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Introduction to Biological Neurons

1.1 Introduction

After a century of research, our knowledge of the human brain is still very much incomplete.
Hundreds of different brain areas have been mapped out in various species. Neurons in these
regions have been classified, sub-classified, and reclassified based on anatomical details,
connectivity, response properties, and the channels, neuropeptides, and other markers they
express. Hundreds of channels have been quantitatively characterized, and the regulation and
gating mechanisms are beginning to be understood. Multi-electrode recordings reveal how
hundreds of neurons in various brain areas respond to stimuli. Despite this wealth of descriptive
data, we still do not have a grasp on exactly how these thousands of neurons are supposed to
accomplish computation. To understand the minimal knowledge about how brain is doing this
enormous computation and signal processing we should have some basic knowledge of biology,
neuroscience, biochemistry, biophysics, signal& systems, networks and information theory
A vast majority of neurons respond to sensory or synaptic inputs by generating a train of
stereotypical responses called action potentials or spikes. Deciphering the encoding process
which transforms continuous, analog signals (photon fluxes, acoustic vibrations, chemical
concentrations and so on) or outputs from other neurons into discrete, fixed-amplitude spike
trains is essential to understand neural information processing and computation, since often the
nature of representation determines the nature of computation possible. Researchers, however,
remain divided on the issue of the neural code used by neurons to represent and transmit
information. Although there are many open problem in this area but to model a problem
analytically is still very much challenging.
The brain is a sophisticated and complex organ that nature has devised. In order to
understand brain function fairly, we must begin by learning how brain cells work individually
and then see how they are assembled to work together. There are mainly two types of cell in
central nervous system: Neuron and Glia. Although there are many neurons in the human brain
(about 100 billion), glia outnumber neurons by tenfold. However, neurons are more important
cells for the major functions of the brain. It is the neurons that sense changes in the environment,
communicate these changes to other neurons, and command the bodys responses to these
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sensations. Glia, or glial cells, are thought to contribute to brain function mainly by insulating,
supporting, and nourishing neighboring neurons.

1.2 Relevant Physiological Aspects

A typical neuron has four parts: (a) cell body or soma, (b) axon, (c) dendrites and (d)
neuronal membrane.


Fig1: Schematic of a neuron structure [1]

(a) Cell body or SOMA

20m diameter, watery fluid inside called cytosol and contains organelles like nucleus,
rough ER, smooth ER, mitochondria and golgi apparatus [1]. When signal from different
dendrites propagate towards axon hillock cellbody assumed to act as a conducting and it also
performs the local energy balancing.

Fig2: Cell Body [2]





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(b) Axon

The axon, a structure found only in neurons that is highly specialized for the transfer of
information over distances in the nervous system. The axon begins with a region called the axon
hillock, which tapers to form the initial segment of the axon proper. It serves as the telegraph
wire that sends information over great distances. The end is called the axon terminal or terminal
button. The terminal is a site where the axon comes in contact with other neurons (or other cells)
and passes information on to them. This point of contact is called the synapse [1].

(c) Dendrite
It acts like a receiver for a neuron. The term dendrite is derived from the Greek for tree,
as these dendrites resemble the branches of a tree extended from the soma. The dendrites of a
single neuron are collectively called a dendritic tree. The branches are covered with thousands of
synapses. The dendritic membrane under the synapse (the postsynaptic membrane) has many
specialized protein molecules called receptors that detect the neurotransmitters in the synaptic
cleft [1].

(d) Neuronal Membrane
The neuronal membrane serves as a barrier to enclose the cytoplasm inside the neuron
and to exclude certain substances that float in the fluid that bathes the neuron. The membrane is
about 5 nm thick and is studded with proteins. The protein composition of the membrane varies
depending on whether it is in the soma, the dendrites, or the axon. Neuronal membrane gives a
neuron the remarkable ability to transfer electrical signals throughout the brain and body [1].

1.3 Action Potential
The Action potential is an electrical signal that conveys information over distances in the
nervous system. The cytosol in the neuron at rest is negatively charged with respect to the extra-
cellular fluid. The action potential is a rapid reversal of this situation such that, for an instant, the
inside of the membrane becomes positively charged with respect to the outside. The action
potential is also often called a spike, a nerve impulse, or a discharge. The action potentials
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generated by a cell are all similar in size and duration, and they do not diminish as they are
conducted down the axon. The frequency and pattern of action potentials constitute the code
used by neurons to transfer information from one location to another. Action potential has certain
identifiable parts, called the rising phase, overshoot, falling phase, undershoot, after- hyper-
polarization [1].

Fig 3: Action potential [1]
1.4 Synapse
The junction between two neurons is called a synapse. With respect to a synapse, we
refer to the sending neuron as the pre-synaptic cell and to the receiving neuron as the
postsynaptic cell. Most synapses occur on the dendrites but some occur on the somas or the
axons of other neurons. The most common type of synapse in the (vertebrate) brain is the
chemical synapse. For this type of synapse, the axon comes very close to the postsynaptic
neuron, leaving only a small gap of about 20-40 nanometers across between pre and postsynaptic
cell membranes, called the synaptic cleft. The pre-synaptic signal is transmitted across the
synaptic cleft by transformation from electrical signal into a chemical one and then back into
electrical signal on the postsynaptic side. The chemical signal is sent in the form of
neurotransmitter molecules. About 5,000 of these molecules are packaged in small spheres called
synaptic vesicles which reside in the pre-synaptic terminal [2].

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Fig 4: Synapse [1]










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Major Developments in Neuroscience and Neural
Information Theory

Review of recent literature [2, 3, 4] suggests that research on neuroscience may be classified in
three broad directions:

2.1 Experimental Neuroscience
Experimental neuroscience is an important discipline with an aim to understand the
molecular, cellular, physiological, structural and behavioral basis of normal function of the
nervous system and its diseases.

2.2 Theoretical Neuroscience
The task of understanding the principles of information processing in the brain poses,
apart from numerous experimental questions, challenging theoretical problems on all levels from
molecules to behavior. This Theoretical Neuroscience concentrates on modeling approaches on
the level of neurons and small populations of neurons, since one think that this is an appropriate
level to address fundamental questions of neuronal coding, signal transmission, or synaptic
plasticity. Neuron is a dynamic element that emits output pulses whenever the excitation exceeds
some threshold. The resulting sequence of pulses or spikes contains all the information that is
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transmitted from one neuron to the next. Signal transmission and signal processing in neuronal
systems need to be understood with the help of distributed network consists of single neurons
[3].

I ntegrate-and-Fire Model of the Neurons

The leaky integrate-and-fire model (LIF) [5] is one of the most elementary spiking
models and has been widely used to gain a better understanding of information processing in
neurons. In this model, the sub-threshold membrane potential of a neuron is governed by a first-
order linear differential equation

( ) - v ( )
( ) = C +
rest
in
v t dv t
i t
dt R
(1)


which corresponds to the circuit in Fig. 5 below [5]:



Fig 5: Equivalent circuit for leaky integrate-and-fire neuron [2]

In this model, the membrane time constant is = RC
m
t . The value of
m
t

is typically 8
20 ms. A solution of above equation is

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0
0
1 1
(t-t ) (t- )
0
1
( ) v + e ( ( ) v ) + e ( )
m m
t
rest rest in
t
v t v t i d
C

t t


=
}
(2)


By redefining the voltage reference, we can instead consider ( ) v
rest
v t . Replacing
( ) v
rest
v t by ( ) v t , we have for
0
t t >

0
0
1 1
(t-t ) (t- )
0
1
( ) e ( ) + e ( )
m m
t
in
t
v t v t i d
C

t t


=
}



| )
0
0 0 ,
1
( ) 1 ( ) + ( ) ( ) * h(t)
in t
i t t v t t t
C
o

| |
=
|
\ .
.(3)

Where
| )
0
1
t
,
h(t) e 1 ( )
m
t
t
t

=
and * denotes convolution. This is true as long as ( ) v t is
less than the threshold. When a neuron has just output a spike at time
0
t 0 =
, we will assume that
the membrane potential is reset to
0
( ) 0 v t = . Then,
1
= * h
in
v i
C
. (4)
as long as < T v where T is the threshold function. In the above notation, we assume that
in
i

is causal; that is, for. Of course, the function h defined above is also causal. Suppose we let

m
t . Then,
| )
0
,
h(t) 1 ( )
t
t

= . This is called the perfect / leakless integrator model. As a

generalization of the leaky integrate-and fire model, we will allow h to be any decaying causal
function and use (4) to define the membrane potential. Note that
in
i is a result of incoming spike
train [2, 3, 5].

Refractory Period

Output spikes from a neuron are usually well separated. Even with strong input, it is
virtually impossible to excite a second spike during or immediately after a first one. This
minimal distance between two spikes is defined as the absolute refractory period of the neuron.
The typical length of this period is about 24 ms. The absolute refractory period is followed by a
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state of relative refractoriness during which it is difficult, but not impossible to generate an
action potential. The relative refractory period may last around 1020ms. Both of these
refractory phases can be modeled in the IF-model by using a decaying threshold function.
Immediately after a spike is generated, we may assume that the threshold is large (possible
infinite), and hence it is impossible for the membrane potential to built up and reach the value of
the threshold in a short amount of time. Using decaying threshold implies that as time passes, the
threshold will be at a lower value and hence it is easier to generate a spike [2].

Energy Consumption

Another important fact is that our nervous system consumes a lot of energy. Human
brains consume 20% of energy consumption for adults and 60% for infant .When we block the
neural signaling by anesthesia, the brains energy consumption is halved. This suggests that
about 50% of the energy is used to drive signals along axons and across synapses. In 1996, Levy
and Baxter included the amount of energy expended by neuron in their study, initiating
theoretical studies of energy-efficient coding in nervous systems [6].

2.3 Neural Information Theory or Living Information Theory [8]
Information theory, the most rigorous way to quantify neural code reliability, is an aspect
of probability theory that was developed in the 1940s as a mathematical framework for
quantifying information transmission in man-made communication systems. The theorys rigor
comes from measuring information transfer precision by determining the exact probability
distribution of outputs given any particular signal or input. Moreover, because of its
mathematical completeness, information theory has fundamental theorems on the maximum
information transferrable in a particular communication channel. In engineering, information
theory has been highly successful in estimating the maximal capacity of communication channels
and in designing codes that take advantage of it. In neural coding, information theory can be used
to precisely quantify the reliability of stimulusresponse functions, and its usefulness in this
context was recognized early. One can argue that this precise quantification is also crucial for
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determining what is being encoded and how. In this respect, researchers have recently taken
greater advantage of information-theoretic tools in three ways-
First, the maximum information that could be transmitted as a function of firing rate has been
estimated and compared to actual information transfer as a measure of coding efficiency.
Second, actual information transfer has been measured directly, without any assumptions about
which stimulus parameters are encoded, and compared to the necessarily smaller estimate
obtained by assuming a particular stimulusresponse model. Such comparisons permit
quantitative evaluation of a models quality[10].
Third, researchers have determined the limiting spike timing precision used in encoding, that
is, the minimum time scale over which neural responses contain information.

I nformation Theory in Living Systems
While applying information theory in living systems we should keep in mind that, basic
concepts and methods of classical information theory developed by Shanon and his fellow
researchers , which is very much effective for man-made communication systems may not be
always applicable to the long standing mysteries of nature. One must think critically before
applying information theoretic concept for analysis of information processing abilities of neurons
and hence our brain. One should always remember two things-
Judicious application of Shannons fundamental concepts of entropy, mutual information,
channel capacity is crucial to gaining an elevated understanding of how living systems handle
sensory information what is the capacity of a single neuron channel [8, 10].
Living systems have little if any need for the elegant block and convolutional coding theorems
and techniques of information theory because, organisms have found ways to perform their
information handling tasks in an effectively Shannon- optimum manner without having to
employ coding in the information-theoretic sense of the term [8, 10].

2.4. Comments on Outstanding Research Issues

1. Proposed models in literature do not consider complete signal flow from axon to axon
terminal and axon terminal to synaptic cleft and synaptic cleft to dendrites or cell body
and dendrite or cell body to axon hillock.
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2. All the signals that reach dendrite or cell body, do not cross threshold and generate action
potential. What happen to these signals? Will they act as jitter for next action potential???
How local energy balancing takes place???

3. Neocortex is known to exhibit memory and a functional element of neocortex is a neuron.
It is not clear from the available literature if there is any memory trace in a single neuron.
Modeling of a single neuron is still an active area of research [1, 3].













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Top-Down and Bottom-Up Approach in Neuroscience

Computational neuroscience is used to bridge the gap between the mathematical
neuroscience and experimental neuroscience. Hodgkin and Huxley combined their experiments
with a mathematical description [5], which they used for simulations on one of the early
computers . One of the central tasks of computational neuroscience is to bridge the different
levels of description by simulation and mathematical theory. The bridge can be built in two
different ways - Bottom-up models and Top-down models. Bottom-up models integrate what is
known on a lower level to explain phenomena observed on a higher level. Top-down models, on
the other hand, start with known cognitive functions of the brain (e.g., working memory), and try
to predict how neurons or group of neurons should behave in order to achieve that function.
Some examples of the top-down approach are theories of associative memory, reinforcement
learning, and sparse coding [11].

3.1. Bottom-Up Approach:

The brain contains billions of neurons that generate short electrical pulses, called action
potentials or spikes to communicate with each other. Hodgkin and Huxleys description of
neuronal action potentials [5] is widely used framework for biophysical neuron models. In these
models, cell membrane of a neuron is described by a number of ion channels, with specific time
constants and gating dynamics that control the momentary state (open or closed) of a channel
(Fig. 6C). By a series of mathematical steps and approximations, theory has sketched a
systematic bottom-up path from such biophysical models of single neurons to macroscopic
models of neural activity [11].
In the first step, biophysical models of spike generation are reduced to integrate-and-fire
models where spikes occur whenever the membrane potential reaches the threshold (Fig. 6B).
In the next step, the population activity A(t)defined as the total number of spikes
emitted by a population of interconnected neurons in a short time windowis predicted from the
properties of individual neurons using mean-field methods known from physics. Each neuron
receives input from many others, it is sensitive only to their average activity (mean field) but
not to the activity patterns of individual neurons [11].
Instead of the spike based interaction among thousands of neurons, network activity can
therefore be described macroscopically as an interaction between different populations Such
macroscopic descriptionsknown as population models, neural mass models, or, in the
continuum limit, neural field models (Fig. 6A)help researchers to gain an intuitive and more
analytical understanding of the principal activity patterns in large networks. Although the
transition from microscopic to macroscopic scales relies on purely mathematical arguments,
simulations are important to add aspects of biological realism (such as heterogeneity of neurons
and connectivity, adaptation on slower time scales, and variability of input and receptive fields)
that are difficult to treat mathematically. However, the theoretical concepts and the essence of
the phenomena are often robust with respect to these aspects [11].
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Fig6: Bottom up approach in nervous system[11]

3.2. Decision-Making: Theory Combines Top-Down and Bottom-Up

Often we have to take a decision between two alternatives (A or B), such as Should I do
it or not?. Psychometric measures of performance and reaction times for two alternative forced-
choice decision-making paradigms can be explained by a phenomenological drift-diffusion
model. This model consists of a diffusion equation describing a random variable that
accumulates noisy sensory data until it reaches one of two boundaries corresponding to a specific
choice (Fig. 7A). Although this model able to describe reaction time distribution, it suffers from
a crucial disadvantage, namely the difficulty in assigning a biological meaning to the model
parameters [11].
Recently, neurophysiological experiments have begun to reveal neuronal correlates of
decision making, in tasks involving visual patterns of moving random dots or vibrotactile or
auditory frequency comparison. Computational neuroscience offers a framework to bridge the
conceptual gap between the cellular and the behavioral level. Explicit simulations of microscopic
models based on local networks with large numbers of spiking neurons can reproduce and
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explain both the neurophysiological and behavioral data. These models describe the interactions
between two groups of neurons coupled through mutually inhibitory connections (Fig. 7C).
Suitable parameters are inferred by studying the dynamical regimes of the system and choosing
parameters consistent with the experimental observations of decision behavior. Thus, the pure
bottom-up model is complemented by the top-down insights of target functions that the network
needs to achieve [11].



Fig 7: Decision making in nervous system[11]

3.3. Large-scale brain networks and cognition

Much of our current knowledge of cognitive brain function has come from the modular
paradigm, in which brain areas are postulated to act as independent processors for specific
complex cognitive functions [15]. Recent research shows that this paradigm has serious
limitations and might in fact be misleading. Even the functions of primary sensory areas of the
cerebral cortex, once thought to be pinnacles of modularity, are being redefined by recent
evidence of cross-modal interactions. A new paradigm is emerging in cognitive neuroscience
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that suggests instead of working in a modular way for a cognitive function brain areas are
working conjointly as a large scale networks [12, 13, 15] .

Large-scale structural brain networks

The neuroanatomical structure of large-scale brain networks give us an idea of connected
brain areas that facilitates signaling along a particular pathway for the service of specific
cognitive functions. It is important to identify the brain areas that constitute structural network
nodes and the connecting paths that serve as structural network edges to know which
configurations of interacting areas are possible. In the past, large-scale structural brain networks
were often schematized by two-dimensional wiring diagrams, with brain areas connected by
lines or arrows representing pathways. Currently, more sophisticated network visualization and
analysis schemes are being developed and used. Principal methods to define structural nodes
and edges in the brain is described first. Some of possible functional consequences of the
structural organization of large-scale brain networks is described then [15].

Nodes

The nodes of large-scale structural brain networks are typically brain areas defined by: (i)
cytoarchitectonics; (ii) local circuit connectivity; (iii) output projection target commonality; and
(iv) input projection source commonality. A brain area can be described as a subnetwork of a
large-scale network; this subnetwork consists of neuron populations (nodes) and connecting
pathways (edges). Despite the complex internal structure of each node, it is often convenient,
particularly in network modeling research, to treat them as unitary neural masses that serve as
spatially undifferentiated (lumped) nodes in large-scale networks. The definition of nodes are
changing time to time as new methods are developed and understanding of structure function
relations in the brain evolves .Techniques used in recent years to determine structural nodes from
neuroanatomical data include: (i) anatomical parcellation of the cerebral cortex using the
Brodmann atlas; (ii) parcellation in standardized Montreal Neurological Institute (MNI) space
using macroscopic landmarks in structural magnetic resonance imaging (sMRI) data; (iii)
subject-specific automated cortical parcellation based on gyral folding patterns; (iv) quantitative
cytoarchitectonic maps; and (v) neurochemical maps showing neurotransmitter profiles .Diverse
tradeoffs arise in the use of these techniques [15]. Classical, but still popular Brodmann
mapping scheme is used for analysis.(Details are given in appendix - 1)

Problem in node selection

A major problem being that of anatomical specificity versus extent of coverage across
the brain. This problem is particularly acute for the cerebral cortex because the borders of most
cortical regions cannot be reliably detected using macroscopic features from sMRI. The choice
of spatial scale for nodal parcellation has important consequences for the determination of
network connectivity [15].
Although newer methods offer a tighter link with the functional architecture of the brain,
but still coverage exists for only a small set of cortical regions and a wide area of human
prefrontal and temporal cortices have not yet been adequately mapped. Most anatomical
parcellation studies have focused on the cerebral cortex. Less attention has been paid to
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subcortical structures such as the basal ganglia and the thalamus, which have only been
demarcated at a coarse level using sMRI. Brainstem systems mediating motivation, autonomic
function and arousal have been poorly studied because they are very difficult to identify using in
vivo techniques. Nonetheless, it is important to identify these structures because they
significantly influence cortical signaling and thus affect cognitive function [15].



Fig 8: Structural nodes of cerebral cortex[15]
Edges

The edges connecting brain areas in large-scale structural networks are long-range axon
pathways. Network edges are directed because axon fiber pathways have direction from the
somata to the synapses, and can be bidirectional when axon pathways run in both directions
between particular brain areas. Each brain area has a unique connection set of other areas with
which it is interconnected. Network edges have variable weights based on the number and size of
axons in the pathways, and the number and strengths of functioning synapses at the axon
terminals [15].
Three main approaches are currently used to trace axon pathways, and thus determine
structural network edges.
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The first is autoradiographic tracing in experimental animals. In the macaque monkey,
this technique has provided a rudimentary map of anatomical links between major cortical areas
and more recently has successfully detailed rostrocaudal and dorsalventral connectivity
gradients between major prefrontal and parietal cortical areas [15].
The second approach uses diffusion-based magnetic resonance imaging methods, such as
diffusion tensor imaging (DTI) and diffusion spectrum imaging (DSI), to determine major fiber
tracts of the human brain in vivo by identifying the density of connections between brain areas
[15]. (Fig. 9).
The third approach to mapping of network edges uses anatomical features such as local
cortical thickness and volume to measure anatomical connectivity. In this approach, which has
evolved during the same recent time period as DTI technology, interregional covariation in
cortical thickness and volume across subjects is used to estimate connectivity [15].

Problem in edge selection

In autoradiographic tracing howevei it is difficult, to extrapolate from macaque
connectional neuroanatomy to that of the human brain because the degree of pathway homology
between macaque and human brains is not well understood.
Diffusionbased tractography of the entire human brain is still in its early days, but rapidly
evolving techniques are providing reliable estimates of the anatomical connectivity of several
hundred cortical nodes [12, 13]. With additional anatomical constraints on seeds and targets
in diffusion- based tractography, it is increasingly possible to make closer links between
projection zones and cytoarchitectonic maps [15].
In the third method edges that are identified might not actually reflect axonal pathways
and precaution is required in interpreting the results. Nevertheless, networks identified using this
approach have revealed stable graph-theoretic properties [15].



Fig 9: Structural edges of cerebral cortex[15]



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Comments on Structural Nodes and Edges

Recent studies have combined both node and edge detection to identify structural
networks, either across the whole brain or within specific brain systems. At the whole-brain
level, network nodes are determined by one of the parcellation methods described above, and
then network edges are determined by DTI or DSI. If, however, structural network nodes are
inferred from DTI or DSI patterns of convergence and divergence, nodes and edges cannot be
independently identified. Within specific functional systems, such as for language or working
memory, the nodes are constrained to lie within the system and then the edges are identified by
diffusion-based tractography . The use of cytoarchitectonic boundaries to define the nodes allows
aspects of brain connectivity that are more closely linked to the underlying neuronal organization
to be uncovered in parallel [12-15].

Large-scale functional brain networks

Human brain has evolved to provide survival strategy to human in a way that one can
survive in a wide varity of ambience changes, act differently in different condition depending on
the situtiation At each moment certain set of conditions must be analyzed by human brain with
the help of perception. The set of perception along with the learned concepts produce an
immediate solution to the immediate problem and act accordingly. It is reasonable to assume that
a set of interconnected brain areas act in tandem to provide these solutions, as well as
corresponding behavior and that they interact dynamically to achieve an action. A large-scale
functional network can therefore be defined as a collection of interconnected brain areas that
interact to perform circumscribed functions. The topological form of functional networks
changes throughout an individuals lifespan and is uniquely shaped by maturational and learning
processes within the large-scale neuroanatomical connectivity matrix for each individual [13-15].

Nodes

The characterization of functional networks in the brain requires identification of
functional nodes. However, there is no commonly agreed definition of what constitutes a
functional node in the brain. Since the advent of advanced functional electrophysiological and
neuroimaging methods, additional methodologies to define functional network nodes have
become available. A network node can be a circumscribed brain region displaying elevated
metabolism in positron emission tomography (PET) recordings, elevated blood perfusion in
functional magnetic resonance imaging (fMRI) recordings, or synchronized oscillatory activity
in local field potential (LFP) recordings. Participation of a brain area in a large-scale functional
network is commonly inferred from its activation or deactivation in relation to cognitive
function. A group of brain areas jointly and uniquely activated or deactivated during cognitive
function with respect to a baseline state can represent the nodes of a large-scale network for that
function [15].




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Problem of selection of Functional nodes

A major challenge is to determine how functional network nodes defined by different
recording modalities are related, and how they relate to structural network nodes. From the
network perspective, cognitive functions are carried out in real time by the operations of
functional networks comprised of unique sets of interacting network nodes. For a brain area to
qualify as a functional network node, it must be demonstrated that, in combination with a
particular set of other nodes, it is engaged in a particular class of cognitive functions. Although it
is not yet known how the various definitions of large-scale functional network nodes derived
from different recording modalities are related, a possible scenario is that the elevated
excitability of neurons within an area leads to elevated metabolic activity, which in turn causes
an increase in local blood oxygen availability. The elevated excitability could also cause
increased interactions between neurons within the area. Interactions between different
populations can produce oscillatory activity and can have important functional consequences if,
for example, the interactions lead to increased sensitivity of neurons within the area to the inputs
that they receive [15].
Much of the work in the field of functional neuroimaging uses the fMRI blood-oxygen-level-
dependent (BOLD) signal to identify the nodes of large-scale functional networks by relating the
joint activation of brain areas to different cognitive functions. fMRI BOLD activation has
revealed network nodes that are involved in such cognitive functions as attention [58], working
memory, language, emotion, motor control and time perception [15].

Edges

The identification of functional network edges comes from different forms of functional
interdependence (or functional connectivity) analysis, which assesses functional interactions
among network nodes. The identification of network edges, like that of network nodes, is highly
dependent on the monitoring methodology. Functional interdependence analysis can identify
network edges from time series data in the time (e.g. cross-correlation function) or frequency
(e.g., spectral coherence or phase synchrony measures) domain. In either domain, the analysis
can use a symmetric measure, in which case significant interdependences are represented as
undirected edges, or an asymmetric measure, in which case they are represented as directed
edges . Methods using directional measures include Granger causality analysis and dynamic
causal modeling . Functional interdependences must be statistically significant for them to
represent the edges of large-scale functional networks. Determination of thresholds for
significance testing of network edges is often fraught with difficulty, and the particular method
used for threshold determination can have an appreciable impact on the resulting large-scale
network. Certain graph-theoretic measures, however, do not suffer from this problem because
they take into account the full weight structure of the network. Fluctuations in neuronal
population activity at different time scales can control the time-dependent variation of
engagement and coordination of areas in large-scale functional networks . Network edges are
possibly best represented by the correlation of time series fluctuations at different time scales,
reflecting different functional network properties. The correlation of slow fluctuations at rest in
fMRI BOLD signals possibly reflects slow interactions necessary to maintain the structural and
functional integrity of networks , whereas the correlation of fast fluctuations could reflect fast
dynamic coupling required for information exchange within the network [12-15].
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Functional interdependence has been observed across a range of time scales from
milliseconds to minutes. Recent evidence suggests that slow intracranial cortical potentials are
related to the fMRI BOLD signal. It is possible that functional networks are organized according
to a hierarchy of temporal scales, with structural edges constraining slow functional edges, which
in turn constrain progressively faster network edges. Studies in both monkeys and humans
support the existence of hierarchical functional organization across time scales [15].

Intrinsic functional brain networks

Functional interdependence analysis has often been used to investigate interactions
between brain areas during task performance. Although task-based analyses have enhanced our
understanding of dynamic context-dependent interactions, they often have not contributed to a
principled understanding of functional brain networks. By focusing on task-related interactions
between specific brain areas, they have tended to ignore the anatomical connectivity and
physiological processes that underlie these interactions. Intrinsic interdependence analysis of
fMRI data acquired from subjects at rest and unbiased by task demands has been used to identify
intrinsic connectivity networks (ICNs) in the brain. ICNs identified in the resting brain include
networks that are also active during specific cognitive operations, suggesting that the human
brain is intrinsically organized into distinct functional networks. One key method for identifying
ICNs in resting-state fMRI BOLD data is independent component analysis (ICA), which has
been used to identify ICNs involved in executive control, episodic memory, autobiographical
memory, self-related processing and detection of salient events. ICA has revealed a sensorimotor
ICN anchored in bilateral somatosensory and motor cortices, a visuospatial attention network
anchored in intra-parietal sulci and frontal eye fields, a higher-order visual network anchored in
lateral occipital and inferior temporal cortices, and a lower-order visual network. This technique
has allowed intrinsic as well as task-related fMRI activation patterns to (Figure 10), (Figure 11),
be used for identification of distinct functionally coupled systems, including a central-executive
network (CEN) anchored in dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex
(PPC), and a salience network anchored in anterior insula (AI) and anterior cingulate cortex
(ACC) [15].



Fig 10: Intrinsic core network[15]
Page 21



Fig 11: Task related network[15]

A second major method of ICN identification is seedbased functional interdependence
analysis. Like ICA, this technique has been used to examine ICNs associated with specific
cognitive processes such as visual orienting attention, memory and emotion. First, a seed region
associated with a cognitive function is identified. Then, a map is constructed of brain voxels
showing significant functional connectivity with the seed region. This approach has
demonstrated that similar networks to those engaged during cognitive task performance are
identifiable at rest, including dorsal and ventral attention systems and hippocampal memory
systems. It has also revealed distinct functional circuits within adjacent brain regions: functional
connectivity maps of the human basolateral and centromedial amygdal [15].
Graph-theoretic studies of resting-state fMRI functional connectivity results have
suggested that human large-scale functional brain networks are usefully described as small-
world. Other graph-theoretic metrics such as hierarchy have been useful in characterizing
subnetwork topological properties, but a consistent view of hierarchical organization in large-
scale functional networks has yet to emerge [15].








Page 22

Problem Formulation and Methodology
In our work we have hypothised human nervous system according the following tree.

Graphical representation of human nervous system is given below-

Fig 12: Human Nervous System(HNS), Graphical representation

Page 23

Problem#1
Model human nervous system(HNS) as a large distributed network and try to predict some of the
cognitive behavior from this network mathematically.

Page 24

Appendix-1(Brodmaan Area)


Areas Broad Parts Location in Brain Functions Remarks
Area- 3,
2, 1
Primary
Somatosensory
Cortex
The lateral
postcentral gyrus
is a prominent
structure in the
parietal lobe of the
human brain and
an important
landmark. It is the
location of the
primary
somatosensory
cortex
the main sensory
receptive area for the
sense of touch

Area- 4 Primary Motor
Cortex
It is located in the
posterior portion
of the frontal lobe.
is about the same
as the precentral
gyrus.
The borders of this
area are: the
precentral sulcus
in front
(anteriorly), the
medial
longitudinal
fissure at the top
(medially), the
central sulcus in
back (posteriorly),
and the lateral
sulcus along the
bottom (laterally).
plan and execute
movements.

Page 25


Area- 5 Somatosensory
Association Cortex
is part of the
parietal cortex in
the human brain.
It is situated
immediately
posterior to the
primary
somatosensory
areas (Brodmann
areas 3, 1, and 2),
and anterior to
Brodmann area 7.
It is involved in
somatosensory
processing and
association.(The
somatosensory system is
a diverse sensory system
comprising the receptors
and processing centres to
produce the sensory
modalities such as touch,
temperature,
proprioception (body
position), and
nociception (pain). The
sensory receptors cover
the skin and epithelia,
skeletal muscles, bones
and joints, internal
organs, and the
cardiovascular system.)

Area- 6 Premotor cortex
and Supplementary
Motor Cortex
(Secondary Motor
Cortex)(Supplemen
tary motor area)
It is part of the
frontal cortex in
the human brain.
Situated just
anterior to the
primary motor
cortex (BA4), it is
composed of the
premotor cortex
and, medially, the
supplementary
motor area, or
SMA.
This large area of the
frontal cortex is believed
to play a role in the
planning of complex,
coordinated movements.
Brodmann
area 6 is also
called
agranular
frontal area 6
in humans
because it
lacks an
internal
granular
cortical layer
(layer IV).
Area- 7 Somatosensory
Association Cortex
is part of the
parietal cortex in
the human brain.
Situated posterior
this region is believed to
play a role in visuo-
motor coordination.
area 7 along with area 5

Page 26

to the primary
somatosensory
cortex (Brodmann
areas 3, 1 and 2),
and superior to the
occipital lobe
has been linked to a wide
variety of high-level
processing tasks,
including activation in
association with language
use.This function in
language has been
theorized to stem from
how these two regions
play a vital role in
generating conscious
constructs of objects in
the world.
Area- 8 Includes Frontal
eye fields
is part of the
frontal cortex in
the human brain.
Situated just
anterior to the
premotor cortex
(BA6)
believed to play an
important role in the
control of eye
movements.

Area- 9 Dorsolateral
prefrontal cortex
part of the frontal
cortex in the
human brain.
DLPFC serves as the
highest cortical area
responsible for motor
planning, organization,
and regulation.
It plays an important role
in the integration of
sensory and mnemonic
information and the
regulation of intellectual
function and action,
especially in relation to
impulse control.
It is also involved in
working memory.
However, DLPFC is not
exclusively responsible

Page 27

for the executive
functions. All complex
mental activity requires
the additional cortical
and subcortical circuits
with which the DL-PFC
is connected.
Area- 10 Anterior prefrontal
cortex (most rostral
part of superior and
middle frontal gyri)
It is the anterior-
most portion of the
prefrontal cortex
in the human
brain.
one of the least well
understood regions of the
human brain".

Present research suggests
that it is involved in
strategic processes in
memory recall and
various executive
functions.
During
human
evolution, the
functions in
this area
resulted in its
expansion
relative to the
rest of the
brain
Area- 11 Orbitofrontal area
(orbital and rectus
gyri, plus part of
the rostral part of
the superior frontal
gyrus)
It is a prefrontal
cortex region in
the frontal lobes in
the brain
It is involved in the
cognitive processing of
decision-making.

Area- 12 Orbitofrontal area
(used to be part of
BA11, refers to the
area between the
superior frontal
gyrus and the
inferior rostral
sulcus)
It occupies the
most rostral
portion of the
frontal lobe.
Not known
Area-
13, 14
Insular cortex In each
hemisphere of the
mammalian brain
the insular cortex
(often called
insula, insulary
cortex or insular
The insulae are believed
to be involved in
consciousness and play a
role in diverse functions
usually linked to emotion
or the regulation of the
body's homeostasis.
Area -14 for
non-human
primates.
Page 28

lobe) is a portion
of the cerebral
cortex folded deep
within the lateral
sulcus (the fissure
separating the
temporal lobe
from the parietal
and frontal lobes).
These functions include
perception, motor
control, self-awareness,
cognitive functioning,
and interpersonal
experience. In relation to
these it is involved in
psychopathology.
Area- 15 Anterior Temporal
Lobe
subdivisions of the
cerebral cortex in
the brain.
Area 15 was
defined by
Brodmann in
the guenon
monkey, but
he found no
equivalent
structure in
humans.
Area- 17 Primary visual
cortex (V1)
is the part of the
cerebral cortex It
is located in the
occipital lobe, in
the back of the
brain.
responsible for
processing visual
information.

Area- 18 Secondary visual
cortex (V2)
It is part of the
occipital cortex in
the human brain.
is the second
major area in the
visual cortex, and
the first region
within the visual
association area.
It receives strong
feedforward connections
from V1 (direct and via
the pulvinar) and sends
strong connections to V3,
V4, and V5. It also sends
strong feedback
connections to V1.

Area- 19 Associative visual
cortex (V3,V4,V5)
It is part of the
occipital lobe
cortex in the
Area 19 has been noted
to receive inputs from the
retina via the superior
colliculus and pulvinar,
In patients
blind from a
young age,
the area has
Page 29

human brain. and may contribute to the
phenomenon of
blindsight.
been found to
be activated
by
somatosensor
y stimuli.
Area- 20 Inferior temporal
gyrus
It is placed below
the middle
temporal gyrus,
and is connected
behind with the
inferior occipital
gyrus; it also
extends around the
infero-lateral
border on to the
inferior surface of
the temporal lobe,
where it is limited
by the inferior
sulcus.
This region believed to
play a part in high-level
visual processing and
recognition memory.
It may also be involved
in face perception, and in
the recognition of
numbers.

Area- 21 Middle temporal
gyrus
Middle temporal
gyrus is a gyrus in
the brain on the
Temporal lobe. It
is located between
the superior
temporal gyrus
and inferior
temporal gyrus
Its exact function is
unknown, but it has been
connected with processes
as different as
contemplating distance,
recognition of known
faces, and accessing
word meaning while
reading.

Area- 22 Superior temporal
gyrus, of which the
caudal part is
usually considered
to contain the
Wernicke's area
The superior
temporal gyrus is
one of three
(sometimes two)
gyri in the
temporal lobe of
the human brain,
which is located
laterally to the
On the left side of the
brain this area helps with
generation and
understanding of
individual words. On the
right side of the brain it
helps to discriminate
pitch and sound intensity,
both of which are

Page 30

head, situated
somewhat above
the external ear.

The superior
temporal gyrus is
bounded by:

the lateral
sulcus above;
the superior
temporal sulcus
(not always
present or visible)
below;
an imaginary
line drawn from
the preoccipital
notch to the lateral
sulcus posteriorly.
necessary to perceive
melody and prosody.
Researchers believe this
part of the brain is active
in processing language.
Area- 23 Ventral posterior
cingulate cortex
The posterior
cingulate cortex is
the backmost part
of the cingulate
cortex, lying
behind the anterior
cingulate cortex.
This is the upper
part of the "limbic
lobe". The
cingulate cortex is
made up of an area
around the midline
of the brain.
Surrounding areas
include the
The posterior cingulate
cortex forms a central
node in the "default
mode" network of the
brain. It has been shown
to communicate with
various brain networks
simultaneously and is
involved in various
functions.[1] Along with
the precuneus, the
posterior cingulate cortex
has been implicated as a
neural substrate for
human awareness in
numerous studies of both

Page 31

retrosplenial
cortex and the
precuneus.
the anesthesized and
vegetative (coma) state.
Imaging studies indicate
a prominent role for the
posterior cingulate cortex
in pain and episodic
memory retrieval.[2] It
has also been revealed
that increased size of
posterior ventral
cingulate cortex is related
to the working memory
performance decline.[3]
Furthermore, the
posterior cingulate may
be involved in the
capacity to understand
what other people
believe.
Area- 24 Ventral anterior
cingulate cortex.
The anterior
cingulate cortex
(ACC) is the
frontal part of the
cingulate cortex,
surrounding the
frontal part of the
corpus callosum.
It appears to play a role
in a wide variety of
autonomic functions,
such as regulating blood
pressure and heart rate,
as well as rational
cognitive functions, such
as reward anticipation,
decision-making,
empathy, impulse
control,[1] and
emotion.[2][3]

Area- 25 Subgenual area
(part of the
Ventromedial
prefrontal cortex
s an area in the
cerebral cortex of
the brain
This region is extremely
rich in serotonin
transporters and is
considered as a governor
for a vast network
involving areas like
hypothalamus and brain
stem, which influences

Page 32

changes in appetite and
sleep; the amygdala and
insula, which affect the
mood and anxiety; the
hippocampus, which
plays an important role in
memory formation; and
some parts of the frontal
cortex responsible for
self-esteem
Area- 26 Ectosplenial portion
of the retrosplenial
region of the
cerebral cortex
It is the
retrosplenial
region of the
cerebral cortex. It
is a narrow band
located in the
isthmus of
cingulate gyrus
adjacent to the
fasciolar gyrus
internally. It is
bounded externally
by the granular
retrolimbic are
Not known
Area- 27 Piriform cortex Not in human
brain
Area- 28 Ventral entorhinal
cortex
located in the
medial temporal
lobe
and functioning as a hub
in a widespread network
for memory and
navigation.
he EC-hippocampus
system plays an
important role in
autobiographical/declarat
ive/episodic memories
and in particular spatial
memories including
memory formation,
The EC is the
main
interface
between the
hippocampus
and
neocortex.
Page 33

memory consolidation,
and memory optimization
in sleep. The EC is also
responsible for the pre-
processing (familiarity)
of the input signals in the
reflex nictitating
membrane response of
classical trace
conditioning, the
association of impulses
from the eye and the ear
occurs in the entorhinal
cortex.
Area- 29 Retrosplenial
cingulate cortex
In the human it is a
narrow band
located in the
isthmus of
cingulate
gyrus.(The
cingulate cortex is
a part of the brain
situated in the
medial aspect of
the cerebral cortex.
It includes the
cortex of the
cingulate gyrus,
which lies
immediately above
the corpus
callosum, and the
continuation of
this in the
cingulate sulcus.
The cingulate
cortex is usually
considered part of
the limbic lobe.)
It receives inputs from
the thalamus and the
neocortex, and projects to
the entorhinal cortex via
the cingulum. It is an
integral part of the limbic
system, which is
involved with emotion
formation and
processing, learning, and
memory. The
combination of these
three functions makes the
cingulate gyrus highly
influential in linking
behavioral outcomes to
motivation (e.g. a certain
action induced a positive
emotional response,
which results in
learning). It also plays a
role in executive function
and respiratory control.
cingulate
cortex highly
important in
disorders
such as
depressionan
d
schizophreni
a.
Page 34

Area- 30 Part of cingulate
cortex
In the human it is a
narrow band
located in the
isthmus of
cingulate gyrus.

Area- 31 Dorsal Posterior
cingulate cortex
In the human it
occupies portions
of the posterior
cingulate gyrus
and medial aspect
of the parietal
lobe. Approximate
boundaries are the
cingulate sulcus
dorsally and the
parieto-occipital
sulcus caudally. It
partially surrounds
the subparietal
sulcus, the ventral
continuation of the
cingulate sulcus in
the parietal lobe.
Cytoarchitecturall
y it is bounded
rostrally by the
ventral anterior
cingulate area 24,
ventrally by the
ventral posterior
cingulate area 23,
dorsally by the
gigantopyramidal
area 4 and
preparietal area 5
and caudally by
the superior
parietal area 7

Page 35

Area- 32 Dorsal anterior
cingulate cortex
In the human it
forms an outer arc
around the anterior
cingulate gyrus.
The cingulate
sulcus defines
approximately its
inner boundary
and the superior
rostral sulcus (H)
its ventral
boundary; rostrally
it extends almost
to the margin of
the frontal lobe.
Cytoarchitecturall
y it is bounded
internally by the
ventral anterior
cingulate area 24,
externally by
medial margins of
the agranular
frontal area 6,
intermediate
frontal area 8,
granular frontal
area 9, frontopolar
area 10, and
prefrontal area 11

Area- 33 Part of anterior
cingulate cortex
It is a narrow band
located in the
anterior cingulate
gyrus adjacent to
the supracallosal
gyrus in the depth
of the callosal
sulcus, near the
genu of the corpus
callosum.

Page 36

Cytoarchitecturall
y it is bounded by
the ventral anterior
cingulate area 24
and the
supracallosal gyrus
Area- 34 Dorsal entorhinal
cortex (on the
Parahippocampal
gyrus)
Area 28
Area- 35 Perirhinal cortex (in
the rhinal sulcus)
Perirhinal cortex is
a cortical region in
the medial
temporal lobe
It receives highly-
processed sensory
information from all
sensory regions, and is
generally accepted to be
an important region for
memory.

Area- 36 Ectorhinal area,
now part of the
perirhinal cortex (in
the rhinal sulcus)
It is located in
temporal region of
cerebral cortex.
With its medial
boundary
corresponding
approximately to
the rhinal sulcus it
is located
primarily in the
fusiform gyrus.
Cytoarchitecturall
y it is bounded
laterally and
caudally by the
inferior temporal
area 20, medially
by the perirhinal
area 35 and
rostrally by the
temporopolar area

Page 37

38
Area- 37 Fusiform gyrus The fusiform
gyrus is part of the
temporal lobe and
occipital lobe
There is still some
dispute over the
functionalities of this
area, but there is relative
consensus on the
following:

processing of color
information
face and body
recognition (see Fusiform
face area)
word recognition (see
Visual word form area)
within-category
identification

Area- 38 Temporopolar area
(most rostral part of
the superior and
middle temporal
gyri)
It is part of the
temporal cortex in
the human brain.
BA 38 is at the
anterior end of the
temporal lobe,
known as the
temporal pole.
The functional
significance of this area
TG is not known, but it
may bind complex,
highly processed
perceptual inputs to
visceral emotional
responses
is unique to
humans
Area- 39 Angular gyrus,
considered by some
to be part of
Wernicke's area
The angular gyrus
is a region of the
brain in the
parietal lobe, that
lies near the
superior edge of
the temporal lobe,
and immediately
posterior to the
supramarginal
it is involved in a number
of processes related to
language, number
processing and spatial
cognition, memory
retrieval, attention, and
theory of mind.

Page 38

gyrus
Area- 40 Supramarginal
gyrus considered by
some to be part of
Wernicke's area
It is part of the
parietal cortex in
the human brain.
The inferior part of
BA40 is in the
area of the
supramarginal
gyrus, which lies
at the posterior end
of the lateral
fissure, in the
inferior lateral part
of the parietal
lobe.
It is probably involved
with language perception
and processing, and
lesions in it may cause
Receptive aphasia or
transcortical sensory
aphasia

Area-
41, 42
Auditory cortex The auditory
cortex is the part
of the cerebral
cortex that
processes auditory
information in
humans and other
vertebrates.
It is located
bilaterally, roughly
at the upper sides
of the temporal
lobes in humans
on the superior
temporal plane,
within the lateral
fissure and
comprising parts
of Heschl's gyrus
and the superior
temporal gyrus,
including planum
polare and planum
A part of the auditory
system, it performs basic
and higher functions in
hearing.

Page 39

temporale
Area- 43 Primary gustatory
cortex
is defined in the
postcentral region
of cerebral cortex.
It occupies the
postcentral gyrus
and the precentral
gyrus between the
ventrolateral
extreme of the
central sulcus and
the depth of the
lateral sulcus at the
insula.
Not known
Area- 44 Pars opercularis,
part of Broca's area
n the human, this
region occupies
the triangular part
of the inferior
frontal gyrus and,
surrounding the
anterior horizontal
limb of the lateral
sulcus, a portion of
the orbital part of
the inferior frontal
gyrus. Bounded
caudally by the
anterior ascending
limb of the lateral
sulcus, it borders
on the insula in the
depth of the lateral
sulcus.
Recent neuroimaging
studies show BA44
involvement in selective
response suppression in
go/no- go tasks and is
therefore believed to play
an important role in the
suppression of response
tendencies.Neuroimaging
studies also demonstrate
that area 44 is related to
hand movements.

Area- 45 Pars triangularis
Broca's area
Brodmann area 45
(BA45), is part of
the frontal cortex
in the human
brain. Situated on
Together with BA 44, it
comprises Broca's area, a
region that is active in
semantic tasks, such as
semantic decision tasks

Page 40

the lateral surface,
inferior to BA9
and adjacent to
BA46.
(determining whether a
word represents an
abstract or a concrete
entity) and generation
tasks (generating a verb
associated with a noun).
Area- 46 Dorsolateral
prefrontal cortex
Brodmann area 46,
or BA46, is part of
the frontal cortex
in the human
brain. It is between
BA10 and BA45.
BA46 is known as
middle frontal area
46. In the human
brain it occupies
approximately the
middle third of the
middle frontal
gyrus and the most
rostral portion of
the inferior frontal
gyrus. Brodmann
area 46 roughly
corresponds with
the dorsolateral
prefrontal cortex
(DLPFC)
The DLPFC plays a role
in sustaining attention
and working memory.
Lesions to the DLPFC
impair short-term
memory and cause
difficulty inhibiting
responses. Lesions may
also eliminate much of
the ability to make
judgements about what's
relevant and what's not as
well as causing problems
in organization.
The DLPFC has recently
been found to be
involved in exhibiting
self-control.

Area- 47 pars orbitalis, part
of the inferior
frontal gyrus
Brodmann area 47,
or BA47, is part of
the frontal cortex
in the human
brain. Curving
from the lateral
surface of the
frontal lobe into
the ventral
(orbital) frontal
BA47 has been
implicated in the
processing of syntax in
oral and sign languages,
and more recently in
musical syntax.

Page 41

cortex. It is below
areas BA10 and
BA45, and beside
BA11.
This area is also
known as orbital
area 47. In the
human, on the
orbital surface it
surrounds the
caudal portion of
the orbital sulcus
(H) from which it
extends laterally
into the orbital part
of inferior frontal
gyrus
Area- 48 Retrosubicular area
(a small part of the
medial surface of
the temporal lobe)
In the human it is
located on the
medial surface of
the temporal lobe.
Not known
Area- 49 Parasubicular area
in a rodent

Area- 52 Parainsular area (at
the junction of the
temporal lobe and
the insula)
It is located in the
bank of the lateral
sulcus on the
dorsal surface of
the temporal lobe.
Its medial
boundary
corresponds
approximately to
the junction
between the
temporal lobe and
the insula.
Not known
Page 42

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