12690 • The Journal of Neuroscience, September 17, 2014 • 34(38):12690 –12700
Serotonin Affects Movement Gain Control in the Spinal Cord
Kunlin Wei,1 Joshua I. Glaser,2,3,4,5 Linna Deng,1 Christopher K. Thompson,5,6 Ian H. Stevenson,2,3,4,5 Qining Wang,1
Thomas George Hornby,2,3,4,5,6 Charles J. Heckman,2,3,4,5 and Konrad P. Kording2,3,4,5
1Department of Psychology, Peking University, Beijing, China 100871, Departments of 2Physical Medicine and Rehabilitation, 3Physiology, and 4Applied
Mathematics, Northwestern University, Chicago, Illinois 60611, 5Rehabilitation Institute of Chicago, Chicago, Illinois 60611, and 6Department of
Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois 60607
A fundamental challenge for the nervous system is to encode signals spanning many orders of magnitude with neurons of limited
bandwidth. To meet this challenge, perceptual systems use gain control. However, whether the motor system uses an analogous mecha-
nism is essentially unknown. Neuromodulators, such as serotonin, are prime candidates for gain control signals during force production.
Serotonergic neurons project diffusely to motor pools, and, therefore, force production by one muscle should change the gain of others.
Here we present behavioral and pharmaceutical evidence that serotonin modulates the input– output gain of motoneurons in humans. By
selectively changing the efficacy of serotonin with drugs, we systematically modulated the amplitude of spinal reflexes. More importantly,
force production in different limbs interacts systematically, as predicted by a spinal gain control mechanism. Psychophysics and phar-
macology suggest that the motor system adopts gain control mechanisms, and serotonin is a primary driver for their implementation in
force production.

Key words: efficient control; gain control; neuromodulation; pharmacology; serotonin; spinal cord
by motoneurons in the ventral horn of the spinal cord, whose A central question in neuroscience is how neurons, with limited axons connect directly to muscle fibers Previous bandwidth, can encode signals that vary over multiple orders of physiological studies and modeling work suggested that neuro- magnitude. Gain control mechanisms, which are present in vir- modulatory gain control is necessary for force production, tually all sensory systems, effectively solve this problem because even the "maximal effort" (maximum current in mo- toneurons) would scarcely produce 40% of maximal force with- However, our motor sys- out neuromodulatory input tem faces an analogous problem . A potent neuromodulatory drive to these motoneu- rons comes from the brainstem via axons projecting mono- The forces we produce vary from fractions of a Newton, e.g., synaptically onto motoneurons and releasing either serotonin when we put a contact lens into our eye, to nearly 5000 N, the (5-HT) or norepinephrine (NE; world record in bench pressing. Because the forces we produce Both of these neuromodulators facilitate vary over multiple orders of magnitude but motor commands voltage-sensitive changes on spinal motoneurons, resulting in from the brain to spinal cord are transmitted by noisy neurons greatly increased input– output excitability, i.e., gain with limited bandwidth, a gain system would reduce noise in motor output. However, it is not currently known how, and even 5-HT is more likely to be involved in gain control, because if, the spinal cord uses such a gain control mechanism to main- 5-HT projection to the spinal cord increases its activity with in- tain accuracy over such a large range of forces.
creasing motor output whereas the NE sys- If the motor system uses a gain control mechanism, how could tem covaries with state of arousal This it do so? All motor output from the trunk and limbs is generated evidence leads to the hypothesis that 5-HT in the spinal cordplays a significant role in a motor output gain control system Received May 7, 2014; revised July 6, 2014; accepted Aug. 4, 2014.
Author contributions: K.W., J.I.G., L.D., C.K.T., I.H.S., Q.W., T.G.H., C.J.H., and K.P.K. designed research; K.W., Here, we first aim to establish that 5-HT alters gain in the J.I.G., L.D., C.K.T., I.H.S., Q.W., T.G.H., and C.J.H. performed research; K.W., J.I.G., L.D., C.K.T., I.H.S., T.G.H., C.J.H., and spinal cord. If this is true, drugs that augment/suppress 5-HT K.P.K. analyzed data; K.W., J.I.G., L.D., C.K.T., I.H.S., Q.W., T.G.H., C.J.H., and K.P.K. wrote the paper.
should also enhance/inhibit spinal reflex, which is heavily influ- The study was supported by National Natural Science Foundation of China Grants 31371020, 31328010, enced by excitability of spinal motoneurons. Second, we aim to 61005082, J1103602, and 61020106005, Beijing Nova Program Grant Z141101001814001, National High Technol-ogy Research and Development Program of China 863 Program Grant 2012AA011602, and National Institutes of show that this spinal gain mechanism is present during force Health Grants R01NS063399, P01NS044393, and R01NS034382. We thank Dr. Hongxiao Jia.
production. If this is true, because of the diffuse projection of The authors declare no competing financial interests.
5-HT into the spinal cord, intense contraction of one muscle Correspondence should be addressed to Kunlin Wei, Department of Psychology, Peking University, Beijing, China group (which requires high gain) should degrade the precision at which a subsequent low-force motor task can be achieved with Copyright 2014 the authors 0270-6474/14/3412690-11$15.00/0 other muscles. Third, we aim to show that 5-HT affects force

Wei et al. • 5-HT and Movement Gain Control in Spinal Cord J. Neurosci., September 17, 2014 • 34(38):12690 –12700 • 12691
nary trials for the experimenter to adjust the vibration head and for subjects to get ac- quainted with experimental procedures.
Experiment 2 measured the tendon reflex response as a function of drug intake in the lower extremity of individuals with reduced descending drive. Seven subjects with chronic(⬎1 year) spinal cord injury participated in two sessions separated by at least 5 d: (1) one session with 20 mg of escitalopram intake; and(2) one with 8 mg of cyproheptadine intake (administrated double-blinded). The order of the two sessions was randomized among sub- jects. In each session, data collection occurred before drug intake and 5 h after drug intake.
Subjects were seated in the adjustable height Figure 1.
Experimental setup in Experiment 1 and its data. a, Hardware setup for wrist tendon vibration. The reflexive response
chair of the testing apparatus (System 3; Biodex is a wrist extension measured by a force transducer fitted on the middle finger. b, Results from Experiment 1. The average reflexive
Medical Systems) with the hips flexed to 45° forces measured at the middle finger are plotted as a function of time in which time 0 is defined as 2 s before the vibration starts.
and the knee positioned at either 90°. Knee ex- The data from the escitalopram and the placebo control condition are plotted separately. Error bars denote mean ⫾ SEM across tension (KE) torques and surface electromyo- n ⫽ 9 subjects. The force rate during ramp-up and the force level during the last 2 s of vibration were significantly larger in the graphic (EMG) data were collected on all escitalopram condition than in the control condition ( p ⬍ 0.01 and 0.05, respectively).
subjects on the more impaired limb as deter-mined during clinical evaluation, with the production through this spinal gain mechanism. If this is true, same limb being tested during all sessions. The distal shank of the tested drugs that augment 5-HT should increase variability in precision limb was secured to the dynamometer arm, which was coupled to a 6 tasks, whereas those that block its effects should decrease variabil- degree of freedom load cell (theta; resolution, 0.025 Nm; ATI) used to ity. Our experiments test these predictions in human subjects.
assess KE torques. Surface EMG was recorded using active bipolar elec-trodes (Delsys) applied over the vastus lateralis (VL), vastus medialis Materials and Methods
(VM), and rectus femoris (RF). A 2-cm-wide convex rubber head was Experiment details. Experiment 1 measured tendon vibration reflexes aligned to the patellar tendon. The head was affixed to a load cell elicited on the left wrist as a function of drug intake. Subjects (n ⫽ 9) (resolution, 0.15 N; Omegadyne), which in turn was attached in series participated in two sessions on 2 consecutive days; (1) one session with to the end of the neodymium slider of a linear motor (model P01- escitalopram intake; and (2) one with placebo (administrated double- 23x160H-HP; LinMot). A position control strategy was used to alter blinded). The order of the two sessions was randomized among subjects, forces delivered to the tendon; forces were varied by moving the initial with four subjects taking the drug in the first session and the other five position of the tapper relative to the tendon using a constant 30 mm taking the drug in the second session. The data collection started 5 h after stroke. Reflex threshold was identified as the minimum distance neces- drug intake when the serum level of escitalopram reached its peak. Sitting sary to elicit EMG responses of at least one KE muscle. The force applied before a desk, subjects put the tip of their left middle fingers snugly into to the tendon was controlled by delivering taps at 11 different positions a metal ring, which was firmly mounted on the desk top ). Each ranging from the starting position of reflex threshold (i.e., 0 mm) and subject's middle finger was also splinted, by two wooden sticks on the moving progressively closer to the tendon in randomly ordered 1 mm lateral sides that were bundled by medical tape, to minimize the move- steps such that responses from 11 different starting positions were as- ments between phalangeal joints. The metal ring was fixed onto a force sessed. The minimum rest between tendon reflexes was 20 s, and re- transducer (resolution, 0.014 N; model Nano 17; ATI) so the reflexive sponses were elicited two to three times at each position in a blocked force could be measured. The left arm straightened out and was sup- ported on the table; the left palm faced rightward and rested against a Experiments 3–5 and the control experiments used similar paradigms.
metal surface. A 2-cm-wide, concave-shaped metal head pointed to and Subjects were seated in front of a table. In separate sessions of Experiment pressed against the left wrist to apply a vibrating stimulus. The head was 3, they either produced a leftward force against a strain gauge (resolution, screwed on one side of a force transducer (resolution, 0.28 N; model 0.056 N; model Gamma; ATI) fixed on the table top with the right index Sensotec 31; Honeywell); the other side of the force transducer was finger or the right palm or lifted the tips of their feet up against a wooden screwed onto a linear motor (model PS01-23x80; LinMot). The data fixture placed directly above the feet. When using the finger or the palm collection was organized as trials. For each trial, the initial position of the to push against the strain gauge, the subject's right forearm was inserted vibration head was adjusted so that the contact force between the head into a customizable polyvinyl chloride tube to prevent arm movement.
and the wrist, measured from the attached force transducer, was above 4 When using two feet, two Nintendo Wii Fit force sensors (resolution, N. Subjects sat idle with eyes closed after hearing a computer speaker- 0.39 N) were placed above the two feet to measure the upward force. The generated beep. After a random period of 2– 4 s, the linear motor started target force levels (low, medium, and high) were set at 5, 35, and 65%, to apply 100 Hz sinusoidal movements vertically to the wrist with a respectively, of MVC for each of the three effectors (finger, palm, and leg) peak-to-peak displacement of 0.6 mm. The vibration lasted 8 s, and the and were represented as a horizontal line on a computer screen placed in data collection continued for another 10 s, until a beep signaled the end front of the subject. The power forces produced by these effectors were of the trial. Subjects were instructed to remain relaxed through each trial.
measured and displayed in real time as a moving cursor on the screen.
The contact force between the vibration head and the wrist was con- The vertical displacement of the cursor was controlled by the force mag- stantly monitored throughout the experiment; if it dropped below 4 N, nitude, and the horizontal displacement was driven by elapsed time. Each the experimenter would adjust the initial position of the head manually trial was randomly assigned a target force level, and the subject was before the next trial started. This ensured that all trials had the same required to ramp up the power force in the first second and to maintain initial contact force. The tendon vibration elicited a wrist extension, it precisely at the target level. At 3 s, a monophonic beep signaled the which in turn generated a pushing force onto the force transducer at- subject to press the left index finger downward on a strain gauge (reso- tached to the finger ring. We also measured the maximum voluntary lution, 0.0035 N; model Nano 17; ATI). This precision force needed to contraction (MVC) of this finger extension before the vibration trials reach its target level (5% MVC, constant across all sessions) in 1 s and be started. A total of 32 vibration trials were collected: eight trials per block maintained there until the 14th second when the trial end. The target with an interblock rest period of 3 min. The first 12 trials were prelimi- level was marked as a red horizontal line on the computer screen. At 5.8 s, 12692 • J. Neurosci., September 17, 2014 • 34(38):12690 –12700
Wei et al. • 5-HT and Movement Gain Control in Spinal Cord a stereophonic tone signaled subjects to stop producing the power force.
from a nonpublic registry housed within the Rehabilitation Institute of As the power force ceased at approximately the 6th second, the two forces Chicago. They were seven males with chronic (⬎1 year) spinal lesions were simultaneously applied for ⬃2 s. The subjects were instructed to above the T10 neurological level. Injuries were incomplete, and all sub- disengage the power force by gently releasing the right index finger, the jects demonstrated residual volitional KE strength in the tested limb as right palm, or two feet from the force sensors, minimizing its impact on determined by the lower extremity motor score the precision force production. To minimize mechanical coupling be- Exclusion criteria included medical history of multiple CNS le- tween the two forces, the power force was applied in the lateral (finger sions, known reaction to study medications, and diagnosis of lower limb and palm) or upward (leg) direction, whereas the precision force was peripheral nerve injury or orthopedic injury that may limit maximal always applied downward. A monetary reward, in reverse proportion to effort during KE contractions.
the variance of the precision force, was shown on the top-left corner of All procedures of Experiment 1 and Experiments 3–5 and control the computer screen after each trial to encourage good performance.
experiments were approved by the ethics committee of Peking Univer- Experiment 3 consisted of three separate sessions, one for each effector sity. All procedures of Experiments 2 and 3 were approved by the Insti- used to produce the power force. The sequence of sessions was random- tutional Review Board of Northwestern University. All experiments were ized among seven subjects. For each session, we first calibrated the force performed in accordance with the Declaration of Helsinki.
sensors by asking subjects to place their left index finger on the strain Data analysis. For Experiment 1, the force elicited by the tendon vi- gauge and their feet below the foot fixture. The forces collected were bration reflex was measured at 1000 Hz. It was low-pass filtered at 5 Hz by averaged for zeroing the readings of the sensors. Then, MVCs of effectors a fifth-order Butterworth filter to remove the measurement noise and the for the power force and for the precision force were collected twice with vibration force transmitted from the wrist to the finger. The force data a mandatory 90 s rest between. The larger force among the two readings were then normalized by dividing by individuals' MVCs. To derive the was taken as the MVC for the session. Before formal data collection, average force curve, all trials were aligned at 2 s before the vibration (time subjects practiced the task on the apparatus for six trials. Trials in one 0). We were particularly interested in the speed of force development session were further partitioned into four blocks of 12 trials each with a immediately after the initiation of the vibration. This force rate was 90 s rest between sessions. The resting time between trials was 10 s. MVCs quantified by fitting a linear slope to the force data between the second were measured again in the middle (immediately after the second ses- and fourth seconds. We also calculated the average force level achieved sion) and after the experiment (immediately after the fourth session).
during the last 2 s of the vibration. Thirteen trials (3.6% of total trials) Experiments 4 and 5 only used the right palm as the effector for the were excluded from analyses because visual inspection revealed that sub- power force. Both experiments had different sets of eight subjects, and jects occasionally failed to follow the instruction, e.g., moving their fin- they were measured in two sessions on 2 successive days: (1) one with gers before the vibration.
drug intake; and (2) the other with placebo intake (administered double- For Experiment 2, the force delivered to the tendon and resulting blind). The two sessions were performed at the same time during the day torque and EMG responses were collected at 1000 Hz. The force signal for each subject. To minimize the learning effect, the order of the two was filtered at 220 Hz, the torque signal was low-pass filtered at 200 Hz, sessions was randomized among subjects, with four subjects taking the and the EMG signals were bandpass filtered at 20 – 450 Hz before digiti- drug on the first day and the other four taking it on the second day. In zation. The peak tap force for each tap was found offline and defined as Experiment 4, data collection started 2 h after oral intake of cyprohepta- tap onset. The peak-to-peak amplitude of the tendon reflex was calcu- dine or the placebo, because serum level of cyproheptadine usually lated for each muscle. To assess the gain of the reflex response, the reflex reaches its peak level in 2 h. For the same reason, data collection for amplitudes at the 11 different tap conditions were plotted against tap Experiment 5 was started 5 h after paroxetine intake. Both experi- force to construct a reflex response curve for each muscle. The gain of the ments used the same protocol as Experiment 3 with minor changes: tendon reflex was calculated as the linear slope of this reflex response subjects practiced for 30 trials before formal data collection to mini- curves for each muscle. One subject was excluded from the analysis in the mize the learning effect, and the number of trials within each block cyproheptadine group because tendon reflexes were unable to be elicited increased to 15.
both before and after medication. To facilitate cross-muscle comparison, Control Experiments A and B had the identical protocol as Experi- we calculated the percentage change in both the amplitude and gain ment 3 with some modifications. Only the palm was used to produce the measurements for each muscle. They were calculated as the difference power force. Control Experiment A reversed the order of the precision between the post-medication and pre-medication values divided by pre- force and the power force: the precision force reached its target level in medication values and expressed as a percentage. We tested whether the the first second and maintained there until the trial end at the 16th percentage change across muscles in reflex amplitude and gain are dif- second. The power force was ramped up between the second and the ferent from 0, after either escitalopram or cyproheptadine administra- third seconds and then dropped at the eighth second. The duration of the tion. Given the sample size and a lack of data normality, Wilcoxon's power force thus remained 5 s to facilitate comparisons between experi- signed-rank tests were used.
ments. Compared with Experiment 3, Control Experiment B switched For Experiments 3–5 and Control Experiments A and B, the precision the roles of two hands: the dominant hand produced the precision force, force was sampled at 200 Hz and the power force at 75 Hz. The precision and the nondominant hand produced the power force. Eight subjects force was bandpass filtered between 2 and 30 Hz with a fifth-order But- participated in Control Experiment A, and a different set of seven sub- terworth filter to remove slow transients and high-frequency, nonphysi- jects participated in Control Experiment B. The same seven subjects then ological measurement noise. The resulting data were aligned to the time performed Control Experiment C in which only the precision force was when the power force dropped to 50% of its target value. The SD was produced with the right finger for 18 trials.
calculated over each second before and after this time. SDs obtained were In Experiment 1, MVCs for the left middle finger extension were then normalized by dividing by the target force magnitude 7.65 ⫾ 0.54 and 7.40 ⫾ 0.65 N with escitalopram intake and without, Thus, force variance is essentially respectively. In Experiment 3, MVCs were 3.98 ⫾ 1.23 (mean ⫾ SD), quantified by the coefficient of variation (CV). This measure takes indi- 10.86 ⫾ 3.30, 23.35 ⫾ 6.87, and 48.66 ⫾ 13.63 N for the left finger, right vidual differences in the target force into account and facilitates the com- finger, right palm, and the average of both legs, respectively. In Experi- parison across participants. The mean over trials of each condition was ment 4, MVCs for the left finger were 4.50 ⫾ 0.88 and 4.61 ⫾ 0.67 N with reported. The criteria for eliminating trials included the following: (1) cyproheptadine intake and without, respectively. MVCs for the right failure to start the precision force or to stop the power force within a 2 s palm were 31.19 ⫾ 5.50 and 31.37 ⫾ 6.89 N, respectively. In Experiment window of the required time; (2) failure to stabilize the precision force 5, MVCs for the left finger were 4.78 ⫾ 0.63 and 5.06 ⫾ 0.29 N with during the 1 s before the power force stopped; and (3) failure to keep the paroxetine intake and without, respectively. MVCs for the right palm precision force within 4 SDs of the target force during the stationary part were 41.12 ⫾ 6.73 and 40.71 ⫾ 5.95 N, respectively. All subjects partici- of the trial after the power force ceased. In total, 6.7, 4.0, and 3.5% of all pated in experiments after providing informed consent. Subjects with trials were eliminated for additional analysis in the three experiments, motor incomplete spinal cord injury in Experiment 2 were recruited respectively. The number of eliminated trials did not differ between three Wei et al. • 5-HT and Movement Gain Control in Spinal Cord J. Neurosci., September 17, 2014 • 34(38):12690 –12700 • 12693
force conditions (one-way ANOVA with p ⫽ 0.94, 0.50, and 0.76, respec- 59.6% (35.3–73.1) and decreased the gain of the tendon reflex by tively). Data were examined for normality before being submitted to 70.1% (51.5– 80.3; p ⫽ 0.0002 and p ⫽ 0.0005, respectively; n ⫽ parametrical statistical analyses. The comparisons between force condi- 6). These data support modification of the gain of tendon tap tions (and between effectors) were conducted by one-sided paired t tests.
reflex by the serotonergic system.
The comparisons between drug and force conditions were conducted bytwo-way (2 drug conditions ⫻ 3 force levels) repeated-measures ANOVAs.
Why would a gain control mechanism be useful?
The comparisons between force conditions in terms of variance changesinduced by drugs were conducted by one-sided paired t tests.
Would the use of two distinct transmission channels (descendingdrives and gain) allow for more efficient transmission? We want to highlight the advantage of gain control with a simple example.
Evidence from spinal reflexes
Let us say we have a transmission system (e.g., motoneurons to To establish that 5-HT serves as a gain control signal on the spinal muscles) that can only transmit a maximal number of spikes motoneuron in humans, we examined the reflex response of ten- during a relevant interval and that we can only produce forces don vibration among healthy subjects under the influence of esci- that are proportional to the number of spikes. Let us say that our talopram (Experiment 1; ). Previous studies in animal system can produce a maximum of 10 spikes, and there is one preparations have established that 5-HT strongly potentiates spi- situation (A) in which we need forces between 0 and 1 N and another situation (B) in which we need forces between 0 and 10 N Escitalopram is a selective 5-HT reuptake inhibitor that can am- ). In this example, if we have a system with a fixed gain, plify the levels of 5-HT. The tendon vibration primarily activates then we must use a gain of 1 N/spike because a lower gain would muscle spindle Ia afferents that monosynaptically project to spi- not support the maximal forces needed in Situation B. However, nal motoneurons and is thus a spinally mediated response this means that, in Situation A, we will only be able to produce Thus, it allows us to experimentally ask how 5-HT integer-valued forces, resulting in errors up to 0.5 N. Without a affects spinal excitability.
gain factor, the need to be able to produce high forces necessitates To establish the methods we are using, we find that subjects high errors for small forces.
produced similar MVCs with and without the drug ( p ⫽ 0.57, If we can instead use a context-dependent gain, then we could paired t test). With tendon vibration, subjects immediately devel- use a gain of 0.1 N/spike in Situation A and 1 N/spike in Situation oped an extension force until reaching its plateau ). The B. In this case, we will make maximal errors in Situation A of 0.05 force dropped gradually after the vibration was turned off. All N, leading to a significant reduction in noise while leaving the subjects reported after the experiment that their hand appeared errors in Situation B unaffected. Thus, in a limited bandwidth to be moved passively, indicating that the tendon vibration reflex transmission system such as the brain, a gain system can result in had been successfully elicited more efficient transmission.
We found that the rate of force development, driven by con- stant tendon vibration stimuli, was significantly higher with esci- Model of force production with gain control
talopram intake than without ( p ⬍ 0.01, paired t test). The To be able to experimentally test the results of gain control, we average force rates were 1.35 ⫾ 0.39 and 2.2 ⫾ 0.45% of MVC per need to specify a model of how gain control affects force output.
second for the placebo and escitalopram conditions, respectively.
With a gain control mechanism, muscular force is jointly deter- The achieved force was also significantly higher as evaluated during mined by descending neural commands and gain signals. In a the last 2 s of vibration (p ⬍ 0.05, paired t test). The average forces simple model, a desired force F is the result of the descending were 4.4 ⫾ 0.76 and 6.8 ⫾ 1.1% of MVC for the placebo and escita- drive multiplied by a spinal output gain: F ⫽ gain ⫻ drive. The lopram conditions, respectively. Hence, the enhanced efficacy of drive needed to produce a given force thus depends on the output 5-HT leads to larger responses of tendon vibration reflex and thus gain: a high descending drive at low gain can yield the same supports 5-HT altering the gain of spinal motoneurons.
average force as a low descending drive at high gain ).
To further establish the role of 5-HT and also show that de- However, these situations may differ in terms of their variability.
scending drive is unlikely to contribute to these findings, we ex- Uncontrolled variability (noise) in force production is not solely amined magnitude and gain of tendon tap reflex responses in defined by the descending drive but can be influenced by gain individuals with reduced descending drive attributable to partial control at the motor output stage in the spinal cord.
spinal injury (Experiment 2). The tap evokes a brief activation of Assuming that the pool of neurons transmitting the drive has the same muscle spindle Ia afferents stimulated by tendon vibra- Poisson-like behavior, as is typical for neurons in both sensory tion Whereas the long duration of the tendon and motor systems the variance in the vibration reflex could potentially evoke non-spinal pathways, the drive is proportional to the mean drive: ␴2 tendon reflex elicited by brief taps is unequivocally spinal, mediated characterizes the Poisson-like behavior (the Fano factor; by monosynaptic EPSPs in motoneurons We sys- For a fixed gain, the SD in the force output relative to tematically varied the amplitude of the tap, allowing direct measure- the target force F will depend on the gain: ment of reflex gain across a wide input– output range Acute administration of serotonergic agents did indeed modify gain 冑␣ ⫽ ␮drive.
both the amplitude and gain of the patellar tendon reflex responseacross the quadriceps muscles After administration of esci- In our model, we find that the lower the gain, the lower the noise.
talopram, the amplitude of the tendon reflex is increased by a me- Thus, we can quantify gain control during force production by ex- dian of 36.3% (range: 18.0 –129.4) across all muscles; likewise, the amining variability because force variability depends on the gain.
gain of the tendon reflex is increased by 196.1% (45.3– 656.0), withboth metrics being significantly greater than 0 (p ⬍ 0.0001 and p Behavioral evidence from across-effector tasks
0.0001, respectively; n ⫽ 7). The opposite effects were observed in Our behavioral experiments were designed based on evidence of response to a 5-HT antagonist. Here, acute administration of a diffuse serotonergic system. Studies in animal preparations cyproheptadine decreased the amplitude of the tendon reflex by have established that the brainstem–spinal neuromodulatory sys- 12694 • J. Neurosci., September 17, 2014 • 34(38):12690 –12700
Wei et al. • 5-HT and Movement Gain Control in Spinal Cord Post Escitalopram Pre Cyproheptadine Post Cyproheptadine Figure 2.
Results of Experiment 2 with individuals with chronic spinal cord injury (SCI). a, Tap forces and elicited EMG responses for quadriceps tendon reflexes in a typical subject with and without
escitalopram intake. Muscles include VL, VM, and RF. b, Similar exemplary trials in the same subject as in a with administration of cyproheptadine. c, The peak-to-peak amplitude of the reflex
response for RF is plotted against tap force, and the reflex gain is calculated as the slope of the linear regression of the linear portion of the reflex curve (filled circles). Data are from the same typical
subject before and after escitalopram intake. d, Similar plot as in c from the same subject before and after cyproheptadine intake. e, Across all subjects, escitalopram intake produces an increase in
amplitude of the tendon reflex, producing a median 56% increase in the RF, 20% increase in the VL, and 36% increase in the VM, whereas after cyproheptadine intake, the amplitude of the tendon
reflex is decreased by 61, 48, and 59% in the RF, VL, and VM, respectively. f, The gain of the reflex was likewise modified by serotonergic agents. After escitalopram intake, the gain of the response
was increased by 196, 283, and 116%, and after cyproheptadine intake, the gain of the response was decreased by 75, 70, and 65% in the RF, VL, and VM, respectively.
tem is highly diffuse in its projection from the brainstem to the expect force production in one effector to alter the gain of the corti- cospinal pathway and thus alter force production in a separate effec- Similarly, studies in humans have sug- tor. Furthermore, this gain effect should last for a short period of gested that the excitability of the corticospinal pathway can be time after the original effector stops its force production.
enhanced with large concurrent force production in a separate In Experiments 3–5, we used a psychophysical task requiring effector This suggests that gain control two successive isometric muscular contractions using separate mechanisms and neuromodulatory signals in particular affect the effectors; we call the first the power force and the second the overall excitability of motor output throughout a limb or even precision force. In Experiment 3, the power force is produced in across the whole body. Furthermore, gain control also changes three separate conditions by the right index finger, the right palm, relatively slowly and affects many neurons at the same time or the two feet, and the intensity of the force is varied ). In it is diffuse in space and time.
Experiments 4 and 5, the power force is produced by the right Therefore, if there is a spinal gain control mechanism, we would palm only, but subjects are required to take the drugs that selec- Wei et al. • 5-HT and Movement Gain Control in Spinal Cord J. Neurosci., September 17, 2014 • 34(38):12690 –12700 • 12695
level. This is, in general, not the case ). We calculated the cross-correlation between two forces when they are simul- taneously on, 0.5 s before the completion of the power force. It is indistinguishable among three force levels, suggesting that the dependency of variance on power force levels is unlikely to be caused by me- chanical coupling.
We performed three control experi- ments to rule out other possible con- Muscle force (normalized) Synaptic input (nA of current) founding factors. The involved transients may affect the cognitive burden. In Con-trol Experiment A, we thus reversed the Figure 3.
Model of gain control. a, A hypothetical scenario with context-dependent gain control. To encode both 10 and 1 N
order of two forces, and the systematic ef- target forces with only 10 spikes (B), the best resolution for the 1 N force is 0.5 N, with a gain of 1 N/spike, which is the lowest gainthat make the 10 N force production possible. Allowing a context-dependent gain of 0.1 N/spike (A), the resolution can be 0.05 N fects of the power force onto the precision for the 1 N force while leaving the solution for the 10 N force unaffected. b, Muscle force plotted as a function of synaptic input and
force are essentially unchanged , at gain according to our model. Depending on the gain, a fixed variance in synaptic inputs translates to different levels of variance in approximately time 0 and onward). The muscle force (variances shown as Gaussian distributions).
critical comparison is for the time afterthe power force is dropped. In addition, tively suppress or enhance the efficacy of 5-HT (see Materials and we observed that the variance of the precision force does not Methods). This allows determining the serotonergic influence on differ when subjects are expecting different levels of power forces gain control.
(at ⫺7 s). This suggests there is no priming effect from upcoming For each trial, subjects ramp up the power force and stabilize it power forces.
for a fixed duration and subsequently produce a precision force Second, the precision force is always performed by the left, with the left index finger ). The power force is then nondominant hand, and thus handedness might affect the vari- switched off while the precision force remains until the end of the ance results. In Control Experiment B, the hands of the two forces trial. How the previous power force modulates the variance of are switched so that the dominant hand performed the precision the precision force is the focus of our analyses. We expected that force and the nondominant hand performed the power force.
the effects of the intense activation of the descending serotonergic The noise level in the precision force still follows a similar pattern system would gradually decline after the end of the power force as in Experiment 3 ).
for two reasons: (1) the activity of the descending system itself Third, primary results are about variance changes in the pre- would likely decline relatively slowly; and (2) there is a slow decay cision force after the power force exits; what is the natural fluc- of the persistent inward current in motoneurons tuation in variance with the precision force only? In Control We focus on the precision Experiment C, the same set of subjects from Control Experiment force variation after the power force is released rather than when B was tested to produce the precision force only. The resulting the two forces are held concurrently to minimize the effect of noise level is indistinguishable from that in the low force condi- divided attention. With these experiments, we can analyze how tion in the dual-force paradigm ), suggesting that natural gain changes in the spinal cord induced by the power force fluctuations in the precision force cannot account for the en- affect the production of a precision force (recall from the hanced noise level associated with power forces. The similarity above equation that a larger gain will lead to a larger variation between the dual-force task (Control Experiment B) and the in force production).
single-force task (Control Experiment C) also suggests that our We find that power forces affect noise levels in the concurrent findings are not a result of divided attention.
precision task (Experiment 3; –e). More importantly, asexpected by our gain control hypothesis, this effect is significant Pharmacological evidence from across-effector tasks
after the drop of power forces, and it decays toward baseline To establish a role for 5-HT in the observed cross-limb interac- within ⬃2 s. The intensity of the power force has a strong effect tions, we directly and selectively manipulated 5-HT activity with on noise levels.
drugs and examined performance in the same dual force produc- This intensity effect is observed no matter which effector is tion task as in Experiment 3. After oral intake of cyproheptadine used for power force production: the contralateral finger, hand, (Experiment 4), a selective 5-HT receptor antagonist, the excit- or the legs. The palm appears to produce the strongest effect.
atory effect of 5-HT is reduced When comparing the CV during the first second for different and the precision effectors in the high force condition, we found a significant dif- force is expected to exhibit less variance ). This variance ference between the finger and the palm ( p ⬍ 0.05). This might reduction should also be more pronounced when the magnitude be expected if assuming an approximate somatotopy in the ra- of the power force, and thus 5-HT levels, increase ).
phe–spinal projections in which the arm muscles (primarily in- We found that subjects show improved precision after cypro- volved for the palm as the effector) has more projections. Thus, heptadine intake and thus performed better after the drop; the we use the palm to elicit gain changes for all our subsequent opposite would be expected from potential side effects, such as analyses and additional experiments (Experiments 4 and 5).
drowsiness, of the drug. In agreement with our hypothesis, there If mechanical coupling was underlying the differential effect was a greater improvement after larger power forces. After oral of the power force on the precision force variance, we would intake of paroxetine (Experiment 5), which is a selective 5-HT expect that the cross-correlation between two forces should be reuptake inhibitor capable of enhancing the excitatory effect of significantly different from zero and scaled by the power force 5-HT, the opposite effect is observed ,d): the variance in 12696 • J. Neurosci., September 17, 2014 • 34(38):12690 –12700
Wei et al. • 5-HT and Movement Gain Control in Spinal Cord Experiment 1: palm d Experiment 1: finger
Precision force (N) e Experiment 1: leg
g Control Experiment 1
h Control Experiment 2 & 3
ficient of V .010 -6.5 -5.5 -4.5 -3.5 -2.5 -1.5 -0.5 0.5 1.5 Figure 4.
Results from Experiment 3 and Control Experiments A-C. a, Experimental setup for Experiments 3–5 and the control experiments. The lines on the screen represent the force instructions
for the precision force (red) and the power force (blue). b, Force signals from a typical subject during the medium power force task. Subjects were instructed to produce a precision force with their
left index finger (mean shown in blue) while first holding and afterward removing the power force. The green trace depicts a typical power force recording, dropping to half of its amplitude at time
0. Gray shading denotes SDs across trials. c– e, Variance (CV) of the precision force during each second before and after switching off the power force produced by the palm (c), the finger (d), and the
leg (e). The moment when the power force drops to its half amplitude is defined as time 0. On the time axis, 0.5 s means that the variance is calculated over the first second after time 0 (between 0
and 1 s). Significant differences have been found between power force intensity levels within the ⫺1, 1, and 2 s (not marked in graph) for all effectors. f, Cross-correlation of the power force and the
precision force is plotted as a function of time lag for three force levels separately. g, Results from Control Experiment A, presented in the same format as in c. The dashed lines represent the force
instructions for the precision force (red) and the power force (blue), which are now in the reverse order as a. Significant differences have been found between power force intensity levels within the
⫺1, 1, and 2 s (not marked in graph). There is no difference found within ⫺7 s. h, Results from Control Experiments B and C, presented in the same format as in c. Significant differences have been
found between power force intensity levels within the ⫺1, 1, and 2 s (not marked in graph). *p ⬍ 0.05, **p ⬍ 0.01, ***p ⬍ 0.001.
precision force production increases in all conditions, and this out a contribution to gain control from the cortex or other increase is significantly larger with larger power force.
components of the movement system but do provide strong We also found that, throughout the entire period, subjects had evidence that spinal motoneurons are strongly involved. We have lower variance on cyproheptadine and higher variance on parox- also shown that this gain mechanism is present during force pro- etine. Two-way repeated-measures ANOVAs (2 drug condi- duction and can manifest itself as across-effector interactions tions ⫻ 3 force levels), conducted for each experiment separately, reveal significant main effects of the drugs at different times dur- Gain control can refer to any phenomenon in which the in- ing a trial (separate tests for the ⫺1, 1, 2, and 6 s; seven of eight put– output relationship gets modulated, and hence there are tests are significant with p ⬍ 0.05 or p ⬍ 0.005, and the last test diverse uses of the concept in movement science. In many closed- comes out marginally significant with p ⫽ 0.071). These results loop situations (e.g., reflexes or perception–action loop), gain is indicate that the reduction and increase in variance induced by used to refer to the effect of feedback on future movement or drugs are significant during the whole trial, before and after the power force is dropped. Therefore, 5-HT also seems to have a reliable baseline influence on resulting variance.
sense, any increasing force can be viewed as a result of changing To rule out the possibility of central or peripheral fatigue, we gain of the muscle as increasingly more motor units get recruited compared the maximum voluntary force before, in the middle of, and after data collection in these dual-task experiments. In Ex- the present study, the gain of force control refers to the slope of periment 3, MVCs of all effectors do not change significantly input– output function between synaptic inputs (descending (one-way ANOVA on timing, p ⫽ 0.588, 0.919, 0.723, and 0.868 drives and afferent signals) and the resulting motor output (force for the right finger, palm, leg, and left finger, respectively). For the or EMG; ). This is a definition similar to what has been two drug experiments (Experiments 4 and 5), we performed a 2 used widely in the perceptual literature (drug) ⫻ 3 (timing) repeated-measures ANOVA on MVCs of the gain is one of two channels rele- finger and the palm. Neither the main effects nor the interactionis significant, indicating that fatigue does not contribute to the vant to information transmission.
observed effects and that MVCs are not affected by cyprohepta- Note that we here specifically refer to the gain control in the dine or paroxetine intake.
spinal cord. In cortical neurons, synaptic noise can markedlydecrease gain in response to input Spinal motoneurons work in a different synaptic processing regimen, Here, we have proposed that gain control in the spinal cord is having long spike afterhyperpolarizations and relatively regular computationally desirable for producing a wide range of mus- spiking outputs (CVs of firing in motoneurons in humans during cular forces and established behavioral and pharmacological voluntary contractions rarely exceed 0.2; paradigms to examine its effects and causes. Using reflex as- Instead, gain control occurs via neuromodulatory inputs, sessments, we provided strong evidence that the gain effect of such as 5-HT, that increase persistent inward currents to amplify 5-HT is based on spinal mechanisms. These results do not rule incoming synaptic current.
Wei et al. • 5-HT and Movement Gain Control in Spinal Cord J. Neurosci., September 17, 2014 • 34(38):12690 –12700 • 12697
-1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 -1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 -1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 Increase in CV .002 -1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 -1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 -1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 Figure 5.
Results from Experiments 4 and 5. a, Variance in the precision force plotted as a function of time, with or without cyproheptadine intake. The data from different power force conditions
are plotted separately. b, Variance reduction (within the 1st second) induced by cyproheptadine intake is plotted as a function of the power force. c, Variance in the precision force as a function of
time, with or without paroxetine intake. d, Variance increase (within the 1st second) induced by paroxetine intake is plotted as a function of the power force. Error bars denote mean ⫾ SEM across
n ⫽ 8 subjects. *p ⬍ 0.05.
Previous studies provide significant neurophysiological evi- in gain is negligible and it is ignored in our simple model (see dence supporting a role for 5-HT in the excitability of motor equation in Results).
Although the neuromodulatory gain control is advantageous havior of the brainstem–spinal neuromodulatory system is state in terms of offering precise control over a large range with limited dependent: quiescent in the sleeping state and tonically active in bandwidth, the obvious disadvantage for this strategy is the un- the waking state In addition, it appears likely necessary coupling between effectors. This unspecific control can that the 5-HT projection to the cord increases its activity with be negated by reciprocal inhibition mediated by spindle Ia affer- increasing motor output ents and Ia interneurons Thus, the brainstem–spinal cord neuromodulatory system Dendritic persistent inward current, which is the main could adaptively match the gain of motoneurons to the demands mechanism of serotonergic control of motoneuron gain, is highly of both precise and intense motor behaviors. This kind of gain sensitive to this inhibition control is particularly useful in cases in which communication Thus, the nervous system can still offer specific control channels are narrow. The descending pyramidal tract, for in- with a diffusive neuromodulation background if the descending stance, contains ⬍106 axons which is relatively motor commands are coupled to both brainstem monoaminer- narrow given that there are both a large number of cortical motor gic nuclei and to reciprocal inhibitory interneurons in the spinal neurons and a large number of involved muscles and fibers.
Adaptive gain control can support generating large motor output Our findings from spinal reflexes provided direct support for without sacrificing precision for small motor output.
a spinal locus for the 5-HT effect. In Experiment 1, we demon- It might be asked whether the introduction of a gain would strated that the response of the tendon vibration reflex can be also introduce noise, which might undo the advantage of using amplified by selectively manipulating 5-HT efficacy. We consider gain control. However, if the gain changes slowly, then the trans- a descending contribution unlikely to account for the gain effect mission of the gain can have a large time constant. Because SEs of we observed in Experiment 1 for two reasons. First, the subject firing rate estimates scale linearly with the inverse square root of was instructed to relax during the whole duration of a trial. The integration time, long integration time constants translate into vibration was applied at a random time in each trial to minimize small variance for slowly changing gains. Thus, the effect of noise anticipation. These measures prevented voluntary intervention 12698 • J. Neurosci., September 17, 2014 • 34(38):12690 –12700
Wei et al. • 5-HT and Movement Gain Control in Spinal Cord of reflexive responses. In fact, the difference in reflexive response ing the MVC, muscle fibers are maximally recruited, and thus the between 5-HT drug conditions is evidenced immediately after force output will not increase further even when the 5-HT effi- application of vibration ), suggesting that the gain effect is cacy is amplified. Conversely, the MVC is still unaffected when not mediated by feedback.
the 5-HT efficacy is reduced by a selective 5-HT reuptake inhib- Second, previous studies on tendon vibration reflex in ani- itor. We postulate in this case that other neuromodulators help in mals and humans established that this type of reflex is essentially amplifying the gain when large force production is demanded, as monosynaptic. In animal preparations, the tendon vibration re- revealed by single-cell studies flex is well established as being attributable to the monosynaptic Thus, this result is consistent with the notion that other connections of Ia afferents onto motoneurons neuromodulators might also play a role in gain control. For in- In humans, vibration must be applied via the skin and thus acti- stance, animal studies typically found that both 5-HT and NE vates additional afferents but the have an amplification effect. Here we focus on 5-HT because NE overall form of the reflex is identical to that in the animal. The is closely related to arousal, making 5-HT a more likely candidate tendon vibration reflexes studied here behaved just as in animal for generic neuromodulatory gain control. Moreover, the 5-HT preparations, including the tendency for a slow increase and then projection to the spinal cord increases its activity with increasing decrease that is a hallmark of the short-term plastic behavior motor output Finally, 5-HT alone can pro- exhibited by the voltage-sensitive Ca channels that generate per- duce an equally strong amplification effect as both 5-HT and NE sistent inward currents combined, as shown in an animal preparation study However, an unconscious contribution in human subjects, although unlikely, is still possible. This possibility was one reason There are many previously described changes in excitability of that prompted us to conduct Experiment 2 with tendon tap re- the human motor system. An intensive volitional contraction will flex, which is much too brief to be affected by changes in descend- result in reflex potentiation in both the contracting ing drives. We applied tendon taps to the knee instead of the wrist because of the complexity of the wrist tendon structure. Experi- ment 2 further demonstrates the spinal loci of gain control of muscles, as well as an enhancement motor output; both the magnitude and the gain of the short- of corticospinal tract excitability latency (⬍50 ms) tendon reflex is either amplified or suppressed with differing 5-HT medications in individuals with reduced cor- The proposed mechanisms underlying this remote altera- tical drive.
tion in the excitability of the motor system range from decreased Although the effect of 5-HT that we discovered in Experi- presynaptic inhibition of Ia terminals to widespread increases in ments 3–5 could in principle also be outside of the spinal cord, previous physiological work We cannot completely exclude potential contributions from these mechanisms; however, the systematic patterns elicited by makes it very likely that the action is in the spinal pharmacologically manipulating the efficacy of 5-HT on both cord. For example, our administration of drugs might affect the volitional and reflexive pathways provide firm support for both cortical control of force. However, for a single dose, their effects the neuromodulatory and spinal origins of our findings. More- are most potent on the spinal cord, because previous studies re- over, our current findings are fully consistent with these previous vealed that a moderate to high dose of 5-HT in an animal prepa- investigations, and the widespread actions of 5-HT on the gain ration can increase motoneuron throughput gain by as much as control of spinal neurons may be an unaccounted for mechanism that would aid in unifying these previous interpretations. It is dition, motoneurons are densely covered in synaptic boutons now clear that future studies on remote effects should take neu- containing 5-HT, which provide direct, monosynaptic connec- romodulatory gain control in the spinal cord into consideration.
tions from the brainstem Targeting the serotonergic system has been shown recently to In fact, the number of 5-HT synapses is larger than the be a promising strategy to improve function and reduce spasticity number of synapses from muscle spindle Ia afferents mediating after spinal cord injury the tendon tap and vibration reflexes In terms of behavior, it is important to realize that, when Hence, although we cannot exclude cortical effect for cross-limb multiple effectors are involved in movement, their noise levels are interaction, previous findings and our results on spinal reflexes not independent from one another, because gain control makes support the role of 5-HT on the spinal level.
them dependent. Gain control in the spinal cord promises to be A possible cortical mechanism is that the variance increase in important topic for research in rehabilitation and motor control.
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108326 2395.2400

Human Reproduction Vol.19, No.10 pp. 2395–2400, 2004 Advance Access publication August 19, 2004 An increase in the absolute count of CD56dimCD161CD691NK cells in the peripheral blood is associated with a poorerIVF treatment and pregnancy outcome M.Y.Thum1,2,3,4, S.Bhaskaran2, H.I.Abdalla1, B.Ford2, N.Sumar2, H.Shehata3and A.S.Bansal2 1Lister Fertility Clinic, Lister Hospital, Chelsea Bridge Road, London SW1W 8RH, 2Immunology Department and 3Women HealthDepartment, Epsom and St Helier University Hospitals NHS Trust, Surrey, UK

The dysplastic nevus: from historical perspective to management in the modern era

The dysplastic nevus: From historical perspective to management in the modern era Part II. Molecular aspects and clinical management Keith Duffy, MD,a and Douglas Grossman, MD, PhDa,b Salt Lake City, Utah The following is a journal-based CME activity presented by the American Academy of Date of release: July 2012 Dermatology and is made up of four phases: Expiration date: July 2015