Motor Response Threshold Research Articles

Predictors of the outcome of percutaneous nerve evaluation for faecal incontinence

The aim was to identify patient-related and operative factors that might predict the outcome of percutaneous nerve evaluation (PNE). Demographic data (age, sex, body mass index), primary cause of incontinence, number and type of incontinence episodes, results of endoanal ultrasonography and manometry, and operative factors from 244 patients who underwent PNE for faecal incontinence were reviewed. Each factor was assessed according to the outcome, and explored by univariable and multivariable analysis to identify predictors. Some 191 patients (78.3 per cent) had a successful PNE. A low amplitude of sensory threshold during PNE (odds ratio (OR) 0.69 (95 per cent confidence interval 0.59 to 0.81); P < 0.001) and lead placement anterior to the sacral cortex (OR 9.06 (4.70 to 17.45); P < 0.001) were positive predictive factors for successful outcome of PNE. Neither a defect nor an abnormality of either the external (OR 0.88 (0.39 to 1.97); P = 0.749) or internal (OR 0.62 (0.27 to 1.42); P = 0.255) anal sphincter was a negative predictive factor. Demographic variables, number of incontinence episodes and the motor response threshold did not predict outcome. No preoperative predictor of PNE outcome could be identified. Predictors were limited to operative lead placement and sensory response during PNE.

Prognostic Value of Neurophysiologic Intraoperative Monitoring in Tethered Cord Syndrome Surgery

Neurophysiologic intraoperative monitoring is used in surgery for tethered cord syndrome. Our objective was to determine if neurophysiologic intraoperative monitoring is helpful in identifying which patients will have worsening symptoms after surgery. The spinal cord was stimulated before and after untethering until a motor response was obtained. The pre- and postoperative neurologic examination findings were noted. The motor response thresholds before and after untethering were compared using Student t tests. Forty patients were identified; 37 had higher motor response thresholds before untethering, whereas in three thresholds were higher after untethering. Of the 37 patients, two had worsening of motor function. All three patients with higher thresholds after untethering had worsening of motor function (P < 0.0001). An increase in the motor response threshold after surgical release of tethered cord syndrome indicates possible worsening of clinical symptoms. Spinal cord stimulation during tethered cord syndrome surgery may help predict neurologic outcome.

Transcranial magnetic stimulation in ALS

To investigate transcranial magnetic stimulation (TMS) measures as clinical correlates and longitudinal markers of amyotrophic lateral sclerosis (ALS). We prospectively studied 60 patients with ALS subtypes (sporadic ALS, familial ALS, progressive muscular atrophy, and primary lateral sclerosis) using single pulse TMS, recording from abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. We evaluated three measures: 1) TMS motor response threshold to the ADM, 2) central motor conduction time (CMCT), and 3) motor evoked potential amplitude (correcting for peripheral changes). Patients were evaluated at baseline, compared with controls, and followed every 3 months for up to six visits. Changes were analyzed using generalized estimation equations to test linear trends with time. TMS threshold, CMCT, and TMS amplitude correlated (p < 0.05) with clinical upper motor neuron (UMN) signs at baseline and were different (p < 0.05) from normal controls in at least one response. Seventy-eight percent of patients with UMN (41/52) and 50% (4/8) of patients without clinical UMN signs had prolonged CMCT. All three measures revealed significant deterioration over time: TMS amplitude showed the greatest change, decreasing 8% per month; threshold increased 1.8% per month; and CMCT increased by 0.9% per month. Transcranial magnetic stimulation (TMS) findings, particularly TMS amplitude, can objectively discriminate corticospinal tract involvement in amyotrophic lateral sclerosis (ALS) from controls and assess the progression of ALS. While central motor conduction time and response threshold worsen by less than 2% per month, TMS amplitude decrease averages 8% per month, and may be a useful objective marker of disease progression.

Determinação dos limiares de percepção sensorial e de resposta motora nas diferentes fases do ciclo menstrual

Determination of sensory perception and motor response thresholds in different phases of the menstrual cycle Objective: To identify the variation of sensory perception and motor response in the different phases of the menstrual cycle. Method: Thirty women aged 18 to 40 years old (23.7 ± 3.60), with body mass index between 18.5 and 25kg/m 2 (21.15 ± 2.32) and menstrual cycle of 21-35 days, participated in this study. A pulse generator was used, with pulsed electric current frequency of 50Hz and variable phases of 20 (L20), 50 (L50), 100 (L100), 300 (L300), 500 (L500), 1000 (L1000) and 3000μs (L3000). The threshold of sensory perception (TSP) was identified as the first sensation of increased current intensity and the threshold of motor response (TMR) as the minimum muscle contraction detected. Five collections were done, at each of the following phases: phase 1- menstrual (P1), phase 2- follicular (P2), phase 3- ovulatory (P3), phase 4- luteal (P4) and phase 5- premenstrual (P5). The data analysis consisted of the Friedman test followed by the Rank test, carried out in the BioStat 4.0 ® software, with a significance level of 5%. Results: The TSP was lower in P5 than in the other menstrual phases, for the L20, L300, L500, L1000 and L3000 currents. For the TMR, there was difference in the L20, L50, L500 and L1000 currents between P5 and all other phases; in the L100 current, between P1 and P5; and in the L300 and L3000 currents for P1, P2 and P3 versus P5. Conclusions: The thresholds of sensory perception and motor response varied systematically through the phases of the menstrual cycle, thus influencing motor-sensory behavior.

Evoked motor response thresholds during transcranial magnetic stimulation in patients with symptomatic partial epilepsy

Transcranial magnetic stimulation (TMS) occupies a leading position among noninvasive neurophysiological methods used for evaluating the balance of processes of cortical inhibition and excitation. The aim of the present work was to assess motor cortical excitability in symptomatic partial epilepsy using TMS in relation to the effects of antiepileptic treatment. A total of 31 patients were studied. A decrease in the motor response threshold was seen in a group consisting of untreated patients, with changes in cortical excitability during seizures. Treated patients showed no difference as compared with healthy subjects. The shorter the interval between a seizure and TMS, the smaller the evoked motor response threshold. The low threshold seen in patients with symptomatic partial epilepsy showed a significant correlation with clinical signs of neuromuscular excitability. The data obtained here provide evidence of changes in the functional state of the cortex and, thus, the motor response threshold, in patients with epilepsy.

Transcranial Magnetic Stimulation in Epilepsy.

Transcranial magnetic stimulation (TMS) seems an attractive tool for the study of seizure disorders. It is simple to perform, relatively inexpensive, and generally safe, with the potential to provide noninvasive clinical measurements of neuronal excitability. Applications in patients with epilepsy include investigation of underlying cortical excitability and determination of the effects of antiepileptic drugs (AEDs); preoperative localization of epileptic foci; and functional mapping. Several review articles have been published on the use of TMS for epilepsy (1, 2, 3, 4, 5). Most intriguingly, TMS could become a new seizure treatment modality. The parameters measured by TMS include motor threshold, which is the minimal threshold for motor response in target muscle and motor evoked potential (MEP) amplitude, both measured using single pulses (see Table 1). The cortical silent period (CSP) is a lapse in electromyogram (EMG), when a TMS pulse is given during tonic voluntary muscle contraction; its duration is related to stimulus intensity. Additional parameters are measured with paired-pulse stimulation techniques. For example, intracortical inhibition (ICI), a decrease in MEP amplitude from the first to the second stimulus, is seen when a subthreshold conditioning pulse is followed by a suprathreshold pulse after a 2- to 5-millisecond delay, whereas intracortical facilitation (ICF) occurs when the pulses are 7 to 20 milliseconds apart. TABLE 1 TMS Parameters

Can inflammatory pain prevent the development of acute tolerance to alfentanil?

Constant pain could, in principle, counteract mobilization of antianalgesia systems and prevent the development of acute tolerance to the analgesic effects of opioids. We sought to determine whether a tonic nociceptive input caused by inflammation inhibits the development of acute tolerance to alfentanil. The inflammation was induced by injection of carrageenan into the rat hind paw. A threshold of motor response to increasing pressure on the paw was used to determine analgesia. Alfentanil was administered IV with an infusion algorithm designed to maintain a constant plasma level of opioid for 4 h. The degree of acute tolerance was determined on the basis of decline in the level of analgesia. The continuous decline of the analgesic effect from its peak at 30 min to the end of the 4-h infusion period was profound, despite the constant-rate infusion of alfentanil. The degrees of decline were very similar in rats with and without carrageenan-induced inflammation (from 242 +/- 31 to 154 +/- 20 g, P < 0.0001; and from 242 +/- 33 to 148 +/- 14 g, P < 0.0001, respectively). The results suggest that inflammatory nociceptive input does not prevent the development of acute tolerance to opioid-induced analgesia measured as an increased reaction threshold to painful pressure. We conclude that acute tolerance to the analgesic effect of opioids is profound and develops very rapidly, even in the presence of constant nociceptive input. We examined whether inflammatory pain can prevent the rapid decline in analgesic effectiveness (acute tolerance) of alfentanil during its IV infusion. We found that acute tolerance to the analgesic effect of alfentanil, in the presence of constant pain caused by inflammation, develops as rapidly as without it.

Effect of Prolonged Nerve Block on Inflammatory Hyperalgesia in Rats

Recent evidence suggests that the duration of the nociceptive block may be an important factor in determining the effect of the block on injury-induced hyperalgesia after block resolution. The authors examined whether a tonicaine nerve block lasting for 12 to 16 h could prevent late inflammatory hyperalgesia. Inflammatory hyperalgesia was induced by injection of carrageenan into the rat paw. A threshold of motor response to increasing pressure was determined for the injected paw, contralateral paw, and tail The development of edema of the paw and an increase in paw temperature also were determined. The block was achieved by simultaneous percutaneous injections of tonicaine (a new long-acting anesthetic agent) or lidocaine at the sciatic nerve (greater trochanter level) and the saphenous nerve (midthigh level). Carrageenan without nerve block caused a profound primary (injected paw) and secondary (contralateral paw and tail) hyperalgesia that lasted for 3-5 days. Tonicaine nerve block administered before carrageenan completely prevented primary and secondary hyperalgesia. Tonicaine block administered 5 h after carrageenan injection reversed secondary hyperalgesia and prevented the development of late (> or = 24 h) primary and secondary hyperalgesia. Edema and temperature of the paw were not significantly affected by the nerve block administered before or after carrageenan. A prolonged nerve block (12-16 h) can prevent the development of long-lasting (3-5 days) inflammatory hyperalgesia. Prevention of late hyperalgesia can be provided not only by the preinjury block but also by the postinjury block administered when hyperalgesia is already well established.

Nocifensive reflex thresholds in rats: measures of central nervous system effects of barbiturates.

To characterize the pharmacodynamic relationships between plasma pentobarbitone and thiopentone concentrations and nocifensive reflexes during emergence from anaesthesia. Forty-nine rats were studied. Plasma barbiturate concentrations were measured with high performance liquid chromatography. Nocifensive reflexes were assessed with the hindlimb withdrawal latency (WL) to heat and the somatic motor response threshold (SMRT) to tail pressure. In Protocol I, SMRT, WL, sedation, and the presence of paw-licking and the righting reflex were assessed in unrestrained rats before and every 10 min for two hours after an intraperitoneal injection of pentobarbitone (30 mg.kg-1). Plasma pentobarbitone kinetics were determined in a separate group of rats. In Protocol II, SMRT and drug concentrations were measured concurrently in partially restrained animals before and for 35 min after a computer-controlled i.v. bolus of thiopentone. In Protocol III the SMRT-plasma thiopentone relationship was determined during increasing and decreasing plasma thiopentone concentrations. Enhancement of both nocifensive reflexes was observed in the unrestrained animals. Enhancement of SMRT was maximal [175% (153-197) of control values] at a mean plasma thiopentone concentration of 11 (9-13) micrograms.ml-1. The SMRT-plasma thiopentone curve showed a mean efflux-influx difference in plasma thiopentone concentration of 4(2.3-5.7) micrograms.ml-1. Barbiturate-associated nocifensive reflex enhancement occurs in unrestrained animals with both thermal and pressure stimuli. The SMRT-plasma thiopentone concentration relationship during emergence from anaesthesia was similar to that observed previously during induction. The thiopentone plasma concentration-SMRT plot showed an equilibrium delay similar to that previously described by others for thiopentone at an electroencephalographic effect site.

Thiopentone induced enhancement of somatic motor responses to noxious stimulation: influence of GABAA receptor modulation

This study was conducted to determine whether hyperalgesic effects of subanaesthetic concentrations of thiopentone could be attributed to GABAA receptor effects. All studies were performed on 50 rats in a prospective, randomized, blinded fashion using saline-injected animals as controls. Using a modified Randall-Selitto technique, the motor behavior stimulated by noxious stimulation was quantified by determining the lowest tail pressure required to provoke a withdrawal response (somatic motor response threshold, SMRT). In the first protocol (21 rats), we studied the effects of 0.5, 1.5 and 5 mg.kg-1 i.v. of the GABAA agonist, muscimol, on SMRT. In the second protocol (20 rats), the effects of administration of saline, muscimol 0.5 mg.kg-1, or the competitive GABAA antagonist, bicuculline 0.25 mg.kg-1, upon the SMRT-reducing effects of a standardized thiopentone infusion were observed. No dose of muscimol produced hyperalgesia. The highest dose of muscimol used (5 mg.kg-1) produced pronounced analgesic effects, raising the SMRT above 750 g. No change in SMRT was detected with the smaller doses of muscimol. Given in combination with muscimol (0.5 mg.kg-1), thiopentone produced analgesia, as shown by an increase in SMRT (P = 0.009). In the bicuculline treated animals, SMRT decreased linearly with increasing plasma thiopentone concentrations (P < 0.001). The slope of the relationship in the bicuculine group was not significantly different from that observed in the saline-treated group, indicating that bicuculline did not block the hyperalgesic effects of thiopentone. The results of these studies suggest that hyperalgesia associated with thiopentone is not mediated primarily by GABAA receptors.

Local cerebral glucose utilization in stimulated rats sedated with thiopental.

Recent studies have suggested that supraspinal structures are involved in barbiturate-induced enhancement of nociceptive processing. The goal of the study was to determine whether cortical and subcortical regions involved in nociception were relatively activated or depressed by noxious stimulation during infusion of small doses of thiopental. Local cerebral glucose utilization (LCGU) was measured with the 14C-2-deoxyglucose radioautographic technique in 14 rats. During the LCGU experiment, pressure was applied to the tail every 2 min, and the somatic motor response threshold was recorded. Seven animals received thiopental infusions to produce a steady-state plasma concentration (target concentrations of 10 micrograms/ml), and seven untreated animals served as controls. A steady-state plasma thiopental concentration (11.1 +/- 1.8 to 13.0 +/- 2.1 micrograms/ml) was accompanied by a decrease in the somatic motor response threshold from 277 +/- 32 g (before thiopental) to 215 +/- 41 g (P < 0.001). The somatic motor response threshold remained unchanged in the control group. Average LCGU was 29% less in the thiopental-treated animals than in the untreated controls (P < 0.001). In cortical regions associated with nociception, LCGU was relatively increased (+3% +/- 14%) during the thiopental infusion in comparison to the visual and auditory cortices (-18% +/- 13%; P < 0.001). Individual structures that showed relative changes during thiopental infusion included the nucleus accumbens (+17%, P < 0.05) and the habenula (-17%, P < 0.05). Heterogenous relative changes (P < 0.05) in LCGU were observed in the auditory system: auditory cortex (-22%), medial geniculate (-16%), lateral lemniscus (+26%), superior olive (+38%). Noxious stimulation during low-dose thiopental infusions relatively increased LCGU in cortical regions postulated to be responsible for processing of noxious stimuli. Nuclei in the descending pain modulating system were not relatively depressed.

Plasma, Brain, and Spinal Cord Concentrations of Thiopental Associated with Hyperalgesia in the Rat

Although low doses of barbiturates are widely believed to increase sensitivity to pain, studies of the electrophysiologic effects of these drugs on the neurons involved in nociception in the spinal cord have detected only depressant effects. The goal of the studies reported here was to quantify the hyperalgesia resulting from low-dose thiopental infusions and to measure the associated concentrations of thiopental in the plasma, brain, and spinal cord. Nociception was measured using the threshold for motor response to pressure stimulation of the tail (nociceptive threshold) and tail flick latency in the rat. Thiopental was administered by intravenous infusions designed to produce plasma concentrations that either slowly increased or remained at a steady state. Plasma and tissue thiopental concentrations were measured by high-performance liquid chromatography. We observed a reduction in nociceptive threshold that was correlated with the plasma thiopental concentration over the range 2-20 micrograms.ml-1 (7.6-76 microM). The relationship was nonlinear. Nociceptive threshold reached a nadir (36% less than control values) at a mean plasma thiopental concentration of 13.7 micrograms.ml-1 (51.9 microM). The steady-state study showed a similar reduction in nociceptive threshold, with an equilibrium plasma thiopental concentration of 7.6 +/- 1.3 micrograms.ml-1 (28.8 +/- 4.9 microM). Concentrations of thiopental in brain and spinal cord samples were 1.7 +/- 0.03 and 3.5 +/- 1.7 micrograms.g-1, respectively. These studies confirm previous reports of hyperalgesia in association with small doses of thiopental. Reductions in nociceptive threshold and tail flick latency were observed in association with spinal cord concentrations of thiopental in a range reported by others to depress the electrophysiologic activity of neurons involved in nociception.

Does midazolam inhibit the development of acute tolerance to the analgesic effect of alfentanil?

Alfentanil-midazolam analgesic interactions were studied in rats with continuous infusions or bolus injections of the drugs. Analgesia was determined by measuring the threshold of motor response to noxious pressure. The continous constant-rate infusion of alfentanil demonstrated that after an initial peak, the analgesia profoundly declined due to the development of acute tolerance. When alfentanil (250 μg·kg −1·h −1) was given together with midazolam (3 mg·kg −1·h −1), the decline in the analgesic effect of alfentanil was attenuated. Following the 4 h period of the constant-rate (250 μg·kg −1·h −1) infusion of alfentanil, when acute tolerance was already developed, midazolam (3 mg·kg −1) given as a bolus injection enhanced the alfentanil-induced anesthesia. At the same time, when alfentanil was given as a bolus injection (30 μg·kg −1) with or without midazolam (3 mg·kg −1) also by bolus injection, no changes were seen to indicate an enhancement of the analgesic effect of alfentanil by midazolam. The results suggest that midazolam attenuates the development of acute tolerance to the analgesic effect of alfentanil.

Acute Tolerance in Morphine Analgesia

This study aimed to determine whether the decline of the analgesic effect of morphine with a continuous infusion or that after a single injection correlates with the changes in brain concentration of morphine. The analgesic effect of morphine and its brain and serum concentrations were determined with a continuous 8-h infusion at a constant rate and after a single subcutaneous injection of the agent. The analgesic effect was determined by measuring the threshold of motor response to noxious stimulation. Brain and serum concentrations of morphine were detected by radioimmunoassay with the use of 125I-labeled morphine. With the constant-rate (4 mg.kg-1.h-1, intravenous) morphine infusion, the peak of analgesia could not be maintained: the increase in the pain threshold at 2 h was 1,003 g and at 8h was 286 g (a decrease in analgesia by 72%, P less than 0.0002). At the same time, the brain morphine concentration tended to increase, to 278 ng/g at 2 h and 329 ng/g at 8 h. After the single morphine injection (6 mg/kg, subcutaneous), recovery from analgesia occurred at a much faster rate than did the decrease in morphine brain concentration; the decrease in pain threshold was 79% at 90 vs. 30 min after the injection (P less than 0.0001), and the corresponding decrease in brain concentration was 28% (NS). The absence of correlation between analgesia and morphine brain concentration both with the constant-rate morphine infusion and after the single injection suggests the development of acute tolerance, which is pharmacodynamic in nature.

Midazolam Antagonizes the Analgesic Effect of Morphine in Rats

The effect of midazolam on morphine analgesia was studied in 54 rats. Analgesia was determined by measuring threshold for motor response to noxious pressure applied to the tail. Midazolam (0.5 mg/kg) decreased the morphine-induced (1 mg/kg) increase in the reaction threshold by one-half. Flumazepil (Ro 15-1788), a specific antagonist of benzodiazepines, prevented inhibition of morphine antinociception by midazolam. These findings demonstrate that midazolam partially antagonizes the analgesic effect of morphine and, in addition, that the antagonism of midazolam on morphine analgesia is mediated by benzodiazepine receptors.

Inhibitory effect of dopamine on the transmission of excitation in isolated rat spinal cord

The effects of dopamine on ventral root potential produced by a single supramaximal dorsal root stimulation of the dorsal root was investigated during experiments on isolated superfused spinal cord segments from 10–16-day old rats. A reciprocal dose-dependent inhibition of the mono- and polysynaptic components of reflex response was also observed. Minimum effective concentration was 1×10−8 M dopamine. Extent of reflex response increased in step with dopamine concentration, so that the amplitude of the monosynaptic component of ventral root potential was decreased by 20% and 87% of baseline level by the action of 10−4 and 10−3 M dopamine respectively on the cord. The amplitude of the polysynaptic component was thereby decreased by an average of 18% and 87%. Findings indicate that dopaminergic brainstem-spinal pathways contribute to the governing of impulse transmission in the segmental reflex arcs. Inhibition of dopaminergic synaptic transmission probably underlies the increase in latency already described in the literature, as well as the increase observed in the threshold of reflex motor response to nociceptive action following either stimulation of the dopaminergic brainstem structures or intravenous administration of dopamine agonists.

Use of intraoperative stimulation in the selection of target sites for CT-guided stereotactic biopsies.

We have utilized intraoperative stimulation to establish the functional nature of tissue to be biopsied in 20 patients undergoing CT-guided stereotactic biopsies. We have performed from 1-4 stimulations at 2-100 Hz using a monopolar and/or bipolar electrode at the intended target sites. Thresholds for motor and sensory response have been obtained. Stimulation results have ranged from sensory changes to tonic/clonic motor activity of the contralateral body and face.

Reticular stimulation in the pregnant rat: Effects on offspring

Increased arousal levels in pregnant rats were produced via electrical stimulation of the reticular formation (RF) on Days 6–16 of gestation. Current levels between 0.02 and 0.06 mA were selected depending on the threshold for overt motor response to stimulation in the individual animal. Offspring were tested at 30 days of age for threshold of flurothyl-induced convulsion, and at 90 days of age for percent avoidance in a shock avoidance task. In comparison to offspring of implanted controls, RF-stimulated offspring had elevated seizure thresholds (males and females) and enhanced avoidance performance (females only). Further studies using fostering showed that the effect on avoidance performance was mediated both prenatally and postnatally. The relative importance of prenatal and postnatal influences on seizure threshold could not be determined. These results are compared to previous studies of the behavioral effects of prenatal chlorpromazine threatment.

Antinociceptive action of oxotremorine and regional turnover of rat brain noradrenaline, dopamine and 5-HT

In the rat, oxotremorine increases the threshold for vocalisation after-discharge (affective component of pain reactions) dose dependently at subtremor doses (30-67 mug/kg s.c.). Doses of 225-506 mug/kg were needed to elevate the thresholds for vocalisation and motor response. 1-Tryptophan, PCPA, alpha-methyl-p-tyrosine, 1-Dopa, pimozide and LSD-25 did not affect the antinociceptive activity of oxotremorine, while phenocybenzamine slightly increased the threshold for vocalisation. Oxotremorine did not change the endogenous brain concentrations of noradrenaline and dopamine or 5-HT but decreased that of 5-HIAA in all brain regions at the time of maximal analgesia. The decrease of 5-HIAA was still present after pretreatment with probenecid. After inhibition of tyrosine hydroxylase, oxotremorine accelerated the depletion of dopamine in telencephalic cortex during maximal antinociceptive activity and of noradrenaline in all brain regions at a time when this activity had vanished. Atropine significantly antagonized the analgesic activity of oxotremorine. It is concluded that oxotremorine antinociceptive activity in the rat is related to a cholinergic compoent, while a monoaminergic component is not directly involved.

The effects of caffeine and theophylline on nociceptive stimulation in the rat.

Abstract: Nociceptive stimulation has been performed in rats with a technique which should allow us to study different pain projection levels within the central nervous system. Three different types of thresholds were studied by electrical stimulation and the stimulus responses were qualitatively and quantitatively divided into a) motor response b) vocalisation and c) vocalisation after‐discharge. Caffeine and theophylline were able to decrease the thresholds for motor response and vocalisation in a dose‐dependent manner. Both drugs were also able to reduce the thresholds for vocalisation after‐discharge. However, caffeine reduced this response to about 50‐60% of the normal, but not in a dose‐dependent manner, which is contrary to theophylline which, in a dose of 100 mg/kg, decreased the threshold to as little as 20 per cent of the normal. In general, maximum effects were obtained 30 minutes after administration and theophylline produced more long‐lasting effects than caffeine.