le
o
K
rap
ain
neuronal depolarization. In published studies in animal models with intracranial electrodes, changes of 0.005
current spatial resolution of about 1 mm achieved in MRI or CT but boundary. Data acquisition is performed through an array of
NeuroImage 47 (2009) 514–522
Contents lists available at ScienceDirect
NeuroIm
e lalso a means to image fast neural activity. Ideally the latter would
have a temporal resolution of about 1 ms so that the envelope of
neural activity could be resolved in neuroanatomical pathways. There
has recently been a development of interest in this goal; source
modelling of the EEG (Baillet et al., 2001) and MEG (Baillet et al.,
2001; Hamalainen et al., 1993), their multimodality fusion with MRI
(Dale and Halgren, 2001), direct mapping with MRI (Hagberg et al.,
2006; Parkes et al., 2007) and diffuse optical tomography (Steinbrink
et al., 2005; Syre et al., 2003) have been investigated. Although there
have been some promising proofs of principle, practical imaging has
electrodes which are attached to the boundary of the imaged object.
Sequences of small insensible currents, typically about of 1 mA, are
injected into the object through these electrodes and the correspond-
ing boundary electric potentials are measured over a predefined set
of electrodes. The process is repeated for numerous different confi-
gurations of applied current. The internal admittivity (or impedivity)
distribution can be inferred using this boundary data. EIT was first
proposed as a medical imaging method by Henderson and Webster
(1978) and was initially applied to chest imaging (Brown et al.,
1985; Brown and Seagar, 1987; Metherall et al., 1996). Potentialnot yet been accomplished. Electrical Impeda
a novel medical imaging method which has
this revolutionary advance, by imaging th
changes over milliseconds (Holder, 1987
⁎ Corresponding author.
E-mail addresses: o.gilad@ucl.ac.uk, origilad@hotma
1053-8119/$ – see front matter © 2009 Elsevier Inc. Al
doi:10.1016/j.neuroimage.2009.04.085greatly in the past two
which could have the
resistivity decreases (Cole and Curtis, 1939).
EIT provides information regarding the internal electrical proper-
ties inside a body based on non-invasive voltage measurements on its
Functional neuroimaging has improved
decades but the ideal would be a methodIntroductionwhich could form the basis for EIT of fast neural activity. Resistance was recorded with scalp electrodes
during 2 Hz pattern visual evoked responses over 10 min using an insensible 1 Hz square wave constant
current of 0.1–1 mA. Significant resistance decreases of 0.0010±0.0005% (0.30±0.15 μV, signal-to-noise
ratio (SNR) of 2:1, n=16 recordings over 6 subjects) (mean±SE) were recorded. These are in broad
agreement with modelling which estimated changes of 0.0039±0.0034% (1.03±0.75 μV) using an
anatomically realistic finite element model. This is the first demonstration of such changes in humans and so
encourages the belief that EIT could be used for neural imaging. Unfortunately, the signal-to-noise ratio was
not sufficient to permit imaging at present because recording over multiple injection sites needed for
imaging would require impractically long recording times. However, in the future, invasive imaging with
intracranial electrodes in animal models or humans and improved signal processing or recording may still
enable imaging; this would constitute a significant advance in neuroscience technology.
© 2009 Elsevier Inc. All rights reserved.
neuronal ion channels open during activity and the cell membraneAvailable online 6 May 2009
was to determine if resistance changes could be recorded non-invasively in humans during evoked activityAccepted 28 April 2009 to 3% have been reported but the amplitude of changes in the human is not known. The purpose of this workRevised 23 April 2009Impedance changes recorded with scalp e
Implications for Electrical Impedance Tom
O. Gilad a,b,c,⁎, D.S. Holder a,b
a Department of Clinical Neurophysiology, University College London Hospitals, London, UK
b Department of Medical Physics and Bioengineering, University College London, London, U
c Abramson Center for Medical Physics, Tel-Aviv University, Tel-Aviv, Israel
a b s t r a c ta r t i c l e i n f o
Article history:
Received 2 December 2008
Electrical Impedance Tomog
fast neural imaging in the br
j ourna l homepage: www.nce Tomography (EIT) is
the potential to achieve
e electrical impedance
) which occur when
il.com (O. Gilad).
l rights reserved.ctrodes during visual evoked responses:
graphy of fast neural activity
hy (EIT) is a recently developed medical imaging method which could enable
by recording the resistance changes which occur as ion channels open during
age
sev ie r.com/ locate /yn imgapplications of EIT for imaging brain function and pathology
include detection and monitoring of cerebral ischemia and
haemorrhage (Gibson et al., 2000; Holder, 1992a; McArdle et al.,
1988; McEwan et al., 2006; Romsauerova et al., 2006), localization
of epileptic foci (Bagshaw et al., 2003; Fabrizi et al., 2006b), normal
haemodynamic brain function (Tidswell et al., 2001) and neuronal
activity (Boone and Holder, 1995; Holder, 1987). See Holder (2005)
for a recent review.

515O. Gilad, D.S. Holder / NeuroImage 47 (2009) 514–522The principle by which EIT could image neuronal activity rests on
the application of low frequency currents below about 100 Hz which
remain in the extracellular space under resting conditions because
they cannot enter significantly into the intracellular space across the
resistive cell membrane. During the action potential or neuronal
depolarization, the membrane resistance diminishes by about 80×
(Cole and Curtis, 1939) so that the applied current enters the intra-
cellular space as well. Over a population of neurones, this will lead to
a net decrease in the resistance during coherent neuronal activity,
such as cortical evoked responses, as the intracellular space will
provide additional conductive ions (Boone and Holder, 1995; Liston
et al., 2000; Liston, 2004).
An important advantage of this potential application of EIT over
inverse source modelling of the EEG or MEG is that this mechanism
effectively rectifies the recording of ionic channel opening —
resistance across the membrane can only fall. In this way, impe-
dance falls irrespective of whether the neurotransmitter giving rise
to the change is excitatory or inhibitory. Neuroelectric or neuro-
magnetic signals cancel out when measured from a distance unless
the neuronal processes are spatially aligned, as in the dendritic tree
of the pyramidal cells. The rectified resistance change could capture
activity in the entire depolarized tissue, regardless of the spatial
arrangement, so the opportunity to record the changes from a
distance are greater.
The magnitude of such fast changes in the brain has been inves-
tigated by modelling and animal studies in our group. Mathematical
modelling, based on cable theory, estimated local resistivity changes
near DC to be 2.8–3.7% for peripheral nerve bundles and 0.06–1.7%
for the cortex during Evoked Potentials (EP) (Boone and Holder,
1995; Liston et al., 2000; Liston, 2004). The analysis also indicated
that recording needed to be undertaken below 100 Hz. This is
because the basis for the resistance change is that current remains
extracellular at rest but passes additionally into the intracellular
space as ion channels open during depolarization. At frequencies
above 100 Hz, applied current starts to enter the intracellular
compartment by passing across the capacitance of cell membranes.
As a result, the method employed in this work was developed in
which recording is made near to DC, using a 1 Hz square wave (as
opposed to DC) in order to reduce electrode and neuronal tissue
polarization.
The predictions of the model were validated in crab peripheral
nerve: decreases of 0.5–1.0% were recorded which were in broad
agreement (Boone, 1995; Holder, 1992b; Liston, 2004). There are
several reports in the literature of attempts to record impedance
changes during evoked activity in neural tissue but there is dis-
agreement between studies and it is not clear that artefactual findings
have been excluded. Resistance decreases of 3.1%±0.8 (SE) were
recorded during direct cortical stimulation in the cat, using a four
electrode system squarewave pulses 0.3–0.7ms in duration (Freygang
and Landau, 1955) which were ascribed to membrane resistance
changes of dendrites. However, no calibration data were presented, so
it is unclear if these unexpectedly large changes were artefactual.
Using a two electrode system (whichmay underestimate the changes)
and a Wheatstone bridge operating at 35 kHz, a decrease of 0.03–0.1%
was reported in frog sciatic nerve (Chailakhian and Iur'ev, 1957). Their
experimental technique was subsequently used by others (Burlakova
et al., 1959; Prudnikova, 1959) to investigate the time relationship
between the action potential and the putative impedance change.
During visual and auditory evoked responses in the cat, and with a
similar recording system operating at 10 kHz, a decrease of 0.003% in
the cortex (Klivington and Galambos, 1967, 1968), and of 0.03% in
subcortical nuclei (Galambos and Velluti, 1968) was observed. The
difference in results may partly be because evoked responses (ER),
with natural stimulation, activate fewer fibres than the electrical
stimuli used by Freygang and Landau (1955). However, a later attempt
on rats using direct electrical stimulation of the cortex and measure-ment at 50 kHz did not show any changes larger than the sensitivity of
the measurement of 0.01% (Holder and Gardner-Medwin, 1988). It is
therefore not clear how large the resistance changes are in practice in
the cortex during neural activity.
Propagation of local resistance changes to the scalp. The amplitude
of the changes locally in the brain is therefore not accurately known
but a reasonable value, based principally on the biophysical cable
theory modelling, could be taken as a 1% decrease during physiolo-
gically evoked activity if recorded with applied current below 100 Hz
(Boone and Holder, 1995; Liston et al., 2000; Liston, 2004). For non-
invasive recording of related changes with scalp electrodes, this
change will be diluted by partial volume effects and by diversion of
applied current by the resistive skull. This has been modelled using an
anatomically realistic Finite Element (FE)model of the head, validated
with a sponge perturbation in a saline filled tank and standing scalp
voltages measured in humans (Gilad et al., 2009b). For the estimated
resistance change of 1% in a 9 cm3 of grey matter in the primary visual
cortex (Andrews et al., 1997) with 10% of active dendrites (Liston,
2004) during visual evoked responses and the maximal permitted
applied current of 1 mA at 1 Hz, the peak scalp voltage changes were
0.0039±0.0034% (1.03±0.75 μV; Mean±1 SD). The SD reflects the
uncertainty in the literature over the conductivity selection for the
different head compartments. The study also suggested that the
greatest changes would be recorded with current injectionwith a pair
of electrodes 5 or 10 cm apart and recording immediately lateral to
these over the occiput (Gilad et al., 2009b).
It therefore appears that there are good grounds for believing that
resistance changes occur in the brain which could produce signals on
the scalp that are sufficiently large to image non-invasively. However,
the amplitude of these changes in the brain and their attenuation to
the surface is not clear. The purpose of this work was to determine,
for the first time, if reproducible resistance changes could be
recorded non-invasively with scalp electrodes during visual evoked
responses in humans. The principal questions were: 1) are there
statistically significant changes in individual impedance measure-
ments from single channels? and 2) if there are any such changes, are
they large enough to be likely to yield accurate EIT images of fast
neural activity in the brain?
Experiments were undertaken in human subjects during pattern
visual evoked responses. According to the cable theory prediction,
resistance was recorded at the very low frequency of 1 Hz with a
square wave applied to one of two positions over the occipital cortex;
the resulting voltages were recorded from 19 other electrodes placed
over the occipital cortex, yielding 18 linearly independent measure-
ment pairs.
Unfortunately, calculation of resistance changes is complicated
because the resulting signal comprises three elements: i) a voltage
resulting from the injected square wave current, which in practice
appeared as a variable decaying exponential due to capacitative
coupling ii) a superimposed resistance change conveyed by this
carrier and iii) the potential due to the evoked response which was in
the same frequency band and so could not be excluded by filtering.
The resistance change was extracted using a subtraction method
(Gilad et al., 2009a) which is described in the next section.
Materials and methods
Rationale
The principle of the method is to inject a constant current square
wave and estimate the resulting resistance changes from the recorded
voltages at different nearby electrodes. Averaging is necessary to
improve the SNR, so the signal is time locked to repeated evoked
neurophysiological activity. The resulting voltage will contain three
elements as above. In principle, the evoked neurophysiological activity
may be subtracted by making a paired recording without the square