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1.  Higher Doses of Lenalidomide Are Associated With Unacceptable Toxicity Including Life-Threatening Tumor Flare in Patients With Chronic Lymphocytic Leukemia 
Lenalidomide is a novel therapeutic agent with uncertain mechanism of action that is clinically active in myelodysplastic syndrome (MDS) and multiple myeloma (MM). Application of high (MM) and low (MDS) doses of lenalidomide has been reported to have clinical activity in CLL. Herein, we highlight life-threatening tumor flare when higher doses of lenalidomide are administered to patients with CLL and provide a potential mechanism for its occurrence.
Patients and Methods
Four patients with relapsed CLL were treated with lenalidomide (25 mg/d for 21 days of a 28-day cycle). Serious adverse events including tumor flare and tumor lysis are summarized. In vitro studies examining drug-induced apoptosis and activation of CLL cells were also performed.
Four consecutive patients were treated with lenalidomide; all had serious adverse events. Tumor flare was observed in three patients and was characterized by dramatic and painful lymph node enlargement resulting in hospitalization of two patients, with one fatal outcome. Another patient developed sepsis and renal failure. In vitro studies demonstrated lenalidomide-induced B-cell activation (upregulation of CD40 and CD86) corresponding to degree of tumor flare, possibly explaining the tumor flare observation.
Lenalidomide administered at 25 mg/d in relapsed CLL is associated with unacceptable toxicity; the rapid onset and adverse clinical effects of tumor flare represent a significant limitation of lenalidomide use in CLL at this dose. Drug-associated B-cell activation may contribute to this adverse event. Future studies with lenalidomide in CLL should focus on understanding this toxicity, investigating patients at risk, and investigating alternative safer dosing schedules.
PMCID: PMC4312490  PMID: 18427150
2.  Necessary, Yet Dissociable Contributions of the Insular and Ventromedial Prefrontal Cortices to Norm Adaptation: Computational and Lesion Evidence in Humans 
The Journal of Neuroscience  2015;35(2):467-473.
Social norms and their enforcement are fundamental to human societies. The ability to detect deviations from norms and to adapt to norms in a changing environment is therefore important to individuals' normal social functioning. Previous neuroimaging studies have highlighted the involvement of the insular and ventromedial prefrontal (vmPFC) cortices in representing norms. However, the necessity and dissociability of their involvement remain unclear. Using model-based computational modeling and neuropsychological lesion approaches, we examined the contributions of the insula and vmPFC to norm adaptation in seven human patients with focal insula lesions and six patients with focal vmPFC lesions, in comparison with forty neurologically intact controls and six brain-damaged controls. There were three computational signals of interest as participants played a fairness game (ultimatum game): sensitivity to the fairness of offers, sensitivity to deviations from expected norms, and the speed at which people adapt to norms. Significant group differences were assessed using bootstrapping methods. Patients with insula lesions displayed abnormally low adaptation speed to norms, yet detected norm violations with greater sensitivity than controls. Patients with vmPFC lesions did not have such abnormalities, but displayed reduced sensitivity to fairness and were more likely to accept the most unfair offers. These findings provide compelling computational and lesion evidence supporting the necessary, yet dissociable roles of the insula and vmPFC in norm adaptation in humans: the insula is critical for learning to adapt when reality deviates from norm expectations, and that the vmPFC is important for valuation of fairness during social exchange.
PMCID: PMC4293403  PMID: 25589742
brain lesion; computational modeling; decision-making; insular cortex; social norms; ventromedial prefrontal cortex
3.  The electrophysiology of language production: what could be improved 
Frontiers in Psychology  2015;5:1560.
PMCID: PMC4292226  PMID: 25628586
EEG; ERP; speech; word production; response time
4.  Corticothalamic phase synchrony and cross-frequency coupling predict human memory formation 
eLife  null;3:e05352.
The anterior thalamic nucleus (ATN) is thought to play an important role in a brain network involving the hippocampus and neocortex, which enables human memories to be formed. However, its small size and location deep within the brain have impeded direct investigation in humans with non-invasive techniques. Here we provide direct evidence for a functional role for the ATN in memory formation from rare simultaneous human intrathalamic and scalp electroencephalogram (EEG) recordings from eight volunteering patients receiving intrathalamic electrodes implanted for the treatment of epilepsy, demonstrating real-time communication between neocortex and ATN during successful memory encoding. Neocortical-ATN theta oscillatory phase synchrony of local field potentials and neocortical-theta-to-ATN-gamma cross-frequency coupling during presentation of complex photographic scenes predicted later memory for the scenes, demonstrating a key role for the ATN in human memory encoding.
eLife digest
Memories, both the mundane and the significant, play an integral role in our daily lives. Scientists have long sought to establish exactly how our memories are formed; how does an experience, with its sights, sounds and feelings, become a mental representation stored within our brain?
One way to investigate this question is to look at the activity of different parts of the brain. Brain imaging techniques have helped researchers identify two key brain regions that are involved in the process of memory formation: the neocortex and the hippocampus. The neocortex forms the outer layer of the brain, and performs complex tasks such as decision-making and language comprehension. The hippocampus, which sits deeper within the brain, deals primarily with memory and navigation. Research has shown that memory formation depends on communication between the neocortex and the hippocampus. However, scientists suspected that additional structures located beneath the neocortex—among them, the anterior thalamic nuclei (ATN)—are also crucial for forming memories. This has been difficult to confirm as the small size of the ATN, and their location deep within the brain, make their activity almost impossible to monitor using standard brain imaging techniques.
One way reliable data can be recorded from the ATN is by inserting electrodes into the brain. Brain surgery of course cannot be carried out on healthy human participants, but occasionally an opportunity arises to study the brain activity of patients who have electrodes inserted for therapeutic purposes. For example, in cases where a patient's epilepsy does not respond to conventional treatments, electrodes may be implanted to electrically stimulate the ATN in an attempt to improve their symptoms.
Sweeney-Reed et al. asked eight volunteers to perform a memory task, and monitored the activity of each volunteer's ATN via electrodes that had already been implanted in their brain to treat epilepsy. Simultaneously, electrodes attached to the scalps of the volunteers recorded the activity of the neocortex. When a memory was successfully stored in the brain, the activity of the two regions became synchronized. This suggests that successful memory formation depends upon communication between the ATN and the neocortex.
While the involvement of the ATN in human memory formation has long been a topic of speculation, Sweeney-Reed et al. now provide direct biological evidence for its crucial role in the process. Consequently, future research into memory formation should focus upon the ATN in addition to the more familiar structures of the neocortex and the hippocampus.
PMCID: PMC4302268  PMID: 25535839
thalamus; memory; synchrony; cross-frequency coupling; human
5.  Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[14C]DTPA 
An intravenous step-down infusion procedure that maintained a constant gadolinium-diethylene-triaminepentaacetic acid (Gd-DTPA) blood concentration and magnetic resonance imaging (MRI) were used to localize and quantify the blood–brain barrier (BBB) opening in a rat model of transient cerebral ischemia (n = 7). Blood-to-brain influx rate constant (Ki) values of Gd-DTPA from such regions were estimated using MRI–Patlak plots and compared with the Ki values of Gd-[14C]DTPA, determined minutes later in the same rats with an identical step-down infusion, quantitative autoradiography (QAR), and single-time equation. The normalized plasma concentration–time integrals were identical for Gd-DTPA and Gd-[14C]DTPA, indicating that the MRI protocol yielded reliable estimates of plasma Gd-DTPA levels. In six rats with a BBB opening, 14 spatially similar regions of extravascular Gd-DTPA enhancement and Gd-[14C]DTPA leakage, including one very small area, were observed. The terminal tissue–plasma ratios of Gd-[14C]DTPA tended to be slightly higher than those of Gd-DTPA in these regions, but the differences were not significant. The MRI-derived Ki values for Gd-DTPA closely agreed and correlated well with those obtained for Gd-[14C]DTPA. In summary, MRI estimates of Gd-DTPA concentration in the plasma and brain and the influx rate are quantitatively and spatially accurate with step-down infusions.
PMCID: PMC4205544  PMID: 19319145
arterial input function; blood–brain barrier; magnetic resonance contrast agents; Patlak plot; rat; stroke
6.  Hidden Markov Model and Support Vector Machine based decoding of finger movements using Electrocorticography 
Journal of neural engineering  2013;10(5):056020.
Support Vector Machines (SVM) have developed into a gold standard for accurate classification in Brain-Computer-Interfaces (BCI). The choice of the most appropriate classifier for a particular application depends on several characteristics in addition to decoding accuracy. Here we investigate the implementation of Hidden Markov Models (HMM)for online BCIs and discuss strategies to improve their performance.
We compare the SVM, serving as a reference, and HMMs for classifying discrete finger movements obtained from the Electrocorticograms of four subjects doing a finger tapping experiment. The classifier decisions are based on a subset of low-frequency time domain and high gamma oscillation features.
Main results
We show that decoding optimization between the two approaches is due to the way features are extracted and selected and less dependent on the classifier. An additional gain in HMM performance of up to 6% was obtained by introducing model constraints. Comparable accuracies of up to 90% were achieved with both SVM and HMM with the high gamma cortical response providing the most important decoding information for both techniques.
We discuss technical HMM characteristics and adaptations in the context of the presented data as well as for general BCI applications. Our findings suggest that HMMs and their characteristics are promising for efficient online brain-computer interfaces.
PMCID: PMC3901317  PMID: 24045504
Hidden Markov Models; ECoG; finger movements; support vector machine; Bakis; event-related potentials; spectral perturbation
7.  Negative Effects of an Exotic Grass Invasion on Small-Mammal Communities 
PLoS ONE  2014;9(9):e108843.
Exotic invasive species can directly and indirectly influence natural ecological communities. Cheatgrass (Bromus tectorum) is non-native to the western United States and has invaded large areas of the Great Basin. Changes to the structure and composition of plant communities invaded by cheatgrass likely have effects at higher trophic levels. As a keystone guild in North American deserts, granivorous small mammals drive and maintain plant diversity. Our objective was to assess potential effects of invasion by cheatgrass on small-mammal communities. We sampled small-mammal and plant communities at 70 sites (Great Basin, Utah). We assessed abundance and diversity of the small-mammal community, diversity of the plant community, and the percentage of cheatgrass cover and shrub species. Abundance and diversity of the small-mammal community decreased with increasing abundance of cheatgrass. Similarly, cover of cheatgrass remained a significant predictor of small-mammal abundance even after accounting for the loss of the shrub layer and plant diversity, suggesting that there are direct and indirect effects of cheatgrass. The change in the small-mammal communities associated with invasion of cheatgrass likely has effects through higher and lower trophic levels and has the potential to cause major changes in ecosystem structure and function.
PMCID: PMC4182540  PMID: 25269073
8.  Extravasation into brain and subsequent spread beyond the ischemic core of a magnetic resonance contrast agent following a step-down infusion protocol in acute cerebral ischemia 
Limiting expansion of the ischemic core lesion by reinstating blood flow and protecting the penumbral cells is a priority in acute stroke treatment. However, at present, methods are not available for effective drug delivery to the ischemic penumbra. To address these issues this study compared the extravasation and subsequent interstitial spread of a magnetic resonance contrast agent (MRCA) beyond the ischemic core into the surrounding brain in a rat model of ischemia-reperfusion for bolus injection and step-down infusion (SDI) protocols.
Male Wistar rats underwent middle cerebral artery (MCA) occlusion for 3 h followed by reperfusion. Perfusion-diffusion mismatched regions indicating the extent of spread were identified by measuring cerebral blood flow (CBF) deficits by arterial spin-labeled magnetic resonance imaging and the extent of the ischemic core by mapping the apparent diffusion coefficient (ADC) of water with diffusion-weighted imaging. Vascular injury was assessed via MRCA, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) penetration, by Look-Locker T1-weighted MR imaging after either a bolus injection (n = 8) or SDI (n = 6). Spatial and temporal expansion of the MRCA front during a 25 min imaging period was measured from images obtained at 2.5 min intervals.
The mean ADC lesion was 20 ± 7% of the hemispheric area whereas the CBF deficit area was 60 ± 16%, with the difference between the areas suggesting the possible presence of a penumbra. The bolus injection led to MRCA enhancement with an area that initially spread into the ischemic core and then diminished over time. The SDI produced a gradual increase in the area of MRCA enhancement that slowly enlarged to occupy the core, eventually expanded beyond it into the surrounding tissue and then plateaued. The integrated area from SDI extravasation was significantly larger than that for the bolus (p = 0.03). The total number of pixels covered by the SDI at its maximum was significantly larger than the pixels covered by bolus maximum (p = 0.05).
These results demonstrate that the SDI protocol resulted in a spread of the MRCA beyond the ischemic core. Whether plasma-borne acute stroke therapeutics can be delivered to the ischemic penumbra in a similar way needs to be investigated.
PMCID: PMC4177725  PMID: 25276343
Blood–brain barrier; Brain drug delivery; Penumbra; Perfusion-diffusion mismatch; Stroke
9.  Dynamic Changes in Phase-Amplitude Coupling Facilitate Spatial Attention Control in Fronto-Parietal Cortex 
PLoS Biology  2014;12(8):e1001936.
Electrocorticography reveals how coupling between two frequencies of neuronal oscillation allows the frontal and parietal areas of the cortex to control visual attention from moment to moment in the human brain.
Attention is a core cognitive mechanism that allows the brain to allocate limited resources depending on current task demands. A number of frontal and posterior parietal cortical areas, referred to collectively as the fronto-parietal attentional control network, are engaged during attentional allocation in both humans and non-human primates. Numerous studies have examined this network in the human brain using various neuroimaging and scalp electrophysiological techniques. However, little is known about how these frontal and parietal areas interact dynamically to produce behavior on a fine temporal (sub-second) and spatial (sub-centimeter) scale. We addressed how human fronto-parietal regions control visuospatial attention on a fine spatiotemporal scale by recording electrocorticography (ECoG) signals measured directly from subdural electrode arrays that were implanted in patients undergoing intracranial monitoring for localization of epileptic foci. Subjects (n = 8) performed a spatial-cuing task, in which they allocated visuospatial attention to either the right or left visual field and detected the appearance of a target. We found increases in high gamma (HG) power (70–250 Hz) time-locked to trial onset that remained elevated throughout the attentional allocation period over frontal, parietal, and visual areas. These HG power increases were modulated by the phase of the ongoing delta/theta (2–5 Hz) oscillation during attentional allocation. Critically, we found that the strength of this delta/theta phase-HG amplitude coupling predicted reaction times to detected targets on a trial-by-trial basis. These results highlight the role of delta/theta phase-HG amplitude coupling as a mechanism for sub-second facilitation and coordination within human fronto-parietal cortex that is guided by momentary attentional demands.
Author Summary
The frontal and parietal areas of the cortex control the ability to focus visuospatial attention, and damage to these areas results in profound attentional disturbances. Although much research has concentrated on where these areas are located, little is known about how these areas may function in humans. Previous studies have demonstrated that neuronal spiking is more likely to occur in specific time windows based upon the phase of lower frequency neural oscillations – rhythmic or repetitive neuronal activity. These low-frequency rhythms are hypothesized to coordinate the timing of neuronal firing within local and across network regions. Here, we investigated how human frontal and parietal cortices use neural oscillations to control visuospatial attention. We identified a high-frequency component of electrical brain activity, broadband high gamma (70–250 Hz) amplitude, that became phase-locked to a slower rhythm, delta/theta (2–5 Hz), over frontal, parietal, and visual areas while the study subjects paid attention to the peripheral visual field. Changes in the strength of the coupling between delta/theta phase and high gamma amplitude predicted the attentional behavior of the subjects across single trials. From these results, we conclude that coupling between delta/theta phase and high gamma amplitude serves to coordinate information within – and perhaps between – frontal and parietal areas during allocation of visuospatial attention.
PMCID: PMC4144794  PMID: 25157678
10.  Preparatory attention after lesions to the lateral or orbital prefrontal cortex – An event-related potentials study 
Brain research  2013;1527:10.1016/j.brainres.2013.06.017.
The prefrontal cortex (PFC) plays a central role in preparatory and anticipatory attentional processes. To investigate whether subregions of the PFC play differential roles in these processes we investigated the effect of focal lesions to either lateral prefrontal (lateral PFC; n=11) or orbitofrontal cortex (OFC; n=13) on the contingent negative variation (CNV), an electrophysiological index of preparatory brain processes. The CNV was studied using a Go/NoGo delayed response task where an auditory S1 signaled whether or not an upcoming visual S2 was a Go or a NoGo stimulus. Neither early (500–1000 ms) nor late (3200–3700 ms) phase Go trial CNV amplitude was reduced for any of the patient groups in comparison to controls. However, the lateral PFC group showed enhanced Go trial early CNV and reduced late CNV Go/NoGo differentiation. These data suggests that normal orienting and evaluation as reflected by the CNV is intact after OFC lesions. The enhanced early CNV after lateral PFC damage may be due to failure in inhibition and the reduced late CNV difference wave confirms a deficit in preparatory attention after damage to this frontal subregion.
PMCID: PMC3816253  PMID: 23831520
Event-related potentials; Contingent negative variation (CNV); Lateral prefrontal cortex; Orbitofrontal cortex
11.  Multiplexed memories: a view from human cortex 
Nature neuroscience  2013;16(3):257-258.
A study recording directly from the human brain shows that connectivity between the prefrontal cortex, parietal cortex and the medial temporal lobe across different frequency bands underlies successful memory retrieval.
PMCID: PMC4090684  PMID: 23434977
12.  Contribution of Subregions of Human Frontal Cortex to Novelty Processing 
Journal of cognitive neuroscience  2011;24(2):378-395.
Novelty processing was studied in patients with lesions centered in either OFC or lateral pFC (LPFC). An auditory novelty oddball ERP paradigm was applied with environmental sounds serving as task irrelevant novel stimuli. Lesions to the LPFC as well as the OFC resulted in a reduction of the frontal Novelty P3 response, supporting a key role of both frontal subdivisions in novelty processing. The posterior P3b to target sounds was unaffected in patients with frontal lobe lesions in either location, indicating intact posterior cortical target detection mechanisms. LPFC patients displayed an enhanced sustained negative slow wave (NSW) to novel sounds not observed in OFC patients, indicating prolonged resource allocation to task-irrelevant stimuli after LPFC damage. Both patient groups displayed an enhanced NSW to targets relative to controls. However, there was no difference in behavior between patients and controls suggesting that the enhanced NSW to targets may index an increased resource allocation to response requirements enabling comparable performance in the frontal lesioned patients. The current findings indicate that the LPFC and OFC have partly shared and partly differential contributions to the cognitive subcomponents of novelty processing.
PMCID: PMC4090805  PMID: 21812562
13.  Multivariate Phase–Amplitude Cross-Frequency Coupling in Neurophysiological Signals 
Phase–amplitude cross-frequency coupling (CFC)—where the phase of a low-frequency signal modulates the amplitude or power of a high-frequency signal—is a topic of increasing interest in neuroscience. However, existing methods of assessing CFC are inherently bivariate and cannot estimate CFC between more than two signals at a time. Given the increase in multielectrode recordings, this is a strong limitation. Furthermore, the phase coupling between multiple low-frequency signals is likely to produce a high rate of false positives when CFC is evaluated using bivariate methods. Here, we present a novel method for estimating the statistical dependence between one high-frequency signal and N low-frequency signals, termed multivariate phase-coupling estimation (PCE). Compared to bivariate methods, the PCE produces sparser estimates of CFC and can distinguish between direct and indirect coupling between neurophysiological signals—critical for accurately estimating coupling within multiscale brain networks.
PMCID: PMC4090099  PMID: 22020662
Cross-frequency coupling (CFC); multiscale brain networks; multivariate analysis; neuronal oscillations; phase–amplitude coupling (PAC)
14.  Age-related frontoparietal changes during the control of bottom-up and top-down attention: an ERP study 
Neurobiology of aging  2012;34(2):477-488.
We investigated age-related changes in frontal and parietal scalp event-related potential (ERP) activity during bottom-up and top-down attention. Younger and older participants were presented with arrays constructed to induce either automatic “pop-out” (bottom-up) or effortful “search” (top-down) behavior. Reaction times (RTs) increased and accuracy decreased with age, with a greater age-related decline in accuracy for the search than for the pop-out condition. The latency of the P300 elicited by the visual search array was shorter in both conditions in the younger than in the older adults. Pop-out target detection was associated with greater activity at parietal than at prefrontal locations in younger participants and with a more equipotential prefrontal-parietal distribution in older adults. Search target detection was associated with greater activity at prefrontal than at parietal locations in older relative to younger participants. Thus, aging was associated with a more prefrontal P300 scalp distribution during the control of bottom-up and top-down attention. Early latency extrastriate potentials were enhanced and N2-posterior-contralateral (N2pc) was reduced in the older group, supporting the idea that the frontal enhancements may be due to a compensation for disinhibition and distraction in the older adults. Taken together these findings provide evidence that younger and older adults recruit different frontal-parietal networks during top-down and bottom-up attention, with older adults increasing their recruitment of a more frontally distributed network in both of these types of attention. This work is in accord with previous neuroimaging findings suggesting that older adults recruit more frontal activity in the service of a variety of tasks than younger adults.
PMCID: PMC4090105  PMID: 22459599
Aging; Event-related potentials (ERPs); Visual pop-out; Visual search; Control of attention; P300; N2pc
15.  Impact of Orbitofrontal Lesions on Electrophysiological Signals in a Stop Signal Task 
Journal of cognitive neuroscience  2014;26(7):1528-1545.
Behavioral inhibition and performance monitoring are critical cognitive functions supported by distributed neural networks including the pFC. We examined neurophysiological correlates of motor response inhibition and action monitoring in patients with focal orbitofrontal (OFC) lesions (n = 12) after resection of a primary intracranial tumor or contusion because of traumatic brain injury. Healthy participants served as controls (n = 14). Participants performed a visual stop signal task. We analyzed behavioral performance as well as event-related brain potentials and oscillations. Inhibition difficulty was adjusted individually to yield an equal amount of successful inhibitions across participants. RTs of patients and controls did not differ significantly in go trials or in failed stop trials, and no differences were observed in estimated stop signal RT. However, electrophysiological response patterns during task performance distinguished the groups. Patients with OFC lesions had enhanced P3 amplitudes to congruent condition go signals and to stop signals. In stop trials, patients had attenuated N2 and error-related negativity, but enhanced error positivity. Patients also showed enhanced and prolonged post-error beta band increases for stop errors. This effect was particularly evident in patients whose lesion extended to the subgenual cingulate cortex. In summary, although response inhibition was not impaired, the diminished stop N2 and ERN support a critical role of the OFC in action monitoring. Moreover, the increased stop P3, error positivity, and post-error beta response indicate that OFC injury affected action outcome evaluation and support the notion that the OFC is relevant for the processing of abstract reinforcers such as performing correctly in the task.
PMCID: PMC4090109  PMID: 24392904
16.  Faces are special but not too special: Spared face recognition in amnesia is based on familiarity 
Neuropsychologia  2010;48(13):3941-3948.
Most current theories of human memory are material-general in the sense that they assume that the medial temporal lobe (MTL) is important for retrieving the details of prior events, regardless of the specific type of materials. Recent studies of amnesia have challenged the material-general assumption by suggesting that the MTL may be necessary for remembering words, but is not involved in remembering faces. We examined recognition memory for faces and words in a group of amnesic patients, which included hypoxic patients and patients with extensive left or right MTL lesions. Recognition confidence judgments were used to plot receiver operating characteristics (ROCs) in order to more fully quantify recognition performance and to estimate the contributions of recollection and familiarity. Consistent with the extant literature, an analysis of overall recognition accuracy showed that the patients were impaired at word memory but had spared face memory. However, the ROC analysis indicated that the patients were generally impaired at high confidence recognition responses for faces and words, and they exhibited significant recollection impairments for both types of materials. Familiarity for faces was preserved in all patients, but extensive left MTL damage impaired familiarity for words. These results suggest that face recognition may appear to be spared because performance tends to rely heavily on familiarity, a process that is relatively well preserved in amnesia. The findings challenge material-general theories of memory, and suggest that both material and process are important determinants of memory performance in amnesia, and different types of materials may depend more or less on recollection and familiarity.
PMCID: PMC4084520  PMID: 20833190
episodic memory; recollection; familiarity; amnesia; face recognition; word recognition
17.  Decoding Speech for Understanding and Treating Aphasia 
Progress in brain research  2013;207:435-456.
Aphasia is an acquired language disorder with a diverse set of symptoms that can affect virtually any linguistic modality across both the comprehension and production of spoken language. Partial recovery of language function after injury is common but typically incomplete. Rehabilitation strategies focus on behavioral training to induce plasticity in underlying neural circuits to maximize linguistic recovery. Understanding the different neural circuits underlying diverse language functions is a key to developing more effective treatment strategies. This chapter discusses a systems identification analytic approach to the study of linguistic neural representation. The focus of this framework is a quantitative, model-based characterization of speech and language neural representations that can be used to decode, or predict, speech representations from measured brain activity. Recent results of this approach are discussed in the context of applications to understanding the neural basis of aphasia symptoms and the potential to optimize plasticity during the rehabilitation process.
PMCID: PMC4043958  PMID: 24309265
aphasia; speech; language; neural encoding; decoding
18.  Proceedings of the Third International Workshop on Advances in Electrocorticography 
Epilepsy & behavior : E&B  2012;25(4):605-613.
The Third International Workshop on Advances in Electrocorticography (ECoG) was convened in Washington, DC, on November 10-11, 2011. As in prior meetings, a true multidisciplinary fusion of clinicians, scientists, and engineers from many disciplines gathered to summarize contemporary experiences in brain surface recordings. The proceedings of this meeting serve as evidence of a very robust and transformative field, but will yet again require revision for the advances that the following year will surely bring.
PMCID: PMC4041796  PMID: 23160096
electrocorticography; brain-computer interface; high-frequency oscillations; brain mapping; seizure detection; gamma-frequency electroencephalography; neuroprosthetics; subdural grid
19.  Spatio-Temporal Information Analysis of Event-Related BOLD Responses 
NeuroImage  2006;34(4):1545-1561.
A new approach for analysis of event related fMRI (BOLD) signals is proposed. The technique is based on measures from information theory and is used both for spatial localization of task related activity, as well as for extracting temporal information regarding the task dependent propagation of activation across different brain regions. This approach enables whole brain visualization of voxels (areas) most involved in coding of a specific task condition, the time at which they are most informative about the condition, as well as their average amplitude at that preferred time. The approach does not require prior assumptions about the shape of the hemodynamic response function (HRF), nor about linear relations between BOLD response and presented stimuli (or task conditions). We show that relative delays between different brain regions can also be computed without prior knowledge of the experimental design, suggesting a general method that could be applied for analysis of differential time delays that occur during natural, uncontrolled conditions. Here we analyze BOLD signals recorded during performance of a motor learning task. We show that during motor learning, the BOLD response of unimodal motor cortical areas precedes the response in higher-order multimodal association areas, including posterior parietal cortex. Brain areas found to be associated with reduced activity during motor learning, predominantly in prefrontal brain regions, are informative about the task typically at significantly later times.
PMCID: PMC4028845  PMID: 17188515
Information theory; Hemodynamic response function; Model free analysis; fMRI; Motor learning
20.  Spatio-Temporal Dynamics of Neural Mechanisms Underlying Component Operations in Working Memory 
Brain research  2008;1206:61-75.
Neuroimaging and neurophysiology evidence suggests that component operations in working memory (WM) emerge from the coordinated interaction of posterior perceptual cortices with heteromodal regions in the prefrontal and parietal cortices. Still, little is known about bottom-up and top-down signaling during the formation and retrieval of WM representations. In the current set of experiments, we combine complementary fMRI and EEG measures to obtain high-resolution spatial and temporal measures of neural activity during WM encoding and retrieval processes. Across both experiments, participants performed a face delayed-recognition WM task in which the nature of sensory input across stages was held constant. In experiment 1, we utilized a latency-resolved fMRI approach to assess temporal parameters of the BOLD response during stage-specific encoding and retrieval waveforms. Relative to the latency at encoding, the PFC exhibited an earlier peak of fMRI activity at retrieval showing stage-specific differences in the temporal dynamics of PFC engagement across WM operations. In experiment 2, we analyzed the first 200ms of the ERP response during this WM task providing a more sensitive temporal measure of these differences. Divergence of the ERP pattern during encoding and retrieval began as early as 60ms post-stimulus. The parallel fMRI and ERP results during memory-guided decisions support a key role of the PFC in top-down biasing of perceptual processing and reveals rapid differences across WM component operations in the presence of identical bottom-up sensory input.
PMCID: PMC4026171  PMID: 18358455
21.  Temporal MRI Assessment of Intracerebral Hemorrhage in Rats 
Background and Purpose
MRI was used to evaluate the effects of experimental intracerebral hemorrhage (ICH) on brain tissue injury and recovery.
Primary ICH was induced in rats (n=6) by direct infusion of autologous blood into the striatum. The evolution of ICH damage was assessed by MRI estimates of T2 and T1sat relaxation times, cerebral blood flow, vascular permeability, and susceptibility-weighted imaging before surgery (baseline) and at 2 hours and 1, 7, and 14 days post-ICH. Behavioral testing was done before and at 1, 7, and 14 days post-ICH. Animals were euthanized for histology at 14 days.
The MRI appearance of the hemorrhage and surrounding regions changed in a consistent manner over time. Two primary regions of interest were identified based on T2 values. These included a core, corresponding to the bulk of the hemorrhage, and an adjacent rim; both varied with time. The core was associated with significantly lower cerebral blood flow values at all post-ICH time points, whereas cerebral blood flow varied in the rim. Increases in vascular permeability were noted at 1, 7, and 14 days. Changes in T1sat were similar to those of T2. MRI and histological estimates of tissue loss were well correlated and showed approximately 9% hemispheric tissue loss.
Although the cerebral blood flow changes observed with this ICH model may not exactly mimic the clinical situation, our results suggest that the evolution of ICH injury can be accurately characterized with MRI. These methods may be useful to evaluate therapeutic interventions after experimental ICH and eventually in humans.
PMCID: PMC3980853  PMID: 18635862
edema; intracerebral hemorrhage; MRI
22.  The role of the lateral prefrontal cortex in inhibitory motor control 
Research on inhibitory motor control has implicated several prefrontal as well as subcortical and parietal regions in response inhibition. Whether prefrontal regions are critical for inhibition, attention or task-set representation is still under debate. We investigated the influence of the lateral PFC in a response inhibition task by using cognitive electrophysiology in prefrontal lesion patients. Patients and age- and education-matched controls performed in a visual Stop-signal task featuring lateralized stimuli, designed to challenge either the intact or lesioned hemisphere. Participants also underwent a purely behavioral Go/Nogo task, which included a manipulation of inhibition difficulty (blocks with 50 vs. 80 % go-trials) and a Change-signal task that required switching to an alternative response. Patients and controls did not differ in their inhibitory speed (stop-signal and change-signal reaction time, SSRT and CSRT), but patients made more errors in the Go/Nogo task and showed more variable performance. The behavioral data stress the role of the PFC in maintaining inhibitory control but not in actual inhibition. These results support a dissociation between action cancellation and PFC- dependent action restraint. Laplacian transformed event-related potentials (ERPs) revealed reduced parietal activity in PFC patients in response to the stop-signals, and increased frontal activity over the intact hemisphere. This electrophysiological finding supports altered PFC- dependent visual processing of the stop-signal in parietal areas and compensatory activity in the intact frontal cortex. No group differences were found in the mu and beta decrease as measures of response preparation and inhibition at electrodes over sensorimotor cortex. Taken together, the data provide evidence for a central role of the lateral PFC in attentional control in the context of response inhibition.
PMCID: PMC3443703  PMID: 22699024
lateral PFC; lesion; SSRT; stop-signal task; cognitive control
23.  Intravenous Administration of Human Umbilical Cord Blood-Derived AC133+ Endothelial Progenitor Cells in Rat Stroke Model Reduces Infarct Volume: Magnetic Resonance Imaging and Histological Findings 
This study examined the effect of AC133+ endothelial progenitor cells derived from human umbilical cord blood on stroke development and resolution in a middle cerebral artery occlusion rat model. It was found that transplanted cells selectively migrated to the ischemic brain parenchyma, where they exerted a therapeutic effect on the extent of tissue damage, regeneration, and time course of stroke resolution.
Endothelial progenitor cells (EPCs) hold enormous therapeutic potential for ischemic vascular diseases. Previous studies have indicated that stem/progenitor cells derived from human umbilical cord blood (hUCB) improve functional recovery in stroke models. Here, we examined the effect of hUCB AC133+ EPCs on stroke development and resolution in a middle cerebral artery occlusion (MCAo) rat model. Since the success of cell therapies strongly depends on the ability to monitor in vivo the migration of transplanted cells, we also assessed the capacity of magnetic resonance imaging (MRI) to track in vivo the magnetically labeled cells that were administered. Animals were subjected to transient MCAo and 24 hours later injected intravenously with 107 hUCB AC133+ EPCs. MRI performed at days 1, 7, and 14 after the insult showed accumulation of transplanted cells in stroke-affected hemispheres and revealed that stroke volume decreased at a significantly higher rate in cell-treated animals. Immunohistochemistry analysis of brain tissues localized the administered cells in the stroke-affected hemispheres only and indicated that these cells may have significantly affected the magnitude of endogenous proliferation, angiogenesis, and neurogenesis. We conclude that transplanted cells selectively migrated to the ischemic brain parenchyma, where they exerted a therapeutic effect on the extent of tissue damage, regeneration, and time course of stroke resolution.
PMCID: PMC3754470  PMID: 23934909
Tissue regeneration; Stem/progenitor cell; Angiogenesis; Umbilical cord blood; Brain ischemia
24.  Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo 
Chinese Journal of Cancer  2014;33(3):148-158.
Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme (GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77 (baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation (n = 8), or underwent no radiation (n = 8). Brain tissues were obtained on day 112 (nonirradiated) or day 133 (irradiated). Immunohistochemistry was performed to determine tumor cell proliferation (Ki-67) and to assess the expression of infiltration marker (matrix metalloproteinase-2, MMP-2) and cell migration marker (CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor (vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was (71 ± 15)% compared with (25 ± 12)% in the nonirradiated group (P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM.
PMCID: PMC3966215  PMID: 24016393
Glioblastoma multiforme; radiation; treatment resistance; invasion
25.  Oscillatory Dynamics Track Motor Performance Improvement in Human Cortex 
PLoS ONE  2014;9(2):e89576.
Improving performance in motor skill acquisition is proposed to be supported by tuning of neural networks. To address this issue we investigated changes of phase-amplitude cross-frequency coupling (paCFC) in neuronal networks during motor performance improvement. We recorded intracranially from subdural electrodes (electrocorticogram; ECoG) from 6 patients who learned 3 distinct motor tasks requiring coordination of finger movements with an external cue (serial response task, auditory motor coordination task, go/no-go). Performance improved in all subjects and all tasks during the first block and plateaued in subsequent blocks. Performance improvement was paralled by increasing neural changes in the trial-to-trial paCFC between theta (; 4–8 Hz) phase and high gamma (HG; 80–180 Hz) amplitude. Electrodes showing this covariation pattern (Pearson's r ranging up to .45) were located contralateral to the limb performing the task and were observed predominantly in motor brain regions. We observed stable paCFC when task performance asymptoted. Our results indicate that motor performance improvement is accompanied by adjustments in the dynamics and topology of neuronal network interactions in the and HG range. The location of the involved electrodes suggests that oscillatory dynamics in motor cortices support performance improvement with practice.
PMCID: PMC3937444  PMID: 24586885

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