Brain tumour microstructure is associated with post-surgical cognition.

Brain tumour microstructure is potentially predictive of changes following treatment to cognitive functions subserved by the functional networks in which they are embedded. To test this hypothesis, intra-tumoural microstructure was quantified from diffusion-weighted MRI to identify which tumour subregions (if any) had a greater impact on participants' cognitive recovery after surgical resection. Additionally, we studied the role of tumour microstructure in the functional interaction between the tumour and the rest of the brain. Sixteen patients (22-56 years, 7 females) with brain tumours located in or near speech-eloquent areas of the brain were included in the analyses. Two different approaches were adopted for tumour segmentation from a multishell diffusion MRI acquisition: the first used a two-dimensional four group partition of feature space, whilst the second used data-driven clustering with Gaussian mixture modelling. For each approach, we assessed the capability of tumour microstructure to predict participants' cognitive outcomes after surgery and the strength of association between the BOLD signal of individual tumour subregions and the global BOLD signal. With both methodologies, the volumes of partially overlapped subregions within the tumour significantly predicted cognitive decline in verbal skills after surgery. We also found that these particular subregions were among those that showed greater functional interaction with the unaffected cortex. Our results indicate that tumour microstructure measured by MRI multishell diffusion is associated with cognitive recovery after surgery.

Tumour-infiltrated cortex participates in large-scale cognitive circuits.

The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas.

High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks.

Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70-250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12-30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries.

Integrated neural dynamics for behavioural decisions and attentional competition in the prefrontal cortex.

In the behaving monkey, complex neural dynamics in the prefrontal cortex contribute to context-dependent decisions and attentional competition. We used demixed principal component analysis to track prefrontal activity dynamics in a cued target detection task. In this task, the animal combined identity of a visual object with a prior instruction cue to determine a target/nontarget decision. From population activity, we extracted principal components for each task feature and examined their time course and sensitivity to stimulus and task variations. For displays containing a single choice object in left or right hemifield, object identity, cue identity and decision were all encoded in population activity, with different dynamics and lateralisation. Object information peaked at 100-200 ms from display onset and was largely confined to the contralateral hemisphere. Cue information was weaker and present even prior to display onset. Integrating information from cue and object, decision information arose more slowly and was bilateral. Individual neurons contributed independently to coding of the three task features. The analysis was then extended to displays with a target in one hemifield and a competing distractor in the other. In this case, the data suggest that each hemisphere initially encoded the identity of the contralateral object. The distractor representation was then rapidly suppressed, with the final target decision again encoded bilaterally. The results show how information is coded along task-related dimensions while competition is resolved and suggest how information flows within and across frontal lobes to implement a learned behavioural decision.

Assessment of neuropsychological function in brain tumor treatment: a comparison of traditional neuropsychological assessment with app-based cognitive screening.

BACKGROUND: Gliomas are typically considered to cause relatively few neurological impairments. However, cognitive difficulties can arise, for example during treatment, with potential detrimental effects on quality of life. Accurate, reproducible, and accessible cognitive assessment is therefore vital in understanding the effects of both tumor and treatments. Our aim is to compare traditional neuropsychological assessment with an app-based cognitive screening tool in patients with glioma before and after surgical resection. Our hypotheses were that cognitive impairments would be apparent, even in a young and high functioning cohort, and that app-based cognitive screening would complement traditional neuropsychological assessment. METHODS: Seventeen patients with diffuse gliomas completed a traditional neuropsychological assessment and an app-based touchscreen tablet assessment pre- and post-operatively. The app assessment was also conducted at 3- and 12-month follow-up. Impairment rates, mean performance, and pre- and post-operative changes were compared using standardized Z-scores. RESULTS: Approximately 2-3 h of traditional assessment indicated an average of 2.88 cognitive impairments per patient, while the 30-min screen indicated 1.18. As might be expected, traditional assessment using multiple items across the difficulty range proved more sensitive than brief screening measures in areas such as memory and attention. However, the capacity of the screening app to capture reaction times enhanced its sensitivity, relative to traditional assessment, in the area of non-verbal function. Where there was overlap between the two assessments, for example digit span tasks, the results were broadly equivalent. CONCLUSIONS: Cognitive impairments were common in this sample and app-based screening complemented traditional neuropsychological assessment. Implications for clinical assessment and follow-up are discussed.

Memory recovery in relation to default mode network impairment and neurite density during brain tumor treatment.

OBJECTIVE: The aim of this study was to test brain tumor interactions with brain networks, thereby identifying protective features and risk factors for memory recovery after resection. METHODS: Seventeen patients with diffuse nonenhancing glioma (ages 22-56 years) underwent longitudinal MRI before and after surgery, and during a 12-month recovery period (47 MRI scans in total after exclusion). After each scanning session, a battery of memory tests was performed using a tablet-based screening tool, including free verbal memory, overall verbal memory, episodic memory, orientation, forward digit span, and backward digit span. Using structural MRI and neurite orientation dispersion and density imaging (NODDI) derived from diffusion-weighted images, the authors estimated lesion overlap and neurite density, respectively, with brain networks derived from normative data in healthy participants (somatomotor, dorsal attention, ventral attention, frontoparietal, and default mode network [DMN]). Linear mixed-effect models (LMMs) that regressed out the effect of age, gender, tumor grade, type of treatment, total lesion volume, and total neurite density were used to test the potential longitudinal associations between imaging markers and memory recovery. RESULTS: Memory recovery was not significantly associated with either the tumor location based on traditional lobe classification or the type of treatment received by patients (i.e., surgery alone or surgery with adjuvant chemoradiotherapy). Nonlocal effects of tumors were evident on neurite density, which was reduced not only within the tumor but also beyond the tumor boundary. In contrast, high preoperative neurite density outside the tumor but within the DMN was associated with better memory recovery (LMM, p value after false discovery rate correction [Pfdr] < 10-3). Furthermore, postoperative and follow-up neurite density within the DMN and frontoparietal network were also associated with memory recovery (LMM, Pfdr = 0.014 and Pfdr = 0.001, respectively). Preoperative tumor and postoperative lesion overlap with the DMN showed a significant negative association with memory recovery (LMM, Pfdr = 0.002 and Pfdr < 10-4, respectively). CONCLUSIONS: Imaging biomarkers of cognitive recovery and decline can be identified using NODDI and resting-state networks. Brain tumors and their corresponding treatment affecting brain networks that are fundamental for memory functioning such as the DMN can have a major impact on patients' memory recovery.

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients' Recovery.

Predicting functional outcomes after surgery and early adjuvant treatment is difficult due to the complex, extended, interlocking brain networks that underpin cognition. The aim of this study was to test glioma functional interactions with the rest of the brain, thereby identifying the risk factors of cognitive recovery or deterioration. Seventeen patients with diffuse non-enhancing glioma (aged 22-56 years) were longitudinally MRI scanned and cognitively assessed before and after surgery and during a 12-month recovery period (55 MRI scans in total after exclusions). We initially found, and then replicated in an independent dataset, that the spatial correlation pattern between regional and global BOLD signals (also known as global signal topography) was associated with tumour occurrence. We then estimated the coupling between the BOLD signal from within the tumour and the signal extracted from different brain tissues. We observed that the normative global signal topography is reorganised in glioma patients during the recovery period. Moreover, we found that the BOLD signal within the tumour and lesioned brain was coupled with the global signal and that this coupling was associated with cognitive recovery. Nevertheless, patients did not show any apparent disruption of functional connectivity within canonical functional networks. Understanding how tumour infiltration and coupling are related to patients' recovery represents a major step forward in prognostic development.

Reward motivation increases univariate activity but has limited effect on coding of task-relevant information across the frontoparietal cortex.

Selection and integration of information based on current goals is fundamental for goal-directed behavior. Reward motivation has been shown to improve behavioral performance, yet the neural mechanisms that link motivation and control processes, and in particular its effect on context-dependent information processing, remain unclear. We used functional magnetic resonance imaging (fMRI) in 24 human volunteers (13 females) to test whether reward motivation enhances the coding of task-relevant information across the frontoparietal cortex, as would be predicted based on previous experimental evidence and theoretical accounts. In a cued target detection task, participants detected whether an object from a cued visual category was present in a subsequent display. The combination of the cue and the object visual category determined the behavioral status of the objects. To manipulate reward motivation, half of all trials offered the possibility of a monetary reward. We observed an increase with reward in overall univariate activity across the frontoparietal control network when the cue and subsequent object were presented. Multivariate pattern analysis (MVPA) showed that behavioral status information for the objects was conveyed across the network. However, in contrast to our prediction, reward did not increase the discrimination between behavioral status conditions in the stimulus epoch of a trial when object information was processed depending on a current context. In the high-level general-object visual region, the lateral occipital complex, the representation of behavioral status was driven by visual differences and was not modulated by reward. Our study provides useful evidence for the limited effects of reward motivation on task-related neural representations and highlights the necessity to unravel the diverse forms and extent of these effects.

Intraoperative mapping of executive function using electrocorticography for patients with low-grade gliomas.

BACKGROUND: Intraoperative functional mapping with direct electrical stimulation during awake surgery for patients with diffuse low-grade glioma has been used in recent years to optimize the balance between surgical resection and quality of life following surgery. Mapping of executive functions is particularly challenging because of their complex nature, with only a handful of reports published so far. Here, we propose the recording of neural activity directly from the surface of the brain using electrocorticography to map executive functions and demonstrate its feasibility and potential utility. METHODS: To track a neural signature of executive function, we recorded neural activity using electrocorticography during awake surgery from the frontal cortex of three patients judged to have an appearance of diffuse low-grade glioma. Based on existing functional magnetic resonance imaging (fMRI) evidence from healthy participants for the recruitment of areas associated with executive function with increased task demands, we employed a task difficulty manipulation in two counting tasks performed intraoperatively. Following surgery, the data were extracted and analyzed offline to identify increases in broadband high-gamma power with increased task difficulty, equivalent to fMRI findings, as a signature of activity related to executive function. RESULTS: All three patients performed the tasks well. Data were recorded from five electrode strips, resulting in data from 15 channels overall. Eleven out of the 15 channels (73.3%) showed significant increases in high-gamma power with increased task difficulty, 26.6% of the channels (4/15) showed no change in power, and none of the channels showed power decrease. High-gamma power increases with increased task difficulty were more likely in areas that are within the canonical frontoparietal network template. CONCLUSIONS: These results are the first step toward developing electrocorticography as a tool for mapping of executive function complementarily to direct electrical stimulation to guide resection. Further studies are required to establish this approach for clinical use.

Individual-subject Functional Localization Increases Univariate Activation but Not Multivariate Pattern Discriminability in the "Multiple-demand" Frontoparietal Network.

The frontoparietal "multiple-demand" (MD) control network plays a key role in goal-directed behavior. Recent developments of multivoxel pattern analysis (MVPA) for fMRI data allow for more fine-grained investigations into the functionality and properties of brain systems. In particular, MVPA in the MD network was used to gain better understanding of control processes such as attentional effects, adaptive coding, and representation of multiple task-relevant features, but overall low decoding levels have limited its use for this network. A common practice of applying MVPA is by investigating pattern discriminability within a ROI using a template mask, thus ensuring that the same brain areas are studied in all participants. This approach offers high sensitivity but does not take into account differences between individuals in the spatial organization of brain regions. An alternative approach uses independent localizer data for each subject to select the most responsive voxels and define individual ROIs within the boundaries of a group template. Such an approach allows for a refined and targeted localization based on the unique pattern of activity of individual subjects while ensuring that functionally similar brain regions are studied for all subjects. In the current study, we tested whether using individual ROIs leads to changes in decodability of task-related neural representations as well as univariate activity across the MD network compared with when using a group template. We used three localizer tasks to separately define subject-specific ROIs: spatial working memory, verbal working memory, and a Stroop task. We then systematically assessed univariate and multivariate results in a separate rule-based criterion task. All the localizer tasks robustly recruited the MD network and evoked highly reliable activity patterns in individual subjects. Consistent with previous studies, we found a clear benefit of the subject-specific ROIs for univariate results from the criterion task, with increased activity in the individual ROIs based on the localizers' data, compared with the activity observed when using the group template. In contrast, there was no benefit of the subject-specific ROIs for the multivariate results in the form of increased discriminability, as well as no cost of reduced discriminability. Both univariate and multivariate results were similar in the subject-specific ROIs defined by each of the three localizers. Our results provide important empirical evidence for researchers in the field of cognitive control for the use of individual ROIs in the frontoparietal network for both univariate and multivariate analysis of fMRI data and serve as another step toward standardization and increased comparability across studies.

Practical Application of Networks in Neurosurgery: Combined 3-Dimensional Printing, Neuronavigation, and Preoperative Surgical Planning.

BACKGROUND: A plethora of cutting-edge neuroimaging analyses have been developed and published, yet they have not hitherto been realized as improvements in neurosurgical outcomes. In this paper we propose a novel interface between neuroimaging and neurosurgery for aiding translational research. Our objective is to create a method for applying advanced neuroimaging and network analysis findings to neurosurgery and illustrate its application through the presentation of 2 detailed case vignettes. METHODS: This interface comprises a combination of network visualization, 3-dimensional printing, and ex-vivo neuronavigation to enable preoperative planning according to functional neuroanatomy. Clinical cases were selected from a prospective cohort study. RESULTS: The first case vignette describes a low-grade glioma with potential language and executive function network involvement that underwent a successful complete resection of the lesion with preservation of network features. The second case describes a low-grade glioma in an apparently noneloquent location that underwent a subtotal resection but demonstrated unexpected and significant impairment in executive function postoperatively that subsequently abated during follow-up. In both examples the neuroimaging and network data highlight the complexity of the surrounding functional neuroanatomy at the individual level, beyond that which can be perceived on standard structural sequences. CONCLUSIONS: The described interface has widespread applications for translational research including preoperative planning, neurosurgical training, and detailed patient counseling. A protocol for assessing its effectiveness and safety is proposed. Finally, recommendations for effective translation of findings from neuroimaging to neurosurgery are discussed, with the aim of making clinically meaningful improvements to neurosurgical practice.

Progressive Recruitment of the Frontoparietal Multiple-demand System with Increased Task Complexity, Time Pressure, and Reward.

A distributed, frontoparietal "multiple-demand" (MD) network is involved in tasks of many different kinds. Integrated activity across this network may be needed to bind together the multiple features of a mental control program (Duncan, 2013). Previous data suggest that, especially with low cognitive load, there may be some differentiation between MD regions (e.g., anterior vs. posterior regions of lateral frontal cortex), but with increasing load, there is progressive recruitment of the entire network. Differentiation may reflect preferential access to different task features, whereas co-recruitment may reflect information exchange and integration. To examine these patterns, we used manipulations of complexity, time pressure, and reward while participants solved a spatial maze. Complexity was manipulated by combining two simple tasks. Time pressure was added by fading away the maze during route planning, and on some of these trials, there was the further possibility of a substantial reward. Simple tasks evoked activity only in posterior MD regions, including posterior lateral frontal cortex, pre-supplementary motor area/anterior cingulate, and intraparietal sulcus. With increasing complexity, time pressure, and reward, increases in activity were broadly distributed across the MD network, though with quantitative variations. Across the MD network, the results show a degree of functional differentiation, especially at low load, but strong co-recruitment with increased challenge or incentive.

An Integrated Neural Framework for Dynamic and Static Face Processing.

Faces convey rich information including identity, gender and expression. Current neural models of face processing suggest a dissociation between the processing of invariant facial aspects such as identity and gender, that engage the fusiform face area (FFA) and the processing of changeable aspects, such as expression and eye gaze, that engage the posterior superior temporal sulcus face area (pSTS-FA). Recent studies report a second dissociation within this network such that the pSTS-FA, but not the FFA, shows much stronger response to dynamic than static faces. The aim of the current study was to test a unified model that accounts for these two functional characteristics of the neural face network. In an fMRI experiment, we presented static and dynamic faces while subjects judged an invariant (gender) or a changeable facial aspect (expression). We found that the pSTS-FA was more engaged in processing dynamic than static faces and changeable than invariant aspects, whereas the OFA and FFA showed similar response across all four conditions. These findings support an integrated neural model of face processing in which the ventral areas extract form information from both invariant and changeable facial aspects whereas the dorsal face areas are sensitive to dynamic and changeable facial aspects.

Beta oscillations in the parkinsonian primate: Similar oscillations across different populations.

Parkinson's disease (PD) is characterized by excessive beta band oscillations (BBO) in neuronal spiking activity across basal ganglia (BG) nuclei. High frequency stimulation of the subthalamic nucleus, an effective treatment for PD, suppresses these oscillations. There is still a heated debate on the origin and propagation of BBO and their association to clinical symptoms. The key prerequisite in addressing these issues is to obtain an accurate estimation of the subpopulation of oscillatory neurons and the magnitude of their oscillations. Studies have shown that neurons in different BG nuclei vary dramatically in the magnitude of their oscillations. However, the stochastic nature of neuronal activity subsamples the oscillatory neuronal rate functions, thus causing standard spectral analysis methods to be dramatically biased by biological and experimental factors such as variations in the neuronal firing rate across BG nuclei. In order to overcome these biases, and directly analyze the expression of BBO within BG nuclei, we used a novel objective method, the modulation index. This method reveals that unlike previous spectral results, individual neurons in the different nuclei display similar magnitudes of oscillations, whereas only the size of the oscillatory subpopulation varies between nuclei. During stimulation, the magnitude of the BBO does not change but the fraction of oscillatory neurons decreases in the globus pallidus internus, leading to a significant change in BG output. This non-biased oscillation quantification thus enables the reconstruction of oscillations at the single neuron and nuclei population levels, and calls for a reassessment of the role of BBO during PD.

Discrimination of Visual Categories Based on Behavioral Relevance in Widespread Regions of Frontoparietal Cortex.

Allocating attentional resources to currently relevant information in a dynamically changing environment is critical to goal-directed behavior. Previous studies in nonhuman primates (NHPs) have demonstrated modulation of neural representations of stimuli, in particular visual categorizations, by behavioral significance in the lateral prefrontal cortex. In the human brain, a network of frontal and parietal regions, the "multiple demand" (MD) system, is involved in cognitive and attentional control. To test for the effect of behavioral significance on categorical discrimination in the MD system in humans, we adapted a previously used task in the NHP and used multivoxel pattern analysis for fMRI data. In a cued-detection categorization task, participants detected whether an image from one of two target visual categories was present in a display. Our results revealed that categorical discrimination is modulated by behavioral relevance, as measured by the distributed pattern of response across the MD network. Distinctions between categories with different behavioral status (e.g., a target and a nontarget) were significantly discriminated. Category distinctions that were not behaviorally relevant (e.g., between two targets) were not discriminated. Other aspects of the task that were orthogonal to the behavioral decision did not modulate categorical discrimination. In a high visual region, the lateral occipital complex, modulation by behavioral relevance was evident in its posterior subregion but not in the anterior subregion. The results are consistent with the view of the MD system as involved in top-down attentional and cognitive control by selective coding of task-relevant discriminations. Significance statement: Control of cognitive demands fundamentally involves flexible allocation of attentional resources depending on a current behavioral context. Essential to such a mechanism is the ability to select currently relevant information and at the same time filter out information that is irrelevant. In an fMRI study, we measured distributed patterns of activity for objects from different visual categories while manipulating the behavioral relevance of the categorical distinctions. In a network of frontal and parietal cortical regions, the multiple-demand (MD) network, patterns reflected category distinctions that were relevant to behavior. Patterns could not be used to make task-irrelevant category distinctions. These findings demonstrate the ability of the MD network to implement complex goal-directed behavior by focused attention.

Clutter modulates the representation of target objects in the human occipitotemporal cortex.

Target objects required for goal-directed behavior are typically embedded within multiple irrelevant objects that may interfere with their encoding. Most neuroimaging studies of high-level visual cortex have examined the representation of isolated objects, and therefore, little is known about how surrounding objects influence the neural representation of target objects. To investigate the effect of different types of clutter on the distributed responses to target objects in high-level visual areas, we used fMRI and manipulated the type of clutter. Specifically, target objects (i.e., a face and a house) were presented either in isolation, in the presence of a homogeneous (identical objects from another category) clutter ("pop-out" display), or in the presence of a heterogeneous (different objects) clutter, while participants performed a target identification task. Using multivoxel pattern analysis (MVPA) we found that in the posterior fusiform object area a heterogeneous but not homogeneous clutter interfered with decoding of the target objects. Furthermore, multivoxel patterns evoked by isolated objects were more similar to multivoxel patterns evoked by homogenous compared with heterogeneous clutter in the lateral occipital and posterior fusiform object areas. Interestingly, there was no effect of clutter on the neural representation of the target objects in their category-selective areas, such as the fusiform face area and the parahippocampal place area. Our findings show that the variation among irrelevant surrounding objects influences the neural representation of target objects in the object general area, but not in object category-selective cortex, where the representation of target objects is invariant to their surroundings.

Dispersed activity during passive movement in the globus pallidus of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primate.

Parkinson's disease is a neurodegenerative disorder manifesting in debilitating motor symptoms. This disorder is characterized by abnormal activity throughout the cortico-basal ganglia loop at both the single neuron and network levels. Previous neurophysiological studies have suggested that the encoding of movement in the parkinsonian state involves correlated activity and synchronized firing patterns. In this study, we used multi-electrode recordings to directly explore the activity of neurons from the globus pallidus of parkinsonian primates during passive limb movements and to determine the extent to which they interact and synchronize. The vast majority (80/103) of the recorded pallidal neurons responded to periodic flexion-extension movements of the elbow. The response pattern was sinusoidal-like and the timing of the peak response of the neurons was uniformly distributed around the movement cycle. The interaction between the neuronal activities was analyzed for 123 simultaneously recorded pairs of neurons. Movement-based signal correlation values were diverse and their mean was not significantly different from zero, demonstrating that the neurons were not activated synchronously in response to movement. Additionally, the difference in the peak responses phase of pairs of neurons was uniformly distributed, showing their independent firing relative to the movement cycle. Our results indicate that despite the widely distributed activity in the globus pallidus of the parkinsonian primate, movement encoding is dispersed and independent rather than correlated and synchronized, thus contradicting current views that posit synchronous activation during Parkinson's disease.

Bicuculline-induced chorea manifests in focal rather than globalized abnormalities in the activation of the external and internal globus pallidus.

Chorea is a basal-ganglia (BG) related hyperkinetic movement disorder characterized by irregular continuous involuntary movements. Chorea and related hyperbehavioral disorders may be induced in behaving primates by local microinjections of the GABA(A) antagonist bicuculline to the globus pallidus externus (GPe). We performed multielectrode extracellular recordings in the GPe and in the globus pallidus internus (GPi) before, during, and after bicuculline microinjections. Bicuculline led to an increase in the firing rate and a change in the firing pattern of GPe neurons. Two types of abnormal neuronal firing patterns were detected in GPe neurons close to the bicuculline microinjection site: continuous high-frequency activity and bistable activity, in which neurons transitioned between high-frequency and complete cessation of firing. Neuronal activity remained uncorrelated within and between the GPe and the GPi, with no evidence for propagation of the focal GPe abnormal activity downstream to the GPi. Despite reduction in the information capacity of bicuculline-affected GPe neurons, the ability to encode behavioral events was maintained. We found similar responses of GPe neurons to bicuculline in vitro in the rat, suggesting a basic cellular mechanism underlying these abnormal firing patterns. These results demonstrate that chorea is associated with focal neuronal changes that are not complemented by global changes in the BG nuclei. This suggests a mechanism of stochastic phasic alteration of BG control leading to the chaotic nature of chorea. Thus rather than imposing a globalized state of cortical excitability, chorea might be associated with changes in internal information processing within the BG.

Generalized framework for stimulus artifact removal.

Stimulation is extensively used in neuroscience research in diverse fields ranging from cognitive to clinical. Studying the effect of electrical and magnetic stimulation on neuronal activity is complicated by large stimulation-derived artifacts on the recording electrodes, which mask the spiking activity. Multiple studies have suggested a variety of solutions for the removal of artifacts and were typically directed at specific stimulation setups. In this study we introduce a generalized framework for stimulus artifacts removal, the Stimulus Artifact Removal Graphical Environment (SARGE). The framework provides an encapsulated environment for a multi-stage removal process, starting from the stimulus pulse detection, through estimation of the artifacts and their removal, and finally to signal reconstruction and the assessment of removal quality. The framework provides the user with subjective graphical and objective quantitative tools for assessing the resulting signal, and the ability to adjust the process to optimize the results. This extendable publicly available framework supports different types of stimulation, stimulation patterns and shapes, and a variety of artifact estimation methods. We exemplify the removal of artifacts generated by electrical micro- and macro-stimulation and magnetic stimulation and different stimulation protocols. The use of different estimation methods, such as averaging and function fitting is demonstrated, and the differences between them are discussed. Finally, the quality of removal is assessed and validated using quantitative measures and combined experimental-simulation studies. The framework marks a shift from "algorithm" and "data" centric approach to a "workflow" centric approach, thus introducing an innovative concept to the artifact removal process.

Short-term depression of synaptic transmission during stimulation in the globus pallidus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates.

High-frequency stimulation (HFS) in the globus pallidus is used to ameliorate clinical symptoms of Parkinson's disease, dystonia, and other disorders. Previous in vivo studies have shown diverse static effects of stimulation on discharge rates and firing patterns of neurons along the corticobasal ganglia loop. In vitro studies, together with other experimental and theoretical studies, have suggested the involvement of synaptic plasticity in stimulation effects. To explore the effects of HFS on synaptic transmission, we studied the dynamic changes in neuronal activity in vivo, using multielectrode recordings during stimulation in the globus pallidus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates. Stimulation effects evolved over time and were pronounced during the first 10 s of stimulation, where 69% of the 249 recorded neurons changed their firing rate and 61% displayed time-locked firing. The time-locked response faded away in 43% of the responding neurons, and its pattern was altered in the remaining cells: the peak response shifted away in time from the stimulus onset, and its amplitude decreased. Repetition of the stimulation protocol revealed a full resetting of the effect, implying short-term synaptic depression. This evolving response is indicative of the transient plasticity of the corticobasal ganglia network in vivo during HFS. Therefore, short-term depression of synaptic transmission may contribute to the mechanism underlying the effects of stimulation during the resulting steady state, altering the balance of neuronal interactions and interfering with pathological information transmission.