Professor Jens P. Dreier, M.D.

Research Group Dreier

Professor Jens P. Dreier, M.D.
Charité, Center for Stroke Research Berlin
Translation in Stroke Research


In addition to DISCHARGE-I, further projects investigate SI (spreading ischemia) in patients (BMBF 01 EO 0801), the brain topical endothelin-1 model in rats (DFG DR 323/6-1), neurovascular mechanisms of small vessel disease (ERA-NET NEURON 01EW1212), SDs (spreading depression) in traumatic brain injury (FP7 no 602150 CENTER-TBI) and the propagation of SD in the human brain (BMBF 01GQ1001C B2).

List of Publications / Charité Research Data Base 


Claudia Altendorf
Claudia Altendorf
Christoph Drenckhahn
Christoph Drenckhahn
Nicole Gase
Nicole Gase
Eun-Jeung Kang
Eun-Jeung Kang
Janos Lückl
Janos Lückl
Christoph Mallmann
Christoph Mallmann
Sebastian Major
Sebastian Major
Denny Milakara
Denny Milakara
Cecilia Nicoletti
Cecilia Nicoletti
Nikolas Offenhauser
Nikolas Offenhauser
Ana I. Oliveira-Ferreira
Ana I. Oliveira-Ferreira
Clemens Reiffurth
Clemens Reiffurth


1.1. '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.

1.2. 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.


Clinical trials

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, rCBF

Animal models

Cranial window models using imaging and microelectrodes Human and animal brain slice models Histology, immunohistochemistry

Cooperation and Research Partners

  • COSBID study group (
  • 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

Selected References

Blood-brain barrier opening to large molecules does not imply blood-brain barrier opening to small ions.

Kang EJ*, Major S*, Jorks D, Reiffurth C, Offenhauser N, Friedman A, Dreier JP (2013)
Neurobiol Dis 52:204-218

Electrochemical failure of the brain cortex is more deleterious when it is accompanied by low perfusion.

Dreier JP, Victorov IV, Petzold GC, Major S, Windmüller O, Fernández-Klett F, Kandasamy M, Dirnagl U, Priller J (2013)
Stroke 44:490-496

Correlates of Spreading Depolarization in Human Scalp Electroencephalography.

Drenckhahn C, Winkler MKL, Major S, Scheel M, Kang EJ, Pinczolits A, Grozea C, Hartings JA, Woitzik J, Dreier JP (2012)
Brain 135:853–868

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 M, Hartings JA, Fabricius M, Speckmann EJ, Gorji A (2012)
Brain 135:259-275

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.

Dreier JP (2011)
Nat Med 17:439-447

Experimental and preliminary clinical evidence of an ischemic zone with prolonged negative DC shifts surrounded by a normally perfused tissue belt with persistent electrocorticographic depression.

Oliveira-Ferreira AI, Milakara D, Alam M, Jorks D, Major S, Hartings JA, Lückl1 J, Martus P, Graf R, Dohmen C, Bohner G, Woitzik J, Dreier JP (2010)
J Cereb Blood Flow Metab 30:1504-1519Opening of the blood-brain barrier preceding a cortical edema in a severe attack of FHM type II.

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 (2009)
Brain 132:1866-81

Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarisations.

Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, Lehmann T-N, Sarrafzadeh A, Willumsen L, Hartings JA, Sakowitz OW, Seemann JH, Thieme A, Lauritzen M, & Strong AJ (2006)
Brain 129:3224-37

Ion changes of spreading ischaemia induce rat middle cerebral arter constriction in absence of NO.

Windmüller O, Lindauer U, Foddis M, Einhäupl KM, Dirnagl U, Heinemann U, Dreier JP (2005)
Brain 128:2042-2051

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, Villringe A, Einhäupl KM, Lauritzen M, Dirnagl U (1998)
J Cereb Blood Flow Metab 18:978-990

Most important project

Protect brain


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.

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