Allogeneic Bone Marrow-Derived Mesenchymal Stem Cell Safety in Idiopathic Parkinson's Disease.

BACKGROUND: Neuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow-derived mesenchymal stem cells can be used as an immunomodulatory therapy. OBJECTIVE: The objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow-derived mesenchymal stem cells in PD patients. METHODS: This was a 12-month single-center open-label dose-escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion. Primary outcome safety measures included transfusion reaction, study-related adverse events, and immunogenic responses. Secondary outcomes included impact on peripheral markers, PD progression, and changes in brain perfusion. RESULTS: There were no serious adverse reactions related to the infusion and no responses to donor-specific human leukocyte antigens. Most common treatment-emergent adverse events were dyskinesias (20%, n = 4) with 1 emergent and 3 exacerbations; and hypertension (20%, n = 4) with 3 transient episodes and 1 requiring medical intervention. One possibly related serious adverse event occurred in a patient with a 4-year history of lymphocytosis who developed asymptomatic chronic lymphocytic leukemia. Peripheral inflammation markers appear to be reduced at 52 weeks in the highest dose including, tumor necrosis factor-α (P < 0.05), chemokine (C-C motif) ligand 22 (P < 0.05), whereas brain-derived neurotrophic factor (P < 0.05) increased. The highest dose seems to have demonstrated the most significant effect at 52 weeks, reducing the OFF state UPDRS motor, -14.4 (P < 0.01), and total, -20.8 (P < 0.05), scores. CONCLUSION: A single intravenous infusion of allogeneic bone marrow-derived mesenchymal stem cells at doses of 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg is safe, well tolerated, and not immunogenic in mild/moderate PD patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Evidence for an Evolutionarily Conserved Memory Coding Scheme in the Mammalian Hippocampus.

Decades of research identify the hippocampal formation as central to memory storage and recall. Events are stored via distributed population codes, the parameters of which (e.g., sparsity and overlap) determine both storage capacity and fidelity. However, it remains unclear whether the parameters governing information storage are similar between species. Because episodic memories are rooted in the space in which they are experienced, the hippocampal response to navigation is often used as a proxy to study memory. Critically, recent studies in rodents that mimic the conditions typical of navigation studies in humans and nonhuman primates (i.e., virtual reality) show that reduced sensory input alters hippocampal representations of space. The goal of this study was to quantify this effect and determine whether there are commonalities in information storage across species. Using functional molecular imaging, we observe that navigation in virtual environments elicits activity in fewer CA1 neurons relative to real-world conditions. Conversely, comparable neuronal activity is observed in hippocampus region CA3 and the dentate gyrus under both conditions. Surprisingly, we also find evidence that the absolute number of neurons used to represent an experience is relatively stable between nonhuman primates and rodents. We propose that this convergence reflects an optimal ensemble size for episodic memories.SIGNIFICANCE STATEMENT One primary factor constraining memory capacity is the sparsity of the engram, the proportion of neurons that encode a single experience. Investigating sparsity in humans is hampered by the lack of single-cell resolution and differences in behavioral protocols. Sparsity can be quantified in freely moving rodents, but extrapolating these data to humans assumes that information storage is comparable across species and is robust to restraint-induced reduction in sensory input. Here, we test these assumptions and show that species differences in brain size build memory capacity without altering the structure of the data being stored. Furthermore, sparsity in most of the hippocampus is resilient to reduced sensory information. This information is vital to integrating animal data with human imaging navigation studies.

Network-based analysis reveals stronger local diffusion-based connectivity and different correlations with oral language skills in brains of children with high functioning autism spectrum disorders.

Neuroimaging has uncovered both long-range and short-range connectivity abnormalities in the brains of individuals with autism spectrum disorders (ASD). However, the precise connectivity abnormalities and the relationship between these abnormalities and cognition and ASD symptoms have been inconsistent across studies. Indeed, studies find both increases and decreases in connectivity, suggesting that connectivity changes in the ASD brain are not merely due to abnormalities in specific connections, but rather, due to changes in the structure of the network in which the brain areas interact (i.e., network topology). In this study, we examined the differences in the network topology between high-functioning ASD patients and age and gender matched typically developing (TD) controls. After quantitatively characterizing the whole-brain connectivity network using diffusion tensor imaging (DTI) data, we searched for brain regions with different connectivity between ASD and TD. A measure of oral language ability was then correlated with the connectivity changes to determine the functional significance of such changes. Whole-brain connectivity measures demonstrated greater local connectivity and shorter path length in ASD as compared to TD. Stronger local connectivity was found in ASD, especially in regions such as the left superior parietal lobule, the precuneus and angular gyrus, and the right supramarginal gyrus. The relationship between oral language ability and local connectivity within these regions was significantly different between ASD and TD. Stronger local connectivity was associated with better performance in ASD and poorer performance in TD. This study supports the notion that increased local connectivity is compensatory for supporting cognitive function in ASD.

A neural link between feeling and hearing.

Hearing and feeling both rely upon the transduction of physical events into frequency-based neural codes, suggesting that the auditory system may be intimately related to the somatosensory system. Here, we provide evidence that the neural substrates for audition and somatosensation are anatomically linked. Using diffusion tensor imaging with both deterministic and probabilistic tractography to measure white matter connectivity, we show that there are extensive ipsilateral connections between the primary auditory cortex and the primary and secondary somatosensory regions in the human cerebral cortex. We further show that these cross-modal connections are exaggerated between the auditory and secondary somatosensory cortex in the lesioned hemisphere of a patient (SR) with acquired auditory-tactile synesthesia, in whom sounds alone produce bodily sensations. These results provide an anatomical basis for multisensory interactions between audition and somatosensation and suggest that cross-talk between these regions may explain why some sounds, such as nails screeching down a chalkboard or an audible mosquito, can induce feelings of touch, especially on the contralesional body surface of patient SR.

Tract-based spatial statistics reveal altered relationship between non-verbal reasoning abilities and white matter integrity in autism spectrum disorder.

Altered brain connectivity accompanies autism spectrum disorders (ASD), but the relationship between connectivity and intellectual abilities, which often differs within ASD, and between ASD and typically developing (TD) children, is not understood. Here, diffusion tensor imaging (DTI) was used to explore the relationship between white matter integrity and non-verbal intelligence quotients (IQ) in children with ASD and in age- and gender-matched TD children. Tract-based spatial statistical analyses (TBSS) of DTI fractional anisotropy (FA) revealed altered relationships between white matter and IQ. Different relationships were found using within-group analyses, where regions of significant (p < .05, corrected) correlations in ASD overlapped minimally with regions of FA-IQ correlations in TD subjects. An additional between-groups analysis revealed significant correlation differences in widespread cortical and subcortical areas. These preliminary findings suggest altered brain connectivity may underlie some differences in intellectual abilities of ASD, and should be investigated further in larger samples as a function of development.

A simultaneous EEG-fMRI study of thalamic load-dependent working memory delay period activity.

Introduction: Working memory (WM) is an essential component of executive functions which depend on maintaining task-related information online for brief periods in both the presence and absence of interfering stimuli. Active maintenance occurs during the WM delay period, the time between stimulus encoding and subsequent retrieval. Previous studies have extensively documented prefrontal and posterior parietal cortex activity during the WM delay period, but the role of subcortical structures including the thalamus remains to be fully elucidated, especially in humans. Methods: Using a simultaneous electroencephalogram (EEG)-functional magnetic resonance imaging (fMRI) approach, we investigated the role of the thalamus during the WM delay period in a modified Sternberg paradigm following low and high memory load encoding of naturalistic scenes. During the delay, participants passively viewed scrambled scenes containing similar color and spatial frequency to serve as a perceptual baseline. Individual source estimation was weighted by the location of the thalamic fMRI signal relative to the WM delay period onset. Results: The effects memory load on maintenance were observed bilaterally in thalamus with higher EEG source amplitudes in the low compared to high load condition occurring 160-390 ms after the onset of the delay period. Conclusion: The main finding that thalamic activation was elevated during the low compared to high condition despite similar duration of perceptual input and upcoming motor requirements suggests a capacity-limited role for sensory filtering of the thalamus during consolidation of stimuli into WM, where the highest activity occurs when fewer stimuli need to be maintained in the presence of interfering perceptual stimuli during the delay. The results are discussed in the context of theories regarding the role of the thalamus in sensory gating during working memory.

Updated Parkinson's disease motor subtypes classification and correlation to cerebrospinal homovanillic acid and 5-hydroxyindoleacetic acid levels.

Introduction: Motor classifications of Parkinson's Disease (PD) have been widely used. This paper aims to update a subtype classification using the MDS-UPDRS-III and determine if cerebrospinal neurotransmitter profiles (HVA and 5-HIAA) differ between these subtypes in a cohort from the Parkinson's Progression Marker Initiative (PPMI). Methods: UPDRS and MDS-UPDRS scores were collected for 20 PD patients. Akinetic-rigid (AR), Tremor-dominant (TD), and Mixed (MX) subtypes were calculated using a formula derived from UPDRS, and a new ratio was developed for subtyping patients with the MDS-UPDRS. This new formula was subsequently applied to 95 PD patients from the PPMI dataset, and subtyping was correlated to neurotransmitter levels. Data were analyzed using receiver operating characteristic models and ANOVA. Results: Compared to previous UPDRS classifications, the new MDS-UPDRS TD/AR ratios produced significant areas under the curve (AUC) for each subtype. The optimal sensitivity and specificity cutoff scores were ≥0.82 for TD, ≤0.71 for AR, and >0.71 and <0.82 for Mixed. Analysis of variance showed that the AR group had significantly lower HVA and 5-HIAA levels than the TD and HC groups. A logistic model using neurotransmitter levels and MDS-UPDRS-III could predict the subtype classification. Conclusions: This MDS-UPDRS motor classification system provides a method to transition from the original UPDRS to the new MDS-UPDRS. It is a reliable and quantifiable subtyping tool for monitoring disease progression. The TD subtype is associated with lower motor scores and higher HVA levels, while the AR subtype is associated with higher motor scores and lower 5-HIAA levels.

Longitudinal Resting-State Functional Magnetic Resonance Imaging Study: A Seed-Based Connectivity Biomarker in Patients with Ischemic and Intracerebral Hemorrhage Stroke.

Objective: The primary aim of the research was to compare the impact of postischemic and hemorrhagic stroke on brain connectivity and recovery using resting-state functional magnetic resonance imaging. Methods and Procedures: We serially imaged 20 stroke patients, 10 with ischemic stroke (IS) and 10 with intracerebral hemorrhage (ICH), at 1, 3, and 12 months (1M, 3M, and 12M) after ictus. Data from 10 healthy volunteers were obtained from a publically available imaging data set. All functional and structural images underwent standard processing for brain extraction, realignment, serial registration, unwrapping, and denoising using SPM12. A seed-based group analysis using CONN software was used to evaluate the default mode network and the sensorimotor network connections by applying bivariate correlation and hemodynamic response function weighting. Results: In comparison with healthy controls, both IS and ICH exhibited disrupted interactions (decreased connectivity) between these two networks at 1M. Interactions then increased by 12M in each group. Temporally, each group exhibited a minimal increase in connectivity at 3M compared with 12M. Overall, the ICH patients exhibited a greater magnitude of connectivity disruption compared with IS patients, despite a significant intrasubject reduction in hematoma volume. We did not observe any significant correlation between change in connectivity and recovery as measured on the National Institutes of Health Stroke Scale (NIHSS) at any time point. Conclusions: These findings demonstrate that the largest changes in functional connectivity occur earlier (3M) rather than later (12M) and show subtle differences between IS and ICH during recovery and should be explored further in larger samples.

Variability of the relationship between electrophysiology and BOLD-fMRI across cortical regions in humans.

The relationship between blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal and the underlying neural electrical activity in humans is a topic of intense interest to systems neuroscience. This relationship has generally been assumed to be invariant regardless of the brain region and the cognitive task being studied. We critically evaluated these assumptions by comparing the BOLD-fMRI response with local field potential (LFP) measurements during visually cued common noun and verb generation in 11 humans in whom 1210 subdural electrodes were implanted. As expected, power in the mid-gamma band (60-120 Hz) correlated positively (r(2) = 0.16, p < 10(-16)) and power in the beta band (13-30 Hz) correlated negatively (r(2) = 0.09, p < 10(-16)) with the BOLD signal change. Beta and mid-gamma band activity independently explain different components of the observed BOLD signal. Importantly, we found that the location (i.e., lobe) of the recording site modulates the relationship between the electrocorticographic (ECoG) signal and the observed fMRI response (p < 10(-16), F(21,1830) = 52.7), while the type of language task does not. Across all brain regions, ECoG activity in the gamma and beta bands explains 22% of the fMRI response, but if the lobar location is considered, 28% of the variance can be explained. Further evaluation of this relationship at the level of individual gyri provides additional evidence of differences in the BOLD-LFP relationship by cortical locus. This spatial variability in the relationship between the fMRI signal and neural activity carries implications for modeling of the hemodynamic response function, an essential step for interregional fMRI comparisons.

Interhemispheric Connectivity Supports Load-Dependent Working Memory Maintenance for Complex Visual Stimuli.

Abstract Introduction: One manipulation used to study the neural basis of working memory (WM) is to vary the information load at encoding, then measure activity and connectivity during maintenance in the delay period. A hallmark finding is increased delay activity and connectivity between frontoparietal brain regions with increased load. Most WM studies, however, employ simple stimuli during encoding and unfilled intervals during the delay. In this study, we asked how delay period activity and connectivity change during low and high load maintenance of complex stimuli. Methods: Twenty-two participants completed a modified Sternberg WM task with two or five naturalistic scenes as stimuli during scalp electroencephalography (EEG). On each trial, the delay was filled with phase-scrambled scenes to provide a visual perceptual control with similar color and spatial frequency as presented during encoding. Functional connectivity during the delay was assessed by the phase-locking value (PLV). Results: Results showed reduced theta/alpha delay activity amplitude during high compared with low WM load across frontal, central, and parietal sources. A network with higher connectivity during low load consisted of increased PLV between (1) left frontal and right posterior temporal sources in the theta/alpha bands, (2) right anterior temporal and left central sources in the alpha and lower beta bands, and (3) left anterior temporal and posterior temporal sources in the theta, alpha, and lower beta bands. Discussion: The findings suggest a role for interhemispheric connectivity during WM maintenance of complex stimuli with load modulation when limited attentional resources are essential for filtering. Impact statement The patterns of brain connectivity subserving working memory (WM) have largely been investigated to date using simple stimuli, including letters, digits, and shapes and during unfilled WM delay intervals. Fewer studies describe functional connectivity changes during the maintenance of more naturalistic stimuli in the presence of distractors. In the present study, we employed a scene-based WM task during electroencephalography in healthy humans and found that during low-load WM maintenance with distractors increased interhemispheric connectivity in frontotemporal networks. These findings suggest a role for increased interhemispheric connectivity during maintenance of complex stimuli when attentional resources are essential for filtering.

Spontaneous Eye Blink Rate During the Working Memory Delay Period Predicts Task Accuracy.

Spontaneous eye blink rate (sEBR) has been linked to attention and memory, specifically working memory (WM). sEBR is also related to striatal dopamine (DA) activity with schizophrenia and Parkinson's disease showing increases and decreases, respectively, in sEBR. A weakness of past studies of sEBR and WM is that correlations have been reported using blink rates taken at baseline either before or after performance of the tasks used to assess WM. The goal of the present study was to understand how fluctuations in sEBR during different phases of a visual WM task predict task accuracy. In two experiments, with recordings of sEBR collected inside and outside of a magnetic resonance imaging bore, we observed sEBR to be positively correlated with WM task accuracy during the WM delay period. We also found task-related modulation of sEBR, including higher sEBR during the delay period compared to rest, and lower sEBR during task phases (e.g., stimulus encoding) that place demands on visual attention. These results provide further evidence that sEBR could be an important predictor of WM task performance with the changes during the delay period suggesting a role in WM maintenance. The relationship of sEBR to DA activity and WM maintenance is discussed.

Visual continuous recognition reveals behavioral and neural differences for short- and long-term scene memory.

Humans have a remarkably high capacity and long duration memory for complex scenes. Previous research documents the neural substrates that allow for efficient categorization of scenes from other complex stimuli like objects and faces, but the spatiotemporal neural dynamics underlying scene memory at timescales relevant to working and longer-term memory are less well understood. In the present study, we used high density EEG during a visual continuous recognition task in which new, old, and scrambled scenes consisting of color outdoor photographs were presented at an average rate 0.26 Hz. Old scenes were single repeated presentations occurring within either a short-term (< 20 s) or longer-term intervals of between 30 s and 3 min or 4 and 10 min. Overall recognition was far above chance, with better performance at shorter- than longer-term intervals. Sensor-level ANOVA and post hoc pairwise comparisons of event related potentials (ERPs) revealed three main findings: (1) occipital and parietal amplitudes distinguishing new and old from scrambled scenes; (2) frontal amplitudes distinguishing old from new scenes with a central positivity highest for hits compared to misses, false alarms and correct rejections; and (3) frontal and parietal changes from ∼300 to ∼600 ms distinguishing among old scenes previously encountered at short- and longer-term retention intervals. These findings reveal how distributed spatiotemporal neural changes evolve to support short- and longer-term recognition of complex scenes.

Frequency-specific electrocorticographic correlates of working memory delay period fMRI activity.

Electrocorticography (ECoG) and functional MRI (BOLD-fMRI) have been used previously to measure brain activity during working memory delay periods. These studies have separately reported oscillation changes in the theta (4-8 Hz) band and BOLD-fMRI increases during delay periods when information is maintained in memory. However, it is not known how intracranial cortical field potential (CFP) changes relate to BOLD-fMRI responses during delay periods. To answer this question, fMRI was obtained from six epilepsy patients during a visual working memory task. Then, following subdural macroelectrode implant, continuous ECoG was used to record CFPs during the same task. Time-frequency analyses showed delay period gamma band oscillation amplitude increases on electrodes located near fMRI activity, while in the theta band changes were higher for electrodes located away from fMRI activation. The amplitude of the ECoG gamma band response was significantly positively correlated with the fMRI response, while a negative correlation was found for the theta band. The findings are consistent with previous reports of local field potential (LFP) coupling in the gamma band with BOLD-fMRI responses during visual stimulation in monkeys, but are novel in that the relationship reported here persists after the disappearance of visual stimuli while information is being maintained in memory. We conclude that there is a relationship between BOLD-fMRI increases and human working memory delay period gamma oscillation increases and theta decreases. The spectral profile change provides a basis for comparison of working memory delay period BOLD-fMRI with field potential recordings in animals and other human intracranial EEG studies.

WITHDRAWN: fMRI correlates of visual working memory: What vs. where.

This article has been withdrawn at the request of the authors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Artifact quantification and tractography from 3T MRI after placement of aneurysm clips in subarachnoid hemorrhage patients.

BACKGROUND: The application of advanced 3T MRI imaging techniques to study recovery after subarachnoid hemorrhage (SAH) is complicated by the presence of image artifacts produced by implanted aneurysm clips. To characterize the effect of these artifacts on image quality, we sought to: 1) quantify extent of image artifact in SAH patients with implanted aneurysm clips across a range of MR sequences typically used in studies of volumetry, blood oxygen level dependent signal change (BOLD-fMRI), and diffusion-weighted imaging (DW-MRI) and 2) to explore the ability to reconstruct white matter pathways in these patients. METHODS: T1- and T2-weighted structural, BOLD-fMRI, and DW-MRI scans were acquired at 3T in two patients with titanium alloy clips in ACOM and left ACA respectively. Intensity-based planimetric contouring was performed on aligned image volumes to define each artifact. Artifact volumes were quantified by artifact/clip length and artifact/brain volume ratios and analyzed by two-way (scan-by-rater) ANOVAs. Tractography pathways were reconstructed from DW-MRI at varying distances from the artifacts using deterministic methods. RESULTS: Artifact volume varied by MR sequence for length (p = 0.007) and volume (p < 0.001) ratios: it was smallest for structural images, larger for DW-MRI acquisitions, and largest on fMRI images. Inter-rater reliability was high (r = 0.9626, p < 0.0001), and reconstruction of white matter connectivity characteristics increased with distance from the artifact border. In both patients, reconstructed white matter pathways of the uncinate fasciculus and inferior fronto-occipital fasciculus were clearly visible within 2 mm of the artifact border. CONCLUSIONS: Advanced 3T MR can successfully image brain tissue around implanted titanium aneurysm clips at different spatial ranges depending on sequence type. White matter pathways near clip artifacts can be reconstructed and visualized. These findings provide a reference for designing functional and structural neuroimaging studies of recovery in aSAH patients after clip placement.

Does rehearsal matter? Left anterior temporal alpha and theta band changes correlate with the beneficial effects of rehearsal on working memory.

Rehearsal during working memory (WM) maintenance is assumed to facilitate retrieval. Less is known about how rehearsal modulates WM delay activity. In the present study, 44 participants completed a Sternberg Task with either intact novel scenes or phase-scrambled scenes, which had similar color and spatial frequency but lacked semantic content. During the rehearsal condition participants generated a descriptive label during encoding and covertly rehearsed during the delay period. During the suppression condition participants did not generate a label during encoding and suppressed (repeated "the") during the delay period. This was easy in the former (novel scenes) but more difficult in the later condition (phase-scrambled scenes) where scenes lacked semantic content. Behavioral performance and EEG delay activity was analyzed as a function of maintenance strategy. Performance during WM revealed a benefit of rehearsal for phase-scrambled but not intact scenes. Examination of the absolute amplitude revealed three underlying sources of activity for rehearsal, including the left anterior temporal (ATL) and left and midline parietal regions. Increases in alpha and theta activity in ATL were correlated with improvement in performance on WM with rehearsal only when labeling was not automatic (e.g., phase-scrambled scenes), which may reflect differences in labeling and rehearsal (i.e., semantic associations vs. shallow labels). We conclude that rehearsal only benefits memory for visual stimuli that lack semantic information, and that this is correlated with changes in alpha and theta rhythms.

Toward a Multimodal Computer-Aided Diagnostic Tool for Alzheimer's Disease Conversion.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is one of the leading sources of morbidity and mortality in the aging population AD cardinal symptoms include memory and executive function impairment that profoundly alters a patient's ability to perform activities of daily living. People with mild cognitive impairment (MCI) exhibit many of the early clinical symptoms of patients with AD and have a high chance of converting to AD in their lifetime. Diagnostic criteria rely on clinical assessment and brain magnetic resonance imaging (MRI). Many groups are working to help automate this process to improve the clinical workflow. Current computational approaches are focused on predicting whether or not a subject with MCI will convert to AD in the future. To our knowledge, limited attention has been given to the development of automated computer-assisted diagnosis (CAD) systems able to provide an AD conversion diagnosis in MCI patient cohorts followed longitudinally. This is important as these CAD systems could be used by primary care providers to monitor patients with MCI. The method outlined in this paper addresses this gap and presents a computationally efficient pre-processing and prediction pipeline, and is designed for recognizing patterns associated with AD conversion. We propose a new approach that leverages longitudinal data that can be easily acquired in a clinical setting (e.g., T1-weighted magnetic resonance images, cognitive tests, and demographic information) to identify the AD conversion point in MCI subjects with AUC = 84.7. In contrast, cognitive tests and demographics alone achieved AUC = 80.6, a statistically significant difference (n = 669, p < 0.05). We designed a convolutional neural network that is computationally efficient and requires only linear registration between imaging time points. The model architecture combines Attention and Inception architectures while utilizing both cross-sectional and longitudinal imaging and clinical information. Additionally, the top brain regions and clinical features that drove the model's decision were investigated. These included the thalamus, caudate, planum temporale, and the Rey Auditory Verbal Learning Test. We believe our method could be easily translated into the healthcare setting as an objective AD diagnostic tool for patients with MCI.

Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.

Inappropriate response tendencies may be stopped via a specific fronto/basal ganglia/primary motor cortical network. We sought to characterize the functional role of two regions in this putative stopping network, the right inferior frontal gyrus (IFG) and the primary motor cortex (M1), using electocorticography from subdural electrodes in four patients while they performed a stop-signal task. On each trial, a motor response was initiated, and on a minority of trials a stop signal instructed the patient to try to stop the response. For each patient, there was a greater right IFG response in the beta frequency band ( approximately 16 Hz) for successful versus unsuccessful stop trials. This finding adds to evidence for a functional network for stopping because changes in beta frequency activity have also been observed in the basal ganglia in association with behavioral stopping. In addition, the right IFG response occurred 100-250 ms after the stop signal, a time range consistent with a putative inhibitory control process rather than with stop-signal processing or feedback regarding success. A downstream target of inhibitory control is M1. In each patient, there was alpha/beta band desynchronization in M1 for stop trials. However, the degree of desynchronization in M1 was less for successfully than unsuccessfully stopped trials. This reduced desynchronization on successful stop trials could relate to increased GABA inhibition in M1. Together with other findings, the results suggest that behavioral stopping is implemented via synchronized activity in the beta frequency band in a right IFG/basal ganglia network, with downstream effects on M1.

Temporal lobe white matter asymmetry and language laterality in epilepsy patients.

Recent studies using diffusion tensor imaging (DTI) have advanced our knowledge of the organization of white matter subserving language function. It remains unclear, however, how DTI may be used to predict accurately a key feature of language organization: its asymmetric representation in one cerebral hemisphere. In this study of epilepsy patients with unambiguous lateralization on Wada testing (19 left and 4 right lateralized subjects; no bilateral subjects), the predictive value of DTI for classifying the dominant hemisphere for language was assessed relative to the existing standard-the intra-carotid Amytal (Wada) procedure. Our specific hypothesis is that language laterality in both unilateral left- and right-hemisphere language dominant subjects may be predicted by hemispheric asymmetry in the relative density of three white matter pathways terminating in the temporal lobe implicated in different aspects of language function: the arcuate (AF), uncinate (UF), and inferior longitudinal fasciculi (ILF). Laterality indices computed from asymmetry of high anisotropy AF pathways, but not the other pathways, classified the majority (19 of 23) of patients using the Wada results as the standard. A logistic regression model incorporating information from DTI of the AF, fMRI activity in Broca's area, and handedness was able to classify 22 of 23 (95.6%) patients correctly according to their Wada score. We conclude that evaluation of highly anisotropic components of the AF alone has significant predictive power for determining language laterality, and that this markedly asymmetric distribution in the dominant hemisphere may reflect enhanced connectivity between frontal and temporal sites to support fluent language processes. Given the small sample reported in this preliminary study, future research should assess this method on a larger group of patients, including subjects with bi-hemispheric dominance.

CSF from Parkinson disease patients differentially affects cultured microglia and astrocytes.

BACKGROUND: Excessive and abnormal accumulation of alpha-synuclein (α-synuclein) is a factor contributing to pathogenic cell death in Parkinson's disease. The purpose of this study, based on earlier observations of Parkinson's disease cerebrospinal fluid (PD-CSF) initiated cell death, was to determine the effects of CSF from PD patients on the functionally different microglia and astrocyte glial cell lines. Microglia cells from human glioblastoma and astrocytes from fetal brain tissue were cultured, grown to confluence, treated with fixed concentrations of PD-CSF, non-PD disease control CSF, or control no-CSF medium, then photographed and fluorescently probed for α-synuclein content by deconvolution fluorescence microscopy. Outcome measures included manually counted cell growth patterns from day 1-8; α-synuclein density and distribution by antibody tagged 3D model stacked deconvoluted fluorescent imaging. RESULTS: After PD-CSF treatment, microglia growth was reduced extensively, and a non-confluent pattern with morphological changes developed, that was not evident in disease control CSF and no-CSF treated cultures. Astrocyte growth rates were similarly reduced by exposure to PD-CSF, but morphological changes were not consistently noted. PD-CSF treated microglia showed a significant increase in α-synuclein content by day 4 compared to other treatments (p ≤ 0.02). In microglia only, α-synuclein aggregated and redistributed to peri-nuclear locations. CONCLUSIONS: Cultured microglia and astrocytes are differentially affected by PD-CSF exposure compared to non-PD-CSF controls. PD-CSF dramatically impacts microglia cell growth, morphology, and α-synuclein deposition compared to astrocytes, supporting the hypothesis of cell specific susceptibility to PD-CSF toxicity.