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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 depolarisation, regional cerebral blood flow, ischaemic stroke, aSAH, epilepsy and migraine.
The role of spreading depolarizations and electrographic seizures in early injury progression of the rat photothrombosis stroke model.
Schoknecht K, Kikhia M, Lemale CL, Liotta A, Lublinsky S, Mueller S, Boehm-Sturm P, Friedman A, Dreier JP.
J Cereb Blood Flow Metab. 2021 Feb;41(2):413-430. doi: 10.1177/0271678X20915801.
The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex.
Lückl J, Lemale CL, Kola V, Horst V, Khojasteh U, Oliveira-Ferreira AI, Major S, Winkler MKL, Kang EJ, Schoknecht K, Martus P, Hartings JA, Woitzik J, Dreier JP.
Brain. 2018 Apr 16. doi: 10.1093/brain/awy102. [Epub ahead of print]
Terminal spreading depolarization and electrical silence in death of human cerebral cortex.
Dreier JP, Major S, Foreman B, Winkler MKL, Kang EJ, Milakara D, Lemale CL, DiNapoli V, Hinzman JM, Woitzik J, Andaluz N, Carlson A, Hartings JA.
Ann Neurol. 2018 Feb;83(2):295-310. doi: 10.1002/ana.25147. Epub 2018 Feb 15.
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.
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.
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 ~55 years). Aneurysmal SAH is often followed by a delayed ischaemic stroke which typically occurs around day seven after the initial haemorrhage. Our recent clinical data demonstrate that initial intracerebral haemorrhage accounts for 24.0 %, early cerebral ischaemic stroke accounts for 33.4 %, and delayed ischaemic stroke accounts for 42.6 % of cumulative brain parenchymal damage after severe aSAH. Brain parenchymal damage is the strongest known predictor of poor patient outcome seven months after aSAH. In other words, delayed ischaemic strokes are causative for a large proportion of severe disability and death after aSAH. Overall, mortality in our cohort of severe aSAHs was 25.9% at seven months. There are only few and almost without exception controversial therapeutic options to prevent delayed ischaemic stroke. The only stronger clinical evidence is for the prophylactic administration of the L-type calcium antagonist nimodipine, which has been performed in most centres since the early 1990s and, according to the literature, can prevent one of three poor clinical outcomes attributable to delayed ischaemic stroke. In addition, delayed ischaemic neurologic deficits in awake patients can sometimes be successfully treated with rescue treatments such as hyperdynamic therapy. However, hyperdynamic therapy not infrequently leads to life-threatening complications such as heart failure and pulmonary oedema. Rescue therapies are more or less unsuitable for comatose patients, as intensive care physicians have practically no chance of knowing at what point the patient develops a delayed ischaemic stroke. According to our data, however, it is especially the comatose patients who suffer delayed ischaemic strokes. Due to the side effects of rescue therapies, I believe it is essential to subject only those patients who actually develop delayed ischaemia to these therapies. Therefore, treatment stratification, which is also suitable for comatose patients, is needed and should be done at the earliest possible stage before the delayed brain injury becomes irreversible. The aim of our work is to provide a new diagnostic toolkit for delayed ischaemic stroke in a very early time window and to test new therapeutic options.
Most important projects
DISCHARGE-I – Depolarizations in ISCHaemia after subARachnoid haemorrhaGE
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.
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.
More information/project description
Spreading Ischemia and the Negative Ultraslow Potential
Spreading depolarisation (SD) 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 aneurysmal subarachnoid haemorrhage (aSAH). Thus, the neuronal discharge triggered severe vasoconstriction/ spreading ischaemia in the rat. In 2009 we published unequivocal evidence for spreading ischaemia in the human brain using novel technology for the first time to measure electrical activity and regional cerebral blood flow in aSAH patients. Our recently published article in Brain (youtube.com) further underscores that spreading ischaemia is of outstanding clinical importance. This is because spreading ischaemia may lead to the so called negative ultraslow potential (NUP). The NUP is initiated by SD and similar to the negative direct potential (DC) shift of prolonged SD, but specifically refers to a negative potential component during progressive recruitment of neurons into cell death in the wake of SD. In the paper, we first quantified the SD-initiated NUP in the DC range and the activity depression in the alternate current (AC) range of the electrocorticogram after middle cerebral artery occlusion in rats. Relevance of these variables to the injury was supported by significant correlations with the cortical infarct volume and neurological outcome after 72 hours of survival. We then identified NUP-containing clusters of SDs in 11 patients with aSAH. We found that NUP-displaying electrodes were significantly more likely to overlie a developing ischaemic lesion than those not displaying a NUP. The NUP was often preceded by an SD cluster with increasingly persistent spreading depressions and progressively prolonged DC shifts and spreading ischaemias. During the NUP, spreading ischaemia lasted for 40.0 (median) (28.0, 76.5, interquartile range) min, cerebral blood flow fell from 57 (53, 65) % to 26 (16, 42) % and the tissue partial pressure of oxygen from 12.5 (9.2, 15.2) to 3.3 (2.4, 7.4) mmHg. Our data suggested that the NUP is the electrophysiological correlate of infarction in human cerebral cortex and a neuromonitoring-detected medical emergency. Currently, we perform more human and animal research to learn more about the underlying mechanisms of spreading ischaemia and NUP.
The importance of vascular risk factors for spreading depolarisation and spreading ischaemia
Aneurysmal SAH is a form of stroke that occurs at a younger age than most other forms of stroke. In addition, aSAH is an unusual form of stroke in that it affects women significantly more often than men. These two factors also apply to the early and late ischaemic strokes that occur following aSAH. In our clinical trial DISCHARGE-1, the average age of patients with early and delayed ischaemic stroke was 57 and 56 years, respectively, and 69.9% and 68.4% of those affected by these complications were women. Arterial hypertension is the most important vascular risk factor for stroke, especially at younger ages. Diabetes mellitus is another important vascular risk factor, especially in the context of vasoconstrictive mechanisms, which play a dominant role after aSAH. In fact, all patients in DISCHARGE-1 who had diabetes mellitus in addition to aSAH suffered ischaemic strokes. Our research group is investigating these influencing factors not only clinically, but also in animal models of arterial hypertension and diabetes mellitus.
Development of epilepsy after aneurysmal subarachnoid haemorrhage
aSAH is one of the strongest known risk factors for the development of epilepsy. In addition to physical disabilities, cognitive and emotional impairments after aSAH, the development of epilepsy has a major impact on the long-term course of the disease. It is not uncommon for the development of epilepsy to lead in a downward spiral to a renewed worsening of existing deficits. Epilepsy is also an independent risk factor for early death in the chronic phase after aSAH. Epileptogenesis is the delayed-onset, long-lasting, maladaptive, dynamic process typically associated with selective loss of specific neuron populations, eventually leading to a chronically reduced threshold for epileptic seizures. We are currently investigating the connection between acute damage development in the neurointensive care unit after aSAH and the later development of epilepsy together with our collaboration partners Alon Friedman (Dalhousie University, Halifax, Canada) and Annamaria Vezzani [Mario Negri Institute for Pharmacological Research (IRCCS), Milan, Italy] in a project funded by Era-Net Neuron.
The brain is the organ of our body that is the most sensitive to a lack of energy. As opposed to other tissues, the network structures that process neural information under physiological conditions, display a form of abrupt, almost complete collapse of the cellular homeostasis under pathological conditions. This almost complete collapse is cytotoxic and shortens the timeframe in which neurons can survive a lack of energy. It is a potentially reversible state between life and death that spreads from neuron to neuron as a giant wave of electrochemical discharge. This process is called spreading depolarisation (SD) (www.braintsunamis.org). The wave is not limited to tissue with an abnormal energy supply, but also continues in an adequately supplied environment. While the principal biophysical and biochemical characteristics stay the same, several properties of the healthy tissue change along this path. These changes make the wave relatively harmless in healthy tissue. Patients who suffered a stroke and traumatic brain injury display the full SD continuum, whereas mainly the benign part of the continuum is observed in cases of migraine with aura. To better treat these diseases, it is necessary to better understand the SD continuum.
In more formal terms, SD is the generic term for waves of abrupt, continuous mass depolarisation of the grey matter in the central nervous system caused by an almost complete collapse of the neuronal transmembrane ionic gradients. In addition, the following occurs: (i) almost complete short-circuit of the nerve cell membrane, (ii) a loss of electrical activity (spreading depression), (iii) engorgement of the neurons with bead-like distensions of the dendrites (cytotoxic oedema), (iv) depolarisation of the neuronal mitochondria, (v) massive glutamate release (excitotoxicity) and (vi) the depolarisation of astrocytes. The massive tissue depolarisation moves through the grey matter like a tsunami with a speed of ~3 mm/min and is measured as a large, negative shift of the extracellular direct current potential (direct current [DC] shift). The electrochemical changes indicate that SD is one of the most fundamental pathological processes of the central nervous system.
"Normal" and "inverse" haemodynamic response to SD
SD occurs when passive cation influx across the cell membrane exceeds ATP-dependent Na+ and Ca2+ pump activity. SD is thus a passive process driven by the electrical force and diffusion forces. Only the subsequent repolarisation increases the energy consumption, as additional Na+ and Ca2+ pump activity has to be recruited. Therefore, ATP falls by ~50% during SD even in otherwise healthy tissue. In healthy tissue, neurons normally repolarise within 1-2 min after the onset of SD. To increase oxygen and glucose availability, SD induces dilatation of resistance vessels ("normal" neurovascular coupling) in healthy tissue. Regional cerebral blood flow (rCBF) therefore increases in response to SD in healthy tissue (= spreading hyperaemia).
The opposite of the "normal" neurovascular response to SD, the "inverse" neurovascular response, results from local dysfunction in the microcirculation. In "inverse" coupling, severe microvascular spasm is coupled to SD instead of vasodilation. This results in spreading ischaemia. The perfusion deficit of spreading ischaemia prolongs the duration of neuronal repolarisation, as oxygen and glucose deficiency further reduce ATP availability. This is reflected in a prolongation of the negative DC potential. Pharmacologically induced spreading ischaemia was sufficient to induce focal necrosis in the rat. This suggests that "inverse" neurovascular coupling is a promising target for therapeutic intervention.
SD-induced spreading ischaemia after aneurysmal subarachnoid haemorrhage
Aneurysmal SAH is considered a model disease for the study of lesion progression in stroke because patients can be observed and monitored invasively in the intensive care unit (ICU) before and throughout the period of delayed infarct development. Proximal vasospasm is thought to be involved in the pathogenesis of DCI, presumably as a result of subarachnoid blood degradation products. However, the positive predictive value of proximal vasospasm on digital subtraction angiography for the development of DCI is low, at 30-50%. A complementary explanation for DCI is offered by the occurrence of SDs that exhibit "inverse" neurovascular coupling with microarterial spasm and arrest of the microcirculation for minutes to hours in the presence of blood breakdown products. This phenomenon has been observed both in animal models and in patients with aSAH (Dreier et al., 1998; Dreier et al., 2009).
Spreading ischaemia with aneurysmal subarachnoid haemorrhage
Delayed cerebral ischaemia (DCI) after an aneurysmal subarachnoid haemorrhage (aSAH) occurred in 33-38% of patients with a maximum reached around day 7 following the bleeding. 10 to 13% of patients develop delayed infarctions in the computed tomography. Aneurysmal SAH is the model disease for the study on lesion progression in stroke, as patients can be intensively observed and monitored in the ICU before and during the entire development period of the delayed infarction. It is assumed that a proximal vasospasm is involved in the pathogenesis of DCI, which probably originates as a result of subarachnoid blood breakdown products. However, the positive predictive value of a proximal vasospasm in a digital subtraction angiography for the occurrence of DCI is only low at 30 to 50%. The occurrence of SDs is a complementary explanation for DCI as they display ‘inverse’ neurovascular coupling with microvascular spasms and suspend the microcirculation for minutes or even hours. This phenomenon is observed in both animal models and patients with aSAH (Dreier et al., 1998; Dreier et al., 2009; Dreier, 2011).
Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induce cortical spreading ischemia when K+ is increased in the subarachnoid space.
Dreier JP, Körner K, Ebert N, Görner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhäupl KM, Lauritzen M, Dirnagl U.
J Cereb Blood Flow Metab. 1998 Sep;18(9):978-90. doi: 10.1097/00004647-199809000-00007.
Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage.
Dreier JP, Major S, Manning A, Woitzik J, Drenckhahn C, Steinbrink J, Tolias C, Oliveira-Ferreira AI, Fabricius M, Hartings JA, Vajkoczy P, Lauritzen M, Dirnagl U, Bohner G, Strong AJ.
Brain. 2009 Jul;132(Pt 7):1866-81. doi: 10.1093/brain/awp102.
Design and conduction of diagnostic and interventional mono-/ multicentric trials in patients with aneurysmal subarachnoid hemorrhage, stroke or migraine. Neuromonitoring on the neurocritical care unit.
Cranial window models using imaging and microelectrodes; human and animal brain slice models; histology, immunohistochemistry, MRI
Cooperations and Partners
- COSBID study group
- Prof. Heiner Audebert, Charité Berlin, Deutschland
- Dr. Baptiste Balança, Centre de Recherches en Neurosciences de Lyon, France
- Prof. Ulrich Dirnagl, Charité Berlin, Deutschland
- Prof. Wolfram Döhner, Charité Berlin, Deutschland
- Prof. Matthias Endres, Charité Berlin, Deutschland
- Prof. Alon Friedman, Beer-Sheva, Israel and Halifax, Kanada
- Prof. Jed Hartings, University of Cincinnati, Ohio, USA
- Prof. Christoph Harms, Charité Berlin, Deutschland
- Dr. Nils Hecht, Charité Berlin, Deutschland
- Dr. Daniel Kondziella, University of Copenhagen, Denmark
- Dr. Agustin Liotta, Charité Berlin, Deutschland
- Dr. Stephane Marinesco, Centre de Recherches en Neurosciences de Lyon, France
- Prof. Peter Martus, Tübingen, Deutschland
- Prof. Andreas Meisel, Charité Berlin, Deutschland
- Prof. Josef Priller, Charité Berlin, Deutschland
- PD Dr. Michael Scheel, Charité Berlin, Deutschland
- Dr. Karl Schoknecht, Universität Leipzig, Deutschland
- Prof. Ilan Shelef, Beer-Sheva, Israel
- Dr. Bob Siegerink, Charité Berlin, Deutschland
- Prof. Peter Vajkoczy, Charité Berlin, Deutschland
- Prof. Annamaria Vezzani, Mario Negri Institute for Pharmacological Research, Milano, Italien
- Prof. Dr. Johannes Woitzik, Charité Berlin, Deutschland
- Dr. Stefan Wolf, Charité Berlin, Deutschland