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PubMed1980

Reflex inotropic responses of the heart from lung inflation in anaesthetized dogs.

In anaesthetized dogs a tracheal divider was inserted to allow inflation of one lung with various pressures. Left ventricular inotropic responses were assessed by measuring the maximum rate of change of left ventricular pressure (dP/dt max) using a preparation in which aortic pressure, carotid sinus pressure and heart rate were held constant. Heart responses to lung inflation were variable. In five dogs there was a consistent tachycardia, in three bradycardia and in six there was no change. In the dogs in which heart rate increased, inflation of one lung with pressures between 0.5 and 2.0kkPa (5 and 20 cm H2O) resulted in no significant change in dP/dt max. In the remaining dogs there was a decrease in dP/dt max which was more pronounced at the higher inflation pressures. The negative inotropic response was shown to be a reflex with afferent nerve endings in the lung and with the efferent pathway in the sympathetic nerves.

Animals↗
PubMed1986

The role of the glycine sensitive area of the ventral medulla in cardiovascular responses to carotid chemoreceptor and peripheral nerve stimulation.

The present study on cats anaesthetised with Althesin, which unlike more commonly used anaesthetics does not prevent reflex activation of the brain-stem defence areas, reaffirmed that carotid chemoreceptor stimulation and radial nerve stimulation can evoke the visceral components of the alerting stage of the defence response (visceral alerting response). This includes tachycardia, mesenteric vasoconstriction but vasodilatation in skeletal muscle which is not secondary to the hyperventilation. However, mild chemoreceptor stimulation which evoked but a weak hyperventilation elicited bradycardia and vasoconstriction is mesentery and in muscle i.e. a response comparable with that evoked by chemoreceptor stimulation under chloralose or barbiturate anaesthesia. This suggests that chemoreceptor stimulation can evoke two separate patterns of response, the visceral alerting response predominating when the defence areas are strongly activated. The efferent pathway from the defence areas is known to synapse in the 'glycine sensitive area' of the ventral medulla which contains neurones whose activity seems to provide the main sympatho-excitatory drive for normal arterial pressure. Bilateral application of glycine to that area produces a pronounced fall in arterial pressure, apnoea and greatly attenuates the response to defence area stimulation, the vasoconstrictor components being abolished. In the present study bilaterally applied glycine abolished the muscle vasodilatation of the visceral alerting response evoked by chemoreceptor and radial nerve stimulation but both stimuli evoked vasoconstriction in mesenteric and muscle vasculature at least until arterial pressure was very low. It is proposed that both chemoreceptor and peripheral nerve stimulation can activate the defence areas to produce a visceral alerting response which is relayed via neurones of the glycine sensitive area.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗
PubMed1988

Axonal damage in severe traumatic brain injury: an experimental study in cat.

Based upon recent clinical findings, evidence exists that severe traumatic brain injury causes widespread axonal damage. In the clinical setting, it has been assumed that such axonal damage is the immediate consequence of traumatically induced tearing. However, in laboratory studies of minor head injury, evidence for primary traumatically induced axonal tearing has not been found. Rather the traumatic event has been linked to the onset of subtle axonal abnormalities, which become progressively severe over time (i.e., 12-24 h). In the light of these discrepant findings, we investigated, in the present study, whether progressive axonal change other than immediate tearing occurs with severe traumatic brain injury. Anesthetized cats were subjected to high intensity fluid-percussion brain injury. Prior to injury all animals received cortical implants of horseradish peroxidase (HRP) conjugated to what germ agglutinin to anterogradely label the major motor efferent pathways. Such an approach provided a sensitive probe for detecting traumatically induced axonal abnormality via both light microscopy (LM) and transmission electron microscopy (TEM). The animals were followed over a 1- to 6-h posttraumatic course, and processed for the LM and TEM visualization of HRP. Through such an approach no evidence of frank traumatically induced tearing was found. Rather, with LM, an initial intra-axonal peroxidase pooling was observed. With time, unilobular HRP-containing pools increased in size and progressed to bi- or multilobulated profiles. Ultimately, these lobulated configurations separated. Ultrastructurally, the initial unilobular pool was associated with organelle accumulation and focal axolemmal distention without frank disruption. Over time, such organelle accumulations increased in size and sequestered into multiple pools reminiscent of the bi- and multilobulated structures seen with LM. Ultimately, these organelle accumulations became detached, resulting in physically separated proximal and distal organelle-laden swellings surrounded by a distended axolemma and thinned myelin sheath. The findings reject the hypothesis that axons are immediately torn upon impact.

Animals↗
PubMed1978

Effects of anesthesia and surgical procedures on intestinal myoelectric activity in rats.

Electrical spiking activity of the duodenum and jejunum was recorded from chronically implanted electrodes in rats during volatile or barbiturate anesthesia and following laparotomy. The normal pattern of electrical spiking activity in the fasted rat, with myoelectric complexes at 15-min intervals, was transiently replaced by quiescence during ethyl ether anesthesia. A slight increase in irregular spiking activity occurred after induction with pentobarbital, and the only effect of thiopental anesthesia was a reduction in the velocity of propagation of the complexes by 20%. Under barbiturate anesthesia, incision of the skin did not inhibit myoelectric activity, but incision of each abdominal muscle layer had an immediate and transient inhibitory effect; the deeper the layer, the longer was the inhibition. Peritoneal incision consistently produced inhibition of spiking activity which was prolonged by exposure of the bowel to air and intestine handling. The inhibitory effects produced by surgery persisted after vagotomy or transection of the spinal cord at the thoracic level but disappeared after splanchnicectomy. The above results suggest that a somatovegetative reflex with efferent pathways in the splanchnic nerves is involved in the first stage of operative inhibition of intestinal myoelectric complexes.

Abdomen↗
PubMedDate not supplied

Identification of a cortical site for stress-induced cardiovascular dysfunction.

The evidence indicating that the insular cortex is a likely candidate to mediate stress-induced cardiovascular responses is reviewed. Both neuroanatomical and electrophysiological investigations demonstrate that the insular cortex receives an organized representation of visceral information. In addition, the insular cortex also receives highly processed association cortex information. The insular cortex is also highly interconnected with many subcortical limbic and autonomic regions. This combination of sensory input and limbic/autonomic connectivity would be necessary to permit the insular cortex to be a critical site for the integration of emotional and autonomic responses. Stimulation of the insular cortex elicits specific cardiovascular and autonomic responses from discrete sites. Phasic stimulation entrained to the cardiac cycle is even capable of causing severe arrhythmias. The efferent pathways and some of the neurotransmitter mechanisms have determined. It appears that the lateral hypothalamic area is the primary site of synapse for responses originating in the insular cortex and this information is relayed by NMDA glutamatergic receptors and modulated by neuropeptides including neuropeptide Y, neurotensin, leu-enkephalin and dynorphin. Finally, a rat stroke model, which includes the insular cortex in the infarct region indicates that disruption of the insula can produce substantial cardiac and autonomic abnormalities, which might be similar to those produced by stress. Some of the chronic neurochemical changes, including increases in opioids, neuropeptide Y and neurotensin in the central nucleus of the amygdala, which might be mediating these cardiovascular disturbances, have been determined.

Animals↗
PubMed1991

Serum gastrin and blood glucose levels during halothane-nitrous oxide anaesthesia and strabismus surgery in children.

The purpose of this study was to determine whether serum gastrin levels are increased by reflexogenic stimuli applied to the extrinsic muscles of the eye. Serum gastrin and blood glucose concentrations were measured in ten normal children aged between 5 and 12 yr during general anaesthesia with halothane and nitrous oxide and during strabismus surgery. Fasting basal concentrations of gastrin (33.6 +/- 14.8 pg.ml-1) and of glucose (4.43 +/- 0.72 mmol.L-1) were in the normal range of values for children. Intravenous atropine (0.01 mg.kg-1), general anaesthesia with halothane in nitrous oxide and oxygen by mask for three minutes, tracheal intubation, extraocular muscle stimulation and surgical stress did not cause any variation in the mean serum gastrin concentration. On the contrary, tracheal intubation and surgical stress increased blood glucose concentrations (P less than 0.05). There was no difference in the serum gastrin levels after extraocular muscle stimulation between children with positive or negative oculocardiac reflexes (44.5 +/- 16.7 pg.ml-1 vs 38 +/- 14.7 pg.ml-1, respectively). The incidence of vomiting predischarge was 60 per cent. Serum gastrin levels did not differ between children who vomited and children who did not (44.3 +/- 18.5 pg.ml-1 vs 47.1 +/- 16.9 pg.ml-1, respectively). Vomiting after strabismus surgery cannot be attributed to high gastrin serum levels. Consequently, it is unlikely that vomiting after strabismus surgery is linked to an "oculogastric reflex" with the vagus nerve as the efferent pathway.

Anesthesia, Inhalation↗
PubMed2003

Uncontrollable high-frequency tachypnea in a case of unilateral medial medullary infarct.

BACKGROUND: Medullary infarcts can be associated with breathing disorders that usually consist in central hypoventilation. PATIENT: We describe the case of a 54-year-old man, fully conscious, presenting with an uncontrollable high frequency and shallow tachypnea (95/min) at the onset of a unilateral medial medullary infarct. This disorder disappeared under inspiratory pressure support mechanical ventilation. MEASUREMENTS AND RESULTS: Respiratory drive (respiratory rate, occlusion pressure, and mean inspiratory flow), efferent pathway (transcranial and cervical magnetic stimulation), and afferent pathway (response to CO(2) and to lung inflation) were investigated. The respiratory drive was increased. The phrenic nerve conduction time was normal. The sensitivity of the central pattern generator to lung inflation and to CO(2) was preserved. The territory of the infarct was supplied by the spinal anterior artery. CONCLUSIONS: An extremely rapid and shallow tachypnea due to the increase in respiratory drive can be associated with unilateral medullary infarction.

Cerebral Infarction↗
PubMed2003

Somatosensory graviception inhibits soleus H-reflex during erect posture in humans as revealed by parabolic flight experiment.

The purpose of this study was to investigate how gravity level affects the excitability of the soleus muscle (SOL) motoneuron pool to Ia afferent input while erect posture is maintained in humans. Three healthy male subjects participated in an experiment whereby three different gravity conditions [microgravity (MG), normal gravity (NG), and hypergravity (HG)] were imposed using a parabolic flight procedure. The SOL H-reflex was evoked every 2 s while the subjects kept an erect posture. The stimulus intensity was controlled automatically on a real-time basis by personal computer to induce the constant amplitude of M-wave (10+/-5% of maximal M-wave amplitude). The background electromyographic activity (BGA) of the SOL was largest during HG, while it was almost absent during MG. The SOL H-reflex amplitude was significantly larger during HG and MG than during NG ( P<0.05). During NG and HG, there was a linear relationship between the BGA and the H-reflex amplitude; the difference in the SOL H-reflex amplitude between both gravity conditions could be explained in terms of the BGA level. However, during MG, despite the absence of BGA, the SOL H-reflex amplitude was larger than that during NG. Furthermore, when the subjects voluntarily activated the SOL by applying a load to the lower limb joints and spine by pulling a handle upward, this H-reflex enhancement almost disappeared. These results suggest that the somatosensory systems detecting a load at the lower limbs and/or vertebral column might play a role in reducing the excitability of the SOL motoneuron pool to Ia afferent inputs by presynaptic inhibition.

Adult↗
PubMed2004

Effects of combined cortical and acoustic stimuli on muscle activity.

Hitherto, it has proven difficult to investigate interactions between cerebral and brainstem motor systems in the human. We hypothesised that transcranial magnetic stimulation (TMS) centred over the dorsal premotor and primary motor cortices might elicit net facilitatory cortico-reticular effects that could interact at the level of the brainstem with a habituated startle to give a reticulospinal discharge and electromyographic (EMG) response with a longer latency than the direct corticospinal response. Conversely, any reticulo-cortical activity evoked by a habituated startle should influence the size of the direct response to cortical TMS. EMG was recorded from active left deltoid muscle in nine healthy volunteers. Acoustic stimulation was delivered binaurally through headphones and repeated until the startle response was habituated. When TMS was centred over the right dorsal premotor or primary motor cortices and delivered 50 ms after the habituated acoustic stimulus, the contralateral direct motor evoked potential was inhibited, compared with the response elicited by TMS alone. The contralateral silent period was shortened and associated with less of a decrease in EMG levels relative to TMS alone. Indeed, an actual increase in EMG over baseline levels occurred in the later half of the silent period in all subjects. We conclude that both cortico-reticular and reticular-cortical effects could be elicited in deltoid through the combination of acoustic stimulation and TMS at short interstimulus intervals. Effects were similar with TMS over premotor and primary motor cortex.

Acoustic Stimulation↗
PubMed2004

Motor cortex inhibition induced by acoustic stimulation.

The influence of the brainstem motor system on cerebral motor areas may play an important role in motor control in health and disease. A new approach to investigate this interaction in man is combining acoustic stimulation activating the startle system with transcranial magnetic stimulation (TMS) over the motor cortex. However, it is unclear whether the inhibition of TMS responses following acoustic stimulation occurs at the level of the motor cortex through reticulo-cortical projections or subcortically, perhaps through reticulo-spinal projections. We compared the influence of acoustic stimulation on motor effects elicited by TMS over motor cortical areas to those evoked with subcortical electrical stimulation (SES) through depth electrodes in five patients treated with deep brain stimulation for Parkinson's disease. SES bypasses the motor cortex, demonstrating any interaction with acoustic stimuli at the subcortical level. EMG was recorded from the contralateral biceps brachii muscle. Acoustic stimulation was delivered binaurally through headphones and used as a conditioning stimulus at an interstimulus interval of 50 ms. When TMS was used as the test stimulus, the area and amplitude of the conditioned motor response was significantly inhibited (area: 57.5+/-12.9%, amplitude: 47.9+/-7.4%, as percentage of unconditioned response) whereas facilitation occurred with SES (area: 110.1+/-4.3%, amplitude: 116.9+/-6.9%). We conclude that a startle-evoked activation of reticulo-cortical projections transiently inhibits the motor cortex.

Acoustic Stimulation↗
PubMed2004

Stretch reflexes in human abdominal muscles.

Homonymous and heteronymous reflex connections of the abdominal muscles were investigated by the application of a tap to the muscle belly and observation of surface electromyographic responses. Reflex responses of the following abdominal muscles were investigated both ipsilateral and contralateral to the tap: rectus abdominis (RA), external oblique (EO) and internal oblique (IO). Reflexes were evoked in each of the homonymous muscles with latencies and estimated conduction velocities compatible with being evoked by Ia muscle afferents and having a monosynaptic component. Short latency heteronymous excitatory reflex connections were also observed in muscles on both ipsilateral and contralateral sides in response to the same stimulus. The latencies of the crossed responses were only marginally longer than responses evoked in the respective ipsilateral muscle. Moreover, the reflexes evoked in the IO muscle from ipsilateral and contralateral IO muscle afferents were of comparable amplitude, as were those reflexes evoked in ipsilateral and contralateral EO and RA muscles when tapping IO. These similarities in the reflex characteristics on the ipsilateral and contralateral sides suggest that abdominal muscle afferents activate similar pathways to muscles on both sides of the body. It follows that if the homonymous stretch reflex of abdominal muscles have a monosynaptic component, then a similar monosynaptic pathway activates synergistic motoneurones, not only ipsilaterally but also contralaterally.

Afferent Pathways↗
PubMed2005

Immunoreactivity for calcium-binding proteins defines subregions of the vestibular nuclear complex of the cat.

The vestibular nuclear complex (VNC) is classically divided into four nuclei on the basis of cytoarchitectonics. However, anatomical data on the distribution of afferents to the VNC and the distribution of cells of origin of different efferent pathways suggest a more complex internal organization. Immunoreactivity for calcium-binding proteins has proven useful in many areas of the brain for revealing structure not visible with cell, fiber or Golgi stains. We have looked at the VNC of the cat using immunoreactivity for the calcium-binding proteins calbindin, calretinin and parvalbumin. Immunoreactivity for calretinin revealed a small, intensely stained region of cell bodies and processes just beneath the fourth ventricle in the medial vestibular nucleus. A presumably homologous region has been described in rodents. The calretinin-immunoreactive cells in this region were also immunoreactive for choline acetyltransferase. Evidence from other studies suggests that the calretinin region contributes to pathways involved in eye movement modulation but not generation. There were focal dense regions of fibers immunoreactive to calbindin in the medial and inferior nuclei, with an especially dense region of label at the border of the medial nucleus and the nucleus prepositus hypoglossi. There is anatomical evidence that suggests that the likely source of these calbindin-immunoreactive fibers is the flocculus of the cerebellum. The distribution of calbindin-immunoreactive fibers in the lateral and superior nuclei was much more uniform. Immunoreactivity to parvalbumin was widespread in fibers distributed throughout the VNC. The results suggest that neurochemical techniques may help to reveal the internal complexity in VNC organization.

Animals↗
PubMed1998

Afferent feedback in the triphasic EMG pattern of leg muscles associated with rapid body sway.

Electromyographic (EMG) patterns of leg muscles associated with rapid body sway were studied in relation to displacement of the center of foot pressure (CFP). Standing subjects were instructed to shift the CFP by swaying their bodies, pivoting at the ankle as rapidly and accurately as possible after an auditory signal. CFP position was designated as N when the subject maintained a relaxed bending posture and as F when a maximally forward-leaning posture was maintained. A serial, stereotyped triphasic EMG pattern was observed in the rapid shift of CFP from N to F: cessation of EMG activity in the gastrocnemius (GC) muscle was followed by a burst in the tibialis anterior (TA) muscle (acceleration phase), and then resumed discharge occurred in the GC muscle with cessation of activity in the TA muscle (deceleration and stop). When the subject shifted the CFP from N to F to different degrees, the duration and amount of EMG activity in the TA muscle during acceleration and the GC muscle in deceleration were proportionate to the amount of CFP displacement associated with forward body sway. To determine the functional roles of sensory inputs from the foot on the triphasic EMG pattern, body sway was studied under the condition of sensory block in the feet induced by ischemia from tourniquets placed bilaterally just above the ankle joints. The triphasic EMG pattern persisted during ischemia. The time of GC cessation and the onset of TA burst at acceleration remained unchanged, but the times of TA cessation and resumption of GC discharge at deceleration were altered during ischemia. Moreover, subjects were unable to stop at F and eventually fell. These results indicate that both amount and duration of EMG activity associated with rapid body sway are functions of the amount of CFP displacement. Somatic sensation from the feet is important for control of burst and cessation timing and duration in leg muscle activity.

Adult↗
PubMed1999

The supplementary motor area in motor and sensory timing: evidence from slow brain potential changes.

The present study investigated the processing of durations on the order of seconds with slow cortical potential changes. The question is whether trial-to-trial fluctuations in temporal productions or judgments correspond to variations in the amplitude of surface Laplacians computed over particular scalp regions. Topographical analyses were done using the source derivation method. Subjects performed three successive tasks: (1) time production, in which they produced a 2.5-s interval separated by two brief trigger presses; (2) time discrimination, in which they detected small differences in intervals delimited by two brief clicks in comparison with a memorized standard interval: and (3) intensity discrimination (control task, devoid of time judgments), in which they detected small differences between the intensity of clicks, in comparison with standard clicks initially memorized. In order to focus on subjective differences, in the two discrimination tasks most comparison stimuli were identical to the standard, without the subjects being aware of it. At FCz, reflecting activity from the mesial frontocentral cortex that mainly includes the supplementary motor area (SMA), larger negativities were found during the longer target intervals, whether these were produced (task 1) or judged so (task 2). Those performance-dependent trends were restricted to the target intervals of the temporal tasks; they appeared neither during the 2 s preceding the target, nor during the control task. The data therefore suggest that the SMA subserves important functions in timing both sensory and motor tasks. We propose that the SMA either provides the "pulse accumulation" process commonly postulated in models of time processing or that it receives output from this process through striatal efferent pathways.

Adult↗
PubMed1997

Changes in baroreceptor vagal reflex performance in the developing rat.

Ontogenesis of both vagal control of heart rate and the baroreceptor vagal reflex were evaluated in rats at postnatal ages (P) of 5/6, 10, 15, 20, 25 and >>42 days anaesthetised with urethane (1.5 g/kg). Between P5/6 and P25 heart rate rose from 372 +/- 12 to 448 +/- 20 beats per minute and mean arterial pressure increased from 33.9 +/- 3.1 to 74.59 +/- 3.25 mm Hg (mean +/- SEM, n = 7 and 11 respectively). Cardiac vagal tone was absent at P10 but significant at P20 (P < 0.05) as revealed with atropine (0.5-1 mg/kg i.v.). Baroreceptor cardiac reflex sensitivity, tested with phenylephrine (10-50 microg/kg i.v.), was attenuated significantly in P10-20 rats compared with P5/6, P25 and mature animals. In P14-17 rats stimulation of neurones in either the solitary tract or ambiguual nuclei, by microinjection of L-glutamate (100-200 pmol), evoked an atropine-sensitive bradycardia indicating a functional integrity of central and peripheral efferent pathways mediating the baroreceptor reflex. Thus, the baroreceptor vagal reflex is functional in P5/6 rats but becomes attenuated between P10-P20, which is coincident with the maturational rise in arterial pressure.

Aging↗
PubMed2005

Anatomical evidence for glutamatergic transmission in primary sensory neurons and onto postganglionic neurons controlling penile erection in rats: an ultrastructural study with neuronal tracing and immunocytochemistry.

In male rats, the dorsal penile nerve (DPN) conveys sensory information from the genitals to the lumbosacral spinal segments of the spinal cord. DPN is the afferent limb of a reflex loop that supports reflexive erections, and that includes a network of spinal interneurons and autonomic and somatic motoneurons to the penis and perineal striated muscles. Autonomic efferent pathways to the penis relay in the major pelvic ganglion (MPG). Glutamate (Glu) is a likely candidate as a neurotransmitter of reflexive erections. Both AMPA and NMDA glutamatergic receptor subunits are present in the lumbosacral spinal cord, and AMPA and NMDA receptor antagonists block reflexive erections. In the present study, we used tract-tracing experiments combined with immunohistochemical and immunocytochemical techniques to ascertain the presence of Glu at two different levels of the network controlling reflexive erections. DPN afferents were localized in the dorsal horn of the lumbosacral cord and displayed the characteristics of either C-fibers or Adelta fibers. DPN terminals (some of them glutamatergic) were mainly distributed in the medial edge of the dorsal horn in the L6 spinal segment. GluR1 subunits were present in some DPN afferents, suggesting that they could be autoreceptors. DPN fibers were also present in the MPG, as were Glu terminals and GluR4 subunits. The results reveal the presence of Glu in DPN fibers and terminals and suggest that both the spinal cord and the MPG use glutamatergic transmission to control reflexive erections.

Animals↗
PubMed1996

Staining in the brain of Pachymorpha sexguttata mediated by an antibody against a Drosophila clock-gene product: labeling of cells with possible importance for the beetle's circadian rhythms.

Central nervous system ganglia within the head of the beetle Pachymorpha sexguttata were labeled using an antibody that recognizes an evolutionarily conserved region of the period (per) gene product of Drosophila melanogaster. per and the protein it encodes (PER) are believed to play a central role in the generation of endogenous circadian rhythms in flies; therefore anti-PER-mediated immunoreactivity may help to uncover cellular components of the circadian clock system in that insect and in others. In the beetle, application of this antibody led to the staining of a distinct set of neurons located in the optic lobes and the central brain, plus small numbers of putative glial cells in the optic lobes. Neuronal perikarya (including their nuclei in a few cases), the axons, and terminal regions of the neurons were stained. The network formed by these labeled cells and processes are candidates for the neuronal basis of the beetle's circadian clock system: the pacemaker region situated next to the medulla neuropil, its connection to the apparent site of Zeitgeber input, and putative efferent pathways projecting to control centers of various effector systems. Anti-PER-mediated labeling and that resulting from application to beetle specimens of an antiserum against pigment-dispersing hormone (PDH) were compared; in the Drosophila brain all "PDH cells" express the per gene as well. In the beetle, however, the set of "PER cells" and PDH ones is at least in part nonoverlapping. The hypothesis that neurons stained by application of anti-PER participate in the control of the beetle's circadian rhythms is discussed in the context of previous electrophysiological and immunohistochemical studies. Also considered are analogies to, and differences from, labeling of the PER protein in fruit flies and PER-like immunoreactivity in other animals.

Animals↗
PubMed2000

Evoked potentials in monitoring multiple sclerosis.

The usefulness of evoked potentials (EPs) in the diagnosis of multiple sclerosis is limited by its relatively low sensitivity to subclinical lesions. However, they are still a good tool to assess the integrity of afferent and efferent pathways and to quantify the severity of white matter involvement. Transversal and longitudinal studies have demonstrated good correlation between EP abnormalities and disability, suggesting that multimodal evoked potentials could be useful in monitoring the disease evolution in single patients and as surrogate end points in clinical trials.

Brain↗