Scientific Commentaries
Brain 2014: 137; 2872–2878
| 2877
Neurovascular regulation is critical for metabolic recovery from spreading depression This scientific commentary refers to ‘Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma’ by Hinzman et al. (doi:10.1093/awu241).
Downloaded from by guest on December 10, 2014
Long after Lea˜o’s 1944 description of spreading depression in rabbit neocortex, scepticism remained over whether this phenomenon could be evoked or observed in the human brain (Somjen, 2001). Although many investigations have been carried out into the initiation, occurrence and spread of spreading depression, the mechanisms of ionic current flow underlying depolarization, and treatment paradigms (Pietrobon and Moskowitz, 2014), it is only recently that recording and imaging techniques have been able to confirm the occurrence of spreading depression in damaged human cortex, particularly in conditions involving trauma, subarachnoid haemorrhage, stroke, and possibly migraine headache with aura (Lauritzen et al., 2011; Eikermann-Haerter et al., 2012; Woitzik et al., 2013). The intense depolarization and loss of ionic gradients in large volumes of brain tissue experiencing spreading depression means that significant substrate and metabolic capacity is required to generate energy for cell recovery (Somjen, 2001). If this metabolic need is unmatched by substrate supply (through neurovascular induction of increased blood flow), then propagation of brain damage can occur (Hossmann, 1994). In this issue of Brain, Hinzman and colleagues report a critical deficit in neurovascular coupling when spreading depression occurs near a traumatic brain lesion, in which decreased blood flow occurs in response to spreading depression (i.e. inverse neurovascular coupling) instead of increased blood flow, limiting the brain’s ability to meet the intense metabolic demand (Hinzman et al., 2014). Although Hinzman and colleagues’ combined blood flow and electrocorticographic (ECoG) recording techniques only effectively worked in 5 of 24 patients, the spectrum of enhanced versus inverted neurovascular coupling in these five patients provides us with excellent examples of how proximity to a developing brain lesion (a cerebral contusion as revealed by CT scan) can affect the response to spreading depression. As in stroke (Woitzik et al., 2013) and subarachnoid haemorrhage (Lauritzen et al., 2011), blood vessel responses to metabolic activation also seem to be abnormal in traumatic brain injury, possibly as a result of blood scavenging of the critical vasodilation intermediate, nitric oxide, or blunting of the neurovascular response to the energetic deficit. In stroke, lack of collateral blood flow in the penumbra and partial depolarization of the region surrounding the ischaemic core, leading to initiation of spreading depression events, also contribute to progressive enlargement of the infarcted region (Hossmann, 1994). Thus, there are several potential reasons for secondary extension of an initial area of brain damage, through inverse neurovascular coupling as described here, or through low blood flow and collateral circulation as in the case of vascular occlusion (Pietrobon and Moskowitz, 2014). Further, Hinzman et al. confirm the importance of assessing cerebral autoregulation (i.e.
independence of blood flow from blood pressure within the autoregulated range), which is absent near injury loci in cortex (Hinzman et al., 2014). Spreading depression can be evoked in normal brain by K+ injection, but typically the brain recovers rapidly if sufficient metabolic reserve can be marshalled (Pietrobon and Moskovitz, 2014). Though multiple initiators of evoked spreading depression have been described, including focal trauma or cortical puncture, direct K+ injection and anoxia, spontaneous episodes of spreading depression occur primarily in areas of brain damage, such as after cortical contusions or stroke, e.g. middle cerebral artery occlusion (Hossmann, 1994). However, many areas of the brain are resistant to evoked episodes of spreading depression, particularly the CA3 region of the hippocampus; this resistance appears to be due to the presence of a more robust Na+-K+ ATPase pump for Na+ ion extrusion than in the neighbouring region, CA1 (Somjen, 2001). The basis of spreading depression has been described as a significant increase in extracellular K+ (to 415 mM) and associated with membrane potential collapse and large inward currents, with a complete, transient loss of ionic gradients (Somjen, 2001), which propagates slowly across the brain surface (typically at rates of 3–6 mm/min). Interestingly, the rates of propagation across the brain surface are consistent in the much larger human brain, as compared to rodent brain (Somjen, 2001; Woitzik et al., 2013). As there are large metabolic requirements to regain the membrane potential following this severe depolarization (to near 0 mV) in virtually every cell in a region, the fate of the cortical region (archicortex or neocortex) depends on adequacy of substrate supply (i.e. glucose, oxygen). Hossmann, for example, described progressive expansion of the stroke penumbra if the collateral circulation around an infarct could not provide sufficient supply to maintain gradients following travelling waves of spreading depression from an ischaemic core (Hossmann, 1994). Typically, to maintain substrate supply, appropriate neurovascular coupling should provide significantly enhanced blood flow (Lauritzen et al., 2011). However, in some species and situations this appropriate neurovascular increase in haemodynamic supply is thwarted by local factors or insufficient vascular supply (i.e. local damage, upstream vessel occlusion) and the metabolic need is unmatched by the supply, leading to propagation of damage (Piilgard et al., 2011). Techniques that have been explored for ascertaining the occurrence of spreading depression include the surgical placement of cortical strips for ECoG measurement and, more recently, direct estimates of blood flow, as described in Hinzman et al. (2014). However, these techniques require a craniotomy and it is often difficult to place the cortical strips adjacent to a cortical contusion; moreover, as indicated by Hinzman et al., the thermal diffusion blood flow probes are prone to malfunction and sensitive to position near blood vessels. Additionally, many patients with severe traumatic brain injury demonstrate primarily diffuse axonal injury or shear rather than cortical contusions, and the importance of
2878
| Brain 2014: 137; 2872–2878
including malignant stroke (Woitzik et al., 2013), subarachnoid haemorrhage (Lauritzen et al., 2011), and severe traumatic brain injury (Hinzman et al., 2014). An increased understanding of spreading depression occurrence, together with improved measurement and treatment capabilities, may herald a significant advance for these difficult to treat conditions at the early neurocritical care level, augmenting traditional neurosurgical methods of intracranial pressure recordings, maintenance of cerebral perfusion and appropriate metabolic conditions, and judicious removal of mass lesions, as well as hemicraniectomy. Hinzman et al. have contributed significantly to our understanding of this path forward. Dennis A. Turner Professor, Neurosurgery and Neurobiology, Duke University Medical Centre, Durham NC 27710, USA E-mail: [email protected] doi:10.1093/brain/awu263
References Eikermann-Haerter K, Can A, Ayata C. Pharmacological targeting of spreading depression in migraine. Expert Rev Neurother 2012; 12: 297–306. Hinzman JM, Andaluz N, Shutter LA, Okonkwo DO, Pahl C, Strong AJ, et al. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain 2014; 137: 2960–72. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994; 36: 557–65. Jeffcote T, Hinzman JM, Jewell SL, Learney RM, Pahl C, Tolias C, et al. Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain. Neurocritical Care 2014; 20: 21–31. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graft R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid hemorrhage, and traumatic brain injury. J Cerebral Bllod Flow Metab 2011; 31: 17–35. Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Neurosci 2014; 15: 379–93. Piilgard H, Witgen BM, Rasmussen P, Lauritzen M. Cyclosporine A, FK506 and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression. J Cerebral Blood Flow Metab 2011; 31: 1588–98. Somjen GG. Mechanisms of spreading depression and hypoxic spreading-depression-like depolarization. Physiol Rev 2001; 81: 1065–96. Takagaki M, Feuerstein D, Kumagai T, Gramer M, Yoshimine T, Graf R. Isofluorane suppresses cortical spreading depolarizations compared to propofol – implications for sedation of neurocritical care patients. Exp Neurol 2014; 252: 12–17. Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK, et al. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 2013; 80: 1095–102.
Downloaded from by guest on December 10, 2014
spreading depression to deeper, white matter injury remains unclear. However, Jeffcote et al. (2014) have also measured spreading depression with depth electrodes that can be placed percutaneously (similar to Licox oxygen electrodes or pressure monitoring devices). This might prove to be a significant advance as placement can be more accurate and possibly combined with standard intracranial pressure recording and oxygen measurement techniques (Jeffcote et al., 2014). Thus, now that preliminary studies in a number of conditions have confirmed the likely presence of spreading depression in humans near areas of cortical injury, the next step will be the use of more accurate recording techniques that may not necessarily require the initial craniotomy, both for ECoG as well as blood flow measurements (Lauritzen et al., 2011; Woitzik et al., 2013). These techniques may then be applicable to a much wider range of patients with closed head injury, stroke and subarachnoid haemorrhage. The next issue to consider regarding the presence of spreading depression and inappropriate neurovascular coupling, beyond its prognostic influence for progressive cerebral dysfunction and extension of cortical damage, will be potential treatment methods, particularly those applicable to the critical care setting. Maintenance of metabolism is essential to allow full recovery from episodes of spreading depression, including sufficient substrate (oxygen and glucose), blood pressure and cerebral perfusion; likewise, spreading depression occurrence and propagation can be reduced by lowered temperatures, which possibly explains some of the hypothermia benefit in head injury (Lauritzen et al., 2011). In animal models suppression of all inward currents and removal of calcium can block spreading depression spread, but such drastic solutions may not be applicable to humans (Somjen, 2001). However, ketamine acts as a partial NMDA antagonist, and may facilitate suppression of spreading depression (Pietrobon and Moskowitz, 2014). Further, Takagaki et al. (2014) report that isoflurane anaesthesia leads to improved suppression of episodes of spreading depression compared to propofol; the possibility that isoflurane could help to halt progression of damage could be tested in a critical care setting. Piilgard et al. (2011) have suggested additional treatment possibilities, including cyclosporin to block mitochondrial permeability transition (to maintain metabolic function) and to enhance neurovascular coupling. Further, a number of treatments aimed at migraine episodes may also act to suppress episodes of spreading depression (Eikermann-Haerter et al., 2012). From a surgical perspective, removing damaged cortical areas in traumatic brain injury outside of eloquent regions may also reduce episodes of spreading depression and brain swelling, preventing further secondary injury (Lauritzen et al., 2011). Once a more reliable combination of measurement techniques is available, potential treatment approaches can be more rigorously tested. The conditions that render the brain susceptible to spreading depression have also proven to be the most difficult to treat,
Scientific Commentaries
Brain 2014: 137; 2872–2878
| 2877
Neurovascular regulation is critical for metabolic recovery from spreading depression This scientific commentary refers to ‘Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma’ by Hinzman et al. (doi:10.1093/awu241).
Downloaded from by guest on December 10, 2014
Long after Lea˜o’s 1944 description of spreading depression in rabbit neocortex, scepticism remained over whether this phenomenon could be evoked or observed in the human brain (Somjen, 2001). Although many investigations have been carried out into the initiation, occurrence and spread of spreading depression, the mechanisms of ionic current flow underlying depolarization, and treatment paradigms (Pietrobon and Moskowitz, 2014), it is only recently that recording and imaging techniques have been able to confirm the occurrence of spreading depression in damaged human cortex, particularly in conditions involving trauma, subarachnoid haemorrhage, stroke, and possibly migraine headache with aura (Lauritzen et al., 2011; Eikermann-Haerter et al., 2012; Woitzik et al., 2013). The intense depolarization and loss of ionic gradients in large volumes of brain tissue experiencing spreading depression means that significant substrate and metabolic capacity is required to generate energy for cell recovery (Somjen, 2001). If this metabolic need is unmatched by substrate supply (through neurovascular induction of increased blood flow), then propagation of brain damage can occur (Hossmann, 1994). In this issue of Brain, Hinzman and colleagues report a critical deficit in neurovascular coupling when spreading depression occurs near a traumatic brain lesion, in which decreased blood flow occurs in response to spreading depression (i.e. inverse neurovascular coupling) instead of increased blood flow, limiting the brain’s ability to meet the intense metabolic demand (Hinzman et al., 2014). Although Hinzman and colleagues’ combined blood flow and electrocorticographic (ECoG) recording techniques only effectively worked in 5 of 24 patients, the spectrum of enhanced versus inverted neurovascular coupling in these five patients provides us with excellent examples of how proximity to a developing brain lesion (a cerebral contusion as revealed by CT scan) can affect the response to spreading depression. As in stroke (Woitzik et al., 2013) and subarachnoid haemorrhage (Lauritzen et al., 2011), blood vessel responses to metabolic activation also seem to be abnormal in traumatic brain injury, possibly as a result of blood scavenging of the critical vasodilation intermediate, nitric oxide, or blunting of the neurovascular response to the energetic deficit. In stroke, lack of collateral blood flow in the penumbra and partial depolarization of the region surrounding the ischaemic core, leading to initiation of spreading depression events, also contribute to progressive enlargement of the infarcted region (Hossmann, 1994). Thus, there are several potential reasons for secondary extension of an initial area of brain damage, through inverse neurovascular coupling as described here, or through low blood flow and collateral circulation as in the case of vascular occlusion (Pietrobon and Moskowitz, 2014). Further, Hinzman et al. confirm the importance of assessing cerebral autoregulation (i.e.
independence of blood flow from blood pressure within the autoregulated range), which is absent near injury loci in cortex (Hinzman et al., 2014). Spreading depression can be evoked in normal brain by K+ injection, but typically the brain recovers rapidly if sufficient metabolic reserve can be marshalled (Pietrobon and Moskovitz, 2014). Though multiple initiators of evoked spreading depression have been described, including focal trauma or cortical puncture, direct K+ injection and anoxia, spontaneous episodes of spreading depression occur primarily in areas of brain damage, such as after cortical contusions or stroke, e.g. middle cerebral artery occlusion (Hossmann, 1994). However, many areas of the brain are resistant to evoked episodes of spreading depression, particularly the CA3 region of the hippocampus; this resistance appears to be due to the presence of a more robust Na+-K+ ATPase pump for Na+ ion extrusion than in the neighbouring region, CA1 (Somjen, 2001). The basis of spreading depression has been described as a significant increase in extracellular K+ (to 415 mM) and associated with membrane potential collapse and large inward currents, with a complete, transient loss of ionic gradients (Somjen, 2001), which propagates slowly across the brain surface (typically at rates of 3–6 mm/min). Interestingly, the rates of propagation across the brain surface are consistent in the much larger human brain, as compared to rodent brain (Somjen, 2001; Woitzik et al., 2013). As there are large metabolic requirements to regain the membrane potential following this severe depolarization (to near 0 mV) in virtually every cell in a region, the fate of the cortical region (archicortex or neocortex) depends on adequacy of substrate supply (i.e. glucose, oxygen). Hossmann, for example, described progressive expansion of the stroke penumbra if the collateral circulation around an infarct could not provide sufficient supply to maintain gradients following travelling waves of spreading depression from an ischaemic core (Hossmann, 1994). Typically, to maintain substrate supply, appropriate neurovascular coupling should provide significantly enhanced blood flow (Lauritzen et al., 2011). However, in some species and situations this appropriate neurovascular increase in haemodynamic supply is thwarted by local factors or insufficient vascular supply (i.e. local damage, upstream vessel occlusion) and the metabolic need is unmatched by the supply, leading to propagation of damage (Piilgard et al., 2011). Techniques that have been explored for ascertaining the occurrence of spreading depression include the surgical placement of cortical strips for ECoG measurement and, more recently, direct estimates of blood flow, as described in Hinzman et al. (2014). However, these techniques require a craniotomy and it is often difficult to place the cortical strips adjacent to a cortical contusion; moreover, as indicated by Hinzman et al., the thermal diffusion blood flow probes are prone to malfunction and sensitive to position near blood vessels. Additionally, many patients with severe traumatic brain injury demonstrate primarily diffuse axonal injury or shear rather than cortical contusions, and the importance of
2878
| Brain 2014: 137; 2872–2878
including malignant stroke (Woitzik et al., 2013), subarachnoid haemorrhage (Lauritzen et al., 2011), and severe traumatic brain injury (Hinzman et al., 2014). An increased understanding of spreading depression occurrence, together with improved measurement and treatment capabilities, may herald a significant advance for these difficult to treat conditions at the early neurocritical care level, augmenting traditional neurosurgical methods of intracranial pressure recordings, maintenance of cerebral perfusion and appropriate metabolic conditions, and judicious removal of mass lesions, as well as hemicraniectomy. Hinzman et al. have contributed significantly to our understanding of this path forward. Dennis A. Turner Professor, Neurosurgery and Neurobiology, Duke University Medical Centre, Durham NC 27710, USA E-mail: [email protected] doi:10.1093/brain/awu263
References Eikermann-Haerter K, Can A, Ayata C. Pharmacological targeting of spreading depression in migraine. Expert Rev Neurother 2012; 12: 297–306. Hinzman JM, Andaluz N, Shutter LA, Okonkwo DO, Pahl C, Strong AJ, et al. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain 2014; 137: 2960–72. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994; 36: 557–65. Jeffcote T, Hinzman JM, Jewell SL, Learney RM, Pahl C, Tolias C, et al. Detection of spreading depolarization with intraparenchymal electrodes in the injured human brain. Neurocritical Care 2014; 20: 21–31. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graft R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid hemorrhage, and traumatic brain injury. J Cerebral Bllod Flow Metab 2011; 31: 17–35. Pietrobon D, Moskowitz MA. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat Neurosci 2014; 15: 379–93. Piilgard H, Witgen BM, Rasmussen P, Lauritzen M. Cyclosporine A, FK506 and NIM811 ameliorate prolonged CBF reduction and impaired neurovascular coupling after cortical spreading depression. J Cerebral Blood Flow Metab 2011; 31: 1588–98. Somjen GG. Mechanisms of spreading depression and hypoxic spreading-depression-like depolarization. Physiol Rev 2001; 81: 1065–96. Takagaki M, Feuerstein D, Kumagai T, Gramer M, Yoshimine T, Graf R. Isofluorane suppresses cortical spreading depolarizations compared to propofol – implications for sedation of neurocritical care patients. Exp Neurol 2014; 252: 12–17. Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK, et al. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology 2013; 80: 1095–102.
Downloaded from by guest on December 10, 2014
spreading depression to deeper, white matter injury remains unclear. However, Jeffcote et al. (2014) have also measured spreading depression with depth electrodes that can be placed percutaneously (similar to Licox oxygen electrodes or pressure monitoring devices). This might prove to be a significant advance as placement can be more accurate and possibly combined with standard intracranial pressure recording and oxygen measurement techniques (Jeffcote et al., 2014). Thus, now that preliminary studies in a number of conditions have confirmed the likely presence of spreading depression in humans near areas of cortical injury, the next step will be the use of more accurate recording techniques that may not necessarily require the initial craniotomy, both for ECoG as well as blood flow measurements (Lauritzen et al., 2011; Woitzik et al., 2013). These techniques may then be applicable to a much wider range of patients with closed head injury, stroke and subarachnoid haemorrhage. The next issue to consider regarding the presence of spreading depression and inappropriate neurovascular coupling, beyond its prognostic influence for progressive cerebral dysfunction and extension of cortical damage, will be potential treatment methods, particularly those applicable to the critical care setting. Maintenance of metabolism is essential to allow full recovery from episodes of spreading depression, including sufficient substrate (oxygen and glucose), blood pressure and cerebral perfusion; likewise, spreading depression occurrence and propagation can be reduced by lowered temperatures, which possibly explains some of the hypothermia benefit in head injury (Lauritzen et al., 2011). In animal models suppression of all inward currents and removal of calcium can block spreading depression spread, but such drastic solutions may not be applicable to humans (Somjen, 2001). However, ketamine acts as a partial NMDA antagonist, and may facilitate suppression of spreading depression (Pietrobon and Moskowitz, 2014). Further, Takagaki et al. (2014) report that isoflurane anaesthesia leads to improved suppression of episodes of spreading depression compared to propofol; the possibility that isoflurane could help to halt progression of damage could be tested in a critical care setting. Piilgard et al. (2011) have suggested additional treatment possibilities, including cyclosporin to block mitochondrial permeability transition (to maintain metabolic function) and to enhance neurovascular coupling. Further, a number of treatments aimed at migraine episodes may also act to suppress episodes of spreading depression (Eikermann-Haerter et al., 2012). From a surgical perspective, removing damaged cortical areas in traumatic brain injury outside of eloquent regions may also reduce episodes of spreading depression and brain swelling, preventing further secondary injury (Lauritzen et al., 2011). Once a more reliable combination of measurement techniques is available, potential treatment approaches can be more rigorously tested. The conditions that render the brain susceptible to spreading depression have also proven to be the most difficult to treat,
Scientific Commentaries
