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Background/aims: Peripheral neuropathies perturbate the sensorimotor system, causing difficulties in walking-related motor tasks and, eventually, falls. Falls result in functional dependency and reliance on healthcare, especially in older persons. We investigated if peripheral neuropathy is a genuine risk factor for falls in the elderly and if quantification of postural control via posturography is helpful in identifying subjects at risk of falls., Methods: Seventeen older persons with a clinical polyneuropathic syndrome of the lower limbs and converging electrophysiology were compared with 14 older persons without polyneuropathy. All participants were characterized via quantitative motor and sensory testing, neuropsychological assessment, and self-questionnaires. Video-nystagmography and caloric test excluded vestibulocochlear dysfunction. For further analysis, all subjects were stratified into fallers and non-fallers. Overall, 28 patients underwent computerized dynamic posturography for individual fall risk assessment. Regression analyses were performed to identify risk factors and predictive posturography parameters., Results: Neuropathy is an independent risk factor for falls in the elderly, while no differences were observed for age, gender, weight, frailty, DemTect test, timed "Up & Go" test, and dizziness-related handicap score. In computerized dynamic posturography, fallers stepped more often to regain postural control in challenging conditions, while the Rhythmic Weight Shift test showed a lack of anterior-posterior bidirectional voluntary control., Interpretation: Our study confirms peripheral neuropathy as a risk factor for older persons' falls. Fallers frequently used stepping to regain postural control. The voluntary control of this coping movement was impaired. Further investigations into these parameters' value in predicting the risk of falls in the elderly are warranted., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18 F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18 F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: The gut microbiome is involved in autoimmunity. Data on its composition in chronic inflammatory demyelinating polyneuropathy (CIDP), the most common chronic autoimmune disorder of peripheral nerves, are currently lacking., Methods: In this monocentric exploratory pilot study, stool samples were prospectively collected from 16 CIDP patients (mean age 58 ± 10 years, 25% female) before and 1 week after administration of intravenous immunoglobulin (IVIg). Gut microbiota were analyzed via bacterial 16S rRNA gene sequencing and compared to 15 age-matched healthy subjects (mean age 59 ± 15 years, 66% female)., Results: The gut microbiota of CIDP patients showed an increased alpha-diversity (p = 0.005) and enrichment of Firmicutes, such as Blautia (p = 0.0004), Eubacterium hallii (p = 0.0004), or Ruminococcus torques (p = 0.03), and of Actinobacteriota (p = 0.03) compared to healthy subjects. IVIg administration did not alter the gut microbiome composition in CIDP in this short-term observation (p = 0.95)., Conclusions: The gut microbiome in IVIg-treated CIDP shows distinct features, with increased bacterial diversity and enrichment of short-chain fatty acid producing Firmicutes. IVIg had no short-term impact on the gut microbiome in CIDP patients. As the main limitation of this exploratory pilot study was small cohort size, future studies also including therapy-naïve patients are warranted to verify our findings and to explore the impact of long-term IVIg treatment on the gut microbiome in CIDP., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Cognitive decline is a frequent and debilitating non-motor symptom for patients with Parkinson's disease (PD). Metabolic alterations in the occipital cortex during visual processing may serve as a biomarker for cognitive decline in patients with PD., Methods: Sixteen patients with PD (Unified Parkinson's Disease Rating Scale Part 3, OFF, 38.69 ± 17.25) and 10 age- and sex-matched healthy controls (HC) underwent 7-T functional magnetic resonance spectroscopy (MRS) utilizing a visual checkerboard stimulation. Glutamate metabolite levels during rest versus stimulation were compared. Furthermore, correlates of the functional MRS response with performance in visuo-cognitive tests were investigated., Results: No differences in static MRS between patients with PD and HC were detected, but a dynamic glutamate response was observed in functional MRS in HC upon visual stimulation, which was blunted in patients with PD (F 1,22  = 7.13, p = 0.014; η p 2  = 0.245). A diminished glutamate response correlated with poorer performance in the Benton Judgment of Line Orientation test in PD (r = -0.57, p = 0.020)., Conclusions: Our results indicate that functional MRS captures even subtle differences in neural processing linked to the behavioral performance, which would have been missed by conventional, static MRS. Functional MRS thus represents a promising tool for studying molecular alterations at high sensitivity. Its prognostic potential should be evaluated in longitudinal studies, prospectively contributing to earlier diagnosis and individual treatment decisions., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: This study assessed the prevalence of anti-SARS-CoV-2 antibodies in therapeutic immunoglobulin and their impact on serological response to COVID-19 mRNA vaccine in patients with intravenous immunoglobulin (IVIg)-treated chronic immune neuropathies., Methods: Forty-six samples of different brands or lots of IVIg or subcutaneous IgG were analyzed for anti-SARS-CoV-2 IgG using enzyme-linked immunosorbent assay and chemiluminescent microparticle immunoassay. Blood sera from 16 patients with immune neuropathies were prospectively analyzed for anti-SARS-CoV-2 IgA, IgG, and IgM before and 1 week after IVIg infusion subsequent to consecutive COVID-19 mRNA vaccine doses and after 12 weeks. These were compared to 42 healthy subjects., Results: Twenty-four (52%) therapeutic immunoglobulin samples contained anti-SARS-CoV-2 IgG. All patients with immune neuropathies (mean age = 65 ± 16 years, 25% female) were positive for anti-SARS-CoV-2 IgG after COVID-19 vaccination. Anti-SARS-CoV-2 IgA titers significantly decreased 12-14 weeks after vaccination (p = 0.02), whereas IgG titers remained stable (p = 0.2). IVIg did not significantly reduce intraindividual anti-SARS-CoV-2 IgA/IgG serum titers in immune neuropathies (p = 0.69). IVIg-derived anti-SARS-CoV-2 IgG did not alter serum anti-SARS-CoV-2 IgG decrease after IVIg administration (p = 0.67)., Conclusions: Our study indicates that IVIg does not impair the antibody response to COVID-19 mRNA vaccine in a short-term observation, when administered a minimum of 2 weeks after each vaccine dose. The infusion of current IVIg preparations that contain anti-SARS-CoV-2 IgG does not significantly alter serum anti-SARS-CoV-2 IgG titers., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Understanding how brain activity translates into behavior is a grand challenge in neuroscientific research. Simultaneous computational modeling of both measures offers to address this question. The extension of the dynamic causal modeling (DCM) framework for blood oxygenation level-dependent (BOLD) responses to behavior (bDCM) constitutes such a modeling approach. However, only very few studies have employed and evaluated bDCM, and its application has been restricted to binary behavioral responses, limiting more general statements about its validity. This study used bDCM to model reaction times in a spatial attention task, which involved two separate runs with either horizontal or vertical stimulus configurations. We recorded fMRI data and reaction times (n= 26) and compared bDCM with classical DCM and a behavioral Rescorla-Wagner model using Bayesian model selection and goodness of fit statistics. Results indicate that bDCM performed equally well as classical DCM when modeling BOLD responses and as good as the Rescorla-Wagner model when modeling reaction times. Although our data revealed practical limitations of the current bDCM approach that warrant further investigation, we conclude that bDCM constitutes a promising method for investigating the link between brain activity and behavior., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: During acute coronavirus disease 2019 (COVID-19) infection, neurological signs, symptoms and complications occur. We aimed to assess their clinical relevance by evaluating real-world data from a multinational registry., Methods: We analyzed COVID-19 patients from 127 centers, diagnosed between January 2020 and February 2021, and registered in the European multinational LEOSS (Lean European Open Survey on SARS-Infected Patients) registry. The effects of prior neurological diseases and the effect of neurological symptoms on outcome were studied using multivariate logistic regression., Results: A total of 6537 COVID-19 patients (97.7% PCR-confirmed) were analyzed, of whom 92.1% were hospitalized and 14.7% died. Commonly, excessive tiredness (28.0%), headache (18.5%), nausea/emesis (16.6%), muscular weakness (17.0%), impaired sense of smell (9.0%) and taste (12.8%), and delirium (6.7%) were reported. In patients with a complicated or critical disease course (53%) the most frequent neurological complications were ischemic stroke (1.0%) and intracerebral bleeding (ICB; 2.2%). ICB peaked in the critical disease phase (5%) and was associated with the administration of anticoagulation and extracorporeal membrane oxygenation (ECMO). Excessive tiredness (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.20-1.68) and prior neurodegenerative diseases (OR 1.32, 95% CI 1.07-1.63) were associated with an increased risk of an unfavorable outcome. Prior cerebrovascular and neuroimmunological diseases were not associated with an unfavorable short-term outcome of COVID-19., Conclusion: Our data on mostly hospitalized COVID-19 patients show that excessive tiredness or prior neurodegenerative disease at first presentation increase the risk of an unfavorable short-term outcome. ICB in critical COVID-19 was associated with therapeutic interventions, such as anticoagulation and ECMO, and thus may be an indirect complication of a life-threatening systemic viral infection., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Illusory figures demonstrate the visual system's ability to integrate disparate parts into coherent wholes. We probed this object integration process by either presenting an integrated diamond shape or a comparable ungrouped configuration that did not render a complete object. Two tasks were used that either required localization of a target dot (relative to the presented configuration) or discrimination of the dot's luminance. The results showed that only when the configuration was task relevant (in the localization task), performance benefited from the presentation of an integrated object. Concurrent functional magnetic resonance imaging was performed and analyzed using dynamic causal modeling to investigate the (causal) relationship between regions that are associated with illusory figure completion. We found object-specific feedback connections between the lateral occipital cortex (LOC) and early visual cortex (V1/V2). These modulatory connections persisted across task demands and hemispheres. Our results thus provide direct evidence that interactions between mid-level and early visual processing regions engage in illusory figure perception. These data suggest that LOC first integrates inputs from multiple neurons in lower-level cortices, generating a global shape representation while more fine-graded object details are then determined via feedback to early visual areas, independently of the current task demands., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Motor recovery after stroke relies on functional reorganization of the motor network, which is commonly assessed via functional magnetic resonance imaging (fMRI)-based resting-state functional connectivity (rsFC) or task-related effective connectivity (trEC). Measures of either connectivity mode have been shown to successfully explain motor impairment post-stroke, posing the question whether motor impairment is more closely reflected by rsFC or trEC. Moreover, highly similar changes in ipsilesional and interhemispheric motor network connectivity have been reported for both rsFC and trEC after stroke, suggesting that altered rsFC and trEC may capture similar aspects of information integration in the motor network reflecting principle, state-independent mechanisms of network reorganization rather than state-specific compensation strategies. To address this question, we conducted the first direct comparison of rsFC and trEC in a sample of early subacute stroke patients (n = 26, included on average 7.3 days post-stroke). We found that both rsFC and trEC explained motor impairment across patients, stressing the clinical potential of fMRI-based connectivity. Importantly, intrahemispheric connectivity between ipsilesional M1 and premotor areas depended on the activation state, whereas interhemispheric connectivity between homologs was state-independent. From a mechanistic perspective, our results may thus arise from two distinct aspects of motor network plasticity: task-specific compensation within the ipsilesional hemisphere and a more fundamental form of reorganization between hemispheres., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: The aim was to assess the organization and short-term changes of motor units in adult patients with spinal muscular atrophy (SMA) treated with nusinersen., Methods: In this single-centre cross-sectional and longitudinal study 15 adult patients with SMA type 3 were assessed and compared to 15 age-matched healthy controls and nine patients with amyotrophic lateral sclerosis. Moreover, 10 patients with SMA were followed up after 4-8 months. All patients were investigated clinically and by the motor unit number estimation method MScanFit of the abductor pollicis brevis muscle., Results: The number of motor units (p < 0.001) was significantly lower in patients with SMA compared to healthy controls at study entry. Mean unit amplitude, median amplitude and largest unit (p < 0.001) were significantly increased in patients with SMA. Patients with amyotrophic lateral sclerosis showed a significant reduction of compound muscle action potential (p = 0.005) and number of motor units (p = 0.03) compared to patients with SMA, accompanied by a larger median amplitude (p = 0.03). A prospective analysis identified patients with the ability to walk to improve the number of motor units (p = 0.046) accompanied by a decreased median amplitude (p = 0.03). Electrophysiological measures showed a moderate to strong correlation with clinical scores., Conclusion: Patients with SMA show loss of motor units in distal muscles. MScanFit variables indicate that compound muscle action potential amplitudes are maintained by collateral sprouting. Prospective analyses suggest that milder affected adult patients with SMA preferentially benefit from nusinersen treatment through recovery of smaller motor units. Correlations with clinical scores underline the potential of MScanFit as a surrogate marker., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Competing Interests: Supported by the Cologne Clinician Scientist Program (CCSP)/ Faculty of Medicine/ University of Cologne. Funded by the German Research Foundation (DFG FI 773/15–1 to JPS and Wi 945/19–1 to BW), and CMMC C18, a CMMC clinical scientist award (to MK), and a Köln‐Fortune doctoral fellowship (to NK). The authors declare that there are no conflicts of interest relevant to this work.

Cognitive performance slows down with increasing age. This includes cognitive processes that are essential for the performance of a motor act, such as the slowing down in response to an external stimulus. The objective of this study was to identify aging-associated functional changes in the brain networks that are involved in the transformation of external stimuli into motor action. To investigate this topic, we employed dynamic graphs based on phase-locking of Electroencephalography signals recorded from healthy younger and older subjects while performing a simple visually-cued finger-tapping task. The network analysis yielded specific age-related network structures varying in time in the low frequencies (2-7 Hz), which are closely connected to stimulus processing, movement initiation and execution in both age groups. The networks in older subjects, however, contained several additional, particularly interhemispheric, connections and showed an overall increased coupling density. Cluster analyses revealed reduced variability of the subnetworks in older subjects, particularly during movement preparation. In younger subjects, occipital, parietal, sensorimotor and central regions were-temporally arranged in this order-heavily involved in hub nodes. Whereas in older subjects, a hub in frontal regions preceded the noticeably delayed occurrence of sensorimotor hubs, indicating different neural information processing in older subjects. All observed changes in brain network organization, which are based on neural synchronization in the low frequencies, provide a possible neural mechanism underlying previous fMRI data, which report an overactivation, especially in the prefrontal and pre-motor areas, associated with a loss of hemispheric lateralization in older subjects., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Stroke patients suffering from hemiparesis may show substantial recovery in the first months poststroke due to neural reorganization. While reorganization driving improvement of upper hand motor function has been frequently investigated, much less is known about the changes underlying recovery of lower limb function. We, therefore, investigated neural network dynamics giving rise to movements of both the hands and feet in 12 well-recovered left-hemispheric chronic stroke patients and 12 healthy participants using a functional magnetic resonance imaging sparse sampling design and dynamic causal modeling (DCM). We found that the level of neural activity underlying movements of the affected right hand and foot positively correlated with residual motor impairment, in both ipsilesional and contralesional premotor as well as left primary motor (M1) regions. Furthermore, M1 representations of the affected limb showed significantly stronger increase in BOLD activity compared to healthy controls and compared to the respective other limb. DCM revealed reduced endogenous connectivity of M1 of both limbs in patients compared to controls. However, when testing for the specific effect of movement on interregional connectivity, interhemispheric inhibition of the contralesional M1 during movements of the affected hand was not detected in patients whereas no differences in condition-dependent connectivity were found for foot movements compared to controls. In contrast, both groups featured positive interhemispheric M1 coupling, that is, facilitation of neural activity, mediating movements of the affected foot. These exploratory findings help to explain why functional recovery of the upper and lower limbs often develops differently after stroke, supporting limb-specific rehabilitative strategies., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Primitive reflexes may reoccur in various neurodegenerative diseases. However, little is known about their structural and functional correlates in the human brain. Notably, the neural mechanisms underlying a positive palmomental reflex (PMR) are poorly understood. As recent studies link Alzheimer's disease (AD)-related primitive reflexes to a dysfunction of the corticostriatal motor circuit (CMC), we conducted the present study to investigate functional and structural correlates of a positive PMR. We hypothesized an involvement of frontostriatal structures and an impairment of the CMC., Methods: Using whole-brain resting-state functional connectivity (FC), hypothesis and FC result-based probabilistic tractography, and voxel-based morphometry analyses, we compared two groups of AD patients with either positive (n = 12) or negative PMR (n = 12)., Results: No significant differences in grey matter volume or structural connectivity (SC) could be observed between the PMR-positive and PMR-negative groups. In contrast, the PMR-positive group showed a decreased seed-to-voxel FC between the bilateral supplementary motor area and parts of the right-hemispherical caudate nucleus and thalamus and a decreased region of interest (ROI)-to-ROI FC between the left putamen and the left superior frontal gyrus., Conclusion: Data suggest that dysfunction of the CMC reflected by decreased FC underlies a positive PMR in patients with AD. The lack of significant grey matter or SC differences might reflect that changes in FC appear before changes in SC in the structures of the CMC and brain atrophy., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Hemispatial neglect, after unilateral lesions to parietal brain areas, is characterized by an inability to respond to unexpected stimuli in contralesional space. As the visual field's horizontal meridian is most severely affected, the brain networks controlling visuospatial processes might be tuned explicitly to this axis. We investigated such a potential directional tuning in the dorsal and ventral frontoparietal attention networks, with a particular focus on attentional reorientation. We used an orientation-discrimination task where a spatial precue indicated the target position with 80% validity. Healthy participants (n = 29) performed this task in two runs and were required to (re-)orient attention either only along the horizontal or the vertical meridian, while fMRI and behavioral measures were recorded. By using a general linear model for behavioral and fMRI data, dynamic causal modeling for effective connectivity, and other predictive approaches, we found strong statistical evidence for a reorientation effect for horizontal and vertical runs. However, neither neural nor behavioral measures differed between vertical and horizontal reorienting. Moreover, models from one run successfully predicted the cueing condition in the respective other run. Our results suggest that activations in the dorsal and ventral attention networks represent higher-order cognitive processes related to spatial attentional (re-)orientating that are independent of directional tuning and that unilateral attention deficits after brain damage are based on disrupted interactions between higher-level attention networks and sensory areas., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

The timeline of brain-wide neural activity relative to a behavioral event is crucial when decoding the neural implementation of a cognitive process. Yet, fMRI assesses neural processes indirectly via delayed and regionally variable hemodynamics. This method-inherent temporal distortion impacts the interpretation of behavior-linked neural timing. Here we describe a novel behavioral protocol that aims at disentangling the BOLD dynamics of the pre- and post-response periods in response time tasks. We tested this response-locking protocol in a perceptual decision-making (random dot) task. Increasing perceptual difficulty produced expected activity increases over a broad network involving the lateral/medial prefrontal cortex and the anterior insula. However, response-locking revealed a previously unreported functional dissociation within this network. preSMA and anterior premotor cortex (prePMV) showed post-response activity modulations while anterior insula and anterior cingulate cortex did not. Furthermore, post-response BOLD activity at preSMA showed a modulation in timing but not amplitude while this pattern was reversed at prePMV. These timeline dissociations with response-locking thus revealed three functionally distinct sub-networks in what was seemingly one shared distributed network modulated by perceptual difficulty. These findings suggest that our novel response-locked protocol could boost the timing-related sensitivity of fMRI., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Healthy aging is accompanied by changes in brain activation patterns in the motor system. In older subjects, unilateral hand movements typically rely on increased recruitment of ipsilateral frontoparietal areas. While the two central concepts of aging-related brain activity changes, "Hemispheric Asymmetry Reduction in Older Adults" (HAROLD), and "Posterior to Anterior Shift in Aging" (PASA), have initially been suggested in the context of cognitive tasks and were attributed to compensation, current knowledge regarding the functional significance of increased motor system activity remains scarce. We, therefore, used online interference transcranial magnetic stimulation in young and older subjects to investigate the role of key regions of the ipsilateral frontoparietal cortex, that is, (a) primary motor cortex (M1), (b) dorsal premotor cortex (dPMC), and (c) anterior intraparietal sulcus (IPS) in the control of hand movements of different motor demands. Our data suggest a change of the functional roles of ipsilateral brain areas in healthy age with a reduced relevance of ipsilateral M1 and a shift of importance toward dPMC for repetitive high-frequency movements. These results support the notion that mechanisms conceptualized in the models of "PASA" and "HAROLD" also apply to the motor system., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Background and Purpose: Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL) and motor and non-motor symptoms in advanced Parkinson's disease (PD). However, its effect on alexithymia and its relationship to other neuropsychiatric symptoms and QoL in PD is unclear., Methods: In this prospective, observational study of 39 patients with PD undergoing STN-DBS, we examined the Parkinson's Disease Questionnaire-8 (PDQ-8), 20-item Toronto Alexithymia Scale (TAS-20), Hospital Anxiety and Depression Scale (HADS), Self-Report Manic Inventory (SRMI), Apathy Evaluation Scale (AES), Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living, UPDRS motor examination and UPDRS complications (UPDRS-II/-III/-IV) and levodopa-equivalent daily dose (LEDD) pre-operatively and at 5-month follow-up. Outcome changes were tested with Wilcoxon signed-rank or paired t-test when parametric tests were applicable and corrected for multiple comparisons. The relationship between outcome changes was explored with bivariate correlations. Additionally, partial correlations between PDQ-8 and TAS-20 were computed controlling for HADS, SRMI and AES change scores. Predictor analyses for PDQ-8 improvement were calculated for all baseline parameters., Results: The baseline prevalence of alexithymia was 17.9%. We observed significant beneficial effects of STN-DBS on PDQ-8, TAS-20, HADS, UPDRS-II, -III and -IV scores and significant LEDD reduction. The correlation between TAS-20 and PDQ-8 improvements remained significant after controlling for all other aforementioned outcomes. Predictor analyses for PDQ-8 improvement were significant for PDQ-8 and TAS-20., Conclusions: This is the first report of beneficial effects of STN-DBS on alexithymia. Alexithymia was significantly associated with QoL outcome independent of anxiety, depression, mania and apathy. Our study highlights the importance of alexithymia for holistic assessments of DBS outcomes., (© 2018 EAN.)

Evidence from neuropsychological and imaging studies indicate that action and semantic knowledge about tools draw upon distinct neural substrates, but little is known about the underlying interregional effective connectivity. With fMRI and dynamic causal modeling (DCM) we investigated effective connectivity in the left-hemisphere (LH) while subjects performed (i) a function knowledge and (ii) a value knowledge task, both addressing semantic tool knowledge, and (iii) a manipulation (action) knowledge task. Overall, the results indicate crosstalk between action nodes and semantic nodes. Interestingly, effective connectivity was weakened between semantic nodes and action nodes during the manipulation task. Furthermore, pronounced modulations of effective connectivity within the fronto-parietal action system of the LH (comprising lateral occipito-temporal cortex, intraparietal sulcus, supramarginal gyrus, inferior frontal gyrus) were observed in a bidirectional manner during the processing of action knowledge. In contrast, the function and value knowledge tasks resulted in a significant strengthening of the effective connectivity between visual cortex and fusiform gyrus. Importantly, this modulation was present in both semantic tasks, indicating that processing different aspects of semantic knowledge about tools evokes similar effective connectivity patterns. Data revealed that interregional effective connectivity during the processing of tool knowledge occurred in a bidirectional manner with a weakening of connectivity between areas engaged in action and semantic knowledge about tools during the processing of action knowledge. Moreover, different semantic tool knowledge tasks elicited similar effective connectivity patterns., (© 2018 Wiley Periodicals, Inc.)

Stroke patients with motor deficits typically feature enhanced neural activity in several cortical areas when moving their affected hand. However, also healthy subjects may show higher levels of neural activity in tasks with higher motor demands. Therefore, the question arises to what extent stroke-related overactivity reflects performance-level-associated recruitment of neural resources rather than stroke-induced neural reorganization. We here investigated which areas in the lesioned brain enable the flexible adaption to varying motor demands compared to healthy subjects. Accordingly, eleven well-recovered left-hemispheric chronic stroke patients were scanned using functional magnetic resonance imaging. Motor system activity was assessed for fist closures at increasing movement frequencies performed with the affected/right or unaffected/left hand. In patients, an increasing movement rate of the affected hand was associated with stronger neural activity in ipsilesional/left primary motor cortex (M1) but unlike in healthy controls also in contralesional/right dorsolateral premotor cortex (PMd) and contralesional/right superior parietal lobule (SPL). Connectivity analyses using dynamic causal modeling revealed stronger coupling of right SPL onto affected/left M1 in patients but not in controls when moving the affected/right hand independent of the movement speed. Furthermore, coupling of right SPL was positively coupled with the "active" ipsilesional/left M1 when stroke patients moved their affected/right hand with increasing movement frequency. In summary, these findings are compatible with a supportive role of right SPL with respect to motor function of the paretic hand in the reorganized brain., (© 2017 Wiley Periodicals, Inc.)

Changes in the size of the attentional focus and task difficulty often co-vary. Nevertheless, the neural processes underlying the attentional spotlight process and task difficulty are likely to differ from each other. To differentiate between the two, we parametrically varied the size of the attentional focus in a novel behavioral paradigm while keeping visual processing difficulty either constant or not. A behavioral control experiment proved that the present behavioral paradigm could indeed effectively manipulate the size of the attentional focus per se, rather than affecting purely perceptual processes or surface processing. Imaging results showed that neural activity in a dorsal frontoparietal network, including right superior parietal cortex (SPL), was positively correlated with the size of the attentional spotlight, irrespective of whether task difficulty was constant or varied across different sizes of attentional focus. In contrast, neural activity in the ventral frontoparietal network, including the right inferior parietal cortex (IPL), was positively correlated with increasing task difficulty. Data suggest that sub-regions in parietal cortex are differentially involved in the attentional spotlight process and task difficulty: while SPL was involved in the attentional spotlight process independent of task difficulty, IPL was involved in the effect of task difficulty independent of the attentional spotlight process. Hum Brain Mapp 38:4996-5018, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

The right temporoparietal junction (rTPJ) has been associated with the ability to reorient attention to unexpected stimuli and the capacity to understand others' mental states (theory of mind [ToM]/false belief). Using activation likelihood estimation meta-analysis we previously unraveled that the anterior rTPJ is involved in both, reorienting of attention and ToM, possibly indicating a more general role in attention shifting. Here, we used neuronavigated transcranial magnetic stimulation to directly probe the role of the rTPJ across attentional reorienting and false belief. Task performance in a visual cueing paradigm and false belief cartoon task was investigated after application of continuous theta burst stimulation (cTBS) over anterior rTPJ (versus vertex, for control). We found that attentional reorienting was significantly impaired after rTPJ cTBS compared with control. For the false belief task, error rates in trials demanding a shift in mental state significantly increased. Of note, a significant positive correlation indicated a close relation between the stimulation effect on attentional reorienting and false belief trials. Our findings extend previous neuroimaging evidence by indicating an essential overarching role of the anterior rTPJ for both cognitive functions, reorienting of attention and ToM. Hum Brain Mapp 37:796-807, 2016. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Several neurobiological factors have been found to correlate with functional recovery after brain lesions. However, predicting the individual potential of recovery remains difficult. Here we used multivariate support vector machine (SVM) classification to explore the prognostic value of functional magnetic resonance imaging (fMRI) to predict individual motor outcome at 4-6 months post-stroke. To this end, 21 first-ever stroke patients with hand motor deficits participated in an fMRI hand motor task in the first few days post-stroke. Motor impairment was quantified assessing grip force and the Action Research Arm Test. Linear SVM classifiers were trained to predict good versus poor motor outcome of unseen new patients. We found that fMRI activity acquired in the first week post-stroke correctly predicted the outcome for 86% of all patients. In contrast, the concurrent assessment of motor function provided 76% accuracy with low sensitivity (<60%). Furthermore, the outcome of patients with initially moderate impairment and high outcome variability could not be predicted based on motor tests. In contrast, fMRI provided 87.5% prediction accuracy in these patients. Classifications were driven by activity in ipsilesional motor areas and contralesional cerebellum. The accuracy of subacute fMRI data (two weeks post-stroke), age, time post-stroke, lesion volume, and location were at 50%-chance-level. In conclusion, multivariate decoding of fMRI data with SVM early after stroke enables a robust prediction of motor recovery. The potential for recovery is influenced by the initial dysfunction of the active motor system, particularly in those patients whose outcome cannot be predicted by behavioral tests., (© 2015 Wiley Periodicals, Inc.)

Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both (18) F-fluorodeoxyglucose (FDG) and (18) F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel-wise correlations between caudate/putamen FDOPA uptake and whole-brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss., (© 2015 Wiley Periodicals, Inc.)

Background and Purpose: Patients with Parkinson's disease (PD) are at high risk for cognitive dysfunction. Non-pharmacological interventions have attracted increasing interest for enhancing PD patients' cognitive functions., Methods: One-year follow-up data (T2 ) of a randomized controlled trial evaluating two 6-week cognitive trainings - a structured (NEUROvitalis, NV) and an unstructured (mentally fit, MF) program - compared with a waiting list control group (CG) in non-demented PD patients (Hoehn and Yahr I-III) are presented. Forty-seven PD patients were examined at T2 . Effects on overall cognitive functions (Mini-Mental State Examination and DemTect) were compared between all groups with repeated measurement analyses of variance. A combined score of the percentage change value from baseline (T0 ) to T2 was calculated to identify patients who retained or improved their cognitive state (responders). The risk of developing mild cognitive impairment (MCI) was analyzed., Results: Significant time × treatment effects on overall cognitive functions were found for both training groups, each compared separately to the CG (DemTect, P < 0.05). Nine patients (56.3%) of the NV group, seven (41.2%) of the MF group and three (21.4%) of the CG were responders. Comparing NV to CG the odds ratio was 4.7 [95% confidence interval (0.8; 33.3)], and comparing MF to CG it was 2.6 [95% confidence interval (0.4; 17.4)]. MCI risk for patients without prior MCI was 40.0% in CG, 18.2% in MF and 18.2% in NV. The odds ratio was 3 comparing NV to CG, MF to CG., Discussion: This study gives evidence that cognitive training may be effective to prevent cognitive decline and onset of MCI in PD patients., (© 2014 EAN.)

Transcranial direct current stimulation (tDCS) is used in numerous clinical studies and considered an effective and versatile add-on therapy in neurorehabilitation. To date, however, the underlying neurobiological mechanisms remain elusive. In a rat model of tDCS, we recently observed a polarity-dependent accumulation of endogenous neural stem cells (NSCs) in the stimulated cortex. Based upon these findings, we hypothesized that tDCS may exert a direct migratory effect on endogenous NSCs towards the stimulated cortex. Using noninvasive imaging, we here investigated whether tDCS may also cause a directed migration of engrafted NSCs. Murine NSCs were labeled with superparamagnetic particles of iron oxide (SPIOs) and implanted into rat striatum and corpus callosum. MRI was performed (i) immediately after implantation and (ii) after 10 tDCS sessions of anodal or cathodal polarity. Sham-stimulated rats served as control. Imaging results were validated ex vivo using immunohistochemistry. Overall migratory activity of NSCs almost doubled after anodal tDCS. However, no directed migration within the electric field (i.e. towards or away from the electrode) could be observed. Rather, an undirected outward migration from the center of the graft was detected. Xenograft transplantation induced a neuroinflammatory response that was significantly enhanced following cathodal tDCS. This inflammatory response did not impact negatively on the survival of implanted NSCs. Data suggest that anodal tDCS increases the undirected migratory activity of implanted NSCs. Since the electric field did not guide implanted NSCs over large distances, previously observed polarity-dependent accumulation of endogenous NSCs in the cortex might have originated from local proliferation. Results enhance our understanding of the neurobiological mechanisms underlying tDCS, and may thereby help to develop a targeted and sustainable application of tDCS in clinical practice., (Copyright © 2014 John Wiley & Sons, Ltd.)

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune-mediated peripheral neuropathy with multifocal involvement. Reliable biomarkers for diagnosis, disease progression, and treatment response remain to be developed. We assessed the utility of corneal confocal microscopy (CCM) as a diagnostic marker for CIDP in 16 patients. CCM parameters including corneal nerve fiber density (NFD), nerve fiber length, number of main nerve trunks, number of nerve branches, nerve tortuosity, and dendritic cell density (DCD) were compared to those from 15 healthy controls and correlated with clinical and electrophysiological findings. CIDP patients had a significantly lower corneal NFD compared to healthy controls. The total nerve fiber length and the number of nerve branches were significantly decreased, whereas nerve tortuosity was increased in patients with CIDP. There was no positive correlation between corneal NFD and clinical or electrophysiological assessments. The average DCD was not significantly different in CIDP patients and controls. CCM measures suggest damage to small sensory afferents in the cornea in CIDP patients. Further studies are needed to compare different neuropathic conditions and to explore longitudinal changes of CCM parameters., (© 2015 Peripheral Nerve Society.)

We used fMRI to investigate both common and differential neural mechanisms underlying two distinct types of switching requirements, namely switching between stimulus categorizations (color vs. form) and switching between response modalities (hand vs. foot responses). Both types of switching induced similar behavioral shift costs. However, at the neural level, switching between stimulus categorizations led to left-hemispheric activations including the inferior frontal gyrus as well as the intraparietal sulcus extending to the superior parietal gyrus and the supramarginal gyrus. In contrast, switching between response modalities was associated mainly with left-hemispheric activation of the intraparietal sulcus and the supramarginal gyrus. A conjunction analysis indicated common activation of the left intraparietal sulcus and the supramarginal gyrus for both types of switching. Together, these results qualify previous claims about a general role of the left prefrontal cortex in task control by suggesting that the left inferior frontal gyrus is specifically involved in switching between stimulus categorizations, whereas parietal cortex is more generally implicated in the selection of action rules., (Copyright © 2012 Wiley Periodicals, Inc.)

Animal models of stroke demonstrated that white matter ischemia may cause both axonal damage and myelin degradation distant from the core lesion, thereby impacting on behavior and functional outcome after stroke. We here used parameters derived from diffusion magnetic resonance imaging (MRI) to investigate the effect of focal white matter ischemia on functional reorganization within the motor system. Patients (n = 18) suffering from hand motor deficits in the subacute or chronic stage after subcortical stroke and healthy controls (n = 12) were scanned with both diffusion MRI and functional MRI while performing a motor task with the left or right hand. A laterality index was employed on activated voxels to assess functional reorganization across hemispheres. Regression analyses revealed that diffusion MRI parameters of both the ipsilesional corticospinal tract (CST) and corpus callosum (CC) predicted increased activation of the unaffected hemisphere during movements of the stroke-affected hand. Changes in diffusion MRI parameters possibly reflecting axonal damage and/or destruction of myelin sheath correlated with a stronger bilateral recruitment of motor areas and poorer motor performance. Probabilistic fiber tracking analyses revealed that the region in the CC correlating with the fMRI laterality index and motor deficits connected to sensorimotor cortex, supplementary motor area, ventral premotor cortex, superior parietal lobule, and temporoparietal junction. The results suggest that degeneration of transcallosal fibers connecting higher order sensorimotor regions constitute a relevant factor influencing cortical reorganization and motor outcome after subcortical stroke., (Copyright © 2011 Wiley Periodicals, Inc.)

Previous brain imaging studies identified the neural networks underlying free choice of self-initiated actions. In contrast, the neural mechanisms underlying free choice of external objects remain to be elucidated. In this event-related functional magnetic resonance imaging study, participants had to choose one out of two different single-colored target squares presented at two of three possible locations. In 50% of the trials the choice was either free or specified, which was indicated by a preceding cue. In order to disentangle processes associated with object choice from those related to motor responses, object-response mapping was orthogonally varied. Processes related to the freedom of choice were isolated by means of an adaptive algorithm: based on the subjects individual choices in the free trials, specified trials were continuously generated in a way that matched the free trials in all aspects but the freedom to choose the object. Comparing free and specified trials revealed enhanced neural activity of a bilateral symmetrical network including the dorsolateral prefrontal, medial frontal, and medial parietal cortex. This network overlaps with that shown previously to be associated with free motor selection. It includes the pre-supplementary motor area (pre-SMA), suggesting that this area is rather associated with a supramodal function of initiating choice than with a specific motor function. Neural activity specifically associated with the freedom to choose an object was found bilaterally in the lateral superior parietal cortex. A psychophysiological interaction (PPI) analysis showed increased functional connectivity of this area with bilateral areas of the extrastriate visual cortex., (Copyright © 2011 Wiley Periodicals, Inc.)

Functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) are well-established tools for investigating the human motor system in-vivo. We here studied the relationship between movement-related fMRI signal changes in the primary motor cortex (M1) and electrophysiological properties of the hand motor area assessed with neuronavigated TMS in 17 healthy subjects. The voxel showing the highest task-related BOLD response in the left hand motor area during right hand movements was identified for each individual subject. This fMRI peak voxel in M1 served as spatial target for coil positioning during neuronavigated TMS. We performed correlation analyses between TMS parameters, BOLD signal estimates and effective connectivity parameters of M1 assessed with dynamic causal modeling (DCM). The results showed a negative correlation between the movement-related BOLD signal in left M1 and resting as well as active motor threshold (MT) obtained for left M1. The DCM analysis revealed that higher excitability of left M1 was associated with a stronger coupling between left supplementary motor area (SMA) and M1. Furthermore, BOLD activity in left M1 correlated with ipsilateral silent period (ISP), i.e. the stronger the task-related BOLD response in left M1, the higher interhemispheric inhibition effects targeting right M1. DCM analyses revealed a positive correlation between the coupling of left SMA with left M1 and the duration of ISP. The data show that TMS parameters assessed for the hand area of M1 do not only reflect the intrinsic properties at the stimulation site but also interactions with remote areas in the human motor system., (Copyright © 2011 Wiley-Liss, Inc.)

Objective: Subarachnoid haemorrhage (SAH) constitutes a neurological emergency. In most cases, the diagnosis is easy to establish; however, in rare cases, verification of the diagnosis is difficult. In this retrospective analysis, we report the clinical characteristics of patients with SAH who were admitted to our neurological intensive care unit. We focus on the additional diagnostic approaches in patients with a high suspicion of SAH but failure of the 'classic' diagnostic tools., Methods: A retrospective chart review was performed for all patients in whom SAH was diagnosed between 1996 and 2008. Two hundred and twenty patients were analysed for presenting symptoms, radiological and laboratory findings, hospital course and outcome., Results: A total of 220 patients were identified (mean age 50.5 years, 127 women). In 217 patients, the diagnosis was based upon cerebral computed tomography (CCT) or lumbar puncture. In three patients, the diagnostic work-up was continued because of distinct clinical signs even though CCT and cerebrospinal fluid (CSF) were negative for SAH. In these patients, vasospasm was detected by transcranial doppler sonography (TCD) and/or diagnosis of aneurysm was confirmed by conventional angiography., Conclusion: Subarachnoid haemorrhage with negative CCT and CSF is a rare presentation of a severe acute neurological emergency. Further diagnostic as TCD/computed tomography (CT)-A or MR-A should be considered in all patients with typical clinical presentation for SAH but unremarkable CCT and CSF as an additional diagnostic tool. Ultimately, a conventional angiography should be performed if distinct clinical signs of SAH are presented., (© 2010 The Author(s). European Journal of Neurology © 2010 EFNS.)

The human amygdala plays a pivotal role in the processing of socially significant information. Anatomical studies show that the human amygdala is not a single homogeneous structure but is composed of segregable subregions. These have recently been functionally delineated by using a combination of functional magnetic resonance imaging (fMRI) and cytoarchitectonically defined probabilistic maps. However, the response characteristics and individual contribution of these subregions to the processing of social-emotional stimuli are little understood. Here, we used this novel technique to segregate intra-amygdalar responses to facial expressions and nonsocial control stimuli. We localized facial expression-evoked signal changes bilaterally in the superficial amygdala, which suggests that this subregion selectively extracts the social value of incoming sensory information.

This study disentangles the prefrontal network underlying executive functions involved in the Wisconsin Card Sorting Test (WCST). During the WCST, subjects have to perform two key processes: first, they have to derive the correct sorting rule for each trial by trial-and-error, and, second, they have to detect when this sorting rule is changed by the investigator. Both cognitive processes constitute key components of the executive system, which is subserved by the prefrontal cortex. For the current fMRI experiment, we developed a non-verbal variant of the WCST. Subjects were instructed either to respond according to a given sorting rule or to detect the correct sorting rule, like in the original version of the WCST. Data were obtained from 14 healthy male volunteers and analysed using SPM and a random effects model. All conditions activated a fronto-parietal network, which was generally more active when subjects had to search for the correct sorting rule than when the rule was announced beforehand. Significant differences between these two conditions were seen in the dorsolateral prefrontal cortex (PFC) and the parietal lobe. In addition, the data provided new evidence for the assumption of differentiated roles of the left and right prefrontal cortex. Although the right PFC showed a general involvement in response selection and the execution of goal directed responses, based on given rules, the left PFC was only activated when inductive reasoning and feedback integration was required., ((c) 2008 Wiley-Liss, Inc.)

Voluntary orienting of visual spatial attention has been shown to be associated with activation in a distributed network of frontal and parietal brain areas. Neuropsychological data suggest that at least some of these areas should be sensitive to the direction in which attention is shifted. The aim of this study was to use rapid event-related functional magnetic resonance imaging to investigate whether spatial attention in the auditory modality is subserved by the same or different brain areas as in the visual modality, and whether the auditory and visual attention networks show any degree of hemispheric lateralisation or sensitivity to the direction of attention shifts. The results suggest that auditory and visual spatial attention shifts are controlled by a supramodal network of frontal, parietal and temporal areas. Areas activated included the precuneus and superior parietal cortex, the inferior parietal cortex and temporo-parietal junction, as well as the premotor and supplementary motor areas and dorsolateral prefrontal cortex (DLPFC). In the auditory task, some of these areas, in particular the precuneus as well as the inferior parietal cortex and temporo-parietal junction, showed 'relative' asymmetry, in that they responded more strongly to attention shifts towards the contralateral than the ipsilateral hemispace. Some areas, such as the right superior parietal cortex and left DLPFC, showed 'absolute' asymmetry, in that they responded more strongly in one than in the other hemisphere., ((c) 2008 Wiley-Liss, Inc.)

Background: A presentation of all aspects of the dorsolateral medulla oblongata syndrome is clinically very rare to find. In most cases patients present with fragmentary symptoms, e.g. ipsilateral axial lateropulsion, nystagmus, dysarthria, dysphagia or hemiataxia. However, the clinical presentation and lesion anatomy at the level of the medulla oblongata is still unsatisfactory. The aim of this study was to correlate the functional deficit with structural MRI-data., Methods: We included thirteen patients (eight male, five female, mean age 65.5) with medulla oblongata infarction with clinically predominant ipsilateral axial lateropulsion and correlated clinical with structural deficits., Results: Magnetic resonance imaging lesion mapping demonstrated ipsilateral axial lateropulsion to result from lesions of the spinocerebellar tract, the inferior cerebellar peduncle or the inferior vestibular nucleus. Nystagmus was associated with lesions of the inferior vestibular nucleus, dissociated sensory loss with the spinothalamic tract and hemiataxia with the spinocerebellar tract., Conclusions: Correlating dysfunction and lesion anatomy is a promising approach to enhance our knowledge on medulla oblongata topography.

Extrastriate, parietal, and frontal brain regions are differentially involved in distinct kinds of body movements and motor cognition. Using functional magnetic resonance imaging, we investigated the neural mechanisms underlying the observation and mental imagery of meaningful face and limb movements with or without objects. The supplementary motor area was differentially recruited by the mental imagery of movements while there were differential responses of the extrastriate body area (EBA) during the observation conditions. Contrary to most previous reports, the EBA responded to face movements, albeit to a lesser degree than to limb movements. The medial wall of the intraparietal sulcus and adjacent intraparietal cortex was selectively recruited by the processing of meaningful upper limb movements, irrespective of whether these were object-related or not. Besides reach and grasp movements, the intraparietal sulcus may thus be involved in limb gesture processing, that is, in an important aspect of human social communication. We conclude that subregions of a frontal-parietal network differentially interact during the cognitive processing of body movements according to the specific motor-related task at hand and the particular movement features involved.

The combination of transcranial magnetic stimulation (TMS) with functional neuroimaging has expanded the potential of TMS for human brain mapping. The precise and reliable positioning of the TMS coil is not a simple task, however. Modern frameless stereotaxic systems allow investigators to base navigation either on the subject's structural magnetic resonance imaging (MRI), functional MRI data, or the use of functional neuroimaging data from the literature, so-called "probabilistic approach." The latter assumes consistency across individuals in the location of task-related "activations" in standardized stereotaxic space. Conventional nonstereotaxic localization of brain areas is also a common method for defining the coil position. Our aim was to evaluate the accuracy of five different localization strategies in one single study. The left primary motor cortex (left M1-Hand) was used as target region. Three approaches were based on real-time frameless stereotaxy using information based on either anatomical or functional MRI. The remaining two strategies relied either on standard cranial landmarks (i.e., the International 10-20 EEG system) or a standardized function-guided procedure (i.e., the spatial relationship between the left and right M1-Hand). The results were compared to a TMS-based mapping of the primary motor cortex; center of gravity of motor-evoked potentials (MEP-CoG) was calculated for each subject (n = 10). Our findings suggest that highest precision can be achieved with fMRI-guided stimulation, which was accurate within the range of millimeters. Very consistent results were also obtained with the "probabilistic" approach. In view of these findings, we discuss the methods and special characteristics of each localization strategy.

Since the brain may engage different neuronal systems for a single behavioral goal, activation may show intersubject variability expressed in the systematic recruitment of multiple distinct networks. We apply a principal component analysis (PCA) to activation over task conditions and subjects to reveal cortical networks that may underlie this intersubject variability. Normal subjects were presented with novel meaningless objects, which appeared in personally familiar or unfamiliar places. During a subsequent, event-related functional MRI (fMRI) experiment, each subject was presented with learned or novel objects in isolation and performed a learned/novel judgment. Recollection of places was not essential for the task, and may exhibit large intersubject variations. The right posterodorsal posterior cingulate cortex (pPCC) and left retrosplenial cortex, whose involvement in place-recognition has been previously established, were selected as regions of interest for the PCA. Neural responses to objects associated with familiar relative to unfamiliar places in pPCC, but not in the retrosplenial cortex, were negatively correlated with task-related activation (common over all objects) in the right anterolateral prefrontal cortex and the left intraparietal sulcus. The latter areas have been implicated previously in cognitive control and object recognition, respectively. These results suggest right prefrontal control over neural processes both in the left parietal cortex, related to object-recognition (enhancement), and pPCC, related to nonessential recollection of place-memory (suppression), but not in the retrosplenial cortex, related to the sense of familiarity. This analysis revealed an important aspect of functional anatomy that was not detectable using a conventional analysis of average activations.

The left hemispheric dominance for complex motor behavior is undisputed. Clinical observations of complex motor deficits in patients with right hemispheric lesions, however, suggest an additional contribution of the right hemisphere to higher motor control. We assessed, using functional MRI (fMRI), which brain regions are implicated in processing the spatial aspects of complex, object-related actions. Using a blocked, factorial design, 17 healthy volunteers were asked to detect either spatial or sequential errors (factor ERROR) in complex activities of daily living, presented as video sequences with the appropriate object(s) or as pantomimes (factor STIMULUS). Observing complex actions (irrespective of stimulus type) activated a bilateral frontoparietal network. Observing actions with objects (relative to pantomimes) differentially increased neural activity in the fusiform gyrus and inferior occipital cortex bilaterally. Observing pantomimes, i.e., the same actions but without any object, differentially activated right prefrontal cortex, anterior cingulate cortex, the precuneus, and left cerebellum. The left cingulate cortex was differentially activated when subjects assessed the sequencing of actions. By contrast, assessing the spatial configuration of complex actions differentially increased neural activity in right posterior parietal cortex. A significant interaction of ERROR and STIMULUS was revealed for the right inferior parietal cortex only. These findings suggest a specific role of the right hemisphere, especially of right posterior parietal cortex, in processing spatial aspects of complex actions and thus provide a physiological basis for the observed apraxic motor deficits in patients with right hemispheric damage., ((c) 2006 Wiley-Liss, Inc.)

The parieto-insular vestibular cortex (PIVC) plays a central role in the cortical vestibular network. Although this region was first defined and subsequently extensively studied in nonhuman primates, there is also ample evidence for a human analogue in the posterior parietal operculum. In this study, we functionally and anatomically characterize the putative human equivalent to macaque area PIVC by combining functional magnetic resonance imaging (fMRI) of the cortical response to galvanic vestibular stimulation (GVS) with probabilistic cytoarchitectonic maps of the human parietal operculum. Our fMRI data revealed a bilateral cortical response to GVS in posterior parieto-insular cortex. Based on the topographic similarity of these activations to primate area PIVC, we suggest that they constitute the functionally defined human equivalent to macaque area PIVC. The locations of these activations were then compared to the probabilistic cytoarchitectonic maps of the parietal operculum (Eickhoff et al. [2005a]: Cereb Cortex, in press; Eickhoff et al. [2005c]: Cereb Cortex, in press), whereby the functionally defined PIVC matched most closely the cytoarchitectonically defined area OP 2. This activation of OP 2 by vestibular stimulation and its cytoarchitectonic features, which are similar to other primary sensory areas, suggest that area OP 2 constitutes the human equivalent of macaque area PIVC., (2005 Wiley-Liss, Inc.)

Autobiographical memory is based on interactions between episodic memory contents, associated emotions, and a sense of self-continuity along the time axis of one's life. The functional neuroanatomy subserving autobiographical memory is known to include prefrontal, medial and lateral temporal, as well as retrosplenial brain areas; however, whether gender differences exist in neural correlates of autobiographical memory remains to be clarified. We reanalyzed data from a previous functional magnetic resonance imaging (fMRI) experiment to investigate gender-related differences in the neural bases of autobiographical memories with differential remoteness and emotional valence. On the behavioral level, there were no significant gender differences in memory performance or emotional intensity of memories. Activations common to males and females during autobiographical memory retrieval were observed in a bilateral network of brain areas comprising medial and lateral temporal regions, including hippocampal and parahippocampal structures, posterior cingulate, as well as prefrontal cortex. In males (relative to females), all types of autobiographical memories investigated were associated with differential activation of the left parahippocampal gyrus. By contrast, right dorsolateral prefrontal cortex was activated differentially by females. In addition, the right insula was activated differentially in females during remote and negative memory retrieval. The data show gender-related differential neural activations within the network subserving autobiographical memory in both genders. We suggest that the differential activations may reflect gender-specific cognitive strategies during access to autobiographical memories that do not necessarily affect the behavioral level of memory performance and emotionality., ((c) 2005 Wiley-Liss, Inc.)

Reaching for a target involves integrative coordinate transformation processes between the representation of the target location, the sensorimotor information of limb of reach, and body space. Although right hemisphere dominance for visuospatial information processing is well established, corresponding right hemisphere dominance for kinesthetic spatial information processing remains to be demonstrated. We explored neural mechanisms of encoding target locations using 15O-butanol positron emission tomography (PET) in normal volunteers in a factorial experiment, where modality (visual/kinesthetic) and hemispace of target presentation (left/right of midsagittal plane) were varied systematically. After target presentation, subjects reached to the encoded target location. PET data analysis using SPM99 showed increased neural activity (P < 0.05, corrected) associated with left hemispace target presentation in right hemisphere areas (sensorimotor, anterior cingulate, insular, and temporo-occipital cortex) only. By contrast, right hemispace target presentation activated bilateral temporo-occipital cortex, which extended into the right temporo-parietal cortex and left sensorimotor cortex. A significant interaction of hemispace and modality of target presentation observed in right temporo-parietal cortex resulted from an increase in neural activity with kinesthetic target presentation in right hemispace. The data support an important role for the right temporo-parietal area in visuospatial processing and suggest a specific role of the right hemisphere in kinesthetic spatial processing., (Copyright 2004 Wiley-Liss, Inc.)