Spatiotemporal dynamics of word retrieval in speech production revealed by cortical high-frequency band activity.

Word retrieval is core to language production and relies on complementary processes: the rapid activation of lexical and conceptual representations and word selection, which chooses the correct word among semantically related competitors. Lexical and conceptual activation is measured by semantic priming. In contrast, word selection is indexed by semantic interference and is hampered in semantically homogeneous (HOM) contexts. We examined the spatiotemporal dynamics of these complementary processes in a picture naming task with blocks of semantically heterogeneous (HET) or HOM stimuli. We used electrocorticography data obtained from frontal and temporal cortices, permitting detailed spatiotemporal analysis of word retrieval processes. A semantic interference effect was observed with naming latencies longer in HOM versus HET blocks. Cortical response strength as indexed by high-frequency band (HFB) activity (70-150 Hz) amplitude revealed effects linked to lexical-semantic activation and word selection observed in widespread regions of the cortical mantle. Depending on the subsecond timing and cortical region, HFB indexed semantic interference (i.e., more activity in HOM than HET blocks) or semantic priming effects (i.e., more activity in HET than HOM blocks). These effects overlapped in time and space in the left posterior inferior temporal gyrus and the left prefrontal cortex. The data do not support a modular view of word retrieval in speech production but rather support substantial overlap of lexical-semantic activation and word selection mechanisms in the brain

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

BACKGROUND:Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS:We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS:We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION:We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING:National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK

Dynamic Changes in Phase-Amplitude Coupling Facilitate Spatial Attention Control in Fronto-Parietal Cortex

<div><p>Attention is a core cognitive mechanism that allows the brain to allocate limited resources depending on current task demands. A number of frontal and posterior parietal cortical areas, referred to collectively as the fronto-parietal attentional control network, are engaged during attentional allocation in both humans and non-human primates. Numerous studies have examined this network in the human brain using various neuroimaging and scalp electrophysiological techniques. However, little is known about how these frontal and parietal areas interact dynamically to produce behavior on a fine temporal (sub-second) and spatial (sub-centimeter) scale. We addressed how human fronto-parietal regions control visuospatial attention on a fine spatiotemporal scale by recording electrocorticography (ECoG) signals measured directly from subdural electrode arrays that were implanted in patients undergoing intracranial monitoring for localization of epileptic foci. Subjects (<i>n</i> = 8) performed a spatial-cuing task, in which they allocated visuospatial attention to either the right or left visual field and detected the appearance of a target. We found increases in high gamma (HG) power (70–250 Hz) time-locked to trial onset that remained elevated throughout the attentional allocation period over frontal, parietal, and visual areas. These HG power increases were modulated by the phase of the ongoing delta/theta (2–5 Hz) oscillation during attentional allocation. Critically, we found that the strength of this delta/theta phase-HG amplitude coupling predicted reaction times to detected targets on a trial-by-trial basis. These results highlight the role of delta/theta phase-HG amplitude coupling as a mechanism for sub-second facilitation and coordination within human fronto-parietal cortex that is guided by momentary attentional demands.</p></div

Electrode coverage and Starry Night Test (SNT).

<p>(<b>a</b>) Overlap of implanted electrodes across all subjects (<i>n</i> = 8) on the lateral and medial surfaces (top, bottom, respectively) in the right and left hemispheres (right, left, respectively) overlaid on a cortical reconstruction of the MNI standardized brain. (<b>b</b>) In the SNT, subjects allocated their visual attention to either the RVF or LVF, as indicated by a cue at fixation, and waited for a target (blue square) to appear somewhere in the visual field. Targets appeared on a dynamic background of red circle distracters. Subjects responded with a button press once they detected the target. Example of a single trial is shown during which the RVF was cued.</p

PAC-behavioral correlations.

<p>Correlations between the strength of delta/theta-HG PAC (measured with PLV) and reaction times (RTs) during SNT performance. Examples of two different electrodes (circled in yellow on each cortical reconstruction) are shown for two different subjects (S3, left panel and S5, right panel) during attention to either the contralateral (top) or ipsilateral (bottom) visual fields. The red circles on each cortical reconstruction indicate all other electrodes in these two subjects that showed significant PAC-RT correlations across trials. The red line on each scatter plot indicates the regression line through each data set.</p

Delta/theta phase-HG amplitude coupling during attentional allocation.

<p>Examples of electrodes with significant delta/theta phase-HG amplitude coupling during attentional allocation. (<b>a,b</b>) Comodulograms for two example electrodes (circled in yellow on each subject's cortical reconstruction), one over lateral frontal cortex and one surrounding the IPS, are shown underneath the respective brain areas of two subjects, S3 (<b>a</b>) and S5 (<b>b</b>). Each comodulogram illustrates PAC strength (measured with PLV) across a range of frequencies (x-axis = frequency for phase signal, y-axis = frequency for amplitude signal). Contour lines represent <i>p</i>-values (outer to inner: <i>p</i> = 0.50, 0.10, 0.05, 0.01, 0.005). Separate comodulograms were calculated for the contralateral and ipsilateral attention conditions. Additional electrodes with significant delta/theta-HG PAC in these two subjects are circled in red. See <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001936#pbio-1001936-g006" target="_blank">Figure 6</a> for the significant electrodes in the remaining subjects. (<b>c</b>) A trough-locked spectrogram from an example electrode over PPC (circled in yellow on the cortical reconstruction of S4). Right, bottom: the trough-locked ERP of the filtered delta/theta signal (2–5 Hz). Right, top: normalized power across a range of frequencies for the corresponding time points of the trough-locked delta/theta signal (below). Additional electrodes with significant delta/theta-HG PAC in S4 are circled in red.</p

Effects of temporal lobectomy on consciousness-impairing and consciousness-sparing seizures in children.

PurposeMost children with medically refractory temporal lobe epilepsy (TLE) become seizure free after temporal lobectomy, but some individuals continue to seize. As studies of temporal lobectomy typically focus on seizure freedom, the effect of surgery on seizure type and frequency among children with persistent seizures is poorly understood. Seizures which impair consciousness are associated with increased morbidity compared to consciousness-sparing seizures.MethodsA retrospective cohort study was performed to evaluate the effects of temporal lobectomy on seizure type and frequency in children with intractable TLE.ResultsAmong 58 pediatric TLE patients with a mean (±SEM) age of 14.0 ± 0.7 years who received temporal lobectomy, 46 (79.3%) individuals achieved an Engel class I seizure outcome, including 38 (65.5%) children who became completely seizure free (Engel IA). Mean follow-up was 2.7 ± 0.4 years. While the number of patients experiencing simple partial seizures (SPSs) (consciousness sparing) decreased by only 23 % after surgery, the number of children having complex partial seizures and generalized tonic-clonic seizures (consciousness impairing) diminished by 87 and 83%, respectively (p &lt; 0.01). SPS was the predominant seizure type in only 11.3% of patients before resection, but in 42.1% of patients with postoperative seizures (p &lt; 0.01). Children with postoperative seizures experienced a 70% reduction in overall seizure frequency compared to baseline (p &lt; 0.05), having consciousness-impairing seizures 94% less frequently (p &lt; 0.05), but having consciousness-sparing seizures 35% more frequently (p = 0.73).ConclusionsSeizure type and frequency are important considerations in the medical and surgical treatment of children with epilepsy, although complete seizure freedom remains the ultimate goal

Epilepsy surgery failure in children: a quantitative and qualitative analysis.

ObjectResection is a safe and effective treatment option for children with pharmacoresistant focal epilepsy, but some patients continue experience seizures after surgery. While most studies of pediatric epilepsy surgery focus on predictors of postoperative seizure outcome, these factors are often not modifiable, and the reasons for surgical failure may remain unclear.MethodsThe authors performed a retrospective cohort study of children and adolescents who received focal resective surgery for pharmacoresistant epilepsy. Both quantitative and qualitative analyses of factors associated with persistent postoperative seizures were conducted.ResultsRecords were reviewed from 110 patients, ranging in age from 6 months to 19 years at the time of surgery, who underwent a total of 115 resections. At a mean 3.1-year follow-up, 76% of patients were free of disabling seizures (Engel Class I outcome). Seizure freedom was predicted by temporal lobe surgery compared with extratemporal resection, tumor or mesial temporal sclerosis compared with cortical dysplasia or other pathologies, and by a lower preoperative seizure frequency. Factors associated with persistent seizures (Engel Class II-IV outcome) included residual epileptogenic tissue adjacent to the resection cavity (40%), an additional epileptogenic zone distant from the resection cavity (32%), and the presence of a hemispheric epilepsy syndrome (28%).ConclusionsWhile seizure outcomes in pediatric epilepsy surgery may be improved by the use of high-resolution neuroimaging and invasive electrographic studies, a more aggressive resection should be considered in certain patients, including hemispherectomy if a hemispheric epilepsy syndrome is suspected. Family counseling regarding treatment expectations is critical, and reoperation may be warranted in select cases

ECoG subjects.

<p>F, female; M, male; L, left; R, right; LH, left hemisphere; RH, right hemisphere; LF, lateral frontal; Md, medial; O, occipital; P, parietal; T, temporal.</p><p>ECoG subjects.</p

ERPs during attentional allocation.

<p>(<b>a</b>) Single-trial and averaged ERPs time-locked to trial onset (left) or target onset (right) for an example electrode in a single subject (yellow circle on the cortical reconstruction of S8). Top: ERPs averaged across all trials in which the target appeared in the attended/cued hemifield (blue traces) or in the unattended/uncued hemifield (red traces). Blue shaded region represents the time points during which there was a significant difference between conditions (all <i>p</i><0.05, corrected). Bottom: Single trial ERPs for attention/cued conditions only. Black tick marks signify target onset (left) and manual response (right). Trials are stacked according to target or response onset. (<b>b</b>) ERPs averaged across all electrodes that showed an individual ERP (<i>n</i> = 77; top) or averaged across all electrodes with significant delta/theta-HG PAC (<i>n</i> = 123; bottom) time-locked to trial onset (left) or target onset (right). All other conventions are the same as in (a).</p