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 Serial Editor

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Institute of Cognitive Neuroscience
University College London
17 Queen Square
London WC1N 3AR UK

Editorial Board

Mark Bear, Cambridge, USA.

Medicine & Translational Neuroscience
Hamed Ekhtiari, Tehran, Iran.
Addiction
Hajime Hirase, Wako, Japan.
Neuronal Microcircuitry
Freda Miller, Toronto, Canada.
Developmental Neurobiology
Shane O’Mara, Dublin, Ireland.
Systems Neuroscience
Susan Rossell, Swinburne, Australia.
Clinical Psychology & Neuropsychiatry
Nathalie Rouach, Paris, France.
Neuroglia
Barbara Sahakian, Cambridge, UK.
Cognition & Neuroethics
Bettina Studer, Dusseldorf, Germany.
Neurorehabilitation
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Computational Neuroscience
Elsevier
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Contributors
A. Alexander
Stanford University, Stanford, CA, United States
S.C. Baraban
Epilepsy Research Laboratory, University of California, San Francisco, CA, United
States
S. Baulac
Sorbonne Universit
es, UPMC Univ Paris 06, UM 75; INSERM, U1127; CNRS,
UMR 7225; ICM (Institut du Cerveau et de la Moelle
epinière); AP-HP Groupe
hospitalier Piti

e-Salp^
etrière, Paris, France
D.A. Coulter
Perelman School of Medicine, University of Pennsylvania; The Research Institute
of the Children’s Hospital of Philadelphia, Philadelphia, PA, United States
C.G. Dengler
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,
United States
J. Ghaziri
Research Centre, Centre hospitalier de l’Universit
e de Montr
eal, Montreal, QC,
Canada
A. Griffin
Epilepsy Research Laboratory, University of California, San Francisco, CA, United
States
F. Gu
Epilepsy Research Laboratories, Stanford University School of Medicine,
Stanford, CA, United States
A.E. Hernan
University of Vermont College of Medicine, Burlington, VT, United States
G.L. Holmes
University of Vermont College of Medicine, Burlington, VT, United States
X. Jiang
Universit

e de Montr

eal; CHU Ste-Justine Research Center, Montr
eal, QC, Canada
C. Krasniak
Epilepsy Research Laboratory, University of California, San Francisco, CA, United
States
M. Lachance
CHU Ste-Justine Research Center, Montr
eal, QC, Canada
M. Maroso
Stanford University, Stanford, CA, United States

v
vi Contributors

H.C. Mefford
University of Washington, Seattle, WA, United States
C.T. Myers
University of Washington, Seattle, WA, United States
D.K. Nguyen
Research Centre, Centre hospitalier de l’Universit
e de Montr
eal; CHUM–H^opital
Notre-Dame, Montreal, QC, Canada
I. Parada
Epilepsy Research Laboratories, Stanford University School of Medicine,
Stanford, CA, United States
D.A. Prince
Epilepsy Research Laboratories, Stanford University School of Medicine,
Stanford, CA, United States
E. Rossignol
Universit

e de Montr

eal; CHU Ste-Justine Research Center, Montr
eal, QC, Canada
I. Soltesz
Stanford University, Stanford, CA, United States
Y. Zerouali
Research Centre, Centre hospitalier de l’Universit
e de Montr
eal; Ecole
Polytechnique de Montr

eal, Montreal, QC, Canada
Preface

The following volume stems from a meeting of the same name “The Neurobiology of
Epilepsy: From Genes to Networks” held in Montreal on May 4–5, 2015, and orga-
nized by Drs. L. Carmant, P. Cossette, E. Rossignol, and J.-C. Lacaille. The editors
would like to acknowledge the support of the Groupe de Recherche sur le Système
Nerveux Central, Universite de Montreal, for the organization of the meeting.
Epilepsy is a brain disease caused by abnormal and excessive electrical discharges
of neurons. The underlying etiologies are multiple, but recent research indicates an
important role for pathological genetic variants causing dysregulation of neuronal
networks. This meeting brought together an international group of clinicians and
basic scientists to share new information on the neurobiological basis of epilepsy,
including clinical aspects, molecular mechanisms, neuronal networks, as well as
animal models and novel therapies. By trying to discuss the “neurobiology” of
epilepsy, we mean to address the fundamental mechanisms underlying the genetic
basis of epilepsy and hopefully lead to an understanding of epilepsy at the molecular,
cellular, and network levels that will be translatable into improved treatment for
patients with epilepsy.
The volume begins with sections covering novelties in the clinical investigation
of patients with epilepsy. Drs. Zerouali, Ghaziri, and Nguyen describe multimodal
imaging techniques involved in the investigation of epileptic networks in patients,
focusing on insular cortex epilepsy. Drs. Myers and Mefford review current knowl-
edge on the genetic investigation techniques used to identify molecular etiologies
in patients with epileptic encephalopathies, and provide an overview of the clinical
features and basic mechanisms of recently described genetic epileptic encephalop-
athies. Dr. Baulac examines how germline and somatic mutations in the genes of the
GATOR1 complex, which regulates the mTOR pathway, cause focal epilepsies with
variable foci.
An understanding of the “neurobiology” of epilepsy must also elucidate seizures
at the microcircuit level and understand how neuronal networks are affected in ep-
ilepsy. The volume continues with three chapters discussing the molecular, cellular,
and network mechanisms involved in the genetics of epilepsy. Drs. Jiang, Lachance,
and Rossignol consider the involvement of cortical GABAergic interneuron disor-
ders in genetic causes of epilepsy; Drs. Alexander, Maroso, and Soltesz discuss work
on the organization and control of epileptic circuits in temporal lobe epilepsy; and
Drs. Dengler and Coulter review the normal and epilepsy-associated pathologic
function of the hippocampal dentate gyrus.
A major justification for elucidating the genetic, molecular, cellular, and network
basis of epilepsies is to develop effective treatment therapies for patients. The vol-
ume then moves into investigations of animal models and therapies. Drs. Hernan and
Holmes examine work on antiepileptic treatment strategies in neonatal epilepsy, and
Drs. Griffin, Krasniak, and Baraban discuss advancement in epilepsy treatment
through personalized genetic zebrafish models.
xi
xii Preface

Finally, the concluding chapter for the volume is from Drs. Prince, Gu, and
Parada, describing antiepileptogenic repair of excitatory and inhibitory synaptic
connectivity after neocortical trauma.

Elsa Rossignol, Lionel Carmant, and Jean-Claude Lacaille

Departement de neurosciences, Universite de Montreal, Montreal, Canada
 CHAPTER

Multimodal investigation of
epileptic networks: The case
of insular cortex epilepsy
Y. Zerouali*,†, J. Ghaziri*, D.K. Nguyen*,{,1
1
*Research Centre, Centre hospitalier de l’Universit

e de Montr

eal, Montreal, QC, Canada
†
Ecole Polytechnique de Montr
eal, Montreal, QC, Canada
{
CHUM–H^ opital Notre-Dame, Montreal, QC, Canada
1
Corresponding author: Tel.: +1-514-890-8000 ext. 25070; Fax: +1-514-338-2694,
e-mail address: d.nguyen@umontreal.ca

Abstract
The insula is a deep cortical structure sharing extensive synaptic connections with a variety of
brain regions, including several frontal, temporal, and parietal structures. The identification of
the insular connectivity network is obviously valuable for understanding a number of cognitive
processes, but also for understanding epilepsy since insular seizures involve a number of re-
mote brain regions. Ultimately, knowledge of the structure and causal relationships within the
epileptic networks associated with insular cortex epilepsy can offer deeper insights into this
relatively neglected type of epilepsy enabling the refining of the clinical approach in managing
patients affected by it.
In the present chapter, we first review the multimodal noninvasive tests performed during
the presurgical evaluation of epileptic patients with drug refractory focal epilepsy, with par-
ticular emphasis on their value for the detection of insular cortex epilepsy.
Second, we review the emerging multimodal investigation techniques in the field of epi-
lepsy, that aim to (1) enhance the detection of insular cortex epilepsy and (2) unveil the archi-
tecture and causal relationships within epileptic networks. We summarize the results of these
approaches with emphasis on the specific case of insular cortex epilepsy.

Keywords
Epilepsy, Insula, Connectivity, Networks, Multimodal, Causality, Neuroimaging

1 EPILEPSY AS A SYSTEMS DISEASE

For most epileptic patients (
70%), anticonvulsive drugs adequately control sei-
zures. However, among the refractory cases, a significant proportion of patients
are eligible for surgical treatment of seizures (Wiebe et al., 2001). The fundamental
Progress in Brain Research, Volume 226, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2016.04.004
© 2016 Elsevier B.V. All rights reserved.
1
2 CHAPTER 1 Insular cortex epileptic networks

question in those cases is to localize the part of the brain that is responsible for pa-
tients’ seizures, which constitutes the central thread of this chapter. Important ad-
vances in the surgical treatment of epilepsy arose from both a better formulation
of this question and the development of methodological tools to answer it. Indeed,
our notion of epilepsy has evolved from a local-based to network-based model, cap-
italizing on the ability of neuroimaging to study brain function at increasingly high
spatial and temporal resolutions.
Early in the last century, the measurement of brain electrical potentials on the
scalp by Berger paved the way for the investigation of the neuroelectric correlates
of epileptic seizures. In addition to seizures, Berger also reported the existence of
sharp electrical transients that are observable on the electroencephalogram (EEG)
of epileptic patients in the absence of seizures. These “spikes” are usually observed
on electrodes that record seizures but this is not always the case. This spatial distinc-
tion between the generators of seizures and spikes was further elaborated with the
advent of intracranial EEG recordings (icEEG). icEEG allows excellent spatial dis-
crimination of the neural generators of epileptic activity, which led Laufs and Rose-
now to propose a “zonal” model to explain the pathophysiology of epilepsy
(Rosenow, 2001). The “zonal” model recognizes different zones associated with
the clinical symptoms (symptomatogenic zone), the interictal spikes (irritative zone),
the initiation of seizures (seizure onset zone—SOZ), and the functional deficits as-
sociated with the epileptic condition (functional deficit zone). Importantly, they de-
fine an “epileptogenic” zone (EZ) that consists of the brain tissue that must be
surgically resected for seizures to be cured. The spatial location of the EZ is usually
estimated using multimodal investigation techniques, as will be described in the
next section, but its true location can only be confirmed through positive surgical
outcome.
Although the zonal concept of epilepsy had an important impact on the clinical
management of epileptic patients, failure rates for epilepsy surgeries remain rela-
tively important, as high as 30% for temporal lobe—TLE (Jeha et al., 2006;
Wiebe et al., 2001) and 50% for frontal lobe—FLE (Jeha et al., 2007; Yun et al.,
2006) and parietal lobe—PLE (Binder et al., 2009; Kim et al., 2004a) epilepsy. In
2002, Spencer formulated the idea that we should envision generators of interictal
and ictal activities as networks of structures rather than single zones (Spencer,
2002). Since the transition from interictal to ictal to postictal brain states occurs
at the time scale of synaptic activity, this idea has two corollaries. First, it implies
that the neural machinery supporting the emergence of epileptogenic networks
(ENs) is hardwired into the brain (Richardson, 2012). Thus, epilepsy is a systems
disease, the symptoms of which result from aberrant connectivity among a set of
anatomical healthy structures (Avanzini and Franceschetti, 2003). Some authors sug-
gest that neural networks are bistable systems that can exhibit both healthy and ep-
ileptiform activity for the same set of parameters (Breakspear et al., 2006; Da Silva
et al., 2003; Marten et al., 2009). Dynamical transitions between these two states are
called bifurcations, and the epileptic condition facilitates such bifurcations.
The second corollary is that the network assembly is a highly flexible process; for
a given set of components, there are a large number of network architectures, all of
 2 Investigating the epileptic networks: Clinical practice 3

which may give rise to different epileptiform activities and clinical symptoms. This
idea has deep implications for clinicians and neuroscientists, since accurate locali-
zation of network components is insufficient for fully describing the pathophysiol-
ogy of epilepsy. For such an endeavor, it is necessary to study time-varying network
dynamics (Halász, 2010).
In order to illustrate the networks concept of epilepsy and the current techniques
used in their investigation, we use the unique case of insular cortex epilepsy (ICE).
The insula is a cortical structure located deep in the sylvian fissure and is hidden by
the frontal, temporal, and parietal opercula. Despite early reports on insular epilep-
tiform activity (Guillaume and Mazars, 1949; Penfield and Faulk, 1955; Penfield and
Jasper, 1954), insulectomy was not considered an efficient surgical approach
(Silfvenius et al., 1964) until the past 15 years. Patient series from Isnard et al.
(2004) and Ryvlin and Kahane (2005) demonstrated that insular ENs include tem-
poral, frontal, and parietal structures and that the sequence of clinical symptoms as-
sociated with insular seizures can be explained by their patterns of propagation.
Throughout this chapter, we will present multimodal investigation techniques used
both for localizing the components of ENs and characterizing their architectures,
with emphasis on ICE. Section 2 presents the investigation techniques that are rou-
tinely used in most epilepsy centers for imaging the epileptogenic brain tissues.
Section 3 presents new experimental investigation techniques that promise enhanced
imaging and understanding of ENs.

2 INVESTIGATING THE EPILEPTIC NETWORKS: CLINICAL

PRACTICE
2.1 PRESURGICAL INVESTIGATION TECHNIQUES
2.1.1 icEEG
The gold standard in the localization of the anatomical components of epileptogenic
networks consists of direct recordings of neuroelectric activity through electrodes in
contact with brain tissue. icEEG records local field potentials that are generated by
neural populations within a 0.5–3 mm radius from the tip of the electrode (Juergens
et al., 1999; Mitzdorf, 1987); thus, achieving the highest spatial resolution among
all neuroimaging techniques used in clinic. The downside of such high resolution
is obviously poor spatial coverage, since only a limited number of electrodes can
be used without risking cerebral hemorrhage or neurological deficits (Wong et al.,
2009). It is thus possible that the epileptogenic zone is not sampled by icEEG,
leading to the wrong selection of surgical target. ICE provides an ideal illustration
of this issue.
Insufficient insular coverage in patients with ICE was associated with a significant
proportion of failed TLE, FLE, and PLE surgeries. Initially, suspicions were raised
by a study on patients with TLE with atypical clinical symptoms that were instead as-
sociated with insular activity (Aghakhani et al., 2004). Despite successive resections
(up to four) of anterior temporal, mesiotemporal, and parietotemporal structures,
4 CHAPTER 1 Insular cortex epileptic networks

patients continued having seizures. Unfortunately, no electrode sampled the insula in

their study although insular hyperperfusion was clearly shown in one patient. The
potential benefit from icEEG recordings in the insula in TLE was further demon-
strated, as about 10% of patients diagnosed with TLE suffered from ICE (Isnard
et al., 2004). TLE-like symptoms in those patients were explained by secondary prop-
agation of ictal activity to surrounding temporal structures. Similar conclusions were
drawn by some studies on PLE and FLE (Roper et al., 1993; Ryvlin et al., 2006).
Based on these reports, our group lowered its decision threshold for insular im-
plantations with depth electrodes in patients with nonlesional TLE, FLE, and PLE.
On a series of 18 patients meeting these criteria, we found that 40% patients who
underwent icEEG recordings had seizures originating from the insula. In addition,
electrical stimulation of the insula proved that insular epileptic discharges replicate
semiology of various extrainsular epilepsies (Nguyen et al., 2009). Our findings,
along with existing literature on this issue suggest that (1) ICE is probably more prev-
alent than presently reported; more extensive studies must be conducted to determine
its frequency, (2) despite extensive presurgical workups, nonlesional ICE is probably
rarely detected, accounting for a significant proportion of failed epilepsy surgeries.
We further review the different investigation techniques used in presurgical workups
and discuss their value for detecting ICE.

2.1.2 EEG
EEG is probably the oldest and most widely used imaging modality in clinical
investigations of brain pathologies, including epilepsy. Over the years, epileptolo-
gists developed expert skills in reading and interpreting EEG seizures, but also
waveforms observed during the interictal state, such as spikes, polyspikes, spike-
and-wave complexes, sharp waves, paroxysmal fast activity (Westmoreland, 1998),
and high-frequency oscillations (Bragin et al., 1999). Advanced biophysical models
and computerized techniques allow unprecedented accuracy in the localization of those
waveforms, as most advanced algorithms can theoretically reach a 10 cm2 resolution
(Grova et al., 2006), thus enabling “electrical source imaging” (ESI).
ESI relies on a biophysical model that relates neural electrical activity, modeled
as a finite number of equivalent current dipoles (ECD), to electrical potentials
recorded outside the head. We distinguish two broad classes of ESI techniques,
according to the number ECD used for modeling brain activity. Single ECDs as-
sume recorded electrical potentials are generated by a single (or a few) neural point
source(s). Although this approach obviously oversimplifies neural generators and
its numerical implementation requires strong heuristics (number of dipoles, initial-
ization), it proved valuable in epilepsy when careful attention is paid to its limita-
tions, as validated by simultaneous EEG and icEEG recordings (Boon et al., 2002;
Ebersole, 1991; Roth et al., 1997). In general, all studies report usefulness of sECD
for epilepsy, with sensitivity and specificity exceeding, respectively, 80% and 60%
for the vast majority of studies (see Kaiboriboon et al., 2012, for a review).
In turn, distributed source modeling (DSM) models neural sources with a large
number of ECDs homogenously distributed in the brain. Despite this mathematical
challenge imposed by the large number of sources, DSM is increasingly being
 2 Investigating the epileptic networks: Clinical practice 5

validated in the clinical management of epileptic patients, benefiting from increased

head coverage of high-density EEG systems and increased accuracy of head model-
ing techniques. In the study with the largest cohort of patients, DSM was shown to
accurately localize the onset of seizures, with sensitivity and specificity both exceed-
ing 80% (Brodbeck et al., 2011), in line with several other reports (Michel et al.,
2004; Sperli et al., 2006). In ICE, EEG was found to be insensitive to spikes gener-
ated from the deep-seated insula; therefore, we did not find any reports on the use-
fulness of ESI for that kind of epilepsy.

2.1.3 MEG
Magnetoencephalography (MEG) is a relatively new imaging modality that records
the magnetic fields generated by electrical currents flowing inside active neurons.
Despite a relatively short history of clinical investigation and higher operation costs
than EEG, MEG has quickly established itself as an important tool in presurgical
evaluation of epilepsy. Owing to the relatively simpler physics of neural magnetic
fields propagation, MEG is sensitive to smaller activated brain regions (
4 cm2
for MEG, Mikuni et al., 1997,
10 cm2 for EEG, Grova et al., 2006). Source local-
ization with DSM showed promising results for the presurgical workup of epilepsy,
which led some authors to suggest that it could obviate icEEG investigations in some
cases (Fujiwara et al., 2012).
Several studies demonstrated the usefulness of sECD modeling with MEG on
different types of epilepsy. Globally, the reported accuracy of sECD is above
75% for the majority of the studies (Knowlton, 2006; Minassian et al., 1999;
Stefan, 1993). In addition, MEG was also shown to be valuable for appropriately
determining the subsequent icEEG coverage zone (Fischer et al., 2005;
Knowlton et al., 2009; Mamelak et al., 2002). Unfortunately, only a few studies
report sECD investigation of ICE. Among those, Heers et al. studied three patients
with cryptogenic epilepsy and hypermotor seizures (Heers et al., 2012). They
showed that MEG can not only identify epileptic foci when other modalities fail
but is also able to localize deep-seated foci such as in the insula (Park et al.,
2012). We recently investigated 14 patients with insular seizures using MEG.
Among those, localization of interictal spikes showed clear insular or perisylvian
focus in all but one patient. Taken together, these studies suggest that MEG is valu-
able for detecting ICE.
In turn, we found substantially fewer reports of DSM, probably due to the fact it is
more recent and less validated. Nonetheless, studies using DSM advocate for its
more extensive use in presurgical workups since it outperformed sECD in at least
two comparative studies (Shiraishi et al., 2005; Tanaka et al., 2009). It was also
shown that patterns of source activity reconstructed with DSM were good predictors
(up to 94%) for subsequent surgical resection (Tanaka et al., 2010).

2.1.4 MRI
Magnetic resonance (MR) scanners exploit the intrinsic magnetic properties (the
spin) of electrons to produce high-resolution images of brain (and body) tissues.
Using a sophisticated combination of spin polarization and perturbation, MR
6 CHAPTER 1 Insular cortex epileptic networks

imaging (MRI) now allows recovering the three-dimensional properties of the brain
with 1 mm resolution. MRI is an essential tool in the evaluation of patients with focal
epilepsy, allowing the visual detection of a variety of epileptogenic brain lesions
such as gliosis from acquired insults, tumors, vascular malformations, or malforma-
tions of cortical development. Globally, the sensitivity of MRI in epilepsy surgery
candidates ranges between 75% and 86% (Bronen et al., 1996; Brooks et al.,
1990; Cascino et al., 1992; Grattan-Smith et al., 1993; Kuzniecky et al., 1993;
Laster et al., 1985; Latack et al., 1986; Ormson et al., 1986; Scott et al., 1999).
Literature on ICE provides contrasting results with respect to the sensitivity of
MRI. We found six studies in which all patients (N ¼ 43) displayed some abnormality
(Cukiert et al., 1998; Duffau et al., 2002; Heers et al., 2012; Kaido et al., 2006; Roper
et al., 1993; von Lehe et al., 2008), two studies (N ¼ 23) with both MRI-positive and
MRI-negative patients (Malak et al., 2009; Mohamed et al., 2013), and seven studies
(N ¼ 19) with exclusively MRI-negative patients (Dobesberger et al., 2008; Isnard
et al., 2000, 2004; Kriegel et al., 2012; Nguyen et al., 2009; Ryvlin et al., 2006;
Zhang et al., 2008). Overall, MRI had a sensitivity of 61%, corresponding to 87%
positive predictive value when considering the results of surgery. Overall, our short
review suggests that MRI is a highly valuable tool for investigating ICE with mod-
erate sensitivity but excellent diagnostic value. However, the relatively larger num-
ber of patients diagnosed with lesional rather than nonlesional ICE might reflect the
fact that nonlesional ICE is a poorly diagnosed disease, and that currently available
investigation tools other than MRI have low diagnostic value for this disease.

2.1.5 PET
Positron-emission tomography (PET) measures the concentration of a specific
source of radiation in the 3D space. The brain property imaged with PET thus
depends on the choice of an appropriate radioligand, such that 3D concentrations
can be interpreted in terms of brain function. In epilepsy, 2-[18F]-fluoro-2-
deoxy-D-glucose (FDG) and [11C]-flumazenil (FLU) are two complimentary and
commonly used radioligands, imaging brain function (glucose consumption), and
structure (neuronal loss), respectively. The epileptic condition is associated with
neuronal loss and, paradoxically, decreased concentrations of FDG in affected brain
regions. Although this last observation is largely consensual, the underlying neuro-
physiological mechanisms are still not understood.
Studies comparing FLU- and FDG-PET for localizing the brain regions involved
in epileptogenic networks report similar performance of both molecules for most
groups of patients. Globally, these two modalities achieve similar sensitivity and
specificity (Ryvlin et al., 1998) and are equally predictive with respect to surgical
outcome (Debets et al., 1997). It was noted however that the only cases where
FLU-PET added new information above that of MRIs are when FDG-PET is nega-
tive, which implies that FDG-PET should be performed first, and FLU-PET only
when FDG-PET is negative.
Since the role of insula has only gained recognition in the last 10 years, early PET
studies reporting changes in metabolism in the insula did not include insular intra-
cranial electrodes (Bouilleret et al., 2002; Didelot et al., 2008; Hur et al., 2013; Joo,
 2 Investigating the epileptic networks: Clinical practice 7

2005; Wong et al., 2010). For this reason, although they provided interesting insights
into the involvement of the insula in the metabolic changes associated with TLE,
they are inconclusive with regard to ICE. We found few reports of ICE with icEEG
and PET data (Dobesberger et al., 2008; Heers et al., 2012), including two studies
from our group (Nguyen et al., 2009; Surbeck et al., 2014). Pooled together, these
studies suggest that FDG-PET has low sensitivity (17%) and specificity (53%)
to ICE.

2.1.6 SPECT
Single-photon emission computerized tomography (SPECT) consists in localizing
the source of gamma-ray emission within the brain. The source consists of a radio-
active tracer (usually the 99mTc-labeled HMPAO—hexamethylpropyleneamine ox-
ime) bound to a molecule that freely crosses the blood-brain barrier, such that it
diffuses into the brain after intravenous injection. Since the tracers used in SPECT
have relatively long half-lives, they distribute spatially in brain regions with higher
blood flow and remain stable for up to a few hours. Patients can thus be EEG-video
monitored and injected at the time of a relevant brain activity (ideally seizure onset)
as seen on the EEG traces. It is generally agreed that the use of SPECT during inter-
ictal brain state is of limited use (Debets et al., 1997; Lascano et al., 2015; Spencer,
1994). In contrast, SPECT is mostly useful when the radioligand is injected at seizure
initiation (Joo et al., 2004; Spencer, 1994). In addition, even better results can be
achieved by subtracting interictal from ictal SPECT images, a technique called SIS-
COM. Such an operation is especially useful in cases where ictal hyperperfusion is
low in epileptogenic zone due to superposition on a preceding hypoperfused state
(Desai et al., 2013; Newey et al., 2013; Spencer, 1994; von Oertzen et al., 2011).
As for PET, there are only a few studies that reported on the value of SPECT in
ICE. We found few reports of ICE with icEEG and PET data (Dobesberger et al.,
2008; Heers et al., 2012), including two studies from our group (Nguyen et al.,
2009; Surbeck et al., 2014). Pooled together, these studies suggest that SPECT
has low sensitivity (23%) and specificity (48%) to ICE.

2.2 ILLUSTRATIVE CASE

A 10-year-old ambidextrous girl with mild language delay started having seizures at
the age of 4 years characterized by an unpleasant tingling sensation in the lower back,
right arm, and both legs followed by fear and complex motor behaviors. Seizures
became predominantly nocturnal after a few weeks and have remained so since, re-
curring in clusters of 4 or 5 (up to 15) every 2–3 days. After failing six adequate anti-
epileptic drug trials, the patient was referred for epilepsy surgery. While the clinical
history might have suggested a frontal lobe focus, video-EEG monitoring revealed
right temporal, central, or centro-temporal discharges interictally and right centro-
temporal rhythmic activity at seizure onset (Fig. 1). High-resolution 3T brain
MRI and volumetric studies failed to disclose an epileptogenic lesion. Interictal
FDG-PET was normal but ictal SPECT showed increased cerebral blood flow over
the right insular region (Fig. 2). Source localization of interictal epileptiform
8 CHAPTER 1 Insular cortex epileptic networks

FIG. 1
EEG recordings of the epileptic activity from the illustrative patient. The time axis (horizontal)
is discontinuous as shown by the double vertical black lines. Interictal and ictal activity
are displayed, respectively, to the left and right of the black lines. A clear temporo-central
spike is displayed between the two vertical orange (light gray in the print version) lines.
A seizure starts right after the vertical red (gray in the print version) bar. From those traces,
EEG does not allow the detection of the insular focus.

FIG. 2
Ictal SPECT images from the illustrative patient. The selected coronal slices are displayed
in the neurological convention (right hemisphere at the right) and span the antero-posterior
axis of the insula. These slice show clear asymmetry in blood perfusion, the right insula
showing clear hyperperfusion as compared to the left side.

discharges recorded during MEG (CTF 275-sensory system, Canada) using an elec-
trical current dipole model revealed a concordant tight cluster at the very posterior
end of the right Sylvian fissure (posterior insula and parietal more than temporal
opercula—Fig. 3). During spikes, combined EEG–fMRI recordings showed (blood
oxygen level-dependent, BOLD) activations over the right posterior insula, the over-
lying perisylvian cortex but also in central regions and the cingulate gyrus (Fig. 4).
Functional MRI for language suggested left-hemisphere dominance. Based on this
multimodal noninvasive evaluation, epilepsy surgery was recommended. With the
removal of the right parietal operculum, temporal operculum, and posterior insula,
seizure-freedom was attained (follow-up 2 years).
 2 Investigating the epileptic networks: Clinical practice 9

FIG. 3
Single-dipole modeling of the interictal spikes recorded from the illustrative patient using
MEG, each dipole corresponding to a single spike. Localized dipoles clearly cluster in the
posterior portion of the insula and in the centro-parietal opercula.

FIG. 4
CombinedEEG–fMRI recordings of interictal spikes from one patient of our cohort of
insular cortex epilepsy. General linear model reveals a single BOLD activation cluster in the
posterior portion of the right insula along with the overlying central operculum. Although they
were found in other patients, activation of other structures, such as the cingulate gyrus did not
reach significance.
10 CHAPTER 1 Insular cortex epileptic networks

3 INVESTIGATING THE EPILEPTIC NETWORKS:

PERSPECTIVES
3.1 ADVANCED LOCALIZATION TECHNIQUES
3.1.1 EEG/MEG fusion
Both EEG and MEG directly address neuronal activity by recording differences in
electrical potentials and magnetic fields, respectively, outside the head. Although
both modalities record activity from the whole brain, they are preferentially sensitive
to different populations of neurons. Indeed, EEG is mainly sensitive to radially ori-
ented sources lying on cortical gyri since they are closer to the sensors while the mag-
netic fields generated by those sources vanish due to the quasi-spherical head shape.
In turn, MEG is mainly sensitive to tangential source lying along the sulci walls
(Ahlfors et al., 2010; Sharon et al., 2007). Thus a cortical region participating in
an EN would only be partially recovered by EEG and MEG if it extends spatially
from the top of a gyrus to a cortical fold. Some studies further observed noticeable
epileptogenic activity on one modality but not the other (Barkley and Baumgartner,
2003; Iwasaki et al., 2005), highlighting the need for simultaneous EEG–MEG re-
cordings. Importantly, it was shown that EEG and MEG acquired simultaneously
are superadditive, ie, they provide more information relevant to source localization
than the sum of unimodal information (Pflieger et al., 2000).
Simultaneous EEG/MEG (MEEG) recordings were introduced in epilepsy with
the aim to better delineate the location and spatial extent of cortical sources partic-
ipating in epileptogenic networks. Using simulations of realistic epileptic spikes,
Chowdhury et al. showed that MEEG provides better localization than EEG or
MEG alone, regardless of the inversion scheme used (Chowdhury et al., 2015). How-
ever, contrary to what is commonly believed they showed that the maximum entropy
on the mean framework (Amblard et al., 2004) not only provides the most accurate
localization of the simulated sources but is also able to recover their spatial extent
(Chowdhury et al., 2013; Ebersole and Ebersole, 2010). In addition, in the same
study on two patients with frontal lobe epilepsy, MEEG was able to track interictal
spike propagation patterns while individual modalities were insensitive to spatiotem-
poral dynamics of the spikes. Similar conclusions were drawn from a recent study
comparing unimodal and multimodal MEEG source localizations with intracranially
recorded EEG on a patient with multifocal refractory epilepsy. The authors show that
MEEG is able to recover most of the regions participating in the generation of spikes,
even when no single modality was able to recover them (Aydin et al., 2015). This
study illustrates the supraadditive nature of MEEG and its potential to recover more
components of ENs.
We recently started exploring the potential of MEEG source imaging of epileptic
spikes to detect insular activations in ICE. Extending the previously cited reports, we
found that EEG and MEG are each able to detect insular activations on subsets but
not all spikes. However, MEEG source imaging provided more robust results and
could detect insular activations in cases where only a single modality was positive
(see Fig. 5A) and even when both modalities were negative (Fig. 5B). These
 3 Investigating the epileptic networks: Perspectives 11

FIG. 5
Combined EEG–MEG source reconstruction of two epileptic spikes from one patient with ICE.
(A) For this spike, the EEG was unable to detect the insular activation and reveals mainly
activity in the orbitofrontal cortex. In turn, both MEG and MEEG could detect activation in the
ventral region of the insula. (B) For this spike, neither EEG nor MEG could detect insular
activation while MEEG clearly displays maxima of power in the ventral and posterior insular
regions.

preliminary results suggest that MEEG source imaging of epileptic spikes is a prom-
ising avenue for the computer-assisted detection of ICE.

3.1.2 Combined EEG and fMRI

A clinical-grade MR magnet is probably among the most hostile environments for
recording scalp potentials with EEG. Indeed, even small movements of the EEG
electrodes inside the scanner as a result of small head movements or
12 CHAPTER 1 Insular cortex epileptic networks

ballistocardiographic effects, translate into current induction in electrodes. In addi-

tion, the on/off switching of the radiofrequency antennas creates even larger artifacts
on the EEG, two orders-of-magnitude larger than the activity of interest. Nonethe-
less, modern signal processing techniques allow for a proper cleaning of EEG data
such that EEG–fMRI can be used for relating hemodynamic and neuroelectric brain
activity. Given the deterministic nature of the gradient artifact, waveform averaging
was introduced (Allen et al., 2000) and validated (Gonçalves et al., 2007; Salek-
Haddadi et al., 2002) to subtract the artifact from the EEG. Other filtering techniques,
applicable to the ballistocardiographic effect, were also proposed based on spectral
domain filtering (Sijbers et al., 1999), wavelet filtering (Kim et al., 2004b), spatial
Laplacian filtering, PCA (Niazy et al., 2005), and ICA (Mantini et al., 2007;
Srivastava et al., 2005).
In the context of epilepsy, one of the most widely used EEG–fMRI paradigms is
to analyze the BOLD signal in an event-related design where the events are EEG-
marked interictal spikes. After preprocessing, spikes are marked on the EEG by
expert epileptologists. The EEG signal is then binarized according to the spike mark-
ing, downsampled to match fMRI time resolution, and convolved with a model of
the hemodynamic response function that is then cast as a regressor in the general
linear model. The most common model is the canonical hemodynamic response
function (HRF), which accounts for local elastic deformation of blood capillaries
and the resultant transient increase in local blood oxygenation in response to neu-
ronal activity—also termed neurovascular coupling (Buxton et al., 1998). However,
it was shown that the shape and onset of the HR can vary significantly among sub-
jects (Aguirre et al., 1998; Lindquist et al., 2009), with respect to: subjects age
(D’Esposito et al., 1999; Jacobs et al., 2008), brain regions (Handwerker et al.,
2004) and brain lesions including epileptogenic lesions (Lemieux et al., 2008;
Masterton et al., 2010). Several alternate models of the HRF were proposed to ac-
count for such variability, including general nonlinear fits of the HRF, multiple
HRFs with varying onset and peak times, HRF along with its time derivatives
(Friston et al., 1998), general basis functions sets (Josephs and Henson, 1999),
and the superposition of three inverse logit functions (Lindquist et al., 2009). These
models are then integrated in a general linear model to infer the response of each
voxel to the epileptic activity (Friston, 1995). Irrespective of the chosen model, use-
fulness of EEG–fMRI to imaging epileptic networks has been demonstrated in sev-
eral studies.
First, it was shown that the BOLD signal provides useful information for confirm-
ing the location of the suspected epileptic focus. Depending on the study, proportions
of patients who display IED-related changes in the BOLD signal ranged from 67% to
83% (Kobayashi et al., 2006; Salek-Haddadi et al., 2006). The most clinically useful
BOLD changes are activations, since identification of a single activation cluster was
found to be concordant with electro-clinical symptoms in over 80% of cases
(Krakow, 1999; Salek-Haddadi et al., 2006; Thornton et al., 2010) and are good pre-
dictors of positive surgical outcome (An et al., 2013). Importantly, a number of stud-
ies showed that EEG–fMRI has the potential to reveal the components of ENs.
Indeed, in mesial TLE, BOLD occasionally displays significant activation clusters
 3 Investigating the epileptic networks: Perspectives 13

in the contralateral temporal and extratemporal regions (Avesani et al., 2014;

Kobayashi et al., 2006; Tousseyn et al., 2014). Those clusters were considered as
patterns of spike propagation since surgical outcomes are good despite sparing those
clusters. Similarly, in patients with intractable generalized epilepsy whose interictal
activity is characterized by sharp spike-wave bursts, BOLD changes show significant
activation of the thalamus while EEG does not (Aghakhani, 2004).
We recently conducted an EEG–fMRI study aimed at revealing the EN associated
with ICE (unpublished results). We recruited 13 ICE patients, as confirmed by sur-
gical outcome after insulectomy. We were able to detect IEDs in 62% of patients,
similarly to what has been reported in studies on other kinds of epilepsies. We found
ipsilateral insular and or perisylvian BOLD activations in six patients while the
remaining two displayed significant BOLD activation in the contralateral insula
(data from one patient is shown in Fig. 4). In addition to insular and perisylvian ac-
tivations, significant BOLD clusters were found in the postcentral gyrus, superior
parietal lobule, middle or superior frontal gyri, and anterior cingulate or medial fron-
tal gyri, all of which were previously shown to share structural connectivity with the
insula (Augustine, 1996; Nieuwenhuys, 2012). We thus think that EEG–fMRI is a
promising tool for revealing complex ENs in ICE.

3.1.3 Quantified icEEG

In principle, icEEG recordings are the gold standard in epilepsy as they allow for
direct sampling of epileptogenic brain regions, assuming coverage is appropriate.
Localization of the seizure onset zone thus amounts to identifying the first contact
displaying epileptiform activity at seizure initiation. However, such activity often
appears nearly simultaneously on a number of contacts and visual identification
of relevant nodes of the EN is a challenging task. Thus, some strategies were pro-
posed for automatically labeling the most important contacts at seizure initiation.
By combining spectral and temporal information at seizure onset, Bartolomei
et al. introduced an empirical index that measures the propensity of each node to ini-
tiate seizures (Bartolomei et al., 2008). More specifically, they computed a ratio of
energy of high frequencies (beta and gamma) over lower frequency bands (delta,
theta, and alpha) at each time bin of the time-frequency decomposition of EEG sig-
nals. This ratio is then normalized and cumulated over time in what is called the
“energy ratio” function. When a seizure is recorded, this function contains a local
maximum at seizure onset, and the amplitude and latency of that maximum are used
to define the so-called epileptogenic index (EI), which measures the involvement in
seizure initiation.
The EI proved useful for the study on epileptogenic networks, especially in me-
sial TLE. Indeed, the number on nodes with high EI was higher for patients with
identified lesions than for patients with normal MRI, which was an important pre-
dictor of surgical outcome (Bartolomei et al., 2008). In addition, the EI captures
some subtleties in the clinical symptomatology of patients, since it can be used to
classify patients with clinical subtypes of mesial TLE (Bartolomei et al., 2010)
and discriminate patients with mesial MTLE from those suffering from other types
of TLE (Vaugier et al., 2009).
14 CHAPTER 1 Insular cortex epileptic networks

3.1.4 Neuroimaging brain networks

Networks can be schematized as a set of nodes connected to each other through spe-
cific links called edges. Nodes and edges are the workhorse of a large research com-
munity studying networks, ranging from air traffic, power plants to brain networks.
In neuroscience, network analyses answer two broad categories of questions: (1) how
does edge strength between a given node and a set of other nodes evolve with respect
to experimental paradigm and (2) how do the global features of networks evolve with
respect to experimental paradigm?
The main challenges here consist in defining relevant nodes and edges. Many
approaches were proposed for designing nodes encompassing random, data-driven
and atlas-based strategies. We note that atlas-based strategies provide regions of
interest (ROIs) that are more easily interpretable in terms of neurophysiology as
they allow for the understanding of neural systems in terms of associations of
broadly specialized functional units. Edges represent the strength of the connectiv-
ity between two nodes, and their interpretation depends on the imaging modality.
Briefly, we distinguish three types of connectivity: functional, effective, and struc-
tural. Functional and effective connectivity are measures of undirected and directed
statistical coupling among signals, respectively, and must be estimated using
multivariate time series (EEG, MEG, and fMRI). In turn, structural connectivity
is defined in terms of anatomical association between ROIs such as fiber tracts
density and is usually estimated through diffusion imaging. One can analyze the
values of edges linking a specific set of nodes, also called “seeds.” Those seed-
based analyses were carried out in a wide variety of epilepsy types, encompassing
“focal” and “generalized” types. In those analyses, variations in edge values are
assessed with respect to experimental paradigms, allowing the interpretation of
pathophysiology and clinical symptoms in terms of brain connectivity. A sample
of those studies is described in the following sections with respect to imaging
modalities.
The complete graph of connections between all available nodes is called a
“connectome” and analyses of such graph are thus termed “connectomics.” This
field of mathematics was originally framed into the so-called graph theory, which
recently raised spectacular interest in neuroscience in general, and epilepsy in par-
ticular. Graph theory provides a variety of metrics that describe interpretable fea-
tures of connectomes, such as the clustering coefficient, which indexes the
tendency of nodes to form “cliques” with dense internal connections, and the aver-
age path length, which measures the average number of relays while trying to go
from one node to another. Strikingly, many networks, including brain networks,
were found to have relatively high clustering coefficient and low average path
length. Those “small-world” networks share fast processing of information within
functional units through dense local connections and the ability to parallelize infor-
mation processing through sparse but efficient long-range connections (Watts and
Strogatz, 1998). In epilepsy, metrics such as “small-worldness,” efficiency, and
modularity shed new light on the large-scale neurophysiological mechanisms at play
during interictal and ictal states.
Another random document with
no related content on Scribd:
ignition systems; Transmission; Tractor arrangement; Lubrication;
Tractor operation; Engine maintenance; Locating trouble; Causes of
trouble. The book is indexed and carefully illustrated.

[2]
WHITMAN, WALT. Gathering of the forces. il
2v *$15 Putnam 814

The books contain the editorials, essays, literary and dramatic

reviews and other material written by Walt Whitman as editor of the
Brooklyn Daily Eagle in 1846 and 1847. The editors of the collection
are Cleveland Rodgers and John Black, the latter contributing a
foreword, inspired by the spirit of Whitman, and the former a sketch
of Whitman’s life and work. The contents fall into seven parts with
classification of the articles as follows: Part 1—Democracy: American
democracy; Europe and America; Government; Patriotism. Part 2—
Humanity: Hanging, prison reform, unfortunates; Education,
children; Labor, female labor; Emigrants; England’s oppression of
Ireland. Part 3—Slavery and the Mexican war: The extension of
slavery; The union of states; War with Mexico; The Oregon boundary
dispute. Part 4—Politics; Political controversies; Two local political
campaigns; Civic interests; Free trade and the currency system. Part
5—Essays, personalities, short editorials; General essays;
Personalities of the time; “The art of health”; Short editorials;
Whitman as a paragrapher. Part 6—Literature, book reviews, drama,
etc. Part 7—Two short stories not included in Whitman’s published
works: The love of Eris; A legend of life and love. The books are
illustrated and indexed.

Reviewed by E. F. Edgett
 Boston Transcript p4 D 24 ’20 1550w

“To those who knew him only by his great and minor poems or by
the stories of his vanities and eccentricities, these volumes will be a
revelation. They reveal his soul as it grew; and nothing will be more
surprising than their conventional form, their respect for the current
conventions of morality, and their unforced and clear style.” M. F.
Egan

+ N Y Times p2 Ja 2 ’21 3000w

“It is a human document, a great side-light on Whitman’s poems,

and incidentally, a mine of information on a host of matters of
temporary and local interest.” F: T. Cooper

+ Pub W 99:168 Ja 15 ’21 600w

WHO was who. *$6.50 Macmillan 920

(Eng ed 20–14622)

“This book fills the gap between the standard biographical

dictionaries and the current Who’s who. It contains the notices,
reprinted from former volumes of Who’s who, of those more or less
well-known persons who died between 1897 and 1916, with the dates
of their deaths. It runs to nearly eight hundred pages of small
type.”—Spec
 “There is no reason why ‘Who was who’ should not be a democratic
work instead of what it is now. There is even no reason why it should
not be readable. Accidental exclusion must always occur; deliberate
ought never. We commend to the editors the ‘Modern English
biography’ of Frederic Boase, as a model of hard fact, of brevity, and
yet of amplitude. At the same time, we recognize the greatness of
their task and the great usefulness (in the right quarter) of their
volume.”

+ − Ath p79 Jl 16 ’20 280w

Reviewed by Ralph Bergengren

Boston Transcript p4 S 22 ’20 2250w

+ − Sat R 130:40 Jl 10 ’20 370w

“As a work of reference it will be found exceedingly useful, all the

more because many of the persons named will never figure in the
‘Dictionary of national biography’ if, as we hope, that great work
should be continued.”

+ Spec 124:88 Jl 17 ’20 90w

“Apart from its utility as an indispensable book of reference for the

man of affairs, ‘Who was who’ will remain as a permanent store
house of information about the personalities of one of the most
important and critical epochs of British history.”

+ The Times [London] Lit Sup p458 Jl 15

’20 220w
 WIDDEMER, MARGARET (MRS ROBERT
HAVEN SCHAUFFLER). Boardwalk. *$1.60
(3½c) Harcourt

20–773

Omitting all the rose-garden atmosphere of her novels, Margaret

Widdemer has written a series of short stories about boys and girls of
high school age. The scene is one of the summer resort towns along
the Atlantic coast during the months of the year when the boardwalk
belongs to the young people who live there the year round. The titles
are: Changeling; Rosabel Paradise; Don Andrews’ girl; Black magic;
The congregation; The fairyland heart; Good times; Oh, Mr
Dreamman; Devil’s hall.

“Clear cut, interesting little sketches into which the same people
step again and again until one knows quite the whole village.”

+ Booklist 16:173 F ’20

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small tragedies and happinesses into what seems a very truthful
representation of an American town. Whether or not these stories
meet with the immediate popularity of ‘The rose garden husband,’ it
must be conceded that Miss Widdemer has done a more difficult
thing and revealed a more mature and a surer art.” D. L. M.

+ Boston Transcript p6 Ja 21 ’20 850w

“It is a sordid, tawdry, unwholesome atmosphere, the sort of

atmosphere that one would shun if the ideas back of the stories and
their psychology, for they are primarily stories of character, were not
really interesting. Is the skill with which it is done a sufficient excuse
for painting dead fish and tinsel?”

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faltering, and her presentation of the less obvious springs of human
emotion is not always convincing, but her distinct penchant for
transferring to paper the elusive quality of personality is
undeniable.”

+ − N Y Times 25:145 Mr 28 ’20 650w

“On the whole, it is a strong and searching collection.”

+ Springf’d Republican p11a Mr 7 ’20

420w

WIDDEMER, MARGARET (MRS ROBERT

HAVEN SCHAUFFLER), comp. Haunted hour.
*$1.75 Harcourt 821.08

20–5609

The little volume presents an anthology of ghost-poems and

contains only such poems as treat of the return of spirits to earth.
Even so no attempt has been made at inclusiveness, but the
selections range from the earliest ballads to the present time. With
an opening poem by Nora Hopper Chesson: “The far away country,”
the poems are arranged under the headings: “The nicht atween the
sancts an’ souls”; “All the little sighing souls”; Shadowy heroes;
“Rank on rank of ghostly soldiers”; Sea ghosts; Cheerful spirits;
Haunted places; “You know the old, while I know the new”; “My love
that was so true”; Shapes of doom; Legends and ballads of the dead.
There is an index.

+ Booklist 16:272 My ’20

+ Nation 111:278 S 4 ’20 70w

“A most unusual anthology of real merit and charm.”

+ Springf’d Republican p10 Ap 29 ’20

120w

WIDDEMER, MARGARET (MRS ROBERT

HAVEN SCHAUFFLER). I’ve married Marjorie.
*$1.75 (3c) Harcourt

20–13699

Married in haste, Marjorie Ellison has had ample leisure to repent

while her soldier husband has been away in France. Now on the eve
of his return she is badly upset at the thought of the reunion. When
Francis comes, it is as bad as she had feared. With the best intentions
on both sides, he frightens her, and she hurts him. Hot tempers and
strained nerves almost complete a tragedy of separation. But Francis
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before giving her up entirely. In a delightful spot in the Canadian
woods, his scheme is tried out, a scheme which leads through storm
and stress to final joy and happiness for both.

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readers will find it light and sentimental.”

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gossamer material. Also it possesses all the old essential ingredients
of cuteness, wistful humor and the necessary serious touch that
brings the theme to a sweet conclusion. But there is a sparkling
sanity about it.”

+ N Y Times p27 Ag 22 ’20 550w

“A lively and amusing tale. Not a big book nor a provable story, but
agreeable ‘summer reading.’”

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Wis Lib Bul 16:196 N ’20 70w

WIENER, LEO. Africa and the discovery of

America. 2v ea $5 Innes & sons 970

20–7013
 The book is archaeological and etymological, showing how many of
the plants believed to have been indigenous to America, and how
much of the language and customs of the Indians, have an African
origin. Besides a long list of the sources quoted, illustrations, a word
and a subject index, the book contains: The journal of the first
voyage and the first letter of Columbus; The second voyage; Tobacco;
The bread roots.

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should not have undertaken to present his material in a more logical
and readable manner. He is not always convincing, and is often
dogmatic.” E. L. Stevenson

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unchallenged, and the soundest of criticism and the most profound
of scholarship should be invoked before an exact estimate can be
made of its value. But the erudition displayed in this volume is
enough to make us wait with impatience Professor Wiener’s second
volume.” G. H. S.

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psychologist with a valuable example of distorted erudition and
methodological incompetence.”

− Dial 69:213 Ag ’20 90w

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 + Nation 111:350 S 25 ’20 390w

WIGMORE, JOHN HENRY. Problems of law;

its past, present, and future. *$1.50 Scribner 340

20–26999

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in America, and its problems as they relate to world legislation and
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hand, for which a considerable amount of new legislation will be
required, and in view of this fact he urges that our legislators must be
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apparently, the work of legislation] as a career for men of talent, (4)
by making their sessions continuous.’” (Review)

“Three clarifying lectures for the thoughtful layman.”

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intellectual rummaging and the queer quirks of his marvelous mind.
The second lecture on ‘Methods of law making’ is intelligible and
sensible.”

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 + N Y Evening Post p26 O 23 ’20 90w

Reviewed by E: S. Corwin

Review 3:449 N 10 ’20 250w

WILDE, OSCAR FINGALL O’FLAHERTIE

WILLS. Critic in Pall Mall. *$1.50 Putnam 824

(Eng ed A20–616)

A selection from the reviews and miscellaneous writings of Oscar

Wilde made by E. V. Lucas. The papers were contributed to the Irish
Monthly, Pall Mall Gazette, Woman’s World and other journals and
date from 1877 to 1890. At the end under the heading Sententiæ Mr
Lucas has grouped a number of briefer extracts from other reviews.

“The extent to which Wilde was a deliberate poseur is made very

clear by this book, for here there is very little pose. In these reviews,
chiefly from the Pall Mall Gazette, we see Wilde as a critic with
strong common sense, general good taste and with an outlook on life
and literature sufficiently ordinary to be indistinguishable from that
of half-a-hundred other critics of his time and of ours.”

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 “There is nothing especially characteristic about the collection
except, perhaps, a lightness of touch that distinguishes its contents
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Wilde’s taste and the sincerity of his delight in art and letters they
reveal his limitations, also, and the shallowness of his intellectual
draught.”

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writings of Oscar Wilde should be sought out and set in order, and
sent forth in a seemly little tome of two hundred pages. Their
resurrection does not add anything to his reputation, nor does it
detract anything. It does not enlarge our knowledge of the writer or
cast any new light upon the character of the man.” Brander Matthews

− + N Y Times 25:69 F 8 ’20 3400w

“These modest criticisms impress one collectively as good-natured,

orthodox, and sensible. Its art vibrates between distinction and
mediocrity—which is another way of saying that it is
undistinguished.”

+ − Review 3:152 Ag 18 ’20 330w

“Collections of this kind usually do no honour to their author. But

in this case the result is a contribution to literature; in the first place,
because the selection has been made by Mr E. V. Lucas, and in the
second place, because it illustrates not only Wilde’s gift for perverse
banter, but also his genuine scholarship and his ability to perform
plain, downright work in an honest, craftsmanlike way.”
 + Spec 124:492 Ap 10 ’20 1450w

“These chapters are slight, but they are models of literary criticism
of the less formal and serious type. Apart from style their superiority
over the contemporary causerie lies chiefly, perhaps, in the cultivated
background that they denote in the writer and presuppose in the
reader.”

+ Springf’d Republican p8 Je 10 ’20 800w

The Times [London] Lit Sup p605 O 30
’19 1350w

WILDMAN, EDWIN. Famous leaders of

industry. il *$2 (3c) Page 926

20–3587

This is a book for boys about boys who have gained success,
wealth, honor, and prestige in the business world. It contains more
than twenty-six sketches of successful men, among them: Philip
Danforth Armour—California pioneer and Chicago packing king; P.
T. Barnum—the world’s greatest showman; Alexander Graham Bell—
immortal telephone inventor, and humanitarian; James Buchanan
Duke—American tobacco and cigarette king; Henry Ford—the
Aladdin of the automobile industry; Hudson Maxim—poet,
philosopher, and wizard of high explosives; John Davison
Rockefeller,—oil king and world’s greatest industrial leader; John
Wanamaker—America’s foremost retail merchant and originator of
the department store; Orville and Wilbur Wright—who achieved
immortal fame as airship inventors. A portrait accompanies each
sketch.

+ Booklist 16:317 Je ’20

“In these conventionally laudatory portraits of a group of

American inventors and business men there is no departure from the
old Sunday school type of ‘helpful’ stories for the young except in a
decided journalistic snappiness of style.” E. S.

+ Survey 44:323 My 29 ’20 140w

WILKINSON, MRS MARGUERITE OGDEN

(BIGELOW). Bluestone. *$1.50 Macmillan 811

20–11184

A volume of lyrics. In her preface the author touches on the

relation of lyric poetry to music as she employs it in the composition
of her poems. Contents: Bluestone; Songs from beside swift rivers;
Songs of poverty; Preferences; Love songs; Songs of an empty house;
Songs of laughter and tears; Whims for poets; California poems; The
pageant.

“Songs with a wide appeal because they are mostly ‘themes of the
folk.’ The appreciation of nature and outdoor feeling are keen.”

+ Booklist 17:63 N ’20

 “There is an undoubted poetic element in these poems of Mrs
Wilkinson, but it is dew rather than flame. And being excellently
even in craftsmanship, there is no poem that fails to satisfy the
reader’s interest in being what it is.” W: S. Braithwaite

+ Boston Transcript p6 Jl 31 ’20 1050w

“Marguerite Wilkinson has decided moral and metrical spring

without conspicuous originality; though she is deeply touching here
in Songs of an empty house, on the childless state.” M. V. D.

+ − Nation 111:248 Ag 28 ’20 70w

“Mrs Wilkinson undoubtedly possesses a deal of talent; it is

evident throughout her work, cropping out in felicitous stanzas here
and rhythmical lines there, but she allows an occasional triteness to
retard the success of the book as a whole.”

+ − N Y Times p16 N 7 ’20 590w

Spec 125:280 Ag 28 ’20 560w

WILLARD, FLORENCE, and GILLETT,

[2]
LUCY HOLCOMB. Dietetics for high schools. il
*$1.32 Macmillan 613.2

20–12948

“Home economics teachers will be interested to learn that a much

needed textbook of dietetics has recently appeared. The content of
the book is especially significant in view of the experience of both
authors as teachers of the subject and of one of them as worker with
actual problems of malnutrition and of family feeding on low
incomes in the Association for improving the condition of the poor.
The book starts with a comparison of the weights and heights of the
girls in the class with the standards for their ages. Following this is a
study of food values as to fuel, protein, mineral, vitamines, and the
requirements of a good diet. Following the general study of the basis
for planning meals, the authors make an interesting and concrete
section of the book by selecting a family containing children of
various ages and discussing the marketing problems of this family.
The high-school girl thus makes application of her earlier nutrition
study to actual food purchase for the family’s need.”—School R

“This book is a distinct contribution to the very small group of

elementary textbooks in nutrition. The work is accurate and up-to-
date. The points are supported and illustrated by suitable tables and
charts in such number as to constitute a unique feature of a
beginner’s book in nutrition. One specially commendable feature is
the fact that it may be used quite as appropriately as a textbook for
boys as for girls.” M. S. Rose

+ J Home Econ 12:513 N ’20 300w

“A splendid and thoroughly scientific body of material makes the

book a well-rounded and teachable text.”

+ School R 28:798 D ’20 360w

WILLIAMS, ARIADNA TYRKOVA- (MRS

HAROLD WILLIAMS). From liberty to Brest-
Litovsk. *$6 Macmillan 947

19–18461

“This is a narrative of events from the first uprisings of the

revolution in March, 1917, to the ratification of the peace with
Germany a year later. Herself a member of the Petrograd municipal
council and the Moscow conference, Mrs Williams has described in
detail the cabinet crises and political vicissitudes of the provisional
government and the steady trend of the socialist center toward
bolshevism. Less complete is her account of the first months of the
bolshevist régime and its negotiations with Germany at Brest-
Litovsk.”—Survey

Ath p1275 N 28 ’19 220w

“Although the book is emotionally coloured with righteous anger

and hatred towards the Bolsheviks, we cannot but welcome it as an
honest attempt to narrate the history of the first year of the Russian
revolution.” S. K.

+ − Ath p1367 D 19 ’19 1100w

“The facts here recorded will be most impressive to all who keep
even an approximately open mind on the Russian question.”

+ − Ind 102:66 Ap 10 ’20 150w

 “She might have made her book a skilful and telling arraignment of
her political opponents if she could have restrained her quite
intelligible hatred and indignation. She betrays her prejudice and
weakens her case most seriously in loading on the Bolsheviki the
blame for all that Russia has suffered since the beginning of the
revolution.” Jacob Zeitlin

− + Nation 110:399 Mr 27 ’20 360w

“When we had finished this long book of Mrs Harold Williams, we

asked ourselves why it left us with the taste of the dust of Dead Sea
apples. The answer is, we believe, that nothing is so barren as
perpetual denunciation. Only a political controversialist could be
quite so self-blind as Mrs Williams.”

− Nation [London] 26:402 D 13 ’19 700w

“This book may be recommended as a storehouse of facts, and it is

to be hoped that the author will in due course produce another
volume, bringing the story down from Brest-Litovsk to the present
day.”

+ Sat R 129:62 Ja 17 ’20 540w

“She shows an intimate knowledge of the political convulsions of

1917, and she describes them in a clear and forcible style. The
dominant note of the book is amazement that the Russian people,
with their many good qualities, could have allowed themselves to be
dominated by a gang of scoundrels.”

+ Spec 123:579 N 1 ’19 1450w

 “Partisan and patriot Mrs Williams is, and the reader will not find
in her description of the storm-tossed waters of the revolution any
clear perception of its deeper currents. But the reader will find in her
book a useful chronicle of events and an interesting and vivid
representation of the political kaleidoscope and of the opinion of no
small part of the Russian intelligentsia during that momentous year.”
Reed Lewis

+ − Survey 44:48 Ap 3 ’20 200w

“A connected account of the first phase of the Russian revolution

has been badly needed. Mrs Williams has a clear picture in her own
mind of what led to Bolshevism, and her main theme is easy to trace
throughout the book. In these days, when many English liberals join
in the foolish denunciation of nearly all Russian liberals as counter-
revolutionaries without examining the positive side of their policy, it
is useful to see the aims and policy of the provisional government
clearly and sympathetically restated.”

+ The Times [London] Lit Sup p618 N 6

’19 1000w

WILLIAMS, BEN AMES. Great accident. *$2

(1½c) Macmillan

20–5226

This is a story of American provincial politics and of education

gone wrong. The way Winthrop Chase, junior, had been brought up
by a well meaning father and mother had brought out strongly the
negative side of his character. He always did the thing he was told
not to do and was fast becoming a drunkard. Shrewd old Ames
Caretall, congressman, returns from Washington just as a mayoral
election is coming on. He resolves to take a gambler’s chance with
young Wint and uses his influence to have him elected mayor over
the head of Wint’s own father. How the “joke” does the trick, knocks
manhood into Wint, and develops him into a sober, unusually
decent, honorable and lovable character is the burden of the story.

“This town and its inhabitants stand out with remarkable

clearness, and it is well worth while for English men and women to
read of it. They will see for themselves how different is their country
from that huge one which speaks the same language.” O. W.

+ Ath p16 Ja 7 ’21 1300w

+ Booklist 16:315 Je ’20

“This is a capital story. There are a number of well-drawn

subsidiary personages, making the life of the small town vivid and
often amusing. Its atmosphere is distinctive and typical.” N. H. D.

+ Boston Transcript p4 S 4 ’20 650w

Dial 69:211 Ag ’20 110w

“It is a perfectly good idea and the characters are interesting

enough, but the author seems to be a little bit tired; it all needs to be
keyed up to a higher pitch.”

+ − Ind 103:53 Jl 10 ’20 110w

 “It will go far toward dispelling in the average reader’s mind the
illusion that a realistic presentation of American life must necessarily
be dull, morbid and unduly sophisticated.”

+ N Y Evening Post p3 My 1 ’20 600w

“The merit of the tale lies in its portrayal of small town life, of the
men who control or try to control the political destinies of the
friendly little town of Hardiston, and in an easy and agreeable style.”

+ N Y Times 25:163 Ap 11 ’20 400w

“Two romances and a broad vein of humor balance the political

narrative, making an entertaining if rather unlifelike American tale.”

+ − Springf’d Republican p8a S 19 ’20 420w

WILLIAMS, GAIL. Fear not the crossing. $1.25

(9c) Clode, E. J. 134

20–1895

A series of spirit communications given to the author through

automatic handwriting by the spirit of a man who had but recently
died, and who found it at first very difficult to adjust himself to
conditions on the other side. The messages are given from day to
day, and describe the life beyond death, its great beauty, satisfying
joy, its boundless service for others, and its superiority to our flesh-
bound existence. Advice is given too for our greater serenity of the
spirit while still in the flesh. Think of God, pray to Him, in order that