Characterizing neuronal firing patterns in the human brain.

A procedure to characterize firing patterns of neuron spikes from the human brain, in both temporal domain and the frequency domain, is presented. The combination of multitaper spectral estimation and the polynomial curve-fitting method is employed to transform the firing patterns to the frequency domain. To generate temporal shapes, eight local maxima are smoothly connected by cubic spline interpolation. We then used a rotated principal component analysis, which removes the orthogonality constraints of traditional PCA, to extract common firing patterns as templates from around 4100 neuron spike signals. Dynamic time warping was used to assign each neuron firings into the closest template without shift error. This technique can be utilized for finding firing similarities in neuroscience applications and in development of a query system.

Atypical speech is rare in individuals with normal developmental histories.

The prevalence of atypical (right, bilateral) speech lateralization is unknown in normal populations. The authors investigated this by studying people with normal developmental histories but a later, specific adult neurologic event leading to intractable epilepsy. Fifty of 836 people receiving intracarotid amobarbital procedures (IAPs) met criteria of normal neurologic histories through age 15 years, with later head trauma or cerebral infection as probable cause of subsequent epilepsy. All 50 patients had left hemispheric speech on IAP. Atypical speech lateralization is rare unless there is also a positive neurologic history.

Anatomic subdivisions in human temporal cortical neuronal activity related to recent verbal memory.

We identified functional anatomical subdivisions of human lateral and basal temporal cortex related to recent verbal memory for object names, text and auditory words. Extracellular neuronal activity was recorded during memory encoding compared to identification, during encoding, storage or recall retrieval stages of the memory task, during recognition memory, and during implicit memory as measured by repetition priming. Changes in frequency of activity during encoding were recorded from most neurons. In lateral temporal cortex, these encoding changes in the dominant hemisphere were more likely to be polymodal, whereas those in nondominant hemisphere were unimodal. There was substantial separation of neurons with changes in other aspects of memory, defining additional subdivisions. Inferior lateral and basal cortex were related to memory stages, and superior-posterior lateral cortex was related to implicit and recognition memory.

Changes in power and coherence of brain activity in human sensorimotor cortex during performance of visuomotor tasks.

Electrocorticograms (ECoG) were recorded using subdural grid electrodes in forearm sensorimotor cortex of six human subjects. The subjects performed three visuomotor tasks, tracking a moving visual target with a joystick-controlled cursor; threading pieces of tubing; and pinching the fingers sequentially against the thumb. Control conditions were resting and active wrist extension. ECoGs were recorded at 14 sites in hand- and arm-sensorimotor area, functionally identified with electrical stimulation. For each behavior we computed spectral power of ECoG in each site and coherence in all pair-wise sites. In three out of six subjects, gamma-oscillations were observed when the subjects started the tasks. All subjects showed widespread power decrease in the range of 11-20 Hz and power increase in the 31-60 Hz ranges during performance of the visuomotor tasks. The changes in gamma-range power were more vigorous during the tracking and threading tasks compared with the wrist extension. Coherence analysis also showed similar task-related changes in coherence estimates. In contrast to the power changes, coherence estimates increased not only in gamma-range but also at lower frequencies during the manipulative visuomotor tasks. Paired sites with significant increases in coherence estimates were located within and between sensory and motor areas. These results support the hypothesis that coherent cortical activity may play a role in sensorimotor integration or attention.

Is the left cerebral hemisphere more prone to epileptogenesis than the right?

PURPOSE: To determine if there is evidence that the left cerebral hemisphere is more prone to epileptogenesis than the right hemisphere. METHODS: We examined 532 patients with localization-related epilepsy, as documented by long-term EEG-video monitor studies. We identified those with interictal epileptiform patterns on EEG confined to one hemisphere, those with clinical seizures that arose only from one side, and individuals with neuropsychological deficits lateralizing more to one cerebral hemisphere than the other. These data were then related to the handedness of the subjects. RESULTS: For left-handed patients, interictal discharges were significantly more likely to be confined to the left side, seizures more frequently arose from only the left hemisphere, and neuropsychological deficits lateralized more often to the left brain. In contrast, for right-handed subjects, there were no significant differences in unilateral localization of either interictal discharges or of seizure onsets, nor did neuropsychological deficits lateralize more often to one side or the other. Although, as a group, left-handers had an earlier age of onset of epilepsy than right-handers, the lateralizing EEG and neuropsychological patterns seen in left-handers were not related to age of onset of epilepsy, febrile seizures, family history of either epilepsy or left-handedness, or other risk factors. CONCLUSION: In localization-related epilepsy, there is a significant association of left-handedness with left hemispheric lateralization of epileptiform EEG patterns and neuropsychological deficits. These findings do not clearly reflect a greater left than right cerebral hemispheric vulnerability to epileptogenesis, except possibly in left-handers.

Temporal lobe epilepsy -current wisdom.

Issues related to resective surgery for patients with medically refractory temporal lobe epilepsy (TLE) who have mesial temporal sclerosis (MTS), those with normal imaging, and the related issue of those at risk for verbal memory deficits are discussed.

Interictal, unifocal spikes in refractory extratemporal epilepsy predict ictal origin and postsurgical outcome.

OBJECTIVES: To evaluate the significance of exclusively unifocal, unilateral, interictal epileptiform patterns on scalp electroencephalography (EEG) in surgical candidates with medically intractable extratemporal epilepsy. METHODS: We reviewed 126 patients with refractory extratemporal partial seizures who underwent epilepsy surgery at our center. All were followed for at least 2 years after resections. Surgery was based on ictal EEG recordings. We examined ictal onsets and surgical outcome in subjects whose preoperative, interictal scalp EEGs during long-term monitoring (LTM) demonstrated only unilateral, well-defined focal discharges, and outcome in patients whose interictal EEGs during LTM showed bilateral, non-localized, or multifocal epileptiform patterns. RESULTS: We found that 26 subjects exhibited only unilateral, unifocal, interictal epileptiform patterns. In all 26 cases (100%) clinical seizures arose from the regions expected by the interictal findings (P<0.0001, Sign test). At last follow-up 77% (20/26) of these patients were seizure-free, while 23% (6/26) had >75% reduction in seizures. This compares to the remaining patients, of whom 34% (34/100) were seizure-free, 41% (41/100) had >75% reduction in seizures, and 25% (25/100) had <75% reduction in seizures (P=0.0001, Fisher's Exact test). CONCLUSIONS: Strictly unifocal, interictal epileptiform patterns on scalp EEG, though seen in a minority of subjects, may be an important, independent factor in evaluating subjects with intractable extratemporal, localization-related epilepsy for surgical therapy. This finding is highly predictive of both ictal onsets and successful postsurgical outcome.

Asymmetry of neuronal activity during extracellular microelectrode recording from left and right human temporal lobe neocortex during rhyming and line-matching.

Recordings of neuronal activity in humans have identified few correlates of the known hemispheric asymmetries of functional lateralization. Here, we examine single-unit activity recorded from both hemispheres during two delayed match-to-sample tasks that show strong hemispheric lateralization based on lesion effects; a line-matching (LM) task related to the right hemisphere, and a rhyming (RHY) task related to the left. Nineteen neuronal populations were recorded with extracellular microelectrodes from the left temporal neocortex of 11 awake patients, and 18 from the right in 9 patients during anterior temporal lobectomy for complex partial seizures under local anesthesia. All subjects were left hemisphere dominant for language. Twelve (32%) populations exhibited statistically significant changes in activity at p <.05. Although changes in firing frequency were recorded from both hemispheres during both tasks, the RHY task elicited changes in activity several hundred milliseconds earlier on the left side than on the right. The LM task, on the other hand, induced changes earlier on the right side than on the left. Both hemispheres contained units active during verbal responses regardless of which behavior elicited the response. Our results indicate that cerebral dominance is reflected in earlier neuronal activity in the anterior temporal lobe during tasks lateralized to that hemisphere.

Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI.

Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.

Intraoperative hippocampal electrocorticography to predict the extent of hippocampal resection in temporal lobe epilepsy surgery.

OBJECT: Among the variety of surgical procedures that are performed for the treatment of medically refractory mesial temporal lobe epilepsy (TLE), no consensus exists as to how much of the hippocampus should be removed. Whether all patients require a maximal hippocampal resection has not yet been determined. METHODS: At the University of Washington, all TLE operations are performed in a tailored fashion, guided by electrocorticography (ECoG). The amount of hippocampal resection is determined intraoperatively by the extent of interictal epileptiform abnormalities on ECoG recorded from that structure, resulting in a hippocampal resection that is individualized for each patient. Using this approach, the authors prospectively observed 140 consecutive patients who underwent surgery for mesial TLE with pathological diagnoses of either mesial temporal sclerosis with neuronal loss (MTS group) or mild gliosis without neuronal loss (non-MTS group) to determine whether the extent of hippocampal resection correlates with outcome when a tailored approach is used. Additionally, the authors analyzed whether the presence of residual interictal epileptiform activity on ECoG following mesial temporal resection predicts poorer seizure control. With at least 18 months of clinical follow up, 67% of the 140 patients were seizure free or had only a single postoperative seizure. There was no correlation between the size of the hippocampal resection and seizure control in the group as a whole or when stratified by pathological subtype. Using an intraoperatively tailored strategy, individuals with a larger hippocampal resection (> 2.5 cm) were not more likely to have seizure-free outcomes than patients with smaller resections (p = 0.9). Additionally, both MTS and non-MTS patients, in whom postoperative ECoG detected residual epileptiform hippocampal (but not cortical or parahippocampal) interictal activity following surgical resection, had significantly worse seizure outcomes (p = 0.01 in the MTS group; p = 0.002 in the non-MTS group). CONCLUSIONS: Intraoperative hippocampal ECoG can predict how much hippocampus should be removed to maximize seizure-free outcome, allowing for sparing of possibly functionally important hippocampus.

The role of the human thalamus in language and memory: evidence from electrophysiological studies.

The data reviewed here indicate that electrical stimulation of the dominant ventrolateral thalamus can produce deficits in language processing that are not seen after similar stimulation of the nondominant ventrolateral thalamus. The nature of the language deficit produced varies, depending upon the rostrocaudal location of the stimulation site. Stimulation of the anterior left ventrolateral thalamus in right-handed patients resulted in production of a repeated erroneous word, stimulation of the medial ventrolateral thalamus evoked perseveration, and stimulation of the posterior ventrolateral thalamus and anterior pulvinar resulted in misnaming and omissions. Additional studies have examined the effect of electrical thalamic stimulation on verbal and nonverbal short-term memory. Left (but not right) ventrolateral thalamic stimulation during verbal memory input greatly decreased subsequent recall errors, while stimulation during verbal memory retrieval increased recall errors. This finding contrasted with those obtained from studies on nonverbal memory, in which right ventrolateral stimulation during memory input decreased recall errors, while left thalamic stimulation at the same stage increased recall errors. Left pulvinar stimulation disrupted verbal memory processing, while right pulvinar stimulation disrupted nonverbal memory processing. Limited evidence suggests that the effects of thalamic electrical stimulation on verbal memory may persist for several days after the stimulation has ended. The lateralization of thalamic functions also affects the motoric aspects of speech production. Left (but not right) ventrolateral thalamic stimulation disrupted speech articulation and increased the expiratory phase of respiration. The fact that these motor effects were evoked from the same general area of the thalamus that produced the language deficits discussed above raises the possibility that the thalamus is involved in coordinating the cognitive and motoric aspects of language production. A model of thalamic function is discussed in which defined regions of the thalamus operate as a "specific alerting response," increasing the input to memory of category-specific material while simultaneously inhibiting retrieval from memory.

Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients.

Changes in the subunit stoichiometry of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) alters its channel properties, and may enhance or reduce neuronal excitability in temporal lobe epilepsy patients. This study determined whether hippocampal NMDA receptor subunit mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsy cases. Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. These findings indicate that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A-D hybridization densities that vary by subfield and clinical-pathological category. In temporal lobe epilepsy patients, these findings support the hypothesis that in dentate granule cells NMDA receptors are increased, and excitatory postsynaptic potentials should be strongly NMDA mediated compared with nonseizure autopsies. HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases.

Activity of neurons in human temporal cortex during identification and memory for names and words.

Extracellular recordings of human temporal cortical neuronal activity during identification and memory for object names or words were obtained from 31 neurons at 18 sites in 12 left language dominant patients undergoing left (10) or right (2) awake craniotomy for epilepsy under local anesthesia. Frequency of activity during identification was compared with perceptual controls, that during the encoding phase of recent memory to identification of the same material. Statistically significant changes in one or more temporal epoch (p < 0.005) of one or more comparisons were present for 27 of the 31 neurons in either hemisphere. Few neurons changed activity in the same direction for both words and names. The instruction to retain an item in recent memory changed activity in most neurons from that during identification of the same material, although the items presented were identical and overtly identified in each task. Any individual neuron usually changed activity in one direction for only one task. There are separate, widely distributed neural networks for identification or recent memory for each type of material. The majority of nearby neurons recorded through the same extracellular microelectrode were related to the networks for different tasks. The temporal characteristics of these changes were also investigated; 31% of the changes were "phasic": temporally related to presentation or response to the item. Most of the remaining neuron changes were sustained throughout a task, often for several minutes. These task-specific sustained changes may reflect effects of thalamo-cortical attentional systems. Individual neurons had both sustained and phasic changes to different tasks.

Increased gamma-range activity in human sensorimotor cortex during performance of visuomotor tasks.

OBJECTIVE: We documented changes in spectral power of human electrocorticograms (ECoG) during performance of sensorimotor tasks. METHODS: In 6 human subjects, ECoGs were recorded simultaneously from 14 subdural cortical sites in forearm sensorimotor cortex. The subjects performed 3 visuomotor tasks: tracking a moving visual target with a joystick-controlled cursor, threading pieces of tubing, and pinching the fingers sequentially against the thumb. Control conditions consisted of passive resting and active extension of the wrist. For each site the spectral power of the ECoG during these behaviors was computed for 5 10 Hz ranges between 10 and 60 Hz. RESULTS: All subjects showed power decreases in the range of 11-20 Hz and power increases in the 31-60 Hz range during performance of the visuomotor tasks, at sites in forearm sensorimotor cortex and adjacent areas. Simple wrist movements often produced little change in power. Three subjects showed episodes of explicit gamma oscillations during the visuomotor tasks. Different sites showed increases in gamma-range power for different tasks, indicating that the spatial distribution of the gamma activity is specific to the tasks. Cross-spectra showed that gamma activity could become synchronized between separate sites during particular tasks. CONCLUSIONS: Synchronized gamma-range activity in human sensorimotor cortex increases with performance of manipulative visuomotor tasks, supporting the hypothesis that coherent gamma oscillations may play a role in sensorimotor integration or attention.

Predicting outcome following reoperation for medically intractable epilepsy.

The purpose of this study was to determine predictors of probable outcome following reoperation for medically intractable partial epilepsy. We reviewed outcome at least 1 year after reoperation in 21 patients with intractable seizures, for whom an earlier operation had failed. We examined age of onset of epilepsy, duration of seizures, gender, details of the history and clinical examination, pre-operative magnetic resonance (MRI) findings, electroencephalographic (EEG) studies obtained before and after the failed surgery, presence or absence of lateralizing neuro-psychological deficits, sites of operation and pathology of resected tissue to identify the factors associated with outcome. We found two factors that were significantly related to outcome: (1) no individual with a history of central nervous system (CNS) infection which predated the onset of epilepsy had a seizure-free outcome after reoperation (P = 0.04). (2) Reoperations that extended previous resections, based on new ictal EEG recordings that were concordant with both EEG ictal onsets and MRI findings obtained before the first, failed surgery resulted in a seizure-free outcome or >95% reduction in seizures for 100% (7/7) of such patients. This compares to 29% (4/14) of the remaining individuals without such concordance who had a similar outcome (P = 0.009). Site of operation (temporal or extratemporal) did not, in and of itself, predict outcome. A portion of patients who fail surgery for intractable partial seizures will achieve significant improvement following reoperation. Furthermore, we may be able to identify those individuals most likely to have an excellent result from a second operation.

Hippocampal or neocortical lesions on magnetic resonance imaging do not necessarily indicate site of ictal onsets in partial epilepsy.

Advances in neuroimaging techniques, particularly high-resolution magnetic resonance imaging (MRI), have proved invaluable in identifying structural brain lesions in patients with epilepsy. The assumption that such focal lesions invariably predict the site of seizure origin may not be correct, however. We report a series of 20 adults with medically intractable partial epilepsy, where high-resolution brain MRI disclosed a unilateral, focal, hippocampal, or neocortical lesion as the only abnormality in each case; nevertheless, based on electroencephalographic (EEG) recordings, ictal onsets arose from a completely different location than that of the MRI lesion. All patients underwent epilepsy surgery, with the operations based on ictal EEG findings, and all were followed at least 2 years after the resection. After the most recent follow-up examination, 50% (10/20) of the patients were completely seizure-free, 35% (7/20) had at least a 75% reduction in the number of seizures, and 15% (3/20) had less than a 75% reduction in the number of seizures. We conclude that the identification of a focal, structural, hippocampal, or neocortical lesion on brain MRI is not always indicative of the site of seizure origin in partial epilepsy. Furthermore, in cases of discordance between MRI and EEG data, a good outcome after epilepsy surgery is possible if EEG ictal onsets are definitive.

Ictal patterns of neocortical seizures monitored with intracranial electrodes: correlation with surgical outcome.

PURPOSE: Numerous factors have been analyzed in attempts to predict the outcome of surgical resections in patients with neocortical epilepsy. We examined the correlation between surgical outcome and electrocorticographic features of neocortical ictal patterns. METHODS: Twenty six patients with neocortical epilepsy underwent monitoring with subdural grid electrodes before surgery. Ictal patterns were analyzed retrospectively and correlated with three types of outcome: seizure free, worthwhile improvement (>75% reduction of seizure frequency), and no worthwhile improvement. The duration of follow-up was 2-5 years. RESULTS: Ictal patterns were divided according to the size of epileptogenic zone (focal, regional, multifocal); velocity and type of seizure propagation (fast contiguous, slow contiguous, noncontiguous); pattern of the onset of ictal activity; part of the cortex involved in the origin of the seizure (frontal, frontocentroparietal, etc.). Spread to medial temporal structures (as assessed by subtemporal strips) also was evaluated in selected cases. Statistically significant correlation with surgical outcome (p = 0.026) was shown for only one variable: type of spread. Patients with slow spread (n = 8) demonstrated the best outcomes (five are seizure free), whereas patients with noncontiguous spread (n = 5) demonstrated the worst outcomes (four did not improve significantly). Patients with fast contiguous spread (n = 13) showed intermediate outcomes. CONCLUSIONS: Types of propagation of ictal neocortical activity correlate with surgical outcome. Analysis of ictal pattern during intracranial recordings may help to predict surgical outcome for neocortical epilepsy.

Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy.

OBJECTIVE: Sodium-coupled transporters remove extracellular neurotransmitters and alterations in their function could enhance or suppress synaptic transmission and seizures. This study determined hippocampal gamma-aminobutyric acid (GABA) and glutamate transporter immunoreactivity (IR) in temporal lobe epilepsy (TLE) patients. METHODS: Hippocampal sclerosis (HS) patients (n = 25) and non-HS cases (mass lesion and cryptogenic; n = 20) were compared with nonseizure autopsies (n = 8). Hippocampal sections were studied for neuron densities along with IR for glutamate decarboxylase (GAD; presynaptic GABA terminals), GABA transporter-1 (GAT-1; presynaptic GABA transporter), GAT-3 (astrocytic GABA transporter), excitatory amino acid transporter 3 (EAAT3; postsynaptic glutamate transporter), and EAAT2-1 (glial glutamate transporters). RESULTS: Compared with autopsies, non-HS cases with similar neuron counts showed: 1) increased GAD IR gray values (GV) in the fascia dentata outer molecular layer (OML), hilus, and stratum radiatum; 2) increased GAT-1 OML GVs; 3) increased astrocytic GAT-3 GVs in the hilus and Ammon's horn; and 4) no IR differences for EAAT3-1. HS patients with decreased neuron densities demonstrated: 1) increased OML and inner molecular layer GAD puncta; 2) decreased GAT-1 puncta relative to GAD in the stratum granulosum and pyramidale; 3) increased GAT-1 OML GVs; 4) decreased GAT-3 GVs; 5) increased EAAT3 IR on remaining granule cells and pyramids; 6) decreased glial EAAT2 GVs in the hilus and CA1 stratum radiatum associated with neuron loss; and 7) increased glial EAAT1 GVs in CA2/3 stratum radiatum. CONCLUSIONS: Hippocampal GABA and glutamate transporter IR differ in TLE patients compared with autopsies. These data support the hypothesis that excitatory and inhibitory neurotransmission and seizure susceptibility could be altered by neuronal and glial transporters in TLE patients.