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Neurovascular coupling in patients with relapsing-remitting multiple sclerosis

Clinical Neurology and Neurosurgery, July 2016, Pages 24 - 28

Highlights

  • A large number of patients with RRMS has included the study.
  • The neurovascular coupling was higher in patients than those of the controls.
  • The results show the hyperactive neurovascular units in patients during an attack.

Abstract

Objectives

Also to the inflammatory demyelinating lesions and degenerative process, altered cerebrovascular reactivity or neurovascular coupling (NVC) might be considered as playing another role in the pathogenesis of multiple sclerosis. The objective of this study is to assess the NVC of patients with relapsing-remitting multiple sclerosis (RRMS) during the acute exacerbation period.

Patients and methods

Four hundred fifty-eight patients with RRMS and 160 healthy subjects were screened for this study during the last 14 years. We performed transtemporal transcranial Doppler recordings from the P2-segments of both posterior cerebral arteries simultaneously during simple or complex visual stimulation. The NVC was defined as a relative increase of the blood flow velocities as a percentage change of the baseline values during visual stimulation.

Results

The NVC to simple visual stimulation was significantly higher in the patients on both sides (37.2 ± 13.5% and 36.0 ± 14.8%; right and left side, respectively) from those of the controls (30.9 ± 9.9% and 30.0 ± 8.8%; right and left side, respectively) (p < 0.01). Similarly, the NVC to complex visual stimulation was significantly higher in the patients (43.3 ± 14.1% and 41.7 ± 13.5%; right and left side, respectively) from those of the controls (38.6 ± 14.2% and 37.6 ± 14.1%; right and left side, respectively) (p<0.05).

Conclusion

Our results suggest that patients with RRMS during exacerbation period have more reactive neurovascular units in the occipital cortex.

Keywords: Multiple sclerosis, Relapsing-remitting, Transcranial Doppler, Neurovascular coupling, Blood flow velocity.

1. Introduction

Multiple sclerosis (MS) is a chronic disease consisting of the inflammatory, demyelinating, and degenerative processes of the central nervous system, with inflammation being constantly present at all stages of MS [1]. The brains of patients with MS show widespread inflammation, microglial activation, astrocytic gliosis, mild demyelination, axonal loss in normal-appearing white matter (NAWM), and in the normal-appearing cortex [2]. Moreover, a close relationship between MS lesions and cerebral vasculature has long been recognized [3]. MS lesions contain evidence of vascular injury and vascular endothelial cell activation [4]. Positron emission tomography (PET) studies in MS patients showed a widespread reduction in the cerebral blood flow (CBF) affecting both grey and white matter [5].

There is a physical relationship between the neuronal activity and regional CBF-related to the metabolic demand: the so-called NVC of functional hyperemia [6] and [7]. Transcranial Doppler (TCD) provides information regarding blood flow velocity changes in individual cerebral arteries as representative of CBF to visual stimulation. Furthermore, TCD can provide continuous information about the dynamics of the response [8] and [9]. A few studies evaluating the NVC in patients with RRMS has been published. These have indicated hyperactivity at the occipital region to visual stimulation during the attack, and after high-dose intravenous corticosteroid treatment [10], [11], and [12]. However, the number of the subjects examined in these studies was relatively small. In the present study, we aimed to assess the NVC in a significant number of patients with relapsing-remitting multiple sclerosis (RRMS) during the acute exacerbation period, by the visually evoked CBF velocity changes in both posterior cerebral arteries (PCA) using TCD monitoring.

2. Patients and methods

There were 458 patients with RRMS, who were admitted to our department of neurology during an exacerbation period of the disease during the last 14 years. A total of 160 healthy subjects who had neither active neurological disease nor history of neurological disease were screened for this study within the same period. An exacerbation was defined as a rapid progressive worsening of the symptoms lasting for more than one day in a particular area that has not had new symptoms within the past month. The diagnosis of RRMS was determined according to the Poser criteria [13] at the beginning of the study; however, McDonald criteria [14] were used later, and the prior diagnosis of the patients was revised according to the McDonald criteria.

All patients were examined clinically, and hematological investigations were performed on all of them. The Expanded Disability Status Scale (EDSS) was also routinely calculated for all the patients [15]. Visually evoked potentials (VEP) and cerebral MRI examinations were conducted on all the patients. Somatosensory evoked potentials and cerebrospinal fluid investigations for the oligoclonal band were performed when needed. All subjects including controls had a normal extracranial ultrasound examination. The evaluation of extracranial vessels was performed by Duplex Color-coded ultrasonography (Acuson X150, Siemens Medical Solutions, USA). Two separate written confirmations from the Local Clinical Research Ethics Committee were received for this study. The first one was at the beginning of the study which had a prospective design, and the last one was a retrospective analysis of the data.

The TCD examination was performed within the first three days of an acute exacerbation and prior to any treatment. All TCD and Duplex Sonography examinations were done by the same person (NU), and the same machine was used in this study. Caffeine and nicotine use prior to TCD examination was not allowed. Subjects lay comfortably in a quiet room. We used a four-channel TCD (DWL Multidop X) with 2-MHz pulsed-wave Doppler transducers affixed to a headband. We performed transtemporal TCD recordings from the P2-segments of both PCAs simultaneously during visual stimulation. The vessels were identified according to the criteria described earlier [16]. Briefly, through the temporal bone both P2 segments of PCA's (flow direction away from the probe) were insonated at a depth of 58–68 mm. The verified PCA insonation was required to assess the velocity increase on both sides during the measurement of the visual evoked flow when the patients’ eyes were open as opposed to being closed.

Two different types of visual stimuli were used for the study; simple visual stimulation was performed with a black and white checkerboard and complex visual stimulation was done with a rotating optokinetic drum. The detailed instrumentation of the simple visual stimulation has been published elsewhere [17]. Concisely, the subjects were seated comfortably 60 cm from the screen and asked to fix their eyes on the small dot in the centre of the computer screen. The visual stimulus was presented on this computer screen which is likewise used for the visual evoked potentials. It consisted white and black checks arranged in a checkerboard pattern, and the reversion rate was 2 Hz (Fig. 1).

Fig. 1

Fig. 1

The procedure of the simple visual stimulus. The subject was seated comfortably 60 cm from the screen and asked to fix their eyes on the small dot in the centre of the computer screen. The visual stimulus consisted white and black checks arranged in a checkerboard pattern. A supplemental video file was also available.

 

A demonstration of the complex procedure can also be seen in the publications by Uzuner et al., [10] and Wolf et al., [18]. The stimulus on and off phases was initiated by an acoustic signal either in simple stimulation or complex stimulation. The subjects were asked to focus on the middle of the optokinetic drum during the stimuli. Either stimuli (simple or complex) were presented for 20 s (‘on’ phase) and were followed by 20 s with closed eyes (‘off’ phase). Ten on-off cycles were performed and averaged for each set of simple or complex visual stimuli (Fig. 2).

Fig. 2

Fig. 2

Continuous recordings of blood flow velocities simultaneously in the both PCA during ten cycles. Each cycle consists of a sequence of rest (20 s), followed by the bilateral stimulus on (20 s) represented by the lower curve. Opening the eyes induced a regular increase of the velocities.

 

The analysis of the visually evoked flow response was performed offline. NVC was defined as a relative increase of the blood flow velocities as a percentage change of the baseline values [NVC = 100*(Vs-Vr)/Vr]. Where Vs indicates the maximum velocity at stimulation (eyes open and stimulus on); the Vr, the minimum velocity at rest (eyes closed). They are calculated by the special software of the TCD system that allows trigger-related blood flow velocity averaging, over an adjustable period of stimulus, when on, compared with an adjustable time period of stimulus when off (rest), following the procedure [19] (Fig. 3).

Fig. 3

Fig. 3

The figure shows the averaged responses of 10 cycles recorded in the P2 segment of the PCA during stimulus on and stimulus off in a subject. A significant increase of BFv of PCA (mean value, the shaded areas indicate ± 2SEM) was clearly seen. The maximum and minimum values were calculated as a single value of stimulation and rest, respectively.

 

Sixty-nine patients with RRMS and ten control subjects were excluded from the analysis because of possible erroneous Doppler examination or incorrect artery insonation. The remaining 389 patients with RRMS and the 150 control subjects were included in the analysis.

The simple visual stimulation group: There were no significant differences between the ages of patients (36.1 ± 9.8 years) and control subjects (36.1 ± 9.8 years) as well as gender (35 female and 15 male in control subjects, and 166 female and 70 male patients with RRMS) in the simple visual stimulation group. The mean number of the attacks were 4.3 (range 2–21), and the average disease duration was 38.3 months (range 3–168 months) at the time of the Doppler examination. The EDSS values of the patients were 2.5 (range 1.0–5.0). Eighty-three patients had mono or hemiparesis, 65 had sensory disturbances, 48 had ataxia, 45 had optic neuritis, 29 had paraparesis, 24 had diplopia, and 2 had trigeminal neuralgia. A combination of more than two symptoms were present in most patients. NVC to simple visual stimulation of patients with optic neuritis only (26 patients) was not significantly different from those of other patients, and therefore, this data was also included in the analysis.

The complex visual stimulation group: There were no significant differences between the ages of patients (35.5 ± 9.9 years) and control subjects (33.3 ± 14.1 years) as well as gender (58 female and 42 male in the control subjects, and 107 female and 46 male patients with RRMS) in the complex visual stimulation group. The mean number of attacks were 3.8 (range 2–10), and the average disease duration was 29.5 months (range 3–144 months) at the time of the Doppler examination. The EDSS values of the patients were 2.3 (range 1–4). Forty-four patients had optic neuritis, 56 had mono or hemiparesis, 8 had paraparesis, 48 had sensory disturbances, 20 had ataxia, and 15 had diplopia. The symptoms were together in most of the patients. The NVC to complex visual stimulation in patients with optic neuritis only (19 patients) were not significantly different from those of other patients, and therefore, this data was also included in the analysis.

A two-tailed t-test for the unpaired samples and the chi-square test were applied for statistical analysis, where appropriate, and p < 0.05 was accepted as the statistical significance.

3. Results

The visual stimulation provided a significant blood flow velocity increase (NVC) on both sides (p < 0.001) in all the subjects irrespective of the stimulus pattern, and NVC was significantly higher in patients on both sides when compared to those of the controls (p < 0.01).

All Doppler data for the simple visual stimulation group is given in Table 1. The velocities at stimulation and rest were found to be lower in MS patients compared to controls. However, these differences did not reach a significant level. Conversely, the NVC to simple visual stimulation was significantly higher in patients on both sides (37.2 ± 13.5 and 36.0 ± 14.8; right and left sides, respectively) from those of the controls (30.1 ± 9.9 and 30.0 ± 8.8; right and left sides, respectively) (p < 0.01).

Table 1

Blood flow velocities to simple visual stimulation of the subjects.

 

Control (n = 50) RRMS (n = 236)
Right side Left side Right side Left side
Velocity at stimulation (cm/s) 48.3 ± 10.1 50.1 ± 11.7 47.4 ± 9.6 47.1 ± 9.6
Velocity at rest (cm/s) 37.5 ± 8.7 39.0 ± 7.4 34.9 ± 7.8 34.9 ± 7.5
NVC (%) 30.1 ± 9.9 30.0 ± 8.8 37.2 ± 13.5* 36.0 ± 14.8*

* significant differences between patients with RRMS and controls (p < 0.01 for all).

RRMS indicates relapsing-remitting multiple sclerosis and NVC neurovascular coupling.

Values are mean ± standard deviation; independent samples test was used.

All Doppler data for the complex visual stimulation group are shown in Table 2. The velocities at stimulation and rest were found to be lower in the patients from that of controls. Only the velocities at rest showed a significant difference (p < 0.01 on both sides). The NVC to complex visual stimulation was significantly higher in the patients on both sides from those of the controls (p < 0.05).

Table 2

Blood flow velocities to complex visual stimulation of the subjects.

 

Control (n = 100) RRMS (n = 153)
Right side Left side Right side Left side
Velocity at stimulation (cm/s) 50.8 ± 11.3 50.0 ± 10.8 49.4 ± 11.2 48.5 ± 10.8
Velocity at rest (cm/s) 36.8 ± 8.1 36.5 ± 8.0 34.6 ± 7.8* 34.4 ± 7.6*
NVC (%) 38.6 ± 14.2 37.6 ± 14.1 43.3 ± 14.1* 41.7 ± 13.5*

* significant differences between patients with RRMS and controls (p < 0.05 for all).

RRMS indicates relapsing-remitting multiple sclerosis and NVC neurovascular coupling.

Values are mean ± standard deviation; independent samples test was used.

All Doppler data for the simple and complex visual stimulation in patients with or without the involvement of the optic nerve are shown in Table 3 and Table 4.

Table 3

Blood flow velocities to simple visual stimulation in patients according to with or without optic nerve involvement.

 

Simple visual stimulation Patients with Optic nerve involvement (n = 26) Patients without Optic nerve involvement (n = 210)
Right side Left side Right side Left side
Velocity at stimulation (cm/s) 47.6 ± 9.7 45.0 ± 10.9 47.4 ± 9.6 47.3 ± 9.4
Velocity at rest (cm/s) 35.5 ± 7.4 34.0 ± 8.4 34.5 ± 7.5 35.0 ± 7.4
NVC (%) 34.8 ± 10.9 33.1 ± 12.5 38.2 ± 13.5 36.2 ± 14.4

RRMS indicates relapsing-remitting multiple sclerosis and NVC neurovascular coupling.

Values are mean ± standard deviation; independent samples test was used.

Table 4

Blood flow velocities to complex visual stimulation in patients according to with or without optic nerve involvement.

 

Complex visual stimulation Patients with Optic nerve involvement (n = 19) Patients without Optic nerve involvement (n = 134)
Right side Left side Right side Left side
Velocity at stimulation (cm/s) 47.8 ± 11.1 48.5 ± 12.4 49.6 ± 11.2 48.5 ± 10.6
Velocity at rest (cm/s) 32.8 ± 7.9 34.7 ± 9.2 34.8 ± 7.7 34.3 ± 7.3
NVC (%) 46.6 ± 12.1 40.6 ± 9.2 43.2 ± 14.3 42.1 ± 14.1

The blood velocities during stimulation and rest were quite similar between patients with optic neuritis or without optic neuritis. As a consequence, there is no significant difference between the neurovascular reactivity of the patients with or without optic neuritis.

4. Discussion

Normal brain activity depends on a continuous supply of oxygen and glucose through CBF, and local brain activity has to be accompanied by a concomitant increase in local CBF. However, the fast CBF changes are paralleled by changes in both oxygenation and blood volume [20]. The signaling from the neurons in the activated brain regions to the local vessels are necessary for the local CBF to increase during neuronal activation. Also, glial activation plays a substantial role in the neurovascular coupling; especially visual stimulation [7] and [21]. Endothelial cells and pericytes are also involved in the neurovascular coupling [22]. Nevertheless, the exact coupling mechanism of the neurovascular unit is not yet fully understood.

In the present study, the NVC obtained during the simple, and complex visual stimulation was significantly higher among patients than those of the controls. In our study, the blood flow velocities in the rest period during the visual stimulation procedure on the MS patients were lower than those of the control subjects at both the simple and complex stimulation procedures. Our study was not intended to determine the perfusion deficits in the MS patients. However, the lower cerebral blood flow velocities during the rest period probably represent cerebral hypoperfusion within the monitored vessels area. The potential explanation is in the elevation of cerebrovascular resistance due to possible vasoconstriction of the distal cortical vessels promoted by endothelin-1. Recently it has been demonstrated that the cerebral hypoperfusion in patients with MS is mediated by endothelin-1 and is significantly released by the reactive astrocytes in the plaques in the patients compared to the controls [23].

The cerebrovascular reactivity could be examined using the functional TCD [24] and [25]. TCD sonography allows for the real-time investigation of the flow velocities in the large cerebral arteries, and the velocity changes after a vasodilatory stimulus such as acetazolamide, CO2, or apnea [26]. Hypoxia caused by breath holding results in an autoregulatory vasodilatation and an increase in CBF in the cortex [27]. The increased CBF can be evaluated by the TCD, and can provide information regarding the vascular reactivity [28]. Recently, normal cerebrovascular reactivity using a breath-holding test in MS patients was published [29]. The authors have conducted TCD examinations during the attack, after a high-dose intravenous corticosteroid treatment, and the attack free period. They did not find any significant differences between patients with MS and the controls. More recently, another group examined cerebral autoregulation during the head-up tilt table testing and the effects of high-dose intravenous corticosteroid treatment [30]. They found no significant differences in the autoregulatory indices between the patients and the controls, or between the pre- and post-steroid results.

The results of the previous studies assessing NVC in MS patients have shown hyperactivity at the occipital region to visual stimulation during an attack, and after a high-dose of intravenous corticosteroid treatment [10], [11], and [12]. They also correlated the velocity changes of the posterior cerebral artery with visual evoked potential data (latency and amplitude) obtained during the attack period. They concluded that this hyperactivity might be a result of long-term inhibition caused by axonal injury and demyelination representing the adaptive changes in the occipital cortical neurons.

Because of the blood flow velocities obtained during rest period lower than those of controls in our study, the increased reactivity in patients seems to be related to the increased vasodilator ability of the vessels. When considering cerebral vascular reactivity is intact, our results support the hyperactive neurovascular unit in the occipital region in MS patients during the attack period, regardless of the intensity of visual stimuli. However, its clinical relevance has yet to be entirely clarified.

5. Conflict of interest

None Declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Appendix A. Supplementary data

The following are Supplementary data to this article:

mmc1

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Footnotes

Eskisehir Osmangazi University, Faculty of Medicine, Department of Neurology, Eskisehir, Turkey

Corresponding author at: Eskisehir Osmangazi University, Faculty of Medicine, Department of Neurology, Meselik, 26480 Eskisehir, Turkey.


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    Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College, Cornell...
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