Nicholas M. Barbaro

High Gamma Power Is Phase-Locked to Theta Oscillations in Human Neocortex

We observed robust coupling between the high- and low-frequency bands of ongoing electrical activity in the human brain. In particular, the phase of the low-frequency theta (4 to 8 hertz) rhythm modulates power in the high gamma (80 to 150 hertz) band of the electrocorticogram, with stronger modulation occurring at higher theta amplitudes. Furthermore, different behavioral tasks evoke distinct patterns of theta/high gamma coupling across the cortex. The results indicate that transient coupling between low- and high-frequency brain rhythms coordinates activity in distributed cortical areas, providing a mechanism for effective communication during cognitive processing in humans.

Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.

The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.

MDR1 Gene Expression in Brain of Patients with Medically Intractable Epilepsy

Summary: Why some patients with seizures are successfully treated with antiepileptic drugs (AEDs) and others prove medically intractable is not known. Inadequate intraparenchymal drug concentration is a possible mechanism of resistance to AEDs. The multiple drug resistance gene (MDRI) encodes P‐glycoprotein, an energy‐dependent efflux pump that exports planar hydrophobic molecules from the cell. If P‐glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are exported by P‐glycoprotein, lower intraparenchymal drug concentrations could contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels > 10 times greater than those in normal brain, as determined by quantitative reverse transcriptase‐polymerase chain reaction (RT‐PCR) method. Immunohistochemistry for P‐glycoprotein from 14 of the patients showed increased staining in capillary endothelium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRNA levels, expression of P‐glycoprotein in astrocytes also was identified. Last, steady‐state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1‐negative cells. MDR1 expression is increased in brain of some patients with medically intractable epilepsy, suggesting that the patients’ lack of response to medication may be caused by inadequate accumulation of AED in brain.

Seizure characteristics and control following resection in 332 patients with low-grade gliomas.

OBJECT Seizures play an important role in the clinical presentation and postoperative quality of life of patients who undergo surgical resection of low-grade gliomas (LGGs). The aim of this study was to identify factors that influenced perioperative seizure characteristics and postoperative seizure control. METHODS The authors performed a retrospective chart review of all cases involving adult patients who underwent initial surgery for LGGs at the University of California, San Francisco between 1997 and 2003. RESULTS Three hundred and thirty-two cases were included for analysis; 269 (81%) of the 332 patients presented with >or=1 seizures (generalized alone, 33%; complex partial alone, 16%; simple partial alone, 22%; and combination, 29%). Cortical location and oligodendroglioma and oligoastrocytoma subtypes were significantly more likely to be associated with seizures compared with deeper midline locations and astrocytoma, respectively (p=0.017 and 0.001, respectively; multivariate analysis). Of the 269 patients with seizures, 132 (49%) had pharmacoresistant seizures before surgery. In these patients, seizures were more likely to be simple partial and to involve the temporal lobe, and the period from seizure onset to surgery was likely to have been longer (p=0.0005, 0.0089, and 0.006, respectively; multivariate analysis). For the cohort of patients that presented with seizures, 12-month outcome after surgery (Engel class) was as follows: seizure free (I), 67%; rare seizures (II), 17%; meaningful seizure improvement (III), 8%; and no improvement or worsening (IV), 9%. Poor seizure control was more common in patients with longer seizure history (p<0.001) and simple partial seizures (p=0.004). With respect to treatment-related variables, seizure control was far more likely to be achieved after gross-total resection than after subtotal resection/biopsy alone (odds ratio 16, 95% confidence interval 2.2-124, p=0.0064). Seizure recurrence after initial postoperative seizure control was associated with tumor progression (p=0.001). CONCLUSIONS The majority of patients with LGG present with seizures; in approximately half of these patients, the seizures are pharmacoresistant before surgery. Postoperatively, >90% of these patients are seizure free or have meaningful improvement. A shorter history of seizures and gross-total resection appear to be associated with a favorable prognosis for seizure control.

Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy.

Neurogenesis in the hippocampal dentate gyrus persists throughout life and is increased by seizures. The dentate granule cell (DGC) layer is often abnormal in human and experimental temporal lobe epilepsy, with dispersion of the layer and the appearance of ectopic granule neurons in the hilus. We tested the hypothesis that these abnormalities result from aberrant DGC neurogenesis after seizure‐induced injury. Bromodeoxyuridine labeling, in situ hybridization, and immunohistochemistry were used to identify proliferating progenitors and mature DGCs in the adult rat pilocarpine temporal lobe epilepsy model. We also examined dentate gyri from epileptic human hippocampal surgical specimens. Prox‐1 immunohistochemistry and pulse‐chase bromodeoxyuridine labeling showed that progenitors migrate aberrantly to the hilus and molecular layer after prolonged seizures and differentiate into ectopic DGCs in rat. Neuroblast marker expression indicated the delayed appearance of chainlike progenitor cell formations extending into the hilus and molecular layer, suggesting that seizures alter migratory behavior of DGC precursors. Ectopic putative DGCs also were found in the hilus and molecular layer of epileptic human dentate gyrus. These findings indicate that seizure‐induced abnormalities of neuroblast migration lead to abnormal integration of newborn DGCs in the epileptic adult hippocampus, and implicate aberrant neurogenesis in the development or progression of recurrent seizures. Ann Neurol 2005

Radiation therapy in the treatment of partially resected meningiomas

To address the question of whether radiation therapy is beneficial in the management of partially resected meningiomas, we reviewed the records of all patients admitted to the University of California, San Francisco, between 1968 and 1978 who had a diagnosis of intracranial meningioma. The patients were divided into three groups: 51 patients had gross total resection and did not receive radiation therapy, 30 patients had subtotal resection and no radiation therapy, and 54 patients had subtotal resection followed by radiation therapy. The subtotal resection groups were similar in average age, male:female ratio, and tumor location, which allowed a valid comparison of the effects of irradiation. The recurrence rate in the total resection group was 4% (2 of 51 patients). Among patients in the subtotal resection groups, 60% of nonirradiated patients had a recurrence, compared with only 32% of the irradiated patients. The median time to recurrence was significantly longer in the irradiated group than in the nonirradiated group (125 vs. 66 months, P less than 0.05). There was no complication related to irradiation. These results provide convincing evidence that radiation therapy is beneficial in the treatment of partially resected meningiomas.

Categorical speech representation in human superior temporal gyrus

Speech perception requires the rapid and effortless extraction of meaningful phonetic information from a highly variable acoustic signal. A powerful example of this phenomenon is categorical speech perception, in which a continuum of acoustically varying sounds is transformed into perceptually distinct phoneme categories. We found that the neural representation of speech sounds is categorically organized in the human posterior superior temporal gyrus. Using intracranial high-density cortical surface arrays, we found that listening to synthesized speech stimuli varying in small and acoustically equal steps evoked distinct and invariant cortical population response patterns that were organized by their sensitivities to critical acoustic features. Phonetic category boundaries were similar between neurometric and psychometric functions. Although speech-sound responses were distributed, spatially discrete cortical loci were found to underlie specific phonetic discrimination. Our results provide direct evidence for acoustic-to–higher order phonetic level encoding of speech sounds in human language receptive cortex.

Five-dimensional neuroimaging : localization of the time–frequency dynamics of cortical activity

The spatiotemporal dynamics of cortical oscillations across human brain regions remain poorly understood because of a lack of adequately validated methods for reconstructing such activity from noninvasive electrophysiological data. In this paper, we present a novel adaptive spatial filtering algorithm optimized for robust source time-frequency reconstruction from magnetoencephalography (MEG) and electroencephalography (EEG) data. The efficacy of the method is demonstrated with simulated sources and is also applied to real MEG data from a self-paced finger movement task. The algorithm reliably reveals modulations both in the beta band (12-30 Hz) and high gamma band (65-90 Hz) in sensorimotor cortex. The performance is validated by both across-subjects statistical comparisons and by intracranial electrocorticography (ECoG) data from two epilepsy patients. Interestingly, we also reliably observed high frequency activity (30-300 Hz) in the cerebellum, although with variable locations and frequencies across subjects. The proposed algorithm is highly parallelizable and runs efficiently on modern high-performance computing clusters. This method enables the ultimate promise of MEG and EEG for five-dimensional imaging of space, time, and frequency activity in the brain and renders it applicable for widespread studies of human cortical dynamics during cognition.

Hyperalgesia during Naloxone-Precipitated Withdrawal from Morphine Is Associated with Increased On-Cell Activity in the Rostral Ventromedial Medulla

Hyperresponsiveness to noxious stimulation (hyperalgesia) is observed with naloxone-precipitated morphine withdrawal in several experimental models, and may be due to changes in central nervous system neurons. Previous studies have demonstrated that certain neurons in the rostral ventromedial medulla (on-cells) discharge just prior to nocifensive withdrawal reflexes and are inhibited by morphine. Because the tail flick latency (TFL) is shorter when on-cells are active, it has been proposed that on-cells facilitate nocifensive reflexes. The present study examined the hypothesis that the hyperalgesia observed following naloxone-precipitated withdrawal from morphine is caused by increased on-cell discharge. Rats were maintained in a lightly anesthetized state with chloral hydrate. Administration of saline (1.25 cc, i.v.) or morphine sulfate (1.25 mg/kg, i.v.) was followed by naloxone (1.0 mg/kg, i.v.). On- and off-cell activity was continuously recorded and was correlated with TFL and paw withdrawal threshold (PWT). As previously reported, morphine increased off-cell activity, blocked on-cell activity, and suppressed the tail flick and paw withdrawal reflexes. When naloxone was given after morphine, TFL and PWT were reduced to values significantly below baseline (hyperalgesia). Both spontaneous and reflex-related on-cell activity increased to levels greater than the premorphine baseline. Spontaneous off-cell activity decreased abruptly to near zero when morphine was followed by naloxone. Linear regression analysis during the hyperresponsive state revealed a significant correlation between increased on-cell activity and reduced TFL, but not between decreased off-cell activity and TFL. These findings are consistent with the hypothesis that on-cells facilitate spinal nocifensive reflexes, and that the naloxone-precipitated hyperalgesia is at least in part accounted for by increased on-cell activity. A neural model of opiate dependence, tolerance, and withdrawal is proposed.

Spatiotemporal dynamics of word processing in the human brain

We examined the spatiotemporal dynamics of word processing by recording the electrocorticogram (ECoG) from the lateral frontotemporal cortex of neurosurgical patients chronically implanted with subdural electrode grids. Subjects engaged in a target detection task where proper names served as infrequent targets embedded in a stream of task-irrelevant verbs and nonwords. Verbs described actions related to the hand (e.g, throw) or mouth (e.g., blow), while unintelligible nonwords were sounds which matched the verbs in duration, intensity, temporal modulation, and power spectrum. Complex oscillatory dynamics were observed in the delta, theta, alpha, beta, low, and high gamma (HG) bands in response to presentation of all stimulus types. HG activity (80–200 Hz) in the ECoG tracked the spatiotemporal dynamics of word processing and identified a network of cortical structures involved in early word processing. HG was used to determine the relative onset, peak, and offset times of local cortical activation during word processing. Listening to verbs compared to nonwords sequentially activates first the posterior superior temporal gyrus (post-STG), then the middle superior temporal gyrus (mid-STG), followed by the superior temporal sulcus (STS). We also observed strong phase-locking between pairs of electrodes in the theta band, with weaker phase-locking occurring in the delta, alpha, and beta frequency ranges. These results provide details on the first few hundred milliseconds of the spatiotemporal evolution of cortical activity during word processing and provide evidence consistent with the hypothesis that an oscillatory hierarchy coordinates the flow of information between distinct cortical regions during goal-directed behavior.