The stroke-migraine depolarization continuum.
Dreier JP, Reiffurth C.
Neuron. 2015 May 20;86(4):902-22. doi: 10.1016/j.neuron.2015.04.004. Review.
Spreading convulsions, spreading depolarization and epileptogenesis in human cerebral cortex.
Dreier JP, Major S, Pannek HW, Woitzik J, Scheel M, Wiesenthal D, Martus P, Winkler MK, Hartings JA, Fabricius M, Speckmann EJ, Gorji A; COSBID study group.
Brain. 2012 Jan;135(Pt 1):259-75. doi: 10.1093/brain/awr303.
The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.
Nat Med. 2011 Apr;17(4):439-47. doi: 10.1038/nm.2333. Review.
Research Group Dreier
Professor Jens P. Dreier, M.D.
Charité, Center for Stroke Research Berlin
Translation in Stroke Research
Dr. Dreier is a professor at the CSB and a consultant at the Department of Neurology at the Charité. His scientific focus has for many years been on clinical and neurophysiological aspects of neurovascular coupling, spreading depolarization, regional cerebral blood flow, ischemic stroke, aSAH, epilepsy and migraine.
List of Publications / Charité Research Data Base
The stroke-migraine depolarization continuum.
More than 50 % of the overall stroke mortality is caused by cerebral haemorrhages. The so-called aneurysmal subarachnoid haemorrhage (aSAH) represents about 30 % of these. Typically, patients are young (average age ~50 years). Aneurysmal SAH is often followed by a delayed ischemic stroke and today we know that delayed ischemia is responsible for about 6 to 7 % of all severe disabilities and deaths among aSAH patients. The therapeutic options to prevent delayed ischemic stroke are few (hyperdynamic therapy), and associated with life-threatening complications such as heart failure and pulmonary edema. I therefore think that it is mandatory to assign only those patients to therapy who develop delayed ischemia. This treatment stratification must occur at the earliest possible time point before delayed brain damage becomes irreversible. I would like to provide new instruments to diagnose delayed ischemic stroke in a very early time window and thus evaluate new therapeutic options
Most Important Project
DISCHARGE-1 is a prospective, clinical, multicenter, ISRCTN-registered, diagnostic trial (Berlin [PIs: Dreier, Vajkoczy], Heidelberg, Frankfurt, Cologne, Beer-Sheva) of the COSBID study group.
More information/project description
Spreading depolarization is associated with a dilatation of cerebral resistance vessels/ increase of cerebral blood flow in healthy tissue. More than a decade ago, we discovered in rats that this normal neurovascular coupling can be inverted under conditions present following aSAH. Thus, the neuronal discharge triggered severe vasoconstriction/ spreading ischemia in the rat. In 2009 we published unequivocal evidence for spreading ischemia in the human brain using novel technology to measure electrical activity and regional cerebral blood flow in aSAH patients for the first time. We will further characterize this phenomenon using measurements of tissue partial pressure of oxygen and direct current (DC) potential recordings in a larger patient population.
Long and short Tsunamis
In the center of a focal ischemia, very prolonged SDs are measured that seem to mediate the brain damage. They become progressively shorter while they propagate against the gradients of oxygen, glucose and perfusion to the increasingly healthy periphery around the focal ischemia. In 2010, we were able to demonstrate these electrophysiological characteristics in the human brain for the first time using novel technology for DC recordings. These electrophysiological characteristics were directly compared with a rodent model of focal ischemia.
'Normal' and 'inverse' neurovascular coupling to CSD
The term 'cortical spreading depolarization' (CSD) describes the loss of function in the brain's gray matter that is triggered when passive cation influx across the cellular membranes exceeds ATP-dependent Na+ and Ca2+ pump activity. Depolarization of neurons and astrocytes results, followed by cellular swelling and cessation of neuronal function. This mass tissue depolarization propagates through gray matter as a wave, or 'brain tsunami', at ~3 mm/min, and is measured as a slow negative shift, 10-20 mV in amplitude, of the extracellular direct current (DC) potential - the largest extracellular signal generated by the brain. CSD is a passive process, driven by electrical and diffusion forces. Subsequent repolarization, however, increases energy consumption because additional Na+ and Ca2+ pumps are recruited to correct their harmful intracellular surge. Thus, even in healthy tissue where full repolarization of cellular membranes is achieved within 1-2 min, ATP falls ~50%. To increase oxygen and glucose availability, CSD induces dilation of resistance vessels in healthy tissue. Hence, regional cerebral blood flow (rCBF) increases in response to CSD resulting in cortical spreading hyperemia (CSH), a process which is termed 'normal' neurovascular coupling. The opposite of the 'normal' neurovascular response, termed 'inverse' neurovascular coupling, occurs when there is local dysfunction of the microvasculature. With 'inverse' coupling, severe microvascular spasm instead of vasodilation is coupled to CSD, resulting in CSI. The perfusion deficit of CSI in turn prolongs the neuronal depolarization since the oxygen-/glucose deprivation further reduces ATP availability (Dreier et al., 1998; Dreier et al., 2000; Windmüller et al., 2005). This is reflected by a prolongation of both the negative DC potential shift and the silencing of neuronal activity. Pharmacologically induced CSI was sufficient to produce widespread focal necrosis in absence of a preceding significant perfusion deficit in rats.2 This suggested that 'inverse' neurovascular coupling is (i) a sufficient condition for CSD to induce cell death, and, thus (ii) a promising target for therapeutic intervention.
Lesion progression in acute brain injury
The concept of lesion progression originates with the discovery of the ischemic penumbra, the region bordering a core cerebral infarct with rCBF reductions sufficient to depress synaptic activity, but adequate to initially maintain membrane polarization. The penumbra is progressively recruited into the core infarction over time, as shown in clinical imaging studies, and is therefore the target for tissue salvage through early restoration of blood flow or neuroprotective drugs. Without intervention, terminal depolarization in the core gives rise to spontaneous depolarization waves (CSD) that propagate through the penumbra and beyond, causing progressive step-wise expansion of the ischemic core. This effect of CSD is proven to be causal. Accordingly, pharmacological treatments which inhibit CSD also reduce infarct volumes. Unfortunately, however, CSDs become increasingly pharmacoresistant with energy depletion. Recently it has been found that CSDs in the ischemic penumbra of both cats and mice are associated with CSI. This result, together with the finding that CSI alone is sufficient to cause cortical pannecrosis, suggests that the vascular response manifested in CSI, rather than the electrochemical phenomenon of CSD itself, is the critical mechanism of lesion progression. Lesion progression is also a well-defined clinical entity in aneurysmal subarachnoid hemorrhage (aSAH). Delayed ischemic neurologic deficits (DIND) occur in 33-38% of patients with a peak occurrence around day 7, and 10-13% develop delayed computed tomography (CT)-proven infarcts. The assumed mechanism of DIND is proximal vasospasm resulting from subarachnoid breakdown products of erythrocytes, although the positive predictive value of digital subtraction angiography for the development of DIND is only between 30-50%. A complementary explanation for DIND is the occurrence of CSD, which in the presence of erythrocyte breakdown products, exhibits 'inverse' neurovascular coupling with microarterial spasm arresting microcirculation for minutes to hours (Dreier et al., 1998, 2000, 2006, 2009; Windmüller et al., 2005). Importantly, aSAH is a model disease for the study of lesion progression, since patients can be monitored prior to and throughout the whole period of delayed infarct development.
Design and conduction of diagnostic and interventional mono-/and multicentric trials in patients with aSAH, stroke or migraine. Invasive and non-invasive analysis of clinical ECoG, rCB.
Cranial window models using imaging and microelectrodes Human and animal brain slice models Histology, immunohistochemistr.
Cooperations and Research Partners
- COSBID study group (www.cosbid.org)
- Prof. Gabriel Curio, Charité Berlin, Germany
- Dr. Markus Dahlem, TU Berlin, Germany
- Prof. Ulrich Dirnagl, Charité Berlin, Germany
- Prof. Wolfram Döhner, Charité Berlin, Germany
- Prof. Matthias Endres, Charité Berlin, Germany
- Prof. Alon Friedman, Beer-Sheva, Israel
- Dr. Georg Bohner, Charité Berlin, Germany
- Prof. Uwe Heinemann, Charité Berlin, Germany
- Prof. Peter Heuschmann, Charité Berlin, Germany
- Prof. Eric Jüttler, Charité Berlin, Germany
- PD Dr. Randolf Klingebiel, Charité Berlin, Germany
- Prof. Golo Kronenberg, Charité Berlin, Germany
- Prof. Ute Lindauer, Munich, Germany
- Prof. Andreas Meisel, Charité Berlin, Germany
- Prof. Christian Meisel, Charité Berlin, Germany
- Dr. Christoph Melzer-Gartzke, Charité Berlin, Germany
- PD Dr. Gabor Petzold, Charité Berlin, Germany
- Dr. Ryszard Pluta, NINDS, Washington, USA
- Prof. Josef Priller, Charité Berlin, Germany
- Dr. Harald Prüss, Charité Berlin, Germany
- PD Dr. Asita Sarrafzadeh, Genf, Switzerland
- Prof. Eckehard Schöll, TU Berlin, Germany
- Dr. Ilan Shelef, Beer-Sheva, Israel
- Prof. Jan Sobesky, Charité Berlin, Germany
- Prof. Peter Vajkoczy, Charité Berlin, Germany
- Prof. Johannes Woitzik, Charité Berlin, Germany