General, spinal or regional anaesthesia does not affect strength performance 6 months after ACL reconstruction.

PURPOSE: The recovery of strength is a key element in successfully returning to sports after ACL reconstruction. The type of anaesthesia has been suspected an influential factor in the post-operative recovery of muscle function. METHODS: In this retrospective analysis, n = 442 consecutive patients undergoing primary isolated ACL reconstruction using a hamstring autograft were analysed by pre- and post-operative isokinetic tests in a single orthopaedic centre. These were subdivided into four cohorts: (1) general anaesthesia (n = 47), (2) general anaesthesia with prolonged (48 h) on-demand femoral nerve block (n = 37), (3) spinal anaesthesia (n = 169) and (4) spinal anaesthesia with prolonged (48 h) on-demand femoral nerve block (n = 185). Primary outcome was the change from pre- to post-operative isokinetic strength during knee extension and flexion. RESULTS: Using one-way ANOVA, there was no significant influence of the type of anaesthesia. The main effect of anaesthesia on change in extension forces was not significant, and effect sizes were very small (n.s.). Similarly, the main effect of anaesthesia on change in flexion forces was statistically not significant (n.s.). CONCLUSIONS: The findings of this study support the interpretation that the type of anaesthesia has no significant effect on the ability to recover thigh muscle strength 6 months after isolated hamstring ACL reconstruction. With regard to the recovery of athletic performance and return-to-sports testing criteria, there is no reason to avoid regional anaesthesia. LEVEL OF EVIDENCE: III.

How limb dominance influences limb symmetry in ACL patients: effects on functional performance.

BACKGROUND: Timing for return to sport (RTS) after anterior cruciate ligament (ACL) injury is paramount for the avoidance of a secondary injury. A common criterion in RTS decision-making is the limb symmetry index (LSI) which quantifies (a)symmetries between the affected and unaffected limb. Limb dominance is one of many factors that may contribute to the recovery of the LSI after ACL reconstruction. The purpose of this study was to examine how limb dominance affects the LSI of functional performance tasks nine months following ACL reconstruction (time of RTS). METHODS: At time of return to sport, n = 100 patients (n = 48 injured the dominant limb, n = 52 injured the non-dominant limb, n = 34 female, n = 66 male) with ACL reconstruction surgery performed isokinetic strength measurements of the knee extensors and flexors, and drop jumps (DJ), single leg hop for distance (SHD) and 6 m timed hop (6MTH) testings. RESULTS: The findings indicated that injury of the dominant leg led to significantly higher LSI values in maximal isokinetic knee extensor strength (p = 0.030). No significant differences were observed for maximal isokinetic knee flexor strength, DJ, SHD or 6MTH performance. Stratifying for sex revealed no significant differences. Simple regression analyses demonstrated that LSI in maximal knee extensor strength significantly predicted LSIs in DJ and SHD while explaining 14% and 18% of the respective variance. CONCLUSIONS: Given that limb dominance affects the LSI of muscle strength suggests that a differentiated interpretation of the LSI with respect to limb dominance should be considered for a safe return to sport. Monoarticular knee extensor strength and multiarticular hop test performance are interrelated and thus can show asymmetries which are not maladaptive but established during years of habituation or training.

Relationship between pre- and post-operative isokinetic strength after ACL reconstruction using hamstring autograft.

BACKGROUND: Anterior cruciate ligament (ACL) ruptures are of major concern in sports. As mostly young and active individuals are affected there is an emphasis on the rapid and safe return to sports (RTS). Strengthening the ventral and dorsal thigh muscles is a prerequisite for a successful RTS after ACL reconstruction (ACLR), as persistent muscle weakness may increase the incidence for secondary injuries and impair performance. Aiming to increase evidence on the importance of preoperative muscle strength and the coaching of patients, the purpose of this study is to compare thigh muscle strength pre- and post-operatively after ACLR. METHODS: We performed a retrospective analysis of 80 patients with primary, isolated ACLR using a four-stranded hamstring autograft. We performed bilateral isokinetic concentric strength measurement (60°/s) before and six months after ACLR. Primary outcomes were the maximal knee extension and flexion torque, hamstrings-to-quadriceps ratio (H/Q ratio) and the corresponding limb symmetry indices (LSI). Pearson correlations were calculated for pre- and post-surgical values. RESULTS: The operated as well as the unaffected leg increased maximal knee extension (+ 18% ± 7% p < 0.05; + 11% ± 5% p < 0.05) and flexion torque (+ 9% ± 5% p < 0.05, + 10% ± 6% p < 0.05) throughout the 6 months of rehabilitation. The H/Q ratio remained unaffected (- 2% ± 3% p = 0.93; - 4% ± 4% p = 0.27). LSI of knee extension strength increased significantly (6% ± 3% p < 0.05), while flexion strength remained unaffected (+ 2% ± 4% p = 0.27). Positive correlations underline the interrelationship between the strength pre- and post-surgery for the knee extension (r = 0.788 p < 0.05) and knee flexion strength (r = 0.637 p < 0.05) after ACLR. CONCLUSIONS: Preoperative leg extension and flexion strength normalized to body mass are strongly correlated to postoperative strength performance after ACLR. Therefore, pre-operative quadriceps and hamstring muscle strength deficits may have a significant negative impact on functional performance following ACLR. This emphasizes the need for intensive preoperative screening and subsequent treatment to achieve the best possible preoperative leg strength before ACLR. TRIAL REGISTRATION: DRKS00020210 .

Acute corticospinal and spinal modulation after whole body vibration.

OBJECTIVES: The objective of this study was to investigate neural effects of acute whole body vibration (WBV) on lower limb muscles regarding corticospinal and spinal excitability. METHODS: In 44 healthy subjects (16 f/ 28 m), motor evoked potentials (MEP) and H-reflexes in m. soleus (SOL) and gastrocnemius medialis (GM) were elicited before (t1), immediately after (t2), 2 (t3), 4 (t4) and 10 min after (t5) WBV. RESULTS: After WBV, MEP amplitudes were significantly increased in SOL (t2+15±30%, t3+22±32%, t4+15±35%, t5+20±30%, P<0.05), but not in GM (t2+32±62%, t3+9±35%, t4+8±36%, t5+22±47%; P=0.07). Contrarily, H-reflexes were significantly reduced in SOL (t2-19±28%, t3-21±22%, t4-20±21%, t5-14±28%, P<0.05) and GM (t2-14±37%, t3-16±25%, t4-18±29%, t5-16±28%, P<0.05). CONCLUSIONS: A temporary sustained enhancement of corticospinal excitability concomitant with spinal inhibition after WBV points towards persisting neural modulation in the central nervous system. This could indicate greater neural modulation over M1 and descending pathways, while the contribution of spinal pathways is reduced.

Improved postural control in response to a 4-week balance training with partially unloaded bodyweight.

Balance training (BT) is successfully implemented in therapy as a countermeasure against postural dysfunctions. However, patients suffering from motor impairments may not be able to perform balance rehabilitation with full body load. The purpose of this study was to investigate whether partial unloading leads to the same functional and neuromuscular adaptations. The impact on postural control of a 4-week BT intervention has been compared between full and partial body load. 32 subjects were randomly assigned to a CON (conventional BT) or a PART group (partially unloaded BT). BT comprised balance exercises addressing dynamic stabilization in mono- and bipedal stance. Before and after training, centre of pressure (COP) displacement and electromyographic activity of selected muscles were monitored during different balance tasks. Co-contraction index (CCI) of soleus (SOL)/tibialis (TA) was calculated. SOL H-reflexes were elicited to evaluate changes in the excitability of the spinal reflex circuitry. Adaptations in response to the training were in a similar extent for both groups: (i) after the intervention, the COP displacement was reduced (P<0.05). This reduction was accompanied by (ii) a decreased CCI of SOL/TA (P<0.05) and (iii) a decrease in H-reflex amplitude (P<0.05). BT under partial unloading led to reduced COP displacements comparable to conventional BT indicating improved balance control. Moreover, decreased co-contraction of antagonistic muscles and reduced spinal excitability of the SOL motoneuron pool point towards changed postural control strategies generally observed after full body load training. Thus, BT considering partial unloading is an appropriate alternative for patients unable to conduct BT under full body load.

The effect of whole body vibration on the H-reflex, the stretch reflex, and the short-latency response during hopping.

The effect of whole body vibration (WBV) on reflex responses is controversially discussed in the literature. In this study, three different modalities of reflex activation with increased motor complexity have been selected to clarify the effects of acute WBV on reflex activation: (1) the electrically evoked H-reflex, (2) the mechanically elicited stretch reflex, and (3) the short-latency response (SLR) during hopping. WBV-induced changes of the H-reflex, the stretch reflex, and the SLR during hopping were recorded in the soleus and gastrocnemius muscles and were analyzed before, during (only the H-reflex), immediately after, 5 min and 10 min after WBV. The main findings were that (1) the H-reflexes were significantly reduced during and at least up to 5 min after WBV, (2) the stretch reflex amplitudes were also significantly reduced immediately after WBV but recovered to their initial amplitudes within 5 min, and (3) the SLR during hopping showed no vibration-induced modulation. With regard to the modalities with low motor complexities, the decreased H- and stretch reflex responses are assumed to point toward a reduced Ia afferent transmission during and after WBV. However, it is assumed that during hopping, the suppression of reflex sensitivity is compensated by facilitatory mechanisms in this complex motor task.

Leg stiffness can be maintained during reactive hopping despite modified acceleration conditions.

AIM: The aim of the present study was to evaluate reactive hops under systematically modified acceleration conditions. It was hypothesized that a high preactivity of the leg extensors and phase-specific adjustments of the leg muscle activation would compensate the alterations caused by the various acceleration levels in order to maintain a high leg stiffness, thus enabling the jumper to perform truly reactive jumps with short ground contact times despite the unaccustomed acceleration conditions. METHODS: Ground reaction forces (GRF), kinematic and electromyographic data of 20 healthy subjects were recorded during reactive hopping in a special sledge jump system for seven different acceleration levels: three acceleration levels with lower than normal gravity (0.7g, 0.8g, 0.9g), one with gravitational acceleration (1g) and three with higher acceleration (1.1g, 1.2g, 1.3g). RESULTS: The increase of the acceleration from 0.7g to 1.3g had no significant effect on the preactivity of the leg extensors, the leg stiffness and the rate of force development. However, it resulted in increased peak GRF (+15%), longer ground contact time (+10%) and increased angular excursion at the ankle and knee joints (+3°). DISCUSSION: Throughout a wide acceleration range, the subjects were able to maintain a high leg stiffness and perform reactive hops by keeping the preactivity constantly high and adjusting the muscle activity in the later phases. In consequence, it can be concluded that the neuromuscular system can cope with different acceleration levels, at least in the acceleration range used in this study.

Electrolytic lesions within central complex neuropils of the cockroach brain affect negotiation of barriers.

Animals must negotiate obstacles in their path in order to successfully function within natural environments. These actions require transitions from walking to other behaviors, many of which are more involved than simple reflexes. For these behaviors to be successful, insects must evaluate objects in their path and then use that information to change posture or re-direct leg movements. Some of this control may occur within a region of the brain known as the central complex (CC). We used discrete electrolytic lesions to examine the role of certain sub-regions of the CC in various obstacle negotiation behaviors. We found that cockroaches with lesions to the protocerebral bridge (PB) and ellipsoid body (EB) exhibit abnormalities in turning and dealing with shelf-like objects; whereas, individuals with lesions to the fan-shaped body (FB) and lateral accessory lobe (LAL), exhibit abnormalities of those behaviors as well as climbing over blocks and up walls to a horizontal plane. Abnormalities in block climbing include decreased success rate, changes in climbing strategy, and delayed response to the block. Increases in these abnormal behaviors were significant in individuals with lesions to the FB and LAL. Although turning abnormalities are present in individuals with lesions to the LAL, EB and the lateral region of the FB, there are some differences in how these deficits present. For instance, the turning deficits seen in individuals with lateral FB lesions only occurred when turning in the direction opposite to the side of the brain on which the lesion occurred. By contrast, individuals with lesions to the EB and LAL exhibited turning abnormalities in both directions. Lesions in the medial region of the FB did not result in directional turning deficits, but in abnormalities in block climbing.

A new sledge jump system that allows almost natural reactive jumps.

AIM: Sledge jump systems (SJS) are often employed to examine the underlying mechanical and neuromuscular mechanisms of the stretch-shortening cycle (SSC) as they allow the systematic variation of impact velocity and energy. However, in existing SJS the jumps are not very comparable to natural jumps because of the long contact times (∼200%), which prevent the storage of kinetic energy. The aim of the present study was to evaluate if an ultra-light sledge, built in a way that joint movement is barely restricted, allows jumps that are comparable to natural jumps. METHODS: Ground reaction forces, kinematic and electromyographic (EMG) data of 21 healthy subjects were compared between normal hoppings (NH) on the ground and hoppings in a custom-built SJS (sledge hoppings, SH). RESULTS: Normalized to NH, the ground contact times for the SH were prolonged (+22%), while the peak forces (-21%) and the preactivity of the soleus and gastrocnemius medialis muscles were reduced (-20% and -22%, respectively). No significant changes were observed for the iEMG of the short latency response of those muscles (+1% and +8%) and the ranges of motion in the ankle, knee and hip joint (differences of 1, 1 and 2 degrees). The reduced peak forces were associated with a reduced leg stiffness (-21%). CONCLUSION: The new system allows reactive jumps that are rather comparable to natural jumps. Therefore, the new SJS seems to be an adequate system in order to examine the SSC under controlled and almost natural conditions.

Characterization of obstacle negotiation behaviors in the cockroach, Blaberus discoidalis.

Within natural environments, animals must be able to respond to a wide range of obstacles in their path. Such responses require sensory information to facilitate appropriate and effective motor behaviors. The objective of this study was to characterize sensors involved in the complex control of obstacle negotiation behaviors in the cockroach Blaberus discoidalis. Previous studies suggest that antennae are involved in obstacle detection and negotiation behaviors. During climbing attempts, cockroaches swing their front leg that then either successfully reaches the top of the block or misses. The success of these climbing attempts was dependent on their distance from the obstacle. Cockroaches with shortened antennae were closer to the obstacle prior to climbing than controls, suggesting that distance was related to antennal length. Removing the antennal flagellum resulted in delays in obstacle detection and changes in climbing strategy from targeted limb movements to less directed attempts. A more complex scenario - a shelf that the cockroach could either climb over or tunnel under - allowed us to further examine the role of sensory involvement in path selection. Ultimately, antennae contacting the top of the shelf led to climbing whereas contact on the underside led to tunneling However, in the light, cockroaches were biased toward tunnelling; a bias which was absent in the dark. Selective covering of visual structures suggested that this context was determined by the ocelli.

Effects of aging on behavior and leg kinematics during locomotion in two species of cockroach.

Aging is often associated with locomotor deficits. Behavior in aged Blaberus discoidalis cockroaches was analyzed during horizontal walking, climbing, righting and inclined walking. Adult animals showed a decrease in spontaneous locomotion with increasing age. Tarsal abnormalities, termed 'tarsus catch', were often present in aged individuals. In 'tarsus catch', the prothoracic leg catches on the mesothoracic leg during the swing phase. This deficit causes alterations of the gait, but animals are able to regain a tripod gait after the perturbation. The tibio-tarsal joint angle in individuals with 'tarsus catch' was significantly less than in intact animals. Structural defects were consistently associated with 'tarsus catch'. The tracheal tubes in the tarsus and around the tibio-tarsal joint were often discolored and the tarsal pads were hardened in aged cockroaches. All aged individuals were able to climb. However, prior to climbing, some animals with 'tarsus catch' failed to show postural changes that are normally seen in young animals. Aged individuals can right as rapidly as 1-week-old adults. However, animals with 'tarsus catch' take longer to right than aged intact individuals. Old cockroaches have difficulty climbing an incline of 45 degrees, and leg slipping is extensive. Slipping may be caused by tarsal degeneration, but animals that are unsuccessful in inclined walking often show uncoordinated gaits during the attempt. Escape behavior was examined in aged American cockroaches (Periplaneta americana). They do not show normal escape. However, after decapitation, escape movements return, suggesting that degeneration in head ganglia may actually interfere with escape. These findings provide evidence for age-related changes both in the periphery and in the central nervous system of cockroaches and stress the importance of multi-level approaches to the study of locomotion.

Descending influences on escape behavior and motor pattern in the cockroach.

The escape behavior of the cockroach is a ballistic behavior with well characterized kinematics. The circuitry known to control the behavior lies in the thoracic ganglia, abdominal ganglia, and abdominal nerve cord. Some evidence suggests inputs may occur from the brain or suboesophageal ganglion. We tested this notion by decapitating cockroaches, removing all descending inputs, and evoking escape responses. The decapitated cockroaches exhibited directionally appropriate escape turns. However, there was a front-to-back gradient of change: the front legs moved little if at all, the middle legs moved in the proper direction but with reduced excursion, and the rear legs moved normally. The same pattern was seen when only inputs from the brain were removed, the suboesophageal ganglion remaining intact and connected to the thoracic ganglia. Electromyogram (EMG) analysis showed that the loss of or reduction in excursion was accompanied by a loss of or reduction in fast motor neuron activity. The loss of fast motor neuron activity was also observed in a reduced preparation in which descending neural signals were reversibly blocked via an isotonic sucrose solution superfusing the neck connectives, indicating that the changes seen were not due to trauma. Our data demonstrate that while the thoracic circuitry is sufficient to produce directional escape, lesion or blockage of the connective affects the excitability of components of the escape circuitry. Because of the rapidity of the escape response, such effects are likely due to the elimination of tonic descending inputs.

Multi-joint coordination during walking and foothold searching in the Blaberus cockroach. I. Kinematics and electromyograms.

Cockroaches were induced to walk or search for a foothold while they were tethered above a glass plate made slick with microtome oil. We combined kinematic analysis of leg joint movements with electromyographic (EMG) recordings from leg extensor muscles during tethered walking and searching to characterize these behaviors. The tethered preparation provides technical advantages for multi-joint kinematic and neural analysis. However, the behavioral relevance of the tethered preparation is an important issue. To address this issue, we evaluated the effects of tethering the animals by comparing kinematic parameters of tethered walking with similar data collected previously from cockroaches walking freely on a treadmill at the same speeds. No significant differences between tethered and treadmill walking were found for most joint kinematic parameters. In contrast, comparison of tethered walking and searching showed that the two behaviors can be distinguished by analysis of kinematics and electrical data. We combined analysis of joint kinematics and electromyograms to examine the change in multi-joint coordination during walking and searching. During searching, middle leg joints extended during swing rather than stance (i.e., walking) and the coordination of movements and extensor motor neuron activity at the coxa-trochanteral and femur tibia joints differed significantly during walking and searching. We also found that the pattern of myographic activity in the middle leg during searching was similar to that in the front legs during walking.

Multi-joint coordination during walking and foothold searching in the Blaberus cockroach. II. Extensor motor neuron pattern.

In a previous study, we combined joint kinematics and electromyograms (EMGs) to examine the change in the phase relationship of two principal leg joints during walking and searching. In this study, we recorded intracellularly from motor neurons in semi-intact behaving animals to examine mechanisms coordinating extension at these leg joints. In particular, we examined the change in the phase of the coxa-trochanter (CTr) and femur-tibia (FT) joint extension during walking and searching. In doing so, we discovered marked similarities in the activity of CTr and FT joint extensor motor neurons at the onset of extension during searching and at the end of stance during walking. The data suggest that the same interneurons may be involved in coordinating the CTr and FT extensor motor neurons during walking and searching. Previous studies in stick insects have suggested that extensor motor neuron activity during the stance phase of walking results from an increase in tonic excitation of the neuron leading to spiking that is periodically interrupted by centrally generated inhibition. However, the CTr and FT extensor motor neuron activity during walking consists of characteristic phasic modulations in motor neuron frequency within each step cycle. The phasic increases and decreases in extensor EMG frequency during stance are associated with kinematic events (i.e., foot set-down and joint cycle transitions) during walking. Sensory feedback associated with these events might be responsible for phasic modulation of the extensor motor neuron frequency. However, our data rule out the possibility that sensory cues resulting from foot set-down are responsible for a decline in CTr extensor activity that is characteristic of the Blaberus step cycle. Our data also suggest that both phasic excitation and inhibition contribute to extensor motor neuron activity during the stance phase of walking.

Characterization of tactile-sensitive interneurons in the abdominal ganglia of the cockroach, Periplaneta americana.

Tactile stimulation of an insect's abdomen evokes various behaviors including grooming and vigorous escape responses. We tested a sample of 37 tactile-sensitive abdominal interneurons for various morphological and physiological characteristics, including their ability to excite thoracic interneurons that are known to integrate wind information conducted by giant interneurons in the classical escape response. The results suggest that abdominal tactile-sensitive interneurons are heterogeneous both in anatomical and physiological properties. In general, these cells are very small interganglionic interneurons that respond to tactile stimulation at more than one abdominal segment. However, the larger population contained virtually all types of cells. Some projected anteriorly, others posteriorly, and still others projected in both directions. For most cells, the soma was on the side opposite to their axons, but in 24% of the cells it was on the same side. Patterns of dendritic arbors also varied among cells. However, tactile sensitivity was in general consistent with the morphological bias noted in dendritic branch patterns. We were able to document the existence of tactile abdominal interneurons that connect directly to thoracic interneurons involved in escape (TI[A]s). However, instances of demonstrated connectivity were rare. One cell that did show connectivity (AI652) was characterized in detail, and its properties were appropriate for conducting tactile signals in a directional escape system. The dendritic arbors were biased to the side that was ipsilateral to the cell's soma and axon. As a result, this cell's abdominal inputs and thoracic outputs are on the same side. This pattern is appropriate for generating the sensory fields recorded previously in TI(A)s. Its axon was located in the ventral median tract, which should bring it close to the integrating region of the TI(A)s.

Leg kinematics and muscle activity during treadmill running in the cockroach, Blaberus discoidalis: I. Slow running.

We have combined high-speed video motion analysis of leg movements with electromyogram (EMG) recordings from leg muscles in cockroaches running on a treadmill. The mesothoracic (T2) and metathoracic (T3) legs have different kinematics. While in each leg the coxa-femur (CF) joint moves in unison with the femurtibia (FT) joint, the relative joint excursions differ between T2 and T3 legs. In T3 legs, the two joints move through approximately the same excursion. In T2 legs, the FT joint moves through a narrower range of angles than the CF joint. In spite of these differences in motion, no differences between the T2 and T3 legs were seen in timing or qualitative patterns of depressor coxa and extensor tibia activity. The average firing frequencies of slow depressor coxa (Ds) and slow extensor tibia (SETi) motor neurons are directly proportional to the average angular velocity of their joints during stance. The average Ds and SETi firing frequency appears to be modulated on a cycle-by-cycle basis to control running speed and orientation. In contrast, while the frequency variations within Ds and SETi bursts were consistent across cycles, the variations within each burst did not parallel variations in the velocity of the relevant joints.

Leg kinematics and muscle activity during treadmill running in the cockroach, Blaberus discoidalis: II. Fast running.

We have combined kinematic and electromyogram (EMG) analysis of running Blaberus discoidalis to examine how middle and hind leg kinematics vary with running speed and how the fast depressor coxa (Df) and fast extensor tibia (FETi) motor neurons affect kinematic parameters. In the range 2.5-10 Hz, B. discoidalis increases step frequency by altering the joint velocity and by reducing the time required for the transition from flexion to extension. For both Df and FETi the timing of recruitment coincides with the maximal frequency seen for the respective slow motor neurons. Df is first recruited at the beginning of coxa-femur (CF) extension. FETi is recruited in the latter half of femur-tibia (FT) extension during stance. Single muscle potentials produced by these fast motor neurons do not have pronounced effects on joint angular velocity during running. The transition from CF flexion to extension was abbreviated in those cycles with a Df potential occurring during the transition. One effect of Df activity during running may be to phase shift the beginning of joint extension so that the transition is sharpened. FETi is associated with greater FT extension at higher running speeds and may be necessary to overcome high joint torques at extended FT joint angles.

Biorobotic approaches to the study of motor systems.

Biorobotics is a promising new area of research at the interface between biology and robotics. Robots can either be used as physical models of biological systems or be directly inspired by biological studies. A great deal of progress has recently been made in biorobotic studies of locomotion, orientation, and vertebrate arm control.

AIT-082, a novel purine derivative with neuroregenerative properties.

Preclinical and clinical evidence support the effectiveness of neurotrophins in Alzheimer's disease (AD) and neurodegenerative diseases. Delivery of neurotrophins to target sites in the brain remains a major obstacle for their use in humans. Development of orally active agents that mimic the effects of nerve growth factor and other neurotrophins provides a promising alternative therapeutic strategy. AIT-082, a purine analogue, has been shown to reverse age-induced memory deficits in mice and is a growth factor-mimetic agent. It is orally active, rapidly penetrates the blood-brain barrier and induces the production of multiple growth factors at the appropriate target site in the central nervous system (CNS).