Camilo Toro

Event-related coherence and event-related desynchronization/synchronization in the 10 Hz and 20 Hz EEG during self-paced movements

To investigate the activity of cortical regions in the control of movement, we studied event-related desynchronization/synchronization (ERD/ERS), event-related coherence (ERC), and phase coherence in 29-channel EEGs from 9 subjects performing self-paced movements of the right index finger. Movement preparation and execution produced ERD over the sensorimotor areas at 10 Hz and 20 Hz, followed by ERS. ERD corresponded spatiotemporally to an increase in coherence over the frontocentral areas. For both frequency bands, ERD began over the left sensorimotor areas and became bilateral at the time of movement onset. The coherence increase with frontal areas began in the left central areas and became symmetrical after EMG onset. The ERD and coherence increase was longer at 10 Hz than at 20 Hz. Phase coherence at 10 Hz showed a lead of anterior regions to posterior regions throughout the time period, and at 20 Hz showed a tendency toward zero phase delay corresponding with the movement. EEG desynchronization parallels functional coupling over sensorimotor and frontal areas. Event-related coherence and phase coherence findings implicate the frontal lobes in control of movement planning and execution. The involvement of different frequency bands with different timings may represent parallel changes in the cortical network.

Task-related coherence and task-related spectral power changes during sequential finger movements.

In order to investigate the activity of cortical regions in the control of complex movements, we studied task-related coherence (TRCoh) and task-related spectral power (TRPow) changes in 8 right-handed subjects during the execution of 4 different finger movement sequences of increasing complexity. All sequences were performed with the right hand and were paced by a metronome at 2 Hz. EEG power spectra and coherence values were computed within alpha (8-12 Hz) and beta (13-20 Hz) frequency bands for 29 scalp EEG positions during the execution of the sequences and were compared with values obtained during a rest (control) condition. Movement sequences were associated with TRPow decreases in the alpha and beta frequency bands over bilateral sensorimotor and parietal areas, with a preponderance over the contralateral hemisphere. Increases of TRCoh occurred over bilateral frontocentral regions. TRCoh decreases were present over the temporal and occipital areas. The spatial extent and the magnitude of TRPow decreases and TRCoh increases in both frequency bands were greater for sequential movements of higher complexity than for simpler ones. These results are consistent with previous findings of bilateral activation of sensorimotor areas during sequential finger movements. Moreover, the present results indicate an active intercommunication between bilateral and mesial central and prefrontal regions which becomes more intense with more complex sequential movements.

The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

Purpose:This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program’s application of genomic technology to establish diagnoses, and details the Program’s success rate during its first 2 years.Methods:Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.Results:Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.Conclusion:The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.Genet Med 2012:14(1):51–59

Topography of the inhibitory and excitatory responses to transcranial magnetic stimulation in a hand muscle

We studied the excitatory motor evoked potentials (MEPs) and the inhibitory (silent period) responses to focal transcranial magnetic stimulation (TMS) in the abductor pollicis brevis (APB) of 5 normal subjects to learn whether the scalp topography of the two responses differed. At the scalp location where stimulation produced the highest-amplitude MEP in the voluntarily activated APB, stimulus intensities below the MEP threshold produced silent periods with little or no preceding facilitation. The silent periods had a mean duration of 26.8 +/- 6.8 msec and a mean onset latency of 27.6 +/- 3.6 msec, which was 7.2 +/- 2.3 msec longer than the latency of MEPs produced in the APB by higher stimulus intensities. A period of excitation, with an onset latency of 50-80 msec, often followed the silent period. On averaged trials, a stimulus intensity just above the threshold of the MEP at its optimal position produced MEPs followed by silent periods at a cluster of scalp locations 1 cm apart on the central scalp (medial area) and silent periods with very slight or no preceding facilitation in 3-9 locations lateral to the MEP area (lateral area). This finding was confirmed in 3 subjects with maps constructed from statistical analysis of multiple trials. These maps also showed that MEPs produced from the medial area occurred 4-6 msec earlier than those produced from the lateral area. The integral of the silent period tended to be larger in the lateral area. The motor representation of APB, as defined by TMS, is not homogeneous but rather contains at least two components that differ physiologically and topographically.

Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases

We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other “mitochondrial” features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.

Event-related desynchronization in reaction time paradigms: a comparison with event-related potentials and corticospinal excitability

OBJECTIVES To study cortical activity in different motor tasks, we compared event-related desynchronization (ERD) and event-related potentials (ERPs) in different reaction time (RT) paradigms with the time course of corticospinal excitability. METHODS Nine right-handed, normal subjects performed right or left thumb extensions in simple, choice and go/no go auditory RT paradigms. Eight subjects had participated in a previous study evaluating changes in corticospinal excitability during the same paradigms. Twenty-nine EEG channels with electrooculogram and bilateral EMG monitoring were collected. ERPs and ERD of 10 and 18-22 Hz bands were obtained with respect to tone administration and EMG onset. RESULTS Trials with movement showed lateralized ERP components, corresponding to the motor potential (MP), both in the averages on the tone and on EMG. The MP corresponded well in time and location to the rise in corticospinal excitability on the moving side observed in the previous study. Sensorimotor ERD, followed by event-related synchronization (ERS), was present for trials with movements and for the no go. ERD was present contralaterally during movement preparation and in no go trials, while it was bilateral during motor execution. No go ERD was followed more rapidly by ERS than in trials with movement. This finding suggests that in no go trials, there is a brief active process in the sensorimotor areas. ERD and ERS do not correspond, respectively, in time and location to increases and decreases in corticospinal excitability. In fact, ERD is bilateral during movement execution, when corticospinal inhibition of the side at rest is observed. Contralateral no go ERS occurs later than corticospinal inhibition, which is bilateral. CONCLUSIONS These findings may suggest that ERD is compatible with both corticospinal activation and inhibition, ERS indicating the removal of either, resulting in cortical idling.

GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine.

Early‐onset epileptic encephalopathies have been associated with de novo mutations of numerous ion channel genes. We employed techniques of modern translational medicine to identify a disease‐causing mutation, analyze its altered behavior, and screen for therapeutic compounds to treat the proband.

Cortical tremor : a common manifestation of cortical myoclonus

Ten patients, three with postural tremor and seven with action myoclonus, had stereotyped involuntary rhythmic movements when attempting to execute a sustained isometric muscle contraction. The movements were characterized by rhythmic EMG bursts lasting less than 50 msec and appearing synchronously in agonist and antagonist muscles at a rate of 9 to 18 Hz. Backaveraging of the EEG activity related to the onset of the rhythmic EMG bursts identified a cortical potential preceding the EMG bursts in all patients. These symptoms and signs fit the description of “cortical tremor,” a variant of cortical reflex myoclonus. Cortical tremor is common in patients with cortical myoclonus and may be a source of functional disability. In two patients in whom we studied the effects of graded levels of isometric force, force recruitment modulated the abnormal EMG bursting frequency, amplitude, and spatial distribution of the myoclonic jerks in the activated limb. Transcranial magnetic and electrical stimulation, but not peripheral nerve stimulation, influenced the abnormal EMG bursting pattern, implying a greater dependence of this rhythmic phenomenon on a central generator than on peripheral feedback loops.

Detecting false positive signals in exome sequencing

Disease gene discovery has been transformed by affordable sequencing of exomes and genomes. Identification of disease‐causing mutations requires sifting through a large number of sequence variants. A subset of the variants are unlikely to be good candidates for disease causation based on one or more of the following criteria: (1) being located in genomic regions known to be highly polymorphic, (2) having characteristics suggesting assembly misalignment, and/or (3) being labeled as variants based on misleading reference genome information. We analyzed exome sequence data from 118 individuals in 29 families seen in the NIH Undiagnosed Diseases Program (UDP) to create lists of variants and genes with these characteristics. Specifically, we identified several groups of genes that are candidates for provisional exclusion during exome analysis: 23,389 positions with excess heterozygosity suggestive of alignment errors and 1,009 positions in which the hg18 human genome reference sequence appeared to contain a minor allele. Exclusion of such variants, which we provide in supplemental lists, will likely enhance identification of disease‐causing mutations using exome sequence data. Hum Mutat 33:609–613, 2012.

Event-related desynchronization (ERD) in the alpha frequency during development of implicit and explicit learning

To understand the role of the motor cortex in implicit and explicit learning, we studied alpha event-related desynchronization (ERD) while 13 right-handed individuals performed a variation of the serial reaction time task (SRTT). EEG signals were recorded simultaneously from 29 scalp locations and the ERD was computed. During data collection, all subjects developed implicit knowledge, demonstrated by shortening of the response time, and explicit knowledge of the test sequence. The average ERD maps of all 13 subjects demonstrated that during the initial learning, there was a decline in alpha band power that was maximal over the contralateral central region. The ERD reached a transient peak amplitude at a point when the subjects attained full explicit knowledge, and diminished subsequently. The transient peak in ERD was highly significant at C3. These electrophysiologic findings support previous studies which have demonstrated that motor activity changes as behavior changes over the course of learning.