PLOS COMPUTATIONAL BIOLOGY

RESEARCH ARTICLE

Uncovering the organization of neural circuits

with Generalized Phase Locking Analysis
Shervin Safavi1,2, Theofanis I. Panagiotaropoulos1,3, Vishal Kapoor1,4, Juan F. Ramirez-
Villegas1,5, Nikos K. Logothetis1,4,6, Michel Besserve ID1,7*
1 Department of Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics,
Tübingen, Germany, 2 IMPRS for Cognitive and Systems Neuroscience, University of Tübingen, Tübingen,
Germany, 3 Cognitive Neuroimaging Unit, INSERM, CEA, CNRS, Université Paris-Saclay, NeuroSpin center,
91191 Gif/Yvette, France, 4 International Center for Primate Brain Research (ICPBR), Center for Excellence
in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Sciences (CAS), Shanghai
a1111111111 201602, China, 5 Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria, 6 Centre
a1111111111 for Imaging Sciences, Biomedical Imaging Institute, The University of Manchester, Manchester, United
a1111111111 Kingdom, 7 Department of Empirical Inference, Max Planck Institute for Intelligent Systems and MPI-ETH
a1111111111 Center for Learning Systems, Tübingen, Germany
a1111111111 * [email protected]

Abstract
OPEN ACCESS
Despite the considerable progress of in vivo neural recording techniques, inferring the bio-
Citation: Safavi S, Panagiotaropoulos TI, Kapoor V,
Ramirez-Villegas JF, Logothetis NK, Besserve M
physical mechanisms underlying large scale coordination of brain activity from neural data
(2023) Uncovering the organization of neural remains challenging. One obstacle is the difficulty to link high dimensional functional con-
circuits with Generalized Phase Locking Analysis. nectivity measures to mechanistic models of network activity. We address this issue by
PLoS Comput Biol 19(4): e1010983. https://doi.
investigating spike-field coupling (SFC) measurements, which quantify the synchronization
org/10.1371/journal.pcbi.1010983
between, on the one hand, the action potentials produced by neurons, and on the other
Editor: Daniele Marinazzo, Ghent University,
hand mesoscopic “field” signals, reflecting subthreshold activities at possibly multiple
BELGIUM
recording sites. As the number of recording sites gets large, the amount of pairwise SFC
Received: June 22, 2022
measurements becomes overwhelmingly challenging to interpret. We develop Generalized
Accepted: February 27, 2023 Phase Locking Analysis (GPLA) as an interpretable dimensionality reduction of this multi-
Published: April 3, 2023 variate SFC. GPLA describes the dominant coupling between field activity and neural
Peer Review History: PLOS recognizes the
ensembles across space and frequencies. We show that GPLA features are biophysically
benefits of transparency in the peer review interpretable when used in conjunction with appropriate network models, such that we can
process; therefore, we enable the publication of identify the influence of underlying circuit properties on these features. We demonstrate the
all of the content of peer review and author
statistical benefits and interpretability of this approach in various computational models and
responses alongside final, published articles. The
editorial history of this article is available here: Utah array recordings. The results suggest that GPLA, used jointly with biophysical model-
https://doi.org/10.1371/journal.pcbi.1010983 ing, can help uncover the contribution of recurrent microcircuits to the spatio-temporal
Copyright: © 2023 Safavi et al. This is an open dynamics observed in multi-channel experimental recordings.
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited. Author summary
Data Availability Statement: The present work is a Modern neural recording techniques give access to increasingly highly multivariate spike
methodological study, and no new data have been data, together with spatio-temporal activities of local field potentials reflecting integrative
generated for it. We provide the MatLab codes to processes. We introduce GPLA as a generalized coupling measure between these point-
regenerate all the figures from scratch (except the

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 1 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

schematic figures and figures contain raw

experimental data) in the public repository https:// process and continuous-time activities to help neuroscientists uncover the distributed
github.com/shervinsafavi/gpla.git. organization of neural networks. We develop statistical analysis and modeling methodolo-
Funding: All authors were supported by the Max gies for this measure and demonstrate its interpretability in simulated and experimental
Planck Society. M.B. was supported by the German multi-electrode recordings.
Federal Ministry of Education and Research
(BMBF) through the funding scheme received by
the Tübingen AI Center, FKZ: 01IS18039B. N.K.L.
and V.K. acknowledge the support from the
Shanghai Municipal Science and Technology Major This is a PLOS Computational Biology Methods paper.
Project (Grant No. 2019SHZDZX02). The funders
had no role in study design, data collection and
analysis, decision to publish, or preparation of the
manuscript.

Competing interests: The authors have declared Introduction

that no competing interests exist.
Understanding brain function requires uncovering the relationships between neural mecha-
nisms at different scales [1–3]: from single neurons to microcircuits [4, 5], from microcircuits
to a single brain area [6], and from a single area to the whole brain [7, 8]. Therefore, it is crucial
to develop tools to investigate the cooperative phenomena that can connect different levels of
organization, such as oscillatory neuronal dynamics [3]. These oscillations are hypothesized to
support neural computations [9–13] and various cognitive functions [14–17] and manifest
themselves in Local Field Potentials (LFP), a mesoscopic extracellular signal [18] resulting
from ionic currents flowing across the cellular membranes surrounding the electrode. LFP
oscillatory activity partly reflects a number of subthreshold processes shared by units belong-
ing to underlying neuronal ensembles and responsible for the coordination of their activity
[19–22]. As a consequence, a large body of empirical investigations support the functional rele-
vance of LFP oscillations (for reviews, see [19, 20, 22–24]).
The synchronization between spiking activity and LFP has been observed experimentally
and led to different theories of cognitive functions. Notably, attention has been hypothesized
to rely on interactions between various neural populations coordinated by network oscillations
[25–28]. However, the exact network mechanisms that govern these spike-field coupling (SFC)
phenomena remain elusive, and notably the role played by the phase of the coupling [29–31].
Arguably two major obstacles are (1) that common SFC measures are pairwise [32–38], which
makes the information conveyed about the network increasingly difficult to grasp as the num-
ber of pairs of channels increases and (2) the link between SFC measurements and the underly-
ing neural circuit mechanisms is not well understood, a problem that we will call biophysical
interpretability.
Elaborating on the first obstacle, pairwise analyses are arguably suboptimal for modern
neural recording datasets, as state-of-the-art multichannel electrophysiology systems [39–41]
allow simultaneous recording of hundreds or even thousands of sites [24, 40, 42, 43]. This rep-
resents an unprecedented opportunity to study the large scale collective organization binding
spiking activity of individual units with mesoscopic spatio-temporal dynamics (e. g. wave pat-
terns [44]), but at the same time generates high dimensional matrices of pairwise connectivity
measurements from which extracting interpretable information is a challenge in itself. More-
over, statistical analysis and significance assessment of parallel spike trains is also challenging
(see [45] for a review) and requires novel, more computationally efficient approaches in the
high dimensional setting.
Elaborating on the second obstacle, this shift in data dimensionality also offers the opportu-
nity to go beyond the phenomenological model of synchronization between these activities, to
achieve a precise account of how network properties shape the detailed spatio-temporal

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 2 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

characteristics of collective phenomena. Such account fits the general framework of constitu-
tive mechanistic explanation in Science [46, 47], where the occurrence of a phenomenon is
explained based on mechanisms governing components of the system under study. However,
this requires simple enough links to be established between high-dimensional observations
and properties of biophysical models, which remains largely unaddressed for large-scale neural
networks [48–51]. To reflect this issue, we will call biophysical interpretability the extent to
which quantities derived from brain activity measurements can be related to properties of a
given biophysical model. While methodologies have been developed that elegantly combine
frequency-based analysis, multi-variate methods and dimensionality reduction techniques
[52–54], the outcomes typically remain only interpreted as mere phenomenological models of
brain activity, broadly built on the idea that the brain processes information through networks
of oscillators coupled at different frequencies. As such, these approaches suffer from critical
limitations when it comes to providing mechanistic insights that relate to a biologically realis-
tic understanding of the underlying neural circuits. To go beyond this limitation, model reduc-
tion approaches are used in physics and biology, including neuroscience [55, 56], to simplify
complex models. While these methods have initially mostly been developed to reduce compu-
tational complexity, they have also started to be used to foster interpretability [57]. The charac-
teristics of biophysical model reductions and advanced multivariate data analyses need to be
carefully chosen to allow biophysical interpretability of high-dimensional measurements, and
have not yet been explored for the case of multivariate spike-field coupling.
Thus, we develop a “Generalized Phase Locking Analysis” (GPLA) to address the need for
an efficient multivariate method that, in conjunction with suitable neural models, allows bio-
physical interpretations of spike-field coupling data. GPLA characterizes and assesses statisti-
cally the coupling between the spiking activity of large populations of units and large-scale
spatio-temporal patterns of LFP.
The benefits of this approach are demonstrated in detail with network models with increas-
ing levels of complexity and biophysical realism, and ultimately with neural data. Each of these
settings is designed to demonstrate certain strengths of GPLA. First we provide a theoretical
motivation and illustrate how to interpret the outcome of the analysis with toy models. Then
we illustrate the statistical benefits of GPLA over uni-variate methods with several simple gen-
erative models of spike and LFP. Thereafter, we turn to biophysical interpretability of GPLA
using an analytical reduction of two population (excitatory-inhibitory) neural field models.
This mechanistic interpretation is exemplified in computational models of hippocampal and
cortical neural networks. In particular, we show how studying the phase of GPLA can untangle
the contribution of recurrent interactions to the observed spatio-temporal dynamics. Based on
these results, application of GPLA to Utah array recordings finally provides evidence of strong
feedback inhibition in the macaque prefrontal cortex.

Results
The overarching motivation of this work is to foster a neuroscientific understanding of experi-
mental data by leveraging biophysical models, i.e. models that comprise equations accounting
for the biophysics of neural activity and measurements. Broadly construed, models can be
ranked according to the chosen trade-off between realism and complexity, with on one end
simplified (e.g. low dimensional, linear, . . .) analytically tractable models, whose dependency
on biophysical properties is easily characterized, and on the opposite end, highly detailed
computational models, where the role of biophysical parameters can only be assessed by run-
ning costly simulations. However, when it comes to the use of models for interpreting data,
another key aspect coming into play is the choice of quantities of interest (QoI) (following

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 3 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 1. Interpretability of multivariate SFC through GPLA. (A) Schematic for the concept of biophysical interpretability. A
biophysical model allows to make predictions about some observable quantity derived from neural data, that we call Quantity of
Interest (QoI). The QoI is biophysically interpretable whenever its variations can be explained by changes in some property of the
model. (B) (Top-left) A coupling matrix is estimated from electrophysiology data by gathering complex SFC estimates of all spike-LFP
pairs in a rectangular matrix. Coefficients (Cnm) contain information similar to complex-valued PLV up to a scaling factor: the
magnitude indicates the strength of coupling, and the angle reflects the average timing of the spike occurrence within the period of the
corresponding LFP oscillation. (Bottom-left) The coupling matrix can be approximated using its largest singular value and the
corresponding singular vectors. Singular vectors represent the dominant LFP (blue array) and spiking patterns (red array) and the
singular value (d1), called generalized Phase Locking Value (gPLV), characterizes the spike-field coupling strength for the phenomenon
under study and the chosen frequency. The magnitude of each vector entry indicates a relative coupling of the corresponding unit/
channel, and the phase indicates the relative timing with respect to other units/channels. By convention, the phase of the LFP vector
coefficients’ average is set to zero, such that the phase of the spike vector average reflects the overall phase shift of the spike pattern with
respect to the LFP pattern. (Top-right) A biophysical model accounts for the underlying network connectivity and dynamics, as well as
the measurement process that leads to the collected data. This leads to a theoretical account of multivariate spike-field coupling.
(Bottom-right) Model reduction entails simplifying assumption, leading to a low-rank description of the coupling in the model based
on the key mechanistic parameters. This description is compared to the left-hand side low-rank decomposition, obtained from
experimental data, to infer parameters and interpret the data. All clip art in this figure was designed and drawn by authors M.B. and
S.S..
https://doi.org/10.1371/journal.pcbi.1010983.g001

[57]), which are used to assess qualitatively or quantitatively the match between experimental
data and candidate models. Indeed, some QoIs may be easier to interpret with a given biophys-
ical model than others, in the sense that they have a more straightforward dependency on bio-
physical parameters. This leads to us introducing the notion of biophysical interpretability,
illustrated in Fig 1A and defined as follows: a QoI is biophysically interpretable for a particular

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 4 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

model whenever we can identify biophysical properties of the model that influence the QoI in a
simple way (the simpler, the more interpretable). By “simple”, we refer to the low complexity
of the functional relationship between the properties and the QoI. To fix ideas, functional rela-
tions containing only few biophysical parameters and monotonous functions will be consid-
ered simple, although the choice of notion of complexity may be adapted to the case at hand.
This interpretability property clearly depends on the model employed, and its benefits for ana-
lyzing experimental data relies on the assumption that the chosen model captures well relevant
properties of the ground truth mechanism, as it is the case for any attempt at understanding
empirical data through mechanistic models. The validity of this assumption can never be fully
guarantied and which aspects to incorporate in the model to address a particular question
should be assessed based on the literature. In this work, we rely on neural field models [55],
which lend themselves to analytical treatment, while still accounting for key aspects of the
underlying biophysical network mechanisms. As neurophysiology experiments rely on an
increasing number of recording channels, the choice of QoI has to be made from a space of
increasingly large dimensions, and we argue that the notion of biophysical interpretability can
guide this choice. Specifically, we will consider QoIs that quantify SFC, and a multidimen-
sional generalization of it.

Generalizing SFC to the multivariate setting

QoIs characterizing the coupling between signals originating from a pair of recording channels
are commonly used in Neuroscience. On the one hand, we consider the instantaneous spike
rate λ(t) of a given unit; and on the other hand, oscillatory activity Lf(t) is derived from the
LFP by band-pass filtering in a narrow band of center frequency f. We assume Lf(t) is the com-
plex analytic signal representation of this oscillation, computed using the Hilbert transform
[58], such that Lf ðtÞ ¼ af ðtÞei�f ðtÞ , where af(t) and ϕf(t) are the instantaneous amplitude and
phase of the oscillation, respectively. The coupling between these signals can be characterized
by the covariance
cðf Þ ¼ hlðtÞLf ðtÞi ¼ hlðtÞaf ðtÞei�f ðtÞ i ¼ jcjeiFc ¼ jcjðcosðFc Þ þ i sinðFc ÞÞ ; ð1Þ

where the h�i indicates averaging across time and experimental trials. The complex number c
then reflects the strength of coupling through its modulus |c|, and the dominant LFP phase of
spiking through its argument Fc (see Fig 1(Top-right)). This coupling measure is a modifica-
tion of the Phase-Locking Value (PLV) [33] (see Eq 13), and differs from the latter mainly
through the incorporation of the amplitude of the oscillation in the averaging, and the absence
of normalization by the spike rate. We consider the coupling defined in Eq 1 as a base quantity
to explain our approach, while normalization will be addressed at the end of this section.
Although λ(t) is a priori unknown, c(f) is straightforward to estimate based on observed spike
times, leading to the empirical estimate denoted ^c ðf Þ (see [59]). However, as more channels
are recorded, the number of PLV values to consider increases dramatically, which poses a chal-
lenges to the their interpretation. Alternatively, using dimensionality reduction to synthesize
the information provided by this large number of couplings may provide a more interpretable
picture of the functioning of the underlying circuits.
As illustrated in Fig 1B, Generalized Phase Locking Analysis (GPLA) is introduced as a
dimensionality reduction technique to estimate the key properties of the coupling matrix C(f)
consisting of the pairwise couplings between a large number of units and LFP channels at fre-
^ Þ of the coupling matrix based on spiking activity is defined as fol-
quency f. The estimate Cðf
lows. Given Nm spike times ftkm g for unit m and the analytic signal Lnf ðtÞ that is filtered around

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 5 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

^ Þ is
frequency f for LFP channel n, the (n, m) coordinate of the coupling matrix’s estimate Cðf
computed by summing the values taken by the analytic signal at all spike times (see Fig 1B
(Top-left)),
X
^ Þ ¼
Cðf Lnf ðtkm Þ :
n;m ð2Þ
k

Next, as schematized in Fig 1B(Bottom-left), the coupling matrix is approximated by the

term with the largest singular value d1 of its Singular Value Decomposition (SVD) leading to
X
^ ¼ UDV H ¼
C dk uk vHk � d1 u1 vH1 ; ð3Þ
k

where vHk indicates the transpose conjugate of the vector vk. In this expression, the singular
value d1 is a positive scalar, that we will call generalized Phase Locking Value (gPLV), and
which quantifies the magnitude of the coupling. In order to assess the effect size of d1, but also
to perform significance analysis, normalization of the coupling matrix Cðf ^ Þ is typically per-
formed, as described in section GPLA for electrophysiology data of Materials and methods. In
particular, the LFP time series can be whitened beforehand, such that the outcome of GLPA is
invariant to the LFP power at each frequency. Table 1 indicates for which experiments such a
normalization is applied. The associated complex valued singular vectors in this factorization
will be respectively called the LFP vector, defined as u = u1 and the spike vector, defined as v =
v1. As illustrated in Fig 1B (bottom), the spike vector indicates the pattern of coordinated spik-
ing activity most coupled to LFP oscillations, while the LFP vector reflects the dominant spa-
tio-temporal pattern of LFP involved in this coupling. Importantly, based on Eq 3, the
difference between the phases of each component of u and v reflects the phase lag between
spiking and LFP activities for the respective channels and units. Notably, this implies that all
units and all LFP channels with non-vanishing coefficients in spike and LFP vectors have cor-
related activities at this frequency, as will be further illustrated in the next section. In particular,
two units with non-zero coefficients in the spike vector typically have correlated spike rates at
this frequency. Multiplication of both singular vectors by the same unit complex number leads
to the exact same approximation as Eq 3, reflecting that GPLA only measures the relative
phase between LFP and spikes. To resolve this ambiguity in our analyses, we adopt the conven-
P
tion of setting the phase of the average across all components of the LFP vector hui ¼ n1c k uk
to zero, as illustrated in Fig 1B (bottom). As a consequence, the phase of the mean of the spike
P
vector coefficients hvi ¼ n1u k vk reflects the difference of mean phases between spiking and
LFP activities. See section GPLA for electrophysiology data in Materials and methods for more
details.

Table 1. Summary of normalization by spike count and whitening application in all figures.
Figure num. Spike count normalization type Whitening applied Equations
Fig 2 1/N No 16
Fig 3 1/N No 16
pffiffiffiffi
Fig 4 1= N Yes 17
pffiffiffiffi
Fig 6 1= N Yes 17
pffiffiffiffi
Fig 7 1= N Yes 17
pffiffiffiffi
Fig 8 1= N Yes 17

https://doi.org/10.1371/journal.pcbi.1010983.t001

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 6 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Importantly, we demonstrate GPLA can simultaneously be applied to a neural field model

(analytically or in simulations), to yield a reduced biophysical model (see Fig 1B(Right)). The
outcome of GPLA applied to neural data can then be interpreted based on this reduction, as
explained in section Reduction of complex models based on linear response theory. Notably, this
can be exploited to study the key network characteristics giving rise to the observed spike-field
coupling. Here, we demonstrate the possibility of this hybrid approach merging modeling and
analysis for a certain class of generative models, while further development is needed to extend
it to a more general setting.

Illustration of GPLA and statistical benefits over univariate SFC

We first illustrate how GPLA provides an intuitive phenomenological model of the coupling
between the population of spiking units and LFPs. We use three simulations in which a tran-
sient global LFP oscillation recorded in a single channel (Fig 2A) modulates the firing proba-
bility in 18 spike trains (attributed to neuron-like units). As described on the left column of
Fig 2C–2F, models instantiate (1) a global oscillation driving a synchronous population of neu-
rons (2) wave-like discharges of neurons (similar to the case of “delayed excitation from a sin-
gle oscillator” described by [44]) (3) groups of cells that fire together predominantly at three
distinct phase values of the LFP. For comparison, a fourth simulation is performed with no
coupling. Exemplary spike trains for each model are displayed in the second column of Fig
2C–2F overlaid on the magnified version of the LFP oscillation.
For all models, the coupling is well reflected by the gPLV magnitude obtained from these
simulations, as shown in Fig 2B. Moreover, the phase of the spike vector components resulting
from GPLA summarizes the coupling structure in an intuitive way in Fig 2C–2F (right col-
umn), showing: (1) all components collapse to a single phase, (2) evenly distributed phases of
the spike vector coefficients over a 180 degrees interval, (3) three distinct phases, (4) an isotro-
pic phase distribution, as predicted by mathematical analysis [59].
These simple simulations demonstrate how to interpret the spike vector. Because there is a
single LFP channel in this setting, GPLA straightforwardly combines univariate coupling mea-
sures of each unit. However, statistical analysis of GPLA is different from the univariate case,
as we show next with a setting similar to the above model (3) of Fig 2E but with weaker cou-
pling of individual neurons to the oscillation, leading to values at the edge of significance
(assessed with the surrogate-based test, see section Significance assessment of gPLV in Materials
and methods). An illustrative simulation in the case of low noise and large number of observed
spikes is shown in Fig 3B, together with the corresponding spike vector in Fig 3C, providing
results similar to Fig 2E.
For quantitative analysis, we consider the setting of a single LFP channel and a handful of
neurons are the focus of the analysis (Fig 3A–3E). Such recordings are still common and valu-
able in human electrophysiology experiments for understanding cognition [60, 61]. While
pooling the spikes from all units into a single spike train to get a pooled Phase-Locking-Value
(pPLV) may result in a higher statistical power, it requires the distribution of the locking phase
to be homogeneous across units (e.g., in the case of Fig 2C, but not for Fig 2D and 2E). In con-
trast, GPLA exploits the spike times from multiple neurons to assess the global coupling
between spikes and LFPs without requiring such homogeneity. We ran 5000 simulations with
only 3 units and compared the coupling assessment based on PLV, pPLV, and gPLV. Fig 3D
represents the estimated PLVs, with averages matching the couplings obtained with a larger
number of spikes in Fig 3C. Performance of each measure is assessed based on its detection
rate, which is defined as the percentage of simulations for which significant coupling is
detected, as assessed using spike-jittered surrogate data (see Materials and methods section

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 7 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 2. Illustration of GPLA on simple simulations. (A) Normalized amplitude of LFP-like oscillatory signals. (B) gPLVs for
different models demonstrated in C-F (C-F) Various scenarios of spike-LFP coupling. Left: schematic representation of the
modulating LFP oscillation (circle), and 6 representative neuron-like-units (indicated by the triangles). The color of each
connecting line indicates the locking phase (see bottom colorbar for color code). Center: LFP-like signals within the window
specified by the blue box in A and spikes are represented by overlaid red vertical lines. Right: resulting spike vector is represented
in the third column. (C) Spiking activity globally synchronized to the trough of the LFP oscillation. (D) Sequential discharge of

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 8 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

spikes coupled to the LFP. (E) Three clusters of neurons discharge at different phases of the LFP oscillation (a similar model was
also used in Fig 3). (F) Spiking activity uncoupled to LFP oscillation (independent homogeneous spike trains). Also see Table A
in S1 Appendix for a methodological summary.
https://doi.org/10.1371/journal.pcbi.1010983.g002

Fig 3. Comparison of GPLA and uni-variate spike-field coupling. (A) Normalized amplitude of LFP-like transient oscillatory signal with
additive Gaussian white noise (used in the first simulation). (B) LFP-like signal and overlaid spike raster (colored vertical lines—colors
indicate each population of units with common locking phase) within the window specified by the blue box in (A). (C) Spike vector
coefficients in the complex plane (colors correspond to B). Each dot represents one coefficient of the spike vector corresponding to a single
neuron (note that within each cluster, dots are overlapping as they are similarly coupled). (D) Complex PLVs represented in the complex
plane. Angles indicate the locking phase and the radius of the PLV. The gray point clouds indicate the PLV of multiple simulations and
larger black dots indicate the average values. (E) Performance comparison (in percentage of simulations with significant coupling) of PLV,
pooled PLV (pPLV) and gPLV, for three individual neurons. (F) Example oscillation, original (blue trace) and noisy (black trace) used in the
second simulation. (G) Example coupling matrix related to simulation with a large amount of noise (σ = 5) (H-I) Comparison of GPLA-
based and PLA-based estimation of PLVs for (H) different number of trials and (I) different levels of firing rate. Signal-to-Noise Ratio (SNR)
is defined as the ratio of coupling strength (PLV) to estimation error (the difference between estimated PLV and the ground truth). Also see
Table A in S1 Appendix for a methodological summary.
https://doi.org/10.1371/journal.pcbi.1010983.g003

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 9 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Significance assessment of gPLV) and with a significance threshold of 5%. As it is demonstrated

in Fig 3E, gPLV detection outperforms the competing approaches (PLV and pPLV).
Beyond improved detection of a significant overall coupling, GPLA-based estimation of
pairwise couplings based on the approximation of Eq 3 may also be more accurate than indi-
vidual estimates when the data is very noisy and multivariate, benefiting from the SVD proce-
dure to disentangle noise from the ground truth coupling (see Eq 16 for the expression of
normalized coupling matrix used here). To demonstrate this, we performed another simula-
tion (Fig 3F–3I), similar to the above, but using 50 LFP channels containing oscillations driv-
ing spike-LFP coupling, contaminated by different levels of noise (i. e. adding Gaussian noise
with different variances to the transient oscillation, see section Simulation of phase-locked spike
trains in S1 Appendix for details), and modulating the firing rates of the units, lower firing
rates leading to a larger amount of estimation variance for the PLV [59]. An example LFP trace
with (black) and without (blue) noise is exemplified in Fig 3F and an example coupling matrix
in the presence of noise is also illustrated in Fig 3G. In this case, the ground-truth coupling
matrix has rank one, as all the units are locked to a single frequency (coupling matrices with
higher ranks can also be achieved and analyzed in a similar way, see Fig 4). We ran the simula-
tions with different amounts of LFP noise (indicated on the x-axis of Fig 3H and 3I), computed
the coupling coefficients (similar to Fig 3G) and compared it to ground truth (based on Equa-
tion S2 in S1 Appendix). The Signal-to-Noise Ratio (SNR) was defined as the ratio of coupling
strength (PLV) to estimation error (the difference between estimated PLV and the ground
truth—for more details see section Computing Signal-to-Noise Ratio in S1 Appendix) and was
used to compare the quality of GPLA-based and univariate estimation (indicated in the y-axis
of Fig 3H and 3I). As this simulation demonstrates, the estimation error of the coupling coeffi-
cients is larger for the univariate estimation than for the GPLA-based approach for a broad
range of noise levels (Fig 3H and 3I). Additionally, we can observe a sharp drop of the estima-
tion quality of the GPLA-based approach as the noise increases, likely reflecting a phase transi-
tion phenomenon in high-dimensional random matrices reported in [59]: above some noise
level threshold, singular value and vector information cannot be retrieved from noisy observa-
tions, while they can be recovered with very good accuracy above it. This property is further
exploited in the next section.

Random matrix theory based fast significance assessment

While in the previous section, GPLA’s significance was assessed using surrogate data, this
approach is computationally expensive and provides limited insights into the statistical proper-
ties of GPLA estimates. We also investigated this question using mathematical analysis, and
exploited it to assess more efficiently the significance of multivariate coupling. Singular values
and vectors estimated by GPLA have an intrinsic variability due to the stochasticity of spiking
activity, which can be investigated through stochastic integration and random matrix theory
[62, 63]. In the absence of coupling between spikes and LFP, appropriate preprocessing allows
deriving analytically the asymptotic distribution of univariate and multivariate coupling mea-
sures [59], including the convergence of the squared singular values to the classical March-
enko-Pastur (MP) law [64]. Based on the MP law, we can define an upper bound on the largest
singular values of the coupling matrix that depends only on its dimensions, such that exceed-
ing this bound indicates the significance of the coupling (for more details see Materials and
methods section Analytical test and [59]), leading to a fast analytical test.
We assessed the performance of this test on simulated spikes and LFPs with or without cou-
pling as follows. Briefly, we synthesized multivariate LFP activity by linearly superimposing
several oscillations (denoted Ok(t) in Fig 4A) with different multiplicative weights applied for

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 10 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 4. Statistical analysis of GPLA with a theoretical significance test. (A) LFPs are synthesized by mixing several oscillatory components (Ok(t)).
The vertical red line evidences the phase shift between them. (B) Two exemplary spike trains (each from one of the coupled populations) and the
corresponding LFPs. In the LFP trace on the top, the oscillatory component with the highest frequency is dominant while the bottom one is
dominated by the lowest frequency component. (C) An exemplary coupling matrix for a simulation with two coupled populations. (D-E) Theoretical
Marchenko-Pastur distribution (red lines) and empirical distribution (gray bars) for (D) simulation without coupling and (E) with coupling between
multivariate spikes and LFP (F) Performance of GPLA for the detection of coupling between spike trains and LFPs for different strength of coupling
(y-axis) and different number of spiking units/LFP channels. (G) Type I error for different numbers of spiking units/LFP channels (x-axis), quantified
as the percentage of simulations wherein a significant coupling between spike trains and LFPs is detected in absence of ground truth coupling. The
horizontal green line indicates the %5 threshold. (H) Mean-squared-error of GPLA-based estimation of the number of populations coupled to LFP
for varying coupling strengths (y-axis) and numbers of coupled populations (x-axis). See also Table A for a methodological summary.
https://doi.org/10.1371/journal.pcbi.1010983.g004

each LFP channel and generated the spike trains of each unit with Poisson statistics. As for the
coupling between spikes and LFPs, 2/5th of the units were coupled to the LFP oscillations
(exemplified in Fig 4B), while the remaining units had homogeneous Poisson spike trains (for
details see S1 Appendix, section Simulation of phase-locked spike trains). The estimated

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 11 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

coupling matrix computed based on Eq 17 for a simulation with 100 spike trains and 100 LFPs
is exemplified in Fig 4C, where we have two coupled populations, one coupled to the lowest-
frequency and one coupled to the highest-frequency oscillatory component of the LFP
(reflected by the top-right and bottom-left bright blocks of the coupling matrix in Fig 4C and
sample spike trains and LFP in Fig 4B).
By computing the SVD of the coupling matrix after application of the preprocessing
explained in S1 Appendix, section LFP pre-processing, we can obtain a spectral distribution for
the squared singular values, which matches the prediction of the theory (Fig 4D and 4E). In
the absence of coupling between spikes and LFP signals (Fig 4D), the distribution of the eigen-
values closely follows the MP law and in the presence of coupling, the largest eigenvalue
exceeds the significance bound predicted by random matrix theory (RMT) (see section Analyt-
ical test in Materials and methods for more details).
We further quantified the type I and II error of this analytical test. For type II error, we ran
the simulations with non-zero coupling between spikes and LFP signals. As shown in Fig 4F,
GPLA was able to detect a significant coupling between spike and LFP even when the coupling
strength was as small as 0.05 (no coupling corresponds to 0 strength and perfect coupling cor-
responds to 1). These results also show the performance of the test does not degrade with the
increasing dimension of the data through the number of recording channels (Fig 4F). This is
in contrast with assessing individually the significance of pairwise couplings, for which correc-
tion for multiple comparisons (e.g., Bonferroni) would typically lead to a degradation of the
power of the test as the number of units/LFPs increases. This is particularly relevant for weaker
couplings, as they may lose significance after correction for multiple comparisons. Addition-
ally, we quantified the type I error of the test by running simulations with no coupling between
spikes and LFP and quantified the number of false positives. Our results show that our analyti-
cal test has a small (< 5%) false positive rate (Fig 4G).
We also quantified the performance of the method for estimating the number of popula-
tions coupled to different rhythms. In this simulation, the number of coupled populations can
be determined by the number of significant singular values (see the section Simulation of
phase-locked spike trains in S1 Appendix and section Analytical test in Materials and methods
for more details). Similar to the simulation explained earlier (Fig 4A–4C), we simulated multi-
ple (1–10) non-overlapping cell assemblies synchronized to different LFP rhythms (with dif-
ferent frequencies within a narrow range of 11–15.5 Hz). When the coupling was larger than a
minimum strength of 0.5, the method was able to capture the number of populations with very
low error, MSE < 0.015 (Fig 4H).

Neural field modeling of SFC

While the above results have addressed GPLA’s outcome from a statistical perspective, its bio-
physical interpretation requires modeling the underlying neural network dynamics. The basis
for this interpretation will be a two-population neural field model: a spatially distributed rate
model of the activity of two interacting homogeneous populations: excitatory pyramidal cells
(E population) and inhibitory interneurons (I population) [65, 66]. The model is governed by
three basic input-output relations (see S1 Appendix, section Analytical neural field modeling of
spike-field coupling) and depicted in Fig 5A: (1) the dynamics of the average somatic mem-
brane potentials VE and VI of each population is governed by exogenous post-synaptic cur-
rents η originating from other cortical or subcortical structures as well as recurrent excitatory
and inhibitory post-synaptic currents (EPSC and IPSC) sE and sI; (2) the population spike rates
λE and λI are a function of their respective membrane potentials; and (3) EPSC and IPSC are
each controlled by the spike rate of their afferent population (E and I respectively). In the

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 12 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 5. Generative model of spike-LFP coupling. (A) A two-population neural field model of neural dynamics. Vk, λk and sk indicate respectively
somatic membrane potential, firing rate and post-synaptic current for Excitatory (k = E) and Inhibitory (k = I) populations. η indicates the exogenous
input to the circuit. Arrows indicate the causal dependence between variables of the model. (B) Schematic representation of the model’s connectivity:
local inhibition and long range excitation, together with the driving by exogenous synaptic currents. (C) Schematic representation of the contribution
of postsynaptic currents to the electric field, affected by the spatial distribution of synapses over the dendritic tree and the geometry of pyramidal cells.
From left to right: Schematic representation of pyramidal neurons, electric field, electrode (gray bar), contribution of each current (EPSC, IPSC and
exogenous current, leak current is also contributing to LFP but is not shown) to the LFP profile along the electrode’s axis (D) Simple microcircuit
structure leading to a temporal ordering of the local activities of different kinds LFP ! excitation ! inhibition (E) Simple microcircuit structure
leading to a temporal ordering of activities of the same kind across space: the location receiving stronger exogenous input leads other locations, such
that amplitude gradient leads to phase gradients.
https://doi.org/10.1371/journal.pcbi.1010983.g005

context of large-scale recordings, the neural population can be distributed across one or several
spatial directions. Following a classical approximation depicted in Fig 5B, inhibitory connec-
tions are assumed local [67–69], such that coupling between cells surrounding distinct record-
ing locations happens exclusively through excitatory axons (sE(x) may depend on λE at other
spatial locations than x) as well as through common exogenous input current η.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 13 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

For the LFP L(t), resulting from the conduction of trans-membrane currents in the extra-
cellular space, we assume the contribution of currents flowing through the membrane of inter-
neurons is negligible, based on the weakness of the anisotropy induced by their dendritic
geometry across the population [70–72]. The LFP thus results exclusively from pyramidal cell’s
membrane currents. Which currents (IPSC, EPSC, leak current, exogenous current) affect the
most the recorded LFP at a given spatial location depends on multiple factors: the geometry of
the cells, the distribution of synapses (inhibitory, excitatory, exogenous) onto them, and the
geometry of the electrodes [19, 20, 23]. Fig 5C provides a schematic of how the differentiated
location of synaptic boutons over the dendritic tree may result in variable algebraic contribu-
tions of each type of current to each recording channel.
In the following simplistic but biophysically interpretable connectivity scenarios, this
model provides insights on how the underlying microcircuit parameters influence SFC prop-
erties. Fig 5D depicts a microcircuit receiving exogenous inputs exclusively onto the pyramidal
cells’ dendrites (no feedforward inhibition), while I cells receive local excitatory inputs, but do
not synapse back onto E cells (no feedback inhibition). If we assume additionally that sub-
threshold activity is dominated by the exogenous input currents and proportional to the mea-
sured LFP, then the lag induced by the membrane potential dynamics then results in a positive
(frequency-dependent) lag of excitatory activity with respect to the LFP (reflecting the input),
while inhibitory activity is itself delayed with respect to excitation. For an exogenous input
oscillating at an arbitrary frequency, this implies a phase lag configuration between the (oscil-
latory) responses of these variables.
Circuit assumptions may also provide insights on how the same variable varies across spa-
tial locations, which we illustrate by extending spatially the previous microcircuit scenario
(with no feedforward and feedback inhibition), by adding horizontal E-E connectivity with a
decreasing strength as a function of distance (see Fig 5E). If we assume the activity results from
a spatially inhomogeneous oscillatory input, with larger input amplitude at a given side (on the
left in Fig 5E), the delay induced by membrane dynamics entails the propagation of the activi-
ties from one side of the circuit to the opposite. This leads to an interesting relationship
between the phase and amplitude of oscillatory activity: the location of the largest amplitude is
ahead of time with respect to the neighboring locations with smaller amplitudes. Interestingly,
these propagation-like patterns are induced by the assumed network horizontal connectivity,
while the input to the structure does not have phase lags at different locations [44]. These sim-
ple connectivity scenarios indicate that phase and amplitude of oscillatory activities, which
GPLA captures through the spike and LFP vectors, are informative about the underlying
microcircuit structure and dynamics. More realistic scenarios must take into account recur-
rent interactions between cell populations, as we will see in the next sections.
Note that up to this point, the developed neural field models can be used to interpret uni-
variate as well as multivariate SFC. When the number of pairs for which SFC can be computed
becomes large, a difficulty of a different nature appears: how can we synthesize the interpreta-
tions that we get from all these pairs? While ad hoc approaches for selecting relevant pairs to
derive interpretations from is an option, we can try instead to establish interpretability of QoIs
derived from GPLA, as we found support for its relevance for describing coupling properties
of the system as a whole.

Reduction of complex models based on linear response theory

In order to analyze more complex circuits, a systematic and quantitative way to link model
parameters to the coupling between network activities at a given frequency is required. We
assume small-amplitude perturbations in the neighborhood of an operating point, such that

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 14 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

the static sigmoidal conversion of membrane potentials into spike rates can be linearized (see
section Analytical neural field modeling of spike-field coupling in S1 Appendix and [55, 73–
75]). This leads to a linear time-invariant model, whose behavior is fully characterized by its
amplitude and phase response to oscillatory inputs at each frequency. When considering the
coupling between firing rate (λE(x1, t)) and field (L(x2, t)) at two locations x1 and x2, linearity
and time invariance entails the existence of transfer functions (denoted HlE and HL respec-
tively), linking the spatial distributions of the time domain Fourier transforms of network
activities, denoted l^ ðx; f Þ and Lðx;
^ f Þ, to the one of the exogenous input Z^ðx; f Þ, as follows:
E
Z Z
^ 0
l E ðx; f Þ ¼ HlE ðx; x ; f Þ^ 0 0 ^
Z ðx ; f Þdx and Lðx; f Þ ¼ HL ðx; x0 ; f Þ^ Z ðx0 ; f Þdx0 : ð4Þ

Next, this model can be simplified by assuming an approximate space-frequency separabil-

ity:
Z^ðx; f Þ � nðxÞ^� ðf Þ ; at each location x and each frequency f : ð5Þ

Using the above transfer functions, this leads to both spike rate and LFP being proportional
to the exogenous input, with respective multiplicative coefficients ψE(x, f) and ψL(x, f) defined
as follows:
Z
^ ^ f Þ � cL ðx; f Þ^� ðf Þ : ð6Þ
l E ðx; f Þ � HlE ðx; x0 ; f Þnðx0 Þ^� ðf Þdx0 ¼ cE ðx; f Þ^� ðf Þ and Lðx;

As a consequence, the coupling between LFP and E spikes at respective locations x1 and x2
writes (up to a multiplicative constant, see section Details for the low rank approximation of
Equation 7 in S1 Appendix)
^ ðx ; f Þ∗ Lðx
Cx1 ;x2 ðf Þ � hl ^ 1 ; f Þi � cL ðx1 ; f ÞcE ðx2 ; f Þ∗ hj^� ðf Þj2 i ; ð7Þ
E 2

where z* denotes the complex conjugate of z. This shows that the coupling between L at x1 and
λE at x2 is separable in the spatial variables (x1, x2), and characterized by two functions of
2
space: one for the field, ψL, and one for the excitatory spiking, ψE. In particular, as hj^� ðf Þj i is a
positive number, the phase of Cx1 ;x2 reflects a property of the underlying circuit irrespective of
its input, and given by the phase difference between ψL and ψE at the considered frequency
and locations. Importantly, the functions ψL and ψE also describe the coupling between the
same variables at different locations, e.g. hl^ ðx ; f Þ∗ l
^ ðx ; f Þi � c ðx ; f Þc ðx ; f Þ∗ hj^� ðf Þj2 i,
E 2 E 1 E 1 E 2
such that their phase distribution across locations informs about the spatial functional connec-
tivity of the network. Likewise, ψI can be defined for inhibitory activity and merged with ψE to
describe the rates of all units of both populations.
In practice, Cx1 ;x2 ðf Þ can be measured at only a finite number of locations, corresponding to
electrode channels where L, λE and λI are recorded. This leads to a rectangular matrix C(f) esti-
mated by multiple pairwise SFC estimations, combining excitatory and inhibitory units. The
above separability Eq 5 then implies that C(f) is a rank-one matrix, such that it can be decom-
posed exactly according to GPLA, where the LFP vector reflects ψL while the spike vector
concatenating E and I units reflects ψE and ψI. Overall, Eq 6 imply that the spatial distribution
of the phase and magnitude spike and LFP vectors is influenced by the underlying network
interactions (shaping the transfer functions such as HlE and HL), as well as by the type of cur-
rents that dominate the LFP. As we will illustrate in the next sections, the analysis of these
GPLA features across frequencies is thus a rich source of information to validate assumptions
about local network organization based on experimental multivariate data.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 15 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Application to spike-field dynamics during sharp wave-ripples

The phenomenon of hippocampal Sharp Wave-Ripples (SWR) is one of the most striking
examples of neural activity entangling spike and LFP dynamics in multiple frequency bands,
attributable to specific mechanisms of the underlying microcircuit [76]. Specifically, SWRs are
brief episodes observed in hippocampal LFP traces combining a high-frequency oscillation
(the ripple) to a low-frequency biphasic deflection (the sharp-wave). Moreover, these LFP
activities are well known to be synchronized with spiking activity, with each cell-type firing at
a specific phase of the ripple oscillation [76], but also with further spike-field couplings at
lower frequencies [77].
We use simulations of in-vivo SWR described in [78] in order to demonstrate what insights
GPLA can provide about the underlying hippocampal network mechanisms. The model gen-
erates realistic spiking and LFP activity in subfields CA1 and CA3, based on populations of
two-compartment Hodgkin-Huxley neurons distributed along two distant one dimensional
grids representing the strata of each subfield. In this model, the connectivity of CA3 is charac-
terized by strong recurrent excitatory auto-associational E − E connections, together with E !
I connections and short-range I ! E and I − I synapses (see Fig 6A for a schematic representa-
tion). In contrast, local E − E connections are absent in CA1, but both E and I cells receive
feedforward excitation from CA3. LFPs were generated from the total trans-membrane cur-
rents using line current density approximation, and measured by two laminar multi-shank
electrodes (see S1 Appendix, section Simulation of hippocampal sharp wave-ripples for more
details).
We first apply GPLA to a single hippocampal subfield, CA1, as various studies suggest
SWRs emerge from it in response to afferent CA2- and CA3-ensemble synchronous discharges
[79, 80]. In this simulation, LFP and unit recordings are distributed along two orthogonal spa-
tial directions (laminar for LFPs and horizontal for units). We use a total of 157 peri-ripple
traces of simulated LFPs and spikes of both populations (inhibitory and excitatory) of duration
approximately 1 sec. Exemplary traces of simulated LFP and population firing rate of the CA1
population (pyramidal cells and inhibitory interneurons belonging to CA1) are shown in
Fig 6B.
GPLA results for representative frequency bands are provided in Fig 6C–6E and for all
bands covering the 1–180Hz interval in S2 Fig. The overall coupling magnitude (gPLV) was
significant for all frequencies (Fig 6C), according to both surrogate (based on spike jittering,
p < 0.05) and analytical (based on random matrix theory) tests. In particular, the strongest
coupling was detected in the ripple band (80–180 Hz), in line with results obtained with classi-
cal univariate techniques on experimental data [76].
The LFP vectors strongly overlap across frequency bands, and exhibit a biphasic electric
potential profile typical of laminar recordings (Fig 6D). This corresponds to the field generated
by the dipolar geometric arrangement of sources and sinks in the parallel two-compartment
models of pyramidal neurons used for this simulation. To check the quantitative agreement
between the LFP vector and the original model of LFP generation in this simulation, we com-
puted analytically the total LFP generated passively by all pyramidal cells using the original
LFP simulation code of [78], and assuming all cells have identical trans-membrane currents
flowing through their somatic and dendritic compartments (see S1 Appendix, section Simula-
tion of hippocampal sharp wave-ripples). While the dendritic current reflects the post-synaptic
input of the cell, somatic currents are taken opposite to preserve the charge neutrality of each
cell. The resulting theoretical LFP profile of the pyramidal populations are highly similar to the
LFP vector (cosine similarity > 0.97 for LFP vector of all three frequencies in Fig 6D). Note
that the sign of the LFP vectors’ coefficients results from our convention of setting the phase of

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 16 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 6. GPLA of hippocampal SWRs generated by a biophysical model of [78]. (A) Hippocampal multi-
compartment model. Top: Canonical circuits of CA1 and CA3. Bottom: Schematic of the whole model (blue,
excitatory connections; red, inhibitory. (B) From top to bottom: Example broad band CA1 LFP trace, band-pass
filtered trace of the CA1 LFP in ripple band (80–180 Hz), and population firing rate of CA1 neurons. (C) CA1 gPLVs.
Triangles indicate the significance assessed based on empirical (blue triangles, p<0.05) and theoretical (red triangles)
tests. (D) LFP vectors for GPLA of CA1 (blue and red curves are overlapping), superimposed to ground truth dipolar
LFP profile passively generated by the two compartment models of the pyramidal cell population. The right-hand side
schematic illustrates the vertical dimensions of one cell’s compartments. (E) Spike vector coefficients for CA1 in
several frequency bands (left: pyramidal cells, right: interneurons). (F) Average phase lag between LFP and spike
vectors across frequencies for: outcome GPLA on hippocampal SWRs, theoretical analysis of Mass2D (without and
with feedforward inhibition) and MassAlpha neural mass models. Dashed green line indicate MassAlpha filtered over
the frequency bands used for GPLA. (G) Difference between phases of E and I populations based on GPLA the
MassAlpha neural mass model filtered in the same bands (IPSP was used as LFP proxy). (H) Spike vector resulting
from GPLA jointly applied to CA1 and CA3 in the gamma band (20–40 Hz). Related Supplementary Figures: S1 Fig,
Use of EPSP as LFP proxy; S2 Fig, Joint GPLA of CA3 and CA1 activities; S3 Fig, Joint GPLA of CA3 and CA1
activities.
https://doi.org/10.1371/journal.pcbi.1010983.g006

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 17 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

its mean to zero (see Fig 1C). As the LFP vector coefficients are divided into two groups of
opposite sign, a positive sign is attributed to the set of coefficients that weight the most in the
overall sum. In the context of laminar recordings, one could as well adopt a different conven-
tion ascribing a fixed sign to coefficients located in the peri-somatic layer (named stratum pyr-
amidale in CA1). This would then lead to a sign consistent with classical analyses, e. g.,
triggered averaging based on spikes or oscillatory peak [81]. These results, inline with recent
studies [82], overall suggest that the LFP vector can be exploited to further study the current
sources and sinks causing the LFP, e. g. through current source density analysis [83, 84]. Nota-
bly, the result of a similar analysis based on uni-variate phase locking analysis leads to a profile
which is incompatible with the ground truth (see S4 Fig).
Moreover, the spike vector components’ distribution in the complex plane (Fig 6E) sup-
ports that both E and I cells are synchronized to CA1 LFP in the ripple band (80–180 Hz), but
at different phases, in line with experimental and simulation results [76, 78]. This extends the
observation made for one-directional E ! I coupling in Fig 5D to a more realistic case of
recurrent E − I interactions. Interestingly, pyramidal cells can be clearly differentiated from
interneurons based only on their components’ respective phase in the spike vector, showing
that interneurons lead pyramidal cells in lower frequency bands, while drastically switch to the
converse in high frequencies (see also Fig 6F). This direct outcome of GPLA avoids the task of
choosing a reference LFP channel on an ad hoc basis to compare the phase of univariate cou-
plings of each units relative to it. Moreover, it can be used not only for inferring cell types
from experimental data [85], but also, based on its biophysical interpretability, to address
mechanistic questions, as we illustrate next.
We focus on the classical question of oscillogenesis, aiming at uncovering the circuit mech-
anisms responsible for the emergence of fast oscillations. The way it is addressed in the litera-
ture is paradigmatic of mechanistic questions: scientists resort to experimentation and
modelling to chose between a restricted number of candidate hypotheses. Two classical candi-
date mechanisms are the Interneuron Network Gamma (ING) relying on the coupling
between inhibitory interneurons under tonic excitation [86], and Pyramidal Interneuron Net-
work Gamma (PING) relying on the interaction between excitatory principal cells and inhibi-
tory interneurons [87, 88]. We take advantage of these biophysically realistic hippocampal
simulations, for which the ING mechanism has been shown to be the generator of high fre-
quency activity [78], to assess how biophysical interpretability can help decide which of the
two above hypothesis is the right one. To do that, we will derive analytically SFC’s phase in lin-
earized neural mass models of the microcircuit activity with different levels of complexity: the
simplest accounting for PING, and the more complex also accounting for ING.
In line with [74], we first designed the Mass2D model, taking into account somatic time
constants (resulting from membrane capacitance and leak currents), but neglecting synaptic
dynamics (see S1 Appendix, section Analysis and simulation of two population neural mass
models). As a result, Mass2D is a 2 dimensional dynamical system, allowing only PING reso-
nance through the interactions between pyramidal cells and interneurons. As shown in Fig 6F
for typical parameters, and demonstrated analytically (see S1 Appendix, section Analysis and
simulation of two population neural mass models) the predicted phase shift across frequencies
could neither account for the driving by interneurons in CA1, nor for phase changes in high
frequencies (> 30Hz). Notably, incorporating strong feedforward inhibition (FFI) did not
improve the qualitative match between the analytical predictions and GPLA’s outcome. The
inappropriateness of Mass2D is in line with the current understanding of SWR emergence in
CA1 through the pacing of pyramidal activity by delayed I − I interactions [89], as Mass2D
does not account for them.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 18 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

The emergence of oscillations through I − I interactions is well understood mathematically,

showing that sufficiently strong delayed recurrent inhibition gives rise to resonance or sus-
tained oscillations [90]. We account for this ING mechanism in an extension of the Mass2D
model, the MassAlpha model, by including an additional synaptic delay and/or a synaptic time
constant for I − I synapses [74], through the use of so-called alpha synapses. (see S1 Appendix,
section Analysis and simulation of two population neural mass models for details). Interest-
ingly, the resulting sign of the phase shift between E and I populations of this model is now in
qualitative agreement with GPLA estimation (Fig 6F), exhibiting a reversal in the lead-lag rela-
tion between populations as frequency grows, thereby providing more support for the ING
oscillogenesis hypothesis than for PING, in line with evidence provided in the original study
[78]. The SFC phase is thus biologically interpretable for the chosen family of neural mass
models, is the sense that a phase reversal across the frequency axis appears when lagged I-I
interactions responsible for ING are introduced. Because this phase reversal also appears in
simulations exhibiting ING that rely on a much more complex model (Hodgkin-Huxley neu-
rons instead of neural masses), this supports the idea that biophysical interpretations of SFC
based on our simplified models may generalize to more realistic settings and to experimental
recordings.
Another interesting property of the network is the phase shift between each individual pop-
ulation and the LFP, which is simply reflected in the phases of the spike vector coefficients
averaged across each population (E and I), due to our chosen phase convention (see Eq 23).
Given that the LFP is a linear combination of all post-synaptic currents of the network, we can
levarage biological interpretability of GPLA to evaluate which of these currents is the most rep-
resentative of the observed spike-LFP phase relation. As shown in Fig 6G, the choice of the
IPSP as an LFP proxy in the MassAlpha model accounts qualitatively, as frequency increases,
for (1) monotonous phase increase of the I population, (2) the phase slope reversal of the E
population (see S1 Fig for a comparison with using the EPSP as LFP proxy). In contrast, using
EPSP as an LFP proxy still fails to reproduce these two aspects (see S1 Fig), illustrating how
GPLA, beyond microcircuit dynamics, may also help address the cellular underpinnings of
experimentally observed LFP [91]. This overall suggests that GPLA combined with neural
mass modeling of a structure can provide insights into the microcircuit dynamics underlying
phenomena as complex as sharp-wave ripples, despite neglecting many biophysical details. We
however emphasize that we restricted ourselves to a qualitative comparison of GPLA features
for choosing from a restricted set of biophysical models, which best matches the ground truth
mechanisms. This approach holds potential for designing a full-fledged GPLA-based model
selection tool, whose development is left to future work.
Importantly, GPLA can also provide further insights when concurrent recordings from
multiple regions are available. It allows investigating the coordination of spiking activities
across structures without relying on an arbitrary choice of reference LFP channel (also see the
analysis of neural data for a realistic demonstration, S8 Fig), by automatically extracting a
multi-channel LFP activity (reflected by the LFP vector) that relates the most to spiking activi-
ties at a given frequency. We illustrate this by running GPLA jointly on spikes and LFPs from
both CA1 and its afferent structure CA3, using the exact same model as above. Fig 6H depicts
coefficients of the resulting spike vector, showing CA1 and CA3 neurons are all coupled to the
field activity with cell-type-specific phases in the gamma band (20–40 Hz) (see S3 Fig) that are
consistent with the GPLA obtained from individual structures (see S2 Fig). This notably sug-
gests that the gamma activity has a dominant coherent component spanning the two structures
consistently with current hypotheses that this rhythm supports communication between sub-
fields during memory trace replay [78, 92].

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 19 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Application to spatio-temporal patterns of neural field models

One context where biophysically interpretable multivariate methods such as GPLA hold
potential is the analysis of cortical spatio-temporal dynamics. Horizontal connectivity is
believed to endow many regions with distributed information processing capabilities [30, 44,
93]. However, how underlying connectivity properties relate to experimentally observed
multi-channel recordings remains largely elusive. We assessed the ability of GPLA to address
this question by first simulating electrode array recordings of a piece of cortical surface with a
2D neural field model, as described in Fig 5. We used an exponentially decaying horizontal
excitatory connectivity with a spatial scale constant r0 = 440μm, following recent analyses of
cortical recordings [91]. The spatio-temporal dynamics were down-sampled spatially on a grid
with a step size Δx = 800μm, representing the inter-electrode distance of a putative electrode
array of 1.2cm size (see S1 Appendix, section Analysis and simulations of neural field models
for details). The field is stimulated by a synchronous excitatory exogenous input with a narrow
(1.4 mm STD) isotropic Gaussian spatial amplitude distribution reaching its maximum at the
center of the field. We compared the spatio-temporal dynamics for two choices of connectivity
for which the input-free network has a stable equilibrium. First, we consider the weak inhibi-
tion case (Fig 7A), for which inhibitory (I) cells have weak feedback inhibition (I ! E), relative
to the self-excitation caused by E − E horizontal connections. The resulting activity is akin to
stochastic fluctuations, due to the exogenous input, around a stable node equilibrium. Second,
in the strong inhibition case (Fig 7B), the larger excitability of inhibitory neurons strengthens
their influence on excitation and leads to activity fluctuating around a stable spiral equilibrium,
reflecting a tendency of perturbations to oscillate around this point (Fig 7B) [94]. In both
cases, the computed excitatory population rate is used to simulate the spike train of one excit-
atory unit per spatial electrode on this grid, in line with the observation that excitatory units
are more easily detected experimentally due to their open field configuration [95]. GPLA is
then computed between this excitatory spiking activity and different LFP proxies. The results
in Fig 7C–7H are computed using the total EPSP resulting from horizontal E-E connections as
LFP proxy (i. e. excluding exogenous excitation). We observe key differences between the
GPLA of the two systems, predicted by linear response theory (see S1 Appendix section Analy-
sis and simulations of neural field models).
First, as reflected in the gPLV values (Fig 7C), spike-field coupling appears stronger in the
lower frequency bands in the case of weak recurrent inhibition, while in the case of strong
recurrent inhibition we observe a stronger coupling at intermediate frequencies. Notably, the
peak of spike-field coupling in intermediate frequencies for strong inhibition is in line with
models of the prefrontal cortex with the same enhanced feedback inhibition [96], exhibiting a
resonance in the beta range (25Hz).
Second, as demonstrated in the previous neural mass model simulation, the global spike-
LFP phase shift may also be informative about the underlying neural circuits. We can compute
the average phase shift between the spike and LFP vectors as a function of the frequency band
to see a clear difference between the two models. Strong recurrent inhibition leads to phase
advance of the spiking activity in the low frequency, in contrast with the weak recurrent inhibi-
tion case showing a consistent lag of excitatory spiking across frequencies (Fig 7E).
Third, the relationship between the spatial variations of modulus and phase of the spike vec-
tor is different across these two networks. In the simulation with strong recurrent inhibition,
the phase of spike vector coefficients as a function of their modulus for the frequency band
associated with maximum gPLV for each model indicates that the phase of the spike vector
coefficients decreases (i. e. the oscillation lags further relative to the LFP) for larger modulus
(p < 10−4, F-test on the linear regression model; N = 69), whereas, in the simulation with weak

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 20 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 7. Neural field simulation using EPSP as LFP proxy. (A) Simulation with weak recurrent inhibition. Example time course at
center location for exogenous input (top), E- and I- populations rates (bottom). (B) Same as A for strong recurrent inhibition. (C)
gPLV as a function of frequency for both models. (D) Phase of spike vector coefficients as a function of their modulus for the
frequency band yielding maximum gPLV for both models (each dot one coefficient, and the continuous lines are plotted based on
linear regression). (E) Shift between averaged phase of spike vector and averaged phase of LFP vector, as a function of frequency. (F)
Schematic of the spike vector’s phase gradient in the two models according to Eq 8. X-axis is the distance from center and y-axis is
the connectivity strength. Line color indicates the phase according to the colorbar on the right. (G) Resulting GPLA in 3 frequency
bands (indicated on the left) for weak recurrent inhibition (model schematized in A). (H) Same as G for strong recurrent inhibition
(model schematized in B). In both G and H, color of pixel code the values of spike/LFP vector coefficients, with colorbar on top of H.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 21 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Colors are represented in HSV mode, in which a complex number (reiϕ) is represented by hue and brightness of a pixel. Hue of a
pixel indicates the phase (ϕ) and the brightness of a pixel indicates the magnitude (r). Related supplementary Figures: S5 Fig, Phase-
modulus relation dependency on level of inhibition; S6 Fig, GPLA using IPSP as LFP proxy.
https://doi.org/10.1371/journal.pcbi.1010983.g007

recurrent inhibition, phase is not correlated with modulus (p > 0.3, F-test on the linear regres-
sion model; N = 69) (Fig 7D).
This last difference between the two connectivity cases can be directly interpreted based on
the spatial maps of spike vector coefficients across the array. Indeed, models exhibit a different
radial phase map in both situations (Fig 7G and 7H), reflecting how phase changes as magni-
tude decreases when going away from the center (the location with the largest input). This gra-
dient can be predicted by theoretical analysis of a one dimensional neural field, as we show in
detail in S1 Appendix, section Spatio-temporal phase analysis in 1D. Briefly, the spike vector
can be approximated by the spatial convolution of the input spatial pattern at a given temporal
frequency f by a kernel of the form
jxjaðf Þ jxjRe½aðf Þ� ijxjIm½aðf Þ�
kðxÞ ¼ e ¼e e : ð8Þ

The first term of this kernel has a negative real number multiplied by distance in the expo-
nential that makes the activity decay away from the locations where exogenous input is the
highest, as intuitively expected from the horizontal connectivity of the circuit. For the second
term of the product in Eq 8, the imaginary number in the argument of the exponential
enforces a spatial phase gradient in response to the input, which depends on the sign of the
imaginary part of a. If this sign is positive, responses at the location of the highest input will be
ahead of time with respect to their surrounding in the considered band, as reflected by their
larger spike vector phase in the top illustration of Fig 7F. On the contrary, if Im[a] is negative,
locations with the highest input are lagging behind (bottom illustration of Fig 7F). Interest-
ingly, these spatial features of the spike vector can be related to the biophysical parameters of
the neural field model. Indeed, we can show that the frequency-dependent complex number a
(f) that controls this behavior satisfies the approximate relation (valid at low frequencies, see
S1 Appendix section Spatio-temporal phase analysis in 1D
1
a2 � ½1 þ nE!I nI!E nE!E i2ptf ð2nE!I nI!E nE!E Þ� : ð9Þ
r02

with r0 the above defined spatial scale of excitatory horizontal connectivity, νP Q the magnitude
of synaptic connectivity from population Q to P. It can be deduced from this expression that the
sign of the imaginary part of a (same as for a2) will depend on the relative strength of recurrent
inhibition onto pyramidal cells, controlled by νE IνI E, with respect to recurrent excitation con-
trolled by νE E. Intuitively, having no recurrent inhibition leads to Im[a] > 0, and classical prop-
agation, mediated by excitatory horizontal connections, away from the location that received an
input. In contrast, large recurrent inhibition leads to 2νE IνI E >>νE E and Im[a] < 0. This
can be interpreted as a tendency of recurrent inhibition to “suppress” the input that created the
response, generating a “wave” converging back to the points where the input was highest. The
theory also predicts that large values of νE IνI E, as used in the strongly recurrent simulation,
can generate strong phase gradients. In contrast, linear stability constrains the values of νE E to
remain small, reflecting our choice for the simulations, and resulting in a comparatively moder-
ate slope for the weakly recurrent case. More quantitatively, we further analyzed in S5 Fig the
relation between the complex number a resulting from a linear approximation of our simulated
neural field models, and the linear regression coefficient of the phase-modulus analysis per-
formed in (Fig 7D), for four choices of recurrent inhibition parameters (see Table 2), ranging

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 22 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Table 2. List of 2D neural field model parameters.

Parameter name Symbol Value (for each level of recurrent inhibition)
weak lower med. upper med. strong
E membrane time constant τE 20ms 20ms 20ms 20ms
I membrane time constant τI 20ms 20ms 20ms 20ms
E-E synaptic strength ~
n E!E 0.2 0.2 0.2 0.2
I-I synaptic strength n I!I
~ 0 0 0 0
E ! I synaptic strength n E!I
~ 0.2 0.2 0.2 0.2
I ! E synaptic strength n I!E
~ 1 1 1 1
E excitability χE 1 1 1 1
I excitability χI 0.1 .33 1 3.33
E sigmoid threshold Vth,E 0 0 0 0
I sigmoid threshold Vth,I 0 1 5 5
E maximum rate QE 20Hz 20Hz 20Hz 20Hz
I maximum rate QI 20Hz 20Hz 20Hz 20Hz
https://doi.org/10.1371/journal.pcbi.1010983.t002

from weak to strong inhibition. The result exhibits a clear monotonous relation between the
regression coefficient and Im[a] as well as Im½a�
Re½a�
. Note however that this relation is not one to one,
as a characterizes the properties of a kernel that is convolved to the exogenous input to the struc-
ture to yield the spike vector, thereby resulting in a spatial smoothing of the phase.
Overall, contrasting multiple cases shows that modifications of the strength of feedback
inhibition are reflected not only in the dominant frequency of spike-LFP synchronization (Fig
7C), but also in the spike-LFP shifts of the GPLA results (Fig 7E), and in the relationship
between modulus and phase of spike vector coefficients (Fig 7D). Notably, these observations
are being made in the absence of specific oscillatory activity nor spatial phase gradient of the
exogenous input (which influences the activity synchronously across the array). Therefore, it
supports that the observation of complex coordinated activity, such traveling waves-like phase
gradients, may emerge from local recurrent interactions in the recorded regions, instead of
resulting from the passive driving by spatio-temporally coordinated activity originating from
other brain regions.
As it has been argued in the literature that LFP activity may in some cases reflect inhibitory
activity [91], we also provide GPLA results when taking the IPSP activity as LFP proxy in S6
Fig. The variations of GPLA features across the frequency axis witness clear differences with
respect to the results of Fig 7C–7E, in particular when it comes to the phase difference between
spike and LFP phases. This suggests that GPLA also provides information that allow to infer
which neural processes are reflected in LFP activity.

Analysis of Utah array data in the prefrontal cortex

The biophysical interpretability of GPLA features demonstrated in the context of neural field
simulations suggests it can provide mechanistic insights about experimental recordings of spa-
tio-temporal cortical activity. Indeed, electrode arrays are able to record the activity of hun-
dreds of units and LFP channels spatially distributed along the cortical surface, and GPLA can
be used to link these activities to recurrent cortical circuits, believed to play a key role in infor-
mation processing. We apply GPLA to Utah array (10 × 10 electrodes, inter-electrode distance
400μm) recordings from the ventrolateral prefrontal cortex of one anaesthetized rhesus mon-
key (see Fig 8A). LFP signals were preprocessed as described in S1 Appendix, section Animal

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 23 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Fig 8. Application to electrophysiological recordings in non-human primate PFC. (A) Location of the Utah array,
anterior to the arcuate sulcus (red line) and inferior to the principal sulcus (green line). (B) Broadband trace of the
recorded LFP (from the recording channels indicated in C). (C) Utah array spatial map identifying channel IDs shown
in B. (D) Spike rasters for all recorded neurons. (E-F) Example spike trains (red bars) and filtered LFP (black traces) in
the frequency ranges (E) 3–5 Hz and (F) 15–30 Hz. (G) gPLV values. Triangles indicate the significance assessed based
on surrogate (blue triangles) and analytical test (red triangles) tests. (H) Phase of spike vector coefficients as a function
of its modulus for the frequencies indicated in the legend (one dot per coefficient, continuous lines indicate linear
regression). (I-K) LFP and spike vectors for frequency (I) 3–5 Hz, (J) 5–15 Hz, and (K) 15–30 Hz. The first column
depicts the LFP (blue dots) and spike (red dots) in the complex plane. The second column depicts the fitted von Mises
distribution to phase of LFP and spike vectors. Third and forth columns respectively represent the spatial distribution
of phase of LFP and spike vectors values on the array (see C). White pixels in the third column (LFP vector) indicate
the recording channels that were not used in the recording and in the fourth column (spike vector), white pixels
indicate the recording channels with insufficient number of spikes (multiunit activity with a minimum of 5 Hz firing).
In the last two columns, colors are represented in HSV mode, in which a complex number (reiϕ) is represented by hue
and brightness of a pixel. The hue of a pixel indicates the phase (ϕ) and the brightness of a pixel indicates the modulus
(r). The colorbar is depicted on the right. Related supplementary Figure: S7 Fig, Analysis of PFC Utah array data.
https://doi.org/10.1371/journal.pcbi.1010983.g008

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 24 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

preparation and intracortical recordings, and multi-unit activity with a minimum of 5 Hz firing
rate was used. Recorded signals are exemplified in Fig 8B–8F. Exemplary LFP traces are illus-
trated in Fig 8B. Each trace is recorded from the location specified in Fig 8C. Spike trains are
also displayed in Fig 8D (for the same epoch used in Fig 8B). As the analysis is performed in
band-limited frequency ranges, we also exemplified band-passed LFP signals (together with
spikes) in Fig 8E and 8F. The dataset consisted of 200 trials of visual stimulation (10 sec) and
inter-trials (10 sec) each 20 sec.
Computing GPLA in different frequency bands revealed that the strongest coupling was in
the alpha range (5–15Hz) (Fig 8G). Furthermore, we assessed the significance of coupling with
both surrogate and analytical tests (see Materials and methods, section Significance assessment
of gPLV). GPLA above 50 or 60 Hz should be considered with caution, as in high frequencies
the spike-LFP relationships may be affected by the contamination of high frequency LFP
bands by spike waveforms of units recorded in the same channel [97, 98]. This may bias spike-
LFP coupling towards the specific relation between the spiking of those specific units and the
surrounding field, instead of capturing the relation of the underlying population rate to this
field, as assumed in neural field models.
Fig 8I–8K further shows the spike and LFP vectors for the three frequencies with the largest
coupling according to their gPLVs (for other frequencies, see S7 Fig). Representing spike and
LFP vectors in the complex plane (Fig 8I–8K first column), suggests that the relative phases of
spike and LFP vectors are different across these three frequencies. To demonstrate the differ-
ence more clearly, we fit von Mises distributions to the pooled phase of all coefficients of the
vectors (Fig 8I–8K second column). The sign of the spike-LFP phase differences changes
across frequencies, with spikes ahead of time with respect to LFP in low frequency, while lag-
ging at higher frequencies. This behavior is similar to the above analysis of strongly recurrent
neural field model (Fig 7G), when EPSP is taken as an LFP proxy.
The spatial mappings of the LFP and spike vectors on the Utah array (Fig 8I–8K, third and
fourth column) also demonstrate a spatial structure in the modulus and phase of the LFP and
spike vectors, revealing localized regions with stronger participation in the locking, in particu-
lar in the beta range 15–30 Hz (green pixels at the middle-top and -bottom in Fig 8K, fourth
column). We hypothesize this is due to a higher activation of spatially localized populations, as
supported by anatomical studies of the PFC [99, 100] and electrophysiological [101] studies.
Notably, capturing this aspect of the circuitry from the neural data based uni-variate phase
locking analysis relies on finding a suitable choice of LFP reference channel, which is typically
challenging (see S8 Fig, for comparison of multi-variate analysis and examples of uni-variate
based on two different choices of reference channel).
Furthermore, in the alpha band (5–15 Hz), exhibiting the strongest coupling between spike
and LFP, the spike vector coefficients’ moduli are significantly negatively correlated with their
phase (Fig 8H, p < 10−6, F-test on the linear regression model; N = 66). Interestingly, we
observe again a similar behavior in the above neural field simulation with strong recurrent
inhibition, but not in the simulation with weak recurrent inhibition (Fig 7D). Notably, the
result of a similar analysis based on uni-variate phase locking analysis leads to a profile incom-
patible with our conclusion based on neural field simulation (see S9 Fig).
Overall, these results suggest a neural field with excitatory horizontal connections and
strong local recurrent inhibition as a plausible model for the recorded prefrontal circuits, in
line with what has been suggested by previous modeling work [96, 102]. This analysis illus-
trates how GPLA can support the mechanistic understanding of high-dimensional experimen-
tal recordings.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 25 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

Discussion
In spite of the relevance of spike-field relationships for assaying coordination mechanisms in
brain networks [19, 20, 22–24], they are still not systematically investigated in the context of
highly multivariate recordings. Potential reasons could be the lack of multivariate methodolo-
gies for investigating such coupling beyond a single pair of spiking unit and a LFP channel,
and interpretability challenges.
In this study, we developed Generalized Phase Locking Analysis (GPLA) as—to the best of
our knowledge—the first multivariate method with demonstrated biophysically interpretabil-
ity for investigating the coupling between spatially distributed spiking and LFP activity.
GPLA summarizes the coupling between multiple LFP spatio-temporal patterns and multiple
spiking units in a concise way. At a given frequency, the spike and LFP vectors represent the
dominant LFP and spiking spatio-temporal distribution, while the generalized Phase Locking
Value (gPLV) characterizes the strength of the coupling between LFP and spike patterns.
Some of the conclusions we draw based on GPLA may to some extent also be achievable with
univariate techniques, but in contrast to GPLA, this typically requires ad hoc decisions or guid-
ing univariate methods with considerable amount of prior knowledge on the structure under
study. For instance, univariate techniques can be used for analyses we described in Fig 6E
and 6H, provided a suitable LFP reference channel is used to assess the coupling of all
recorded units. Choosing such channel is not trivial unless it is justified, for example, by
prior knowledge on the hippocampal circuitry. Even in such case, prior knowledge may not
reflect accurately the properties of the recordings and bias the analysis. An arbitrary choice of
reference channel will not faithfully reflect the dominant coherent activity with units primar-
ily synchronize. Certainly, such caveats are even more pronounced when investigating struc-
tures with less prior knowledge and with recording techniques yielding a larger number of
channels.
We demonstrated that GPLA’s outcome features, such as the overall spike-LFP phase shift,
the phase shift between different cell types (excitatory and inhibitory), and the spatial phase
gradients, provide information about the overall organization of the recorded structure that
are not easily quantifiable with simpler measurements.
First, application to realistic simulations of hippocampal SWR revealed various characteris-
tics of hippocampal circuitry with minimal prior knowledge. Second, in order to better inter-
pret spike and LFP vectors’ spatial distribution, we also simulated spatially extended neural
field models and demonstrated that phase gradients of spike and LFP vectors in these neural
field models reflect properties of the underlying microcircuit connectivity (such as the strength
of recurrent interactions). Finally, the application of GPLA to experimental recordings sug-
gests a global coupling between spiking activity and LFP traveling wave in vlPFC in line with
our simulations of a neural field endowed with strong recurrent inhibition.
Statistical properties of gPLV were investigated to develop an empirical and theoretical
framework for assessing the significance of coupling. The theoretical statistical test built upon
Random Matrix Theory [59] makes the method applicable to high dimensional electrophysiol-
ogy data with low run-time complexity, which is important for modern probes such as Neuro-
pixel, featuring 960 recording sites [40]. In contrast, conventional statistical testing procedures
based on the generation of surrogate data become computationally expensive as the number of
recorded neurons increases.

Comparison to existing approaches

To the best of our knowledge, there are very few studies that include the information of multi-
ple LFP channels and multiple spiking units for investigating spike-LFP interactions. In

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 26 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

particular, among approaches exploiting multiple LFP channels, none fully exploit the statisti-
cal relation between spiking activity recorded from multiple sites.
The Spike-Triggered Average (STA) of LFP is one of the common multivariate technique
for characterizing spike-LFP relationship [103, 104]. It has moreover been interpreted as a
measure of functional connectivity [104] (but also see [105] and [106]). Although STA can
exploit multivariate LFP signals, it can only be computed based on a single spike train, thereby
ignoring the information provided by the remaining units. Similarly, even sophisticated exten-
sions of spike-triggered averaging of LFP [91] still rely on the information of individual spiking
units. In a similar vein, the study of [107], which showed that the probability of spiking can be
statistically related to the LFP phase in multiple distant regions, was also limited to spiking
units taken individually.
This appears clearly as a limitation, because statistical relationships between the spiking
activity of different units, such as lags between the activity of different types of neurons (e. g.
excitatory and inhibitory neurons) [108] can inform us about the organization of the neural
circuit. Notably, this is supported by our simulations and previous experimental work [85].
Apart from works that specifically target spike-field coupling, a body of methodological
studies by van der Meij and colleagues use the idea of extracting a dominant frequency cou-
pling structure with dimensionality reduction techniques [52–54], akin to GPLA’s principle.
In spite of the similarities between these methodologies from a data analysis perspective,
GPLA-based investigation of spike-LFP coupling further leads to a biophysical interpretations
in terms of underlying circuit properties, while this key question is left unaddressed by other
approaches. This is due to the ability of GPLA to allow both dimensionality reduction (of
experimental recordings) and model reduction (of neural field model) such that the outcome
of both reductions can be related.

Limitations and potential extensions

One limitation of GPLA is that it considers the underlying network dynamics to be fixed for
the analyzed data. Although the use of GPLA on simulation of Hippocampal Sharp Wave-Rip-
ples demonstrates that an application on even such transient and aperiodic signals is insightful
(Fig 6), but certainly due to the non-stationarity of neural dynamics, the time-resolved analysis
of spike-LFP data (that likely required further methodological development) may improve our
understanding of the underlying processes. As an alternative, it is however possible to apply
the present methodology to portions of recordings containing identified transient phenomena,
such as hippocampal Sharp Wave-Ripples, that are likely key to understand brain function
[109, 110]. For example, as LFPs result from the superposition of electric potentials from mul-
tiple sources and can capture various coordinated or cooperative phenomena, LFP decomposi-
tion techniques can temporally isolate these epochs of coordinated activity and application of
GPLA to these epochs can characterize how each neuron is participating in the collective activ-
ity and/or to what degree, it is coupled to the larger-scale dynamics.
Another limitation comes from the nature of SVD, leading to orthogonal singular vectors
that may or may not capture the properties of distinct physiological processes. We therefore
mostly limited the scope of this study to capturing the dominant coupling between spikes and
LFP, reflected in the largest SV and corresponding vectors. However, as simulations used in
Fig 4 demonstrate in simple cases, the number of significant SVs may correctly identify the
number of neuronal population coupled to different rhythms. In general, the amount of infor-
mation neglected by limiting the analysis to the largest singular value, highly depends on the
settings under study. We have demonstrated a variety of them in this manuscript. For instance,
the simulation used in Fig 3 exemplifies a small loss, and for Fig 6 a large one. Certainly, more

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 27 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

quantitative approaches can also be taken, for instance, by quantifying this loss by the ratio of
the largest singular value to the sum of all singular values.
Furthermore, GPLA can also be improved by exploiting a better univariate estimation
method. Various novel methodologies for assessing pairwise spike-field coupling have been
developed in recent years [34–38, 111, 112] each providing some improvements over classical
measures such as PLV. For instance, [38] proposed a bias-free estimation of spike-LFP cou-
pling in the low firing rate regime. Replacing the coefficients of coupling matrix (Eq 17) with
these improved pairwise estimates may bring those benefits to GPLA as well. Nevertheless, the
pairwise estimate used in the present paper has the benefit of yielding well behaved statistical
properties as the number of recording channels gets large, allowing to quickly assess the signif-
icance of the coupling using Random Matrix Theory. Alternative pairwise coupling estimates
would likely need to be adapted in order to preserve the statistical benefits of our approach.
This typically requires calculating the asymptotic distribution of the coupling statistics and
devising and appropriate normalization thereafter. In case the new coupling measures are not
adaptable to the analytical test, the surrogate-based test remains applicable at the expense of
heavier computational costs.

Neuroscientific interpretation of GPLA

Due to the complexity of the structure and dynamics of spatially extended neural networks,
interpreting the outcome of statistically sound approaches such as GPLA in terms of biological
mechanisms remains challenging. Thanks to the analysis of neural mass/field models, we
could link several features of GPLA to a mechanistic interpretation. First, we applied this strat-
egy to simulations from a biophysically realistic model of hippocampal ripples in order to use
a system for which the underlying mechanism are well understood, but more complex than
the neural field models used to interpret GPLA results. Despite the discrepancy between mod-
els, this showed that increasing the complexity of neural mass models using properties that are
qualitatively in line with the key ground truth underlying mechanisms (e. g. inhibitory synap-
tic delays), allowed reproducing qualitatively GPLA results of these simulations, making the
approach interpretable. This allowed in particular (1) to relate the LFP vector to the laminar
distribution of field potential generated by current dipoles, (2) to link the phases of the spike
vector to cell types and recurrent I-I dynamics.
Next, we used neural field simulations in order to find interpretations of GPLA characteris-
tics that can be exploited in the context of cortical electrode array recordings. This is an impor-
tant step as the mechanisms underlying spatio-temporal phenomena observed in vivo remain
largely elusive. While keeping the complexity of these models minimal (using exponentially
decaying horizontal excitation and local inhibition), we could already observe that altering the
microcircuit structure resulted in interpretable qualitative modifications of GPLA’s outcome,
in particular regarding the phase gradients of spike and LFP vectors across the array. Finally,
our analysis of Utah array recordings suggests the key GPLA features exhibited in simulation
can also be estimated in real data and provide insights into the underlying organization of the
recorded circuits.
As mentioned when introducing the concept of biophysical interpretability, the reliability
of mechanistic interpretations drawn from GPLA crucially depends on the ability of the
reduced biophysical models that we use to approximate key ground truth mechanisms under-
lying the data. Although no absolute guarantees can be provided, we showed in two sets of sim-
ulated data that the linearized neural field approximations provided qualitative insights in line
with ground truth mechanisms, which were based on more complex (notably non-linear)
models. Overall, the simple rate models we investigated have the benefit of lending themselves

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 28 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

to approximate analytical treatment, providing direct insights into the role played by network
parameters in GPLA characteristics. Neural mass modeling has of course inherent limitations
due to approximating local population activity by their mean rate, such as their typical inability
to account for synchronization of spike times. However, multiple refinements of these models
have been developed and offer potential for improving biological realism. Notably, next gener-
ation neural mass models are able to capture event-related synchronization between neurons
[113, 114] and can incorporate the dynamics of intrinsic currents that are key to modeling
complex phenomena empirically observed, such as spindle oscillations [115]. In addition, neu-
ral field models can be improved in light of the knowledge about the horizontal connectivity of
the structure, which may not be monotonous (for example see recent findings on non-monot-
onous correlation structure in V1 [116] and PFC [101]), and heterogeneous [117].
More generally, a mechanistic interpretation of GPLA results in a given structure strongly
relies on the accuracy of the assumptions made to perform analytical and/or computational
modeling. One aspect that entails limitations is the linear response theory on which we base
our interpretations in the present work. Linearization is typically justified for a stable system
exhibiting low amplitude fluctuations around its equilibrium point. However, non-linear
model reduction techniques such as the Galerkin method [118] allows to extend low dimen-
sional, interpretable approximations of high-dimensional systems to more general settings.
The investigation of more complex models will benefit from incorporating systematic
parameter estimation approaches, taking inspiration from inference techniques that have been
developed for modeling the activity of one or several neurons [119, 120] and combining them
with the present model and dimensionality reduction approaches to ensure tractable
estimation.
Ultimately, our results support the relevance of GPLA for studying distributed information
processing in higher-tier cortical areas such as PFC and hippocampus, where spike-LFP inter-
actions have proven key to elucidating the neural basis of cognitive functions such as working
memory [121, 122], memory consolidation and spatial navigation [123, 124]. This approach is
likely to provide further insights about coordination mechanisms by shifting the focus from
properties of individual units to characteristics of spatially extended networks taken as a
whole.

Materials and methods

Ethics statement
The neural data used in this study were recorded from the ventrolateral prefrontal cortex
(vlPFC) of one anaesthetised adult, male rhesus monkey (macaca mulatta) by using Utah
microelectrode arrays [Blackrock Microsystems [125]] (more details on these experiments are
provided in a previous study exploiting this data by [101]). All experiments were approved by
the local government authorities (Regierungspräsidium, Tübingen, Baden-Württemberg, Ger-
many), and were in full compliance with the guidelines of the European Community (EUVD
86/609/EEC) for the care and use of laboratory animals.

GPLA for electrophysiology data

GPLA proceeds in several steps: preprocessing of multi-channel LFP signals, construction of
the coupling matrix, and its low-rank approximation. Finally, parameters of this low-rank
approximation are standardized following specific normalization conventions allowing their
easy interpretation and comparison. These steps are described in the following subsections.
LFP pre-processing. Prior to computing couplings, the LFP signal is pre-processed, first
by filtering in the frequency band of interest. The choice of the filter bandwidth for the purpose

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 29 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

of extracting the instantaneous phase or analytic signal in a particular band is subjected to a

trade-off. On one hand, the signal requires a narrow enough band-pass filtering to provide us
a proper estimate of the phases [58]. On the other hand, the filtered signal should preserve the
temporal dynamics in the frequency of interest. The second step extracts the analytical signal
using the Hilbert transform, resulting in a complex-valued signal containing both the ampli-
tude and phase of LFP. In the optional third step (see section Necessity of whitening and post-
processing), we whiten the LFPs. We need to decorrelate LFP signals recorded in different
channels by applying a whitening operator. Whitening is only necessary to be able to use tools
from Random Matrix Theory [62] for the purpose of statistical analysis, otherwise generalized
phase locking value, spike and LFP vectors can all be calculated in the original channel space.
In both cases, GPLA outputs can be interpreted in the channel space (by inverting the whiten-
ing operation if it has been applied). For more detail on the rationale for the inclusion of the
whitening step, see section Analytical test and [59].
We consider LFPs and spiking units are recorded repeatedly over K trials, and each trial has
length T (number of time-points). We represent LFPs of trial k by L(k), which is a (nc × T)
matrix, where nc is the number of LFP recording channels. To simplify the notations, by L(k)
we refer to analytical signals, i. e. band-passed in a particular frequency range and Hilbert
transformed signals. We denote the collection of NmðkÞ spike times of unit m at trial k by
ftjm;ðkÞ gj¼1:::N ðkÞ (ftjm;ðkÞ g contains the time-point indices of the LFP data for which spikes occur).
m

We introduce a reduced-ranked whitening operator which is a modified version of the con-

ventional whitening that decorrelates the data, in this case, LFP signals. We customized this
procedure in order to accommodate GPLA’s needs, i. e. (1) avoid over-amplification of noise
components of LFP (which are reflected in smaller eigenvalues of LFP covariance matrix) in
the whitening operator, and (2) eliminate factors of variability that are not consistent across
trials.
In our reduced-ranked whitening, we first reduce the rank of the LFP covariance matrix, by
truncating the eigenvalue decomposition of LFP covariance matrix. We choose the number of
components such that 99% of variance is explained with the reduced rank covariance matrix.
In order to find the number of components that account for 99% of the total variance of the
LFP covariance matrix, we concatenate LFPs of all trials into a larger nc × KT matrix, denoted
by L and compute the eigenvalue decomposition of the covariance matrix,
1 H
CovðLÞ ¼ LL ; ð10Þ
T

where .H indicates the transpose complex conjugate (should be noted that, analytical signal L,
is a complex-valued matrix). We denote the number of components needed to explain 99% of
variance of LFP covariance matrix by neffc . We find the reduced number of components, nc ,
eff

eff
based on all trials, and we use nc to define the whitening operator of individual trials. The
reduced rank single-trial LFP covariance matrix is denoted by Covred ðLðkÞ Þ, and computed as
follows,
eff
nc
X
ðkÞ H
red
Cov ðL Þ ¼ lðkÞ
ðkÞ ðkÞ
p xp ðxp Þ ;
ð11Þ
p¼1

ðkÞ
where lðkÞ
k and xk respectively denote the eigenvalue and eigenvectors of the LFP covariance
matrix of trial k. We denote the whitened LFP of trial k by LðkÞ
w , and compute it as follows,

1 H
ðkÞ 2
LðkÞ ðkÞ
w ¼ ðL Þ ðX Þ L
ðkÞ
; ð12Þ

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 30 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

where Λ(k) is a neff eff

c � nc diagonal matrix containing the eigenvalues of the above single-trial
reduced rank LFP covariance matrix, and X(k) is a nc � neff
c matrix containing the eigenvectors

xkðkÞ .
Coupling matrix. Given the spike times of a single spike train ftjðkÞ gj¼1:::N ðkÞ and LðkÞ
w a sin-
gle channel pre-processed LFP analytic signal (as explained in section LFP pre-processing) and
its phase ϕ (= ∠L), the conventional measure of spike-LFP coupling, Phase Locking Value
(PLV), defined as follows:
N ðkÞ � �
1 X K X
ðkÞ
PLV ¼ tot exp i� ðkÞ ; ð13Þ
N k¼1 j¼1 tj

where, i is the imaginary unit (i2 = −1), and N(k) is the number of spikes occurring during the
trial k, Ntot is the total number of spikes occurred across all trials, i. e.
X
K
N tot ¼ N ðkÞ : ð14Þ
k¼1

In addition to PLV, we introduce a similar coupling statistics, denoted by c,

ðkÞ
1 X K X
N
c ¼ pffiffiffiffiffiffiffi LðkÞ
ðkÞ ; ð15Þ
N tot k¼1 j¼1 tj

to be used when the theoretical significance test is intended to be used (see section Analytical
test) (for summary on type of normalization used in different figures see Table 1). The cou-
pling statistics c is different from PLV in two ways. First, in PLV only the phase information
from the continuous signal is used, while for c, we use both the phase and amplitude of the
LFP signal. This is motivated by evidence that inclusion of the amplitude can improve the cou-
pling measure [126, 127] by weighting the contribution of spikes in the coupling measure by
the LFP amplitude at the correspond spike time, as well as by theoretical considerations (see
section Analytical test for more details). The second difference is, for c we have normalization
pffiffiffiffiffiffiffi
by square root of the number of spikes rather the number of spikes (division by N tot in Eq 15
p ffi ffiffi ffi ffiffi ffi
versus Ntot in Eq 13). Basically, a scaling by N tot is needed to normalize the variance of entires
of the coupling matrix to 1, in order to be able to use tools from Random Matrix Theory [62]
(see [59] for more details).
A multivariate generalization of the coupling statistics, could be achieved by collecting the
coupling statistics between all spiking units and LFP signals. Given spike times ftjm;ðkÞ gj¼1:::N ðkÞ ,
m

�ðkÞ ðkÞ
w LFP phase, and Lw the analytical LFP, we can define the coupling matrix C, based on PLV
(Eq 13, also similar to [82]) as follows,
ðkÞ
Nm � �
1 X K X
ðkÞ
ðCÞn;m ¼ tot exp ið� Þn;tðkÞ ; ð16Þ
Nm k¼1 j¼1 j

or based on c (Eq 15),

ðkÞ
N
1 X K X
m

ðCÞn;m ¼ pffiffiffiffitot
ffiffiffi ðLðkÞ Þn;tðkÞ ; ð17Þ
Nm k¼1 j¼1 j

where m, j and n respectively indicate the index of spiking unit, index of spike time and index

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 31 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

of LFP channel and Nm refers to number of spikes recorded in spiking unit m. Readers can
also refer to [59, Section 4] for a different formulation.
Let nc and ns be the number of LFP channels and number of spiking units, respectively, C is
thus a nc × ns complex-valued matrix (or neff eff
c � ns if whitening is applied). As nc (or nc ) and ns
are not necessarily equal in electrophysiological datasets, the coupling matrix is not square in
general.
Our coupling matrix is thus designed as a multivariate generalization of univariate coupling
measures in order to capture the overall synchronization between the spiking activity and the
phase of a global oscillatory dynamics in a given frequency band.
Low rank decomposition. Each column of the coupling matrix C has a common spiking
unit whose locking is computed with respect to different LFP channels (called LFP vectors).
Conversely, each row collects the phase locking values of all spiking channels to a common
LFP reference channel. In order to achieve a compact and interpretable representation of this
high dimensional object, we compute the Singular Value Decomposition (SVD) of the cou-
pling matrix of the form

X
p

C ¼ UDV H ¼ dk uk vHk ; ð18Þ

k¼1

where (dk) is a tuple of positive scalars, the singular values (SV), listed in decreasing order. The
complex valued vectors uk and vk are, respectively, the nc/neffc - and ns-dimensional singular vec-
tors associated to a given SV dk. One important property of SVD is that keeping only the first
term in Eq (18), with SV d1, achieves the best rank-one approximation of the matrix,
C � d1 u1 vH1 , in the least square sense [128, Theorem 7.29].
Post-processing. In order to make the outputs of GPLA interpretable, we introduce a few
post-processing steps. An unwhitening and rescaling procedure is introduced to reverse some
normalization discussed in previous sections LFP pre-processing, Coupling matrix, and Low
rank decomposition, and a rotational transformation is introduced in order to represent the
singular vectors in a more interpretable fashion.
Representation of singular vectors: Following the conventional mathematical representation
of SVD in Eq 3, U and V are unitary matrices i. e. UHU = I and VHV = I. This implies that all
singular vectors are unit norm, and all the information regarding the strength of coupling is
absorbed in the singular values on the diagonal matrix D. As explained in main text (see sec-
tions Reduction of complex models based on linear response theory and Generalizing SFC to the
multivariate setting), the relative magnitude and phase of singular vectors coefficients can be
used to interpret the relative contribution of individual LFP channel and individual spiking
unit to the coordinated pattern captured by the largest singular value.
We can summarize the coupling matrix with three quantities:

C � ðgPLVÞ:vLFP vspike H : ð19Þ

However the coefficient of both singular vectors can be rotated of the same arbitrary angle
in the complex plane, as the rotation transformation in the complex plane does not change the
SVD factorization, i. e.
H
udvH ¼ udvH e iy0 iy0
e ¼e iy0
udðe iy0
vÞ : ð20Þ

We exploit this free parameter to make the GPLA more neuroscientifically interpretable by
shifting the phase of both spike and LFP vectors with �LFP , where �LFP and �spike are the

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 32 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

average spike and LFP phases, defined as,

X
nc

�LFP ¼ ff ðvLFP Þi ; ð21Þ

i¼1

X
nu

�spike ¼ ff ðvspike Þi : ð22Þ

i¼1

The rationale behind it is to center the coefficient of the rotated LFP vector
i�LFP
vLFP ¼ vLFP e
(g ) around zero phase in the complex plane and the rotated spike vector,
i�LFP
vg
spike ¼ vspike e ð23Þ

preserves the angular difference of Fd of the spikes with respect to the LFP, defined as

Fd ¼ �LFP �spike : ð24Þ

With this chosen convention, we obtain the final GPLA factorization

H
vLFP vg
C � ðgPLVÞ:g spike : ð25Þ

We can also apply the phase difference between average LFP and spike vectors (Fd) to
gPLV as it can summarize the overall phase shift between LFP and spikes. Given that gPLV is
always a real positive value, by this convention, we add an extra information to gPLV.
We thus define a complex gPLV (gPLV g ¼ gPLVe iFd ) whose magnitude indicates the cou-
pling strength between spikes and LFPs as in phase locking value (PLV) and its angle indicates
the overall phase difference between spiking activity and LFP which is similar to locking phase
in classical univariate phase locking analysis. This is an arbitrary choice to some degree, never-
theless it allows to interpret the GPLA output similarly to classical univariate phase locking
analysis. Needless to mention, when the magnitude of gPLV is small, this overall phase differ-
ence is not meaningful (similar to the case where PLV is small, the locking phase is not
meaningful).
Unwhitening: As discussed in section LFP pre-processing, due to theoretical considerations,
and in particular for applicability of our analytical significance test (see Significance assess-
ment of gPLV), we whiten the LFPs prior to any other processing. In order to retrieve the orig-
inal structure of the LFP i. e. retrieve all the correlations that were present in the original LFP
signals but was diminished by the whitening, we need to “revert” the whitening i. e. unwhiten
the LFP vector resulting from GPLA. This can be achieved by computing the unwhitening
operator W−1 and apply it to the LFP vector,
unwhiten
vLFP ¼ W 1 vLFP : ð26Þ

In order to find this operator, we first concatenate whitened LFPs of all trials (resulting
−1
from Eq 12) into a larger matrix Lw (neffc � KT). Then we estimate W by using a linear regres-
−1
sion with unwhitned and whitened LFPs (W is the nc � neff c matrix of coefficient for
regression).
Rescaling: As introduced in Eq 15, the coefficients of the coupling matrix are normalized by
the square root of the number of spikes. This choice of normalization is different from the one
used in conventional PLV (Eq 13). This will lead to inhomogeneous weighting of spiking units
according to their variability of their firing rate. We “revert” this weighting later on by dividing

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 33 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

the spike vector by the square root of number of spikes,

vrescaled
Spike
~;
¼ vSpike � N ð27Þ

where � is the (entrywise) Hadamard division and N ~ ¼ fNmtot gm¼1;...;n , which is a vector con-
s

sisting of total spike counts (similar to Eq 14) of all the neurons (indexed by m) used in GPLA.
Furthermore, to preserve the original norm of the spike vector (unit magnitude), we also need
to normalize the spike vector by its norm,
vrescaled
Spike
vfinal
Spike ¼ : ð28Þ
k vrescaled
Spike k

Necessity of whitening and post-processing. The whitening (and the subsequent post-
processing) is necessary to have the advantage of applicability of the analytical significance
test. LFPs are typically very correlated signals, leading to strong statistical dependencies
between the coefficients of the estimated coupling matrix C, which affects the statistics of the
singular values (and consequently gPLV). Whitening removes correlations before computing
spike-LFP coupling. However, if statistical testing based on surrogate data is intended, it is pos-
sible to skip the whitening step and proceed directly with constructing the coupling matrix
and low rank estimation (see Fig 3). In that case, entries of the coupling can be filled by con-
ventional PLVs (see Eq 16), or other choices of spike-LFP coupling measures [34–38, 111, 112]
(also see the section Limitations and potential extensions for further elaboration). In this case,
whitening of the LFP can be skipped and subsequent “Unwhitening and rescaling” discussed
in section Post-processing is not necessary anymore.
Optional normalization for gPLV. As gPLV is a singular value of a matrix, it grows with
the dimensions of the coupling matrix. This makes the comparison of gPLV resulting from dif-
ferent datasets difficult. For instance, assume the hypothetical situation of having two datasets
recorded from two homogeneous populations of neurons, if the strength of coupling is the
same in two populations, the populations with a larger amount of recorded neurons (therefore
larger dimension of the coupling matrix) will have larger gPLV. Certainly, this can be mislead-
ing for investigating the spike-LFP coupling with GPLA when datasets with variable number
of spiking units and/or LFP channels. To overcome this issue, we suggest normalizing the
gPLV to become independent of the size of the neural population (dimension of the coupling
matrix) and the number of channels. When we consider the entries of coupling matrix, C, to
be PLV (LFPs are not whitened and Eq 16 is used for constructing the coupling matrix), pair-
wise coupling static is bounded (|PLV| � 1). When all the entities of the coupling matrix C
attain their maximum value, gPLV will also gain the maximum possible value. Therefore, we
can exploit it to normalize the gPLV. For a coupling matrix having maximum coupling for all
pffiffiffiffiffiffiffiffi
pairs ((C)n,m = 1 and C, a nc × ns matrix), then gPLVmax ¼ nc ns . Therefore, if we normalize
pffiffiffiffiffiffiffiffi
the original gPLV by the maximum value it can achieve (gPLVmax ¼ nc ns , calculated is based
on the dimensionality of the matrix C), then the gPLV will be bounded by 1 as well. Moreover,
with this normalization, gPLV is also comparable to PLV (if we have a homogeneous popula-
tion of neurons, otherwise these quantities are not comparable).

Significance assessment of gPLV

In order to statistically assess the significance of the coupling between spikes and LFP based on
gPLV, we develop a surrogate- and a Random Matrix Theory (RMT)-based statistical testing
framework exposed in [59]. Hypothesis testing based on the generation of surrogate data is a

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 34 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

common method for significant assessment in neuroscience. Nevertheless, not only generating
appropriate surrogate data can be challenging (for a review see [45]), but also computationally
expensive. This motivates the development of an “analytical” test exploiting minimal computa-
tional resources.
Surrogate-based test. In contrast to univariate methods for which the distribution under
a null hypothesis is more likely to be (possibly approximately) derived based on theoretical
analysis (e.g., Rayleigh test for PLV [129, Chapter 4]), such approaches are usually unavailable
in multi-variate settings (nevertheless, we have developed one for gPLV, see section Analytical
test). Following a common alternative approach, we build the null distribution by generating
many surrogate datasets [45]. The resulting gPLVs values forms an empirical H0 distribution
that can be used to compute the p-value for statistical assessment of the significance gPLV in
the data. Importantly, the choice of appropriate surrogates according to characteristics of neu-
ral data is critical. For instance, generating surrogate data by shuffling inter-spike-intervals
(ISI) is not an appropriate method when we have non-stationarity in firing rates [45].
In this work, we used an interval-jittering rather than a spike-centered-jittering (interval-
and spike-centered-jittering are also known as hard and soft dithering, respectively), as the for-
mer was reported to be more reliable for detecting temporal structures in spike data [130]. We
devised the two following spike-jittering-based methods for GPLA. We also verified the appro-
priateness of our jittering approach with various simulations (see the Results).
Simple interval jitter. Each surrogate dataset is generated by jittering all the spikes (from
all neurons) with a particular jittering window (or dither width). In the interval jittering, per
each spike, a new spike time is drawn within the jittering window around the spike. The timing
of jittered spikes should be drawn from a uniform distribution. The size of the jittering win-
dow can be specified by the frequency wherein the spike-LFP coupling is being investigated.
The smallest jittering window (or dither width) that can be used in order to destroy the tempo-
ral structure potentially exists in the range of frequency-of-interest. In the phase-locking analy-
sis of electrophysiological data we usually extract the analytic signal or instantaneous phase of
LFP by applying Hilbert transform on band-limited LFP signals [58]. The central frequency of
the band-limited filter can be used for specifying the jittering window (or dither width), i. e. jit-
tering window is the inverse of this central frequency.
Group preserved jitter. Similar to “simple interval jitter” we generate each surrogate
dataset by relocating all the spikes within a window. For each surrogate data, we first divide
the spike trains into equally-sized windows. Then we circularly shift the spike sequence within
each window for all neurons together using a uniformly distributed time shift. Notably, we use
a single random value for circular shifting of all neuron’s spiking within the window. This size
of this window should be chosen similar to the previous method (“simple interval jitter”) i. e.
based on the central frequency of the band-limited filter. The rationale behind this method of
generation surrogate data is relative timing of the spikes could be associated to a large degree
to the ansamble activity irrespective of the coupling to the LFP. Therefore, the relative timing
of the spikes might not be impaired in the absence of coupling to global dynamics of the LFP.
With “group preserved jittering” the relative timing is preserved and the coupling to the LFP is
destroyed.
Analytical test. Challenges in generation of surrogate data [45] and considerable increase
in the dimensionality of datasets [24, 40, 42, 43], suggest that deriving mathematically (asymp-
totic) properties of GPLA under the null hypotheses, as is done for univariate testing (e. g. Ray-
leigh test for PLV [129, Chapter 4]) is an interesting alternative.
In a companion work [59], by using martingale theory [131] we derive an asymptotic distri-
bution for the entries of the coupling matrix in fairly general settings. Furthermore, by exploit-
ing RMT [62] we can find a good approximation of the distribution of eigenvalues (or singular

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 35 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

values) of the coupling matrix in absence of coupling between spikes and LFPs. This provides
a null hypothesis for the statistical testing of the largest eigenvalues (or singular values) of the
coupling matrix, which corresponds to gPLV in our setting.
As mathematical details are described in [59, Theorem 2], we restrict ourselves to a brief
explanation. When the LFP signal is whitened, and under a null hypothesis reflecting an
absence of coupling, the coupling matrix which is constructed based on Eq 15, asymptotically
converges to a matrix with i.i.d. complex standard normal coefficients [59 Theorem 3], and the
Marchenko-Pastur (MP) law then provides an approximation of the distribution of its squared
singular values [59, Theorem 3].
This law [64] has density
8 pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
dmMP < 1
> ðb xÞðx aÞ ; a � x � b;
ðxÞ ¼ 2pax ð29Þ
dx >
:
0; otherwise ;
pffiffi 2 pffiffi 2
with a ¼ ð1 aÞ and b ¼ ð1 þ aÞ which are the upper and low bounds of the support of
the distribution. Based on the these bounds we can define a significance threshold, θDET, for
the largest eigenvalue of hermitian matrix, S ¼ nKu CCH :
pffiffi 2
yDET ¼ ð1 þ aÞ : ð30Þ

The null hypothesis can be rejected if, the largest eigenvalue of S (denoted by ℓ1) is superior
to the significance threshold:
‘1 ðSn Þ > yDET : ð31Þ

Therefore, there is a significant coupling between the multi-channel spikes and LFPs, if
pffiffiffiffiffiffiffiffiffiffiffiffi
gPLV > nu yDET : ð32Þ

As mentioned above, to be able to use the result of [59], we need to whiten the LFP signal
first, as described in LFP pre-processing. Furthermore, satisfying this theorem requires the
coupling matrix to be normalized appropriately based on the spike rate of each unit (as defined
in Eq 17).
For computing α on neural data, the reduced ranked neff c < nc entailed by the whitening pro-
cedure (see LFP pre-processing for more details), the effective dimensionality of the coupling
matrix changes from nc × nu to neff
c � nu (which depends on the spectral content of the LFP).
This leads to a modification of Eq 30 as follows:
pffiffiffiffiffiffi 2
yDET ¼ ð1 þ aeff Þ ; ð33Þ

where aeff ¼ neff

c =nu .

Supporting information
S1 Appendix. Contains method details and analytical developments.
(PDF)
S1 Fig. Use of EPSP as LFP proxy. Difference between phase of excitatory and inhibitory neu-
rons/populations based on GPLA and the excitatory and inhibitory populations in the MassAl-
pha neural mass model. In this simulation EPSP has been used for the LFP proxy.
(PDF)

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 36 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

S2 Fig. GPLA of CA3 and CA1 activities. For this analysis, CA1 and CA3 data were separately
injected into GPLA. (A) Spike vectors represented in polar plots similar to Fig 6E, but for all
frequencies (indicated on the left). (B) LFP vectors, similar to Fig 6D, but for all frequencies
(indicated in legend in the bottom). (C) gPLV for different frequency ranges of LFPs, similar
to Fig 6C. Triangles indicated the significance assessed based on empirical (blue triangles, with
significance threshold of 0.05) and theoretical (red triangles) tests. (left) for CA3 and (right)
for CA1.
(PDF)
S3 Fig. Joint CA1-CA3 analysis of hippocampal SWRs. For this analysis, CA1 and CA3 data
were injected to GPLA together. (A) Spike vectors represented in polar plots similar to Fig 6E,
but for all frequencies (indicated on the left). (B) LFP vectors, similar to Fig 6D, but for all fre-
quencies (indicated in legend in the bottom). (C) gPLV for different frequency ranges of LFPs
Fig 6C. Triangles indicated the significance assessed based on empirical (blue triangles, with
significance threshold of 0.05) and theoretical (red triangles) tests.
(PDF)
S4 Fig. GPLA vs. PLA comparison for hippocampal SWR simulation. Similar to Fig 6D but
based on uni-variate phase locking analysis (rather than multivariate GPLA). Each line depicts
the phase locking value (PLV) for a fixed spiking units across all LFP channels. Colors indicate
the frequency of filtered LFP.
(PDF)
S5 Fig. Phase-modulus relation dependency on level of inhibition. Related to Fig 7D. (A)
Same as Fig 7C. for simulations at intermediate levels of recurrent inhibition. (B) Same as Fig
7D. for simulations at intermediate levels of recurrent inhibition. (C) Same as Fig 7E. for simu-
lations at intermediate levels of recurrent inhibition. (D) Magnitude of phase modulus regres-
sion coefficient (rescaled by 180/π to have it in radians) as a function of imaginary part of a
derived from Eq 9. (E) Same as (A) for Im[a]/Re[a] instead of Im[a].
(PDF)
S6 Fig. GPLA using IPSP as LFP proxy. To be compared with Fig 7C–7E. (A) gPLV as a func-
tion of frequency for both models. (B) Phase of spike vector coefficients as a function of its
modulus for the frequency band associated with maximum gPLV for each model (each dot
one coefficient, and the continuous lines are plotted based on linear regression). (C) Shift
between the averaged phase of spike vector and averaged phase of LFP vector, as a function of
frequency.
(PDF)
S7 Fig. Analysis of PFC Utah array data. LFP and spike vectors for frequencies indicated on
the right. First column depict the LFP (blue dots) and spike (red dots) in the complex plane.
Second column depict fitted von Mises distribution to phase of LFP and spike vectors. Third
and forth column respectively represnting phase of LFP and spike vectors which remapped to
real configuration of electrodes on Utah array (see Fig 8C).
(PDF)
S8 Fig. GPLA vs. PLA comparison for PFC Utah array data for revealing the spatial pattern
of coupling. Similar to Utah array maps in Fig 8I but based on uni-variate phase locking analy-
sis (rather than multivariate GPLA). Panels in the first row depict the spatial distribution of
phase locking value (PLV) or magnitude of the spike-field coupling on the array (see Fig 8C).
Panels in the second row depict the spatial distribution of locking phase on the array. White
pixels in all panels indicate the recording channels with insufficient number of spikes

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 37 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

(multiunit activity with a minimum of 5 Hz firing), as it was used in Fig 8I. The colorbars indi-
cate the coupling strength in the first row; and locking phase in the second row. First column,
depicts the results based on multivariate GPLA, and second and third column depicts the
results based on uni-variate phase locking analysis, but for two different choices of LFP refer-
ence channel. The result from ‘Example 2’ is close to what is captured based on GPLA, how-
ever result from ‘Example 1’ does not, due to a lack of global coupling.
(PDF)
S9 Fig. GPLA vs. PLA comparison for PFC Utah array data for characterizing the strength
of recurrent inhibition in PFC circuits. Similar to Fig 8H but based on uni-variate phase
locking analysis (rather than multivariate GPLA). Each row corresponds to analysis in different
frequency (the same frequencies used in Fig 8H), i. e., 3–5 Hz, 5–15 Hz, and 15–30 Hz, respec-
tively, first, second and third row. First column indicates the results based on GPLA (notably
pairwise coupling measure used here is exactly PLV), and imply the negative slope, similar to Fig
8H. The second and third columns demonstrate a similar analysis based on phase locking analy-
sis, i. e., locking phase plotted versus strength of coupling (PLV) with two example of LFP refer-
ence channels (the same used in S8 Fig) Notably, none are compatible with our mean-field
analysis (Fig 7). PLA is thus not conclusive about the strength of recurrent inhibition.
(PDF)

Acknowledgments
We thank Britni Crocker for help with preprocessing of the data and spike sorting; Joachim
Werner and Michael Schnabel for their excellent IT support; Andreas Tolias for help with the
initial implantation’s of the Utah arrays.

Author Contributions
Conceptualization: Shervin Safavi, Theofanis I. Panagiotaropoulos, Michel Besserve.
Data curation: Shervin Safavi, Theofanis I. Panagiotaropoulos, Vishal Kapoor, Michel
Besserve.
Formal analysis: Shervin Safavi, Michel Besserve.
Funding acquisition: Nikos K. Logothetis.
Investigation: Shervin Safavi, Theofanis I. Panagiotaropoulos, Vishal Kapoor, Michel
Besserve.
Methodology: Shervin Safavi, Juan F. Ramirez-Villegas, Michel Besserve.
Project administration: Theofanis I. Panagiotaropoulos, Michel Besserve.
Resources: Nikos K. Logothetis.
Software: Shervin Safavi, Michel Besserve.
Supervision: Theofanis I. Panagiotaropoulos, Michel Besserve.
Visualization: Shervin Safavi, Michel Besserve.
Writing – original draft: Shervin Safavi, Michel Besserve.
Writing – review & editing: Shervin Safavi, Theofanis I. Panagiotaropoulos, Vishal Kapoor,
Juan F. Ramirez-Villegas, Nikos K. Logothetis, Michel Besserve.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 38 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

References
1. Einevoll GT, Destexhe A, Diesmann M, Grün S, Jirsa V, de Kamps M, et al. The Scientific Case for
Brain Simulations. Neuron. 2019; 102(4):735–744. https://doi.org/10.1016/j.neuron.2019.03.027
PMID: 31121126
2. D’Angelo E, Jirsa V. The quest for multiscale brain modeling. Trends in Neurosciences. 2022;.
3. Safavi S. Brain as a Complex System, harnessing systems neuroscience tools & notions for an empiri-
cal approach. PhD Thesis, Universität Tübingen; 2022. Available from: https://tobias-lib.ub.uni-
tuebingen.de/xmlui/handle/10900/128071
4. Rasch MJ, Gretton A, Murayama Y, Maass W, Logothetis NK. Inferring Spike Trains from Local Field
Potentials. J Neurophysiol. 2008; 99(3):1461–76. https://doi.org/10.1152/jn.00919.2007 PMID:
18160425
5. Rasch M, Logothetis NK, Kreiman G. From Neurons to Circuits: Linear Estimation of Local Field
Potentials. J Neurosci. 2009; 29:13785–96. https://doi.org/10.1523/JNEUROSCI.2390-09.2009
PMID: 19889990
6. Li CY, Poo MM, Dan Y. Burst Spiking of a Single Cortical Neuron Modifies Global Brain State. Science.
2009; 324(5927):643–6. https://doi.org/10.1126/science.1169957 PMID: 19407203
7. Schwalm M, Schmid F, Wachsmuth L, Backhaus H, Kronfeld A, Aedo Jury F, et al. Cortex-Wide
BOLD fMRI Activity Reflects Locally-Recorded Slow Oscillation-Associated Calcium Waves. In: eLife.
vol. 6; 2017. https://doi.org/10.7554/eLife.27602 PMID: 28914607
8. Zerbi V, Floriou-Servou A, Markicevic M, Vermeiren Y, Sturman O, Privitera M, et al. Rapid Reconfigu-
ration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation. Neuron. 2019;
103(4):702–718.e5. https://doi.org/10.1016/j.neuron.2019.05.034 PMID: 31227310
9. Sejnowski TJ, Paulsen O. Network oscillations: emerging computational principles. Journal of Neuro-
science. 2006; 26(6):1673–1676. https://doi.org/10.1523/JNEUROSCI.3737-05d.2006 PMID:
16467514
10. Chalk M, Gutkin B, Deneve S. Neural oscillations as a signature of efficient coding in the presence of
synaptic delays. Elife. 2016; 5:e13824. https://doi.org/10.7554/eLife.13824 PMID: 27383272
11. Muller L, Chavane F, Reynolds J, Sejnowski TJ. Cortical travelling waves: mechanisms and computa-
tional principles. Nature Reviews Neuroscience. 2018; 19(5):255–268. https://doi.org/10.1038/nrn.
2018.20 PMID: 29563572
12. Peterson EJ, Voytek B. Healthy Oscillatory Coordination Is Bounded by Single-Unit Computation.
bioRxiv [Preprint]. 2018; p. 309427. https://doi.org/10.1101/309427
13. Safavi S, Chalk M, Logothetis N, Levina A. Signatures of criticality in efficient coding networks. bioRxiv
[Preprint]. 2023; p. 2023–02. https://doi.org/10.1101/2023.02.14.528465
14. Engel AK, Fries P, Konig P, Brecht M, Singer W. Temporal binding, binocular rivalry, and conscious-
ness. Conscious Cogn. 1999; 8(2):128–51. https://doi.org/10.1006/ccog.1999.0389 PMID: 10447995
15. Dwarakanath A, Kapoor V, Werner J, Safavi S, Fedorov LA, Logothetis NK, et al. Bistability of prefron-
tal states gates access to consciousness. Neuron. 2023; https://doi.org/10.1016/j.neuron.2023.02.027
PMID: 36921603
16. Niebur E, Koch C, Rosin C. An oscillation-based model for the neuronal basis of attention. Vision Res.
1993; 33(18):2789–802. https://doi.org/10.1016/0042-6989(93)90236-P PMID: 8296473
17. Buzsaki G. Rhythms of the Brain. Oxford University Press; 2006.
18. Liljenstroem H. Mesoscopic brain dynamics. Scholarpedia. 2012; 7(9):4601. https://doi.org/10.4249/
scholarpedia.4601
19. Buzsaki G, Anastassiou CA, Koch C. The origin of extracellular fields and currents–EEG, ECoG, LFP
and spikes. Nat Rev Neurosci. 2012; 13(6):407–20. https://doi.org/10.1038/nrn3241 PMID:
22595786
20. Einevoll GT, Kayser C, Logothetis NK, Panzeri S. Modelling and analysis of local field potentials for
studying the function of cortical circuits. Nat Rev Neurosci. 2013; 14(11):770–85. https://doi.org/10.
1038/nrn3599 PMID: 24135696
21. Hagen E, Dahmen D, Stavrinou ML, Lindén H, Tetzlaff T, Albada V, et al. Hybrid Scheme for Modeling
Local Field Potentials from Point-Neuron Networks. Cereb Cortex. 2016; 26(12):4461–4496. https://
doi.org/10.1093/cercor/bhw237 PMID: 27797828
22. Herreras O. Local Field Potentials: Myths and Misunderstandings. Front Neural Circuits. 2016;
10:101. https://doi.org/10.3389/fncir.2016.00101 PMID: 28018180
23. Buzsaki G, Logothetis N, Singer W. Scaling brain size, keeping timing: evolutionary preservation of
brain rhythms. Neuron. 2013; 80(3):751–64. https://doi.org/10.1016/j.neuron.2013.10.002 PMID:
24183025

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 39 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

24. Pesaran B, Vinck M, Einevoll GT, Sirota A, Fries P, Siegel M, et al. Investigating Large-Scale Brain
Dynamics Using Field Potential Recordings: Analysis and Interpretation. Nature Neuroscience. 2018;
p. 1. https://doi.org/10.1038/s41593-018-0171-8 PMID: 29942039
25. Fries P. A Mechanism for Cognitive Dynamics: Neuronal Communication through Neuronal Coher-
ence. Trends Cogn Sci. 2005; 9(10):474–80. https://doi.org/10.1016/j.tics.2005.08.011 PMID:
16150631
26. Fries P. Rhythms for Cognition: Communication through Coherence. Neuron. 2015; 88:220–35.
https://doi.org/10.1016/j.neuron.2015.09.034 PMID: 26447583
27. Womelsdorf T, Schoffelen JM, Oostenveld R, Singer W, Desimone R, Engel AK, et al. Modulation of
Neuronal Interactions through Neuronal Synchronization. Science. 2007; 316:1609–12. https://doi.
org/10.1126/science.1139597 PMID: 17569862
28. Ito J, Maldonado P, Singer W, Grün S. Saccade-Related Modulations of Neuronal Excitability Support
Synchrony of Visually Elicited Spikes. Cereb Cortex. 2011; 21(11):2482–2497. https://doi.org/10.
1093/cercor/bhr020 PMID: 21459839
29. Tiesinga PH, Sejnowski TJ. Mechanisms for phase shifting in cortical networks and their role in com-
munication through coherence. Frontiers in human neuroscience. 2010; 4:196. https://doi.org/10.
3389/fnhum.2010.00196 PMID: 21103013
30. Besserve M, Lowe SC, Logothetis NK, Schölkopf B, Panzeri S. Shifts of gamma phase across primary
visual cortical sites reflect dynamic stimulus-modulated information transfer. PLoS biology. 2015;
13(9):e1002257. https://doi.org/10.1371/journal.pbio.1002257 PMID: 26394205
31. Igarashi KM. Plasticity in oscillatory coupling between hippocampus and cortex. Current opinion in
neurobiology. 2015; 35:163–168. https://doi.org/10.1016/j.conb.2015.09.005 PMID: 26425996
32. Zeitler M, Fries P, Gielen S. Assessing Neuronal Coherence with Single-Unit, Multi-Unit, and Local
Field Potentials. Neural Comput. 2006; 18:2256–81. https://doi.org/10.1162/neco.2006.18.9.2256
PMID: 16846392
33. Ashida G, Wagner H, Carr CE. Processing of Phase-Locked Spikes and Periodic Signals. In: Analysis
of Parallel Spike Trains. Springer Series in Computational Neuroscience. Springer, Boston, MA;
2010. p. 59–74.
34. Vinck M, van Wingerden M, Womelsdorf T, Fries P, Pennartz CM. The Pairwise Phase Consistency: A
Bias-Free Measure of Rhythmic Neuronal Synchronization. Neuroimage. 2010; 51(1):112–22. https://
doi.org/10.1016/j.neuroimage.2010.01.073 PMID: 20114076
35. Vinck M, Battaglia FP, Womelsdorf T, Pennartz C. Improved Measures of Phase-Coupling between
Spikes and the Local Field Potential. J Comput Neurosci. 2012; 33(1):53–75. https://doi.org/10.1007/
s10827-011-0374-4 PMID: 22187161
36. Jiang H, Bahramisharif A, van Gerven MAJ, Jensen O. Measuring Directionality between Neuronal
Oscillations of Different Frequencies. NeuroImage. 2015; 118:359–367. https://doi.org/10.1016/j.
neuroimage.2015.05.044 PMID: 26025291
37. Li Z, Cui D, Li X. Unbiased and Robust Quantification of Synchronization between Spikes and Local
Field Potential. J Neurosci Methods. 2016; 269:33–8. https://doi.org/10.1016/j.jneumeth.2016.05.004
PMID: 27180930
38. Zarei M, Jahed M, Daliri MR. Introducing a Comprehensive framework to measure Spike-LFP Cou-
pling. Frontiers in Computational Neuroscience. 2018; 12. https://doi.org/10.3389/fncom.2018.00078
PMID: 30374297
39. Dickey AS, Suminski A, Amit Y, Hatsopoulos NG. Single-Unit Stability Using Chronically Implanted
Multielectrode Arrays. Journal of Neurophysiology. 2009; 102(2):1331–1339. https://doi.org/10.1152/
jn.90920.2008 PMID: 19535480
40. Jun JJ, Steinmetz NA, Siegle JH, Denman DJ, Bauza M, Barbarits B, et al. Fully Integrated Silicon
Probes for High-Density Recording of Neural Activity. Nature. 2017; 551:232–236. https://doi.org/10.
1038/nature24636 PMID: 29120427
41. Juavinett AL, Bekheet G, Churchland AK. Chronically Implanted Neuropixels Probes Enable High-
Yield Recordings in Freely Moving Mice. eLife. 2019; 8:e47188. https://doi.org/10.7554/eLife.47188
PMID: 31411559
42. Buzsáki G. Large-Scale Recording of Neuronal Ensembles. Nature Neuroscience. 2004; 7(5):446–
451. https://doi.org/10.1038/nn1233 PMID: 15114356
43. Fukushima M, Chao ZC, Fujii N. Studying Brain Functions with Mesoscopic Measurements: Advances
in Electrocorticography for Non-Human Primates. Current Opinion in Neurobiology. 2015; 32:124–
131. https://doi.org/10.1016/j.conb.2015.03.015 PMID: 25889531

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 40 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

44. Ermentrout GB, Kleinfeld D. Traveling electrical waves in cortex: insights from phase dynamics and
speculation on a computational role. Neuron. 2001; 29(1):33–44. https://doi.org/10.1016/S0896-6273
(01)00178-7 PMID: 11182079
45. Grün S. Data-Driven Significance Estimation for Precise Spike Correlation. Journal of Neurophysiol-
ogy. 2009; 101(3):1126–1140. https://doi.org/10.1152/jn.00093.2008 PMID: 19129298
46. Salmon WC. Scientific explanation and the causal structure of the world. Princeton University Press;
1984.
47. Craver C. Constitutive explanatory relevance. Journal of Philosophical Research. 2007; 32:3–20.
https://doi.org/10.5840/jpr20073241
48. Stevenson IH, Kording KP. How Advances in Neural Recording Affect Data Analysis. Nature Neurosci-
ence. 2011; 14(2):139–142. https://doi.org/10.1038/nn.2731 PMID: 21270781
49. O’Leary T, Sutton AC, Marder E. Computational Models in the Age of Large Datasets. Current Opinion
in Neurobiology. 2015; 32:87–94. https://doi.org/10.1016/j.conb.2015.01.006 PMID: 25637959
50. Gao P, Ganguli S. On Simplicity and Complexity in the Brave New World of Large-Scale Neurosci-
ence. Current Opinion in Neurobiology. 2015; 32:148–155. https://doi.org/10.1016/j.conb.2015.04.003
PMID: 25932978
51. Williamson RC, Doiron B, Smith MA, Yu BM. Bridging Large-Scale Neuronal Recordings and Large-
Scale Network Models Using Dimensionality Reduction. Current Opinion in Neurobiology. 2019;
55:40–47. https://doi.org/10.1016/j.conb.2018.12.009 PMID: 30677702
52. van der Meij R, Kahana M, Maris E. Phase-Amplitude Coupling in Human Electrocorticography Is Spa-
tially Distributed and Phase Diverse. J Neurosci. 2012; 32(1):111–123. https://doi.org/10.1523/
JNEUROSCI.4816-11.2012 PMID: 22219274
53. van der Meij R, Jacobs J, Maris E. Uncovering Phase-Coupled Oscillatory Networks in Electrophysio-
logical Data. Hum Brain Mapp. 2015; 36(7):2655–2680. https://doi.org/10.1002/hbm.22798 PMID:
25864927
54. van der Meij R, Voytek B. Uncovering Neuronal Networks Defined by Consistent Between-Neuron
Spike Timing from Neuronal Spike Recordings. eNeuro. 2018; 5(3):ENEURO.0379–17.2018. https://
doi.org/10.1523/ENEURO.0379-17.2018 PMID: 29789811
55. Jirsa VK, Haken H. Field theory of electromagnetic brain activity. Physical Review Letters. 1996; 77
(5):960–963. https://doi.org/10.1103/PhysRevLett.77.960 PMID: 10062950
56. Karasözen B. Model order reduction in neuroscience. In: Model order reductionApplications. Volume
3: Applications. De Gruyter; 2020. p. 237–250.
57. Transtrum MK, Qiu P. Bridging mechanistic and phenomenological models of complex biological sys-
tems. PLoS computational biology. 2016; 12(5):e1004915. https://doi.org/10.1371/journal.pcbi.
1004915 PMID: 27187545
58. Chavez M, Besserve M, Adam C, Martinerie J. Towards a proper estimation of phase synchronization
from time series. J Neurosci Methods. 2006; 154(1-2):149–60. https://doi.org/10.1016/j.jneumeth.
2005.12.009 PMID: 16445988
59. Safavi S, Logothetis NK, Besserve M. From Univariate to Multivariate Coupling between Continuous
Signals and Point Processes: A Mathematical Framework. Neural Computation. 2021; p. 1–67. PMID:
34411270
60. Mukamel R, Fried I. Human Intracranial Recordings and Cognitive Neuroscience. Annual Review of
Psychology. 2011; 63(1):511–537. https://doi.org/10.1146/annurev-psych-120709-145401 PMID:
21943170
61. Fried I, Rutishauser U, Cerf M, Kreiman G, editors. Single Neuron Studies of the Human Brain: Prob-
ing Cognition. The MIT Press; 2014.
62. Anderson GW, Guionnet A, Zeitouni O. An Introduction to Random Matrices. Cambridge University
Press; 2010.
63. Capitaine M, Donati-Martin C. Spectrum of deformed random matrices and free probability. arXiv [pre-
print] arXiv:160705560. 2016;.
64. Marchenko VA, Pastur LA. Distribution of eigenvalues for some sets of random matrices. Matemati-
cheskii Sbornik. 1967; 114(4):507–536.
65. Nunez PL, Srinivasan R. Electric fields of the brain: the neurophysics of EEG. Oxford University
Press; 2006.
66. Wilson HR, Cowan JD. A mathematical theory of the functional dynamics of cortical and thalamic ner-
vous tissue. Kybernetik. 1973; 13(2):55–80. https://doi.org/10.1007/BF00288786 PMID: 4767470

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 41 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

67. Sik A, Penttonen M, Ylinen A, Buzsaki G. Hippocampal CA1 Interneurons: An in Vivo Intracellular
Labeling Study. Journal of Neuroscience. 1995; 15(10):6651–6665. https://doi.org/10.1523/
JNEUROSCI.15-10-06651.1995 PMID: 7472426
68. Schomburg EW, Anastassiou CA, Buzsáki G, Koch C. The Spiking Component of Oscillatory Extracel-
lular Potentials in the Rat Hippocampus. Journal of Neuroscience. 2012; 32(34):11798–11811. https://
doi.org/10.1523/JNEUROSCI.0656-12.2012 PMID: 22915121
69. Taxidis J, Coombes S, Mason R, Owen MR. Modeling Sharp Wave-Ripple Complexes through a CA3-
CA1 Network Model with Chemical Synapses. Hippocampus. 2012; 22(5):995–1017. https://doi.org/
10.1002/hipo.20930 PMID: 21452258
70. Nó RLD. Action Potential of the Motoneurons of the Hypoglossus Nucleus. Journal of Cellular and
Comparative Physiology. 1947; 29(3):207–287. https://doi.org/10.1002/jcp.1030290303
71. Lindén H, Tetzlaff T, Potjans TC, Pettersen KH, Grün S, Diesmann M, et al. Modeling the Spatial
Reach of the LFP. Neuron. 2011; 72(5):859–872. https://doi.org/10.1016/j.neuron.2011.11.006 PMID:
22153380
72. Mazzoni A, Linden H, Cuntz H, Lansner A, Panzeri S, Einevoll GT. Computing the Local Field Potential
(LFP) from Integrate-and-Fire Network Models. PLoS Comput Biol. 2015; 11(12):e1004584. https://
doi.org/10.1371/journal.pcbi.1004584 PMID: 26657024
73. Moran RJ, Kiebel SJ, Stephan KE, Reilly R, Daunizeau J, Friston KJ. A neural mass model of spectral
responses in electrophysiology. NeuroImage. 2007; 37(3):706–720. https://doi.org/10.1016/j.
neuroimage.2007.05.032 PMID: 17632015
74. Ledoux E, Brunel N. Dynamics of networks of excitatory and inhibitory neurons in response to time-
dependent inputs. Frontiers in Computational Neuroscience. 2011; 5:25. https://doi.org/10.3389/
fncom.2011.00025 PMID: 21647353
75. Pinotsis DA, Moran RJ, Friston KJ. Dynamic causal modeling with neural fields. Neuroimage. 2012; 59
(2):1261–1274. https://doi.org/10.1016/j.neuroimage.2011.08.020 PMID: 21924363
76. Buzsáki G, Horváth Z, Urioste R, Hetke J, Wise K. High-frequency network oscillation in the hippocam-
pus. Science. 1992; 256(5059):1025–1027. https://doi.org/10.1126/science.1589772 PMID: 1589772
77. Ramirez-Villegas JF, Logothetis NK, Besserve M. Diversity of Sharp-Wave-Ripple LFP Signatures
Reveals Differentiated Brain-Wide Dynamical Events. Proc Natl Acad Sci U S A. 2015; 112:E6379–
87. https://doi.org/10.1073/pnas.1518257112 PMID: 26540729
78. Ramirez-Villegas JF, Willeke KF, Logothetis NK, Besserve M. Dissecting the Synapse- and Fre-
quency-Dependent Network Mechanisms of In Vivo Hippocampal Sharp Wave-Ripples. Neuron.
2018; 100(5):1224–1240.e13. https://doi.org/10.1016/j.neuron.2018.09.041 PMID: 30482688
79. Csicsvari J, Hirase H, Mamiya A, Buzsáki G. Ensemble Patterns of Hippocampal CA3-CA1 Neurons
during Sharp Wave–Associated Population Events. Neuron. 2000; 28(2):585–594. https://doi.org/10.
1016/S0896-6273(00)00135-5 PMID: 11144366
80. Oliva A, Fernandez-Ruiz A, Buzsaki G, Berenyi A. Role of Hippocampal CA2 Region in Triggering
Sharp-Wave Ripples. Neuron. 2016; 91:1342–55. https://doi.org/10.1016/j.neuron.2016.08.008
PMID: 27593179
81. Sullivan D, Csicsvari J, Mizuseki K, Montgomery S, Diba K, Buzsáki G. Relationships between hippo-
campal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical
activity. Journal of Neuroscience. 2011; 31(23):8605–8616. https://doi.org/10.1523/JNEUROSCI.
0294-11.2011 PMID: 21653864
82. Davis ZW, Dotson NM, Franken T, Muller L, Reynolds J. Spike-phase coupling patterns reveal laminar
identity in primate cortex. bioRxiv [Preprint]. 2022;. https://doi.org/10.1101/2022.10.26.513932
83. Wójcik DK. Current Source Density (CSD) Analysis. In: Jaeger D, Jung R, editors. Encyclopedia of
Computational Neuroscience. New York, NY: Springer; 2013. p. 1–10.
84. Hindriks R, Arsiwalla XD, Panagiotaropoulos T, Besserve M, Verschure PF, Logothetis NK, et al. Dis-
crepancies between Multi-Electrode LFP and CSD Phase-Patterns: A Forward Modeling Study. Front
Neural Circuits. 2016; 10:51. https://doi.org/10.3389/fncir.2016.00051 PMID: 27471451
85. Varga C, Oijala M, Lish J, Szabo GG, Bezaire M, Marchionni I, et al. Functional Fission of Parvalbumin
Interneuron Classes during Fast Network Events. eLife. 2014; 3. https://doi.org/10.7554/eLife.04006
PMID: 25375253
86. Whittington MA, Traub RD, Kopell N, Ermentrout B, Buhl EH. Inhibition-based rhythms: experimental
and mathematical observations on network dynamics. International journal of psychophysiology.
2000; 38(3):315–336. https://doi.org/10.1016/S0167-8760(00)00173-2 PMID: 11102670
87. Traub RD, Whittington MA, Buhl EH, Jefferys JG, Faulkner HJ. On the mechanism of the gamma -->
beta frequency shift in neuronal oscillations induced in rat hippocampal slices by tetanic stimulation.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 42 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

The Journal of Neuroscience. 1999; 19(3):1088–1105. https://doi.org/10.1523/JNEUROSCI.19-03-

01088.1999 PMID: 9920671
88. Börgers C, Kopell N. Synchronization in networks of excitatory and inhibitory neurons with sparse, ran-
dom connectivity. Neural computation. 2003; 15(3):509–538. https://doi.org/10.1162/
089976603321192059 PMID: 12620157
89. Stark E, Roux L, Eichler R, Senzai Y, Royer S, Buzsáki G. Pyramidal cell-interneuron interactions
underlie hippocampal ripple oscillations. Neuron. 2014; 83(2):467–480. https://doi.org/10.1016/j.
neuron.2014.06.023 PMID: 25033186
90. Brunel N, Wang XJ. What determines the frequency of fast network oscillations with irregular neural
discharges? I. Synaptic dynamics and excitation-inhibition balance. Journal of Neurophysiology. 2003;
90(1):415–430. https://doi.org/10.1152/jn.01095.2002 PMID: 12611969
91. Teleńczuk B, Dehghani N, Le Van Quyen M, Cash SS, Halgren E, Hatsopoulos NG, et al. Local Field
Potentials Primarily Reflect Inhibitory Neuron Activity in Human and Monkey Cortex. Scientific
Reports. 2017; 7:40211. https://doi.org/10.1038/srep40211 PMID: 28074856
92. Carr MF, Karlsson MP, Frank LM. Transient Slow Gamma Synchrony Underlies Hippocampal Mem-
ory Replay. Neuron. 2012; 75(4):700–713. https://doi.org/10.1016/j.neuron.2012.06.014 PMID:
22920260
93. Zeraati R, Shi YL, Steinmetz NA, Gieselmann MA, Thiele A, Moore T, et al. Intrinsic timescales in the
visual cortex change with selective attention and reflect spatial connectivity. Nat Commun. 2023; 14
(1):1858. https://doi.org/10.1038/s41467-023-37613-7
94. Onslow AC, Jones MW, Bogacz R. A canonical circuit for generating phase-amplitude coupling. PloS
one. 2014; 9(8):e102591. https://doi.org/10.1371/journal.pone.0102591 PMID: 25136855
95. Logothetis NK, Panzeri S. Local Field Potential, Relationship to BOLD Signal. In: Dieter Jaeger RJ,
editor. Encyclopedia of Computational Neuroscience. Springer New York; 2014. p. 1–11.
96. Sherfey JS, Ardid S, Hass J, Hasselmo ME, Kopell NJ. Flexible Resonance in Prefrontal Networks
with Strong Feedback Inhibition. PLOS Computational Biology. 2018; 14(8):e1006357. https://doi.org/
10.1371/journal.pcbi.1006357 PMID: 30091975
97. Zanos TP, Mineault PJ, Pack CC. Removal of Spurious Correlations between Spikes and Local Field
Potentials. J Neurophysiol. 2011; 105(1):474–86. https://doi.org/10.1152/jn.00642.2010 PMID:
21068271
98. Ray S, Maunsell JHR. Different Origins of Gamma Rhythm and High-Gamma Activity in Macaque
Visual Cortex. PLOS Biology. 2011; 9(4):e1000610. https://doi.org/10.1371/journal.pbio.1000610
PMID: 21532743
99. Elston GN. Pyramidal Cells of the Frontal Lobe: All the More Spinous to Think With. J Neurosci. 2000;
20:RC95. https://doi.org/10.1523/JNEUROSCI.20-18-j0002.2000 PMID: 10974092
100. Elston GN. Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal func-
tion. Cerebral Cortex. 2003; 13(11):1124–1138. https://doi.org/10.1093/cercor/bhg093 PMID:
14576205
101. Safavi S, Dwarakanath A, Kapoor V, Werner J, Hatsopoulos NG, Logothetis NK, et al. Nonmonotonic
Spatial Structure of Interneuronal Correlations in Prefrontal Microcircuits. Proceedings of the National
Academy of Sciences. 2018; p. 201802356. https://doi.org/10.1073/pnas.1802356115 PMID:
29588415
102. Sherfey J, Ardid S, Miller EK, Hasselmo ME, Kopell NJ. Prefrontal Oscillations Modulate the Propaga-
tion of Neuronal Activity Required for Working Memory. Neurobiology of Learning and Memory. 2020;
173:107228. https://doi.org/10.1016/j.nlm.2020.107228 PMID: 32561459
103. Jin JZ, Weng C, Yeh CI, Gordon JA, Ruthazer ES, Stryker MP, et al. On and off Domains of Geniculate
Afferents in Cat Primary Visual Cortex. Nature Neuroscience. 2008; 11(1):88–94. https://doi.org/10.
1038/nn2029 PMID: 18084287
104. Nauhaus I, Busse L, Carandini M, Ringach DL. Stimulus Contrast Modulates Functional Connectiv-
ity in Visual Cortex. Nat Neurosci. 2009; 12(1):70–6. https://doi.org/10.1038/nn.2232 PMID:
19029885
105. Ray S, Maunsell JH. Network Rhythms Influence the Relationship between Spike-Triggered Local
Field Potential and Functional Connectivity. J Neurosci. 2011; 31(35):12674–82. https://doi.org/10.
1523/JNEUROSCI.1856-11.2011 PMID: 21880928
106. Nauhaus I, Busse L, Ringach DL, Carandini M. Robustness of Traveling Waves in Ongoing Activity of
Visual Cortex. J Neurosci. 2012; 32(9):3088–94. https://doi.org/10.1523/JNEUROSCI.5827-11.2012
PMID: 22378881

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 43 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

107. Canolty RT, Ganguly K, Kennerley SW, Cadieu CF, Koepsell K, Wallis JD, et al. Oscillatory Phase
Coupling Coordinates Anatomically Dispersed Functional Cell Assemblies. Proc Natl Acad Sci U S A.
2010; 107:17356–61. https://doi.org/10.1073/pnas.1008306107 PMID: 20855620
108. Klausberger T, Magill PJ, Marton LF, Roberts JD, Cobden PM, Buzsaki G, et al. Brain-State- and Cell-
Type-Specific Firing of Hippocampal Interneurons in Vivo. Nature. 2003; 421(6925):844–8. https://doi.
org/10.1038/nature01374 PMID: 12594513
109. Harris KD. Neural Signatures of Cell Assembly Organization. Nat Rev Neurosci. 2005; 6(5):399–407.
https://doi.org/10.1038/nrn1669 PMID: 15861182
110. Buzsaki G. Neural Syntax: Cell Assemblies, Synapsembles, and Readers. Neuron. 2010; 68(3):362–
85. https://doi.org/10.1016/j.neuron.2010.09.023 PMID: 21040841
111. Grasse DW, Moxon KA. Correcting the Bias of Spike Field Coherence Estimators Due to a Finite Num-
ber of Spikes. J Neurophysiol. 2010; 104(1):548–58. https://doi.org/10.1152/jn.00610.2009 PMID:
20484529
112. Lepage KQ, Kramer MA, Eden UT. The Dependence of Spike Field Coherence on Expected Intensity.
Neural Comput. 2011; 23(9):2209–41. https://doi.org/10.1162/NECO_a_00169 PMID: 21671792
113. Shao K, Ramirez Villegas JF, Logothetis NK, Besserve M. A model of Ponto-Geniculo-Occipital
waves supports bidirectional control of cortical plasticity across sleep-stages. bioRxiv [Preprint]. 2021.
https://doi.org/10.1101/2021.03.16.432817
114. Byrne Á, O’Dea RD, Forrester M, Ross J, Coombes S. Next-generation neural mass and field model-
ing. Journal of neurophysiology. 2020; 123(2):726–742. https://doi.org/10.1152/jn.00406.2019 PMID:
31774370
115. Costa MS, Weigenand A, Ngo HVV, Marshall L, Born J, Martinetz T, et al. A Thalamocortical Neural
Mass Model of the EEG during NREM Sleep and Its Response to Auditory Stimulation. PLOS Compu-
tational Biology. 2016; 12(9):e1005022. https://doi.org/10.1371/journal.pcbi.1005022
116. Rosenbaum R, Smith MA, Kohn A, Rubin JE, Doiron B. The Spatial Structure of Correlated Neuronal
Variability. Nat Neurosci. 2017; 20:107–114. https://doi.org/10.1038/nn.4433 PMID: 27798630
117. Qubbaj MR, Jirsa VK. Neural Field Dynamics with Heterogeneous Connection Topology. Phys Rev
Lett. 2007; 98:238102. https://doi.org/10.1103/PhysRevLett.98.238102 PMID: 17677938
118. Marion M, Temam R. Nonlinear galerkin methods. SIAM Journal on numerical analysis. 1989; 26
(5):1139–1157. https://doi.org/10.1137/0726063
119. Ladenbauer J, McKenzie S, English DF, Hagens O, Ostojic S. Inferring and validating mechanistic
models of neural microcircuits based on spike-train data. Nature communications. 2019; 10(1):1–17.
https://doi.org/10.1038/s41467-019-12572-0 PMID: 31666513
120. Gonçalves PJ, Lueckmann JM, Deistler M, Nonnenmacher M, Öcal K, Bassetto G, et al. Training deep
neural density estimators to identify mechanistic models of neural dynamics. Elife. 2020; 9:e56261.
https://doi.org/10.7554/eLife.56261 PMID: 32940606
121. Liebe S, Hoerzer GM, Logothetis NK, Rainer G. Theta Coupling between V4 and Prefrontal Cortex
Predicts Visual Short-Term Memory Performance. Nature Neuroscience. 2012; 15(3):456–462, S1–2.
https://doi.org/10.1038/nn.3038 PMID: 22286175
122. Markowitz DA, Curtis CE, Pesaran B. Multiple Component Networks Support Working Memory in Pre-
frontal Cortex. Proc Natl Acad Sci U S A. 2015. https://doi.org/10.1073/pnas.1504172112 PMID:
26283366
123. Taxidis J, Anastassiou CA, Diba K, Koch C. Local Field Potentials Encode Place Cell Ensemble Acti-
vation during Hippocampal Sharp Wave Ripples. Neuron. 2015; 87(3):590–604. https://doi.org/10.
1016/j.neuron.2015.07.014 PMID: 26247865
124. Fernández-Ruiz A, Oliva A, Nagy GA, Maurer AP, Berényi A, Buzsáki G. Entorhinal-CA3 Dual-Input
Control of Spike Timing in the Hippocampus by Theta-Gamma Coupling. Neuron. 2017; 93(5):1213–
1226.e5. https://doi.org/10.1016/j.neuron.2017.02.017 PMID: 28279355
125. Maynard EM, Nordhausen CT, Normann RA. The Utah intracortical electrode array: a recording struc-
ture for potential brain-computer interfaces. Electroencephalography and clinical neurophysiology.
1997; 102(3):228–239. https://doi.org/10.1016/S0013-4694(96)95176-0 PMID: 9129578
126. Denker M, Roux S, Timme M, Riehle A, Grun S. Phase Synchronization between LFP and Spiking
Activity in Motor Cortex during Movement Preparation. Neurocomputing. 2007; 70(10-12):2096–2101.
https://doi.org/10.1016/j.neucom.2006.10.088
127. Denker M, Roux S, Lindén H, Diesmann M, Riehle A, Grün S. The Local Field Potential Reflects Sur-
plus Spike Synchrony. Cereb Cortex. 2011; 21(12):2681–2695. https://doi.org/10.1093/cercor/bhr040
PMID: 21508303
128. Datta BN. Numerical Linear Algebra and Applications; 2010.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 44 / 45

PLOS COMPUTATIONAL BIOLOGY Generalized Phase Locking Analysis

129. Fisher NI. Statistical Analysis of Circular Data. Cambridge University Press; 1995.
130. Platkiewicz J, Stark E, Amarasingham A. Spike-Centered Jitter Can Mistake Temporal Structure.
Neural Computation. 2017; 29(3):783–803. https://doi.org/10.1162/NECO_a_00927 PMID:
28095192
131. Aalen OO, Borgan Ø, Gjessing HK. Survival and event history analysis: a process point of view. Statis-
tics for Biology and Health. New York, NY: Springer; 2008.

PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.1010983 April 3, 2023 45 / 45