Data processing techniques impact quantification of cortico-cortical evoked potentials.

BACKGROUND: Cortico-cortical evoked potentials (CCEPs) are a common tool for probing effective connectivity in intracranial human electrophysiology. As with all human electrophysiology data, CCEP data are highly susceptible to noise. To address noise, filters and re-referencing are often applied to CCEP data, but different processing strategies are used from study to study. NEW METHOD: We systematically compare how common average re-referencing and filtering CCEP data impacts quantification. RESULTS: We show that common average re-referencing and filters, particularly filters that cut out more frequencies, can significantly impact the quantification of CCEP magnitude and morphology. We identify that high cutoff high pass filters (> 0.5 Hz), low cutoff low pass filters (< 200 Hz), and common average re-referencing impact quantification across subjects. However, we also demonstrate that the presence of noise may impact CCEP quantification, and preprocessing is necessary to mitigate this. We show that filtering is more effective than re-referencing or averaging across trials for reducing most common types of noise. COMPARISON WITH EXISTING METHODS: These results suggest that existing CCEP processing methods must be applied with care to maximize noise reduction and minimize changes to the data. We do not test every available processing strategy; rather we demonstrate that processing can influence the results of CCEP studies. We emphasize the importance of reporting all processing methods, particularly re-referencing methods. CONCLUSIONS: We propose a general framework for choosing an appropriate processing pipeline for CCEP data, taking into consideration the noise levels of a specific dataset. We suggest that minimal gentle filtering is preferable.

Post-operative seizure after first time endoscopic third ventriculostomy in pediatric patients.

PURPOSE: Post-operative seizure rates after endoscopic third ventriculostomy (ETV) are not definitively known. We analyzed our institution's experience for all causes of hydrocephalus in pediatric patients undergoing ETV to determine rates of post-ETV seizure. METHODS: A retrospective review of institutional pediatric patients undergoing ETV from May 2014 to December 2018. Included were < 21 years, with 1-year follow-up. Exclusion criteria included ventriculoperitoneal shunts (VPS) prior to ETV, VPS within 7 days post-ETV, and prior seizure disorder. Data included age, gender, diagnosis, early post-operative seizure (within 7 days post-ETV), late post-operative seizures (after first 7 days and within first year post-ETV), concomitant choroid plexus cauterization (CPC), VPS conversion within 1 year, and administration of prophylactic antiepileptics. RESULTS: Sixty of 81 ETV cases were included; 41% underwent concomitant CPC. Of these, 53% (n = 32) were male, 46% (n = 28) female, averaging 5.8 years, with the most common diagnosis neoplasm-related obstructive hydrocephalus (38.3%, n = 23). Early post-operative seizure occurred in 6.7% (n = 4); late post-operative seizure occurred in 8.3% (n = 5). Late post-operative seizures were higher in patients experiencing early post-operative seizure versus those without (75% vs 3.7%, p = 0.003). Late post-operative seizure occurred in 13.6% (n = 3 patients) requiring VPS versus 5.3% (n = 2 patients) with successful ETV (p = 0.36). Rates did not correlate with pathology. No patients received prophylactic antiepileptics prior to surgery or exhibiting a seizure. CONCLUSIONS: Patients with early post-operative seizures have an increased likelihood of developing late post-operative seizures. Pediatric ETV patients may have a lower rate of both early and late post-operative seizure; underlying pathology may influence these rates.

HCN Channel Phosphorylation Sites Mapped by Mass Spectrometry in Human Epilepsy Patients and in an Animal Model of Temporal Lobe Epilepsy.

Because hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels modulate the excitability of cortical and hippocampal principal neurons, these channels play a key role in the hyperexcitability that occurs during the development of epilepsy after a brain insult, or epileptogenesis. In epileptic rats generated by pilocarpine-induced status epilepticus, HCN channel activity is downregulated by two main mechanisms: a hyperpolarizing shift in gating and a decrease in amplitude of the current mediated by HCN channels, Ih. Because these mechanisms are modulated by various phosphorylation signaling pathways, we hypothesized that phosphorylation changes occur at individual HCN channel amino acid residues (phosphosites) during epileptogenesis. We collected CA1 hippocampal tissue from male Sprague Dawley rats made epileptic by pilocarpine-induced status epilepticus, and age-matched naïve controls. We also included resected human brain tissue containing epileptogenic zones (EZs) where seizures arise for comparison to our chronically epileptic rats. After enrichment for HCN1 and HCN2 isoforms by immunoprecipitation and trypsin in-gel digestion, the samples were analyzed by mass spectrometry. We identified numerous phosphosites from HCN1 and HCN2 channels, representing a novel survey of phosphorylation sites within HCN channels. We found high levels of HCN channel phosphosite homology between humans and rats. We also identified a novel HCN1 channel phosphosite S791, which underwent significantly increased phosphorylation during the chronic epilepsy stage. Heterologous expression of a phosphomimetic mutant, S791D, replicated a hyperpolarizing shift in Ih gating seen in neurons from chronically epileptic rats. These results show that HCN1 channel phosphorylation is altered in epilepsy and may be of pathogenic importance.

Signal recovery from stimulation artifacts in intracranial recordings with dictionary learning.

OBJECTIVE: Electrical stimulation of the human brain is commonly used for eliciting and inhibiting neural activity for clinical diagnostics, modifying abnormal neural circuit function for therapeutics, and interrogating cortical connectivity. However, recording electrical signals with concurrent stimulation results in dominant electrical artifacts that mask the neural signals of interest. Here we develop a method to reproducibly and robustly recover neural activity during concurrent stimulation. We concentrate on signal recovery across an array of electrodes without channel-wise fine-tuning of the algorithm. Our goal includes signal recovery with trains of stimulation pulses, since repeated, high-frequency pulses are often required to induce desired effects in both therapeutic and research domains. We have made all of our code and data publicly available. APPROACH: We developed an algorithm that automatically detects templates of artifacts across many channels of recording, creating a dictionary of learned templates using unsupervised clustering. The artifact template that best matches each individual artifact pulse is subtracted to recover the underlying activity. To assess the success of our method, we focus on whether it extracts physiologically interpretable signals from real recordings. MAIN RESULTS: We demonstrate our signal recovery approach on invasive electrophysiologic recordings from human subjects during stimulation. We show the recovery of meaningful neural signatures in both electrocorticographic (ECoG) arrays and deep brain stimulation (DBS) recordings. In addition, we compared cortical responses induced by the stimulation of primary somatosensory (S1) by natural peripheral touch, as well as motor cortex activity with and without concurrent S1 stimulation. SIGNIFICANCE: Our work will enable future advances in neural engineering with simultaneous stimulation and recording.

Concurrent control of a brain-computer interface and natural overt movements.

OBJECTIVE: A primary control signal in brain-computer interfaces (BCIs) have been cortical signals related to movement. However, in cases where natural motor function remains, BCI control signals may interfere with other possibly simultaneous activity for useful ongoing movement. We sought to determine if the brain could learn to control both a BCI and concurrent overt movement execution in such cases. APPROACH: We designed experiments where BCI and overt movements must be used concurrently and in coordination to achieve a 2D centre out control. Power in the 70-90 Hz band of human electrocorticography (ECoG) signals, was used to generate BCI control commands for vertical movement of the cursor. These signals were deliberately recorded from the same human cortical site that produced the strongest movement related activity associated with the concurrent overt finger movements required for the horizontal movement of the cursor. MAIN RESULTS: We demonstrate that three subjects were able to perform the concurrent BCI task, controlling BCI and natural movements simultaneously and to a large extent independently. We conclude that the brain is capable of dissociating the original control signal dependency on movement, producing specific BCI control signals in the presence of motor related responses from the ongoing overt behaviour with which the BCI signal was initially correlated. SIGNIFICANCE: We demonstrate a novel human brain-computer interface (BCI) which can be used to control movement concurrently and in coordination with movements of the natural limbs. This demonstrates the dissociation of cortical activity from the behaviour with which it was originally associated despite the ongoing behaviour and shows the feasibility of achieving simultaneous BCI control of devices with natural movements.

Local functional connectivity as a pre-surgical tool for seizure focus identification in non-lesion, focal epilepsy.

Successful resection of cortical tissue engendering seizure activity is efficacious for the treatment of refractory, focal epilepsy. The pre-operative localization of the seizure focus is therefore critical to yielding positive, post-operative outcomes. In a small proportion of focal epilepsy patients presenting with normal MRI, identification of the seizure focus is significantly more challenging. We examined the capacity of resting state functional MRI (rsfMRI) to identify the seizure focus in a group of four non-lesion, focal (NLF) epilepsy individuals. We predicted that computing patterns of local functional connectivity in and around the epileptogenic zone combined with a specific reference to the corresponding region within the contralateral hemisphere would reliably predict the location of the seizure focus. We first averaged voxel-wise regional homogeneity (ReHo) across regions of interest (ROIs) from a standardized, probabilistic atlas for each NLF subject as well as 16 age- and gender-matched controls. To examine contralateral effects, we computed a ratio of the mean pair-wise correlations of all voxels within a ROI with the corresponding contralateral region (IntraRegional Connectivity - IRC). For each subject, ROIs were ranked (from lowest to highest) on ReHo, IRC, and the mean of the two values. At the group level, we observed a significant decrease in the rank for ROI harboring the seizure focus for the ReHo rankings as well as for the mean rank. At the individual level, the seizure focus ReHo rank was within bottom 10% lowest ranked ROIs for all four NLF epilepsy patients and three out of the four for the IRC rankings. However, when the two ranks were combined (averaging across ReHo and IRC ranks and scalars), the seizure focus ROI was either the lowest or second lowest ranked ROI for three out of the four epilepsy subjects. This suggests that rsfMRI may serve as an adjunct pre-surgical tool, facilitating the identification of the seizure focus in focal epilepsy.

Direct electrical stimulation of the somatosensory cortex in humans using electrocorticography electrodes: a qualitative and quantitative report.

OBJECTIVE: Recently, electrocorticography-based brain-computer interfaces have been successfully used to translate cortical activity into control signals for external devices. However, the utility of such devices would be greatly enhanced by somatosensory feedback. Direct stimulation of somatosensory cortex evokes sensory perceptions, and is thus a promising option for closing the loop. Before this can be implemented in humans it is necessary to evaluate how changes in stimulus parameters are perceived and the extent to which they can be discriminated. APPROACH: Electrical stimulation was delivered to the somatosensory cortex of human subjects implanted with electrocorticography grids. Subjects were asked to discriminate between stimuli of different frequency and amplitude as well as to report the qualitative sensations elicited by the stimulation. MAIN RESULTS: In this study we show that in humans implanted with electrocorticography grids, variations in the amplitude or frequency of cortical electrical stimulation produce graded variations in percepts. Subjects were able to reliably distinguish between different stimuli. SIGNIFICANCE: These results indicate that direct cortical stimulation is a feasible option for sensory feedback with brain-computer interface devices.

Tract-based spatial statistical analysis of diffusion tensor imaging in pediatric patients with mitochondrial disease: widespread reduction in fractional anisotropy of white matter tracts.

BACKGROUND AND PURPOSE: Often diagnosed at birth or in early childhood, mitochondrial disease presents with a variety of clinical symptoms, particularly in organs and tissues that require high energetic demand such as brain, heart, liver, and skeletal muscles. In a group of pediatric patients identified as having complex I or I/III deficits on muscle biopsy but with white matter tissue appearing qualitatively normal for age, we hypothesized that quantitative DTI analyses might unmask disturbance in microstructural integrity. MATERIALS AND METHODS: In a retrospective study, DTI and structural MR brain imaging data from 10 pediatric patients with confirmed mitochondrial disease and 10 clinical control subjects were matched for age, sex, scanning parameters, and date of examination. Paired TBSS was performed to evaluate differences in FA, MD, and the separate diffusion direction terms (λr and λa). RESULTS: In patients with mitochondrial disease, significant widespread reductions in FA values were shown in white matter tracts. Mean diffusivity values were significantly increased in patients, having a sparser distribution of affected regions compared with FA. Separate diffusion maps showed significant increase in λr and no significant changes in λa. CONCLUSIONS: Despite qualitatively normal-appearing white matter tissues, patients with complex I or I/III deficiency have widespread microstructural changes measurable with quantitative DTI.

High gamma mapping using EEG.

High gamma (HG) power changes during motor activity, especially at frequencies above 70 Hz, play an important role in functional cortical mapping and as control signals for BCI (brain-computer interface) applications. Most studies of HG activity have used ECoG (electrocorticography) which provides high-quality spatially localized signals, but is an invasive method. Recent studies have shown that non-invasive modalities such as EEG and MEG can also detect task-related HG power changes. We show here that a 27 channel EEG (electroencephalography) montage provides high-quality spatially localized signals non-invasively for HG frequencies ranging from 83 to 101 Hz. We used a generic head model, a weighted minimum norm least squares (MNLS) inverse method, and a self-paced finger movement paradigm. The use of an inverse method enables us to map the EEG onto a generic cortex model. We find the HG activity during the task to be well localized in the contralateral motor area. We find HG power increases prior to finger movement, with average latencies of 462 ms and 82 ms before EMG (electromyogram) onset. We also find significant phase-locking between contra- and ipsilateral motor areas over a similar HG frequency range; here the synchronization onset precedes the EMG by 400 ms. We also compare our results to ECoG data from a similar paradigm and find EEG mapping and ECoG in good agreement. Our findings demonstrate that mapped EEG provides information on two important parameters for functional mapping and BCI which are usually only found in HG of ECoG signals: spatially localized power increases and bihemispheric phase-locking.

Decoding flexion of individual fingers using electrocorticographic signals in humans.

Brain signals can provide the basis for a non-muscular communication and control system, a brain-computer interface (BCI), for people with motor disabilities. A common approach to creating BCI devices is to decode kinematic parameters of movements using signals recorded by intracortical microelectrodes. Recent studies have shown that kinematic parameters of hand movements can also be accurately decoded from signals recorded by electrodes placed on the surface of the brain (electrocorticography (ECoG)). In the present study, we extend these results by demonstrating that it is also possible to decode the time course of the flexion of individual fingers using ECoG signals in humans, and by showing that these flexion time courses are highly specific to the moving finger. These results provide additional support for the hypothesis that ECoG could be the basis for powerful clinically practical BCI systems, and also indicate that ECoG is useful for studying cortical dynamics related to motor function.

Bi-phase locking - a tool for probing non-linear interaction in the human brain.

We present a novel method for detecting frequency-frequency coupling between the electrical output of cortical areas as measured by electrocorticography (ECoG), electroencephalography (EEG) and magnetoencephalography (MEG), the biphase-locking value (bPLV). Our method is an extension of the well known phase-locking value (PLV) and is specifically sensitive to non-linear interactions, i.e. quadratic phase coupling across frequencies. Due to its sensitivity to non-linear interactions, it is robust to spurious synchronization arising from linear crosstalk, which is an especially useful property when analyzing data recorded by EEG/MEG. We discuss the statistical properties of the bPLV, specifically the distribution of the bPLV under assumption of random phases between the signals of interest. We also compare the bPLV to the PLV for cortical interactions that are computed for simulated EEG/MEG data. These data were mapped to the cortex using an inverse solution. We demonstrate our method for event related ECoG data recorded from the motor cortex of an epileptic patient, who performed a cued finger movement task. We find highly significant, movement related increase of the bPLV between the alpha (12 Hz) and high gamma (77 Hz) band in a pre-motor area, coupling to high gamma at 89 Hz in the motor cortex.

Decoupling the cortical power spectrum reveals real-time representation of individual finger movements in humans.

During active movement the electric potentials measured from the surface of the motor cortex exhibit consistent modulation, revealing two distinguishable processes in the power spectrum. At frequencies <40 Hz, narrow-band power decreases occur with movement over widely distributed cortical areas, while at higher frequencies there are spatially more focal power increases. These high-frequency changes have commonly been assumed to reflect synchronous rhythms, analogous to lower-frequency phenomena, but it has recently been proposed that they reflect a broad-band spectral change across the entire spectrum, which could be obscured by synchronous rhythms at low frequencies. In 10 human subjects performing a finger movement task, we demonstrate that a principal component type of decomposition can naively separate low-frequency narrow-band rhythms from an asynchronous, broad-spectral, change at all frequencies between 5 and 200 Hz. This broad-spectral change exhibited spatially discrete representation for individual fingers and reproduced the temporal movement trajectories of different individual fingers.

Testing for nested oscillation.

Nested oscillation occurs when the amplitude of a faster rhythm is coupled to the phase of a slower rhythm. It has been proposed to underlie the discrete nature of perception and the capacity of working memory and is a phenomenon observable in human brain imaging data. This paper compares three published methods for detecting nested oscillation and a fourth method proposed in this paper. These are: (i) the modulation index, (ii) the phase-locking value (PLV), (iii) the envelope-to-signal correlation (ESC) and (iv) a general linear model (GLM) measure derived from ESC. We applied the methods to electrocorticographic (ECoG) data recorded during a working-memory task and to data from a simulated hippocampal interneuron network. Further simulations were then made to address the dependence of each measure on signal to noise level, coupling phase, epoch length, sample rate, signal nonstationarity, and multi-phasic coupling. Our overall conclusion is that the GLM measure is the best all-round approach for detecting nested oscillation.

Two-dimensional movement control using electrocorticographic signals in humans.

We show here that a brain-computer interface (BCI) using electrocorticographic activity (ECoG) and imagined or overt motor tasks enables humans to control a computer cursor in two dimensions. Over a brief training period of 12-36 min, each of five human subjects acquired substantial control of particular ECoG features recorded from several locations over the same hemisphere, and achieved average success rates of 53-73% in a two-dimensional four-target center-out task in which chance accuracy was 25%. Our results support the expectation that ECoG-based BCIs can combine high performance with technical and clinical practicality, and also indicate promising directions for further research.

Decoding two-dimensional movement trajectories using electrocorticographic signals in humans.

Signals from the brain could provide a non-muscular communication and control system, a brain-computer interface (BCI), for people who are severely paralyzed. A common BCI research strategy begins by decoding kinematic parameters from brain signals recorded during actual arm movement. It has been assumed that these parameters can be derived accurately only from signals recorded by intracortical microelectrodes, but the long-term stability of such electrodes is uncertain. The present study disproves this widespread assumption by showing in humans that kinematic parameters can also be decoded from signals recorded by subdural electrodes on the cortical surface (ECoG) with an accuracy comparable to that achieved in monkey studies using intracortical microelectrodes. A new ECoG feature labeled the local motor potential (LMP) provided the most information about movement. Furthermore, features displayed cosine tuning that has previously been described only for signals recorded within the brain. These results suggest that ECoG could be a more stable and less invasive alternative to intracortical electrodes for BCI systems, and could also prove useful in studies of motor function.

Evaluating functional MRI procedures for assessing hemispheric language dominance in neurosurgical patients.

Two methods of quantifying hemispheric language dominance (HLD) in neurosurgical patients are compared: (1) an average magnitudes (AM) method, which is a calculation of the average signal intensity variation in regions of interest for each patient that were predefined in a group analysis for each task, and (2) a lateralization indices (LI) method, which is based on the number of activated pixels in regions of interest predefined in each individual patient. Four language tasks [a living/nonliving (LNL) judgment, word stem completion (WSC), semantic associate (SA) and a phonological associate (PA) task] were compared with "gold standard" measures such as the Wada test or electrocortical stimulation. Results showed that the LI method was more accurate (73% agreement with gold standard methods) than the AM method (only 40% agreement) across tasks and subjects. Furthermore, by varying the threshold used for determining laterality, the ability of functional magnetic resonance imaging (fMRI) to predict HLD was influenced for the AM method, whereas the LI method was relatively unaffected by changing the threshold. Using the LI method, the SA task was the most accurate for quantifying HLD (100% agreement with gold standard methods) with respect to the other three language tasks (80% accuracy for WSC, 65% for the LNL and 63% for phonological task). Depending on the method and the task, fMRI may be a promising tool for assessing HLD in neurosurgical patients.

Pathophysiology of parkinsonism due to hydrocephalus.

We report a patient with hydrocephalus who developed levodopa responsive parkinsonism and severe bradyphrenia associated with shunt malfunction and revision. Magnetic resonance imaging revealed periaqueductal edema involving medial substantia nigra. [18F]dopa positron emission tomography demonstrated reduced uptake in the caudate and putamen with relative sparing of the posterior putamen. Hydrocephalus associated with shunt malfunction can cause a distinct parkinsonian syndrome with greater dysfunction of projections from the medial substantia nigra to anterior striatum than in idiopathic Parkinson's disease.

Functional MRI reveals an interhemispheric dissociation of frontal and temporal language regions in a patient with focal epilepsy.

We report the case of a patient with frontal lobe epilepsy in whom the Wada test failed to lateralize representation of language (fluent speech was observed after amobarbital injection on both the right and left side). Functional magnetic resonance imaging (fMRI) during a lexical processing task revealed an atypical organization of language represented by an interhemispheric dissociation of language regions with a right frontal dominance and a left temporal dominance. Consistent with the fMRI results, the patient's ability to name pictures was not reliably impaired by electrocortical stimulation (ECS) of left frontal cortex. The findings from Wada, fMRI, and ECS were confirmed by a lack of language impairment after left frontal lobectomy for seizures. This case illustrates that fMRI can precisely map cortical language networks in epileptic patients and that fMRI may be used to help interpret laterality results provided by the Wada procedure.

A critical analysis of 'normal' radionucleotide shuntograms in patients subsequently requiring surgery.

BACKGROUND: Shuntograms are performed when patients present with symptoms suggestive of, but inconclusive for, shunt malfunction, without confirmatory radiological evidence. METHODS: Shuntograms over the past 3.5 years were reviewed. Patient records were reviewed for revision in proximity to a negative (normal) study. RESULTS: One hundred and fifteen out of 149 tests were negative. Thirty-four surgeries (in 31 patients) occurred subsequent to a negative shuntogram. In 18 out of 34 revisions the shunt was functional: 13 surgeries were for overdrainage, 4 were for unrelated reasons with shunt function confirmed incidentally and 1 was an exploration for cognitive deterioration. In 16 cases (13 patients) the shunt was not functional: 12 had proximal catheter occlusion in which, on subsequent review, there was no ventricular reflux present and the remaining had distal malfunctions. CONCLUSIONS: The false negative rate for shuntograms was 16 out of 115 (14%) with proximal occlusion most common. This estimate of the predictive value of a normal flow study may influence the decision to revise a shunt.

Wada testing reveals frontal lateralization for the memorization of words and faces.

Neuroimaging studies have suggested that specific regions of the frontal and medial temporal cortex are engaged during memory formation. Further, there is specialization across these regions such that verbal materials appear to preferentially engage the left regions while nonverbal materials primarily engage the right regions. An open question, however, has been to what extent frontal regions contribute to successful memory formation. The present study investigates this question using a reversible lesion technique known as the Wada test. Patients memorized words and unfamiliar faces while portions of their left and right hemispheres were temporarily anesthetized with sodium amytal. Subsequent memory tests revealed that faces were remembered better than words following left-hemisphere anesthesia, whereas words were remembered better than faces following right-hemisphere anesthesia. Importantly, inspection of the circulation affected by the amytal further suggests that these memory impairments did not result from direct anesthetization of the medial temporal regions. Taken in the context of the imaging findings, these results suggest that frontal regions may also contribute to memory formation in normal performance.