INSIGHTS | PERSPECTIVES
1196 13 MARCH 2020 • VOL 367 ISSUE 6483 sciencemag.org SCIENCE
PHOTO: YUKI MORIOnce 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. jREFERENCES AND NOTES- W. Hacke et al., Arch. Neurol. 53 , 309 (1996).
- H. Mestre et al., Science 367 , eaax7171 (2020).
- J. J. Iliff et al., Sci. Transl. Med. 4 , 147ra111 (2012).
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ACKNOWLEDGMENTS
The authors are funded by the UK Dementia Research Institute.10.1126/science.aba8801THERMOELECTRICSSeeking new,
highly effective
thermoelectrics
Operating across a
wide temperature range
is a priority for
thermoelectric materials
By Yu Xi a o and Li-Dong ZhaoT
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