Scopolamine abolishes cerebral blood flow response to somatosensory stimulation in anesthetized cats: PET study

The effect of the cholinergic blocker, scopolamine on the cerebral blood flow (CBF) response to vibrotactile stimulation of a fore paw was studied using high-resolution positron emission tomography and H₂¹⁵O in 5 pentobarbital-anesthetized cats. Before scopolamine injection, the CBF response to the stimulation was found in the contralateral somatosensory cortex (mean ratio (contralateral/ipsilateral) control: stimulated1.02 ± 0.02: 1.17 ± 0.05; P < 0.01). After intravenous injection of scopolamine (0.35 mg/kg), the CBF response was abolished. However, the cerebral metabolic rate of glucose (CMRGlu) response to the same stimulation was unchanged after scopolamine injection in the same cats. We concluded that scopolamine abolishes the CBF response but not neuronal response to stimulation. We suggest that cholinergic mechanisms may play an important role for mediating CBF coupling to neuronal activity during physiological stimulation.     

Effect of lidocaine on somatosensory evoked response and cerebral blood flow after canine cerebral air embolism.

BACKGROUND AND PURPOSE: Victims of air embolism often recover rapidly on hyperbaric treatment then deteriorate again, even if hyperbaric treatment is continued. In previous animal experiments, lidocaine has been shown to improve recovery of somatosensory evoked response amplitude after air embolism. However, animals in these experiments rarely deteriorated. We have shown that the induction of air embolism and transient hypertension in canines produces deterioration despite hyperbaric treatment, and we decided to test the effect of lidocaine on somatosensory evoked potential recovery and cerebral blood flow in this model. METHODS: Dogs were treated with repeated doses of lidocaine or equivalent volumes of saline during hyperbaric therapy after internal carotid air embolism and transient hypertension. The investigators were unaware of treatment group assignment during the experiments. The amplitude of the median nerve somatosensory evoked potential and cerebral blood flow measured with carbon-14-labeled iodoantipyrine autoradiography were used to assess effect of therapy. RESULTS: Lidocaine-treated dogs recovered 60 +/- 10% (mean +/- 95% confidence limits) of the baseline somatosensory evoked potential amplitude 220 minutes after air embolism; saline-treated dogs recovered 32 +/- 10% (a significant difference at p less than 0.01). Lidocaine-treated dogs also had higher cerebral blood flow values than saline-treated dogs 220 minutes after air embolism. CONCLUSIONS: Lidocaine ameliorated the delayed deterioration of evoked potential associated with air embolism and hypertension in this canine model. The improved cerebral blood flow may be a mechanism of action of lidocaine or an associated effect of improved neuronal survival.     

Attention modulates somatosensory cerebral blood flow response to vibrotactile stimulation as measured by positron emission tomography

In human primary somatosensory cortex, the cerebral blood flow response to vibrotactile stimulation of the fingers (110 Hz), as measured by positron emission tomography and H2(15)O, was 13% higher (p less than 0.025) when the subjects attended to the stimulus, compared to when they were simultaneously engaged in a distraction task. This suggests that the physiological response of a primary cortical area can be modulated by the attentive behavior of the subject.     

Early temporal characteristics of cerebral blood flow and deoxyhemoglobin changes during somatosensory stimulation.

The close correspondence between neural activity in the brain and cerebral blood flow (CBF) forms the basis for modern functional neuroimaging methods. Yet, the temporal characteristics of hemodynamic changes induced by neuronal activity are not well understood. Recent optical imaging observations of the time course of deoxyhemoglobin (HbR) and oxyhemoglobin have suggested that increases in oxygen consumption after neuronal activation occur earlier and are more spatially localized than the delayed and more diffuse CBF response. Deoxyhemoglobin can be detected by blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI). In the present study, the temporal characteristics of CBF and BOLD changes elicited by somatosensory stimulation in rat were investigated by high-field (9.4 T) MRI. With use of high-temporal-resolution fMRI, it was found that the onset time of the CBF response in the somatosensory cortex was 0.6 +/- 0.4 seconds (n = 10). The CBF changes occurred significantly earlier than changes in HbR concentration, which responded after 1.1 +/- 0.3 seconds. Furthermore, no early increases in HbR (early negative BOLD signal changes) were observed. These findings argue against the occurrence of an early loss of hemoglobin oxygenation that precedes the rise in CBF and suggest that CBF and oxygen consumption increases may be dynamically coupled in this animal model of neural activation.     

Influences of caffeine, acetazolamide and cognitive stimulation on cerebral blood flow velocities

Assessment of cerebral blood flow velocities (CBFV) can be used as a non-invasive tool to evaluate specific drug effects, like caffeine (CAF), acetazolamide (AA) as well as cognition. Their influences on each others CBFV were evaluated in detail, using a randomized, double-blind, double-dummy, placebo-controlled three-fold cross-over study design in 18 right-handed healthy male volunteers. CBFV (maximal, mean, minimal) and pulsatility index of both middle cerebral arteries were recorded by transcranial Doppler ultrasound simultaneously, during a verbal memory test, oral CAF, intravenous AA or placebo. AA led to increase in CBFV of 25-32%. Caffeine resulted in decreased V(mean) and V(min) of 10-13%. Cognitive stimulation resulted in a slight increase of CBVF of about 4%, but was overruled by effects of AA and CAF. We conclude that pharmacological effects can easily be assessed by TCD during clinical pharmacological studies of vasoactive drugs. However intraindividual variability and effects of neuropsychological stimulation needs to be taken into account.     

Frequency-dependent changes in cerebral blood flow and evoked potentials during somatosensory stimulation in the rat.

Contrary to the concept of neuronal-vascular coupling, cortical evoked potentials do not always correlate with blood flow responses during somatosensory stimulation at changing stimulus rates. The goal of this study is to clarify the effects of stimulus frequency on the relationship between somatosensory evoked potentials (SEPs) and cerebral blood flow. In rats anesthetized with alpha-chloralose, we measured SEPs by signal-averaging field potentials recorded with an electrode placed on dura overlying the hindlimb somatosensory cortex. Regional blood flow was simultaneously assessed in the same region with a laser-Doppler flow (LDF) probe. The contralateral sciatic nerve was stimulated with 0.1 A pulses at the frequencies of 1, 2, 5, 10 and 20 Hz. SEPs (both P1 and N1 components) declined with increasing frequency regardless whether stimulus duration (20 s) or number (100) were kept constant, suggesting that frequency is an important determinant of neuronal activity. In contrast, LDF responses increased to a maximum at 5 Hz, and do not correlate with SEPs. Because CBF should reflect integrated neuronal activity, we computed the sum of SEPS (summation operatorSEP = SEP x stimulus frequency) as an index of total neuronal activity at each frequency. Summation operatorSEP indeed correlates positively (P<0.001) with LDF responses. Thus, during somatosensory stimulation at various frequencies, cerebral blood flow is coupled to integrated neuronal activity but not to averaged evoked potentials.     

Non-uniform response of regional cerebral blood flow to stimulation of cervical sympathetic nerve

Regional cerebral blood flow (CBF) was measured by an autoradiographic method in nine adult cats, using antipyrine-¹⁴C as a diffusible indicator. In seven of the cats, CBF measurements were made during stimulation of a cervical sympathetic trunk. Stimulation caused minor regional decreases of CBF in at least five of these seven cats. The decreases were non-uniform and occurred almost exclusively in cortical structures. Although constriction of cervical arteries probably accounts for some of the effects of sympathetic stimulation, the present study indicates that there is also an effect on cerebral regulatory arterioles. However, there is no convincing evidence that function of the autonomic nervous system is necessary for the normal regulation of the cerebral circulation.     

Regulation of cerebral blood flow response to somatosensory stimulation through the cholinergic system: a positron emission tomography study in unanesthetized monkeys

The effects of scopolamine, a muscarinic cholinergic receptor antagonist and physostigmine, a cholinesterase inhibitor, on the regional cerebral blood flow (rCBF) response to vibrotactile stimulation of the forepaw were studied in the brain of unanesthetized monkeys using ¹⁵O-labeled water and high resolution positron emission tomography. Before scopolamine administration, vibrotactile stimulation produced a significant increase in the rCBF response in the contralateral somatosensory cortex of the monkey brain. Intravenous administration of scopolamine at doses ranging from 1 to 500 μg/kg resulted in a dose-dependent reduction of the rCBF response. The rCBF response abolished by scopolamine (50 μg/kg) was recovered by administration of physostigmine (10 μg/kg). On the other hand, the regional cerebral metabolic rate of glucose (rCMRglc) response, measured with [¹⁸F]-2-fluoro-2-deoxy-d-glucose, to the same stimulation was unchanged by administration of either scopolamine and/or physostigmine. These results suggested that cholinergic mechanisms might be involved in regulation of the coupling between neuronal activity and rCBF response, not between the activity and rCMRglc response.     

Effect of cold face stimulation on cerebral blood flow in humans

BACKGROUND AND PURPOSE: In humans, activation of the diving reflex by a cold stimulus to the face results in bradycardia, peripheral vasoconstriction and an increase in blood pressure. However, responses of the cerebral blood flow have not yet been evaluated. We undertook this study to assess the effect of cold face stimulation on the cerebral circulation in humans. METHODS: Seventeen healthy volunteers, aged 27+/-5 years were evaluated during application of a cold stimulus (0 degrees C) to the forehead for 60s. We continuously monitored mean arterial pressure (MAP), mean flow velocity (MFV) of the middle cerebral artery, cardiac output, skin blood flow, heart rate and end-tidal CO2. Total peripheral resistance (TPR) was calculated as MAP divided by cardiac output. Cerebrovascular resistance index (CVRi) was calculated as MAP divided by MFV. RESULTS: Cold face stimulation did not significantly affect cardiac output but resulted in significant decreases in heart rate and skin blood flow and an increase in MAP. MFV in the mid-cerebral artery showed a slight, but significant increase. The maximum increase in CVRi (14.2+/-11.4%) was significantly (P<0.01) less than the maximum increase in TPR (23.9+/-5.7%). End-tidal CO2 did not change significantly during the cold stimulation. CONCLUSIONS: In contrast to other sympathetic stimulations (e.g. lower body negative pressure), facial cooling results in an increase in cerebral blood flow. The amount of cerebral vasoconstriction was less than the amount of total peripheral vasoconstriction. These results suggest that although there is some constriction of the cerebral resistance vessels during cold face stimulation, cerebral perfusion was maintained, possibly by opposing parasympathetic activation.     

Differential effects of intranasal insulin and caffeine on cerebral blood flow

Insulin is an important modulator of brain functions such as memory and appetite regulation. Besides the effect on neuronal activity, it is also possible that insulin has a direct vasodilatory effect on cerebral blood flow (CBF). We investigated the impact of increased insulin levels in the central nervous system on basal and task-induced CBF as well as blood oxygenation level-dependent (BOLD) response in the visual cortex using pulsed arterial spin-labeling MRI. An intranasal insulin application was used to avoid peripheral hyperinsulinaemia, which would lead to a cascade of hormonal changes. In a control experiment, caffeine was applied due to its well-known impact on the vasculature of the brain leading to a reliable reduction of CBF. Eight lean subjects were included in the study. On 2 separate days, intranasal human insulin or caffeine tablets were given to the subjects after fasting over night. On each day, basal CBF and task-induced CBF were measured before and 30 min after application of insulin or caffeine in each subject. During the task condition, a flickering checkerboard was presented. Insulin had no effect on basal CBF and task-induced CBF in comparison with drug-free baseline measurement in the visual cortex and control regions. After caffeine application, however, there was a significant decrease of CBF during stimulation in the visual cortex. The BOLD response was not altered by insulin or caffeine between pre- and postdose measurements. In conclusion, we found no evidence for a direct vasodilatory effect of intranasal insulin on the cerebral vascular system in this study.     

Effect of monoamine oxidase inhibition on the regional cerebral blood flow response to circulating noradrenaline

The effect of an acute i.v. infusion of noradrenaline (NA) on regional cerebral blood flow (rCBF) was investigated in the awake rat using [¹⁴C]iodoantipyrine as diffusible tracer. The contribution of vascular monoamine oxidase (MAO) to the efficiency of the enzymatic blood-brain barrier (BBB) to catecholamines was assessed by measuring the multiregional cerebrovascular response to circulating NA given alone or after i.v. administration of the monoamine oxidase inhibitor, clorgyline. Since i.v. infusion of NA elevates blood pressure, the influence of NA on the cerebrovascular bed was first studied by determining the relationship between rCBF and the mean arterial pressure (MAP). When the MAP was only slightly increased (to approximately 130 mm Hg), a trend to flow decrease under NA infusion was observed. Secondly, we compared the effects of NA or rCBF in animals treated or not treated with clorgyline. This was performed under moderate hypertension (within the ‘autoregulated’ range of MAP) to avoid any risk of mechanical damage to the BBB. Clorgyline administration alone did not significantly modify rCBF, but the subsequent i.v. infusion of NA induced an increase in rCBF (weighted mean 14%) in all structures investigated. The differences being statistically significant (P < 0.05) in 5 out of 13 structures by up to 20%. Compared to studies involving disruption of the morphological BBB in which plasma NA elicits a widespread important increase in blood flow, the weak cerebrovascular effects we observed provide indirect evidence for the efficiency of the BBB to catecholamines in the conscious rat within the autoregulated range of arterial pressure. Conversely, the NA-induced vasodilation obtained after inhibition of vascular MAO shows that the enzymatic BBB participates in the overall restriction of the permeability to NA, with a fairly homogeneous regional distribution.     

5Effect of gastric electrical stimulation on cerebral blood flow in patients with gastroparesis

Introduction: Gastric electrical stimulation is a safe and efficient treatment option in medically refractory gastroparesis. Several controlled and open label trials have shown the effectiveness of gastric electrical stimulation in symptom palliation for patients with gastroparesis. Initial settings were established based on experiences in the animal model. We reviewed our experience using higher stimulator settings on symptom reduction after implantation of gastric electrical stimulators. Methods: 42 consecutive patients (38 females and 4 males, mean age 43 ± 1.8 years) with medically refractory gastroparesis were followed after implantation of gastric electrical stimulator between 1999 and 2005. The 42 patients included 29 patients with idiopathic gastroparesis and 13 patients with diabetic gastroparesis Baseline stimulation settings were 14 Hz, 5 mAmps, 330 micro‐sec pulse width, 0.1 sec on, and 5 sec off. At each follow‐up gastrointestinal symptom scores were assessed. If symptoms were unsatisfactory, stimulator settings were increased according to a standardized protocol. Dose response relationships were evaluated. Results: After a mean follow‐up of 19 ± 2.6 months, 83% of patients had higher settings (p < 0.001, Fisher's exact test). Solid gastric emptying time during this period decreased from 195 ± 45 to 106 ± 38 minutes (T1/2 value, p < 0.05, paired t‐test) along with an average weight change from 64 ± 5.3 to 62 ± 5.6 kg (p > 0.05, paired t‐test). There were 258 stimulator interrogations with a stepwise improvement in total symptom score (R² = 0.08, p < 0.001). Multivariate regression analysis showed that frequency of electric stimulation was independently associated with improvement of total symptom score (R² = 0.06, p < 0.02). A prolonged cycle on time correlated with worsening of nausea score (R² = 0.09, p < 0.02) and vomiting score (R² = 0.13, p < 0.001). A measurement of high impedance independently correlated with a low vomiting score (R² = 0.19, p < 0.0001). Though not statistically significant, most patients’ symptoms were optimized at mean current of 10 mAmps, frequency of 55 Hz, pulse width of 330 micro‐sec, cycle on time of 0.1 sec, and cycle off time of 1 sec. Conclusion: The majority of patients seem to benefit from higher than baseline settings. Optimal settings of the implanted device must be determined on an individual basis, but based upon experience in humans seem to be 10 mAmps, 55 Hz, 0.1 sec on, 0.4 to 1 sec off.     

Effect of hemisphere-selective repetitive magnetic brain stimulation on middle cerebral artery blood flow velocity

The changes of cerebral hemodynamics following repetitive hemisphere-selective magnetic stimulation over the motor cortex were investigated in 8 healthy volunteers. Bilateral simultaneous monitoring of middle cerebral artery blood flow velocity was done using transcranial Doppler ultrasonography during magnetic stimulation with single, double and triple stimuli with interstimulus intervals of 100 msec. Magnetic cortex stimulation was followed by a significant increase of ipsilateral flow velocity ranging from 5.3% ± 2.7% for single stimuli up to 8.5% ± 4.1% for triple stimuli and by a smaller increase of contralateral flow velocity. The ipsilateral increases are comparable to those measured previously during voluntary finger movements and indicate a physiological cortex stimulation. In parallel, the average sum of the baseline to peak hand motor response amplitudes increased from 1.5 ± 0.7 mV (single stimuli) to 4.5 ± 3.2 mV (triple stimuli). The increase of flow velocity in the non-stimulated hemisphere occurred during the absence of motor responses and might reflect a transcallosal activation of inhibitory neuronal structures. The occurrence of maximum velocity responses within 2–3 heartbeats following the first cortex stimulus points to a fast adjustment of cerebral perfusion in response to transcranial brain stimulation. No significant change of flow velocity was observed following motor responses evoked by unilateral magnetic stimulation of the brachial plexus or following acoustic artifacts of the coil discharge.     

Effect of nicergoline on cerebral blood flow

Cerebral blood flow (CBF) was measured before and after intravenous injection of the cerebral vasodilator nicergoline in 13 patients with cerebrovascular disease. CBF increased in seven. The possibility that the effect of the drug in the remainder may have been masked by a fall of CBF which occurs during sequential measurement of patients at rest is discussed.     

Effect of nitric oxide blockade by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension.

The importance of nitric oxide (NO) for CBF variations associated with arterial carbon dioxide changes was investigated in halothane-anesthetized rats by using an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (NOLAG). CBF was measured by intracarotid injection of 133Xe. In normocapnia, intracarotid infusion of 1.5, or 7.5, or 30 mg/kg NOLAG induced a dose-dependent increase of arterial blood pressure and a decrease of normocapnic CBF from 85 +/- 10 to 78 +/- 6, 64 +/- 5, and 52 +/- 5 ml 100 g-1 min-1, respectively. This effect lasted for at least 2 h. Raising PaCO2 from a control level of 40 to 68 mm Hg increased CBF to 230 +/- 27 ml 100 g-1 min-1, corresponding to a percentage CBF response (CO2 reactivity) of 3.7 +/- 0.6%/mm Hg PaCO2 in saline-treated rats. NOLAG attenuated this reactivity by 32, 49, and 51% at the three-dose levels. Hypercapnia combined with angiotensin to raise blood pressure to the same level as the highest dose of NOLAG did not affect the CBF response to hypercapnia. L-Arginine significantly prevented the effect of NOLAG on normocapnic CBF as well as blood pressure and also abolished its inhibitory effect on hypercapnic CBF. D-Arginine had no such effect. Decreasing PaCO2 to 20 mm Hg reduced control CBF to 46 +/- 3 ml 100 g-1 min-1 with no further reduction after NOLAG. Furthermore, NOLAG did not change the percentage CBF response to an extracellular acidosis induced by acetazolamide (50 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Excessive oxygen or glucose supply does not alter the blood flow response to somatosensory stimulation or spreading depression in rats

We investigated the influence of hyperoxia (arterial pO₂ 446 ± 43 mmHg) and hyperglycemia (blood glucose 19.4 mmol/l) on somatosensory stimulation (whisker deflection) employing laser Doppler flowmetry (LDF). Our aim was to test the hypothesis that a possible substrate-sensing mechanism for glucose and oxygen contributes to the coupling between cortical activity and regional cerebral blood flow (rCBF) in order to match increased demand with substrates. In addition, we looked at the influence of hyperglycemia (blood glucose 17.9 mmol/l) and hypercapnia (arterial pCO₂ 62 mmHg) on rCBF (LDF) and regional cerebral blood oxygenation changes (rCBO) in the even stronger metabolic stimulus of cortical spreading depression (CSD). For the latter we employed the new non-invasive technique of near infrared spectroscopy (NIRS). All experiments were done using chloralose/urethane-anesthetized rats. Somatosensory stimulation increased rCBF by about 20% of baseline, in the case of both norm- and hyperoxia as well as both normo- and hyperglycemia. The blood-flow response to CSD consisted of a temporary sharp increase in rCBF to more than 400%. At the same time, the concentration of oxyhemoglobin [HbO₂] increased, while deoxyhemoglobin [Hb] decreased, indicating excessive oxygenation. Hyperglycemia altered neither the rCBF nor the rCBO response. Preexisting hypercapnia, however, produced reductions in both hyperperfusion (rCBF) and hyperoxygenation (rCBO) during CSD. We found that, for experimental hyperglycemia, i.v. may be superior to i.p. application of glucose because of the latter's side effects in connection with blood flow. Our findings cannot support the hypothesis of a substrate sensing mechanism in coupling.