Shaping the excitability of human motor cortex with premotor rTMS

Recent studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsal premotor cortex has a lasting influence on the excitability of specific neuronal subpopulations in the ipsilateral primary motor hand area (M1 _HAND ). Here we asked how these premotor to motor interactions are shaped by the intensity and frequency of rTMS and the orientation of the stimulating coil. We confirmed that premotor rTMS at 1 Hz and an intensity of 90% active motor threshold (AMT) produced a lasting decrease in corticospinal excitability probed with single-pulse TMS over the left M1 _HAND . Reducing the intensity to 80% AMT increased paired-pulse excitability at an interstimulus interval (ISI) of 7 ms. Opposite effects occurred if rTMS was given at 5 Hz: at 90% AMT, corticospinal excitability increased; at 80% AMT, paired-pulse excitability at ISI = 7 ms decreased. No effects were seen if rTMS was applied at the same intensities to prefrontal or primary motor cortices. These findings indicate that the intensity of premotor rTMS determines the net effect of conditioning on distinct populations of neurones in the ipsilateral M1 _HAND , but it is the frequency of rTMS that determines the direction of the induced change. By selecting the appropriate intensity and frequency, premotor rTMS allows to induce a predictable up- or down-regulation of the excitability in distinct neuronal circuits of human M1 _HAND .     

Timing of bimanual movements in human and non-human primates in relation to neuronal activity in primary motor cortex and supplementary motor area

It has been established that repeated presentation of a transient target motion stimulus such as a constant-velocity ramp leads to the build up of steady state (SS), anticipatory smooth pursuit eye movements after two or three presentations. Each SS response is then composed of the anticipatory component of nonvisual origin, a visual component associated with the stimulus presentation and another nonvisual component that represents the decay of the response after extinction of the stimulus. Here we investigated the interactions that occur when each motion stimulus was itself a sequence containing more than one ramp component. Ramp components had a velocity of 15 degrees /s or 30 degrees /s to left or right and were separated by gaps of 200 ms duration. In an initial experiment, responses to 2-ramp stimuli were examined and compared with responses to the single-ramp stimuli from which they were constituted. We present evidence that the anticipatory, nonvisual components of the double-ramp response result from the linear summation of the nonvisual components of the responses to the constituent single-ramp components. In a 2nd experiment, we examined responses to a wide variety of 4-ramp sequences and again found evidence that, in the SS, the responses were formed from the linear summation of the constituent single-ramp components. Regression analysis performed on the velocity at onset of each ramp component indicated that this nonvisual part of the response was predictive of the upcoming ramp component. To confirm this, unexpected changes were introduced into single ramp components of the 4-ramp sequence after at least five prior presentations of the sequence had allowed a SS response to be established. Subjects continued to initiate a response to the modified component that was appropriate in velocity and direction for the corresponding part of the previous sequence and inappropriate for the newly modified stimulus. This preprogrammed response persisted unmodified for more than 170 ms after onset of the modified ramp component. In contrast, in the second presentation of the new sequence, the anticipatory component of the response was highly correlated with the SS response of the new sequence, but not with that of the prior sequence, showing that the preprogrammed response had been modified very rapidly. Similar behaviour was observed whichever of the 4-ramp components was modified, indicating that the velocity and direction of the anticipatory response to each component had been preprogrammed. The results suggest that velocity information related to at least four elements of a sequence can be temporarily stored and subsequently released with appropriate temporal order to form an anticipatory response throughout the whole sequence.     

The remembered pursuit task: evidence for segregation of timing and velocity storage in predictive oculomotor control

Regular, repeated presentation of identical constant-velocity target motion stimuli (ramps) appears to allow build up of an internal store, release of which can be used to generate anticipatory smooth pursuit prior to subsequent target onset. Here, we examine whether release of the anticipatory response can be controlled by timing cues unrelated to the motion stimulus itself. In experiment 1, the target moved in alternate directions and was exposed for 480 ms as it passed through centre; otherwise subjects were in darkness. Inter-stimulus interval (ISI) was either regular (3.6 s) or randomized (2.7–4.3 s). Presentations were given with or without audio cues that occurred at a constant cue time (CT) prior to target appearance. Even when ISI was randomized, cues could be used to generate anticipatory smooth pursuit. Eye velocity (V100) measured 100 ms after target onset (just prior to visual feedback influence) was greater with cues than without and decreased significantly as CT increased from 240–960 ms. In experiment 2, we assessed the effects of fixation between presentations and eccentricity of target starting position, using unidirectional ramps. The target was visible for 400 ms and started on, ended on or straddled the midline. Subjects held fixation on the midline until an audio cue signalled that preparation for ensuing target appearance could begin. There was no difference in V100 between starting positions or between presence/absence of fixation. In experiment 3, we compared the effects of using audio, visual or tactile cues. All types of cue evoked anticipatory smooth pursuit, but the response to the visual cue was significantly delayed compared with the others. However, V100 was not significantly different between cues. In all experiments, V100 was scaled in proportion to target velocity over the range 12.5–50°/s, showing that this was a truly predictive response. The results provide evidence that timing and velocity storage can be independently controlled through different sensory channels and suggest that the two functions are probably carried out by separate neural mechanisms. Received: 3 December 1998 / Accepted: 11 May 1999     

Predictive smooth ocular pursuit during the transient disappearance of a visual target

When a moving target disappears and there is a complete absence of visual feedback signals, eye velocity decays rapidly but often recovers to previous levels if there is an expectation the target will reappear further along its trajectory Given that eye velocity cannot be maintained under such circumstances, the anticipatory recovery may function to minimize the developing velocity error. When there is a change in target velocity during a transient, any recovery should ideally be scaled and hence predictive of the expected target velocity at reappearance. This study confirmed that subjects did not maintain eye velocity close to target velocity for the duration of the inter-stimulus interval (ISI). The majority of subjects exhibited an initial reduction in eye velocity followed by a scaled recovery prior to target reappearance. Eye velocity during the ISI was, therefore, predictive of the expected change in target velocity. These behavioral data were simulated using a model in which gain applied to the visuomotor drive is reduced after the loss of visual feedback and then modulated depending on subject's expectation regarding the target's future trajectory.     

Volitional control of anticipatory ocular smooth pursuit after viewing, but not pursuing, a moving target: evidence for a re-afferent velocity store

 Although human subjects cannot normally initiate smooth eye movements in the absence of a moving target, previous experiments have established that such movements can be evoked if the subject is required to pursue a regularly repeated, transient target motion stimulus. We sought to determine whether active pursuit was necessary to evoke such an anticipatory response or whether it could be induced after merely viewing the target motion. Subjects were presented with a succession of ramp target motion stimuli of identical velocity and alternating direction in the horizontal axis. In initial experiments, the target was exposed for only 120 ms as it passed through centre, with a constant interval between presentations. Ramp velocity was varied from ±9 to 45°/s in one set of trials; the interval between ramp presentations was varied from 640 to 1920 ms in another. Subjects were instructed either to pursue the moving target from the first presentation or to hold fixation on another, stationary target during the first one, two or three presentations of the moving display. Without fixation, the first smooth movement was initiated with a mean latency of 95 ms after target onset, but with repeated presentations anticipatory smooth movements started to build up before target onset. In contrast, when the subjects fixated the stationary target for three presentations of the moving target, the first movement they made was already anticipatory and had a peak velocity that was significantly greater than that of the first response without prior fixation. The conditions of experiment 1 were repeated in experiment 3 with a longer duration of target exposure (480 ms), to allow higher eye velocities to build up. Again, after three prior fixations, the anticipatory velocity measured at 100 ms after target onset (when visual feedback would be expected to start) was not significantly different to that evoked after the subjects had made three active pursuit responses to the same target motion, reaching a mean of 20°/s for a 50°/s target movement. In a further experiment, we determined whether subjects could use stored information from prior active pursuit to generate anticipatory pursuit in darkness if there was a high expectancy that the target would reappear with identical velocity. Subjects made one predictive response immediately after target disappearance, but very little response thereafter until the time at which they expected the target to reappear, when they were again able to re-vitalise the anticipatory response before target appearance. The findings of these experiments provide evidence that information related to target velocity can be stored and used to generate future anticipatory responses even in the absence of eye movement. This suggests that information for storage is probably derived from a common pre-motor drive signal that is inhibited during fixation, rather than an efference copy of eye movement itself. Furthermore, a high level of expectancy of target appearance can facilitate the release of this stored information in darkness. Received: 14 January 1997 / Accepted: 30 April 1997     

The influence of cues and stimulus history on the non-linear frequency characteristics of the pursuit response to randomized target motion

When humans pursue motion stimuli composed of alternating constant velocity segments of randomised duration (RD), they nevertheless initiate anticipatory eye deceleration before stimulus direction changes at a pre-programmed time based on averaging prior stimulus timing. We investigated, in both the time and frequency domains, how averaging interacts with deceleration cues by comparing responses to stimuli composed of segments that were either constant-velocity ramps or half-cycle sinusoids. RDs were randomized within 6 ranges, each comprising 8 RDs and having differing mean RD. In sine responses, deceleration cues could be used to modulate eye velocity for long-range stimuli (RD = 840–1,200 ms) but in the shortest range (RD = 240–660 ms) cues became ineffective, so that sine responses resembled ramp responses, and anticipatory timing was primarily dependent on averaging. Additionally, inclusion of short duration (240 ms) segments reduced peak eye velocity for all RDs within a range, even when longer RDs in the range (up to 1,080 ms) would normally elicit much higher velocities. These effects could be attributed to antagonistic interactions between visually driven pursuit components and pre-programmed anticipatory deceleration components. In the frequency domain, the changes in peak velocity and anticipatory timing with RD range were translated into non-linear gain and phase characteristics similar to those evoked by sum-of-sines stimuli. Notably, a reduction in pursuit gain occurred when high-frequency components associated with short duration segments were present. Results appear consistent with an adapted pursuit model, in which pre-programmed timing information derived from an internally reconstructed stimulus signal is stored in short-term memory and controls the initiation of predictive responses.     

Anticipatory VOR suppression induced by visual and nonvisual stimuli in humans

We compared the predictive behavior of smooth pursuit (SP) and suppression of the vestibuloocular reflex (VOR) in humans by examining anticipatory smooth eye movements, a phenomenon that arises after repeated presentations of sudden target movement preceded by an auditory warning cue. We investigated whether anticipatory smooth eye movements also occur prior to cued head motion, particularly when subjects expect interaction between the VOR and either real or imagined head-fixed targets. Subjects were presented with horizontal motion stimuli consisting of a visual target alone (SP), head motion in darkness (VOR), or head motion in the presence of a real or imagined head-fixed target (HFT and IHFT, respectively). Stimulus sequences were delivered as single cycles of a velocity sinusoid (frequency: 0.5 or 1.0 Hz) that were either cued (a sound cue 400 ms earlier) or noncued. For SP, anticipatory smooth eye movements developed over repeated trials in the cued, but not the noncued, condition. In the VOR condition, no such anticipatory eye movements were observed even when cued. In contrast, anticipatory responses were observed under cued, but not noncued, HFT and IHFT conditions, as for SP. Anticipatory HFT responses increased in proportion to the velocity of preceding stimuli. In general, anticipatory gaze responses were similar in cued SP, HFT, and IHFT conditions and were appropriate for expected target motion in space. Anticipatory responses may represent the output of a central mechanism for smooth-eye-movement generation that operates during predictive SP as well as VOR modulations that are linked with SP even in the absence of real visual targets.     

Age-related change in duration of afterhyperpolarization of human motoneurones

Motor unit (MU) potentials were recorded from brachial biceps of healthy subjects aged 5.5–79 years. The subjects were subdivided into young (5.5–19 year) and adult (37.5–79 year) groups, between which single MU discharge characteristics were compared. Firing rates were in the ranges of 8.3–21.7 s⁻¹ (mean 12.87 s⁻¹) and 5.9–18.7 s⁻¹ (mean 11.08 s⁻¹) for young and adult groups, respectively. Standard deviations ( s.d. ) of interspike intervals (ISIs) were in the range 4.84–11.57 ms (mean 8.39 ms) for the young group and 4.26–12.23 ms (mean 7.76 ms) for the adult group. Both differences were statistically significant ( P < 0.001). Special attention was paid to the previously developed method of ISI variability analysis, which enabled the comparison of MUs with respect to afterhyperpolarization (AHP) duration of their motoneurones (MNs). The results show that AHP duration increases gradually with increasing age, which is in line with the transformation of muscle properties towards a slower phenotype. This transformation seems to be a continuous process, covering the entire lifespan of a human being, from childhood to senescence. The results presented here are significant for their insight into the ageing process of the neuromuscular system. The age-related change in AHP duration has not been investigated previously in human studies and has been met with ambiguous results in animal studies.     

Scaling of smooth anticipatory eye velocity in response to sequences of discrete target movements in humans

We investigated the ability to generate anticipatory smooth pursuit to sequences of constant velocity (ramp) stimuli of increasing complexity. Previously, it was shown that repeated presentation of sequences composed of four ramps with two speeds in two directions, evoked anticipatory smooth pursuit after only one or two presentations. Here, sequences of four or six ramps, each having a choice of four speeds and either one or two directions (uni- or bi-directional) were examined. The components of each sequence were presented as discrete ramps (duration: 400 ms; randomised velocity: 10–40°/s), each starting from the centre with 1,200 ms periods of central fixation between ramps, allowing anticipatory activity to be segregated from prior eye movement. Auditory warning cues occurred 600 ms prior to each target presentation. Anticipatory smooth eye velocity was assessed by calculating eye velocity 50 ms after target onset (V ₅₀), prior to the availability of visual feedback. Despite being required to re-fixate centre during inter-ramp gaps, subjects could still generate anticipatory smooth pursuit with V ₅₀ comparable to single speed control sequences, but with less accuracy. In the steady state V ₅₀ was appropriately scaled in proportion to upcoming target velocity for each ramp component and thus truly predictive. Only one to two repetitions were required to attain a steady-state for unidirectional sequences (four or six ramps), but three or four repeats were required for bi-directional sequences. Results suggest working memory can be used to acquire multiple levels of velocity information for prediction, but its use in rapid prediction is compromised when direction as well as speed must be retained.     

Predicting the duration of ocular pursuit in humans

This study examines the effects of expectation on the timing of ocular pursuit termination. Human subjects pursued repeated, constant velocity (15 or 30°/s) target motion stimuli (ramps), moving left or right. Ramps were of constant duration (RD=240, 480, 720 or 960 ms), resulting in anticipatory slowing of eye velocity prior to ramp termination and target extinction. At unexpected intervals RD was increased or decreased, but velocity remained constant. When RD increased eye velocity continued to decline, even though the target remained visible and continued to move. It took ~180 ms before eye velocity started to recover towards the steady state velocity level for the continued target motion. When RD decreased, eye velocity continued as if for a longer ramp duration, again taking ~180 ms before eye velocity started to decrease. These results suggest that timing of the response to the expected ramp duration had been pre-programmed on the basis of prior experience of ramp duration. Moreover, adjustments to timing occurred rapidly, within the second presentation of the new RD. Responses were compared to control conditions with randomised ramp duration. Eye velocity declined later in the controls for RD720 ms, as expected, but exhibited similar decline in predictable and randomised conditions for RD=960 ms. Further controls established that eye velocity could only be reliably maintained until the end of the ramp when the target was expected to continue in motion after the end of the ramp. The results suggest that estimates of stimulus duration are made continuously in all conditions, based on expectancy of target termination.     

Quantitative characterization of low-threshold mechanoreceptor inputs to lamina I spinoparabrachial neurons in the rat

It has been suggested that primary afferent C-fibres that respond to innocuous tactile stimuli are important in the sensation of pleasurable touch. Although it is known that C-tactile fibres terminate in the substantia gelatinosa (lamina II) of the spinal cord, virtually all of the neurons in this region are interneurons, and currently it is not known how impulses in C-mechanoreceptors are transmitted to higher centres. In the current study, I have tested the quantitative response properties of 'wide dynamic range' projection neurons in lamina I of the spinal cord to graded velocity brushing stimuli to identify whether low-threshold mechanoreceptor input to these neurons arises from myelinated or umyelinated nerve fibres. Graded velocity brushing stimuli (6.6–126 cm s⁻¹) were used to characterize the mechanoreceptor inputs to 'wide dynamic range' neurons in lamina I of the dorsal horn that had axons that projected to the contralateral parabrachial nucleus. The most effective tactile stimuli for activation of 'wide dynamic range' lamina I spinoparabrachial neurons were low velocity brush strokes: peak discharge occurred at a mean velocity of 9.2 cm s⁻¹ (range 6.6–20.4 cm s⁻¹, s.d. 5.0 cm s⁻¹), and declined exponentially as brush velocity increased. The data indicate that C-fibres, but not A-fibres, conveyed low-threshold mechanoreceptor inputs to lamina I projection neurons.     

A-Type potassium currents active at subthreshold potentials in mouse cerebellar purkinje cells

Voltage-dependent and calcium-independent K⁺ currents were whole-cell recorded from cerebellar Purkinje cells in slices. Tetraethylammonium (TEA, 4 m m ) application isolated an A-type K⁺ current ( I _{k ( a )}) with a peak amplitude, at +20 mV, of about one third of the total voltage-dependent and calcium-independent K⁺ current. The I _{k ( a )} activated at about −60 mV, had a V _0.5 of activation of −24.9 mV and a V _0.5 of inactivation of −69.2 mV. The deactivation time constant at −70 mV was 3.4 ± 0.4 ms, while the activation time constant at +20 mV was 0.9 ± 0.2 ms. The inactivation kinetics was weakly voltage dependent, with two time constants; those at +20 mV were 19.3 ± 3.1 and 97.6 ± 9.8 ms. The recovery from inactivation had two time constants of 60.8 ms (78.4%) and 962.3 ms (21.6%). The I _{k ( a )} was blocked by 4-aminopyridine with an IC₅₀ of 67.6 μM. Agitoxin-2 (2 n m ) blocked 17.4 ± 2.1% of the I _{k ( a )}. Flecainide completely blocked the I _{k ( a )} with a biphasic effect with IC₅₀ values of 4.4 and 183.2 μM. In current-clamp recordings the duration of evoked action potentials was affected neither by agitoxin-2 (2 n m ) nor by flecainide (3 μM), but action potentials that were already broadened by TEA were further prolonged by 4-aminopyridine (100 μM). The amplitude of the hyperpolarisation at the end of depolarising steps was reduced by all these blockers.     

Neurokinin-1 receptor desensitization to consecutive microdialysis infusions of substance P in human skin

Unloaded shortening velocity ( V ₀) of human triceps surae muscle was measured in vivo by applying the 'slack test', originally developed for determining V ₀ of single muscle fibres, to voluntary contractions at varied activation levels (ALs). V ₀ was measured from 10 subjects at five different ALs defined as a fraction (5, 10, 20, 40 and 60%) of the maximum voluntary contraction (MVC) torque. Although individual variability was apparent, V ₀ tended to increase with AL  ( R ²= 0.089; P = 0.035)  up to 60%MVC (8.6 ± 2.6 rad s⁻¹). This value of V ₀ at 60%MVC was comparable to the maximum shortening velocity of plantar flexors reported in the previous studies. Electromyographic analysis showed that the activities of soleus, medial gastrocnemius and lateral gastrocnemius muscles increased with AL during isometric contraction and after the application of quick release in a similar manner. Also, it showed that the activity of an antagonist, tibialis anterior muscle, was negligible, even though a slight increase took place after the quick release of agonist. Correlation analysis showed that there were no significant correlations between V ₀ and MVC torque normalized with respect to body mass, although the correlation coefficient was relatively high at low ALs. The results suggest that in human muscle, V ₀ represents the unloaded velocity of the fastest muscle fibres recruited, and increases with AL possibly because of progressive recruitment of faster fibres. Individual variability may be explained, at least partially, by the difference in fibre-type composition.     

Ocular pursuit responses to repeated, single-cycle sinusoids reveal behavior compatible with predictive pursuit

The link between anticipatory smooth eye movements and prediction in sinusoidal pursuit was investigated by presentation of series of identical, single-cycle, sinusoidal target motion stimuli. Stimuli occurred at randomized intervals (1.2-2.8 s) but were preceded by an audio warning cue 480 ms before each presentation. Cycle period (T) varied from 0.64 to 2.56 s and target displacement from 4 to 20 degrees in separate series. For T /=205 ms. In C, the amplitude of the single sinusoid was unexpectedly increased or decreased. When it decreased, eye velocity throughout the first half-cycle of the response was close to that executed in response to prior stimuli of higher velocity and did not return to an appropriate level for 382-549 ms. Conversely, when amplitude increased, eye velocity remained inappropriately low for the first half-cycle. Results of A and C indicate that subjects are able to use velocity information stored from prior presentations to initiate an oculomotor drive that predominates over visual feedback for the first half-cycle. Results of B indicate that the second part of the cycle is also preprogrammed because it continued despite efforts to suppress it by fixation. The results suggest that initial retinal velocity error information can be sampled, stored, and subsequently replayed as a bi-directional anticipatory pattern of movement that reduces temporal delay and could account for predictive control during sinusoidal pursuit.     

Change in contractile properties of human muscle in relationship to the loss of power and slowing of relaxation seen with fatigue

Slow relaxation from an isometric contraction is characteristic of acutely fatigued muscle and is associated with a decrease in the maximum velocity of unloaded shortening ( V _max) and both these phenomena might be due to a decreased rate of cross bridge detachment. We have compared the change in relaxation rate with that of various parameters of the force–velocity relationship over the course of an ischaemic series of fatiguing contractions and subsequent recovery using the human adductor pollicis muscle working in vivo at approximately 37°C in nine healthy young subjects. Maximal isometric force ( F ₀) decreased from 91.0 ± 1.9 to 58.3 ± 3.5 N (mean ± s.e.m. ). Maximum power decreased from 53.6 ± 4.0 to 17.7 ± 1.2 (arbitrary units) while relaxation rate declined from −10.3 ± 0.38 to −2.56 ± 0.29 s⁻¹. V _max showed a smaller relative change from 673 ± 20 to 560 ± 46 deg s⁻¹ and with a time course that differed markedly from that of slowing of relaxation, showing very little change until late in the series of contractions. Curvature of the force–velocity relationship increased ( a/F ₀ decreasing from 0.22 ± 0.02 to 0.11 ± 0.02) with fatigue and with a time course that was similar to that of the loss of power and the slowing of relaxation. It is concluded that for human muscle working at a normal physiological temperature the change in curvature of the force–velocity relationship with fatigue is a major cause of loss of power and may share a common underlying mechanism with the slowing of relaxation from an isometric contraction.     

Thermoregulatory Control of Sympathetic Fibres Supplying the Rat's Tail

We investigated the thermoregulatory responses of sympathetic fibres supplying the tail in urethane-anaesthetised rats. When skin and rectal temperatures were kept above 39 °C, tail sympathetic fibre activity was low or absent. When the trunk skin was cooled episodically by 2–7 °C by a water jacket, tail sympathetic activity increased in a graded fashion below a threshold skin temperature of 37.8 ± 0.6 °C, whether or not core (rectal) temperature changed. Repeated cooling episodes lowered body core temperature by 1.3–3.1 °C, and this independently activated tail sympathetic fibre activity, in a graded fashion, below a threshold rectal temperature of 38.4 ± 0.2 °C. Tail blood flow showed corresponding graded vasoconstrictor responses to skin and core cooling, albeit over a limited range. Tail sympathetic activity was more sensitive to core than to trunk skin cooling by a factor that varied widely (24-fold) between animals. Combined skin and core cooling gave additive or facilitatory responses near threshold but occlusive interactions with stronger stimuli. Unilateral warming of the preoptic area reversibly inhibited tail sympathetic activity. This was true for activity generated by either skin or core cooling. Single tail sympathetic units behaved homogeneously. Their sensitivity to trunk skin cooling was 0.3 ± 0.08 spikes s⁻¹°C⁻¹ and to core cooling was 2.2 ± 0.5 spikes s⁻¹°C⁻¹. Their maximum sustained firing rate in the cold was 1.82 ± 0.35 spikes s⁻¹.     

A kinetic study of blinking responses in cats

Reflexively evoked and eye-related eyelid responses were recorded using the search coil in a magnetic field technique in alert cats. The downward phase of a blink was a large (up to 21 deg), fast (up to 2000 deg s⁻¹) eyelid displacement in the closing direction, with an almost fixed rise time duration (15-20 ms); its maximum velocity was achieved in ≈10 ms. Upward eyelid motion was separated into two phases. The first phase consisted of a fast eyelid displacement, with a short duration (≈30 ms) and a maximum velocity up to 900 deg s⁻¹. The second phase had an exponential-like form, lasting for 200–400 ms, and a maximum velocity ranging between 30 and 250 deg s⁻¹. Maximum blink velocity in the downward direction was linearly related to maximum velocity of the first upward phase. The first phase in the upward direction was never observed if the eyelid stayed closed for a long period (> 50 ms) or moved slowly in the closing direction before it started to open. In these two cases, the upswing motion of the blink reflex contained only the exponential-like movement characteristic of the second upward phase, and maximum velocity in the downward direction was not related to that of the eyelid upward displacement. Mean duration of eyelid downward saccades was ≈130 ms, and their peak velocities ranged between 50 and 440 ms. A physiological model is presented explaining the active and passive forces involved in both reflex and saccadic eyelid responses. A second-order system seems to be appropriate to describe the postulated biomechanical model.     

Temperature enhances exocytosis efficiency at the mouse inner hair cell ribbon synapse

Hearing relies on fast and sustained neurotransmitter release from inner hair cells (IHCs) onto the afferent auditory nerve fibres. The temperature dependence of Ca²⁺ current and transmitter release at the IHCs ribbon synapse has not been investigated thus far. To assess the influence of temperature on calcium-triggered exocytosis, patch-clamp recordings of voltage-gated L-type Ca²⁺ influx and exocytic membrane capacitance changes were performed at room (25°C) and physiological (35–37°C) temperatures. An increase in temperature within this range increased the L-type Ca²⁺ current amplitude of IHCs ( Q ₁₀= 1.3) and accelerates the activation kinetics. Fast exocytosis, probed by 20 ms depolarization, was enhanced at physiological temperature with a Q ₁₀ of 2.1. The amplitude of fast release was elevated disproportionately to the increase in Ca²⁺ influx. In contrast, the rate of sustained exocytosis (exocytic rate between 20 and 100 ms of depolarization) did not show a significant increase at physiological temperature. Altogether, these data indicate that the efficiency of fast exocytosis is higher at physiological temperature than at room temperature and suggest that the number of readily releasable vesicles available at the active zone is higher at physiological temperature.     

Kinetics of the Reaction between a Monoclonal IgM Anti-I and Rabbit Red Cells

Covalently linked subunits, subunits aggregated from two half subunits, half subunits, F(ab'μ)₂ and Fab'μ were prepared. K-values 1900–5800 times lower than those for intact IgM and rabbit red cells were found for the covalently linked subunits, the aggregated subunits, and F(ab'μ)₂ and 12,500–38,500 times lower for half subunits and Fab'μ. Only whole subunits and F(ab'μ)₂ agglutinated rabbit red cells; compared to intact IgM the titre was reduced markedly, but from the calculated amount of molecules bound per red cell, IgM was found to be on a weight basis only twice as effective as the subunits and F(ab'μ)₂ in agglutinating the cells.     

Response linearity in primary auditory cortex of the ferret

The responses of neurons within the primary auditory cortex (A1) of the ferret elicited by broadband dynamic spectral ripple stimuli were examined over a range of ripple spectral densities and ripple velocities. The large majority of neurons showed modulated responses to these stimuli and responded most strongly at low ripple densities and velocities. The period histograms of their responses were subjected to Fourier analysis, and the ratio of the magnitudes of the f ₁ and f ₀ (DC) components of these responses were calculated to give a quantitative index of response linearity. For 82 out of 396 neurons tested (20.7%) this ratio remained above 1.0 over the entire range of ripple densities and velocities. These neurons were classified as 'consistently linear'. A further 134/396 (33.8%) of neurons maintained an f ₁/ f ₀ ratio above 1.0 for either a range of ripple densities at a fixed ripple velocity, or over a range of ripple velocities at a specific ripple density, and were classified as 'locally linear'. Interestingly, for the superficial layers of the primary auditory cortex, consistently linear and locally linear neurons outnumbered nonlinear neurons by a 2:1 ratio. The converse was true for the deep layers. Unlike in primary visual cortex, where f ₁/ f ₀ ratios have been reported to exhibit a bimodal distribution with a minimum at   f ₁/ f ₀≈ 1  , f ₁/ f ₀ ratios for A1 are unimodally distributed with a peak at   f ₁/ f ₀≈ 1  .