB region connects to typical fiber pathways that have been addressed before in therapeutic DBS in major depression. Left frontal volume growth might indicate intrinsic activity upon disconnection form the main emotional network. The results are significant since for the first time we found an informed feature that might allow to identify and phenotype future responders for slMFB DBS. This is a clear step into the direction of personalized treatments.

Transcranial magnetic stimulation (TMS) is a well-established tool in probing cortical plasticity in vivo . Changes in corticomotor excitability can be induced using paired associative stimulation (PAS) protocol, in which TMS over the primary motor cortex is conditioned with an electrical peripheral nerve stimulation of the contralateral hand. PAS with an inter-stimulus interval of 25 ms induces long-term potentiation (LTP)-like effects in cortical excitability. However, the response to a PAS protocol tends to vary substantially across individuals. In this study, we used univariate and multivariate data-driven methods to investigate various previously proposed determinants of inter-individual variability in PAS efficacy, such as demographic, cognitive, clinical, neurophysiological, and neuroimaging measures. Forty-one right-handed participants, comprising 22 patients with amnestic mild cognitive impairment (MCI) and 19 healthy controls (HC), underwent the PAS protocol. Prior to stimulation, demographic, genetic, clinical, as well as structural and resting-state functional MRI data were acquired. The two groups did not differ in any of the variables, except by global cognitive status. Univariate analysis showed that only 61% of all participants were classified as PAS responders, irrespective of group membership. Higher PAS response was associated with lower TMS intensity and with higher resting-state connectivity within the sensorimotor network, but only in responders, as opposed to non-responders. We also found an overall positive correlation between PAS response and structural connectivity within the corticospinal tract, which did not differ between groups. A multivariate random forest (RF) model identified age, gender, education, IQ, global cognitive status, sleep quality, alertness, TMS intensity, genetic factors, and neuroimaging measures (functional and structural connectivity, gray matter (GM) volume, and cortical thickness as poor predictors of PAS response. The model resulted in low accuracy of the RF classifier (58%; 95% CI: 42 - 74%), with a higher relative importance of brain connectivity measures compared to the other variables. We conclude that PAS variability in our sample was not well explained by factors known to influence PAS efficacy, emphasizing the need for future replication studies.

Objectives: The Tower of London (TOL) test has probably become the most often used task to assess planning ability in clinical and experimental settings. Since its implementation, efforts were made to provide a task version with adequate psychometric properties, but extensive normative data are not publicly available until now. The computerized TOL-Freiburg Version (TOL-F) was developed based on theory-grounded task analyses, and its psychometric adequacy has been repeatedly demonstrated in several studies but often with small and selective samples., Method: In the present study, we now report reliability estimates and normative data for the TOL-F stratified for age, sex, and education from a large population-representative sample collected in the Gutenberg Health Study in Mainz, Germany (n=7703; 40-80 years)., Results: The present data confirm previously reported adequate indices of reliability (&gt;.70) of the TOL-F. We also provide normative data for the TOL-F stratified for age (5-year intervals), sex, and education (low vs. high education)., Conclusions: Together, its adequate reliability and the representative age-, sex-, and education-fair normative data render the computerized TOL-F a suitable diagnostic instrument to assess planning ability. (JINS, 2019, 25, 520-529).

Cognitive control is proposed to rely on a rostral-to-caudal hierarchy of neural processing within the prefrontal cortex (PFC), with more rostral parts exerting control over more caudal parts. Anatomical and functional data suggest that this hierarchical organization of the PFC may be separated into a ventral and a dorsal component. Furthermore, recent studies indicate that the apex of the hierarchy resides within the mid-lateral rather the rostral PFC. However, investigating the hierarchical aspect of rostro-to-caudal processing requires quantification of the directed interactions between PFC regions. Using functional near-infrared spectroscopy (fNIRS) in a sample of healthy young adults we analyzed directed interactions between rostral and caudal PFC during passive watching of nature documentaries. Directed coherence (DC) as a measure of directed interaction was computed pairwise between 38 channels evenly distributed over the lateral prefrontal convexity. Results revealed an overall predominance of rostral-to-caudal directed interactions in the PFC that further dissociated along a ventro-dorsal axis: Dorsal regions exerted stronger rostro-caudally directed interactions on dorsal than on ventral regions and vice versa. Interactions between ventral and dorsal PFC were stronger from ventral to dorsal areas than vice versa. Results further support the notion that the mid-dorsolateral PFC constitutes the apex of the prefrontal hierarchy. Taken together these data provide novel evidence for parallel dorsal and ventral streams within the rostro-caudal hierarchical organization of the PFC. FNIRS-based analyses of directed interactions put forward a new perspective on the functional architecture of the prefrontal hierarchy and complement previous insights from functional magnetic resonance imaging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous lesion studies suggest that semantic and phonological fluency are differentially subserved by distinct brain regions in the left temporal and the left frontal cortex, respectively. However, as of yet, this often implied double dissociation has not been explicitly investigated due to mainly two reasons: (i) the lack of sufficiently large samples of brain-lesioned patients that underwent assessment of the two fluency variants and (ii) the lack of tools to assess interactions in factorial analyses of non-normally distributed behavioral data. In addition, previous studies did not control for task resource artifacts potentially introduced by the generally higher task difficulty of phonological compared to semantic fluency. We addressed these issues by task-difficulty adjusted assessment of semantic and phonological fluency in 85 chronic patients with ischemic stroke of the left middle cerebral artery. For classical region-based lesion-behavior mapping patients were grouped with respect to their primary lesion location. Building on the extension of the non-parametric Brunner-Munzel rank-order test to multi-factorial designs, ANOVA-type analyses revealed a significant two-way interaction for cue type (semantic vs. phonological) by lesion location (left temporal vs. left frontal vs. other as stroke control group). Subsequent contrast analyses further confirmed the proposed double dissociation by demonstrating that (i) compared to stroke controls, left temporal lesions led to significant impairments in semantic but not in phonological fluency, whereas left frontal lesions led to significant impairments in phonological but not in semantic fluency, and that (ii) patients with frontal lesions showed significantly poorer performance in phonological than in semantic fluency, whereas patients with temporal lesions showed significantly poorer performance in semantic than in phonological fluency. The anatomical specificity of these findings was further assessed in voxel-based lesion-behavior mapping analyses using the multi-factorial extension of the Brunner-Munzel test. Voxel-wise ANOVA-type analyses identified circumscribed parts of left inferior frontal gyrus and left superior and middle temporal gyrus that significantly double-dissociated with respect to their differential contribution to phonological and semantic fluency, respectively. Furthermore, a main effect of lesion with significant impairments in both fluency types was found in left inferior frontal regions adjacent to but not overlapping with those showing the differential effect for phonological fluency. The present study hence not only provides first explicit evidence for the anatomical double dissociation in verbal fluency at the group level but also clearly underlines that its formulation constitutes an oversimplification as parts of left frontal cortex appear to contribute to both semantic and phonological fluency., (Copyright © 2019. Published by Elsevier Inc.)

Objective: Autism spectrum (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders with a high rate of comorbidity. To date, diagnosis is based on clinical presentation and distinct reliable biomarkers have been identified neither for ASD nor ADHD. Most previous neuroimaging studies investigated ASD and ADHD separately. Method: To address the question of structural brain differences between ASD and ADHD, we performed FreeSurfer analysis in a sample of children with ADHD ( n = 30), with high-functioning ASD ( n = 14), with comorbid high-functioning ASD and ADHD ( n = 15), and of typically developed controls (TD; n = 36). With FreeSurfer, an automated brain imaging processing and analyzing suite, we reconstructed the cerebral cortex and calculated gray matter volumes as well as cortical surface parameters in terms of cortical thickness and mean curvature. Results: A significant main effect of the factor ADHD was detected for the left inferior frontal gyrus (Pars orbitalis) volume, with the ADHD group exhibiting smaller Pars orbitalis volumes. Dimensional measures of autism (SRS total raw score) and ADHD (DISYPS-II FBB-ADHD score) had no significant influence on the left Pars orbitalis volume. Both, ASD and ADHD tended to have an effect on cortical thickness or mean curvature, which did not survive correction for multiple comparisons. Conclusion: Our results underline that ADHD rather than ASD is associated with volume loss in the left inferior frontal gyrus (Pars orbitalis). This area might play a relevant role in modulating symptoms of inattention and/or impulsivity in ADHD. The effect of comorbid ADHD in ASD samples and vice versa, on cortical thickness and mean curvature, requires further investigation in larger samples.

Background and Purpose- To date, no clinical score has become widely accepted as an eligible prehospital marker for large vessel occlusion (LVO) and the need of mechanical thrombectomy (MT) in ischemic stroke. On the basis of pathophysiological considerations, we propose that cortical symptoms such as aphasia and neglect are more sensitive indicators for LVO and MT than motor deficits. Methods- We, thus, retrospectively evaluated a consecutive cohort of 543 acute stroke patients including patients with ischemia in the posterior circulation, hemorrhagic stroke, transient ischemic attack, and stroke mimics to best represent the prehospital setting. Results- Cortical symptoms alone showed to be a reliable indicator for LVO (sensitivity: 0.91; specificity: 0.70) and MT (sensitivity: 0.90; specificity: 0.60) in acute stroke patients, whereas motor deficits showed a sensitivity of 0.85 for LVO (specificity: 0.53) and 0.87 for MT (specificity: 0.48). Conclusions- We propose that in the prehospital setting, the presence of cortical symptoms is a reliable indicator for LVO and its presence justifies transportation to an MT-capable center.

As quantitative measures derived from fiber tractography are increasingly being used to characterize the structural connectivity of the brain, it is important to establish their reproducibility. However, no such information is as yet available for global tractography. Here we provide the first comprehensive analysis of the reproducibility of streamline counts derived from global tractography as quantitative estimates of structural connectivity. In a sample of healthy young adults scanned twice within one week, within-session and between-session test-retest reproducibility was estimated for streamline counts of connections based on regions of the AAL atlas using the intraclass correlation coefficient (ICC) for absolute agreement. We further evaluated the influence of the type of head-coil (12 versus 32 channels) and the number of reconstruction repetitions (reconstructing streamlines once or aggregated over ten repetitions). Factorial analyses demonstrated that reproducibility was significantly greater for within- than between-session reproducibility and significantly increased by aggregating streamline counts over ten reconstruction repetitions. Using a high-resolution head-coil incurred only small beneficial effects. Overall, ICC values were positively correlated with the streamline count of a connection. Additional analyses assessed the influence of different selection variants (defining fuzzy versus no fuzzy borders of the seed mask; selecting streamlines that end in versus pass through a seed) showing that an endpoint-based variant using fuzzy selection provides the best compromise between reproducibility and anatomical specificity. In sum, aggregating quantitative indices over repeated estimations and higher numbers of streamlines are important determinants of test-retest reproducibility. If these factors are taken into account, streamline counts derived from global tractography provide an adequately reproducible quantitative measure that can be used to gauge the structural connectivity of the brain in health and disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Stroke patients frequently display spatial neglect, an inability to report, or respond to, relevant stimuli in the contralesional space. Although this syndrome is widely considered to result from the dysfunction of a large-scale attention network, the individual contributions of damaged grey and white matter regions to neglect are still being disputed. Moreover, while the neuroanatomy of neglect in right hemispheric lesions is well studied, the contributions of left hemispheric brain regions to visuospatial processing are less well understood. To address this question, 128 left hemisphere acute stroke patients were investigated with respect to left- and rightward spatial biases measured as severity of deviation in the line bisection test and as Center of Cancellation (CoC) in the Bells Test. Causal functional contributions and interactions of nine predefined grey and white matter regions of interest in visuospatial processing were assessed using Multi-perturbation Shapley value Analysis (MSA). MSA, an inference approach based on game theory, constitutes a robust and exact multivariate mathematical method for inferring functional contributions from multi-lesion patterns. According to the analysis of performance in the Bells test, leftward attentional bias (contralesional deficit) was associated with contributions of the left superior temporal gyrus and rightward attentional bias with contributions of the left inferior parietal lobe, whereas the arcuate fascicle was contributed to both contra- and ipsilesional bias. Leftward and rightward deviations in the line bisection test were related to contributions of the superior longitudinal fascicle and the inferior parietal lobe, correspondingly. Thus, Bells test and line bisection tests, as well as ipsi- and contralesional attentional biases in these tests, have distinct neural correlates. Our findings demonstrate the contribution of different grey and white matter structures to contra- and ipsilesional spatial biases as revealed by left hemisphere stroke. The results provide new insights into the role of the left hemisphere in visuospatial processing., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

These data provide estimations of test-retest reproducibility of streamline counts based on diffusion weighted imaging (DWI) data using a global tractography algorithm in a sample of young healthy adults. Data on descriptive statistics and factorial analyses of within-session and between-session reproducibility in terms of intra-class correlation coefficients for the absolute agreement between measurements are provided. The effect of several exemplary methodological parameters pertaining to different steps along the tractography processing pipeline on reproducibility are considered. These data are related to the research article entitled 'Probing the reproducibility of quantitative estimates of structural connectivity derived from global tractography' (Schumacher et al., Neuroimage, 175 (2018) 215-229).

Compensation implies the recruitment of additional neuronal resources to prevent the detrimental effect of age-related neuronal decline on cognition. Recently suggested statistical models comprise behavioral performance, brain activation, and measures related to aging- or disease-specific pathological burden to characterize compensation. Higher chronological age as well as the APOE ε4 allele are risk factors for Alzheimer's disease. A more biological approach to characterize aging compared with chronological age is the brain age gap estimation (BrainAGE), taking into account structural brain characteristics. We utilized this estimate in an fMRI experiment together with APOE variant as measures related to pathological burden and aimed at identifying compensatory regions during working memory (WM) processing in a group of 34 healthy older adults. According to published compensation criteria, better performance along with increased brain activation would indicate successful compensation. We examined the moderating effects of BrainAGE on the relationship between task performance and brain activation in prefrontal cortex, as previous studies suggest predominantly frontal compensatory activation. Then we statistically compared them to the effects of chronological age (CA) tested in a previous study. Moreover, we examined the effects of adding APOE variant as a further moderator. Herewith, we strived to uncover neuronal compensation in healthy older adults at risk for neurodegenerative disease. Higher BrainAGE alone was not associated with an increased recruitment in prefrontal cortex. When adding APOE variant as a second moderator, we found an interaction of BrainAGE and APOE variant, such that ε4 carriers recruited right inferior frontal gyrus with higher BrainAGE to maintain WM performance, thus showing a pattern compatible with successful neuronal compensation. Exploratory analyses yielded similar patterns in left inferior and bilateral middle frontal gyrus. These results contrast those from a previous study, where we found no indication of compensation in prefrontal cortex in ε4 carriers with increasing CA. We conclude that BrainAGE together with APOE variant can help to reveal potential neuronal compensation in healthy older adults. Previous results on neuronal compensation in frontal areas corroborate our findings. Compensatory brain regions could be targeted in affected individuals by training or stimulation protocols to maintain cognitive functioning as long as possible.

Background: Magnetic resonance (MR) relaxometry is of increasing scientific relevance in neurodegenerative disorders but is still not established in clinical routine. Several studies have investigated relaxation time alterations in disease-specific areas in Parkinson's disease (PD), all using manually drawn regions of interest (ROI). Implementing MR relaxometry into the clinical setting involves the reduction of time needed for postprocessing using an investigator-independent and reliable approach. The aim of this study was to evaluate an automated, atlas-based ROI method for evaluating T2* relaxation times in patients with PD., Method: Automated atlas-based ROI analysis of quantitative T2* maps were generated from 20 PD patients and 20 controls. To test for the accuracy of the atlas-based ROI segmentation, we evaluated the spatial overlap in comparison with manually segmented ROIs using the Dice similarity coefficient (DSC). Additionally, we tested for group differences using our automated atlas-based ROIs of the putamen, globus pallidus, and substantia nigra., Results: A good spatial overlap accuracy was shown for the automated segmented putamen (mean DSC, 0.64 ± 0.04) and was inferior but still acceptable for the substantia nigra (mean DSC, 0.50 ± 0.17). Based on our automated defined ROI selection, a significant decrease of T2* relaxation time was found in the putamen as well as in the internal and external globus pallidus in PD patients compared with healthy controls., Conclusion: Automated digital brain atlas-based approaches are reliable, more objective and time-efficient, and therefore have the potential to replace the time-consuming manual drawing of ROIs.

Imitation of tool-use gestures (transitive; e.g., hammering) and communicative emblems (intransitive; e.g., waving goodbye) is frequently impaired after left-hemispheric lesions. We aimed 1) to identify lesions related to deficient transitive or intransitive gestures, 2) to delineate regions associated with distinct error types (e.g., hand configuration, kinematics), and 3) to compare imitation to previous data on pantomimed and actual tool use. Of note, 156 patients (64.3 ± 14.6 years; 56 female) with first-ever left-hemispheric ischemic stroke were prospectively examined 4.8 ± 2.0 days after symptom onset. Lesions were delineated on magnetic resonance imaging scans for voxel-based lesion-symptom mapping. First, while inferior-parietal lesions affected both gesture types, specific associations emerged between intransitive gesture deficits and anterior temporal damage and between transitive gesture deficits and premotor and occipito-parietal lesions. Second, impaired hand configurations were related to anterior intraparietal damage, hand/wrist-orientation errors to premotor lesions, and kinematic errors to inferior-parietal/occipito-temporal lesions. Third, premotor lesions impacted more on transitive imitation compared with actual tool use, pantomimed and actual tool use were more susceptible to lesioned insular cortex and subjacent white matter. In summary, transitive and intransitive gestures differentially rely on ventro-dorsal and ventral streams due to higher demands on temporo-spatial processing (transitive) or stronger reliance on semantic information (intransitive), respectively., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Spatial disorientation is a frequent symptom in Alzheimer's disease and in mild cognitive impairment (MCI). In the clinical routine, spatial orientation is less often tested with real-world navigation but rather with 2D visuoconstructive tasks. However, reports about the association between the two types of tasks are sparse. Additionally, spatial disorientation has been linked to volume of the right hippocampus but it remains unclear whether right hippocampal subregions have differential involvement in real-world navigation. Yet, this would help uncover different functional roles of the subregions, which would have important implications for understanding the neuronal underpinnings of navigation skills. We compared patients with amnestic MCI (aMCI; n = 25) and healthy elderly controls (HC; n = 25) in a real-world navigation task that engaged different spatial processes. The association between real-world navigation and different visuoconstructive tasks was tested (i.e., figures from the Consortium to Establish a Registry for Alzheimer's Disease; CERAD, the Rey-Osterrieth Complex Figure task; and clock drawing). Furthermore, the relation between spatial navigation and volume of right hippocampal subregions was examined. Linear regression and relative weight analysis were applied for statistical analyses. Patients with aMCI were significantly less able to correctly navigate through a route compared to HC but had comparable map drawing and landmark recognition skills. The association between visuoconstructive tasks and real-world navigation was only significant when using the visuospatial memory component of the Rey figure. In aMCI, more volume of the right hippocampal tail was significantly associated with better navigation skills, while volume of the right CA2/3 region was a significant predictor in HC. Standard visuoconstructive tasks (e.g., the CERAD figures or clock drawing) are not sufficient to detect real-world spatial disabilities in aMCI. Consequently, more complex visuoconstructive tasks (i.e., the Rey figure) should be routinely included in the assessment of cognitive functions in the context of AD. Moreover, in those elderly individuals with impaired complex visuospatial memory, route finding behaviour should be evaluated in detail. Regarding the contribution of hippocampal subregions to spatial navigation, the right hippocampal tail seems to be particularly important for patients with aMCI, while the CA2/3 region appears to be more relevant in HC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In mild cognitive impairment (MCI), small benefits from cognitive training were observed for memory functions but there appears to be great variability in the response to treatment. Our study aimed to improve the characterization and selection of those participants who will benefit from cognitive intervention. We evaluated the predictive value of disease-specific biological factors for the outcome after cognitive training in MCI (n = 25) and also considered motivation of the participants. We compared the results of the cognitive intervention group with two independent control groups of MCI patients (local memory clinic, n = 20; ADNI cohort, n = 302). The primary outcome measure was episodic memory as measured by verbal delayed recall of a 10-word list. Episodic memory remained stable after treatment and slightly increased 6 months after the intervention. In contrast, in MCI patients who did not receive an intervention, episodic memory significantly decreased during the same time interval. A larger left entorhinal cortex predicted more improvement in episodic memory after treatment and so did higher levels of motivation. Adding disease-specific biological factors significantly improved the prediction of training-related change compared to a model based simply on age and baseline performance. Bootstrapping with resampling (n = 1000) verified the stability of our finding. Cognitive training might be particularly helpful in individuals with a bigger left entorhinal cortex as individuals who did not benefit from intervention showed 17% less volume in this area. When extended to alternative treatment options, stratification based on disease-specific biological factors is a useful step towards individualized medicine.

Inter-hemispheric asymmetries are a common phenomenon of the human brain. Some evidence suggests that neurodegeneration related to aging and disease may preferentially affect the left-usually language- and motor-dominant-hemisphere. Here, we used activation likelihood estimation meta-analysis to assess gray matter (GM) loss and its lateralization in healthy aging and in neurodegeneration, namely, mild cognitive impairment (MCI), Alzheimer's dementia (AD), Parkinson's disease (PD), and Huntington's disease (HD). This meta-analysis, comprising 159 voxel-based morphometry publications (enrolling 4,469 patients and 4,307 controls), revealed that GM decline appeared to be asymmetric at trend levels but provided no evidence for increased left-hemisphere vulnerability. Regions with asymmetric GM decline were located in areas primarily affected by neurodegeneration. In HD, the left putamen showed converging evidence for more pronounced atrophy, while no consistent pattern was found in PD. In MCI, the right hippocampus was more atrophic than its left counterpart, a pattern that reversed in AD. The stability of these findings was confirmed using permutation tests. However, due to the lenient threshold used in the asymmetry analysis, further work is needed to confirm our results and to provide a better understanding of the functional role of GM asymmetries, for instance in the context of cognitive reserve and compensation. Hum Brain Mapp 38:5890-5904, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Huntington's disease (HD) is a progressive neurodegenerative disorder that can be genetically confirmed with certainty decades before clinical onset. This allows the investigation of functional and structural changes in HD many years prior to disease onset, which may reveal important mechanistic insights into brain function, structure and organization in general. While regional atrophy is present at early stages of HD, it is still unclear if both hemispheres are equally affected by neurodegeneration and how the extent of asymmetry affects domain-specific functional decline. Here, we used whole-brain voxel-based analysis to investigate cross-sectional and longitudinal hemispheric asymmetries in grey matter (GM) volume in 56 manifest HD (mHD), 83 pre-manifest HD (preHD), and 80 healthy controls (HC). Furthermore, a regression analysis was used to assess the relationship between neuroanatomical asymmetries and decline in motor and cognitive measures across the disease spectrum. The cross-sectional analysis showed striatal leftward-biased GM atrophy in mHD, but not in preHD, relative to HC. Longitudinally, no net 36-month change in GM asymmetries was found in any of the groups. In the regression analysis, HD-related decline in quantitative-motor (Q-Motor) performance was linked to lower GM volume in the left superior parietal cortex. These findings suggest a stronger disease effect targeting the left hemisphere, especially in those with declining motor performance. This effect did not change over a period of three years and may indicate a compensatory role of the right hemisphere in line with recent functional imaging studies.