Differential Sources for 2 Neural Signatures of Target Detection: An Electrocorticography Study.

Electrophysiology and neuroimaging provide conflicting evidence for the neural contributions to target detection. Scalp electroencephalography (EEG) studies localize the P3b event-related potential component mainly to parietal cortex, whereas neuroimaging studies report activations in both frontal and parietal cortices. We addressed this discrepancy by examining the sources that generate the target-detection process using electrocorticography (ECoG). We recorded ECoG activity from cortex in 14 patients undergoing epilepsy monitoring, as they performed an auditory or visual target-detection task. We examined target-related responses in 2 domains: high frequency band (HFB) activity and the P3b. Across tasks, we observed a greater proportion of electrodes that showed target-specific HFB power relative to P3b over frontal cortex, but their proportions over parietal cortex were comparable. Notably, there was minimal overlap in the electrodes that showed target-specific HFB and P3b activity. These results revealed that the target-detection process is characterized by at least 2 different neural markers with distinct cortical distributions. Our findings suggest that separate neural mechanisms are driving the differential patterns of activity observed in scalp EEG and neuroimaging studies, with the P3b reflecting EEG findings and HFB activity reflecting neuroimaging findings, highlighting the notion that target detection is not a unitary phenomenon.

Ictal propagation of high frequency activity is recapitulated in interictal recordings: effective connectivity of epileptogenic networks recorded with intracranial EEG.

Seizures are increasingly understood to arise from epileptogenic networks across which ictal activity is propagated and sustained. In patients undergoing invasive monitoring for epilepsy surgery, high frequency oscillations have been observed within the seizure onset zone during both ictal and interictal intervals. We hypothesized that the patterns by which high frequency activity is propagated would help elucidate epileptogenic networks and thereby identify network nodes relevant for surgical planning. Intracranial EEG recordings were analyzed with a multivariate autoregressive modeling technique (short-time direct directed transfer function--SdDTF), based on the concept of Granger causality, to estimate the directionality and intensity of propagation of high frequency activity (70-175 Hz) during ictal and interictal recordings. These analyses revealed prominent divergence and convergence of high frequency activity propagation at sites identified by epileptologists as part of the ictal onset zone. In contrast, relatively little propagation of this activity was observed among the other analyzed sites. This pattern was observed in both subdural and depth electrode recordings of patients with focal ictal onset, but not in patients with a widely distributed ictal onset. In patients with focal ictal onsets, the patterns of propagation recorded during pre-ictal (up to 5 min immediately preceding ictal onset) and interictal (more than 24h before and after seizures) intervals were very similar to those recorded during seizures. The ability to characterize epileptogenic networks from interictal recordings could have important clinical implications for epilepsy surgery planning by reducing the need for prolonged invasive monitoring to record spontaneous seizures.

EEG analysis reveals widespread directed functional interactions related to a painful cutaneous laser stimulus.

During attention to a painful cutaneous laser stimulus, event-related causality (ERC) has been detected in recordings from subdural electrodes implanted directly over cortical modules for the treatment of epilepsy. However, these studies afforded limited sampling of modules and did not examine interactions with a nonpainful stimulus as a control. We now sample scalp EEG to test the hypothesis that attention to the laser stimulus is associated with poststimulus ERC interactions that are different from those with attention to a nonpainful stimulus. Subjects attended to (counted) either a painful laser stimulus (laser attention task) or a nonpainful electrical cutaneous stimulus that produced distraction from the laser (laser distraction task). Both of these stimuli were presented in random order in a single train. The intensities of both stimuli were adjusted to produce similar baseline salience and sensations in the same cutaneous territory. The results demonstrated that EEG channels with poststimulus ERC interactions were consistently different during the laser stimulus versus the electric stimulus. Poststimulus ERC interactions for the laser attention task were different from the laser distraction task. Furthermore, scalp EEG frontal channels play a driver role while parietal temporal channels play a receiver role during both tasks, although this does not prove that these channels are connected. Sites at which large numbers of ERC interactions were found for both laser attention and distraction tasks (critical sites) were located at Cz, Pz, and C3. Stimulation leading to disruption of sites of these pain-related interactions may produce analgesia for acute pain.

Reorganisation of cortical motor and language distribution in human brain.

BACKGROUND: The locations of cortex controlling motor, sensory, or language functions can change in adult humans under some circumstances, such as expanding tumours, trauma or continuous focal seizures. It is not clear what other circumstances might result in changes in cortical functional maps. METHODS: The results of extraoperative cortical mappings of motor, sensory, and language functions were compared in two epilepsy patients who underwent cortical resections on two separate occasions and who did not have brain tumours. RESULTS: It was found that the locations of motor functions could differ between the first and second procedures, but the locations of language functions were quite similar. The changes were not necessarily in or adjacent to epileptogenic regions or adjacent to resection boundaries. CONCLUSIONS: These findings support previous evidence indicating that cortical functional representations can change over time in humans, and suggest that these changes cannot be explained solely by lesion effects.

Analysis of synchrony demonstrates that the presence of "pain networks" prior to a noxious stimulus can enable the perception of pain in response to that stimulus.

Our previous study has shown that directed attention to a painful stimulus is associated with increased synchrony between electrocorticographic (ECoG) oscillations in pain-related cortical structures. We now test the hypothesis that the synchrony or functional connectivity of this pain network differs between events during which pain is or is not perceived (pain or non-pain events) in response to a noxious cutaneous laser stimulus. ECoG recordings were made through subdural electrodes implanted in a patient for the treatment of epilepsy. The patient was instructed that the stimulus could be painful or non-painful on any given presentation. Synchrony between ECoG signals at different sites was measured during the pre-stimulus interval, and the difference in the number of sites with significant pre-stimulus synchrony was compared between pain and non-pain events. Pre-stimulus synchrony was more common during pain versus non-pain events among electrodes overall, and in the subset of electrodes at which laser-evoked potentials (LEPs) were recorded. This difference between pain and non-pain events was also significant for the subset of electrodes over medial cortex, including anterior cingulate cortex (ACC), but not for subsets of electrodes over the superior and inferior convexity, including primary somatosensory (S1) and parasylvian cortex (PS), respectively. These results suggest that dynamic changes in the functional connectivity between ACC and other cortical regions enable the perception of pain in response to noxious stimuli.

Estimation of short-time cross-correlation between frequency bands of event related EEG.

Simultaneous variations of the event-related power changes (ERD/ERS) are often observed in a number of frequency bands. ERD/ERS measures are usually based on the relative changes of power in a given single frequency band. Within such an approach one cannot answer questions concerning the mutual relations between the band-power variations observed in different frequency bands. This paper addresses the problem of estimating and assessing the significance of the average cross-correlation between ERD/ERS phenomena occurring in two frequency bands. The cross-correlation function in a natural way also provides estimation of the delay between ERD/ERS in those bands. The proposed method is based on estimating the short-time cross-correlation function between relative changes of power in two selected frequency bands. The cross-correlation function is estimated in each trial separately and then averaged across trials. The significance of those mean cross-correlation functions is evaluated by means of a nonparametric test. The basic properties of the method are presented on simulated signals, and an example application to real EEG and ECoG signals is given.

Computationally efficient approaches to calculating significant ERD/ERS changes in the time-frequency plane.

This paper addresses some practical issues related to the calculation, display and assessment of the significance of changes in the average time-frequency energy density of event-related brain activity. Using scalp EEG and subdural ECoG example datasets, parametric tests are evaluated as a replacement for previously applied computer-intensive resampling methods. The performance of different estimates of energy density, based on matching pursuit, scalogram and spectrogram, and their Box-Cox transformations is evaluated with respect to the assumption of normality required for the t-test, and the consistency of the final results.

Severe tetanus in immunized patients with high anti-tetanus titers.

Severe (grade III) tetanus occurred in three immunized patients who had high serum levels of anti-tetanus antibody. The disease was fatal in one patient. One patient had been hyperimmunized to produce commercial tetanus immune globulin. Two patients had received immunizations 1 year before presentation. Anti-tetanus antibody titers on admission were 25 IU/ml to 0.15 IU/ml by hemagglutination and ELISA assays; greater than 0.01 IU/ml is considered protective. Even though one patient had seemingly adequate anti-tetanus titers by in vitro measurement (0.20 IU), in vivo mouse protection bioassays showed a titer less than 0.01 IU/ml, implying that there may have been a hole in her immune repertoire to tetanus neurotoxin but not to toxoid. This is the first report of grade III tetanus with protective levels of antibody in the United States. The diagnosis of tetanus, nevertheless, should not be discarded solely on the basis of seemingly protective anti-tetanus titers.

Electrocorticographic gamma activity during word production in spoken and sign language.

OBJECTIVE: To investigate the functional-neuroanatomic substrates of word production using signed versus spoken language. METHODS: The authors studied single-word processing with varying input and output modalities in a 38-year-old woman with normal hearing and speech who had become proficient in sign language 8 years before developing intractable epilepsy. Subdural electrocorticography (ECoG) was performed during picture naming and word reading (visual inputs) and word repetition (auditory inputs); these tasks were repeated with speech and with sign language responses. Cortical activation was indexed by event-related power augmentation in the 80- to 100-Hz gamma band, and was compared with general principles of functional anatomy and with subject-specific maps of the same or similar tasks using electrical cortical stimulation (ECS). RESULTS: Speech outputs activated tongue regions of the sensorimotor cortex, and sign outputs activated hand regions. In addition, signed word production activated parietal regions that were not activated by spoken word production. Posterior superior temporal gyrus was activated earliest and to the greatest extent during auditory word repetition, and the basal temporal-occipital cortex was activated similarly during naming and reading, reflecting the different modalities of input processing. With few exceptions, topographic patterns of ECoG gamma were consistent with ECS maps of the same or similar language tasks. CONCLUSIONS: Spoken and signed word production activated many of the same cortical regions, particularly those processing auditory and visual inputs; however, they activated different regions of sensorimotor cortex, and signing activated parietal cortex more than did speech. This study illustrates the utility of electrocorticographic gamma for studying the neuroanatomy and processing dynamics of human language.

Amplitudes of laser evoked potential recorded from primary somatosensory, parasylvian and medial frontal cortex are graded with stimulus intensity.

Intensity encoding of painful stimuli in many brain regions has been suggested by imaging studies which cannot measure electrical activity of the brain directly. We have now examined the effect of laser stimulus intensity (three energy levels) on laser evoked potentials (LEPs) recorded directly from the human primary somatosensory (SI), parasylvian, and medial frontal cortical surfaces through subdural electrodes implanted for surgical treatment of medically intractable epilepsy. LEP N2* (early exogenous/stimulus-related potential) and LEP P2** (later endogenous potential) amplitudes were significantly related to the laser energy levels in all regions, although differences between regions were not significant. Both LEP peaks were also significantly correlated with the pain intensity evoked by the laser stimulus, excepting N2* over the parasylvian region. Peak latencies of both LEP peaks were independent of laser energy levels. N2* and P2** amplitudes of the maxima in all regions showed significant positive linear correlations with laser energy, excepting N2* over the parasylvian region. The lack of correlation of parasylvian cortical N2* with laser energy and pain intensity may be due to the unique anatomy of this region, or the small sample, rather than the lack of activation by the laser. Differences in thresholds of the energy correlation with amplitudes were not significant between regions. These results suggest that both exogenous in endogenous potentials evoked by painful stimuli, and recorded over SI, parasylvian, and medial frontal cortex of awake humans, encode the intensity of painful stimuli and correlate with the pain evoked by painful stimuli.

Attention to a painful cutaneous laser stimulus modulates electrocorticographic event-related desynchronization in humans.

OBJECTIVE: To test the hypothesis that attention to painful cutaneous laser stimuli enhances event-related desynchronization (ERD) in cortical regions receiving nociceptive input. METHODS: We used wavelet time-frequency analysis and bandpass filtering to measure ERD quantitatively in subdural electrocorticographic recordings while subjects either attended to, or were distracted from, a painful cutaneous laser stimulus. RESULTS: ERD were observed over primary somatosensory and parasylvian (PS) cortices in all 4 subjects, and over medial frontal cortex in 1 subject. Laser-evoked potentials were also observed in all 3 regions. In all subjects, ERD was more widespread and intense, particularly over PS, during attention to laser stimuli (counting stimuli) than during distraction from the stimuli (reading for comprehension). CONCLUSIONS: These findings suggest that pain-associated ERD is modulated by attention, particularly over PS. SIGNIFICANCE: This study suggests that thalamocortical circuits are involved in attentional modulation of pain because of the proposed role of these circuits in the mechanisms of ERD.

Induced electrocorticographic gamma activity during auditory perception. Brazier Award-winning article, 2001.

OBJECTIVE: To define the spatial, temporal, and functional characteristics of induced gamma (>30 Hz) activity during functional activation of the left superior temporal gyrus. METHODS: Electrocorticographic (ECoG) recordings were made in 4 clinical subjects during auditory tone and phoneme discrimination tasks, and event-related changes in the ECoG band power were calculated. The topography and temporal sequence of event-related power changes in different gamma bands were contrasted with those of auditory evoked potentials (AEPs), and with those of event-related power changes in the alpha band (8-12 Hz). RESULTS: Auditory stimuli induced a broadband power augmentation that included 40 Hz, as well as higher (80-100 Hz) gamma frequencies. The topography of gamma augmentation was similar, but not identical, to that of the AEP, and was more focused than that of alpha power suppression. Its temporal onset coincided with the N100, but outlasted it. Phonemes produced greater gamma augmentation than tones, while a similar difference was not observed in the N100. CONCLUSIONS: Auditory perception induces ECoG gamma activity not only at 40 Hz, but also in higher gamma frequencies. This activity appears to be an index of cortical activation that reflects task-specific processing in the human auditory cortex more closely than the AEP or alpha power suppression.

Studies of properties of "Pain Networks" as predictors of targets of stimulation for treatment of pain.

Two decades of functional imaging studies have demonstrated pain-related activations of primary somatic sensory cortex (S1), parasylvian cortical structures (PS), and medial frontal cortical structures (MF), which are often described as modules in a "pain network." The directionality and temporal dynamics of interactions between and within the cortical and thalamic modules are uncertain. We now describe our studies of these interactions based upon recordings of local field potentials (LFPs) carried out in an epilepsy monitoring unit over the one week period between the implantation and removal of cortical electrodes during the surgical treatment of epilepsy. These recordings have unprecedented clarity and resolution for the study of LFPs related to the experimental pain induced by cutaneous application of a Thulium YAG laser. We also used attention and distraction as behavioral probes to study the psychophysics and neuroscience of the cortical "pain network." In these studies, electrical activation of cortex was measured by event-related desynchronization (ERD), over SI, PS, and MF modules, and was more widespread and intense while attending to painful stimuli than while being distracted from them. This difference was particularly prominent over PS. In addition, greater perceived intensity of painful stimuli was associated with more widespread and intense ERD. Connectivity of these modules was then examined for dynamic causal interactions within and between modules by using the Granger causality (GRC). Prior to the laser stimuli, a task involving attention to the painful stimulus consistently increased the number of event-related causality (ERC) pairs both within the SI cortex, and from SI upon PS (SI > PS). After the laser stimulus, attention to a painful stimulus increased the number of ERC pairs from SI > PS, and SI > MF, and within the SI module. LFP at some electrode sites (critical sites) exerted ERC influences upon signals at multiple widespread electrodes, both in other cortical modules and within the module where the critical site was located. In summary, critical sites and SI modules may bind the cortical modules together into a "pain network," and disruption of that network by stimulation might be used to treat pain. These results in humans may be uniquely useful to design and optimize anatomically based pain therapies, such as stimulation of the S1 or critical sites through transcutaneous magnetic fields or implanted electrodes.

Fear conditioning is associated with dynamic directed functional interactions between and within the human amygdala, hippocampus, and frontal lobe.

The current model of fear conditioning suggests that it is mediated through modules involving the amygdala (AMY), hippocampus (HIP), and frontal lobe (FL). We now test the hypothesis that habituation and acquisition stages of a fear conditioning protocol are characterized by different event-related causal interactions (ERCs) within and between these modules. The protocol used the painful cutaneous laser as the unconditioned stimulus and ERC was estimated by analysis of local field potentials recorded through electrodes implanted for investigation of epilepsy. During the prestimulus interval of the habituation stage FL>AMY ERC interactions were common. For comparison, in the poststimulus interval of the habituation stage, only a subdivision of the FL (dorsolateral prefrontal cortex, dlPFC) still exerted the FL>AMY ERC interaction (dlFC>AMY). For a further comparison, during the poststimulus interval of the acquisition stage, the dlPFC>AMY interaction persisted and an AMY>FL interaction appeared. In addition to these ERC interactions between modules, the results also show ERC interactions within modules. During the poststimulus interval, HIP>HIP ERC interactions were more common during acquisition, and deep hippocampal contacts exerted causal interactions on superficial contacts, possibly explained by connectivity between the perihippocampal gyrus and the HIP. During the prestimulus interval of the habituation stage, AMY>AMY ERC interactions were commonly found, while interactions between the deep and superficial AMY (indirect pathway) were independent of intervals and stages. These results suggest that the network subserving fear includes distributed or widespread modules, some of which are themselves "local networks." ERC interactions between and within modules can be either static or change dynamically across intervals or stages of fear conditioning.

Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus.

The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus. Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre-stimulus causal influence upon the hippocampus, consistent with an attention-related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala.

Intracranial mapping of auditory perception: event-related responses and electrocortical stimulation.

OBJECTIVE: We compared intracranial recordings of auditory event-related responses with electrocortical stimulation mapping (ESM) to determine their functional relationship. METHODS: Intracranial recordings and ESM were performed, using speech and tones, in adult epilepsy patients with subdural electrodes implanted over lateral left cortex. Evoked N1 responses and induced spectral power changes were obtained by trial averaging and time-frequency analysis. RESULTS: ESM impaired perception and comprehension of speech, not tones, at electrode sites in the posterior temporal lobe. There was high spatial concordance between ESM sites critical for speech perception and the largest spectral power (100% concordance) and N1 (83%) responses to speech. N1 responses showed good sensitivity (0.75) and specificity (0.82), but poor positive predictive value (0.32). Conversely, increased high-frequency power (>60Hz) showed high specificity (0.98), but poorer sensitivity (0.67) and positive predictive value (0.67). Stimulus-related differences were observed in the spatial-temporal patterns of event-related responses. CONCLUSIONS: Intracranial auditory event-related responses to speech were associated with cortical sites critical for auditory perception and comprehension of speech. SIGNIFICANCE: These results suggest that the distribution and magnitude of intracranial auditory event-related responses to speech reflect the functional significance of the underlying cortical regions and may be useful for pre-surgical functional mapping.

Transforming electrocortical mapping data into standardized common space.

Subdural grid electrodes are implanted routinely for the pre-surgical work up of epilepsy. While different approaches are available, many centers, including ours, visualize electrode locations by co-registering pre-operative 3-D MR images with post-implantation 3-D CT images. This method allows the determination of the electrode positions in relation to the individual patient's anatomy, but does not easily allow comparison across patients. The goal of this study was to develop and validate a method for transforming electrode positions derived from 3-D CT images into standardized space. We analyzed data from twelve patients with subdurally implanted electrodes. Volumetric CT and MRI images were co-registered and then normalized into common stereotactic space. Electrode locations were verified statistically by comparing distances between the anterior commissure and a representative sampling of 8 electrode sites per patient. Results confirm the accuracy of our co-registration method for comparing electrode locations across patients.

Analysis of synchrony demonstrates 'pain networks' defined by rapidly switching, task-specific, functional connectivity between pain-related cortical structures.

Imaging studies indicate that experimental pain is processed in multiple cortical areas which are often characterized as a network. However, the functional connectivity within the network and the other properties of the network is poorly understood. Substantial evidence demonstrates that synchronous oscillations between two cortical areas may indicate functional connectivity between those areas. We test the hypothesis that cortical areas with pain-related activity are functionally connected during attention to a painful stimulus. We stimulated with a painful, cutaneous, laser stimulus and recorded the response directly from the cortical surface (electrocorticography--ECoG) over primary somatosensory (SI), parasylvian (PS), and medial frontal (MF) cortex through subdural electrodes implanted for treatment of epilepsy. The results demonstrate synchrony of ECoGs between cortical structures receiving input from nociceptors, as indicated by the occurrence of laser-evoked potentials (LEPs) and/or event-related desynchronization (ERD). Prior to the stimulus, directed attention to the painful stimulus consistently increased the degree of synchrony between SI and PS regions, as the subject anticipated the stimulus. After the laser stimulus, directed attention to the painful stimulus consistently increased the degree of synchrony between SI and MF cortex, as the subject responded by counting the stimulus. Therefore, attention to painful stimuli always enhanced synchrony between cortical pain-related structures. The pattern of this synchrony changed as the patient switched tasks from anticipation of the stimulus to counting the stimulus. These results are the first compelling evidence of pain networks characterized by rapidly switching, task-specific functional connectivity.

Transient unilateral hearing loss induced by electrocortical stimulation.

A 32-year-old patient with seizures experienced decreased right-ear hearing during electrocortical stimulation mapping of the left lateral superior temporal gyrus. Audiometric testing under headphones confirmed a reversible, moderate unilateral hearing loss. Under binaural listening conditions, auditory comprehension was impaired at the same site, whereas word repetition, environmental sound recognition, naming, and spontaneous speech remained intact.