Roberto Esposti

Pharmacokinetics of orally administered melatonin in critically ill patients

Abstract:u2002 Critically ill patients exhibit reduced melatonin secretion, both in nocturnal peaks and basal daytime levels. Oral melatonin supplementation may be useful for known sedative and antioxidant properties. Its early enteral absorption and daily pharmacokinetics were determined in two cohorts of six high‐risk patients in this prospective trial. During their third and fourth Intensive Care Unit (ICU) day, they underwent two different sets of repeated blood samples to detect serum melatonin levels through radio‐immuno‐assay. Cohort 1: samples taken at 20:00, 20:45, 21:30, 24:00, 03:00, 06:00, 14:00, 20:00 to describe the daily pharmacokinetics. Cohort 2: 20:00, 20:05, 20:10, 20:20, 20:30, 20:45 to study the early absorption. On ICU day 3, endogenous levels were measured, while the absorption of exogenous melatonin was determined on ICU day 4 after administration, at 20:00, of 3u2003mg melatonin. All basal levels were below the expected values. Following enteral administration, pharmacological levels were already reached in 5u2003min, with a serum peak after 16u2003min (half‐absorption time: 3u2003min 17u2003s). The maximum serum level observed was 11040u2003pg/mL and the disappearance rate indicated a half‐elimination time of 1u2003hr 34u2003min. Serum melatonin levels decreased significantly after midnight; pharmacological levels were maintained up to 10u2003hr following administration. No excessive sleepiness was reported in this patient group. Critically ill patients exhibited reduced melatonin secretion, as reported in the literature. Despite the critical illness, the oral bioavailability was satisfactory: serum levels after oral administration showed basically unchanged intestinal absorption, while disappearance rate was slower than reported elsewhere in healthy volunteers.

Anticipatory postural adjustments in arm muscles associated with movements of the contralateral limb and their possible role in interlimb coordination

While sitting on a turnable stool, with both shoulders flexed at 90° or, alternatively, with arms parallel to the trunk and the elbows flexed at 90°—the hands being semisupine—subjects performed unidirectional and cyclic movements on the horizontal plane of the right arm (adduction–abduction) or hand (flexion–extension). The left arm was still, in a position symmetrical to that of the right limb and with the hand contacting a fixed support by the palmar or dorsal surface. During both unidirectional and cyclic arm or hand movements, activation of the prime mover muscles (right Pectoralis Major for arm adduction and Infraspinatus for abduction; right Flexor Carpi Radialis and Extensor Carpi Radialis for the hand movements) was accompanied by activation of the homologous muscles of the contralateral arm and inhibition of antagonists. The contralateral activities (1) regularly preceded the burst in the movement prime movers and (2) were organised in fixation chains that, exerting forces on the hand fixed support, will counterbalance the rotatory action exerted on the trunk by the primary movement. Based on these features, these activities may be classified as anticipatory postural adjustments (APAs). The observed APAs distribution is such as to favour the preferential (mirror symmetrical) coupling of upper limb movements on the horizontal plane. The possible role of these APAs in determining the different constraints experienced when performing mirror symmetrical versus isodirectional coupling is discussed.

Transcranial direct current stimulation of SMA modulates anticipatory postural adjustments without affecting the primary movement.

Recent works provide evidences that anticipatory postural adjustments (APAs) are programmed with the prime mover recruitment as a shared posturo-focal command. However the ability of the CNS to adjust APAs to changes in the postural context implies that the postural and voluntary components should take different pathways before reaching the representation of single muscles in the primary motor cortex. Here we test if such bifurcation takes place at the level of the supplementary motor area (SMA). TDCS was applied over the SMA in 14 subjects, who produced a brisk index-finger flexion. This activity is preceded by inhibitory APAs, carved in the tonic activity of Biceps Brachii and Anterior Deltoid, and by an excitatory APA in Triceps Brachii. Subjects performed a series of 30 flexions before, during and after 20 min of tDCS in CATHODAL, ANODAL or SHAM configuration. The inhibitory APA in Biceps and the excitatory APA in Triceps were both greater in ANODAL than in SHAM and CATHODAL configurations, while no difference was found among the latter two (ANODAL vs. SHAM: biceps +26.5%, triceps +66%; ANODAL vs. CATHODAL: biceps +20.5%, triceps: +63.4%; for both muscles, ANOVA p<0.02, Tukey p<0.05). Instead, the APA in anterior deltoid was unchanged in all configurations. No changes were observed in prime mover recruitment and index-finger kinematics. Results show that the SMA is involved in modulating APAs amplitude. Moreover, the differential effect of tDCS observed on postural and voluntary commands suggests that these two components of the motor program are already separated before entering SMA.

Hand immobilization affects arm and shoulder postural control

It is a common experience, immediately after the removal of a cast or a splint, to feel motor awkwardness, which is usually attributed to muscular and joint immobilization. However, the same feeling may also be perceived after a brief period of immobilization. We provide evidence that this last effect stems from changes in the cortical organization of the focal movement as well as in the associated anticipatory postural adjustments. Indeed, these two aspects of the motor act are strongly correlated, although scaled in different manners. In fact, they are both shaped in the primary motor cortex, they both undergo similar amplitude and latency modulation and, as we will show, they are both impaired by the immobilization of the lone prime mover. Neuromuscular effects of limb immobilization are well known; however, most papers focus on changes occurring in the pathways projecting to the prime mover, which acts on the immobilized joint. Conversely, this study investigates the effect of immobilization on anticipatory postural adjustments. Indeed, we show that 12xa0h of wrist and fingers immobilization effectively modify anticipatory postural adjustments of the elbow and the shoulder, that is, those joints not immobilized within the fixation chain. Accordingly, the motor impairment observed after short-term immobilization most likely stems from the unbalance between anticipatory postural adjustments and the focal movement.

Accuracy of pointing movements relies upon a specific tuning between anticipatory postural adjustments and prime mover activation

Equilibrium‐perturbing forces associated with a voluntary upper‐limb movement can be strong enough to displace the whole‐body centre of mass. In this condition, anticipatory postural adjustments (APAs), developing in muscles other than the prime mover, are essential in maintaining the whole‐body balance. Here, we test the hypothesis that APAs preceding an upper‐limb target‐reaching movement could play a role also in controlling the movement accuracy.

Temporal disruption of upper-limb anticipatory postural adjustments in cerebellar ataxic patients

Voluntary movements induce postural perturbations, which are counteracted by anticipatory postural adjustments (APAs) that preserve body equilibrium. Little is known about the neural structures generating APAs, but several studies suggested a role of sensory–motor areas, basal ganglia, supplementary motor area and thalamus. However, the role of the cerebellum still remains an open question. The aim of this present paper is to shed further light on the role of cerebellum in APAs organization. Thus, APAs that stabilize the arm when the index finger is briskly flexed were recorded in 13 ataxic subjects (seven sporadic cases, four dominant ataxia type III and two autosomal recessive), presenting a slowly progressive cerebellar syndrome with four-limb dysmetria, and compared with those obtained in 13 healthy subjects. The pattern of postural activity was similar in the two groups [excitation in triceps and inhibition in biceps and anterior deltoid (AD)], but apparent modifications in timing were observed in all ataxic subjects in which, on average, triceps brachii excitation lagged the onset of the prime mover flexor digitorum superficialis by about 27xa0ms and biceps and AD inhibition were almost synchronous to it. Instead, in normal subjects, triceps onset was synchronous to the prime mover and biceps and AD anticipated it by about 40xa0ms. The observed disruption of the intra-limb APA organization confirms that the cerebellum is involved in APA control and, considering cerebellar subjects as a model of dysmetria, also supports the view that a proper APA chain may play a crucial role in refining movement metria.

Synchrony of hand-foot coupled movements: is it attained by mutual feedback entrainment or by independent linkage of each limb to a common rhythm generator?

BackgroundSynchrony of coupled oscillations of ipsilateral hand and foot may be achieved by controlling the interlimb phase difference through a crossed kinaesthetic feedback between the two limbs, or by an independent linkage of each limb cycle to a common clock signal. These alternative models may be experimentally challenged by comparing the behaviour of the two limbs when they oscillate following an external time giver, either alone or coupled together.ResultsTen subjects oscillated their right hand and foot both alone and coupled (iso- or antidirectionally), paced by a metronome. Wrist and ankle angular position and Electromyograms (EMG) from the respective flexor and extensor muscles were recorded. Three phase delays were measured: i) the clk-mov delay, between the clock (metronome beat) and the oscillation peak; ii) the neur (neural) delay, between the clock and the motoneurone excitatory input, as inferred from the EMG onset; and iii) the mech (mechanical) delay between the EMG onset and the corresponding point of the limb oscillation. During uncoupled oscillations (0.4 Hz to 3.0 Hz), the mech delay increased from -7° to -111° (hand) and from -4° to -83° (foot). In contrast, the clk-mov delay remained constant and close to zero in either limb since a progressive advance of the motoneurone activation on the pacing beat (neur advance) compensated for the increasing mech delay. Adding an inertial load to either extremity induced a frequency dependent increase of the limb mechanical delay that could not be completely compensated by the increase of the neural phase advance, resulting in a frequency dependent increment of clk-mov delay of the hampered limb. When limb oscillations were iso- or antidirectionally coupled, either in the loaded or unloaded condition, the three delays did not significantly change with respect to values measured when limbs were moved separately.ConclusionThe absence of any significant effect of limb coupling on the measured delays suggests that during hand-foot oscillations, both iso- and antidirectionally coupled, each limb is synchronised to the common rhythm generator by a private position control, with no need for a crossed feedback interaction between limbs.

Postural adjustments in arm and leg muscles associated with isodirectional and antidirectional coupling of upper limb movements in the horizontal plane

The hypothesis that anticipatory postural adjustments (APAs) may concur in generating the directional preference experienced during limb coupled movements was tested by measuring the electromyographic and mechanic postural actions elicited when moving: (1) one single arm/hand and, (2) both limbs, iso- or antidirectionally coupled. During fast adduction of the right arm in the horizontal plane (prime mover, pectoralis Major, rPM) APAs were recorded in the contralateral lPM as well as in the right ischiocruralis (rIC) muscle. This last action was associated to a transient increase of Tz (torque around body vertical axis) in the direction opposite to arm rotation. Both the APAs in rIC and the Tz changes nearly doubled in size when arms were coupled isodirectionally (adduction of one arm and abduction on the other) while they vanished when both arms were simultaneously adducted (antidirectional coupling). Conformably, during rhythmic arm oscillations APAs and Tz were cyclically modulated when movements were isodirectional, the modulation amplitude being strongly enhanced by increasing the movement frequency. When oscillations were antidirectional neither APAs nor Tz changes were observed, even if frequency was incremented. The postural actions linked to unidirectional or cyclic movements of the hand were affected by either coupling or frequency in the same way as arm movements, albeit much smaller in size. In conclusion, during antidirectional movements APAs in prime movers are synergic with voluntary activation and no postural engagement is requested to leg muscles. Conversely, during isodirectional movements, APAs in prime movers conflict with the voluntary commands and a strong, frequency-dependent, postural effort is required to leg muscles. How these factors may co-operate in determining the preference for antidirectional coupling is discussed.

Ischemic block of the forearm abolishes finger movements but not their associated anticipatory postural adjustments

Voluntary movement is known to induce postural perturbations that are counteracted by unconscious anticipatory postural adjustments (APAs). Thus, for every movement, two motor commands are dispatched: a voluntary command recruiting the prime mover and a postural command driving the APAs. These commands are classically thought to be separated; this study investigates whether they could be instead considered as two elements within the same motor program. We analyzed the APAs in biceps brachii, triceps brachii and anterior deltoid that stabilize the arm when briskly flexing the index finger (prime mover flexor digitorum superficialis). APAs and prime mover activation were recorded before, under and after ischemic block of the forearm. Ischemia paralyzed the prime mover, thus suppressing the finger movement and the ensuing postural perturbation. If the two commands had been separated, it would have been expected that after a few failed attempts to flex the index finger, the APAs were suppressed too, being purposeless without postural perturbation. APAs were still present under ischemia even after 60 movement trials. No significant changes were found in APA amplitude in biceps and triceps among different conditions, or in the average APA latency. Inhibitory APA in anterior deltoid was reduced but still present under ischemia. In addition, the pharmacologic block of the sole median nerve produced similar effects. APAs were instead almost abolished when applying a fixation point to the wrist. The observation that APAs remained tailored to the expected perturbation even when that perturbation did not occur supports the idea of a functionally unique motor command driving both the prime mover and the muscles of the APA chain.

Partition of voluntary command to antagonist muscles during cyclic flexion-extension of the hand

Activity distribution between wrist movers during rhythmic flexion-extension of the wrist has been analysed in three different mechanical conditions. Wrist angular position and surface EMG from Extensor Carpi Radialis (ECR) and Flexor Carpi Radialis (FCR) were recorded. In the first condition (hand prone, flexion-extension in a vertical parasagittal plane) the hand passive equilibrium position was ~50° in flexion. During hand oscillations FCR and ECR were alternatively recruited to move the hand symmetrically away from the equilibrium and de-recruited to allow conservative forces to restore the equilibrium. Switching between antagonists occurred at the centre of the oscillation (equilibrium crossing). In the second condition (hand semi-prone, flexion-extension in a horizontal transversal plane) the hand equilibrium was attained over an angle of about 26°. When the hand was oscillated symmetrically around this equilibrium range, each muscle was recruited when the hand entered the equilibrium range and switching between antagonists therefore occurred in advance of the oscillation centre. Both vertical and horizontal oscillations were also performed all externally to the equilibrium position or range: in these cases only one muscle was recruited over the entire cycle, the EMG burst starting at the onset of the related movement. In the third condition (hand semi-prone, flexion-extension in a horizontal transversal plane) a frictional load added to the platform pivot expanded the equilibrium range to encompass the entire hand oscillation. Now concentric muscle contraction was needed throughout each phase of the movement and switching between antagonists occurred at the movement reversal, i.e. ~90° in advance of the oscillation centre. The above descriptions held for oscillation frequencies from 0.2 Hz to 3.0 Hz, once the frequency-dependent effects of viscosity and inertia were accounted for. In all the three conditions, contractile forces started developing when an intrinsic or external resistance had to be overcome in order to continue the movement. To account for this control, a neural network is proposed that compares the afferent information about joint position with a position central command, thus detecting the position error caused by the forces that resist to movement. From the sign and amplitude of the error signal the network determines the direction (agonist vs antagonist) and the amount of motor activation.