Professor Jens P. Dreier, M.D.

Research Group Dreier

Prof. Jens P. Dreier, M.D.
Charité, Center for Stroke Research Berlin
Translation in Stroke Research
jens.dreier(at)charite.de

Profile

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

Selected Publications

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]
PMID:29668855

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.
PMID:29331091

Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction.
Hartings JA, York J, Carroll CP, Hinzman JM, Mahoney E, Krueger B, Winkler MKL, Major S, Horst V, Jahnke P, Woitzik J, Kola V, Du Y, Hagen M, Jiang J, Dreier JP.
Brain. 2017 Oct 1;140(10):2673-2690. doi: 10.1093/brain/awx214.
PMID:28969382

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.
PMID:25996134

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.
Dreier JP.
Nat Med. 2011 Apr;17(4):439-47. doi: 10.1038/nm.2333. Review.
PMID:21475241

Impetus

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

Protect brain

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.
More information/project description

Further Projects

Spreading Ischemia and the Negative Ultraslow Potential
Spreading depolarization (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 ischemia in the rat. In 2009 we published unequivocal evidence for spreading ischemia 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 (doi:10.1093/brain/awy102; https://www.youtube.com/watch?v=l06FWV9sowY) further underscores that spreading ischemia is of outstanding clinical importance. This is because spreading ischemia 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 ischemic 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 ischemias. During the NUP, spreading ischemia 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 ischemia and NUP.

Background

Spreading depolarisation

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 toxic and shortens the timeframe in which neurons can survive a lack of energy. It is a potentially reversible semi-conscious state between life and death, which drifts from neuron to neuron like a gigantic 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 improve the treatment of these diseases, we must be able 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 make it clear that SD is one of the most fundamental pathological processes of the central nervous system.

 

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).

Team

Sebastian Major
Sebastian Major
Clemens Reiffurth
Clemens Reiffurth
Karl Schoknecht
Karl Schoknecht
Coline Lemale
Coline Lemale

Methods

Clinical Trials

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.

Animal Models

Cranial window models using imaging and microelectrodes; human and animal brain slice models; histology, immunohistochemistry, MRI

Cooperations and Research 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. 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
  • Prof. Ilan Shelef, Beer-Sheva, Israel
  • Dr. Bob Siegerink, Charité Berlin, Deutschland
  • Prof. Peter Vajkoczy, Charité Berlin, Deutschland
  • PD Dr. Johannes Woitzik, Charité Berlin, Deutschland
  • Dr. Stefan Wolf, Charité Berlin, Deutschland
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