Science 13Mar2020

INSIGHTS | PERSPECTIVES

1196 13 MARCH 2020 • VOL 367 ISSUE 6483 sciencemag.org SCIENCE

PHOTO: YUKI MORI

Once initiated, why does the CSF influx
wave follow the wave of spreading depo-
larization across the brain? Mestre et al.
posit that this is due to spreading depolar-
ization causing vasoconstriction of surface
and penetrating arterioles (spreading isch-
emia) ( 6 , 7 ). They demonstrate that vaso-
constriction in distal arteries is sufficient
to increase surface arteriole perivascular
spaces, which creates a pressure gradient to
increase CSF flow in the perivascular spaces
of penetrating arterioles. For this increased
CSF flow to translate into greater influx into
the brain, AQP4 channels are key. In mice
engineered with a deletion of Aqp4, and
exposed to stroke, CSF in the perivascular
spaces was decreased, CSF influx into the
brain was reduced, and no edema occurred
within 15 min after strok e.

The overall contribution of CSF influx to
early poststroke edema, and its dependence
on the wave of spreading depolarization,
may be relevant to other conditions display-
ing spreading depolarizations ( 8 ). For ex-
ample, traumatic brain injury (TBI) can be
exacerbated by cerebral edema, and many
mechanisms for this have been proposed, in-
cluding spreading depolarization ( 9 ). AQP4
expression is increased after TBI , but its po-
larized expression favoring astrocytic end-
feet is lost, so if CSF influx is a factor in TBI
edema, it may be through a different route
than after stroke ( 10 ). Waves of spreading
depolarization also underlie the aura of mi-
graine [which doubles the risk of ischemic
stroke ( 11 )] and are followed by a brief in-
crease and then prolonged decrease of blood
flow, but without edema. It is possible that
these waves are accompanied by more subtle
CSF influxes into the brain, which are ad-
equately removed by the glymphatic system.
It is important to remember that vaso-
genic edema is a substantial contributor

to later edema following stroke. In their

stroke-model mouse, Mestre et al. show

that the vasogenic component of edema

becomes more pronounced 24 hours after

stroke (see the figure). This might be par-

ticularly relevant when considering more

targeted treatments for human poststroke

recovery. In spinal cord injury, where there

is also edema, inhibition of AQP4 expres-

sion reduces cytotoxic edema, but increased

AQP4 expression is beneficial for water re-

absorption during vasogenic edema ( 12 ),

suggesting that therapeutically targeting

AQP4 after stroke for beneficial effect may

be difficult.

Can CSF-induced edema in stroke be

therapeutically targeted? Surgical decom-

pression hemicraniectomy to reduce gen-

eral brain edema after stroke saves lives

( 13 ), and cisternostomy to drain CSF has its

proponents in TBI ( 14 ), but could a less in-

vasive nonsurgical approach be developed?

Perhaps it may be helpful to therapeuti-

cally target the spreading ischemia and/or

depolarization using drugs that act on ion

channels (e.g., Na+, K+, Cl−, and Ca2+ chan-

nels) and neurotransmitter receptors [e.g.,

adrenergic, serotonergic, sigma-1, calcitonin

gene-related peptide, g-aminobutyric acid

(GABA), and N-methyl-D-aspartate recep-

tors], as has been suggested for other dis-

eases in which this occurs ( 15 ). The caveat

is that the time window for intervention

may be short—although perhaps longer in

humans than in mice. Nevertheless, Mestre

et al. have begun decoding the mechanism

by which a CSF source might contribute to

cytotoxic edema in stroke, and the continu-

ation of this work should improve the op-

portunities to improve long-term prognoses

for the survivors of stroke by shutting the

floodgates and protecting the brain. j

REFERENCES AND NOTES

1. W. Hacke et al., Arch. Neurol. 53 , 309 (1996).


2. H. Mestre et al., Science 367 , eaax7171 (2020).


3. J. J. Iliff et al., Sci. Transl. Med. 4 , 147ra111 (2012).


4. J. J. Iliff et al., J. Neurosci. 34 , 16180 (2014).


5. J. P. Dreier, C. Reiffurth, Neuron 86 , 902 (2015).


6. H. K. Shin et al., J. Cereb. Blood Flow Metab. 26 , 1018
   (2006).


7. P. Dreier et al., Neurosurg. 93 , 658 (2000).


8. D. R. Kramer et al., J. Clin. Neurosci. 24 , 22 (2016).


9. R. M. Jha et al., Neuropharmacology 145 , 230 (2019).


10. Z. Ren et al., J. Cereb. Blood Flow Metab. 33 , 834 (2013).


11. T. Kurth et al., Lancet Neurol. 11 , 92 (2012).


12. Y. Huang et al., Front. Neurosci. 13 , 584 (2019).


13. National Institute for Health and Care Excellence (NICE),
    “Stroke and transient ischaemic attack in over 16s:
    diagnosis and initial management” (NICE, 2019); http://www.
    nice.org.uk/guidance/ng128/evidence/h-surgery-
    decompressive-hemicraniectomy-pdf-6777399573.


14. I. Cherian et al., J. Neurosci. Res. 96 , 744 (2018).


15. C. Costa et al., J. Headache Pain 62 , 14 (2013).

ACKNOWLEDGMENTS

The authors are funded by the UK Dementia Research Institute.

10.1126/science.aba8801

THERMOELECTRICS

Seeking new,

highly effective

thermoelectrics

Operating across a

wide temperature range

is a priority for

thermoelectric materials

By Yu Xi a o and Li-Dong Zhao

T

hermoelectric technology can directly

and reversibly convert heat to electri-

cal energy. Although thermoelectric

energy conversion will never be as ef-

ficient as a steam engine ( 1 ), improv-

ing thermoelectric performance can

potentially make a technology commercially

competitive. Thermoelectric conversion ef-

ficiency is estimated by the so-called dimen-

sionless figure of merit, ZT = S^2 sT/k, where

S, s, T, and k denote the Seebeck coefficient,

electrical conductivity, working tempera-

ture, and thermal conductivity, respectfully.

These parameters are strongly coupled, and

improving the final ZT is challenging as a

result. Strategies for boosting thermoelec-

tric performance include nanostructuring,

band engineering, nanomagnetic compos-

iting, high-throughput screening, and oth-

ers ( 2 ). Many of these strategies create a

high ZT in a narrow range of temperatures,

limiting the overall energy conversion.

Finding materials with wider operating

temperature ranges may require rethinking

development strategies.

A thermoelectric device is assembled with

many cascading n-type and p-type couples.

The device efficiency is closely related to

the performance of thermoelectric materi-

als. Thermoelectric materials are categorized

into three temperature ranges depending on

their working temperatures. Bismuth tel-

lurides are typical thermoelectric materials

that operate under 400 K. Lead chalcogen-

ides are typical for the 600 to 900 K range.

Silicon-germanium and Zintl phases exhibit

the best performance above 1000 K. The best

thermoelectric performance at the optimal

working temperature is restricted by the

bandgap (Eg) owing to intrinsic excitation.

School of Materials Science and Engineering,

Beihang University, Beijing 100191, China.

Email: [email protected]

After stroke in live mice, cerebral spinal fluid (yellow)
enters the brain along the perivascular spaces of
cerebral blood vessels (red).

Published by AAAS