Effect of an α1-adrenergic blocker on plasticity elicited by motor training
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- Sawaki, L., Werhahn, K.J., Barco, R. et al. Exp Brain Res (2003) 148: 504. doi:10.1007/s00221-002-1328-x
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Recovery of motor function elicited by motor training after cortical lesions in rats is enhanced by norepinephrine (neurotransmitter mediating α1-adrenergic function) and downregulated by α1-adrenergic antagonists. In spite of this, α1-adrenergic antagonists are used to treat elderly patients with hypertension and prostate hyperplasia in stroke settings. The purpose of this study was to determine the effects of a single oral dose of the α1-adrenergic antagonist prazosin on training-dependent plasticity in intact humans, a function thought to contribute to recovery of motor function after cortical lesions. We report that prazosin decreased the ability of motor training to elicit training-dependent plasticity relative to a drug-free condition. These data suggest caution when using α1-adrenergic blockers in rehabilitative clinical settings following brain lesions.
KeywordsPlasticityMotor trainingTranscranial magnetic stimulationLearningStroke
The mammalian brain can reorganize to compensate for lost function and to adapt to new environmental challenges, a process referred to as plasticity (Karni et al. 1995; Nudo et al. 2001). In the last few years, new strategies were developed to enhance processes (Butefisch et al. 2002; Hovda et al. 1989; Walker-Batson et al. 2001). For example, animal studies raised our attention to the role of central neurotransmitters such as norepinephrine in mediating the facilitatory effects of amphetamine on motor recovery after brain injury (Feeney et al. 1993; Goldstein 2000). Additionally, norepinephrine appears to play an important role in memory consolidation (Izumi and Zorumski 1999; Sara 1998). If drugs with an α1-adrenergic function enhance these plasticity processes, it is conceivable that those with antagonistic effects play a deleterious role on human plasticity, as suggested by previous animal studies (Feeney et al. 1993). Similarly, β-adrenergic neurotransmision has been reported as influencing synaptic plasticity (Ikegaya et al. 1997).
Interestingly, drugs that antagonize the effects of norepinephrine, and also β-blockers, are used in the elderly (i.e., to treat hypertension and prostate hyperplasia) (Akduman and Crawford 2001, Ebbs 2001) associated with stroke and during neurorehabilitative treatments geared to maximize learning and recovery of motor function. This study was designed to evaluate the effects of two such drugs, prazosin, an α1-adrenergic blocker, and propranolol, a β-blocker, on human corticomotor excitability and on the ability of the intact motor cortex to experience training-dependent plasticity.
Five healthy volunteers, four of them male, with a mean age of 38 years (range 30–45) gave written informed consent and participated in this double-blind, randomized study. The protocol was approved by the National Institute of Neurological Disorders and Stroke institutional review board.
This study evaluated the effects of the α1-adrenergic blocker prazosin on motor excitability and training-dependent plasticity, in comparison with a drug-free condition. Results under prazosin were additionally compared with those obtained under the effects of propranolol, a β-blocker. Each subject was tested in three different sessions separated by at least 48 h, under the effects of 5 mg prazosin (p.o.), 40 mg propranolol (p.o.) or in a drug-free condition. Testing was started 90 min after administration of each drug, at a time when plasma concentrations are maximal for both drugs (Riva et al. 1980; Vincent et al. 1985). Subjects were continuously monitored for blood pressure and heart rate and kept in a supine position for 6–8 h after receiving each drug.
Measures of corticomotor excitability
We measured resting and active motor thresholds, intracortical inhibition and facilitation (Kujirai et al. 1993), recruitment curves of motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) (Ridding and Rothwell 1997), and the cortically induced silent period (Inghilleri et al. 1993). The electromyograph (EMG) was recorded in the right first dorsal interosseus (FDI) muscle using Ag/AgCl surface electrodes in a belly-tendon montage. Signals were amplified and filtered (bandpass 50 Hz to 1 kHz) using a Counterpoint Electromyograph (Dantec Electronics, Skovlunde, Denmark), digitized (sampling rate 5 kHz), and input into a laboratory computer for offline analysis. TMS was delivered using a figure-of-eight shaped coil connected to two Magstim-200 stimulators (Magstim Co., Whitland, Dyfed, Wales, UK) via a Bistim module. The coil was placed at the optimal scalp position for stimulation of the right FDI and rotated by 45° to the sagittal plane (Werhahn et al. 1994).
Measures of corticomotor excitability under the different treatment conditions in the absence of training. Values represent means ±SEM (MEP motor-evoked potential amplitude, test pulse; RC recruitment curves as percentage of resting motor threshold in mV; ns not significant, P>0.05)
Resting motor threshold (% of output)
Active motor threshold (% of output)
MEP amplitude (mV)
Intracortical inhibition (% of baseline)
Intracortical facilitation (% of baseline)
Drug effects on resting and active motor threshold, intracortical inhibition and facilitation at each ISI were compared using 2-tailed paired Wilcoxon statistics. Recruitment curves were compared using an analysis of variance (ANOVA) model with repeated measures (main effects intervention and stimulus intensity). Results were considered significant at the level of P<0.05.
Plasticity elicited by motor training
Subjects were tested in a supine position with the right forearm supported and semipronated in a molded arm cast. Four fingers were immobilized in slight extension while the thumb was kept completely unrestrained. EMG activity was recorded from surface electrodes placed over the belly of the extensor pollicis brevis and flexor pollicis brevis muscles, and the signal amplified, bandpass-filtered between 10–3000 Hz, and input into a laboratory computer for offline analysis. Thumb movements were recorded with a three-dimensional accelerometer mounted on the distal phalanx of the thumb (Kistler Instrument Corporation, Amherst, NY, USA). The direction of TMS-evoked and of voluntary thumb movements was calculated from the first-peak acceleration vector. Acceleration signals were recorded in the vertical (extension and flexion) and horizontal (adduction and abduction) axes and digitized at 3000 Hz. Data were analyzed using a data collection–analysis program written in LabView (National Instruments, Austin, TX, USA). TMS was delivered from a custom-built magnetoelectric stimulator (Cadwell Laboratories, Kennewick, WA, USA) through a figure-of-eight magnetic coil held on the scalp overlying the left motor cortex, at the optimal scalp position for eliciting mild and isolated right thumb movements (Classen et al. 1998). Movement thresholds were defined as the minimum stimulation intensity able to elicit consistent thumb movements. Coil position and stability were ensured using a tridimensional laser coordinate system. The head was stabilized in position with a band and soft-tip marks on the scalp. Subjects included in this experiment fulfilled the following inclusion criteria: (1) consistent (reproducible) direction of TMS-evoked thumb movements in the baseline condition, and (2) post-training TMS-evoked movement directions matched the training direction.
Subjects' relaxation was closely monitored by both EMG and auditory feedback. Trials with background EMG activity were discarded from analysis. After identifying the baseline TMS-evoked movement direction, subjects began the training period by performing voluntary brisk thumb movements in a direction opposite to baseline for 30 min at 1 Hz (Butefisch et al. 2000; Classen et al. 1998). Following each voluntary movement, the thumb returned to the start position by relaxation, as confirmed by EMG. Direction and magnitude of each voluntary training movement were monitored online, and subjects were encouraged to perform accurately and consistently. To monitor the consistency of training kinematics across conditions, we measured the angular difference between training and baseline directions, dispersion of training movement directions, and magnitude of the first-peak acceleration of these movements. After completing the training period, TMS-evoked movement directions were determined again (TMS delivered at 0.1 Hz for 10 min for a total of 60 trials).
To describe the training effects on TMS-evoked movement directions, we defined a training target zone (TTZ) as a window of ±20° centered on the training direction. Our endpoint measure was the increase in the proportion of TMS-evoked movements that fell within the TTZ after training, relative to baseline (Butefisch et al. 2000). This measure describes the ability of the motor cortex to encode the kinematic details of the practiced movements, an elementary motor memory (Classen et al. 1998).
Increases in the proportion of TMS-evoked movements in the TTZ, amplitude of MEPs, dispersion of training movement directions and the magnitude of the first-peak acceleration of these movements were analyzed using repeated measures ANOVA and post hoc tests. All data are expressed as means ±SE. Results were considered significant when P<0.05.
The results from this experiment showed that under our conditions neither prazosin nor propranolol alone, in the absence of training, elicited significant changes in resting and active motor thresholds, recruitment curves, intracortical inhibition and facilitation or silent periods when compared with those of drug-free sessions (Table 1).
Plasticity elicited by motor training
Measures of motor excitability before training under the different treatment conditions. Motor threshold (MT) and movement thresholds (MovT) in muscles mediating movements in the training direction (agonist) and in the baseline direction (antagonist) are expressed as percentage of maximal stimulator output (% Stim output). MovT is additionally expressed as percentage of MTantagonist. The motor-evoked potential (MEP) for each direction is also shown. Data are means ±SE
(% Stim output)
(% Stim output)
(% Stim output)
Training kinematics under the different treatment conditions. Peak acceleration is expressed in m/s2. Angular dispersion is expressed as length of unit vector. Data are means ±SE
The present results in a healthy population demonstrate that a single oral dose of the α1-adrenergic blocker prazosin depressed training-dependent plasticity in the intact human motor cortex in the absence of global measurable changes in corticomotor excitability. A similar non-significant trend was identified with propranolol.
It has been proposed that learning and memory (Izumi and Zorumski 1999; Sara 1998), as well as training-dependent functional recovery following brain injury (Feeney et al. 1993; Goldstein 2000), rely heavily on norepinephrine neurotransmission. Drugs that enhance α1-adrenergic function promote these cognitive processes (Kobayashi and Kobayashi 2001) while those that downregulate it could conceivably lead to deleterious effects (Feeney et al. 1993; Goldstein 2000). Similarly, it has been reported that drugs that act as β-adrenergic receptor antagonists may antagonize plastic processes (Ikegaya et al. 1997). In the absence of studies testing the effects of these compounds on human plasticity, they are often used in settings of stroke.
The purpose of this study was to evaluate the effects of the α1-adrenergic blocker prazosin and the β-blocker propranolol on a training-dependent form of human plasticity. In this paradigm, a short period of training consisting of voluntary thumb movements results in reorganization in the intact human motor cortex that encodes the kinematic details of the practiced movements and configures an elementary motor memory (Classen et al. 1998). Training-dependent plasticity is thought to play an important role in recovery of motor function following cortical lesions (Nudo et al. 2001). Therefore, drugs that limit training-dependent plasticity might have deleterious effects on motor recovery (Feeney et al. 1993).
Our results in healthy volunteers are consistent with the idea that a single oral dose of prazosin, and possibly of propranolol, substantially reduced the ability of training to encode an elementary motor memory. The magnitude of this reduction is similar to that elicited by administration of NMDA and muscarinic receptor antagonists and GABAergic agents, all known to downregulate synaptic plasticity (Butefisch et al. 2000; Sawaki et al. 2002). Interestingly, attenuation of training-dependent plasticity by prazosin and propranolol was not due to an overall change in cortical motor excitability since the drugs did not modify either resting or active motor thresholds, recruitment curves, intracortical inhibition or intracortical facilitation compared to the drug-free condition. Additionally, prazosin and propranolol did not affect motor training kinematics (as measured by the dispersion of training movement directions and magnitude of the first-peak acceleration of voluntary training movements), indicating consistency of training and attentional drive across conditions. These results extend previous reports indicating that α1-adrenergic blockers impair memory processes and recovery of motor function after brain lesions in animal models (Feeney et al. 1993; Goldstein 2000). Although the present investigation was conducted on healthy volunteers, our results are consistent with preliminary data from a multicenter study suggesting that patients who received α1-adrenergic blockers in the early stages following stroke may experience worse functional recovery than those who did not (Goldstein et al. 2002). The non-significant trend for propranolol to reduce training-dependent plasticity is also consistent with previous reports that demonstrate inhibitory effects of β-blockers on synaptic plasticity (Ikegaya et al. 1997). On the other hand, non-selective β-adrenergic receptor antagonists such as propranolol have no known detrimental effects on functional recovery after brain injury (Feeney and Westerberg 1990).
We wish to thank our subjects for their participation in the study, and M. Hallett for critical comments. We also gratefully acknowledge A.H. Burstein, R.Villadiego and N. Dang for invaluable technical support and D.G. Schoenberg for skillful editing. This work was partially supported by a grant from the Office of Alternative Medicine, National Institutes of Health, USA (OAM-NIH).