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Abstract

Cortical hypersensitivity and absent habituation to different stimuli have been observed in migraine patients. These features might also be transmitted to the cerebral vasoreactivity, but results are conflicting so far. Transcranial Doppler ultrasound (TCD) was used to assess cerebral blood flow velocity (CBFV) changes in the middle (MCA) and posterior cerebral arteries (PCA) in relation to repetitive checkerboard visual stimulation. Stimulation consisted of 10 consecutive cycles, each comprising 10 s stimulation and 10 s rest. TCD recordings were analysed using stimulus-related averaging algorithm. Data of 19 interictal migraineurs with aura were compared to those of 19 headache-free healthy volunteers. The CBFV increase in PCA and in MCA during visual stimulation was significantly larger and steeper in migraineurs than in controls (P = 0.017 and P = 0.005). The response in PCA remained stable over the 10 stimulation cycles, both in migraineurs and in controls. The response in MCA was stable only in migraineurs. In controls it decreased over the last 5 stimulation cycles compared with the first 5 cycles (P = 0.04). Migraineurs with aura exhibit a larger cerebrovascular response to repetitive visual stimulation compared to headache-free subjects. A reduced adaptation to environmental stimuli in migraine is suggested, since there was no habituation in migraineurs in contrast to healthy controls.

Keywords

Cerebral haemodynamics fTCD migraine with aura visual stimulation

Introduction

Current pathophysiological concepts define migraine as a primary neuronal hypersensitivity to different intrinsic and extrinsic stimuli probably on the basis of hereditary ion channel dysfunctions (1). The mechanisms that relate such neuronal hypersensitivity to the activation of the trigeminovascular system, i.e. to pain generation, have been intensively studied (2).

Recent electrophysiological studies using multimodal evoked and event-related potentials found an increased cortical excitability and absent habituation in the headache-free interval in migraineurs (3–6). Whether these neuronal disturbances are directly forwarded to the cerebral blood vessels, i.e. whether the vasoneuronal coupling is altered as well, is unsatisfactorily investigated yet.

The few studies using TCD that had addressed this question reported heterogeneous results. Probably it was due to different stimulation and recording procedures, small sample sizes, lack of control for medication and absence of matched control groups (7–9). In addition, the inclusion of both migraineurs with and without aura may have contributed to the heterogeneity of the results.

A recently published study, however, seemed to have overcome the above mentioned limitations (10). The main finding of this study was the alt-ered cerebrovascular response pattern in interictal migraine during visual stimulation. In particular, the authors observed an increase of the cerebral blood flow velocity (CBFV) in the middle cerebral artery (MCA) of migraineurs, while normal subjects showed a habituation of the CBFV response. Neither migraine patients, nor headache-free persons exhibited a habituation of the CBFV response in the PCA. As demonstrated by functional magnetic resonance imaging (fMRI), the visual cortex appears to play a special role in the pathogenesis of migraine, especially of migraine with aura (11). In the light of these findings, it was rather surprising that the difference between migraineurs and healthy persons regarding habituation was observed in the MCA, but not in the PCA. Therefore, these results need confirmation with a different stimulation methodology and patient selection. We used a standardized, well controlled stimulation and recording paradigm (12), and painstakingly controlled for stimulus independent influencing factors, which are known to obfuscate reproducible responses (13). Assuming different cerebrovascular reactivity in patients with and without aura, we focused on migraineurs with aura.

The present study was designed to test two hypotheses: First, habituation of the cerebrovascular response in migraine patients is altered when applying short-lasting visual stimuli. Second, habituation to repetitive visual stimuli should be found in the PCA, if it is a modality specific phenomenon.

Patients and methods

Patients

Twenty-six patients with a diagnosis of migraine with aura gave informed consent to participate in the present study. In 19 (10 women, 9 men; mean (± SD) age 35.8 ± 7.8 years) the temporal bone window allowed a stable transcranial Doppler signal of good quality to be obtained from the left posterior cerebral artery (PCA) and, with a second probe, simultaneously from the right middle cerebral artery (MCA). The diagnosis of migraine with aura was established according to the criteria of the International Headache Society (14). Patients had one to six migraine attacks per month and a history of migraine ranging from 1 to 30 years. Four patients had an aura in 80% of the attacks, while the other 15 patients experienced an aura in every attack. All patients were free of any prophylactic medication and were studied in the headache-free interval, with at least 1 week since the last migraine attack. On the day of the TCD-examination they were instructed to abstain from cigarette smoking and coffee consumption.

The control group consisted of 19 headache-free volunteers (8 women, 11 men, mean (± SD) age 32.6 ± 5.9 years), recruited from hospital staff, who also abstained from medication, smoking and coffee consumption.

This study was approved by the ethics committee of the canton of Bern, Switzerland.

Experimental conditions

The tests were performed in a darkened, quiet room and the patients were comfortably sitting in an armchair. Two 2-MHz ultrasound probes were placed at the temporal bone window by means of a latex head band. The MCA was insonated at a depth of 50–55 mm; the angles of insonation were adjusted to obtain a maximal signal intensity at the predetermined insonation depth. The PCA was identified at a depth of 64–70 mm by its flow direction, angle of insonation and transmission of oscillatory waves to the recorded PCA signals during a rapid repetitive compression of the left vertebral artery near the mastoid (15). The cerebral blood flow velocities (CBFV) were measured simultaneously in the right MCA and left PCA. During the recording patients could not hear the Doppler audio signal. Furthermore, we paid attention to avoid any additional stimulation via any sensory modality. A commercially available TCD unit (Multi-DOP X/TCD 7, DWL, Sipplingen, Germany) was used. The maximal velocities, i.e. the spectral outline curves of the Doppler recordings were recorded with a sampling rate of 10 per second and were stored as wave files for off-line analysis.

We did not control for changes of blood pressure, heart rate and end-tidal CO₂. Neither Bäcker et al. (10), nor previous studies by our group using functional TCD (12, 16) observed significant changes of these parameters, when controlling for them during the stimulation.

Stimulation procedure

Subjects were seated 1 m in front of a 14″ TFT computer screen. Stimuli were binocularly presented as a checkerboard reversal pattern of black and white rectangles (reversal frequency 1 Hz) each subtending 2.86° × 3.21° of visual angle. Subjects were instructed to fix their gaze to the middle of the screen. Stimuli were presented in 10 sequential cycles, each comprising 10 s of checkerboard stimulation (‘stimulus on’), followed by 10 s rest (‘stimulus off’, i.e. black screen). During the ‘stimulus off’ phase subjects were asked to close their eyes.

Data analysis

The Doppler spectral outline curves were evaluated off-line after reading the wave file. Data analysis was performed with the standard algorithm implemented in the TCD 7 software of the ultrasound device. Following this algorithm, the Doppler recordings are segmented into epochs of 20 s that correspond to the stimulation cycles, i.e. each cycle consists of 10 s ‘stimulus on’ and 10 s ‘stimulus off’. The velocity values obtained from the MCA and the PCA are averaged for each time point over 10 cycles. The results are expressed graphically as an averaged curve (SD), separately for PCA, MCA and PCA/MCA ratio (Fig. 1).

Figure 1

Averaged velocity curve (SD) obtained fron the left PCA of a headache-free control person during 10 stimulation cycles.

The following variables from the averaged velocity curves were analysed

baseline velocity (Vb), i.e. the average velocity at 0.1 s after the start of stimulation

peak velocity (Vp), i.e. the highest average velocity during the ‘stimulus on’ phase

percentage velocity increase (amplitude) (ΔV/Vb)

latency to Vp, i.e. the time from onset of the stimulation to the point of the peak velocity (ΔT)

slope of the velocity increase (ΔV/Vb.ΔT) (Fig. 1).

The averaged PCA/MCA ratio curve was analysed in an identical manner

baseline (Rb)

peak (Rp)

percentage increase (ΔR/Rb)

latency to Rp (ΔT)

slope of the relative increase (ΔR/Rb.ΔT)

To test for possible habituation, the above listed variables of the first 5 stimulation cycles (5’Cy) were compared with those of the last 5 cycles (5″Cy).

Statistical methods

Data were evaluated for normality of distribution by the Kolmogorov-Smirnov test. Differences between groups were analysed by the two-tailed Students t-test for independent samples. Differences between the first 5 stimulation cycles and the last 5 stimulation cycles within the group were analysed by the t-test for paired samples. P-values of <0.05 were considered statistically significant. All analyses were performed with SPSS 10 for MacIntosh statistical software, copyright © 2001, SPSS Inc.

Results

The variables that characterize the cerebrovascular response of PCA and MCA during 10 stimulation cycles in the two groups are given in Table 1.

Table 1

Cerebrovascular response of PCA and MCA during 10 stimulation cycles

	PCA		P-value	MCA
Variable	Migraineurs	Controls	Migraineurs	Controls	P-value
Vb (cm/s)	38.0 (8.8)	37.1 (8.3)	n.s.	38.4 (9.4)	43.9 (18.6)	n.s.
ΔV/Vb (%)	18.8 (6.2)	14.2 (4.8)	0.017	7.0 (3.5)	3.5 (3.8)	0.005
ΔT (s)	8.0 (2.3)	7.8 (2.3)	n.s.	8.1 (2.4)	7.8 (2.3)	n.s.
ΔV/Vb.ΔT (%/s)	3.0 (1.0)	2.2 (1.0)	0.04	0.8 (0.7)	0.4 (0.5)	0.05

Values are given as mean (SD). Vb indicates the baseline velocity; ΔV/Vb, velocity increase; ΔT, latency to the peak velocity; ΔV/Vb.ΔT, slope of the averaged curve.

In the PCA, the baseline velocities (Vb) did not differ between migraineurs and healthy volunteers. The velocity increase (ΔV/Vb) was significantly higher in migraine patients than in headache-free subjects (P = 0.017), and this increase was steeper (i.e. the ΔV/Vb.ΔT was higher) (P = 0.04). In the MCA, again, the velocity increase was higher and steeper in migraine patients than in healthy subjects (P = 0.005 and P = 0.05) (Table 1).

The variables that were used to describe the averaged PCA/MCA ratio curve (Rb, Rp, ΔR/Rb, ΔT, and ΔR/Rb.ΔT) did not differ between migraine patients and headache-free controls (Table 2).

Table 2

PCA/MCA ratio during 10 stimulation cycles

Variable	Migraineurs	Controls	P-value
Rb	97.9 (6.7)	90.6 (17.7)	n.s.
ΔR/Rb (%)	11.9 (5.8)	11.2 (5.3)	n.s.
ΔT (s)	8.3 (1.4)	7.8 (2.0)	n.s.
ΔR/Rb.ΔT (%/s)	1.6 (1.2)	1.5 (0.7)	n.s.

Values are given as mean (SD). Rb indicates the averaged PCA/MCA ratio at 0.1 s]ΔR/Rb, increase of PCA/MCA during the stimulation]ΔT, latency to the peak]ΔR/Rb.ΔT, slope of the averaged curve.

When the first 5 stimulation cycles were compared with the second five, migraineurs with aura exhibited a stable cerebrovascular response both in PCA and MCA. The amplitude (ΔV/Vb) and the slope (ΔV/Vb.ΔT) of the averaged curves remained unchanged over the 10 stimulation cycles (Fig. 2a,b).

Figure 2

(a) Velocity increase (ΔV/Vb) in migraine patients in the first five (5’Cy) and the second five stimulation cycles (5”Cy). (b) Slope of the averaged curves (ΔV/Vb.ΔT) obtained in migraine patients in the first five (5’Cy) and the second five stimulation cycles (5”Cy). — MCA] —— PCA.

In headache-free controls, ΔV/Vb in the MCA decreased significantly during the second five stimulation cycles compared with the first five cycles (P = 0.04) (Fig. 3a). The slope of the averaged MCA curve was higher during 5′Cy than during 5″Cy (P = 0.04) (Fig. 3b). The cerebrovascular response in the PCA remained unchanged over the entire stimulation (Fig. 3a,b).

Figure 3

(a) Velocity increase (ΔV/Vb) in headache-free subjects in the first five (5’Cy) and the second five stimulation cycles (5”Cy). (b) Slope of the averaged curves (ΔV/Vb.ΔT) obtained in headache-free subjects in the first five (5’Cy) and the second five stimulation cycles (5”Cy). — MCA] —— PCA.

Discussion

Visual stimulation using short cycles of checkerboard reversal evoked a definite flow response both in PCA and MCA. The amplitude and the slope of these responses were significantly higher in migraineurs with aura than in controls.

Compared to headache-free persons, interictal migraineurs showed increased cerebral vasoreactivity to CO₂ stimuli in some studies (17-21), but not in others (8, 22, 23). In response to cardiovascular autonomic tests such as head-up tilt, cold pressure or Valsalva manoeuver, the results were again conflicting (24, 25).

Using various (mental, motor, visual) cerebral activation paradigms, previous functional TCD studies observed increased or unchanged vasoreactivity in interictal migraineurs compared to controls (7, 8, 21, 26). Methodological issues such as different stimulus characteristics and stimulation periods, insufficient temporal resolution, insufficient control of stimulus-independent factors or inclusion of both migraine with and migraine without aura might have contributed to the heterogeneity of the results.

Bäcker et al. (10) evaluated the cerebrovascular response pattern to visual stimuli with a well standardized methodology. This is the first TCD study to show habituation. The authors examined 19 migraine patients (6 patients with migraine with aura, 13 patients with migraine without aura) and compared them with an age- and sex-matched control group of headache-free individuals. They controlled for prophylactic medication, time interval since the last migraine attack and monitored the blood pressure during the stimulation. The stimulation periods lasted for 57 s, followed by a resting phase of 57 s. Data obtained during 3 on-off cycles were then averaged. The fact that habituation in healthy subjects was confined to the MCA territory is surprising and in conflict with electrophysiological findings (27). Replicability of this important finding using a different methodological setup would provide arguments for interpreting the mechanisms of habituation. Critical issues in Bäcker's study are: the application of a simple stimulation paradigm (flash stimuli), which has led to relatively small CBFV changes, the small number of averaged stimulation cycles (3 on-off cycles), which might be insufficient to correct for systemic and stimulus-independent changes, the relatively long stimulation period of 57 s that could allow changes in general and focused attention and fatigue to flaw the influence of habituation in the strict sense. To improve the averaging power we applied 10 stimulation blocks with a shorter duration (10 s ‘stimulus on’ and 10 s ‘stimulus off’). We also used a more complex stimulus. Compared to the flash light stimuli used by Bäcker et al. (10), the checkerboard reversal stimulation evoked higher velocity responses both in the PCA and in the MCA (Table 1).

Using this stimulation methodology we found an altered cerebral vasomotor reactivity in the interictal phase in migraineurs with aura. However, the range of the individual responses in both groups was broad with an overlap precluding the definition of diagnostic values for migraineurs. Despite efforts toward standardization of the experimental conditions, an overlap between migraineurs and controls has consistently been reported (7, 10, 28). It seems to be an unavoidable hindrance for the wider implementation of the functional TCD in the diagnostic work-up of migraine patients.

One of the aims of the present study was to retest the findings of Bäcker et al. (10) that normal subjects in contrast to migraineurs do habituate their cerebrovascular response to visual stimulation, however, in the MCA but not in the PCA. In electrophysiological trials migraine patients showed absent habituation or even a potentiation of the response to repetitive stimuli (29). Absence of habituation has been interpreted as a dysfunction of the cortical information processing (5). It seems to be more pronounced in the interictal phase and tends to normalize just before and during the migraine attack (30). The significance of these electrophysiological findings for the cerebral perfusion and their relation to vasomotor reactivity is open, although close coupling has been observed, e.g. during seizures (31, 32).

In consistence with the findings of Bäcker et al. (10) we observed a habituation of the cerebrovascular response in the MCA in healthy subjects, when using repetitive short-lasting stimuli, which was absent in migraine patients. Thus our first hypothesis that habituation is altered in migraine patients could be proved also when applying short-lasting visual stimuli. And again, there was no habituation detected in the PCA, neither in controls nor in migraineurs with aura. These findings are in line with the hypothesis indicating that a high level of cortical arousal or alertness is responsible for the absent habituation in migraineurs (33). Habituation can be regarded as a reaction of adaptation to a stimulus that has proved innocuous (34). It implies both attentive and cognitive aspects and is not confined to the cortical areas involved in the processing of the specific (e.g. visual) stimulus. The latter would explain, why changes suggestive for habituation were seen in the MCA of healthy subjects. In migraine patients, in whom an altered capacity for adaptation to environmental condition is suspected, such a reaction was not evident (35). Our results suggest that absent habituation in the MCA of migraineurs could be observed with any stimuli applied, e.g. auditory or somatosensory. Therefore, according to our second hypothesis, habituation to visual stimuli seems not to be a modality specific phenomenon. A comparison between migraineurs and headache-free persons using multimodal stimulation could provide more insight into the question whether habituation is a focal phenomenon of the primary cortical areas, or is a general feature of the information processing network. To address the question which cortical areas are subject to visual habituation further studies, admittedly very sophisticated in design, are needed.

Changes in the CBFV are not only determined by the regional cerebral activation, but also by systemic factors. Our averaging procedure using 10 stimulation blocks attenuates the effects of systemic factors with random transitions, but there might be also changes that appear synchronously with the stimulation. For this reason, we analysed the PCA/MCA ratio. Since systemic factors would affect both arteries equally, the changes of the PCA/MCA ratio are not dependent on them but most likely represent specific activation due to the task. However, the ratio cannot distinguish between regional changes appearing in the PCA and in the MCA. For example, in our study the averaged PCA/MCA curve did not differ between migraine patients and healthy subjects (Table 2). On the other hand, the cerebrovascular responses in both PCA and MCA were significantly higher in migraine patients than in controls (Table 1). There are two possible interpretations of this observation: firstly, the autonomous reaction was more pronounced in migraineurs, i.e. systemic factors such as blood pressure, heart rate, PCO₂, intracranial pressure, etc. have caused a velocity increase in both arteries, or secondly, the cerebral activation was higher in migraineurs, but it was not confined to areas supplied by the PCA. Accordingly, the PCA/MCA ratio was similar in migraine patients and in healthy subjects. Our results cannot prove which explanation is correct.

In conclusion, patients with a diagnosis of migraine with aura exhibit a stronger cerebrovascular response to visual stimuli compared to headache-free controls. Higher level of cortical arousal or autonomous hyperreactivity may be the cause. Absent habituation to visual stimuli in both MCA and PCA in migraineurs suggest a widespread mechanism involved.

Footnotes

Acknowledgements

We thank Pietro Ballinari, PhD, for statistical advice. This study is funded in part by a grant from the Swiss National Science Foundation (SNF 3100-66348.01)

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Cerebrovascular Response to Repetitive Visual Stimulation in Interictal Migraine with Aura

Abstract

Keywords

Introduction

Patients and methods

Patients

Experimental conditions

Stimulation procedure

Data analysis

Statistical methods

Results

Discussion

Footnotes

Acknowledgements

References