To speak, or not to speak? The feasibility of imaging overt speech in children with epilepsy.

We systematically compared fMRI results for covert (silent) and overt (spoken) versions of a language task in a representative sample of children with lesional focal epilepsy being considered for neurosurgical treatment (N=38, aged 6-17 years). The overt task was advantageous for presurgical fMRI assessments of language; it produced higher quality scans, was more sensitive for identifying activation in core language regions on an individual basis, and provided an online measure of performance crucial for improving the yield of presurgical fMRI.

The mismatch negativity (MMN)--a unique window to disturbed central auditory processing in ageing and different clinical conditions.

In this article, we review clinical research using the mismatch negativity (MMN), a change-detection response of the brain elicited even in the absence of attention or behavioural task. In these studies, the MMN was usually elicited by employing occasional frequency, duration or speech-sound changes in repetitive background stimulation while the patient was reading or watching videos. It was found that in a large number of different neuropsychiatric, neurological and neurodevelopmental disorders, as well as in normal ageing, the MMN amplitude was attenuated and peak latency prolonged. Besides indexing decreased discrimination accuracy, these effects may also reflect, depending on the specific stimulus paradigm used, decreased sensory-memory duration, abnormal perception or attention control or, most importantly, cognitive decline. In fact, MMN deficiency appears to index cognitive decline irrespective of the specific symptomatologies and aetiologies of the different disorders involved.

Long-term intellectual outcome after temporal lobe surgery in childhood.

OBJECTIVE: Temporal lobe resection is an established treatment for medication-resistant temporal lobe epilepsy, which in recent years has increasingly been performed in children. However, little is known about the long-term outcome in these children. The aim of this study was to characterize intellectual and psychosocial functioning of children after temporal lobe resection as they progress into late adolescence and adulthood. METHODS: We report the long-term follow-up of 42 children who underwent temporal lobe surgery after an average postoperative period of 9 years. Longitudinal change in IQ was documented, psychosocial outcome including quality of life was assessed, and preoperative and postoperative T1-weighted MRI brain scans were evaluated quantitatively. A well-matched nonsurgical comparison group of 11 children with similar clinical characteristics was also assessed. RESULTS: At follow-up, 86% of the surgical group were seizure-free, and 57% were no longer taking antiepileptic medication. A significant increase in IQ was found in the surgical group after an extended follow-up period of >5 years. This IQ change was not found in the nonsurgical comparison group. IQ increases were associated with cessation of antiepileptic medication and changes in MRI-derived gray matter volume. The surgical group also reported better psychosocial outcome including quality of life, which was more strongly associated with seizure freedom rather than surgery per se. CONCLUSIONS: Surgery for temporal lobe epilepsy performed in childhood results in excellent long-term seizure control and favorable cognitive outcome along with positive effects on brain development. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that temporal lobectomy in children with temporal lobe epilepsy is associated with improved long-term intellectual outcomes compared with those undergoing standard medical treatment.

A role for sleep disruption in cognitive impairment in children with epilepsy.

Early-onset epilepsy is associated with a poor cognitive outcome, with the cumulative burden of both ictal and interictal epileptiform discharges likely to contribute significantly. Memory consolidation has been shown to occur during sleep in healthy children, with an associated electroencephalographic signature. This may be disrupted in children with epilepsy, who exhibit a high incidence of sleep disorders, whether directly related to their seizures or as a comorbidity. Conversely, seizure semiology may be influenced by sleep. In this review we present clinical and experimental evidence that suggests that the disruption of sleep architecture by epileptiform discharges may be an important factor contributing to cognitive impairment in children with epilepsy.

Detecting seizure origin using basic, multiscale population dynamic measures: preliminary findings.

Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.

Recall and recognition confabulation in psychotic and bipolar disorders: evidence for two different types without unitary mechanisms.

Several forms of confabulation have been identified recently in schizophrenic patients, but it has not yet been investigated whether these forms are specific to schizophrenia. Furthermore, the origin of confabulation is unclear. The present study investigated recall and recognition confabulation and their relations with symptomatology, cognitive domains (abstraction and flexibility, verbal fluency, verbal memory, motor activity, and visual-motor processing/attention), computed tomographic (CT) measures (ventricular, cerebral, and Sylvian fissure size), and auditory event-related potentials (amplitudes and latencies of peak components in oddball paradigms) in 33 schizophrenic patients, 35 bipolar I patients, eight schizoaffective patients, and seven patients with other psychotic disorders. We found that neither type of confabulation was specific of any diagnostic group. Recall confabulation was mainly predicted by the predominance of positive symptoms, while recognition confabulation was predicted by a delay in P300 latency and the doses of antipsychotics used. Our results suggest two different mechanisms for both types of confabulation based on interference with the adequate retrieval of information and slowness in early stimulus detection.

Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study.

It is widely assumed that following extensive damage to the left hemisphere sustained in early childhood, language functions are likely to reorganize and develop in the right hemisphere, especially if the lesion affects the classical Broca's or Wernicke's language areas. In the present study, functional MRI (fMRI) was used to examine language lateralization in 10 children and adolescents with intractable epilepsy who sustained an early lesion in the left hemisphere. Lesions were adjacent to or within anterior language cortex in five patients, while they were remote from both Broca's and Wernicke's areas in the remainder. A lateralization index was calculated on the basis of the number of voxels activated in the left and right inferior frontal gyri when performing a covert verb generation task. Only two patients were right-handed, suggesting a high incidence of functional reorganization for motor control in the remaining patients. Five out of 10 showed bilateral or right language lateralization, but lateralization could not be inferred from the proximity of lesions to classical language areas on an individual basis. Lesions in or near Broca's area were not associated with inter-hemispheric language reorganization in four out of five cases, but with perilesional activation within the damaged left hemisphere. Paradoxically, lesions remote from the classical language areas were associated with non-left language lateralization in four out of five cases. Finally, handedness, age at onset of chronic seizures, and site of EEG abnormality also showed no obvious association with language lateralization. In conclusion, it is difficult to infer intra- versus inter-hemispheric language reorganization on the basis of clinical observations in the presence of early pathology to the left hemisphere.

A direct test for lateralization of language activation using fMRI: comparison with invasive assessments in children with epilepsy.

This study introduces a direct method of assessing cerebral lateralization for language based on fMRI activation. The method, derived from a voxel-based morphometry study by C. H. Salmond et al. (2000, Hum. Brain Mapping 11, 223-232), bases lateralization on the direct statistical comparison of the magnitude of task-induced activation in homotopic regions of the two hemispheres. Lateralization results obtained with this direct method were compared to those obtained with a widely used method which involves the calculation of a laterality index (LI) based on the number of significantly activated voxels in the inferior frontal gyrus of each hemisphere. In order to compare the validity of the two methods, a covert verb-generation task was performed by eight children with epilepsy whose language lateralization was examined using invasive techniques. Lateralization results derived from fMRI activation showed that the calculation of a LI presented some limitations. Importantly, the LI value was dependent on the activation threshold chosen to calculate that LI. As a consequence, the correlation between the LI and the invasive methods could vary with the chosen threshold. By contrast, the proposed direct method gave some indication of the reliability of the lateralization and provided results that, in all eight children, were consistent with those obtained using invasive techniques. It is suggested that the direct method could be used in future fMRI studies to establish hemispheric lateralization for cognitive functions.

Electrophysiological evidence of serotonergic impairment in long-term MDMA ("ecstasy") users.

OBJECTIVE: "Ecstasy," or 3,4-methylenedioxymethamphetamine (MDMA), causes long-term impairment to the serotonin (5-HT) system in rats, dogs, and nonhuman primates. 5-HT dysfunction has also been observed in human recreational users of the drug, but whether 5-HT dysfunction in humans is caused by MDMA has not been established, since dysfunction may have preceded MDMA exposure. This ambiguity about causation is particularly important in MDMA research, because 5-HT deficiency is a predictor of risky behavior. METHOD: The 5-HT function of 22 long-term MDMA users was compared to that of 20 drug-naive comparison subjects and 19 cannabis users. 5-HT function was assessed with the intensity dependence paradigm, a tool that measures 5-HT-related attenuation of neural response to auditory stimuli (measured with EEG). RESULTS: Long-term MDMA users exhibited 5-HT dysfunction, relative to both cannabis users and drug-naive comparison subjects. This dysfunction was related to total MDMA consumption (after removing the effect of frequency of use) but not to frequency of use (after removing the effect of total consumption). CONCLUSIONS: These data show that 5-HT dysfunction occurs in MDMA users, is related to users' MDMA consumption, and is independent of cannabis use. The results do not suggest that self-medication explains this relationship, because the deficit was related to total MDMA consumption but not frequency of consumption. The results are thus consistent with the thesis that MDMA consumption causes 5-HT impairment in humans.

A possible role for gap junctions in generation of very fast EEG oscillations preceding the onset of, and perhaps initiating, seizures.

PURPOSE: We propose an experimentally and clinically testable hypothesis, concerning the origin of very fast (> approximately 70 Hz) EEG oscillations that sometimes precede the onset of focal seizures. These oscillations are important, as they may play a causal role in the initiation of seizures. METHODS: Subdural EEG recordings were obtained from children with focal cortical dysplasias and intractable seizures. Intra- and extracellular recordings were performed in rat hippocampal slices, with induction of population activity, as follows: (a) bath-applied tetramethylamine (an intracellular alkalinizing agent, that opens gap junctions); (b) bath-applied carbachol, a cholinergic agonist; and (c) focal pressure ejection of hypertonic K+ solution. Detailed network simulations were performed, the better to understand the cellular mechanisms underlying oscillations. A major feature of the simulations was inclusion of axon-axon gap junctions between principal neurons, as supported by recent experimental data. RESULTS: Very fast oscillations were found in children before seizure onset, but also superimposed on bursts during the seizure, and on interictal bursts. In slice experiments, very fast oscillations had previously been seen on interictal-like bursts; we now show such oscillations before, between, and after epileptiform bursts. Very fast oscillations were also seen superimposed on gamma (30-70 Hz) oscillations induced by carbachol or hypertonic K+, and in the latter case, very fast oscillations became continuous when chemical synapses were blocked. Simulations replicate these data, when axonal gap junctions are included. CONCLUSIONS: Electrical coupling between principal neurons, perhaps via axonal gap junctions, could underlie very fast population oscillations, in seizure-prone brain, but possibly also in normal brain. The anticonvulsant potential of gap-junction blockers such as carbenoxolone, now in clinical use for treatment of ulcer disease, should be considered.

Pathway-specific habituation of induced gamma oscillations in the hippocampal slice.

Brief tetanic stimulation (eight pulses at 100 Hz) of afferent fibers innervating area CA1 of the hippocampus produce gamma oscillations. When delivered every minute the oscillation habituated markedly after the first stimulus. This habituation could be transiently reversed by stimulating a different pathway to the recorded area. Gamma oscillation-induced beta frequency oscillations were only seen in response to the first (novel) stimulus and the gamma oscillation itself was markedly attenuated by on-going, non-oscillogenic, synaptic activity. The NMDA receptor antagonist ketamine abolished the response to novel stimuli but left the habituated response relatively unaffected. The pattern of habituation parallelled that seen for sensory induced gamma and beta oscillations in the clinical EEG.

Gamma and beta frequency oscillations in response to novel auditory stimuli: A comparison of human electroencephalogram (EEG) data with in vitro models.

Investigations using hippocampal slices maintained in vitro have demonstrated that bursts of oscillatory field potentials in the gamma frequency range (30-80 Hz) are followed by a slower oscillation in the beta 1 range (12-20 Hz). In this study, we demonstrate that a comparable gamma-to-beta transition is seen in the human electroencephalogram (EEG) in response to novel auditory stimuli. Correlations between gamma and beta 1 activity revealed a high degree of interdependence of synchronized oscillations in these bands in the human EEG. Evoked (stimulus-locked) gamma oscillations preceded beta 1 oscillations in response to novel stimuli, suggesting that this may be analogous to the gamma-to-beta shift observed in vitro. Beta 1 oscillations were the earliest discriminatory responses to show enhancement to novel stimuli, preceding changes in the broad-band event-related potential (mismatch negativity). Later peaks of induced beta activity over the parietal cortex were always accompanied by an underlying gamma frequency oscillation as seen in vitro. A further analogy between in vitro and human recordings was that both gamma and beta oscillations habituated markedly after the initial novel stimulus presentation.

Neural consequences of competing stimuli in both visual hemifields: a physiological basis for visual extinction.

We used positron emission tomography in healthy volunteers to test hemispheric rivalry theories for normal and pathological spatial attention, which provide an influential account of contralesional extinction on bilateral stimulation after unilateral brain injury. Subjects reported visual characters presented either unilaterally or bilaterally. An extinction-like pattern was found behaviorally, with characters in one hemifield reported less accurately when competing characters appeared in the other hemifield. Differences in neural activity for unilateral minus bilateral conditions revealed greater activation of striate and extrastriate areas for stimuli presented without competing stimuli in the other hemifield. Thus, simultaneous bilateral stimulation led to a significant reduction in response by spatiotopic visual cortex contralateral to a particular stimulus. These data provide physiological support for interhemispheric rivalry in the intact human brain, and demonstrate that such competition impacts at early levels of perceptual processing.

Differential changes in frontal and sub-temporal components of mismatch negativity.

Novel evidence is reported showing changes in the mismatch negativity (MMN) event-related potential (ERP) that followed a different time course in frontal and sub-temporal (mastoid) electrodes. MMN recorded in frontal electrode sites, assumed to originate predominantly in the superior temporal gyrus, showed amplitude enhancement from the first to the second recording block. In contrast, the amplitude of the sub-temporal, mastoid component (termed mismatch positivity, MMP) diminished. In addition to these changes in the MMN elicited by tone duration deviants, there were also significant changes in the ERP to the standard stimulus. The positivity in the standard ERP between 50 and 150 ms increased in bilateral mastoid electrodes but showed no reliable change in frontal electrodes. This suggests that more than one generator underpins the two mismatch components, and that the sub-temporal mismatch component does not only represent a polarity reversal of the main MMN component in the superior temporal gyrus.

Impaired auditory frequency discrimination in dyslexia detected with mismatch evoked potentials.

Deficits in phonological skills appear to be at the heart of reading disability; however, the nature of this impairment is not yet known. The hypothesis that dyslexic subjects are impaired in auditory frequency discrimination was tested by using an attention-independent auditory brain potential, termed mismatch negativity (MMN) while subjects performed a visual distractor task. In separate blocks, MMN responses to graded changes in tone frequency or tone duration were recorded in 10 dyslexic and matched control subjects. MMN potentials to changes in tone frequency but not to changes in tone duration were abnormal in dyslexic subjects. This physiological deficit was corroborated by a similarly specific impairment in discriminating tone frequency, but not tone duration, which was assessed separately. Furthermore, the pitch discrimination and MMN deficit was correlated with the degree of impairment in phonological skills, as reflected in reading errors of regular words and nonwords. It is possible that in dyslexia a persistent sensory deficit in monitoring the frequency of incoming sound may impair the feedback control necessary for the normal development of phonological skills.

Risk of HIV dementia and opportunistic brain disease in AIDS and zidovudine therapy.

OBJECTIVE: To determine the incidence of HIV dementia and opportunistic brain disease in AIDS relative to the use of licensed antiretoviral medication (zidovudine, zalcitabine, didanosine, and stavudine). METHOD: Medical records were evaluated retrospectively in a longitudinal cohort of 1109 patients with AIDS during the period 1991-4. Treatment groups were defined by start and duration of zidovudine treatment, the drugs used most often during this period were: (a) no zidovudine, (b) zidovudine before AIDS, (c) zidovudine before and after AIDS, and (d) zidovudine used in AIDS. Main outcome measures were cumulative incidence and survival from AIDS to onset of HIV dementia, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, and primary CNS lymphoma. RESULTS: Risk of brain disease including HIV dementia and opportunistic brain disease was reduced in patients who started zidovudine before AIDS and continued in AIDS (relative risk (RR) 0.55, 95% confidence interval (95% CI) 0.36-0.84) as well as zidovudine initiated in AIDS (RR 0.27, 95% CI 0.17-0.45) compared with untreated subjects. Treatment effects were not constant over time, decreasing by 14%-32% for each six months of follow up. This was supported by unadjusted incidences across groups stratified by duration of zidovudine use, indicating reduced risk with treatment for up to 18 months but not with longer duration of use of zidovudine. Other antiretroviral drugs had no significant effect, although these were used by only 14% of patients in this cohort. CONCLUSION: The time limited but effective neuroprotection offered by zidovudine monotherapy for <18 months suggests that non-specific mechanisms of cerebral immunological defence may benefit from antiretroviral treatment. Due to the limitations of a retrospective study these findings require confirmation and further investigation in the context of current combination drug treatments.

Alpha EEG activity and subcortical pathology in HIV infection.

Quantitative electroencephalographic (QEEG) investigations of patients with HIV-1-infections were made to detect early signs of HIV brain involvement. QEEG data were recorded in a prospective controlled cohort study together with standardised clinical, immunological and neuropsychological tests. Subject groups were HIV-seronegative controls, HIV-seropositive subjects with asymptomatic infection, and HIV-seropositive subjects with symptomatic infection exclusing AIDS defining illnesses. Marked increase in background alpha amplitude preceded cognitive and neurological impairment in the symptomatic stage of infection. Elevation of alpha amplitude was also associated with change in psychiatric status. Antiretroviral medication suppressed this alpha elevation, supporting the usefulness of QEEG in monitoring drug CNS effects. In the context of clinical, neuropathological and brain imaging data it is suggested that these changes in the alpha rhythm are the earliest, albeit unspecific, signs of HIV brain involvement, reflecting the predominantly subcortical prominence of the pathological process.