Journal: Journal of neurophysiology
We tested the hypothesis that the nervous system, and the cortex in particular, is a critical determinant of muscle strength/weakness and that a high level of corticospinal inhibition is an important neurophysiologic factor regulating force generation. A group of healthy individuals underwent 4-weeks of wrist-hand immobilization to induce weakness. Another group also underwent 4-weeks of immobilization, but they also performed mental imagery of strong muscle contractions five days/wk. Mental imagery has been shown to activate several cortical areas that are involved with actual motor behaviors- including premotor and M1 regions. A control group, who underwent no interventions, also participated in this study. Before, immediately after, and one-week following immobilization, we measured wrist flexor strength, VA, and the cortical silent period (SP; a measure that reflect corticospinal inhibition quantified via transcranial magnetic stimulation). Immobilization decreased strength 45.1±5.0%, impaired VA 23.2±5.8%, and prolonged the SP 13.5±2.6%. Mental imagery training, however, attenuated the loss of strength and VA by ~ 50% (23.8±5.6% and 12.9±3.2% reductions, respectively), and eliminated prolongation of the SP (4.8±2.8% reduction). Significant associations were observed between the changes in muscle strength and VA (r=0.56) and SP (r=-0.39). These findings suggest neurological mechanisms, most likely at the cortical level, contribute significantly to disuse-induced weakness, and that regular activation of the cortical regions via imagery attenuates weakness and VA by maintaining normal levels of inhibition.
Two-Photon Processor (TPP) is a versatile, ready-to-use and freely available software package in MATLAB to process data from in vivo two photon calcium imaging. TPP includes routines to search for cell bodies in full-frame (SeNeCA - Search for Neural Cells Accelerated) and line-scan acquisition, routines for calcium signal calculations, filtering, spike-mining and routines to construct parametric fields. Searching for somata in artificial in vivo data, our algorithm achieved better performance than human annotators. SeNeCA copes well with uneven background brightness and in-plane motion artifacts, the major problems in simple segmentation methods. In the fast mode, artificial in vivo images with a resolution of 256x256 containing ~100 neurons can be processed at a rate up to 175 frames per second (tested on Intel i7, 8 threads, magnetic HDD). This speed of a segmentation algorithm could bring new possibilities into the field of in vivo optophysiology. With such a short latency (down to 5-6 ms in an ordinary PC) and using some contemporary optogenetic tools, it will allow experiments in which a control program can continuously evaluate the occurrence of a particular spatial pattern of activity (a possible correlate of memory or cognition) and subsequently inhibit/stimulate the entire area of the circuit or inhibit/stimulate a different part of the neuronal system. Two-Photon Processor will be freely available on our public website. Similar all-in-one and freely available software has not yet been published.
Tactile stimulation of the hand evokes highly precise and repeatable patterns of activity in mechanoreceptive afferents; the strength (i.e., firing rate, Muniak et al. 2007) and timing (Johansson and Birznieks 2004; Mackevicius et al. 2012; Saal et al. 2009) of these responses have been shown to convey stimulus information. To achieve an understanding of the mechanisms underlying the representation of tactile stimuli in the nerve, we developed a two-stage computational model consisting of a nonlinear mechanical transduction stage followed by a generalized integrate-and-fire mechanism. The model improves upon a recently published counterpart (Kim et al. 2010) in two important ways. First, complexity is dramatically reduced (at least one order of magnitude fewer parameters). Second, the model comprises a saturating non-linearity and therefore can be applied to a much wider range of stimuli. We show that both the rate and timing of afferent responses are predicted with remarkable precision, and observed adaptation patterns and threshold behavior are well captured. We conclude that the responses of mechanoreceptive afferents can be understood using a very parsimonious mechanistic model, which can then be used to accurately simulate the responses of afferent populations.
Echoes and sounds of independent origin often obscure sounds of interest, but echoes can go undetected under natural listening conditions, a perception called the precedence effect. How does the auditory system distinguish between echoes and independent sources? To investigate, we presented two broadband noises to barn owls (Tyto alba) while varying the similarity of the sounds' envelopes. The carriers of the noises were identical except for a 2 or 3 ms delay. Their onsets and offsets were also synchronized. In owls, sound localization is guided by neural activity on a topographic map of auditory space. When there are two sources concomitantly emitting sounds with overlapping amplitude spectra, space map neurons discharge when the stimulus in their receptive field is louder than the one outside it and when the averaged amplitudes of both sounds are rising. A model incorporating these features calculated the strengths of the two sources' representations on the map (Nelson and Takahashi 2010). The target localized by the owls could be predicted from the model’s output. The model also explained why the echo is not localized at short delays: when envelopes are similar, peaks in the leading sound mask corresponding peaks in the echo, weakening the echo’s space map representation. When the envelopes are dissimilar, there are few or no corresponding peaks, and the owl localizes whichever source is predicted by the model to be less masked. Thus, the precedence effect in the owl is a byproduct of a mechanism for representing multiple sound sources on its map.
Skin on the foot sole plays an important role in postural control. Cooling the skin of the foot is often used to induce anaesthesia to determine the role of skin in motor and balance control. The effect of cooling on the four classes of mechanoreceptor in the skin is largely unknown and thus the aim of the current study was to characterize the effects of cooling on individual skin receptors in the foot sole. Such insight will better isolate individual receptor contributions to balance control. Using microneurography, we recorded 39 single nerve afferents innervating mechanoreceptors in the skin of the foot sole in humans. Afferents were identified as fast- or slowly-adapting type I or II (FA I n=16, FA II n=7, SA I n=6, SA II n=11). Receptor response to vibration was compared before and after cooling the receptive field (2-20 minutes). Overall, firing response was abolished in 30% of all receptors and this was equally distributed across receptor type (p=0.69). Longer cooling times were more likely to reduce firing response below 50% of baseline however some afferents responses were abolished with shorter cooling times (2-5 min.). Skin temperature was not a reliable indicator of the level of receptor activation, and often became uncoupled from receptor response levels, cautioning the use of this parameter as an indicator of anesthesia. When cooled, receptors preferentially coded lower frequencies in response to vibration. In response to a sustained indentation, SA receptors responded more like FA receptors, primarily coding ‘on-off’ events.
The Reticular Thalamic Nucleus (RTN) of the mouse is characterized by an overwhelming majority of GABAergic neurons receiving afferences from both the thalamus and the cerebral cortex and sending projections mainly on thalamo-cortical neurons. The RTN neurons express high levels of the “slow Ca(2+) buffer” parvalbumin (PV) and are characterized by low-threshold Ca(2+) currents, IT. We performed extracellular recordings in Ketamine/Xylazine anesthetized mice in the rostro-medial portion of the RTN. In the RTN of wildtype and PV knockout (PVKO) mice we distinguished 4 types of neurons characterized on the basis of their firing pattern: irregular firing , medium bursting, long bursting and tonically firing. In the PVKOs we observed more medium than long bursting type and that inter-spike intervals within burst were longer, with similar number of spikes/burst. This suggests that PV may affect the firing properties of RTN neurons via a mechanism associated with the kinetics of burst discharges. The immuno electron-microscopy analysis showed that Cav3.2 channels were localized at active axo-somatic synapses, thus suggesting that the differential localization of Cav3.2 in the PVKOs affects bursting dynamics. Cross-correlation analysis of simultaneously recorded neurons from the same electrode tip showed that about one third of the cell pairs tended to fire synchronously in both genotypes, independent of PV expression. In summary, PV deficiency does not affect the functional connectivity of the thalamo-cortical circuit but affects the distribution of Cav3.2 channels and the dynamics of burst discharges of RTN cells, which in turn regulate the activity in the thalamo-cortical circuit.
We investigated the ionic mechanisms that allow dynamic regulation of action potential (AP) amplitude as a means of regulating energetic costs of AP signaling. Weakly electric fish generate an electric organ discharge (EOD) by summing the APs of their electric organ cells (electrocytes). Some electric fish increase AP amplitude during active periods or social interactions and decrease AP amplitude when inactive, regulated by melanocortin peptide hormones. This modulates signal amplitude and conserves energy. The gymnotiform Eigenmannia virescens generates EODs at frequencies that can exceed 500 Hz, which is energetically challenging. We examined how E. virescens meets that challenge. E. virescens electrocytes exhibit a voltage-gated Na(+) current with extremely rapid recovery from inactivation (τ(recov) = 0.3 msec) allowing complete recovery of Na(+) current between APs even in fish with the highest EOD frequencies. Electrocytes also possess an inwardly rectifying K(+) current, and a Na(+)-activated K(+) current (I(KNa)) the latter not yet identified in any gymnotiform species. In vitro application of melanocortins increases electrocyte AP amplitude and the magnitudes of all three currents, but increased I(KNa) is a function of enhanced Na(+) influx. Numerical simulations suggest that changing I(Na) magnitude produces corresponding changes in AP amplitude and that K(Na) channels increase AP energy efficiency (10-30% less Na(+) influx/AP) over model cells with only voltage-gated K(+) channels. These findings suggest the possibility that E. virescens reduces the energetic demands of high-frequency APs through rapidly recovering Na(+) channels and the novel use of K(Na) channels to maximize AP amplitude at a given Na(+) conductance.
A key property of neurons in primary visual cortex (V1) is the distinction between simple and complex cells. Recent reports in cat visual cortex indicate the categorization of simple and complex can change depending on stimulus conditions. We investigated the stability of the simple/complex classification with changes in drive produced by either contrast or modulation by the extra-classical receptive field (eCRF). These two conditions were reported to increase the proportion of simple cells in cat cortex. The ratio of the modulation depth of the response (F1) to the elevation of response (F0) to a drifting grating (F1/F0 ratio) was used as the measure of simple/complex. The majority V1 complex cells remained classified as complex with decreasing contrast. Near contrast threshold an equal proportion of simple and complex cells changed their classification. The F1/F0 ratio was stable between optimal and large stimulus areas even for those neurons that showed strong eCRF suppression. There was no discernable overall affect of surrounding spatial context on the F1/F0 ratio. Simple - complex cell classification is relatively stable across a range of stimulus drives, either produced by contrast or eCRF suppression.
Cervical spinal cord injury (SCI) in humans typically damages both sides of the spinal cord resulting in asymmetrical functional impairments in the arms. Despite this well accepted notion and the growing emphasis on the use of bimanual training strategies, how movement of one arm affects the motion of the contralateral arm after SCI remains unknown. Using kinematics and multi-channel electromyographic (EMG) recordings we studied unilateral and bilateral reach-to-grasp movements of a small and large cylinder in individuals with asymmetric arm impairments due to cervical SCI and age-matched controls. We found that the stronger arm of SCI subjects showed movement durations longer than controls during bilateral compared with unilateral trials. Specifically, movement duration was prolonged when opening and closing the hand when reaching for a large and a small object, respectively, accompanied by deficient activation of finger flexor and extensor muscles. In subjects with SCI, inter-limb coordination was reduced compared with controls, and individuals with lesser coordination between hands were those who showed prolonged times to open the hand. Although the weaker arm showed movement durations during bilateral compared with unilateral trials that were proportional to controls, the stronger arm was excessively delayed during bilateral reaching. Altogether, our findings demonstrate that during bilateral reach-to-grasp movements the more impaired arm has detrimental effects on hand opening and closing of the less impaired arm, and that they are related, at least in part, to deficient control of EMG activity of hand muscles. We suggest that hand opening might provide a time to drive bimanual coordination-adjustments after human SCI.
Although anatomically well described, the functional role of the mammalian efferent vestibular system (EVS) remains unclear. Unlike in fish and reptiles, the mammalian EVS does not seem to play a role in modulation of primary afferent activity in anticipation of active head movements. However, it could play a role in modulating long-term mechanisms requiring plasticity such as vestibular adaptation. We measured the efficacy of vestibulo-ocular reflex (VOR) adaptation in α9-knockout mice. These mice carry a missense mutation of the gene encoding the α9 nicotinic acetylcholine receptors (nAChRs) subunit. The α9-nAChR subunit is expressed in the vestibular and auditory periphery, and its loss of function could compromise peripheral input from the predominantly-cholinergic EVS. We measured the VOR gain (eye-velocity/head-velocity) in 26 α9-knockout mice and 27 cba129 controls. Mice were randomly assigned to one of three groups: gain-increase adaptation (x1.5), gain-decrease adaptation (x0.5) or no adaptation (baseline, x1). Following adaptation training, (horizontal rotations at 0.5Hz with peak-velocity 20°/s) we measured the sinusoidal (0.2-10Hz, 20-100°/s) and transient (1500-6000°/s(2)) VOR in complete darkness. α9-knockout mice had significantly lower baseline gains compared to control mice. This difference increased with stimulus frequency (~5%<1Hz to ~25%>1Hz). Moreover, vestibular adaptation (difference in VOR gain of gain-increase and gain-decrease adaptation groups as a percentage of gain-increase) was significantly reduced in α9-knockout mice (17%) compared to controls (53%), a reduction of ~70%. Our results show that the loss of alpha9-nAChRs moderately affects the VOR, but severely affects VOR adaptation, suggesting the EVS plays a crucial role in vestibular plasticity.