Peka Christova

Discharge pattern of human motor units during dynamic concentric and eccentric contractions.

OBJECTIVES A total of 45 motor units (MUs) from the human biceps brachii muscle were investigated during isovelocity concentric and eccentric movements performed by means of a device implementing an external torque in the direction of the extension proportionally to the elbow angle changes. The effects of movement velocity on the recruitment and decruitment thresholds (RT and DT) and the corresponding discharge patterns were determined. METHODS A wire branched electrode placed subcutaneously was used to discriminate the potentials from a single MV. RESULTS The majority of MUs (91%) were recruited at lower torque values with the increase of movement velocity. The decrease of RT was statistically significant for 47% of the investigated MUs. A typical discharge pattern of short first interspike interval (ISI) followed by a longer one was observed for 93% of all MUs. After the first 2-3 spikes the rate of the MU discharge was approximately constant regardless of the fact that the muscle force gradually increased until the end of the concentric movement. CONCLUSIONS There are differences in the muscle force control during shortening and lengthening contractions. For 82% of the investigated MUs DT was smaller at faster movements and for 21 MUs (47%) the decrease of DT was significant. The gradually declined MU discharge rate throughout the entire movement with a very long last ISI was demonstrated for 93% of the investigated MUs.

Motor unit activity during long-lasting intermittent muscle contractions in humans

Abstract Changes accompanying long-lasting intermittent muscle contractions (30%–50% of the maximal) were investigated by tracing the activity of 38 motor units (MU) of the human biceps brachii muscle recorded from fine-wire branched electrodes. The motor task was a continuous repetition of ramp-and-hold cycles of isometric flexion contractions. During ramp-up phases a significant decline in recruitment thresholds was found with no changes in the discharge pattern. During ramp-down phases the unchanged mean value of derecruitment thresholds during the task was accompanied by increased duration of the last two interspike intervals (ISI). These findings would suggest that during fatigue development the main compensatory mechanism during ramp-up contractions is space coding while for ramp-down contractions it is rate coding. During the steady-state phases the mean value of ISI, as well as the firing variability, had increased by the end of the task in most of the MU investigated . In addition 17 recruited MU were also investigated. These units revealed a lower initial discharge rate and a faster decrease in the mean discharge rate with the development of fatigue. The gradual reduction of the recruitment threshold of already active MU and the recruitment of new units demonstrated an increased excitability of the motorneuron pool during fatigue. A typical recruitment pattern (a first short ISI followed by a long one) was observed during ramp-up contractions in units active from the very beginning of the task, as well as during sustained contractions at the onset of the stable discharge of the additionally recruited MU.

Novel CACNA1A Mutation Causes Febrile Episodic Ataxia with Interictal Cerebellar Deficits

Episodic ataxia type 2 (EA2) is a dominantly inherited disorder, characterized by spells of ataxia, dysarthria, vertigo, and migraines, associated with mutations in the neuronal calcium‐channel gene CACNA1A. Ataxic spells lasting minutes to hours are provoked by stress, exercise, or alcohol. Some patients exhibit nystagmus between spells and some develop progressive ataxia later in life. At least 21 distinct CACNA1A mutations have been identified in EA2. The clinical and genetic complexities of EA2 have offered few insights into the underlying pathogenic mechanisms for this disorder. We identified a novel EA2 kindred in which members had ataxic spells induced by fevers or high environmental temperature. We identified a novel CACNA1A mutation (nucleotides 1253+1 G→A) that was present in all subjects with febrile spells or ataxia. Moreover, we found that, regardless of age or interictal clinical status, all affected subjects had objective evidence of abnormal saccades, ocular fixation, and postural stability. These findings suggest that early cerebellar dysfunction in EA2 results from the intrinsically abnormal properties of the CACNA1A channel rather than a degenerative process.

Discharge rate of selected motor units in human biceps brachii at different muscle lengths

Action potentials of selected motor units (MUs) from biceps brachii muscle were recorded and analysed at three different elbow angles: 90, 120 and 150 degrees, corresponding to short, control and long muscle length, respectively. Using branched and conventional bipolar wire electrodes, superficial and deep-situated MUs were selectively recorded at relatively equal torques (the torque values were normalized to the corresponding maximal torque for a given muscle length). A total of 138 MUs (74 superficial and 64 deep) were investigated. The mean interspike intervals were significantly shorter at 90 degrees for the majority (52.2%) of the investigated MUs than at the other two angles. This increased discharge rate compensates for the reduction of twitch duration of evoked contraction at short muscle length. The other MUs were divided into three almost equal groups: two with significantly higher discharge rates at 120 and 150 degrees and one with discharge rates unaffected by the joint angle. No significant difference in the discharge rate of superficial and deep MUs at a fixed joint angle was found.

Human motor unit recruitment and derecruitment during long lasting intermittent contractions

Seven healthy subjects were investigated in cyclic ramp-and-hold long lasting isometric contractions. Wire branched electrodes were used for selective recording of single motor unit (MU) potentials from m. biceps brachii. MU behaviour was defined in terms of recruitment/derecruitment thresholds (RT and DT) and the duration of interspike intervals (ISI). A total of 63 MUs was investigated: 40 units were active from the beginning of the task performance and another 23 were recruited later. There were no changes in the recruitment pattern of MUs with fatigue development - a short first ISI followed by a very long second one and an almost constant firing rate after this transient phase. The tendency of RT to gradually decrease dominates the results. Thus, the required constant rate of force increase with fatigue development was maintained mostly by the mechanisms of space coding (i.e., decrease of RT and recruitment of additional MUs). Oppositely, the time behaviour of the DT changes was not uniform and rate coding was an essential mechanism in the adaptation of MU activity to muscle fatigue during relaxation phases. The recruitment pattern and fatigue related behaviour of the additionally recruited MUs were similar to those of MUs active from the first cycle of the motor task performance.

Impaired Eye Movements in Presymptomatic Spinocerebellar Ataxia Type 6

BACKGROUND Early detection of impaired neurological function in neurodegenerative diseases may aid in understanding disease pathogenesis and timing of therapeutic trials. OBJECTIVE To identify early abnormalities of ocular motor function in individuals who have the spinocerebellar ataxia type 6 (SCA6) gene (CACNA1A) but no clinical symptoms. DESIGN Physiological techniques were used to record and analyze eye movements and postural sway. PATIENTS Four presymptomatic and 5 ataxic patients with SCA6, genetically identified, and 10 healthy controls. RESULTS Presymptomatic individuals had normal postural sway but definite ocular motor abnormalities. Two had a low-amplitude horizontal gaze-evoked nystagmus, 1 of whom had a significantly decreased eye velocity for upward saccades and an abnormal frequency of square-wave jerks. Another had abnormal square-wave jerks and a fourth had a reduced gain for pursuit tracking. Not all of the presymptomatic patients had the same findings, but a multivariate analysis discriminated the presymptomatic patients, as a group, from healthy controls and the ataxic patients. CONCLUSIONS Among the earliest functional deficits in SCA6 are eye movement abnormalities, including impaired saccade velocity, saccade metrics, and pursuit gain. This suggests that early functional impairments are caused by cellular dysfunction and/or loss in the posterior cerebellar vermis and flocculus. These findings might help to determine the timing of a treatment and to define variables that could be used as outcome measures for the efficacy of therapeutic trials.

True associations between resting fMRI time series based on innovations

We calculated voxel-by-voxel pairwise crosscorrelations between prewhitened resting-state BOLD fMRI time series recorded from 60 cortical areas (30 per hemisphere) in 18 human subjects (nine women and nine men). Altogether, more than a billion-and-a-quarter pairs of BOLD time series were analyzed. For each pair, a crosscorrelogram was computed by calculating 21 crosscorrelations, namely at zero lag ± 10 lags of 2 s duration each. For each crosscorrelogram, in turn, the crosscorrelation with the highest absolute value was found and its sign, value, and lag were retained for further analysis. In addition, the crosscorrelations at zero lag (irrespective of the location of the peak) were also analyzed as a special case. Based on known varying density of anatomical connectivity, we distinguished four general brain groups for which we derived summary statistics of crosscorrelations between voxels within an area (group I), between voxels of paired homotopic areas across the two hemispheres (group II), between voxels of an area and all other voxels in the same (ipsilateral) hemisphere (group III), and voxels of an area and all voxels in the opposite (contralateral) hemisphere (except those in the homotopic area) (group IV). We found the following. (a) Most of the crosscorrelogram peaks occurred at zero lag, followed by ± 1 lag; (b) over all groups, positive crosscorrelations were much more frequent than negative ones; (c) average crosscorrelation was highest for group I, and decreased progressively for groups II-IV; (d) the ratio of positive over negative crosscorrelations was highest for group I and progressively smaller for groups II-IV; (e) the highest proportion of positive crosscorrelations (with respect to all positive ones) was observed at zero lag; and (f) the highest proportion of negative crosscorrelations (with respect to all negative ones) was observed at lag = 2. These findings reveal a systematic pattern of crosscorrelations with respect to their sign, magnitude, lag and brain group, as defined above. Given that these groups were defined along a qualitative gradient of known overall anatomical connectivity, our results suggest that functional interactions between two voxels may simply reflect the density of such anatomical connectivity between the areas to which the voxels belong.

A voxel-by-voxel parametric fMRI study of motor mental rotation: hemispheric specialization and gender differences in neural processing efficiency

Differences between men and women in brain size, cognitive performance and lateralization of brain activation have been perennial and controversial issues. Here we show that in a motor mental rotation task where women and men performed equally well, the slope of the functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) signal per degree of mental rotation was overall 2.4× higher in men than in women. This was attributed to the much more inefficient engagement (i.e. higher slopes) of the right hemisphere by men (mainly the frontal lobe). These findings indicate that women process information much more efficiently than men, which could offset smaller brain size.

Surface EMG recorded by branched electrodes during sustained muscle activity

The purpose of the present investigation is to use surface interference EMG recorded by branched electrodes for assessment of muscle fatigue during sustained voluntary isometric contractions at different levels. Level-trigger averaging and turn/amplitude analysis have been applied. The conduction velocity (CV) of excitation was calculated from the time shift of the negative peaks of the averaged potentials (AvPs) derived from the EMG recorded by two electrodes placed along the muscle fibers. The recruitment of new motor units affects the negative amplitude (NA) of AvPs, the number of turns per second and the mean amplitude of turns in a different way depending on the level of sustained contractions. In contrast, the CV declined at all levels of sustained contractions and was the most appropriate parameter for the muscle fatigue assessment. There was a good correlation between CV decrease and torque reduction during sustained maximal efforts. The level-trigger averaging technique of the interference EMG recorded by surface branched electrodes is easy and non-invasive, thus being very convenient for routine application.

Human Leukocyte Antigen (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans

Background Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990–91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes. Methods Seventy-six Gulf War veterans (55 with GWI and 21 healthy controls) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N = 11) and without (N = 65) HLA class II allele DRB1*13:02. Findings We found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P = 0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P = 0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect. Interpretation These findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between GWI and other immune-related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity. Funding source U.S. Department of Defense (W81XWH-15-1-0520), Department of Veterans Affairs, American Legion Brain Sciences Chair, and University of Minnesota.