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Abstract

Nitroglycerin has been widely used as a model of experimental migraine. Studies combining measurement of flow velocity using transcranial Doppler (TCD) concurrently with measures of cerebral blood flow (CBF) are uncommon. We report the results of a study combining TCD and positron emission tomography (PET). Healthy volunteers with no personal or family history of migraine underwent measurement of CBF using H2¹⁵O PET, and velocity using TCD. Measurements were done at baseline, and following i.v. nitroglycerin at 0.125, 0.25 and 0.5 μg/kg per min. Subcutaneous sumatriptan (6 mg) was injected, with CBF and velocity measured 15, 30, and 60 min later. Nitroglycerin was terminated and measurements obtained 30 min later. Six male and six female subjects were studied. Nitroglycerin increased global CBF while flow velocities decreased. Sumatriptan did not have a significant effect on these values. Regions of increased flow included the anterior cingulate, while regions of decreased flow included the occipital cortex. Our data suggest that nitroglycerin induces regional changes in CBF that are similar to changes reported in spontaneous migraine, but produces distinctly different effects on global CBF and velocity.

Keywords

Tomography emission computed nitroglycerin sumatriptan

Introduction

Investigation of the aetiology and treatment of migraine headache (HA) is complicated by the debilitating, intermittent nature of attacks, and the lack of widely accepted experimental models. Numerous agents have been used in attempts to develop such a model, including acetazolamide (1), histamine (2), iodinated contrast media (3), m-chloro-phenylpiperazine (4), red wine (5), reserpine (4), visual stimulation (6) and nitroglycerin (GTN) (7–12). Of these agents, studies using GTN have been the most widely published.

Several factors make GTN an attractive agent for the study of headache. The drug has a short half-life (2–3 min) and a well-established record of safety. A pulsatile headache following exposure to all forms of nitrates is widely recognized; moreover, GTN has been reported to provoke migraine (13) and cluster (14) headache in susceptible individuals. The mechanism by which GTN produces headache is not fully understood; however, GTN is rapidly metabolized into nitric oxide (NO^–), an endogenous, endothelially derived relaxing factor (15). A smooth muscle relaxant, GTN acts as a venodilator at all doses (16), with dilation of conduction arteries and resistance arterioles occurring at higher doses (17, 18), along with dilation of arteriovenous anastomoses (19). In addition to vasodilator properties, NO^– may have secondary effects on systems implicated in migraine headache. Trigeminal activation has been associated with increased release of calcitonin gene-related peptide (CGRP), substance P and neurokinin A. It appears that GTN administration can increase the release of at least CGRP (20), although to date this effect has been reported only in cluster headache patients (14, 21).

The utility of any experimental model is in part determined by the accuracy with which it mimics the condition of interest. GTN headache induced in healthy volunteers differs from the International Headache Society (IHS) criteria for migraine in several respects, including bilateral presentation, modest intensity, and the lack of associated symptoms such as photo- or phonophobia (22) (although nausea has been reported in some instances). These differences do not invalidate the model. They do, however, underscore the need for careful investigation of the model to understand fully its limitations.

The primary objective of this study was to measure cerebral blood flow and velocity in an experimental model of GTN-induced HA using positron emission tomography (PET) and transcranial Doppler (TCD), respectively. A secondary objective was to examine regional blood flow changes in this same experimental model.

Methods

Twelve healthy volunteers were recruited by advertising via handbills and website. Prior to inclusion, all subjects gave written informed consent and underwent screening consisting of a medical history, physical examination, laboratory measurements, and a 12-lead electrocardiogram. The protocol was approved by the Institutional Review Board of the Veterans Administration Medical Center (VAMC). Volunteers were excluded from the study on the basis of the history, or presence of significant medical, neurological or psychiatric disorders; a history of migraine HA in the subject, or in a parent or sibling; current medication or tobacco use, history of drug or ethanol abuse, age < 18 years, or> 45 years, or participation in a research study in the previous 4 weeks. Subjects were not tested for responsiveness to GTN as part of the screening process.

Following screening, subjects presented to the PET Center of the VAMC. Subjects underwent catheterization of a radial artery (under local anaesthesia) for withdrawal of blood during scanning. Blood was withdrawn though 0.4 mm i.d. Teflon tubing (Alltech, Deerfield, IL, USA) at a rate of 12 ml/min across a β detector (23). Volunteers were then positioned in a CTI/Siemens ECAT 951-31R scanner (CTI, Knoxville, TN, USA), using a set of targeting lasers referenced to the orbitomeatal line. A thermoplastic face mask (Tru-Scan, Annapolis, MD, USA) extending approximately from nose-tip to hairline was custom fitted for each subject, and fixed to the scan table. All studies were performed under conditions of reduced sensory input (dimmed room lights, eyes open, no conversation permitted during scans, ambient room noise) (24). Subjects underwent a 120-s image acquisition following a bolus, i.v. injection of 60–80 mCi of H₂ ¹⁵O. Attenuation correction was performed using a transmission scan from each subject. Images were reconstructed in 31 planes, using a 128 × 128 matrix with a Hann filter of 0.4 and a zoom factor of 2.5. Post-reconstruction processing of PET images was accomplished using SPM99. Images were realigned within subject, with normalization to a standard stereotactic space. A 15-mm Gaussian smoothing kernal was applied to conform to statistical assumptions of the analysis and to account for between subject anatomical variations. ancova was used to adjust regional cerebral blood flow (rCBF) values to a given mean.

All radionuclides were prepared using a 30-mEv cyclotron (IBA, Brussels, Belgium) and routine radiochemical techniques. Quantitative modelling was done on SUN workstations (Palo Alto, CA, USA). CBF was modelled according to the method of Kanno et al. (23).

TCD insonations of the right and left middle cerebral arteries (RMCA and LMCA, respectively) were made immediately following each PET measurement via a portal cut into the face mask. TCD (MedaSonics, Inc., Freemont, CA, USA) was done on all subjects by the same experienced individual (K.B.). Blood pressure and heart rate determinations were made at baseline, at the time of each dosage change, and following each PET scan.

Prior to each PET measurement, volunteers were queried to the presence of HA pain, and asked to rate the pain on a four-point scale (0–3), commonly used in clinical trials of abortive migraine therapy, where 0 represents a pain-free state, and 3, severe pain (25, 26). Subjects were also asked about the presence of photo- and phonophobia, and the presence of nausea.

Statistical analysis

Statistical analysis was done using StatView® (27). The paired t-test was used to compare quantified values with baseline measurements. For all quantified variables, α=0.05 was designated as the level of significance.

Assessment of regional effects was undertaken on non-quantified images using a standardized technique of statistical parametric mapping (SPM99, London, UK) (28), with significance set at P < 0.001, with a minimal extent threshold of 500 voxels. Regions of significant change were mapped using the atlas of Talairach and Tournoux.

Drug administration strategy

After baseline measurements, subjects received an i.v. infusion of GTN (Baxter Healthcare, Deerfield, IL, USA) via infusion pump (Imed, San Diego, CA, USA), using a non-adsorbing infusion set (Imed). The infusion was begun at a rate of 0.125 µg/kg per min. Stepwise increases to 0.25, and 0.5 µg/kg per min were made at approximately 15-min intervals. TCD and CBF measurements were made at the end of each dosing level. This titration model was based on the early GTN headache model proposed by Iversen et al. (8).

Following up-titration of GTN, the infusion was maintained at 0.5 µg/kg per min. Subjects then received 6 mg of sumatriptan (Glaxo Wellcome, Research Triangle Park, NC, USA) by subcutaneous injection. CBF and TCD measurements were made 15, 30 and 60 min after sumatriptan. Following the 60-min post-sumatriptan measurements, the GTN infusion was terminated, and a final set of measurements was taken 30 min later.

Results

Twelve subjects (six male, six female, mean age 27.5 (8.7) years) participated in the study. Arterial blood activity sampling failed in one volunteer, precluding quantification of CBF in this subject (TCD and regional PET analysis were not affected). All continuous variables are reported as the mean (SD) unless otherwise noted. Blood pressure was unchanged from baseline throughout the study. TCD measurement and PET images were obtained in all subjects.

Cerebral blood flow

CBF measurements from individual subjects are presented in Table 1, and represented by box plot in Fig. 1. CBF increased by 10.8 (9.3) ml/min per 100 kg following 0.125 µg/kg per min of GTN, an increase of approximately 23% (P < 0.01). CBF remained increased from baseline by 10.5 (7.3) and 9.9 (7.1) ml/min per 100 g, respectively (P < 0.01) following an increases in infusion rate to 0.25 and 0.5 µg/kg per min. However, CBF did not increase proportional to infusion rate. Following sumatriptan, CBF remained significantly increased from baseline by 9.1 (13.5) and 8.4 (9.3) ml/min per 100 g, 15 min and 60 min, respectively (P < 0.05). The 30-min post-sumatriptan CBF increase of 4.7 (8.5) ml/min per 100 g was not statistically different from baseline (P = 0.097). CBF 30 min following discontinuation of GTN remained increased from baseline by 5.3 (7.3) ml/min per 100 g (P < 0.05).

Table 1

Cerebral blood flow (CBF) (ml/min per 100 g) measurements in individual subjects

Subject	Baseline	GTN125∗	GTN250∗	GTN500∗	SUM15∗∗	SUM30	SUM60∗∗	H2OPost∗∗
1299	40.40	59.20	50.50	54.90	50.52	45.96		41.84
1326	52.79	64.40	53.67	57.45	52.28	52.77	52.08	55.62
1179	53.50	50.40	54.50	64.50	40.47	45.00	61.30	52.70
1169	49.30	72.40	74.60	68.80	76.90	70.20	78.90	59.00
1164	43.10	46.00	45.10	48.00	47.60	44.00	45.80	44.60
1171	50.10	78.00	58.40	61.30	72.40	62.70	65.30	58.10
1412	42.20	50.70	54.00	49.90	70.90	56.50	42.60	61.70
1366	46.60	55.80	61.20	57.50	46.10	43.80	45.80	38.30
1491	59.10	62.60	71.90	57.60	68.90	57.50	66.70	70.40
1500	49.84	61.50	66.22	65.24	65.16	55.47	59.62	56.74
1498	39.73	44.48	51.51	41.18	36.38	44.46	51.96	46.25
Mean	47.88	58.68	58.33	57.73	56.98	52.58	57.01	53.20
SD	6.00	11.00	9.00	9.00	14.00	9.00	11.00	10.00

^∗ P < 0.01;

^∗∗ P < 0.05, comparison with baseline value.

Figure 1

Box plot of cerebral blood flow (CBF) (ml/min per 100 g) in healthy volunteers at nitroglycerin (GTN) infusion rates of 0.125, 0.25, 0.5 µg/kg per min. Plots labelled SUM15, etc., represent CBF 15, 30, and 60 min following 6 mg SQ sumatriptan. H2OPost represents flow measured 30 min after termination of the GTN infusion. ∗P < 0.01, comparison with baseline value; ∗∗P < 0.05, comparison with baseline values.

Transcranial Doppler

TCD measurements (mean flow velocities) for the RMCA and LMCA are represented graphically in Fig. 2. TCD velocities were significantly reduced from baseline following GTN in a step-wise fashion in both the right and left middle cerebral arteries. Mean velocity was reduced in both the RMCA and LMCA by 11.7% (R) 13.9% (L) at 0.125 µg/kg per min, 18.4% (R) 16.5% (L) at 0.25 µg/kg per min, and 18.7% (R) 20.8% (L) at 0.5 µg/kg per min. Flow velocity remained significantly reduced (P < 0.01) following administration of sumatriptan, and remained so 30 min after discontinuation of GTN infusion. Peak velocity measurements mirrored the findings seen in mean velocity. Pulsatility index was unchanged from baseline measurement at any point in the study.

Figure 2

Box plots of mean blood flow velocity in the right and left middle cerebral arteries (RMCAMN, LMCAMN) at baseline (BL), and following nitroglycerin (GTN) at 0.125, 0.25, and 0.5 µg/kg per min, and then 15, 30 and 60 min following sumatriptan. Post-nitroglycerin (PS) values were measured 30 min after termination of the GTN infusion. ∗P < 0.01, comparison with baseline value.

Regional effects

Significant increases in regional blood flow were observed beginning at the 0.25 µg/kg per min infusion rate (Table 2). From this time point forward, GTN produced increases in flow in regions corresponding to the anatomic location of the internal carotid and basilar arteries at the level of the brain stem. Fifteen minutes following the administration of sumatriptan, and for the duration of the measurements, bilateral activation of the anterior cingulate was observed (Fig. 3). Increases in flow were significant in the region of the posterior cerebral artery at this same time point, but not forward to the remainder of the study.

Table 2

Regions of increased flow compared with the baseline condition

Infusion rate	Talairach co-ordinates X, Y, Z	Peak voxel Z score	P-value
0.25 µg/kg per min GTN	−10, −20, −24	3.70	0.002
0.5 µg/kg per min GTN	2, −14, −28	4.18	<0.001
15 min post-sumatriptan	6, 2, −22	6.44	<0.001
30 min post-sumatriptan	−2, 30, −10	5.62	<0.001
60 min post-sumatriptan	−2, 30, −8	4.98	<0.001
30 min post-GTN	0, 22, −8	5.81	<0.001

Co-ordinates of regions of significantly increased cerebral blood flow compared with baseline conditions.

Figure 3

Regions of increased blood flow projected onto a T1 weighted magnetic resonance imaging template image. The image to the left represents regional increases in flow at nitroglycerin (GTN) infusion rate of 0.5 µg/kg per min. These regions correspond anatomically to the internal carotid and basilar arteries. The image on the right shows regional increases in blood flow 15 min following administration of sumatriptan with additional flow increases in the anterior cingulate gyrus and the posterior cerebral artery.

Reduced flow was observed bilaterally in the occipital cortex and in the right mesial temporooccipital region, beginning at 0.5 µg/kg per min of GTN, and reaching a maximal effect at the next measurement (Fig. 4, Table 3). This reduction was not changed 30 min following administration of sumatriptan; however, at 60 min post-sumatriptan the regional reductions were reduced below statistical significance. Thirty minutes following termination (and 90 min following sumatriptan) reductions had again passed the a priori levels of significance.

Table 3

Co-ordinates of regions of significantly decreased cerebral blood flow compared with baseline conditions

Infusion rate	Talairach co-ordinates X, Y, Z	Peak voxel Z score	Cluster level P-value
0.5 µg/kg per min GTN	46, −6, −42	4.26	0.013
0.5 µg/kg per min GTN	40, −92, 22	4.04	0.038
15 min post-sumatriptan	42, −92, 20	5.3	0.005
	−44, −12, −44	5.23	0.028
	−50, −78, 18	4.64	0.001
30 min post-sumatriptan	−48, −14, −44	4.99	0.04
	−38, −92, 22	4.57	0.001
	−48, 38, 16	3.73	0.009
60 min post-sumatriptan	6, −4, 8	5.03	0.051
	−46, −12, −44	4.88	0.057
	−48, −34, 20	4.08	0.084
30 min post-GTN	−44, −10, −44	5.68	0.009
30 min post-GTN	−54, −78, 16	4.1	<0.001

Figure 4

Regions of reduced flow projected onto a T1 weighted magnetic resonance imaging template. Reduced flow was observed bilaterally in the occipital cortex and in the right mesial temporooccipital region, beginning at peak nitroglycerin infusion, and reaching a maximal effect at the next measurement.

No subject reported HA pain or associated symptoms prior to the initiation of GTN infusion. Discomfort was mild, and reported by the majority of patients only at the 0.5 mg/kg per min rate, and 15 min following sumatriptan. Pain scores rapidly returned to 0 following sumatriptan, with all but one subject who reported pain following GTN reporting complete pain relief. One subject experienced a transient episode of nausea and vomited during GTN infusion. No subjects reported aura, photo- or phonophobia or other adverse effects. In all cases, the reported pain was bilateral

Discussion

GTN infusion has been reported to increase the diameter of medium to large-sized arteries such as the radial (10) and temporal arteries (24). In healthy volunteers, intravenous GTN at 0.5 µg/kg per min produced a 13–20% reduction in mean MCA flow velocity (9, 11), and a 7.1% reduction in the flow velocities of the ophthalmic artery (11). These reductions in flow velocity are comparable to those observed in this study, and consistent with what would be anticipated with administration of a vasodilator.

Increases in global CBF might be expected following administration of a vasodilator, but two previous CBF studies using ¹³³Xe found no change in CBF following GTN infusion in spite of a 20% decrease in flow velocity (9, 29). While the reason for this discrepancy can be explained by the recognized limitations of ¹³³Xe imaging, largely due to the lower energy emitted by single photon emitters such as ¹³³Xe (3), a more recent study using H₂ ¹⁵O PET reported no significant effect of GTN on blood flow (30). This study differed from the current investigation in several respects, which may explain the differences from our findings. The first is that White et al. administered an infusion of saline to offset GTN-induced changes in blood pressure (maintaining it within 5 mm of baseline). The volume of saline administered was not reported, making it difficult to assess the impact of this intervention. The study acquired data in a 3D acquisition mode, an approach that can degrade image resolution due to the effect of random and scattered photons (31). Sample size may also be an issue, since the subjects were split into two regimens, a low dose and a higher dose. This resulted in two very small subgroups of four subjects each. Both groups received GTN for a far shorter interval, and were significantly older (mean age 65.5 years) than the present investigation. Finally, the study was not designed with migraine or other neurological conditions in mind. As a result, while subjects were carefully screened for the presence or history of vascular disease, no screening for a history or presence of neurological conditions (including migraine) was noted.

In our investigation, administration of sumatriptan reduced, but did not eliminate, the increase in global CBF produced by GTN. Only the CBF measurement made 30 min following sumatriptan was reduced to non-significant levels. Animal studies have suggested even less of an interactive effect (32). Studies of sumatriptan in spontaneous migraine have likewise shown no effect on global CBF (33).

Onset of regional effects differed from those seen with global CBF and flow velocity. Significant regional increases in flow were not detectable at the lowest dose of GTN. The regional increases were initially limited to regions of the internal carotid and basilar arteries, consistent with that seen following GTN challenge in cluster headache patients (34). Activation of the cingulate was observed only with prolonged administration of nitroglycerin, suggesting either a secondary effect of GTN or a direct effect of sumatriptan. Arguing against a sumatriptan effect is the activation of the cingulate reported following facial injection of capsaicin in healthy volunteers and in GTN-induced headache in cluster headache patients in the cluster phase (35–37).

Regional reductions in CBF were the most pharmacologically unexpected. Reductions in the occipital region are consistent with those reported in migraine. No subject reported visual changes during the study. However, this is not unexpected given the lack of migraine history. As with regions of increased flow, the possibility that the regional reductions may have been in part due to sumatriptan cannot be ruled out, but these reductions were observed prior to administration of sumatriptan, and these reductions were diminished 60 min following sumatriptan, suggesting that, if anything, the opposite effect may have been true.

In spontaneous migraine, studies utilizing PET have consistently reported decreased CBF in migraineurs during spontaneous migraine HA (38–40). This technique represents an improvement over older approaches for measuring CBF, which have reported both increased CBF (41, 42) and decreased flow (43, 44). Overall, it appears that the higher energy of photons imaged in PET along with greater spatial resolution may allow for a more reliable imaging of events in migraine or surrogate models.

In our study, and in other investigations of GTN administration, a consistent reduction in flow velocity was observed. Given our observation of unchanged heart rate, blood pressure, and increased CBF, this finding is consistent with a vasodilatory effect of GTN. Findings of flow velocity in spontaneous migraine headaches using TCD have been variable. Measurements made have reported both increased and decreased flow velocities in cerebral arteries (43, 45). Possible causes include the measurement of only discrete segments of vessels with TCD, the timing of the measurement relative to the onset of the headache episode, and the technician-dependent nature of the measurement. Some studies of velocity in spontaneous migraine treated with sumatriptan have shown a reversal of reduced velocity following treatment (33). While our CBF findings are consistent with sumatriptan acting as a vasoconstrictor primarily on large conductance vessels, sumatriptan did not produce a significant reversal in the GTN-induced reduction in velocity, a finding that has also been reported in some investigations of sumatriptan (12, 24). A possible limitation of our findings is that only the middle cerebral artery was insonated. This was due to the restrictions imposed by taking measurements on subjects who were positioned in a PET scanner.

One challenging observation in this study was the changes in global CBF and velocity as well as regional effects observed 30 min following discontinuation of GTN. This is far longer than could be explained by a direct effect of GTN, suggesting a secondary mechanism such as a release of CGRP induced by GTN. While this vasodilatory peptide has a longer half-life than GTN, only studies using direct jugular sampling have demonstrated its presence in migraine, and no increase was detected in cluster headache patients given GTN while out of the active cluster phase (14).

Diagnostic criteria for migraine with and without aura established by the IHS are well known. While only two of 12 subjects experienced moderate to severe pain, and only one subject experienced nausea, a pulsatile quality to the pain was noted in all who experienced HA, and all subjects who experienced HA experienced relief following sumatriptan. Likewise, while no subject experienced a unilateral presentation or aura, participants in this study were screened for a history of migraine in both themselves and first-degree relatives. It would not be unexpected for migraineurs to have a different response to infusion of GTN, suggesting the need for both careful screening of non-migraine study groups, and further study of this model in both migraineurs and non-migraineurs.

Conclusions

GTN infusion increases global CBF as measured by PET. This effect is only modestly diminished by sumatriptan. TCD-measured blood flow velocity is reduced in both the right and left middle cerebral artery following GTN, with sumatriptan having an insubstantial effect on velocity. Regional increases in CBF appear to be limited to large vessels early following GTN, with later regional activation extending to the anterior cingulate. Regional reductions include the occipital cortex, with effects diminishing 60 min after sumatriptan.

The effects of GTN on global CBF and velocity are expected given the known pharmacology of GTN. Regional effects show changes similar to those observed in reports of spontaneous migraine. Multimodal measurement techniques may lead to further understanding of the role of GTN in the investigation of migraine headache, the pathophysiology of migraine, and the role of pharmacological interventions.

Footnotes

Acknowledgements

The assistance of Paul Galantowicz, Mark Javier, Rene Marcucci, and the chemistry staff of the Center for Positron Emission Tomography at the University at Buffalo are gratefully acknowledged. This research was supported by a grant from the National Headache Foundation

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Brain Blood Flow in the Nitroglycerin (Gtn) Model of Migraine: Measurement Using Positron Emission Tomography and Transcranial Doppler

Abstract

Keywords

Introduction

Methods

Statistical analysis

Drug administration strategy

Results

Cerebral blood flow

Transcranial Doppler

Regional effects

Discussion

Conclusions

Footnotes

Acknowledgements

References