Intraoperative cerebral blood flow monitoring in neurosurgery: A review of contemporary technologies and emerging perspectives.

Intraoperative monitoring of cerebral blood flow (CBF) has become an invaluable adjunct to vascular and oncological neurosurgery, reducing the risk of postoperative morbidity and mortality. Several technologies have been developed during the last two decades, including laser-based techniques, videomicroscopy, intraoperative MRI, indocyanine green angiography, and thermography. Although these technologies have been thoroughly studied and clinically applied outside the operative room, current practice lacks an optimal technology that perfectly fits the workflow within the neurosurgical operative room. The different available technologies have specific strengths but suffer several drawbacks, mainly including limited spatial and/or temporal resolution. An optimal CBF monitoring technology should meet particular criteria for intraoperative use: excellent spatial and temporal resolution, integration in the operative workflow, real-time quantitative monitoring, ease of use, and non-contact technique. We here review the main contemporary technologies for intraoperative CBF monitoring and their current and potential future applications in neurosurgery.

[Cortical spreading depolarization: an underestimated phenomenon after human brain injury?]. / Les ondes lentes de dépolarisation corticale : un phénomène sous-estimé chez les patients cérébrolésés ?

BACKGROUND AND PURPOSE: Cortical spreading depolarization waves (CSD) are massive temporary neuronal depolarizations that slowly propagate through cerebral cortex from brain injured tissue. CSD waves cause temporary brain electrical silence, local tissue hemodynamic responses and metabolic increases required for cellular repolarization. Due to this metabolic imbalance in compromised tissue, CSD could participate in the extension of secondary insults after brain injury. From the analysis of the human literature, we aimed at determine the CSD incidences in brain injured patients. METHODS: Medline(®) research: "cortical spreading depolarization" and "brain injury", and "human" limits from 1980 to 2011. RESULTS: Ten original studies were found. CSD occurred in more than 50% of patients monitored for CSD after different brain injury (traumatic, subarachnoid haemorrhage, malignant stroke, spontaneous intracranial haemorrhage). When detected, CSD were associated with a significantly worse neurological outcome. To be identified, CSD required specific devices that directly record cortical electrical depression by a multipolar electrode positioned at the cortex surface or by indirect analysis of hemodynamic and metabolic consequences of the CSD. CONCLUSIONS: When monitoring tools are available, CSD occur in more than 50% of brain injured patients. Today results come from clinical research. Future studies are necessary to determine the impact of CSD detection on care and potential therapeutics aimed at counteracting these adverse events.

Microbiosensor based on glucose oxidase and hexokinase co-immobilised on platinum microelectrode for selective ATP detection.

ATP determination is of great importance since this compound is involved in a number of vital biological processes. To monitor ATP concentration levels, we have developed a microbiosensor based on cylindrical platinum microelectrode, covered with a layer of poly-m-phenylendiamine (PPD), and layer of co-immobilised glucose oxidase and hexokinase. Conditions for biosensor measurement of ATP (pH, Mg(2+) and substrates concentration) in vitro and microbiosensor characteristics such as sensitivity, selectivity, reproducibility, storage stability were studied and optimized. Under optimal conditions the microbiosensor can measure ATP concentrations down to a 2.5 microM detection limit with response time about 15 s. Interferences by electroactive compounds like biogenic amines and their metabolites, ascorbic acid, uric acid and L-cystein are rejected in general by the PPD layer. The microbiosensor developed is insensitive to ATP analogues (or substances with similar structure), such as ADP, AMP, GTP and UTP, too. It can be used for ATP analysis in vitro in the reactions consuming or producing macroergic triphosphate molecules to study kinetics of the process and in drug design concerning development of inhibitors specific to target kinases and others target enzymes.

Influence of a 1-h immobilization stress on sleep and CLIP (ACTH(18-39)) brain contents in adrenalectomized rats.

Basal sleep amounts in adrenalectomized rats (AdX), as compared to intact animals, exhibit a significant increase in slow-wave sleep (SWS), a tendency towards an increase in paradoxical sleep (PS), and circadian rhythms (SWS and PS) flattened in amplitude. An immobilization stress (IS) of 1 h, imposed on AdX rats at the beginning of the dark period, is accompanied by an intense polygraphic waking. Just after the IS, SWS amount become significantly higher than in control rats (+44%/11 h of darkness) whereas significant increases of PS occur only 5-10 h after the IS (+24%/11 h of darkness). A specific radioimmunoassay for CLIP (corticotropin-like intermediate lobe peptide or ACTH(18-39)) was performed in biopsies taken either from the nucleus raphe dorsalis (nRD) or the arcuate nucleus (AN). In the nRD, just after the IS, phosphorylated CLIP (Ph-CLIP) concentration exhibits a decreasing tendency, but 4 h later, it increases significantly (+22%, p<0.05). In the AN, Ph-CLIP concentration remains unchanged after the IS as well as 4 h later. These results differ from those previously reported in intact animals also submitted to a 1-h IS, that is, a SWS rebound less marked (+27%/11 h of darkness), a PS rebound more important starting immediately after the IS (+46%/11 h of darkness) and a significant increase in Ph-CLIP occurring just after the end of the restraint. In conclusion, data obtained after a restraint stress either in AdX or in control rats point out the dependence of the PS rebound on the nRD Ph-CLIP concentration.

Influence of stress duration on the sleep rebound induced by immobilization in the rat: a possible role for corticosterone.

In rats, recovery from short intense stress usually involves a sleep rebound characterized by an increase in slow-wave sleep and paradoxical sleep duration. However, a large body of evidence indicates that stressful situations lasting for several days or weeks can have deleterious effects on sleep quantity and quality, probably leading to an impairment of the sleep rebound. In this study, using immobilization as a stress model in the rat, we sought to determine the stress duration beyond which the sleep rebound disappears, as well as the mechanisms responsible for this suppression. In a first series of experiments, rats were immobilized for 30 min, 1h, 2h or 4 h. Slow-wave sleep rebounds evidenced after the different immobilization periods were, respectively, +32%, +25%, +9% and -0.2% and paradoxical sleep rebounds +57%, +88%, +103% and +21% compared with control recordings of the same animals. The sleep rebound thus disappeared when the duration of immobilization reached 4 h. In a second series of experiments, adrenalectomized rats were subjected to a 1 h immobilization, and showed an increased slow-wave sleep rebound ( + 44% compared to intact ones), whereas the paradoxical sleep rebound was slightly decreased and delayed. When glucocorticoid action was replaced by an intramuscular injection of dexamethasone, a glucocorticoid receptor agonist, the sleep rebound was suppressed (-3% in slow-wave sleep and -37% in paradoxical sleep). Lastly, in a third series of experiments, plasma corticosterone concentration was evaluated at different times in rats immobilized for 1 h or 4 h. Corticosterone concentration was higher in stressed animals than in control ones (+92%) and returned to baseline 4 h earlier in animals immobilized for 1 h compared with those stressed for 4 h. Therefore, corticosterone is probably involved in the suppression of the sleep rebound after long immobilization periods since (i) dexamethasone suppressed the stress-induced sleep rebound, and (ii) corticosterone was elevated for a longer period in the 4 h immobilization group. It is concluded that the reparative sleep rebound is suppressed after long and intense stress periods and that a prolonged glucocorticoid secretion could be one of the factors responsible for this effect. This deleterious effect on sleep could impair normal recovery and quick adaptation to a new situation, and could participate in the development of stress-related pathologies in humans.

Effects of tianeptine, sertraline and clomipramine on brain serotonin metabolism: a voltammetric approach in the rat.

Tianeptine is a substance enhancing the serotonir uptake while sertraline and clomipramine inhibit it. By means of 5-hydroxyin-doleacetic acid (5-HIAA) voltammetric measurements, this study investigated their influence on serotonin metabolism which depends mainly upon the activity of monoamine oxidase type A. After tianeptine injection the 5-HIAA signal increased by about 60%. This effect was maintained when the animals were pre-treated with MDL 72145 (an inhibitor of monoamine oxidase type B) but reduced when clorgyline (an inhibitor of monoamine oxidase type A) was administered after tianeptine. Administration of sertraline or clomipramine reduced the 5-HIAA signal by about 30-50%, whether the animals were pre-treated with MDL 72145 or not. It is to be concluded that tianeptine, sertraline and clomipramine can regulate the 5-HT fraction present in the synaptic cleft, not only by acting at the level of the serotoninergic neurons, but also by favoring or reducing the access of the amine to monoamine oxidase type A which is synthesized within non-serotoninergic neurons and glial cells.

[Voltametric detection of cerebral NO in rats. Variations of the signal throughout the sleep-wakefulness cycle]. / Détection voltamétrique du NO cérébral chez le rat. Variations du signal à travers le cycle veille-sommeil.

Nitric oxide (NO) is synthesized in the neurons by constitutive NO synthase (NOS). Within given neuronal sets, this enzyme is colocalized with different other neurotransmitters such as, for example, GABA, acethylcholine or serotonin. Our attention has been focused on the fact that serotoninergic neurons, well known for their involvement in sleep triggering and maintenance, synthesize also NO. In order to evaluate the modalities of release of this compound throughout the rat sleep-waking cycle, we prepared a sensor allowing its specific detection in freely moving animals. The active part of this sensor is a carbon fiber (phi = 30 microns) successively coated with porphyrin nickel and nafion. In vitro, together with differential normal pulse voltammetric measurements, it allows the detection of a 650 mV signal varying linearly in NO solutions ranging from 5.10(-7) to 10(-4) M. At physiological concentrations, L-arginine, L-citrulline, nitrites and nitrates do not yield a signal at 650 mV. Similarly, the compounds administered to the animals, hydroxylamine, L-arginine p-nitroanilide (L-ANA) and L-N omega-nitro arginine methyl ester (L-NAME) are not electroactive at 650 mV. L-ANA and L-NAME, also appear to be trapping agents for NO while leaving the electrochemical properties of the sensor untouched. In vivo, in the frontal cortex of the anesthetized rat, a signal is measured at 650 mV. The administration of hydroxylamine (40 mg/kg, i.p.) induces a 100% increase in its height. The administration of L-ANA (100 mg/kg, i.p.) produces its complete disappearance within 50 min. Finally, the administration of L-NAME (100 mg/kg, i.p.) is without effect. This last aspect might be dependent upon the inability of L-NAME to cross the blood brain barrier. On the contrary, the increase in the signal height obtained with hydroxylamine and its disappearance with L-ANA support that it might depend upon NO. In vivo, and in animals also equipped with polygraphic electrodes, the signal measured in the same area of the cortex exhibits the highest height during the waking state and decreases during either slow-wave sleep (-6%) or paradoxical sleep (-9%). These mild variations might represent the mean of several NO sources (cortical GABAergic interneurons, cholinergic and serotoninergic axonal nerve endings), each of them varying differently throughout the sleep-waking cycle.

Evidence for a sleep-promoting influence of stress.

In the present review the data supporting the existence at the central level of a stress-sleep relation are reported and discussed. An immobilization stress of 1 or 2 hour(s) is accompanied by a marked polygraphic waking and followed by a significant sleep rebound concerning mainly paradoxical sleep (PS). During the restraint, an important release of 5-hydroxyindoles [5-OHles, a good index of serotonin (5-HT) release] occurs in the basal hypothalamus (BH). This release, produced by the nerve endings originating from the nucleus raphe dorsalis (nRD), might secondarily influence the release and/or the synthesis of hypnogenic substances directly involved in the sleep rebound production. Corticotropin-like intermediate lobe peptide (CLIP, or ACTH18-39) is a peptide possessing hypnogenic properties and derived from proopiomelanocortin (POMC) whose perikarya are contained within the BH (arcuate nucleus). The POMC nerve endings impinge on the nucleus raphe dorsalis, a structure containing sleep permissive components upon which CLIP acts to trigger sleep. It remains to be defined how the activity of the neuronal loop described above is impaired under chronic stress conditions.

Is the nucleus raphe dorsalis a target for the peptides possessing hypnogenic properties?

Several peptides exhibiting hypnogenic properties when administered i.p., i.v. or i.c.v. are now known. No data, however, are available concerning their targets in the brain. In the present work we hypothesize that the nucleus raphe dorsalis (nRD) may be one such target since it contains 2 sleep permissive components that must be influenced for sleep to occur. One of these components is serotoninergic in nature and gates the occurrence of ponto-geniculo-occipital (PGO) waves. The other, of unknown nature, influences tonic sleep phenomena. For hypnogenic peptides, a putative mechanism permitting the triggering and maintenance of sleep might consist of influencing both the above components. In the present work, 3 hypnogenic substances, CLIP (corticotropin-Like intermediate lobe peptide), VIP (vasoactive intestinal polypeptide) and DSIP (delta sleep inducing peptide), were injected into the nRD in order to determine whether these compounds still induce sleep by local administration. To verify that such local injections do not spread outside the nRD, radiolabelled CLIP and VIP were also injected. Autoradiograms obtained with either labeled CLIP or VIP indicate that these compounds, injected in a 0.2 microliter volume, do not spread outside the nRD. The sleep data obtained confirm that CLIP, at a dose of 10 ng, induces an increase in duration of paradoxical sleep (PS); this effect is observed only for injection sites located in the dorsolateral part of the nRD, an area where CLIP immunoreactive (IR) fibers are present. VIP, at a dose of 100 ng, also increases PS duration, whereas at 10 ng, only slow wave sleep duration is increased. In this case, the positive injection sites are scattered throughout the entire nRD as are the VIP-IR fibers. With DSIP, no sleep effect was found whatever the dose used or the site injected; in the same manner, no DSIP-IR fibers have been located in this structure. These data suggest that the nRD is a target for the expression of the hypnogenic properties of CLIP and VIP, but not for DSIP. The nature of the possible mechanisms permitting such expression are discussed.