Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model.

Dodecafluoropentane emulsion (DDFPe) nanodroplets are exceptional oxygen transporters and can protect ischemic brain in stroke models 24 h without reperfusion. Current stroke therapy usually fails to reach patients because of delays following stroke onset. We tested using DDFPe to extend the time window for tissue plasminogen activator (tPA). Longer treatment windows will allow more patients more complete stroke recovery. We test DDFPe to safely extend the time window for tPA thrombolysis to 9 h after stroke. With IACUC approval, randomized New Zealand white rabbits (3.4-4.7 kg, n = 30) received angiography and 4-mm blood clot in the internal carotid artery for flow-directed middle cerebral artery occlusion. Seven failed and were discarded. Groups were IV tPA (n = 11), DDFPe + tPA (n = 7), and no therapy controls (n = 5). DDFPe (0.3 ml/kg, 2 % emulsion) IV dosing began at 1 h and continued at 90 min intervals for 6 doses in one test group; the other received saline injections. Both got standard IV tPA (0.9 mg/kg) therapy starting 9 h post stroke. At 24 h, neurological assessment scores (NAS, 0-18) were determined. Following brain removal percent stroke volume (%SV) was measured. Outcomes were compared with Kruskal-Wallis analysis. For NAS, DDFPe + tPA was improved overall, p = 0.0015, and vs. tPA alone, p = 0.0052. For %SV, DDFPe + tPA was improved overall, p = 0.0003 and vs. tPA alone, p = 0.0018. NAS controls and tPA alone were not different but %SV was, p = 0.0078. With delayed reperfusion, DDFPe + tPA was more effective than tPA alone in preserving functioning brain after stroke. DDFPe significantly extends the time window for tPA therapy.

Nicotine suppresses the P13 auditory evoked potential by acting on the pedunculopontine nucleus in the rat.

We identified a potential novel site of action for nicotine (NIC) since (a) systemic injection of NIC led to a dose-dependent decrease in the amplitude of the sleep state-dependent, vertex-recorded, P13 midlatency auditory evoked potential (generated by the reticular activating system, RAS), (b) localized injections of a nicotinic receptor antagonist into the pedunculopontine nucleus (PPN, the cholinergic arm of the RAS) blocked the effects of systemic NIC on the P13 potential (a measure of level of arousal), and (c) localized injection of a nicotinic receptor agonist into the PPN also led to a decrease in the amplitude of the P13 potential, an effect blocked by PPN injection of a nicotinic receptor antagonist. There were minor changes in the manifestation of the startle response (SR) at the concentrations used; however, NIC did decrease the hippocampal N40 potential, although its effects were not affected by antagonist or agonist injections into the PPN. These results suggest a potential mechanism underlying the anxiolytic effects of NIC-suppression of the cholinergic arm of the RAS.

The P50 midlatency auditory evoked potential in patients with chronic low back pain (CLBP).

OBJECTIVE: Patients with Chronic Low Back Pain (CLBP) show arousal, attentional and cognitive disturbances. The sleep state-dependent P50 midlatency auditory evoked potential was used to determine if patients with CLBP [with and without co-morbid depression (DEP)] show quantitative disturbances in the manifestation of the P50 potential. METHODS: P50 potential latency, amplitude and habituation to repetitive stimuli at 250, 500 and 1000ms interstimulus intervals (ISIs) was recorded, along with the McGill Pain Questionnaire-Short Form (MPQ-SF). CLBP subjects (n=42) were compared with Controls (n=43), and with subjects with DEP only (n=6). Of the CLBP subjects, 20/42 had clinical depression (CLBP+DEP); 8/20 were taking anti-depressant medication (CLBP+DEP+med), the others were not (CLBP+DEP-med). RESULTS: There were no differences (ANOVA) in age, sex or P50 potential latency, although there was a trend towards increased latencies in CLBP groups. P50 potential amplitude was lower in CLBP groups, but not in sub-groups, again indicating a trend. P50 potential habituation was decreased in the DEP only subjects at the 250m ISI, and decreased in CLBP+DEP-med subjects at the 500ms ISI. This difference was not present in CLBP+DEP+med subjects. The MPQ-SF revealed that patients with CLBP and CLBP+DEP-med showed lower pain scores than CLBP+DEP+med patients. CONCLUSIONS: There is decreased habituation of the P50 potential habituation in unmedicated patients with CLBP+DEP compared to Controls. SIGNIFICANCE: Patients with CLBP+DEP-med may be less able to disregard incoming sensory information, including painful sensations, but anti-depressant medications help correct this deficit. However, their perception of pain may be increased by medication.

The feline fictive startle response and its related potential in the pedunculopontine nucleus.

The human P1/P50 midlatency auditory evoked potential and the auditory startle response (SR) have been used for investigating sensory gating and sensorimotor modulation which is impaired in various psychiatric diseases. In the present study, we demonstrated that auditory stimulation was capable of eliciting excitation of flexor and extensor neurograms from the hindlimb nerves in the paralyzed decerebrate cat, a phenomenon which corresponds to a "fictive" startle response (FSR). Previous studies have shown that the SR consists of distinct excitatory components, "early" and "late", separated by an inhibitory phase. However, in the FSR, unlike the SR in the intact preparation, the "late" excitatory phase never occurred. Recordings from the pedunculopontine nucleus (PPN) simultaneously with the FSR revealed the presence of an auditory evoked potential at a 20-25 ms latency, presumably the depth-recorded equivalent of the vertex-recorded wave A, which has been shown to be the feline equivalent of the human P1 potential. The depth-recorded wave A appeared to share neurological substrates with the excitatory phase of the FSR, since both responses were facilitated in a similar manner by increasing stimulus duration. We previously reported that, in the intact rat, the vertex-recorded P13 potential, the putative rodent equivalent of the human P1 potential, is generated, at least in part, by outputs of the PPN, and that the P13 potential shares neurological substrates with the "early" excitatory phase of the SR. Taken together, the results of the present study indicate that, along with the SR and the P13 potential in the intact rat, the FSR and the depth-recorded wave A in the paralyzed cat may be unique animal models for further examining, in the absence of neural structures rostral to the precollicular decerebration, the cellular basis of startle behavior.

Sensory gating of the P13 midlatency auditory evoked potential and the startle response in the rat.

The human P1/P50 midlatency auditory evoked potential and the startle response (SR) have been used as measures of sensory and sensorimotor gating, respectively. In the present study, both prepulse and paired stimulus paradigms were used in order to investigate the relationship between sensory gating mechanisms of the P13 potential, the putative rodent equivalent of the P1 potential, and those of the SR. In addition, these were compared to the properties of the N40 potential, another measure of sensory gating. Simultaneous recordings from the vertex (P13 potential and N40 potential) and neck musculature (SR) showed that (1) in a prepulse paradigm, increasing the intensity of the prepulse or decreasing the interstimulus interval resulted in increased inhibition of the P13 potential, N40 potential (to a lesser degree) and the SR (to a greater degree), (2) when using a low signal-to-noise ratio between the prepulse intensity and the background level, prepulse inhibition of the SR was reduced or absent while that of the P13 potential was present, (3) the amplitude of the 'prepulse evoked' P13 potential was significantly correlated with prepulse inhibition of the P13 potential, the N40 potential and the SR, (4) in a paired identical stimulus paradigm, decreasing the interstimulus interval resulted in increased habituation of the P13 potential, N40 potential (to a lesser degree) and the SR, and (5) increasing the intensity of the paired stimulation resulted in increased habituation of the P13 potential and the N40 potential (to a lesser degree), but not of the SR. These results demonstrate the presence of prepulse inhibition of the P13 potential, the N40 potential and the SR in a parallel manner, but show certain specific differences in their responses to parametric changes.

A middle-latency auditory-evoked potential in the rat.

Previous studies have established the presence of a middle-latency auditory-evoked potential that is characterized by a) sleep-state dependence, b) low following frequency (i.e., rapid habituation to repetitive stimulation), and c) blockade by the cholinergic antagonist, scopolamine. A vertex-recorded evoked potential having these characteristics was described in humans at a 50-80 ms latency (termed the P1 or.P50 potential) and in the cat at a 20-25 ms latency (termed wave A). These studies were undertaken to determine if a click stimulus-evoked potential having the same characteristics was present in the intact rat. Vertex and auditory cortex recordings in intact rats studied in a sound-attenuating chamber and exposed to free-field click stimuli showed a) the presence of a vertex recorded potential at a 11-15 ms latency, termed P13, and of an auditory cortex recorded potential at a 7-11 ms latency, termed Pa; b) the P13 was present during waking and paradoxical sleep but absent in slow-wave sleep, while Pa was present in all sleep-wake states; c) the P13 habituated markedly at stimulation rates above 1 Hz while Pa did not; and d) the P13 was blocked by low doses of scopolamine while Pa was not. These studies demonstrate the presence of a P1-like potential in the rat at a 13 +/- 2 ms latency.

Stimulation-induced setting of postural muscle tone in the decerebrate rat.

These studies demonstrate the presence of pontomedullary areas in the rat brainstem which, when stimulated electrically, serve to set postural muscle tone in the hindlimbs. Low amplitude stimulation of the dorsal tegmental field (DTF) was found to inhibit postural muscle tone and, in some rats, was found to decrease mean arterial pressure. Low amplitude stimulation of the ventral tegmental field (VTF) was found to increase postural muscle tone and, in all cases tested, was found to increase mean arterial pressure.