The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH).
Primary ICH was induced in 27 male Wistar rats by stereotactic injection of 100 µL of autologous blood into the striatum. Rats were divided into three groups (n= 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phosphate buffered saline daily starting 24-hours post-ICH and continuing daily for the next 3 days. On the fourth day, the animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blotting was performed.
MRI data for animals receiving simvastatin treatment showed significantly reduced BBB dysfunction and improved CBF in the ICH rim compared to controls (P<0.05) 4 days after ICH. Simvastatin also significantly reduced edema (T2) in the rim at 4 days after ICH (P<0.05). Both statin-treated groups demonstrated increased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB function (P<0.05) and increased number of blood vessels (P<0.05).
Simvastatin treatment administered acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by MRI measurement.
Intracerebral hemorrhage; Atorvastatin; Occludin; Simvastatin; Blood brain barrier
The long-term impact of thalidomide plus dexamethasone (thal/dex) as primary therapy for newly diagnosed multiple myeloma (MM) is unknown. The goal of this study was to compare thalidomide plus dexamethasone versus placebo plus dexamethasone (placebo/dex)as primary therapy for newly diagnosed MM.
Patients and Methods
In this double-blind, placebo-controlled trial, patients with untreated symptomatic MM were randomized to thal/dex (arm A) or to placebo plus dexamethasone (dex) (arm B). Patients in arm A received oral thalidomide 50 mg daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2 (28-day cycles). Oral dex 40 mg was administered on days 1 through 4, 9 through 12, and 17 through 20 during cycles 1 through 4 and on days 1 through 4 only from cycle 5 onwards. Patients in arm B received placebo and dex, administered as in arm A. The primary end point of the study was time to progression. This study is registered at http://ClinicalTrials.gov (NCT00057564).
A total of 470 patients were enrolled (235 randomly assigned to thal/dex and 235 to placebo/dex). The overall response rate was significantly higher with thal/dex compared with placebo/dex (63% v 46%), P < .001. Time to progression (TTP) was significantly longer with thal/dex compared with placebo/dex (median, 22.6 v 6.5 months, P < .001). Grade 4 adverse events were more frequent with thal/dex than with placebo/dex (30.3% v 22.8%).
Thal/dex results in significantly higher response rates and significantly prolongs TTP compared with dexamethasone alone in patients with newly diagnosed MM.
Whether humans adjust their behavior in response to unaware errors remains a controversial issue relevant to insight in neuropsychiatric conditions. Initial error awareness studies found that the error-related negativity (ERN), an event-related potential (ERP) originating in the medial prefrontal cortex after errors, activated equally for aware and unaware errors, suggesting a candidate preconscious mechanism. However, recent studies demonstrate that the ERN decreases after unaware errors. We hypothesized that the ERN is dependent upon awareness, and predicted that previous discrepancies might be due to unaware errors not being differentiated from perceptually uncertain, low-confidence responses that might increase the ERN amplitude. Here we addressed this hypothesis by distinguishing between aware errors, unaware errors, and uncertain responses, and using stimuli (faces) associated with well established sensory ERPs to evaluate the degree of stimulus processing for each trial type. We found that while aware and unaware errors were related to failures at the time of response, uncertain responses were due to failures at the time of stimulus processing indexed by lower amplitude sensory ERPs. Moreover, uncertain responses showed similar ERN activity as aware errors, in comparison with decreased activity for unaware errors. Finally, compared with aware errors, uncertain responses and unaware errors showed reduced neural compensations, such as alpha suppression. Together these findings suggest that the ERN is activated by aware motor errors as well as sensory failures, and that both awareness and certainty are necessary for neural adaptations after errors.
Selective processing of task-relevant stimuli is critical for goal-directed behavior. We used electrocorticography to assess the spatio-temporal dynamics of cortical activation during a simple phonological target detection task, in which subjects press a button when a prespecified target syllable sound is heard. Simultaneous surface potential recordings during this task revealed a highly ordered temporal progression of high gamma (HG, 70– 200 Hz) activity across the lateral hemisphere in less than 1 sec. The sequence demonstrated concurrent regional sensory processing of speech syllables in the posterior superior temporal gyrus (STG) and speech motor cortex, and then transitioned to sequential task-dependent processing from prefrontal cortex (PFC), to the final motor response in the hand sensorimotor cortex. STG activation was modestly enhanced for target over nontarget sounds, supporting a selective gain mechanism in early sensory processing, whereas PFC was entirely selective to targets, supporting its role in guiding response behavior. These results reveal that target detection is not a single cognitive event, but rather a process of progressive target selectivity that involves large-scale rapid parallel and serial processing in sensory, cognitive, and motor structures to support goal-directed human behavior.
Phase/amplitude coupling (PAC) is emerging as an important electrophysiological measure of local and long-distance neuronal communication. Current techniques for calculating PAC provide a numerical index that represents an average value across an arbitrarily long time period. This requires researchers to rely on block design experiments and temporal concatenation at the cost of the sub-second temporal resolution afforded by electrophysiological recordings. Here we present a method for calculating event-related phase/amplitude coupling (ERPAC) designed to capture the temporal evolution of task-related changes in PAC across events or between distant brain regions that is applicable to human or animal electromagnetic recording.
phase/amplitude coupling; cross-frequency coupling; electrophysiology; electrocorticography; theta; alpha; gamma
Breakdown of the blood-brain barrier (BBB) is present in several neurological disorders such as stroke, brain tumors, and multiple sclerosis. Non-invasive evaluation of BBB breakdown is important for monitoring disease progression and evaluating therapeutic efficacy in such disorders. One of the few techniques available for non-invasively and repeatedly localizing and quantifying BBB damage is magnetic resonance imaging (MRI). This usually involves the intravenous administration of a gadolinium-containing MR contrast agent such as Gd-DTPA, followed by dynamic contrast-enhanced MR imaging (DCE-MRI) of brain and blood, and analysis of the resultant data to derive indices of blood-to-brain transfer. There are two advantages to this approach. First, measurements can be made repeatedly in the same animal; for instance, they can be made before drug treatment and then again after treatment to assess efficacy. Secondly, MRI studies can be multiparametric. That is, MRI can be used to assess not only a blood-to-brain transfer or influx rate constant (Ki or K1) by DCE-MRI but also complementary parameters such as: 1) cerebral blood flow (CBF), done in our hands by arterial spin-tagging (AST) methods; 2) magnetization transfer (MT) parameters, most notably T1sat, which appear to reflect brain water-protein interactions plus BBB and tissue dysfunction; 3) the apparent diffusion coefficient of water (ADCw) and/or diffusion tensor, which is a function of the size and tortuosity of the extracellular space; and 4) the transverse relaxation time by T2-weighted imaging, which demarcates areas of tissue abnormality in many cases. The accuracy and reliability of two of these multiparametric MRI measures, CBF by AST and DCE-MRI determined influx of Gd-DTPA, have been established by nearly congruent quantitative autoradiographic (QAR) studies with appropriate radiotracers. In addition, some of their linkages to local pathology have been shown via corresponding light microscopy and fluorescence imaging. This chapter describes: 1) multiparametric MRI techniques with emphasis on DCE-MRI and AST-MRI; 2) the measurement of the blood-to-brain influx constant and CBF; and 3) the role of each in determining BBB permeability.
Apparent diffusion coefficient; Arterial spin tagging; Blood-brain barrier; Cerebral blood flow; Cerebral ischemia; Gd-DTPA; Hemorrhagic transformation; Influx constant; Look-Locker; Magnetic resonance contrast agents; Magnetization transfer; Patlak plot; Quantitative autoradiography; Rat; T1; T1sat; T1WI; T2; TOMROP
We employed an EEG paradigm manipulating predictive context to dissociate the neural dynamics of anticipatory mechanisms. Subjects either detected random targets or targets preceded by a predictive sequence of three distinct stimuli. The last stimulus in the 3-stimulus sequence (decisive stimulus) did not require any motor response but 100% predicted a subsequent target event. We show that predictive context optimizes target processing via the deployment of distinct anticipatory mechanisms at different times of the predictive sequence. Prior to the occurrence of the decisive stimulus, enhanced attentional preparation was manifested by reductions in the alpha oscillatory activities over visual cortices, resulting in facilitation of processing of the decisive stimulus. Conversely, the subsequent 100% predictable target event did not reveal deployment of attentional preparation in the visual cortices, but elicited enhanced motor preparation mechanisms, indexed by an increased contingent negative variation (CNV) and reduced mu oscillatory activities over motor cortices before movement onset. The present results provide evidence that anticipation operates via different attentional and motor preparation mechanisms by selectively pre-activating task-dependent brain areas as predictability gradually increases.
attention; motor preparation; alpha; mu; beta
The authors have investigated the usefulness of in vivo chemical exchange saturation transfer MRI for detecting gliomas using a dual-modality imaging contrast agent.
Materials & methods
A paramagnetic chemical exchange saturation transfer MRI contrast agent, Eu-1,4,7,10-tetraazacclododecane-1,4,7,10-tetraacetic acid-Gly4 and a fluorescent agent, DyLight® 680, were conjugated to a generation 5 polyamidoamine dendrimer to create the dual-modality, nano-sized imaging contrast agent.
The agent was detected with in vivo chemical exchange saturation transfer MRI in an U87 glioma model. These results were validated using in vivo and ex vivo fluorescence imaging.
This study demonstrated the merits of using a nano-sized imaging contrast agent for detecting gliomas and using a dual-modality agent for detecting gliomas at different spatial scales.
brain tumor; contrast agent; dendrimer; MRI; pharmacokinetic
Empathy refers to the ability to perceive and share another person’s affective state. Much neuroimaging evidence suggests that observing others’ suffering and pain elicits activations of the anterior insular and the anterior cingulate cortices associated with subjective empathetic responses in the observer. However, these observations do not provide causal evidence for the respective roles of anterior insular and anterior cingulate cortices in empathetic pain. Therefore, whether these regions are ‘necessary’ for empathetic pain remains unknown. Herein, we examined the perception of others’ pain in patients with anterior insular cortex or anterior cingulate cortex lesions whose locations matched with the anterior insular cortex or anterior cingulate cortex clusters identified by a meta-analysis on neuroimaging studies of empathetic pain perception. Patients with focal anterior insular cortex lesions displayed decreased discrimination accuracy and prolonged reaction time when processing others’ pain explicitly and lacked a typical interference effect of empathetic pain on the performance of a pain-irrelevant task. In contrast, these deficits were not observed in patients with anterior cingulate cortex lesions. These findings reveal that only discrete anterior insular cortex lesions, but not anterior cingulate cortex lesions, result in deficits in explicit and implicit pain perception, supporting a critical role of anterior insular cortex in empathetic pain processing. Our findings have implications for a wide range of neuropsychiatric illnesses characterized by prominent deficits in higher-level social functioning.
anterior cingulate cortex; anterior insular cortex; empathy; meta-analysis; necessity
Anthropogenic modifications to landscapes intended to benefit wildlife may negatively influence wildlife communities. Anthropogenic provisioning of free water (water developments) to enhance abundance and distribution of wildlife is a common management practice in arid regions where water is limiting. Despite the long-term and widespread use of water developments, little is known about how they influence native species. Water developments may negatively influence arid-adapted species (e.g., kit fox, Vulpes macrotis) by enabling water-dependent competitors (e.g., coyote, Canis latrans) to expand distribution in arid landscapes (i.e., indirect effect of water hypothesis). We tested the two predictions of the indirect effect of water hypothesis (i.e., coyotes will visit areas with free water more frequently and kit foxes will spatially and temporally avoid coyotes) and evaluated relative use of free water by canids in the Great Basin and Mojave Deserts from 2010 to 2012. We established scent stations in areas with (wet) and without (dry) free water and monitored visitation by canids to these sites and visitation to water sources using infrared-triggered cameras. There was no difference in the proportions of visits to scent stations in wet or dry areas by coyotes or kit foxes at either study area. We did not detect spatial (no negative correlation between visits to scent stations) or temporal (no difference between times when stations were visited) segregation between coyotes and kit foxes. Visitation to water sources was not different for coyotes between study areas, but kit foxes visited water sources more in Mojave than Great Basin. Our results did not support the indirect effect of water hypothesis in the Great Basin or Mojave Deserts for these two canids.
Two pivotal, phase III, randomised, placebo-controlled, registration trials (MM-009 and MM-010) showed that lenalidomide plus dexamethasone was more effective than placebo plus dexamethasone in the treatment of patients with relapsed or refractory multiple myeloma. This pooled, retrospective subanalysis of MM-009 and MM-010 analysed outcomes according to patient age. A total of 704 patients (390 aged <65 years, 232 aged 65–74 years, and 82 aged ≥75 years) received lenalidomide or placebo, both in combination with dexamethasone. The overall response rate (ORR) was significantly higher in patients treated with lenalidomide plus dexamethasone versus placebo plus dexamethasone in all age groups (P < 0.0001 for all). Median progression-free survival (PFS) and median time-to-progression (TTP) were similar, and both were significantly longer with lenalidomide plus dexamethasone in all age groups (P < 0.001 for all). Median overall survival (OS) favoured lenalidomide plus dexamethasone in all age groups, although the difference was not statistically significant. Adverse events of anaemia, febrile neutropenia, deep-vein thrombosis, neuropathy, and gastrointestinal disorders increased with age. Lenalidomide combined with dexamethasone improved the ORR and prolonged PFS, TTP, and OS compared with placebo plus dexamethasone, irrespective of age. This finding was consistent with the overall MM-009 and MM-010 populations.
Lenalidomide; Elderly; Multiple myeloma; Relapsed; Refractory
Both emotion and reward are primary modulators of cognition: emotional word content enhances word processing, and reward expectancy similarly amplifies cognitive processing from the perceptual up to the executive control level. Here, we investigate how these primary regulators of cognition interact. We studied how the anticipation of gain or loss modulates the neural time course (event-related potentials, ERPs) related to processing of emotional words. Participants performed a semantic categorization task on emotional and neutral words, which were preceded by a cue indicating that performance could lead to monetary gain or loss. Emotion-related and reward-related effects occurred in different time windows, did not interact statistically, and showed different topographies. This speaks for an independence of reward expectancy and the processing of emotional word content. Therefore, privileged processing given to emotionally valenced words seems immune to short-term modulation of reward. Models of language comprehension should be able to incorporate effects of reward and emotion on language processing, and the current study argues for an architecture in which reward and emotion do not share a common neurobiological mechanism.
emotion; reward expectancy; word processing; event-related potentials
In previous studies on a rat model of transient cerebral ischemia, the blood and brain concentrations of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) following intravenous bolus injection were repeatedly assessed by dynamic contrast-enhanced (DCE)-MRI, and blood-to-brain influx rate constants (Ki) were calculated from Patlak plots of the data in areas with blood–brain barrier (BBB) opening. For concurrent validation of these findings, after completing the DCE-MRI study, radiolabeled sucrose or α-aminoisobutyric acid was injected intravenously, and the brain disposition and Ki values were calculated by quantitative autoradiography (QAR) assay employing the single-time equation. To overcome two of the shortcomings of this comparison, the present experiments were carried out with a radiotracer virtually identical to Gd-DTPA, Gd-[14C]DTPA, and Ki was calculated from both sets of data by the single-time equation. The protocol included 3 h of middle cerebral artery occlusion and 2.5 h of reperfusion in male Wistar rats (n = 15) preceding the DCE-MRI Gd-DTPA and QAR Gd-[14C]DTPA measurements. In addition to Ki, the tissue-to-blood concentration ratios, or volumes of distribution (VR), were calculated. The regions of BBB opening were similar on the MRI maps and autoradiograms. Within them, VR was nearly identical for Gd-DTPA and Gd-[14C]DTPA, and Ki was slightly, but not significantly, higher for Gd-DTPA than for Gd-[14C]DTPA. The Ki values were well correlated (r = 0.67; p = 0.001). When the arterial concentration–time curve of Gd-DTPA was adjusted to match that of Gd-[14C]DTPA, the two sets of Ki values were equal and statistically comparable with those obtained previously by Patlak plots (the preferred, less model-dependent, approach) of the same data (p = 0.2–0.5). These findings demonstrate that this DCE-MRI technique accurately measures the Gd-DTPA concentration in blood and brain, and that Ki estimates based on such data are good quantitative indicators of BBB injury.
arterial input function; blood–brain barrier; cerebral blood flow; cerebral ischemia; DCE-MRI; magnetic resonance contrast agents; neurovascular unit; Patlak plot
The Nucleus Accumbens (NAcc) is an important structure for the transfer of information between cortical and subcortical structures, especially the prefrontal cortex and the hippocampus. However, the mechanism that allows the NAcc to achieve this integration is not well understood. Phase-amplitude cross-frequency coupling (PAC) of oscillations in different frequency bands has been proposed as an effective mechanism to form functional networks to optimize transfer and integration of information. Here we assess PAC between theta and high gamma oscillations as a potential mechanism that facilitates motor adaptation. To address this issue we recorded intracranial field potentials directly from the bilateral human NAcc in three patients while they performed a motor learning task that varied in the level of cognitive control needed to perform the task. As in rodents, PAC was observable in the human NAcc, transiently occurring contralateral to a movement following the motor response. Importantly, PAC correlated with the level of cognitive control needed to monitor the action performed. This functional relation indicates that the NAcc is engaged in action monitoring and supports the evaluation of motor programs during adaptive behavior by means of PAC.
phase-amplitude coupling; nucleus accumbens; cognitive control; action monitoring; learning
The role of lateral prefrontal cortex (LPFC) in speech monitoring has not been delineated. Recent work suggests that medial frontal cortex (MFC) is involved in overt speech monitoring initiated before auditory feedback. This mechanism is reflected in an event-related potential (ERP), the error negativity (Ne), peaking within 100 ms after vocal-onset. Critically, in healthy individuals the Ne is sensitive to the accuracy of the response; it is larger for error than correct trials. By contrast, patients with LPFC damage are impaired in non-verbal monitoring tasks showing no amplitude difference between the Ne measured in correct vs. error trials. Interactions between the LPFC and the MFC are assumed to play a necessary role for normal action monitoring. We investigated whether the LPFC was involved in speech monitoring to the same extent as in non-linguistic actions by comparing performance and EEG activity in patients with LPFC damage and in aged-matched controls performing linguistic (Picture Naming) and non-linguistic (Simon) tasks. Controls did not produce enough errors to allow the comparison of the Ne or other ERP in error vs. correct trials. PFC patients had worse performance than controls in both tasks, but their Ne was larger for error than correct trials only in Naming. This task-dependent pattern can be explained by LPFC-dependent working-memory requirements present in non-linguistic tasks used to study action monitoring but absent in picture naming. This suggests that LPFC may not be necessary for speech monitoring as assessed by simple picture naming. In addition, bilateral temporal cortex activity starting before and peaking around vocal-onset was observed in LPFC and control groups in both tasks but was larger for error than correct trials only in Naming, suggesting the temporal cortex is associated with on-line monitoring of speech specifically when access to lexical representations is necessary.
on-line speech monitoring; prefrontal lesions; error negativity; electroencephalography; brain networks; overt picture-naming
Frontal lobe lesions impair recognition memory but it is unclear whether the deficits arise from impaired recollection, impaired familiarity, or both. In the current study, recognition memory for verbal materials was examined in patients with damage to the left or right lateral prefrontal cortex. Words were incidentally encoded under semantic or phonological orienting conditions, and recognition memory was tested using a 6-point confidence procedure. Receiver operating characteristics (ROCs) were examined in order to measure the contributions of recollection and familiarity to recognition memory. In both encoding conditions, lateral prefrontal cortex damage led to a deficit in familiarity but not recollection. Similar deficits were observed in left and right hemisphere patients. The results indicate that the lateral prefrontal cortex plays a critical role in the monitoring or decision processes required for accurate familiarity-based recognition responses.
recognition memory; lateral prefrontal cortex; recollection; familiarity; receiver operating characteristics
The apparent forward transfer constant,
Katrans, for albumin was measured in 9L cerebral tumors in 15 rats. An MRI study using gadolinium-labeled bovine serum albumin (Gd-BSA) was followed by terminal quantitative autoradiography (QAR) using radioiodinated serum albumin (RISA). Look-Locker MRI estimates of T1 followed Gd-BSA blood and tissue concentration. QAR and MRI maps of
Katrans were co-registered, a region of interest (ROI) that included the tumor and its surround was selected, and the two estimates of
Katrans from the ROI on QAR and MRI maps were compared by either mean per animal ROI or on pixel-by-pixel data using a generalized estimating equation (GEE).
An ROI analysis showed a moderate correlation between the two measures (r = 0.57, p = 0.026); pixel-by-pixel GEE analysis concurred (r = 0.54, p < 0.0001). The estimates of QAR with MRI of last time points (e.g., 25 minutes) showed a moderate correlation (ROI r = 0.55, p < 0.035; GEE r = 0.58, p < 0.0001). Differences between the QAR and MRI estimates of
Katrans did not differ from zero, but the MRI 25 minute estimate was significantly lower than the QAR estimate. Thus, noininvasive MRI estimates of vascular permeability can serve as a surrogate for QAR measures.
TOMROP; relaxation time; transfer constant; Patlak plot; 9L glioblastoma
We investigated whether both the contingent negative variation (CNV), an event-related potential index of preparatory brain activity, and event-related oscillatory EEG activity differentiated Go and NoGo trials in a delayed response task. CNV and spectral power (4–100 Hz) were calculated from EEG activity in the preparatory interval in 16 healthy adult participants. As previously reported, CNV amplitudes were higher in Go compared to NoGo trials. In addition, event-related spectral power of the Go condition was reduced in the theta to low gamma range compared to the NoGo condition, confirming that preparing to respond is associated with modulation of event-related spectral activity as well as the CNV. Altogether, the impact of the experimental manipulation on both slow event-related potentials and oscillatory EEG activity may reflect coordinated dynamic changes in the excitability of distributed neural networks involved in preparation.
The functional significance of electrical rhythms in the mammalian brain remains uncertain. In the motor cortex, the 12–20 Hz beta rhythm is known to transiently decrease in amplitude during movement, and to be altered in many motor diseases. Here we show that the activity of neuronal populations is phase-coupled with the beta rhythm on rapid timescales, and describe how the strength of this relation changes with movement. To investigate the relationship of the beta rhythm to neuronal dynamics, we measured local cortical activity using arrays of subdural electrocorticographic (ECoG) electrodes in human patients performing simple movement tasks. In addition to rhythmic brain processes, ECoG potentials also reveal a spectrally broadband motif that reflects the aggregate neural population activity beneath each electrode. During movement, the amplitude of this broadband motif follows the dynamics of individual fingers, with somatotopically specific responses for different fingers at different sites on the pre-central gyrus. The 12–20 Hz beta rhythm, in contrast, is widespread as well as spatially coherent within sulcal boundaries and decreases in amplitude across the pre- and post-central gyri in a diffuse manner that is not finger-specific. We find that the amplitude of this broadband motif is entrained on the phase of the beta rhythm, as well as rhythms at other frequencies, in peri-central cortex during fixation. During finger movement, the beta phase-entrainment is diminished or eliminated. We suggest that the beta rhythm may be more than a resting rhythm, and that this entrainment may reflect a suppressive mechanism for actively gating motor function.
We have long known that there are rhythmic oscillations in the mammalian brain. Although the power in these rhythms changes during behavior, their relevance for brain function has been something of a mystery. In this study, the particular role of rhythms in human motor cortex was studied both during rest and during engagement in different finger movements. Arrays of electrocorticographic electrodes were placed directly on frontal, temporal, and parietal brain surfaces to measure the electrical potential. These measurements reveal that movement of different fingers produces spatially focal and finger-specific changes in local neuronal population activity, along with spatially diffuse and finger-nonspecific decreases in 12–20 Hz β-rhythm power. Apart from these power changes, there are independent interactions between the β-rhythm and local cortical activity. During rest, 5–20% of the variation in local cortical activity is due to entrainment on the phase of the β-rhythm over the pre- and post-central gyri, but the interaction is significantly diminished during movement. This shifting entrainment suggests that the β-rhythm is not simply a background process that is suppressed during movement, but rather that the β-rhythm plays an active and important role in motor processing.
A fundamental organizational principle of the primate motor system is cortical control of contralateral limb movements. Motor areas also appear to play a role in the control of ipsilateral limb movements. Several studies in monkeys have shown that individual neurons in primary motor cortex (M1) may represent, on average, the direction of movements of the ipsilateral arm. Given the increasing body of evidence demonstrating that neural ensembles can reliably represent information with a high temporal resolution, here we characterize the distributed neural representation of ipsilateral upper limb kinematics in both monkey and man. In two macaque monkeys trained to perform center-out reaching movements, we found that the ensemble spiking activity in M1 could continuously represent ipsilateral limb position. Interestingly, this representation was more correlated with joint angles than hand position. Using bilateral EMG recordings, we excluded the possibility that postural or mirror movements could exclusively account for these findings. In addition, linear methods could decode limb position from cortical field potentials in both monkeys. We also found that M1 spiking activity could control a biomimetic brain-machine interface reflecting ipsilateral kinematics. Finally, we recorded cortical field potentials from three human subjects and also consistently found evidence of a neural representation for ipsilateral movement parameters. Together, our results demonstrate the presence of a high-fidelity neural representation for ipsilateral movement and illustrates that it can be successfully incorporated into a brain-machine interface.
Ipsilateral; Ensemble; Motor Control; Brain-Machine Interface; Electrophysiology; Primary Motor Cortex
Effects of grouping on unilateral neglect were investigated in 8 neurological patients with right hemisphere damage. It is well documented that arranging items to form a group spanning the midline decreases the magnitude of neglect. In the present study we examined how clusters of groups within the left or right visual field affect neglect and whether isolated groups within the neglected field deflect attention from right-sided displays. We orthogonally varied the strength of grouping on the right and left sides of a display and measured the time to find a predesignated target in one of those groups. Groups on the neglected left side did not affect right-sided target detection any more than an empty left page. However, strength of grouping did affect left sided target detection. These findings are discussed as they relate to attention and preattention in unilateral visual neglect.
Endothelial progenitors cells (EPCs) are important for the development of cell therapies for various diseases. However, the major obstacles in developing such therapies are low quantities of EPCs that can be generated from the patient and the lack of adequate non-invasive imaging approach for in vivo monitoring of transplanted cells. The objective of this project was to determine the ability of cord blood (CB) AC133+ EPCs to differentiate, in vitro and in vivo, toward mature endothelial cells (ECs) after long term in vitro expansion and cryopreservation and to use magnetic resonance imaging (MRI) to assess the in vivo migratory potential of ex vivo expanded and cryopreserved CB AC133+ EPCs in an orthotopic glioma rat model.
Materials, Methods and Results
The primary CB AC133+ EPC culture contained mainly EPCs and long term in vitro conditions facilitated the maintenance of these cells in a state of commitment toward endothelial lineage. At days 15–20 and 25–30 of the primary culture, the cells were labeled with FePro and cryopreserved for a few weeks. Cryopreserved cells were thawed and in vitro differentiated or IV administered to glioma bearing rats. Different groups of rats also received long-term cultured, magnetically labeled fresh EPCs and both groups of animals underwent MRI 7 days after IV administration of EPCs. Fluorescent microscopy showed that in vitro differentiation of EPCs was not affected by FePro labeling and cryopreservation. MRI analysis demonstrated that in vivo accumulation of previously cryopreserved transplanted cells resulted in significantly higher R2 and R2* values indicating a higher rate of migration and incorporation into tumor neovascularization of previously cryopreserved CB AC133+ EPCs to glioma sites, compared to non-cryopreserved cells.
Magnetically labeled CB EPCs can be in vitro expanded and cryopreserved for future use as MRI probes for monitoring the migration and incorporation to the sites of neovascularization.
Recent studies suggest that cross-frequency coupling (CFC) may serve a functional role in neuronal computation, communication, and learning. In particular, the strength of phase-amplitude CFC differs across brain areas in a task-relevant manner, changes quickly in response to sensory, motor, and cognitive events, and correlates with performance in learning tasks. Importantly, while high-frequency brain activity reflects local domains of cortical processing, low-frequency brain rhythms are dynamically entrained across distributed brain regions by both external sensory input and internal cognitive events. CFC may thus serve as a mechanism to transfer information from large-scale brain networks operating at behavioral timescales to the fast, local cortical processing required for effective computation and synaptic modification, thus integrating functional systems across multiple spatiotemporal scales.
How and where object and spatial information are perceptually integrated in the brain is a central question in visual cognition. Single-unit physiology, scalp EEG, and fMRI research suggests that the prefrontal cortex (PFC) is a critical locus for object-spatial integration. To test the causal participation of the PFC in an object-spatial integration network, we studied ten patients with unilateral PFC damage performing a lateralized object-spatial integration task. Consistent with single-unit and neuroimaging studies, we found that PFC lesions result in a significant behavioral impairment in object-spatial integration. Furthermore, by manipulating inter-hemispheric transfer of object-spatial information, we found that masking of visual transfer impairs performance in the contralesional visual field in the PFC patients. Our results provide the first evidence that the PFC plays a key, causal role in an object-spatial integration network. Patient performance is also discussed within the context of compensation by the non-lesioned PFC.
Longitudinal multiparametric magnetic resonance imaging (MRI) and histological studies were performed on simvastatin- or atorvastatin-treated rats to evaluate vascular repair mechanisms after experimental intracerebral hemorrhage (ICH).
Primary ICH was induced in adult Wistar rats by direct infusion of 100 µL of autologous blood into the striatal region adjacent to the subventricular zone. Atorvastatin (2 mg/kg), simvastatin (2 mg/kg), or PBS was given orally at 24 hours post-ICH and continued daily for 7 days. The temporal evolution of ICH in each group was assessed by MRI measurements of T2, T1sat, and cerebral blood flow (CBF) in brain areas corresponding to the bulk of the hemorrhage (core), and edematous border (rim). Rats were sacrificed after the final MRI scan at 28 days and histological studies were performed. A small group of sham-operated animals was also studied. Neurobehavioral testing was performed in all animals. Analysis of variance methods were used to compare results from the treatment and control groups, with significance inferred at p ≤ 0.05.
Using histological indices, animals treated with simvastatin and atorvastatin had significantly increased angiogenesis and synaptogenesis in the hematoma rim compared to the control group (p ≤ 0.05). The statin-treated animals exhibited significantly increased CBF in the hematoma rim at 4 weeks, while blood-brain barrier permeability (T1sat) and edema (T2) in the corresponding regions were reduced. Both statin-treated groups showed significant neurological improvement from 2 weeks post-ICH onward.
The results of the present study demonstrate that simvastatin and atorvastatin significantly improve the recovery of rats from ICH, possibly via angiogenesis and synaptic plasticity. In addition, in-vivo multiparametric MRI measurements over time can be effectively applied to the experimental ICH model for longitudinal assessment of the therapeutic intervention.
hematoma; multiparametric MRI; synaptophysin; vWF