Francois Alexandre
email: francois.alexandre@5-sante.fr

Nelly Heraud

Alain Varray

Is nocturnal desaturation a trigger for neuronal damage in chronic obstructive pulmonary disease?

Patients with chronic obstructive pulmonary disease (COPD) present many neurological disorders of unknown origin. Although hypoxemia has long been thought to be responsible, several studies have shown evidence of neuronal damage and dysfunction even in nonhypoxemic patients with COPD. Adaptive mechanisms protect the brain from hypoxia: when arterial oxygen tension (PaO 2 ) decreases, the cerebral blood flow (CBF) increases, ensuring continuously adequate oxygen delivery to the brain. However, this mechanism is abolished during non-rapid eye movement (NREM) sleep. Any drop in PaO 2 during NREM sleep is therefore not compensated by increased CBF, causing decreased cerebral oxygen delivery with subsequent brain hypoxia. Patients with may therefore be exposed to neuronal damage during this critical time. This mechanism is of vital importance for patients with COPD because of the potentially deleterious cortical effects. Nocturnal desaturation is quite frequent in COPD and affects approximately one out of two patients who are not hypoxemic during wakefulness. Although the prevalence of NREM sleep desaturation has never been specifically assessed in COPD, current data suggest that at least half of the nocturnal desaturation in desaturating patients occurs during NREM sleep. This review presents the rationale for the hypothesis that nocturnal desaturation during NREM sleep promotes neuronal damage and dysfunction in COPD.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death 2 worldwide. COPD is not restricted to the lung but instead has major systemic repercussions, 3 and it is now considered to be a multi-component syndrome. Accordingly, the predictors of 4 COPD survival include not only the degree of airflow obstruction, but also body mass index, 5 dyspnea, exercise capacity, peripheral muscle size and strength, and the level of hypoxemia.

6

Brain impairment is a well-documented secondary outcome of the disease, but surprisingly 7 this is often forgotten (1). Yet recent reports have irrefutably confirmed severe anatomical 8 brain impairment in COPD (2, 3) with significant functional repercussions that are not limited 9 to cognitive disorders; for example, both peripheral muscle strength (4) and driving abilities 10 (5) can be affected. The mechanisms of brain impairment are still not well understood, absence of cerebrovascular O 2 reactivity during NREM sleep stages (12-14), we hypothesize 27 that nocturnal desaturation during NREM sleep may act as a trigger for neuronal damage and 28 dysfunction in COPD (Figure 1).

29 30 Arguments to support the hypothesis 31 Anatomical brain impairment in COPD 32 Patients with COPD present many anatomical brain alterations. The neuronal damage in 33 COPD was first characterized as periventricular white matter lesions (20) and cerebral 34 metabolic abnormalities (21). Levels of N-acetyl aspartate, a marker of neuronal density, were 35 also reported to be lower in patients with COPD compared with healthy controls (21). More 36 recently, improvements in magnetic resonance imaging analyses through diffusion tensor 37 imaging and voxel-based morphometry have provided better descriptions of the structural 38 brain damage in COPD (2, 3, 22). Zhang et al. (22) found that gray matter volume was 39 reduced bilaterally in the frontal cortex, the cingulate cortex and the left insular cortex in 40 patients with COPD. They also identified gray matter deficits in many subcortical areas such 41 as the right thalamus and left amygdala (22). Hippocampal atrophy was observed and 42 associated with an increased level of serum S100b, a peripheral marker of glial cell have focused on cognitive dysfunction (see Dodd et al. (25) for review). The results of 51 generic questionnaires such as the mini-mental state assessment (MMSE) or the Montreal 52 cognitive assessment (MoCA) have shown globally impaired cognitive function in patients 53 with COPD (23, 26). The P300 component of the event-related brain potential is a useful, 54 objective clinical tool to assess cognitive function. Two studies reported longer P300 latency 55 and lower P300 amplitude in patients with COPD compared with healthy controls, and both 56 these measures are known to reflect attention deficits and impaired decision-making processes 57 (7, 27). Another recent study found impairments in processing speed, working and episodic 58 memory, and executive functions (2), with memory and attention capacities being most 59 impaired (28). It should be noted that brain impairment is not systematic in COPD. Borson et 60 al. (29) found no differences in hippocampal volume or white matter lesions between patients 61 with COPD and healthy controls. Similarly, other studies have observed no significant 62 differences in MMSE scores between patients with COPD and healthy controls (30). Recent 63 studies have estimated the prevalence of cognitive dysfunction as being in the range of 27 to 64 36% (26, 31).

65

As noted above, the functional repercussions of neuronal damage are not restricted to 66 cognitive functioning. For instance, driving ability may be severely impaired in patients with 67 COPD (5, 32). Some studies have reported alterations in resting motor cortex excitability in 68 these patients (33, 34), and another found a lower level of voluntary activation of the knee 69 extensor muscles (35). In a recent study from our laboratory, we assessed the neural activity 70 of the motor cortex during maximal voluntary contractions of the knee extensors and recorded 71 lower motor cortical output in the patients with COPD (4). Taken together, these data support 72 the hypothesis that cerebral processes are involved in COPD muscle weakness.

73

Introduction

however, and it is therefore essential to determine their origins so that they can be better 12 anticipated, with the ultimate goal being to prevent their deleterious effects. Although 13 hypoxemia has long been thought to be responsible for brain impairment [START_REF] Zheng | Chronic hypoxia-hypercapnia influences cognitive related potential, P300 analysis[END_REF], several studies 14 have shown evidence of neuronal damage and dysfunction even in non-hypoxemic patients [START_REF] Matsuo | Changes in cerebral hemoglobin indices in 292 obstructive sleep apnea syndrome with nasal continuous positive airway pressure 293 treatment[END_REF] with COPD [START_REF] Dodd | 257 Brain structure and function in chronic obstructive pulmonary disease: a multimodal 258 cranial magnetic resonance imaging study[END_REF]7,[START_REF] Liesker | Cognitive performance in patients with 276 COPD[END_REF]. Adaptive mechanisms protect the brain from hypoxia: when arterial 16 oxygen tension (PaO 2 ) decreases, the cerebral blood flow (CBF) increases, ensuring 17 continuously adequate oxygen delivery to the brain [START_REF] Harris | Cerebral blood flow response to acute hypoxic 278 hypoxia[END_REF][START_REF] Poulin | Influence of cerebral blood flow on the ventilatory response 280 to hypoxia in humans[END_REF][START_REF] Shapiro | Cerebrovascular response to 282 acute hypocapnic and eucapnic hypoxia in normal man[END_REF]. However, this mechanism is 18 abolished during non-rapid eye movement (NREM) sleep [START_REF] Hajak | Sleep apnea 285 syndrome and cerebral hemodynamics[END_REF][START_REF] Meadows | Cerebral 287 blood flow response to isocapnic hypoxia during slow-wave sleep and wakefulness[END_REF][START_REF] Corfield | Control of cerebral blood flow during sleep and the 290 effects of hypoxia[END_REF]. Therefore, any drop in PaO 2 during NREM sleep is not compensated by increased CBF, causing decreased cerebral 20 oxygen delivery with subsequent brain hypoxia [START_REF] Matsuo | Changes in cerebral hemoglobin indices in 292 obstructive sleep apnea syndrome with nasal continuous positive airway pressure 293 treatment[END_REF][START_REF] Olopade | Noninvasive determination of brain tissue 295 oxygenation during sleep in obstructive sleep apnea: A near-infrared spectroscopic 296 approach[END_REF]. Given the high prevalence of nocturnal desaturation in patients with COPD [START_REF] Lacasse | Evaluating nocturnal oxygen 298 desaturation in COPD--revised[END_REF][START_REF] Levi-Valensi | Sleep-related oxygen desaturation and 300 daytime pulmonary haemodynamics in COPD patients[END_REF][START_REF] Chaouat | Sleep-related O2 desaturation and 303 daytime pulmonary haemodynamics in COPD patients with mild hypoxaemia[END_REF] and the impairment [START_REF] Li | The unique alterations of hippocampus and cognitive impairment in 314 chronic obstructive pulmonary disease[END_REF]. In addition, a high prevalence of cerebral microbleeds and small cerebral 44 vessel disease was found in patients with COPD [START_REF] Lahousse | Chronic obstructive pulmonary 316 disease and cerebral microbleeds. The Rotterdam Study[END_REF], which is consistent with reports of both 45 the decrease in microstructural integrity and the increase in white matter ultrastructural damage in several cortical and subcortical areas [START_REF] Dodd | 257 Brain structure and function in chronic obstructive pulmonary disease: a multimodal 258 cranial magnetic resonance imaging study[END_REF][START_REF] Ryu | Microstructural change of the brain in chronic 261 obstructive pulmonary disease: a voxel-based investigation by MRI[END_REF].

Functional repercussions of brain impairment

The structural brain damage have several functional repercussions, although most studies Although evidence of a major brain impairment in COPD has steadily accumulated since the 76 first study by Fix et al. (36), the trigger for these cerebral alterations remains unknown [START_REF] Rodriguez-Roisin | Changes in your breathing can change 352 your brain[END_REF] in isocapnic conditions, the increase in global and regional CBF can reach up to 200% [START_REF] Harris | Cerebral blood flow response to acute hypoxic 278 hypoxia[END_REF][START_REF] Poulin | Influence of cerebral blood flow on the ventilatory response 280 to hypoxia in humans[END_REF][START_REF] Shapiro | Cerebrovascular response to 282 acute hypocapnic and eucapnic hypoxia in normal man[END_REF].

108

It is assumed that the adaptation of CBF during acute hypoxic exposure is protective, 109 maintaining the stable cerebral oxygen delivery that is a prerequisite for normal brain function 110 [START_REF] Harris | Cerebral blood flow response to acute hypoxic 278 hypoxia[END_REF](45)(46)(47). In contrast, it has been suggested that the increase in CBF in response to a PaCO 2 111 increase causes CO 2 washout from brain tissue in order to attenuate the level of central CO 2 112 [START_REF] Poulin | Influence of cerebral blood flow on the ventilatory response 280 to hypoxia in humans[END_REF], thereby preventing the deleterious effects of excessive PaCO 2 levels on brain tissue (48, 113 49). However, it is noteworthy that the deleterious effects were reported for PaCO 2 levels were reported when the patients breathed room air and when they breathed oxygen to prevent 156 desaturation [START_REF] Vogiatzis | Cerebral cortex oxygen delivery and 421 exercise limitation in patients with COPD[END_REF]. This confirms the brain protection against acute hypoxemia in COPD.

157

Regarding the effect of chronic hypoxemia on CBF, a study reported higher CBF velocity and 158 larger cerebral artery diameter using transcranial Doppler in chronic hypoxemic patients with 159 COPD compared with healthy controls [START_REF] Albayrak | Extracranial carotid Doppler ultrasound 423 evaluation of cerebral blood flow volume in COPD patients[END_REF]. This study showed that the mechanisms of 160 cerebral vasodilation persist in patients with COPD during chronic blood gas changes. In 161 addition, the highest CBF levels were found in the hypoxemic-hypercapnic patients, 162 indicating a possible cumulative effect of chronic hypoxemia-hypercapnia on the 163 cerebrovascular vasodilative response [START_REF] Albayrak | Extracranial carotid Doppler ultrasound 423 evaluation of cerebral blood flow volume in COPD patients[END_REF]. Nevertheless, this response is sometimes difficult 164 to observe because of confounding factors [START_REF] Antonelli Incalzi | Cognitive impairment in chronic 426 obstructive pulmonary disease--a neuropsychological and spect study[END_REF][START_REF] Ortapamuk | Brain perfusion abnormalities in chronic obstructive 429 pulmonary disease: comparison with cognitive impairment[END_REF]. For example, CBF is closely coupled with 165 cerebral metabolism: the lower the cerebral metabolism, the lower the CBF is. As patients 166 with COPD exhibit lower resting cerebral metabolism [START_REF] Shim | Cerebral metabolic abnormalities in COPD patients 308 detected by localized proton magnetic resonance spectroscopy[END_REF][START_REF] Karakas | Examining cerebral metabolic 432 abnormalities in chronic obstructive pulmonary disease (COPD) patients by localized 433 proton magnetic resonance spectroscopy (MRS)[END_REF][START_REF] Sinha | Proton magnetic resonance 435 spectroscopy of brain to study the cerebral metabolic abnormalities in COPD patients: 436 a case control study in north India[END_REF], the resting CBF can be 74), but nocturnal desaturation can also occur in patients with COPD who are 201 normoxic while awake [START_REF] Lacasse | Evaluating nocturnal oxygen 298 desaturation in COPD--revised[END_REF]. The prevalence of patients with COPD who are normoxic while 202 awake and who spend at least 30% of the total sleep time (TST) with a mean pulsed oxygen 203 saturation (SpO 2 ) below 90% ranges from 38 to 70% [START_REF] Lacasse | Evaluating nocturnal oxygen 298 desaturation in COPD--revised[END_REF][START_REF] Levi-Valensi | Sleep-related oxygen desaturation and 300 daytime pulmonary haemodynamics in COPD patients[END_REF][START_REF] Chaouat | Sleep-related O2 desaturation and 303 daytime pulmonary haemodynamics in COPD patients with mild hypoxaemia[END_REF]. Based on the same criteria, it is Moreover, a follow-up study with correction of NREM sleep desaturation in the desaturating patients, for example by oxygen therapy, would be of great interest. A few studies assessed 225 the effects of oxygen therapy on cognitive function in COPD but the results were inconclusive 226 [START_REF] Thakur | COPD and cognitive impairment: the role of 459 hypoxemia and oxygen therapy, International journal of chronic obstructive 460 pulmonary disease[END_REF][START_REF] Heaton | Psychologic effects of[END_REF][START_REF] Incalzi | Predicting 465 cognitive decline in patients with hypoxaemic COPD[END_REF][START_REF] Incalzi | Chronic 468 obstructive pulmonary disease. An original model of cognitive decline[END_REF]. In these studies, the oxygen flow rate was not adapted to the specific needs during 227 sleep which are often higher than during the waking state [START_REF] Plywaczewski | Incidence of 450 nocturnal desaturation while breathing oxygen in COPD patients undergoing long-451 term oxygen therapy[END_REF]. Therefore, manually or

114

  above 100 mmHg (49), values rarely reached in humans. 115 116 Effects of hypoxic exposure on CBF in healthy individuals 117 Isocapnia during acute hypoxic exposure is a very rare phenomenon in healthy humans. Acute 118 hypoxemia normally induces an increase in ventilation, which in turn leads to hypocapnia to 119 improve blood oxygenation (47, 50, 51). This occurrence of hypocapnia during hypoxic 120 exposure subsequently hampers the increase of CBF velocity caused by lower PaO 2 , as 121 hypoxemia and hypocapnia have opposite effects on CBF (52, 53). In addition, as CBF is 122 more sensitive to changes in PaCO 2 than in PaO 2 , this heightens the risk of inadequate oxygen 123 delivery to the brain during acute hypoxemia-hypocapnia (53). Nevertheless, more recent studies have shown that the modest increase in CBF velocity during acute hypoxemia-125 hypocapnia is compensated by a greater increase in the caliber of cerebral arteries to ensure 126 normal oxygen delivery to the brain (46, 50). 127 During chronic hypoxia in healthy humans, cerebral oxygen delivery also remains preserved 128 compared to sea-level values (47, 50, 54, 55). The mechanisms suggest that the adaptations 129 differ from those that occur during acute hypoxic exposure, since a progressive return of CBF 130 toward sea-level values has been observed after several days of hypoxic exposure (54-56). 131 This fall in CBF is nevertheless compensated by an increase in arterial oxygen content, 132 mainly due to respiratory acclimatization and a slight rise in hemoglobin concentration (55), 133 resulting in adequate cerebral oxygen delivery (47, 50, 54, 55). Thus, taken together, the 134 aforementioned findings do not support the occurrence of cerebral hypoxia under either acute 135 or chronic hypoxic exposure.

136 137

 136 Effects of hypoxemia on CBF in patients with COPD138 Patients with COPD can experience acute hypoxemia (e.g., during exercise-induced oxygen 139 desaturation) and the most severe patients may even experience chronic hypoxemia. In 140 patients with COPD acute and chronic hypoxemia are generally accompanied by normocapnia 141 or hypercapnia, rather than hypocapnia compared to healthy individuals. This is due to 142 ventilation-perfusion mismatch and impaired ventilatory muscle function (57). The 143 combination of hypoxemia and hypercapnia increases CBF much more than hypoxemia or 144 hypercapnia alone, since these two phenomena have cumulative vasodilator effects (56). It is 145 thus possible to speculate that the COPD brain is normally much more protected from 146 cerebral hypoxia than the healthy human brain, on condition that both acute and chronic 147 cerebrovascular reactivity are preserved in COPD. Many studies have provided evidence of 148 cerebrovascular CO 2 reactivity in COPD (58-62), although this response seems mitigated reactivity, one study reported a similar CBF increase in patients with COPD and healthy 151 controls in response to arterial oxygen saturation (SaO 2 ) changes, supporting a preserved 152 response (58). In addition, another study reported higher CBF velocity and an increase in 153 cerebral artery diameter in recently exacerbated patients with COPD (63). More recently, 154 comparable levels of cerebral oxygen delivery during exercise-induced oxygen desaturation 155

167

  lowered in both hypoxemic[START_REF] Antonelli Incalzi | Cognitive impairment in chronic 426 obstructive pulmonary disease--a neuropsychological and spect study[END_REF][START_REF] Ortapamuk | Brain perfusion abnormalities in chronic obstructive 429 pulmonary disease: comparison with cognitive impairment[END_REF] and non-hypoxemic (62) patients.168To conclude, acute and chronic cerebrovascular O 2 reactivity is preserved in COPD, 169 indicating that cerebral oxygen delivery is adequate during hypoxemia in patients with COPD 170[START_REF] Vogiatzis | Cerebral cortex oxygen delivery and 421 exercise limitation in patients with COPD[END_REF]. Hence, hypoxemia per se does not induce cerebral hypoxia in COPD and this may explain why the involvement of hypoxemia in triggering neuronal damage in COPD has never 172 been demonstrated.

  cited above have shown, changes in diurnal blood gases are well tolerated by 177 the brain through CBF adaptations. However, this mechanism may be hampered during sleep. prevent cerebral hypoxia in patients with cardiorespiratory disorders who experience oxygen 188 desaturation during NREM sleep. Cerebral hypoxia has been reported during sleep in patients 189 with OSA (15, 16). It should be noted that this response seems very specific to the NREM 190 sleep stages, as cerebrovascular reactivity is not impaired during rapid eye movement (REM) 191 sleep (12). 192 In summary, cerebrovascular reactivity is impaired and even abolished during NREM sleep in 193 humans (13). In patients who experience hypoxemia or desaturation during NREM sleep, 194 cerebral hypoxia can occur and may induce neuronal damage (14). We thus propose that 195 nocturnal desaturation during NREM sleep can act as a trigger for neuronal damage and 196 cerebral dysfunction in patients with COPD (Figure 1).

197 198

 197 Desaturation during NREM sleep in COPD: does it exist and, if so, does it matter?Patients with COPD who are hypoxemic in the waking state usually become more hypoxemic 200 during sleep (

204

  also notable that nocturnal desaturation in COPD is observed in approximately half of the 205 patients undergoing long-term oxygen therapy because the diurnal flow rate is often 206 insufficient to prevent nocturnal desaturation (75). However, it is quite difficult to determine 207 the percentage of patients with COPD who desaturate during the NREM sleep stages because 208 all the studies to date have considered the total sleep time, thus including REM sleep. Indeed, 209 as the deepest desaturations occur during REM sleep, this sleep stage has logically been taken 210 as the main marker of COPD sleep abnormalities (74, 76, 77). Nevertheless, it is reasonable to 211 assume that desaturation during NREM sleep occurs in patients with nocturnal desaturation in 212 COPD, even though this has never been specifically assessed. The usual criterion to diagnose 213 sleep desaturation is oxygen desaturation for at least 30% of the total sleep time. As REM 214 sleep represents only approximately 13% of the total sleep time in COPD (78), more than half 215 of the desaturation time is likely to occur during NREM sleep in patients with COPD and 216 significant sleep desaturation.

Future studies to test the hypothesis 219

 219 The abolition of cerebrovascular O 2 reactivity during NREM sleep was demonstrated in 220 humans[START_REF] Meadows | Cerebral 287 blood flow response to isocapnic hypoxia during slow-wave sleep and wakefulness[END_REF] and then specifically in patients who experience nocturnal desaturation[START_REF] Shapiro | Cerebrovascular response to 282 acute hypocapnic and eucapnic hypoxia in normal man[END_REF]. 221 Transcranial Doppler (58) or near-infrared spectroscopy (64) could be used to assess the 222 extent to which CBF decreases during NREM sleep desaturation in patients with COPD.

228

  automated oxygen flow titration should be considered to accurately adjust oxygen delivery 229 during NREM sleep (83). Beyond hypothesis testing, the demonstration that preventing 230 NREM sleep desaturation improves cerebral function (or at least stops the decline in function) 231 would constitute a first step in developing new treatments for the neuronal damage and 232 dysfunction of COPD.

  cerebrovascular reactivity to blood gas changes is a mechanism that prevents 236 brain hypoxia in awake humans. During NREM sleep, however, this reactivity is reduced or 237 even totally abolished. Consequently, any oxygen desaturation during this sleep stage will 238 favor neuronal damage. As abnormal blood oxygenation during NREM sleep is a common 239 feature in COPD and a decreased oxygen supply might not be compensated by an increase in 240 cerebral blood flow, the patient's brain is potentially exposed to hypoxic stress. The 241 hypothesis developed above considers NREM sleep desaturation as a potential trigger for 242 neuronal damage and dysfunction in COPD. 243 No conflict of interest, financial or otherwise, is declared by the authors. No funding was received for this study. 252 function: a possible new model of cognitive dysfunction in chronic obstructive 270 pulmonary disease, Med Hypotheses. (2008);

412[ 61 ]FiguresFigure 1 :Figure 2 :

 6112 Figures

. Although the evidence that hypoxia in vitro induces cellular 91 necrosis is indisputable, it has long been established that hypoxia exposure alone is not able to

  . A 77 model including vascular disease, inflammation, smoking and hypoxia was proposed to 78 explain COPD neuronal damage and dysfunction (25), yet Dodd et al. (2) reported the 79 persistence of neuronal damage and cognitive dysfunction in COPD even after controlling for 80 smoking and stroke risks. Another study found higher cognitive dysfunction in O 2 -dependent 81 patients with COPD than in non-dependent patients, with comparable level of systemic 82 inflammation in the two groups (29). This indicates that chronic inflammation, although 83 probably implicated (38), is not the main mechanism of the brain impairment. It also raises 84 doubt about the effectiveness of long-term O 2 supplementation in preventing or correcting

	101	perfusion despite blood pressure changes within the normal range (42). However, during
	102	changes in arterial blood gases, cerebral autoregulation mechanisms adjust cerebral blood
	103	flow (CBF) through CBF velocity and regulate artery caliber to ensure adequate blood gas
	104	delivery to the brain (43). When PaO 2 decreases, CBF increases, and when arterial carbon
	105	dioxide tension (PaCO 2 ) increases, CBF increases. These responses are called cerebrovascular
	106	O 2 reactivity and cerebrovascular CO 2 reactivity, respectively. This close coupling between
	107	CBF and arterial blood gases was first described by Kety et al. (44). When PaO 2 is decreased
	87
	88	hypercapnia (6, 28), neither direct evidence nor explanatory mechanisms could be clearly
	89	provided. Moreover, several studies have reported brain impairment and cognitive
	90	dysfunction in non-hypoxemic patients with COPD, raising further doubt about the credibility
	of this hypothesis (2, 7, 8)92
	93	induce neuronal damage in vivo. Indeed, a fall in arterial oxygen tension (PaO 2 ) without
	94	ischemia or a drop in blood pressure (which may cause ischemia) does not induce neuronal
	95	death/necrosis (39-41). In this sense, it appears that abnormal perfusion is an essential
	96	condition for neuronal damage in vivo. The exact mechanisms are examined in detail below.
	97
	98	Brain protection against hypoxemia during wakefulness: mechanisms and differences
		between patients with COPD and healthy individuals

85

cerebral alterations, perhaps because hypoxemia per se is not fully responsible for COPD 86 brain impairment. Indeed, while most studies have blamed chronic hypoxemia and

  71: 111-113.

	398	sustain cerebral oxygen delivery --Severinghaus revisited, Comp Biochem Physiol A
	399	Mol Integr Physiol. (2002); 132: 221-229.
		[56] Brugniaux JV, Hodges AN, Hanly PJ , Poulin MJ. Cerebrovascular responses to

271

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Gupta PP, Sood S, Atreja A , Agarwal D. A comparison of cognitive functions in non-272 hypoxemic chronic obstructive pulmonary disease (COPD) patients and age-matched 400 altitude, Respir Physiol Neurobiol. (2007); 158: 212-223. 401 [57] Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, 402 and prevention of chronic obstructive pulmonary disease: GOLD executive summary, 403 Am J Respir Crit Care Med. (2007); 176: 532-555. 404 [58] Bernardi L, Casucci G, Haider T, et al. Autonomic and cerebrovascular abnormalities 405 in mild COPD are worsened by chronic smoking, Eur Respir J. (2008); 32: 1458-406 1465. 407 [59] Clivati A, Ciofetti M, Cavestri R , Longhini E. Cerebral vascular responsiveness in 408 chronic hypercapnia, Chest. (1992); 102: 135-138. 409 [60] Hartmann SE, Pialoux V, Leigh R , Poulin MJ. Decreased cerebrovascular response to 410 CO2 in post-menopausal females with COPD: role of oxidative stress, Eur Respir J. 411 (2012); 40: 1354-1361.

acute changes in arterial blood gases, J Physiol. (2012); 590: 3261-3275.

Mechanisms responsible for brain impairment in COPD: an incomplete view

Cerebral autoregulation is the physiological mechanism that maintains constant cerebral compared with that in healthy controls (59, 60). Regarding acute cerebrovascular O 2 Contrary to the adaptations that occur in the waking state, the oxygen desaturation during 179 non-rapid eye movement (NREM) sleep is not accompanied by an increase in CBF (Figure 2).


Lionel Bureau

Friction as a probe of surface properties of a polymer glass

We probe the temperature dependence of friction at the interface between a glassy poly(methylmethacrylate) lens and a flat substrate coated with a methyl-terminated self-assembled monolayer. The monolayer exhibits density defects which act as pinning sites for the polymer chains. We show that the shear response of such an interface supports the existence, at the surface of the glassy polymer, of a nanometer-thick layer of mobile chains. Friction can be ascribed to the interplay between viscouslike dissipation in this layer and depinning of chains adsorbed on the substrate. We further show that the pinning dynamics is controlled by β rotational motions localized at the interface.

INTRODUCTION

Polymeric materials are encountered in a variety of situations in which their tribological behavior is of importance, from sliding of rubber components [1,2,3] to lubrication via surface modification using polymer thin films [4,5,6]. The fundamental understanding of polymer friction has been the scope of a number of studies over the past fifty years, from which the following two main pictures emerge.

Rubber friction involves the combination of an interfacial molecular process and of bulk viscoelastic losses, the respective weight of these two mechanisms depending on the roughness of the substrate on which the elastomer slides [1]. Schallamach described the interfacial process as the thermally activated formation and breaking, under the applied shear stress, of molecular bonds between the rubber and the countersurface [7]. Such a pinning/depinning mechanism, which serves as a basis for more refined models [8,9], is consistent with the velocitydependent friction reported in experimental studies of rubbers sliding on smooth substrates [1,2].

Friction of glassy polymers is usually related to plasticity [4,10,11,12]. In the absence of ploughing (or indentation) of the material, i.e. in the absence of bulk dissipation, friction is found to be controlled by the yield properties of a nanometer-thick polymer layer confined at the interface between the solids [12,13,14,15]. Now, the issue of surface properties of glassy polymers has recently attracted much attention [17,18,19]. Various techniques have been used for this purpose: glass transition temperature measurements on ultra-thin films [18,20,21], density gradient determination [22], nanoscale contact mechanics [23], creep [24] and buckling [25] of thin films , or friction force microscopy [26,27,28]. Though some of the results are still a matter of debate, there is a consensus that a glassy polymer exhibits a nanometer-thick surface layer in which the chain mobility differs from that of the bulk. Moreover, the dynamics in this layer is strongly influenced by the nature of the chemical interactions between the polymer and the substrate: mobility appears to be enhanced near a free polymer sur-face or an interface with a low energy substrate, whereas chain dynamics seems to be slowed down in the case of strong polymer/substrate interactions [20,29,30].

In this context, we have recently shown that such a dependence of surface chain mobility on interactions has a clear signature on friction [31]. We have performed friction experiments in which a poly(methylmethacrylate) (PMMA) solid slides on smooth surfaces presenting different densities of pinning sites available for polymer/substrate bond formation. We have found that:

(i) at high pinning level, frictional dissipation occurs through the sudden flips of molecular-sized bistable regions localized in a nm-thick layer of confined chains, which responds to shear as an elasto-plastic solid [14,[START_REF] Persson | Sliding friction[END_REF], and (ii) in situations of weak pinning, dissipation appears to be governed by a process akin to that proposed for rubber friction. This suggests that some "glass-to-rubber" transition occurs at the polymer surface when its interaction with the substrate goes from strong to weak.

In the present paper, we investigate further the regime of weak pinning by probing the temperature dependence of friction at an interface between PMMA and a silicon wafer grafted with an organic self-assembled monolayer (SAM). The contact configuration of our experiments, in which a smooth lens of polymer is pressed, under low contact pressure, on a rigid flat substrate, allows us to probe the shear response of the polymer surface without inducing bulk dissipation during sliding. Our results provide strong support for the presence of a nanometer-thick layer at the polymer surface, which, in the case of weak interaction with the countersurface, exhibits a frictional rubberlike response. This response results from the combination of viscous flow in this surface layer, and of a pinning/depinning mechanism. Moreover, we show that the pinning dynamics of the polymer chains is controlled by localized β rotational motions at the interface.

EXPERIMENTAL SECTION

Setup

The experiments were performed using a home-built tribometer which is sketched on Fig. 1. A lens of poly(methylmethacrylate) is fixed on a transparent holder attached to a load cell made of two double cantilever springs of stiffness K N = 2.10 4 N.m -1 and K T = 1.7 × 10 4 N.m -1 . The load cell is mounted on a vertical motorized translation stage which is used to bring the lens in contact with a flat horizontal substrate. The value of the applied normal force, F N , is deduced from the spring deflection, measured by means of a capacitive displacement gauge. The range of accessible normal forces F N is 4.10 -3 -3 N. The silicon wafer used as a substrate is fixed to a horizontal translation stage and is moved at constant velocity V in the range 3.10 -2 -10 2 µm.s -1 . The resulting tangential force F T is measured to within 10 -3 N by means of a capacitive sensor. In order to work at constant normal load during sliding, and to compensate for parallelism defects of the mechanical setup, a digital feedback loop controls the position of the vertical stage which drives the loading spring.

The silicon substrate is mounted on the top plate of a heating/cooling unit made of a thermoelectric element and a water-circulating heat exchanger. The temperature of the plate is measured by means of a thermistor glued on its surface, and is controlled to within 0.1 • C in the range from -20 • C to 100 • C. In order to avoid moisture or ice formation at low temperature, the whole experimental setup is enclosed in a glovebox purged with dry argon, which allows us to keep the relative humidity below 5%.

The contact area A between the polymer lens and the wafer is monitored in reflection by means of a long working distance optics and a computer-interfaced CCD camera. The lenses have radii of curvature on the order of a millimeter (see section below), which -for F N in the range given above -yields contact areas typically ranging from 3.10 2 to 3.10 4 µm 2 . Contact areas are determined with a ±2% accuracy by image processing.

Note that the elastic contrast between the polymer lens (Young modulus E ≃ 3 GPa) and the substrate (E ≃ 100 GPa), along with the smoothness of both surfaces in contact (see below), ensures that no ploughing of the polymer occurs during sliding.

Samples

Polymer lenses are made as follows: about 10 mm 3 of poly(methylmethacrylate) (PMMA) powder (M w =93 kg.mol -1 , M n = 46 kg.mol -1 , T g ≃ 110 • C, from Sigma-Aldrich) is brought to T=200 • C at p=10 -1 mbar until a clear and homogeneous melt is obtained. The melt is then transferred on a clean glass slide and allowed to FIG. 1: Experimental setup: a PMMA lens is pressed against a silanized substrate under a constant normal load. The substrate is mounted on a temperature-controled stage, and is driven at velocity V . The contact area is monitored optically.

spread at T=180 • C and atmospheric pressure. During the first minutes of spreading, the highly viscous polymer melt forms a spherical cap, which radius of curvature increases with the spreading time. Once the spherical cap has reached a roughly millimetric radius of curvature, it is cooled to 80

• C (at ∼ 2 • C.mn -1
) and left at this annealing temperature for 12 hours. The root-mean-square roughness of the lenses at their apex is found to be of 2-3 Å, as measured by atomic force microscopy over a 1 µm 2 scan (see Fig. 2a).

The substrate is a 2" silicon wafer covered by an alkylsilane layer. The wafer is first cleaned as follows: rinsing with toluene, drying in nitrogen flux, 15 minutes of sonication in a dilute solution of detergent in deionized water, 15 minutes of sonication in ultra-pure water, drying in nitrogen flux, 30 minutes in a UV/O 3 chamber. We then graft a self-assembled monolayer (SAM) of octadecyltrichlorosilane (OTS, Sigma-Aldrich), following a procedure akin to that described by Silberzan et al. [32] and Davidovits et al. [33]: the wafer is exposed to a flux of humid oxygen for 2 minutes immediately after UV/O 3 exposure, and is then immersed in a solution composed of 70 ml of hexadecane, 15 ml of carbon tetrachloride, 200 µl of OTS. It is left for 5 minutes in this reaction bath at 18 • C, then rinsed with carbon tetrachloride. All the reagents are anhydrous grade (Sigma-Aldrich) and used as received. The reaction is conducted in a glovebag under dry nitrogen. Under such conditions, the thickness of the OTS layer, measured by ellipsometry, is 21±1 Å. Atomic force microscopy (Fig. 2b) reveals that the SAM is actually formed of islands of high areal density of OTS molecules (approximately 10-50 nm in size), separated by regions of much lower coverage density or even bare substrate (also tens of nm in size).

RESULTS

We present results obtained as follows: under a constant normal stress p = F N /A (p = 25 MPa for all the results reported hereafter), we measure, at a given temperature, the mean shear stress σ = F T /A as a function of velocity V in steady sliding. We have done so for six different temperatures ranging from -18 to 40 • C. The results are presented on Fig. 3.

We first see that the mean shear stress level increases as T decreases from 40 to -18 • C. In order to show how the velocity dependence of the shear stress is affected by temperature, the data of Fig. 3 have been split into two seperate sets on Fig. 4. Fig. 4a that, T = 40 • C, σ increases when V increases from 10 to 100 µm.s -1 , and displays a plateau below 10 µm.s -1 . Unstable sliding (i.e. stick-slip oscillations) is observed at V < 3 µm.s -1 . The presence of stick-slip at low V indicates that, below 3 µm.s -1 , the shear stress is a decreasing function of velocity, which is the source of the sliding instability. The plateau between 3 and 10 µm.s -1 therefore separates a velocity-weakening from a velocitystrengthening regime, and the shear stress is minimum in this region.

Such a minimum is clearly visible for T = 29 • C, at V c = 1 µm.s -1 . A steady velocity-weakening regime (V < V c ) is observed for velocities down to 0.3 µm.s -1 , below which stick-slip sets in.

Decreasing temperature below 29 • C shifts the minimum, as well as the stick-slip regime, to lower velocities. At T = 21 • C, V c = 0.3 µm.s -1 and stick-slip appears for V ≤ 0.05µm.s -1 . At T = 5 • C, σ(V ) only exhibits a plateau on its low velocity side (see Fig. 4b). Stickslip is observed at V = 0.03 µm.s -1 , which signals that V c lies between 0.03 and 0.1 µm.s -1 . Moreover, we note that at high velocities, σ increases as V α , with α ≃ 0.1. For T ≤ -4 • C sliding is steady over the whole range of accessible velocities, and only the V α regime is observed (see Fig. 4b). The exponent α does not display any clear sensitivity to temperature.

In order to better quantify the temperature dependence of the shear stress level, we have performed measurements of σ at a fixed sliding velocity V 0 = 10 µm.s -1 , and extended the temperature range up to 70 • C. Measurements at T > 70 • C were not possible due to bulk creep effects which prevented us from maintaining a constant normal stress during experiments. σ(V 0 , T ) is plotted on Fig. 5. We see that, in agreement with the above results, the shear stress displays a fourfold decrease when T varies from -20 to 50 • C. However, we observe that, at T = 50 • C, the trend is reversed, as σ starts to increase with increasing temperatures above 50 • C.

DISCUSSION

Glass transition measurements in supported ultrathin films of poly(methylmethacrylate) indicate that, at the interface with a low energy substrate, the chain mobility is enhanced with respect to that of the bulk [20]. This agrees with recent positron lifetime measurements which point to the existence of a 2 nm-thick surface layer of lower density [22]. In our experiments, the polymer lens is in contact with a chemically heterogeneous surface (see Fig. 2): the PMMA chains interact with methylterminated islands of OTS separated by coverage defects. In these defects, which exhibit a much lower silane density, silanol groups (Si-OH) are available to form hydrogen bonds with the carbonyls of the PMMA sidegroups. The coverage defects thus act as sites on which the poly- mer chains can get pinned via H-bonding. This recently led us to propose, in the spirit of Schallamach's model [3,7,14], that friction at such an interface is the result of two combined mechanisms [13,31]:

(i) Viscous dissipation in a thin polymer layer made of chain ends and loops, which yields a velocitystrengthening contribution to the shear stress.

(ii) Shear induced depinning of surface chains which are adsorbed on the defects. The dynamics of bond formation is governed by a characteristic pinning time τ . Upon sliding, the faster the chain is driven, the smaller the time available for bond formation. The number of bonds formed at the interface is thus a decreasing function of velocity, which leads to a velocity-weakening contribution to σ(V ). This mechanism is expected to contribute negligibly to frictional dissipation at sliding velocities above V c = D/τ , where D is an average capture radius (∼ 10 nm, the size of a coverage defect). The position of the minimum in the σ(V ) curve thus indicates the crossover between pinning-controlled and viscosity-controlled friction. Such a picture was found to be consistent with the following observations [31]: (i) decreasing the size of the pinning sites D shifts the crossover to lower velocities, (ii) increasing the contact pressure p, which reduces the molecular mobility and increases τ , also lowers V c , and (iii) the observed power-law dependence of σ on V , above V c , is consistent with the shearthinning response of strongly confined polymer melts, whose effective viscosity grows with increasing pressure [34,35]. This supports the existence of a liquidlike surface layer, as suggested by recent experiments [23].

The results of the present study give further support to this interpretation.

Fig. 4a shows that the position of the minimum in the σ(V ) curves depends on temperature: when T increases, V c shifts to higher velocities. This is in agreement with the expected decrease of the pinning time τ when increasing temperature. The presence of a minimum in the σ(V 0 , T ) curve of Fig. 5 can be understood as follows. The position of the minimum in σ(V ) gradually shifts from below to above the chosen velocity of 10 µm.s -1 as temperature increases from below to above 50 • C. At T > 50 • C, V 0 enters the pinning-controlled velocity-weakening regime, which leads to the observed stress increase at high temperature.

For sliding velocities above V c , the shear stress increases with velocity as a weak power-law (see Fig. 3c), as already observed in previous experiments. In this regime, the effect of decreasing the temperature is to shift the σ(V ) curves to higher shear stress. This is in qualitative agreement with the fact that, above V c , friction results from viscous dissipation in a non-newtonian thin poly-mer layer confined at the interface, the effective viscosity of which increases when temperature decreases. A more quantitative analysis, in order to estimate the effective viscosity of this nanometer-thick layer, would require the precise knowledge of the slip boundary condition at the wall, i.e. the slip-length [37], a quantity that cannot be accessed in our experiments.

The existence of a velocity-weakening regime, and of stick-slip oscillations, for V ≤ V c is the signature of the interfacial pinning/depinning process. If we use V c to define a pinning time τ = D/V c , taking D ≃ 10 nm, we find: τ in the range 10 -3 -3.10 -3 s for T = 40 • C, τ ≃ 10 -2 s for T = 29 • C, 3.10 -2 s for T = 21 • C, and τ in the range 10 -1 -3.10 -1 s at T = 5 • C. Figure 6 shows that this pinning time follows an Arrhenius temperature dependence, from which we extract an activation energy E a ≃20 kcal.mol -1 . Such an activation energy coincides with that of the β relaxation process in PMMA, which corresponds to the hindered rotation of the -COOCH 3 side groups [26,38,39]. Furthermore, the values of the pinning time are themselves found to be in good agreement with τ β (see Fig. 6). This leads us to conclude that pinning of polymer segments on the substrate is governed by β rotational motions along the backbone of surface chains. A pinning dynamics controlled by β motions is indeed consistent with the fact that -C=O groups have to be favorably oriented with respect to silanols in order to form H-bonds. Besides, we note that σ(V ) exhibits a minimum when D/V ∼ τ β , from which we conclude that the bulk β-relaxation, which would give rise to a peak [26], has a negligible contribution to frictional dissipation.

CONCLUSIONS

We have shown that macroscopic friction can be a very sensitive probe of the dynamics at the surface of a glassy polymer. This requires a contact configuration that allows to avoid bulk mechanical losses during sliding. This is achieved, in our experiments, by using a smooth macroscopic lens of polymer which deforms elastically when it is brought in contact under low pressure with a rigid substrate. This contrasts with previous studies of glassy polymers using friction force microscopy, where indentation of the surface by the scanning tip can be such that friction is entirely attributable to bulk dissipation [26]. Our results are consistent with the presence of a nanometer-thick layer at the polymer surface, which, in the case of weak interaction with the countersurface, exhibits a frictional "rubberlike" behavior. Frictional dissipation can be ascribed to the combination of (i) viscouslike flow of the layer, and (ii) shear induced depinning of polymer chains which can adsorb on defects of the substrate. A quantitative analysis of our data leads us to conclude that the pinning dynamics is governed by β rotational motions at the interface.

The author wish to thank Arnaud Arvengas for his contribution to the experiments during his stay at INSP, and T. Baumberger and C. Caroli for fruitful comments and discussions.

FIG. 2 :

 2 FIG. 2: AFM topographic images (tapping mode) of (a) the surface of a PMMA lens, and (b) the OTS layer grafted on a silicon wafer. Height scale is 28 Å from black (low) to white (high).

FIG. 3 :

 3 FIG. 3: Shear stress as a function of velocity, for p = 25 MPa. ( ) T = 40 • C; (•) T = 29 • C; (•) T = 21 • C; ( ) T = 5.5 • C; ( ) T = -4 • C; ( ) T = -18 • C. Velocity is plotted on a log scale.

FIG. 4 :

 4 FIG. 4: Shear stress as a function of velocity, for p = 25 MPa. (a) ( ) T = 40 • C; (•) T = 29 • C; (•) T = 21 • C. Velocity is plotted on a log scale. Error bars correspond to the amplitude of stress fluctuations observed when sliding at constant V , due to large scale (millimeter) chemical heterogeneities of the substrate. (b) ( ) T = 5.5 • C; ( ) T = -4 • C; ( ) T = -18 • C . σ and V plotted on log scales. Solid lines are power law fits.

FIG. 5 :

 5 FIG. 5: Shear stress as a function of temperature at p = 25 MPa and V = 10 µm.s -1 . Error bars are of the size of the symbols.

FIG. 6 :

 6 FIG. 6: Natural logarithm of the pinning time as a function of the inverse of the temperature (•). The (•) symbol corresponds to a value of τ β taken from reference [38]. Error bars on (•) symbols correspond to the uncertainty on Vc at 5 and 40 • C. The line is an arrhenius fit to our the data.