**Brain Circuits Responsible for Seizure Generation, Propagation, and Control: Insights from Preclinical Research**

Patrick A. Forcelli and Karen Gale

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/58584

#### **1. Introduction**

stimulation and other neuromodulatory therapies in epilepsy management, non-epileptic seizures, and, no less important to the individual, some of the psychosocial issues that con‐ front the patient and his or her family. This volume is not intended be a comprehensive overview of the field of epilepsy, but each discussion is focused and will be valuable to both

> **Mark D. Holmes MD** Regional Epilepsy Center Department of Neurology University of Washington Seattle, Washington, USA

investigators and practitioners.

VIII Preface

In the early 1870s, John Hughlings Jackson, the father of modern epileptology wrote, that a seizure is "a symptom, and implies only that there is an occasional, an excessive, and a disorderly discharge of nerve tissue" [1]. When one considers that he wrote this more than 50 years before the first human electroencephalographic recordings [2], his level of insight is quite remarkable. Indeed, his later definition of epilepsy as "the name for occasional, sudden, excessive, rapid, and local discharge of grey matter" [3] could be used without alteration today.

There is a key difference between Jackson's two definitions: his later definition no longer included the concept of seizures as "disorderly". While seizures are a symptom of a disorder, the temporal pattern of signs and symptoms of seizures are far from disorderly or disorgan‐ ized; this was evident to Jackson in the march of seizure activity through somatosensory cortex [1,4]. Today, relying not only on seizure semiology, but also electroencephalographic, neuro‐ imaging, and animal models, we can without hesitation state that seizure activity does not spread randomly through the brain, but moves through anatomically constrained pathways and networks.

These pathways are the focus of this chapter; we will discuss specific brain networks that are capable of seizure generation, seizure propagation, and seizure suppression. From the perspective of preclinical research, we will emphasize several points:


© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**3.** How do emerging technologies enable translation of network-level manipulations to the clinic?

**1.** Changes observed in association with repeated or recurrent seizures cannot be readily

Brain Circuits Responsible for Seizure Generation, Propagation, and Control: Insights from Preclinical Research

http://dx.doi.org/10.5772/58584

3

**2.** The great deal of variability across patients and studies with respect to diagnosis, etiology,

Animal models overcome these limitations. For example, it is only by directly manipulating a brain pathway or region that one can determine whether the structure is necessary for seizure initiation, amplification, distribution, or inhibitory (feedback) control. These direct manipu‐ lations include circumscribed lesions, electrical stimulation, pharmacological inactivation/

When these techniques are applied to intact, normal animals, their impact on the circuitry can be evaluated uncompromised by preexisting pathologies. Moreover, the effect of the manip‐ ulation can be studied in both animals with a seizure profile and in control animals that are

Four major types of animal models have been used in epilepsy research: genetic (naturallyoccurring and engineered), evoked epileptogenesis, and evoked seizures. Entire texts have been written on this subject (see for example, [20]), so our discussion below is by no means

Naturally-occurring and inbred models are seen in a variety of species, ranging from mouse (e.g., the El mouse [21–24]; and others [25]), rats (e.g., GEPR rats [26–28]; Wistar Audiogenic Rats [29,30]), gerbils [31], dogs [32], and non-human primates (e.g., baboons [33]). The truly spontaneous seizures that occur in these cases suggest that the circuitry that produces epilepsy

Transgenic models of epilepsy are of increasing importance as new mutations for inherited epilepsies are discovered. These models have been used to identify abnormalities at the microcircuit level (e.g., interneurons in the SCN1A knockout mice [34]), but abnormalities at

Models that evoke epileptogenesis are vital when the goal is to identify what neuroplas‐ tic changes, if any, lead to epilepsy. However, if the goal is to delineate networks through which seizures preferentially propagate, then the use of an acute or subacute seizure model is most appropriate, especially a model that does not cause brain injury. It may be worthwhile to compare the pattern of seizure propagation in an injured vs uninjured brain, but for this purpose, the injury should be highly controlled and reproducible. Unfortunate‐ ly, models such as status-epilepticus (SE) induced spontaneous seizures suffer from some of the one of the same drawbacks associated with studies in patient populations, e.g., heterogeneity of injury. Moreover, SE can cause severe and widespread damage that often exceeds the level of damage seen clinically [35]. The need for highly reproducible and focal epileptogenic insults may potentially be filled by controlled models of traumatic brain injury, which provide greater control over the location and extent of damage [36-38].

the macrocircuit level still require investigation for most of these models.

seizure naïve, allowing one to determine how pathology changes circuit function.

identified as cause, effect, or compensation.

**3.** The inability to use matched controls for invasive procedures.

and treatment.

silencing, and optogenetic approaches.

intended to be comprehensive.

has been highly conserved over phylogeny.

#### **2. Identifying seizure circuits**

Seizure semiology can provide insight into the brain networks impacted for a given seizure type: for example, the "fencing posture" seen in patients with frontal lobe seizures involving pre-motor cortex can be recapitulated by selective stimulation of pre-motor cortex [5,6]. Similarly, sensory-specific auras e.g., odors in temporal lobe epilepsy can be localized to piriform cortex, [7,8], complex visual hallucinations in anteromedial temporal lobe, occipito‐ temporal and occipital epilepsy [9]. These symptoms provide an index of regions impacted by seizures, and the temporal order of the occurrence of these symptoms can provide a measure of seizure spread. However, working backwards from these symptoms to identify the path and origin of seizure propagation is a near impossible challenge.

Take, for example, electrical wiring in a house as an anology: a surge of power may cause the lights to flicker in the living room, but that does not necessitate (or even indicate) that the surge started in the living room. Indeed, we know that both parallel and serial wires exist in the house, connecting power sources to fuse boxes to distribution nodes. Various signs and symptoms (burnt wiring, a tripped circuit breaker, etc.) may represent primary causes or secondary effects. Troubleshooting a circuit problem in the house, as complex as it may be, is feasible because there are wiring diagrams to guide you. Without these wiring diagrams tracing a problem would be much more complicated.

At the present, we are working, at best, with very incomplete wiring diagrams for the brain. Thus, we assert that understanding how seizure networks are wired in the "normal" brain is essential to determine how faults in this wiring leads to chronic seizures.

A variety of "mapping" approaches have been employed to identify brain regions engaged by seizures, including electrographic, metabolic (e.g., 2-deoxyglucose), immediate early gene (e.g., fos, zif), and functional magnetic resonance imaging [10–19]. While informative, these approaches, in isolation, only identify areas activated by seizures. Mapping approaches alone cannot determine the role of a region in initiation, propagation, or seizure suppression; these determinations can only be made on the basis of circuit manipulations. The need for circuitlevel manipulations is one of several reasons that animal models are vital for deciphering seizure circuitry.

#### **3. Importance of preclinical research using animal models**

Studies in human patients have provided many valuable insights into the networks supporting seizures, but the conclusions that can be drawn from these studies are limited by the following:


**3.** How do emerging technologies enable translation of network-level manipulations to the

Seizure semiology can provide insight into the brain networks impacted for a given seizure type: for example, the "fencing posture" seen in patients with frontal lobe seizures involving pre-motor cortex can be recapitulated by selective stimulation of pre-motor cortex [5,6]. Similarly, sensory-specific auras e.g., odors in temporal lobe epilepsy can be localized to piriform cortex, [7,8], complex visual hallucinations in anteromedial temporal lobe, occipito‐ temporal and occipital epilepsy [9]. These symptoms provide an index of regions impacted by seizures, and the temporal order of the occurrence of these symptoms can provide a measure of seizure spread. However, working backwards from these symptoms to identify the path

Take, for example, electrical wiring in a house as an anology: a surge of power may cause the lights to flicker in the living room, but that does not necessitate (or even indicate) that the surge started in the living room. Indeed, we know that both parallel and serial wires exist in the house, connecting power sources to fuse boxes to distribution nodes. Various signs and symptoms (burnt wiring, a tripped circuit breaker, etc.) may represent primary causes or secondary effects. Troubleshooting a circuit problem in the house, as complex as it may be, is feasible because there are wiring diagrams to guide you. Without these wiring diagrams

At the present, we are working, at best, with very incomplete wiring diagrams for the brain. Thus, we assert that understanding how seizure networks are wired in the "normal" brain is

A variety of "mapping" approaches have been employed to identify brain regions engaged by seizures, including electrographic, metabolic (e.g., 2-deoxyglucose), immediate early gene (e.g., fos, zif), and functional magnetic resonance imaging [10–19]. While informative, these approaches, in isolation, only identify areas activated by seizures. Mapping approaches alone cannot determine the role of a region in initiation, propagation, or seizure suppression; these determinations can only be made on the basis of circuit manipulations. The need for circuitlevel manipulations is one of several reasons that animal models are vital for deciphering

Studies in human patients have provided many valuable insights into the networks supporting seizures, but the conclusions that can be drawn from these studies are limited by the following:

essential to determine how faults in this wiring leads to chronic seizures.

**3. Importance of preclinical research using animal models**

and origin of seizure propagation is a near impossible challenge.

tracing a problem would be much more complicated.

clinic?

2 Epilepsy Topics

seizure circuitry.

**2. Identifying seizure circuits**

Animal models overcome these limitations. For example, it is only by directly manipulating a brain pathway or region that one can determine whether the structure is necessary for seizure initiation, amplification, distribution, or inhibitory (feedback) control. These direct manipu‐ lations include circumscribed lesions, electrical stimulation, pharmacological inactivation/ silencing, and optogenetic approaches.

When these techniques are applied to intact, normal animals, their impact on the circuitry can be evaluated uncompromised by preexisting pathologies. Moreover, the effect of the manip‐ ulation can be studied in both animals with a seizure profile and in control animals that are seizure naïve, allowing one to determine how pathology changes circuit function.

Four major types of animal models have been used in epilepsy research: genetic (naturallyoccurring and engineered), evoked epileptogenesis, and evoked seizures. Entire texts have been written on this subject (see for example, [20]), so our discussion below is by no means intended to be comprehensive.

Naturally-occurring and inbred models are seen in a variety of species, ranging from mouse (e.g., the El mouse [21–24]; and others [25]), rats (e.g., GEPR rats [26–28]; Wistar Audiogenic Rats [29,30]), gerbils [31], dogs [32], and non-human primates (e.g., baboons [33]). The truly spontaneous seizures that occur in these cases suggest that the circuitry that produces epilepsy has been highly conserved over phylogeny.

Transgenic models of epilepsy are of increasing importance as new mutations for inherited epilepsies are discovered. These models have been used to identify abnormalities at the microcircuit level (e.g., interneurons in the SCN1A knockout mice [34]), but abnormalities at the macrocircuit level still require investigation for most of these models.

Models that evoke epileptogenesis are vital when the goal is to identify what neuroplas‐ tic changes, if any, lead to epilepsy. However, if the goal is to delineate networks through which seizures preferentially propagate, then the use of an acute or subacute seizure model is most appropriate, especially a model that does not cause brain injury. It may be worthwhile to compare the pattern of seizure propagation in an injured vs uninjured brain, but for this purpose, the injury should be highly controlled and reproducible. Unfortunate‐ ly, models such as status-epilepticus (SE) induced spontaneous seizures suffer from some of the one of the same drawbacks associated with studies in patient populations, e.g., heterogeneity of injury. Moreover, SE can cause severe and widespread damage that often exceeds the level of damage seen clinically [35]. The need for highly reproducible and focal epileptogenic insults may potentially be filled by controlled models of traumatic brain injury, which provide greater control over the location and extent of damage [36-38].

## **4. Types of models and manifestations: what is seizure-related and what is due to compensatory mechanisms?**

**6. Multiple seizure networks**

supporting tonic-clonic seizures [50–52].

While a seizure can appear to "progress" on a continuum from complex partial to generalized tonic-clonic, the progression actually results from successive engagement of independent and dissociable seizure networks: one network supporting complex partial seizures and another

Brain Circuits Responsible for Seizure Generation, Propagation, and Control: Insights from Preclinical Research

http://dx.doi.org/10.5772/58584

5

For example, complex partial seizures can be evoked by stimulation of the piriform cortex [43], while activation of the inferior colliculus [53] and/or reticular nuclei [54] triggers tonic-clonic seizures. While it is striking that such focal manipulations can trigger these seizures, the independence of these seizure networks is even more impressive. In both the cat and rat, disconnection of the forebrain from the hindbrain via precollicular transections does not impede the ability of the forebrain to show characteristic EEG seizure responses to focal or systemic chemoconvulsant treatment [50,52,55]. Thus, communication with the hindbrain is not necessary for forebrain seizures. Moreover, these animals are still capable of demonstrating normal tonic-clonic and running/bouncing clonus. Thus, communication with the forebrain is not necessary for hindbrain seizures. These data provide a compelling argument for the independence of these seizure networks, an observation that has been supported by localiza‐ tion of focal trigger zones and circuits for these various seizure types. This leads us to the

question, are these seizure "trigger zones" necessarily the same as a "seizure focus"?

It is often assumed that the first site to show ictal activity is the site of seizure initiation. By focally evoking seizures from piriform cortex in the rat, we have found that this is not necessarily the case. Shortly after bicuculline microinjection, piriform cortex displays an interictal like pattern, while ictal activity can be seen in other limbic brain regions. Thus the first

Clinically, sites of histopathology are often examined as presumptive seizure foci. While in some cases the site(s) of pathology may indeed be the site(s) of seizure onset, animal models have demonstrated that this is not true in all cases. For example, in the tish rat (a model of cortical heterotopia), the *normotopic* neurons, not the heterotopic neurons, are more likely to display epileptiform activity [56]. Moreover, suppression of activity within the heterotopias reduces epileptiform activity *only within the heterotopia* and not within normotopic cortex; conversely, suppression of activity within normotopic cortex suppresses epileptiform activity

Indeed, even in a highly controlled animal model (e.g., electrically-induced self-sustained status epilepticus), the site within the limbic network showing earliest ictal electrographic activity can vary both between and within subjects [57]. Together, these findings suggest that pathology is not by necessity a clear indicator of the site of seizure initiation. While this does not preclude the possibility that a seizure *can* begin at the site of pathology, it underscores that

**7. Insights into seizure foci from animal models**

in both normotopic and heterotopic cortex.

this is not necessarily the case.

ictal activity can appear in a site distal to the site that triggers a seizure.

Determining how seizure networks are changed by epileptogenesis is a necessary step in understanding epilepsy, however, this can only be understood in the context of a comparison between the "normal" and "disease" state. The need to examine seizure propagation in a "normal" network is one of several reasons that evoked seizure models are a powerful tool in modern preclinical epileptology. In addition to this utility, evoked seizure models may be preferable for examining network mechanisms because they offer experimental control of seizure timing, severity, etc. This contrasts with most models of epileptogenesis, in which seizures occur spontaneously and unpredictably.

#### **5. Seizure models evoked by pharmacological agents**

In rats and mice, systemic administration of GABA-A receptor antagonists (bicuculline, pentylenetetrazole, picrotoxin, beta-carbolines) trigger, in a dose-dependent manner, myo‐ clonic, clonic (complex partial/limbic-motor), and tonic-clonic seizures (for a review see: [39]). These compounds have been used to screen virtually every anticonvulsant drug currently available for clinical use. At least one of these compounds (pentylenetetrazole, Metrazol) has been used to trigger tonic-clonic seizures in human patients. In the non-human primate, most of these compounds trigger generalized tonic-clonic response at the lowest effective dose; this may reflect higher sensitivity of hindbrain seizure networks as compared to limbic forebrain networks in the monkey (discussed below).

Other chemoconvulsants (e.g., pilocarpine, kainate) have been widely used for modeling epileptogenesis, and have also been used to examine seizure circuitry [40,41]. Non-convulsant seizure triggering agents (e.g., gammabutyrolactone) have been used to evaluate circuitry underlying thalamocortical spike-and-wave seizures [42].

Focal application of drugs or electrical stimulation of discrete brain nuclei allows for highly controlled and reproducibly evoked seizures of focal or partial onset. This approach also allows for multiple sites within a network to be manipulated. An example of an especially sensitive and circumscribed site in the forebrain effective for triggering complex partial seizures is "Area Tempestas". This functionally defined region is located in the anterior deep piriform cortex and has been identified in rodents and non-human primates [43–48]. Interestingly, fMRI and PET data suggest that an anatomically homologous area exists in human patients with epilepsy [49]. Moreover, unruptured aneurysms of the middle cerebral artery, located in close proximity to piriform cortex, have been associated with unilateral olfactory auras and complex partial seizures (e.g., [7,8]).

### **6. Multiple seizure networks**

**4. Types of models and manifestations: what is seizure-related and what is**

Determining how seizure networks are changed by epileptogenesis is a necessary step in understanding epilepsy, however, this can only be understood in the context of a comparison between the "normal" and "disease" state. The need to examine seizure propagation in a "normal" network is one of several reasons that evoked seizure models are a powerful tool in modern preclinical epileptology. In addition to this utility, evoked seizure models may be preferable for examining network mechanisms because they offer experimental control of seizure timing, severity, etc. This contrasts with most models of epileptogenesis, in which

In rats and mice, systemic administration of GABA-A receptor antagonists (bicuculline, pentylenetetrazole, picrotoxin, beta-carbolines) trigger, in a dose-dependent manner, myo‐ clonic, clonic (complex partial/limbic-motor), and tonic-clonic seizures (for a review see: [39]). These compounds have been used to screen virtually every anticonvulsant drug currently available for clinical use. At least one of these compounds (pentylenetetrazole, Metrazol) has been used to trigger tonic-clonic seizures in human patients. In the non-human primate, most of these compounds trigger generalized tonic-clonic response at the lowest effective dose; this may reflect higher sensitivity of hindbrain seizure networks as compared to limbic forebrain

Other chemoconvulsants (e.g., pilocarpine, kainate) have been widely used for modeling epileptogenesis, and have also been used to examine seizure circuitry [40,41]. Non-convulsant seizure triggering agents (e.g., gammabutyrolactone) have been used to evaluate circuitry

Focal application of drugs or electrical stimulation of discrete brain nuclei allows for highly controlled and reproducibly evoked seizures of focal or partial onset. This approach also allows for multiple sites within a network to be manipulated. An example of an especially sensitive and circumscribed site in the forebrain effective for triggering complex partial seizures is "Area Tempestas". This functionally defined region is located in the anterior deep piriform cortex and has been identified in rodents and non-human primates [43–48]. Interestingly, fMRI and PET data suggest that an anatomically homologous area exists in human patients with epilepsy [49]. Moreover, unruptured aneurysms of the middle cerebral artery, located in close proximity to piriform cortex, have been associated with unilateral olfactory auras and complex partial

**due to compensatory mechanisms?**

4 Epilepsy Topics

seizures occur spontaneously and unpredictably.

networks in the monkey (discussed below).

seizures (e.g., [7,8]).

underlying thalamocortical spike-and-wave seizures [42].

**5. Seizure models evoked by pharmacological agents**

While a seizure can appear to "progress" on a continuum from complex partial to generalized tonic-clonic, the progression actually results from successive engagement of independent and dissociable seizure networks: one network supporting complex partial seizures and another supporting tonic-clonic seizures [50–52].

For example, complex partial seizures can be evoked by stimulation of the piriform cortex [43], while activation of the inferior colliculus [53] and/or reticular nuclei [54] triggers tonic-clonic seizures. While it is striking that such focal manipulations can trigger these seizures, the independence of these seizure networks is even more impressive. In both the cat and rat, disconnection of the forebrain from the hindbrain via precollicular transections does not impede the ability of the forebrain to show characteristic EEG seizure responses to focal or systemic chemoconvulsant treatment [50,52,55]. Thus, communication with the hindbrain is not necessary for forebrain seizures. Moreover, these animals are still capable of demonstrating normal tonic-clonic and running/bouncing clonus. Thus, communication with the forebrain is not necessary for hindbrain seizures. These data provide a compelling argument for the independence of these seizure networks, an observation that has been supported by localiza‐ tion of focal trigger zones and circuits for these various seizure types. This leads us to the question, are these seizure "trigger zones" necessarily the same as a "seizure focus"?

#### **7. Insights into seizure foci from animal models**

It is often assumed that the first site to show ictal activity is the site of seizure initiation. By focally evoking seizures from piriform cortex in the rat, we have found that this is not necessarily the case. Shortly after bicuculline microinjection, piriform cortex displays an interictal like pattern, while ictal activity can be seen in other limbic brain regions. Thus the first ictal activity can appear in a site distal to the site that triggers a seizure.

Clinically, sites of histopathology are often examined as presumptive seizure foci. While in some cases the site(s) of pathology may indeed be the site(s) of seizure onset, animal models have demonstrated that this is not true in all cases. For example, in the tish rat (a model of cortical heterotopia), the *normotopic* neurons, not the heterotopic neurons, are more likely to display epileptiform activity [56]. Moreover, suppression of activity within the heterotopias reduces epileptiform activity *only within the heterotopia* and not within normotopic cortex; conversely, suppression of activity within normotopic cortex suppresses epileptiform activity in both normotopic and heterotopic cortex.

Indeed, even in a highly controlled animal model (e.g., electrically-induced self-sustained status epilepticus), the site within the limbic network showing earliest ictal electrographic activity can vary both between and within subjects [57]. Together, these findings suggest that pathology is not by necessity a clear indicator of the site of seizure initiation. While this does not preclude the possibility that a seizure *can* begin at the site of pathology, it underscores that this is not necessarily the case.

#### **8. Translating semiology and terminology across species**

Much of the terminology that is used to describe seizures in animal models has been borrowed from the clinic. However, because seizure semiology differs across species, accurate mapping of terms presents a challenge.

seizures lack the prominent tonic-extensor phase (which requires brainstem engagement) seen in secondarily generalized seizures in monkeys and humans, we suggest that the repeated clonus and rearing/loss of balance that is characteristic of these seizures should not be considered tonic-clonic. On this basis, we suggest that focal limbic seizures (e.g., seizures early in kindling that do not engage the basal ganglia) are akin to simple partial seizures, seizures that spread to the basal ganglia are akin to complex partial seizures (as they are still confined to the forebrain), and only when hindbrain circuits are engaged should these seizures be

Brain Circuits Responsible for Seizure Generation, Propagation, and Control: Insights from Preclinical Research

http://dx.doi.org/10.5772/58584

7

**10. Manipulating circuits with focal stimulation as a therapeutic**

of specificity in cell-type and pathway-specific targeting [64-70].

With the success of deep brain stimulation trials in epilepsy (e.g., stimulation of the anterior nucleus of the thalamus), focal manipulation of circuitry for the control of epilepsy has become a reality. However, identifying the best locations for targeting is a work-in-progress. Contin‐ ued circuit analysis in animals is essential, not only for identifying targets, but also for examining newer approaches (e.g., optogenetics, chemical-genetics) that offer exciting levels

One approach that remains underexplored clinically is enhancing the function of seizuresuppressive network nodes that have been identified in animal models. One such node is the substantia nigra pars reticulata [71–76]. Suppression of activity within this region is potently anticonvulsant in a variety of seizure models, and across several species. This structure is particularly compelling for further investigation because it is positioned at the interface of two different seizure networks (i.e., the forebrain network, with heavy interconnections to limbic structures, and the hindbrain network, projections to colliculus and brainstem targets). This anatomical position may underlie the anticonvulsant effects that this region exerts across seizure types: it decreases the duration of tonic hindlimb extension triggered by maximal electroshock and it decreases seizures focally evoked from piriform cortex. As we continue to refine our circuit maps, we open the door to therapeutic approaches such as suppressing activity in seizure "distribution" nodes or activation of endogenous "surge suppressors". These possibilities that can only be realized through the use of appropriate animal models.

Department of Pharmacology & Physiology, Georgetown University, Washington DC, USA

considered truly generalized.

**intervention**

**Author details**

Patrick A. Forcelli\*

and Karen Gale

\*Address all correspondence to: paf22@georgetown.edu

For example, there are behavioral differences in seizures evoked from area tempestas in the monkey as compared to rodents. In the monkey, these seizures are characterized by facial automatisms and arm posturing – behaviors that are strikingly similar to those seen during complex partial seizures in humans. These seizures have high face validity. AT-evoked seizures in the rat are typical limbic-motor seizures, similar to those seen after low doses of systemically-administered bicuculline, pentylenetetrazole, kainate, or after electrical kindling [43,58]. These seizures are characterized by facial clonus (perhaps akin to lip smacking seen in patients and monkeys), forelimb clonus (perhaps akin to arm posturing), and rearing with loss of balance. The rearing and loss of balance seen in rats is strikingly different than the behaviors observed in primate species.

Thus, by examining AT-evoked seizures across species, it has become clear that complex partial seizures have species-specific behavioral manifestations but share the qualities of focal automatisms and engage the same brain network.

#### **9. Species specific nature of seizure spread: What is a generalized seizure?**

In human patients, complex partial seizures that secondarily generalize have two characteristic features: 1) involvement of the whole brain when the seizure generalizes and 2) tonic-clonic manifestations when the seizure generalizes (as compared to automatisms prior to generali‐ zation).

In the monkey, AT-evoked seizures can secondarily generalize showing bilaterally asynchro‐ nous tonic-clonic and electrographic features. This pattern fits both the electrographic and behavioral definitions used for secondary generalization in humans. In contrast, in the rat, ATevoked seizures do not show tonic-clonic (brainstem) manifestations, but rapidly show bilateral synchronization of the limbic/cortical EEG and associated motor automatisms with rearing and loss of balance. Thus, in the rat, it appears that the "path of least resistance" for seizure propagation is transcallosal or commissural (hence bilaterally synchronized limbic motor and electrographic manifestations) whereas in the primate it appears to be down the neuraxis (hence the involvement of brainstem seizure networks).

Can, then, the limbic motor seizure with rearing and loss of balance in the rat (i.e., a Racine Stage 5 seizure) be considered a secondarily generalized tonic-clonic seizure? Some have suggested that because these seizures engage basal ganglia, they should be considered generalized [59,60]. However, seizure activity in limbic-evoked motor seizures (i.e., Stage 5 amygdala kindled) engages basal ganglia substrates (substantia nigra pars reticulata) even before other limbic structures (such as hippocampus) [61–63]. Moreover, because these seizures lack the prominent tonic-extensor phase (which requires brainstem engagement) seen in secondarily generalized seizures in monkeys and humans, we suggest that the repeated clonus and rearing/loss of balance that is characteristic of these seizures should not be considered tonic-clonic. On this basis, we suggest that focal limbic seizures (e.g., seizures early in kindling that do not engage the basal ganglia) are akin to simple partial seizures, seizures that spread to the basal ganglia are akin to complex partial seizures (as they are still confined to the forebrain), and only when hindbrain circuits are engaged should these seizures be considered truly generalized.

## **10. Manipulating circuits with focal stimulation as a therapeutic intervention**

With the success of deep brain stimulation trials in epilepsy (e.g., stimulation of the anterior nucleus of the thalamus), focal manipulation of circuitry for the control of epilepsy has become a reality. However, identifying the best locations for targeting is a work-in-progress. Contin‐ ued circuit analysis in animals is essential, not only for identifying targets, but also for examining newer approaches (e.g., optogenetics, chemical-genetics) that offer exciting levels of specificity in cell-type and pathway-specific targeting [64-70].

One approach that remains underexplored clinically is enhancing the function of seizuresuppressive network nodes that have been identified in animal models. One such node is the substantia nigra pars reticulata [71–76]. Suppression of activity within this region is potently anticonvulsant in a variety of seizure models, and across several species. This structure is particularly compelling for further investigation because it is positioned at the interface of two different seizure networks (i.e., the forebrain network, with heavy interconnections to limbic structures, and the hindbrain network, projections to colliculus and brainstem targets). This anatomical position may underlie the anticonvulsant effects that this region exerts across seizure types: it decreases the duration of tonic hindlimb extension triggered by maximal electroshock and it decreases seizures focally evoked from piriform cortex. As we continue to refine our circuit maps, we open the door to therapeutic approaches such as suppressing activity in seizure "distribution" nodes or activation of endogenous "surge suppressors". These possibilities that can only be realized through the use of appropriate animal models.

#### **Author details**

**8. Translating semiology and terminology across species**

of terms presents a challenge.

6 Epilepsy Topics

observed in primate species.

zation).

automatisms and engage the same brain network.

neuraxis (hence the involvement of brainstem seizure networks).

Much of the terminology that is used to describe seizures in animal models has been borrowed from the clinic. However, because seizure semiology differs across species, accurate mapping

For example, there are behavioral differences in seizures evoked from area tempestas in the monkey as compared to rodents. In the monkey, these seizures are characterized by facial automatisms and arm posturing – behaviors that are strikingly similar to those seen during complex partial seizures in humans. These seizures have high face validity. AT-evoked seizures in the rat are typical limbic-motor seizures, similar to those seen after low doses of systemically-administered bicuculline, pentylenetetrazole, kainate, or after electrical kindling [43,58]. These seizures are characterized by facial clonus (perhaps akin to lip smacking seen in patients and monkeys), forelimb clonus (perhaps akin to arm posturing), and rearing with loss of balance. The rearing and loss of balance seen in rats is strikingly different than the behaviors

Thus, by examining AT-evoked seizures across species, it has become clear that complex partial seizures have species-specific behavioral manifestations but share the qualities of focal

**9. Species specific nature of seizure spread: What is a generalized seizure?**

In human patients, complex partial seizures that secondarily generalize have two characteristic features: 1) involvement of the whole brain when the seizure generalizes and 2) tonic-clonic manifestations when the seizure generalizes (as compared to automatisms prior to generali‐

In the monkey, AT-evoked seizures can secondarily generalize showing bilaterally asynchro‐ nous tonic-clonic and electrographic features. This pattern fits both the electrographic and behavioral definitions used for secondary generalization in humans. In contrast, in the rat, ATevoked seizures do not show tonic-clonic (brainstem) manifestations, but rapidly show bilateral synchronization of the limbic/cortical EEG and associated motor automatisms with rearing and loss of balance. Thus, in the rat, it appears that the "path of least resistance" for seizure propagation is transcallosal or commissural (hence bilaterally synchronized limbic motor and electrographic manifestations) whereas in the primate it appears to be down the

Can, then, the limbic motor seizure with rearing and loss of balance in the rat (i.e., a Racine Stage 5 seizure) be considered a secondarily generalized tonic-clonic seizure? Some have suggested that because these seizures engage basal ganglia, they should be considered generalized [59,60]. However, seizure activity in limbic-evoked motor seizures (i.e., Stage 5 amygdala kindled) engages basal ganglia substrates (substantia nigra pars reticulata) even before other limbic structures (such as hippocampus) [61–63]. Moreover, because these

Patrick A. Forcelli\* and Karen Gale

\*Address all correspondence to: paf22@georgetown.edu

Department of Pharmacology & Physiology, Georgetown University, Washington DC, USA

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**Chapter 2**

**Role of EEG in Epilepsy**

http://dx.doi.org/10.5772/57430

**1. Introduction**

Manjari Tripathi and Man Mohan Mehendiratta

cortical excitability that underlie epilepsy (Smith, 2005) [1].

patterns, such as alpha rhythm and sleep spindles.

must be used in conjunction with clinical data.

**2. How can EEG help in epilepsy?**

**•** Diagnosis of epilepsy

The human electroencephalogram (EEG) was discovered by the German psychiatrist, Hans Berger, in 1929. Its potential applications in epilepsy rapidly became clear, when Gibbs and colleagues in Boston demonstrated 3 per second spike wave discharge in what was then termed petit mal epilepsy. EEG continues to play a central role in diagnosis and management of patients with seizure disorders—in conjunction with the now remarkable variety of other diagnostic techniques developed over the last 30 or so years – because it is a convenient and relatively inexpensive way to demonstrate the physiological manifestations of abnormal

The electroencephalograph records spontaneous electrical activity generated in cerebral cortex. This activity reflects the electrical currents that flow in the extracellular spaces of the brain, and these reflect the summated effects of innumerable excitatory and inhibitory synaptic potentials upon cortical neurons. This spontaneous activity of cortical neurons is much influenced and synchronized by subcortical structures, particularly the thalamus and high brainstem reticular formation. Afferent impulses from these deep structures are probably responsible for entraining cortical neurons to produce characteristic rhythmic brain wave

The EEG provides confirmation of Hughlings Jackson's concept of epilepsy – that it represents a recurrent, sudden, excessive discharge of cortical neurons; but like other ancillary tests, it

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

#### **Chapter 2**

## **Role of EEG in Epilepsy**

Manjari Tripathi and Man Mohan Mehendiratta

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57430

#### **1. Introduction**

The human electroencephalogram (EEG) was discovered by the German psychiatrist, Hans Berger, in 1929. Its potential applications in epilepsy rapidly became clear, when Gibbs and colleagues in Boston demonstrated 3 per second spike wave discharge in what was then termed petit mal epilepsy. EEG continues to play a central role in diagnosis and management of patients with seizure disorders—in conjunction with the now remarkable variety of other diagnostic techniques developed over the last 30 or so years – because it is a convenient and relatively inexpensive way to demonstrate the physiological manifestations of abnormal cortical excitability that underlie epilepsy (Smith, 2005) [1].

The electroencephalograph records spontaneous electrical activity generated in cerebral cortex. This activity reflects the electrical currents that flow in the extracellular spaces of the brain, and these reflect the summated effects of innumerable excitatory and inhibitory synaptic potentials upon cortical neurons. This spontaneous activity of cortical neurons is much influenced and synchronized by subcortical structures, particularly the thalamus and high brainstem reticular formation. Afferent impulses from these deep structures are probably responsible for entraining cortical neurons to produce characteristic rhythmic brain wave patterns, such as alpha rhythm and sleep spindles.

The EEG provides confirmation of Hughlings Jackson's concept of epilepsy – that it represents a recurrent, sudden, excessive discharge of cortical neurons; but like other ancillary tests, it must be used in conjunction with clinical data.

### **2. How can EEG help in epilepsy?**

**•** Diagnosis of epilepsy

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

	- **◦** Assessing risk of recurrence after an unprovoked seizure
	- **◦** Selection of antiepileptic treatment
	- **◦** Likelihood of seizure relapse if medication is withdrawn
	- **◦** Identification of epileptogenic region in epilepsy surgery candidates
	- **◦** Investigation of cognitive decline
	- **◦** Detection of non-convulsive status
	- **◦** Monitoring in convulsive status

Although the diagnosis of seizures and epileptic syndromes is primarily made from careful history and examination, the EEG remains an important investigative tool. The EEG often provides supportive evidence of seizure disorder and assists with classification of seizures and epilepsy. Moreover, EEG findings are important for determination of seizure focus and may also help with prognosis under certain circumstances. (Sundaram M et al, 1999) [2]

approximately 2 cm anterior to the site of entry of the sphenoidal electrode) and anterior temporal electrodes (placed 1 cm above one third the distance from the external auditory meatus to the external canthus) are also useful for demonstrating epileptiform discharges (ED) from the temporal lobe and the yield appears comparable to that from sphenoidal electrodes

Role of EEG in Epilepsy

17

http://dx.doi.org/10.5772/57430

**Figure 1.** Figure of 10x20 system, 10x10, 10x5; neonatal-10-20, 10-5 placement

**Figure 2.** Measurement landmarks10-20 landmarks, measurements, deformity adjustment

Digital recording machines are rapidly replacing the traditional "paper" systems.

(Krauss et al, 1992) [7].

**3.2. Digital EEG**

#### **3. Technical considerations**

#### **3.1. Electrodes**

The international ten-twenty system of electrode placement, originally proposed in 1958 (Jasper, 1958) [3], is now widely used and is the recommended standard method for recording scalp EEG. The American EEG Society has recently advocated slight modifications to the original alphanumeric nomenclature (American EEG Society) [4] The original T3, T4, T5 and T6 are now referred to as T7, T8, P7 and P8 respectively. This modification allows standardized extension of electrode placement in the sub-temporal region (e.g., F9, T9, P9, F10, T10, P10) and designates named electrode positions in the intermediate coronal lines between the standard coronal lines (e.g., AF7, AF3, FT9, FT7, FC5, FC3, FC1, TP9, TP7, CP5, CP3, CP1, PO7, PO3 and so on). Additional and more closely spaced scalp electrodes placed midway between the standard electrodes of the 10-20 system often provide further localization of epileptiform discharges in patients with partial seizures (Morris et al, 1987) [5]. Several electrodes are available for demonstrating temporal lobe activity. Sphenoidal electrodes are particularly useful for detecting mediobasal temporal discharges and are inserted under the mandibular notch (app. 2.5 to 3 cm anterior to the tragus) and directed posterosuperiorly towards the foramen ovale (Rovit et al, 1961). [6] Anterior "cheek" electrodes (placed on the maxilla approximately 2 cm anterior to the site of entry of the sphenoidal electrode) and anterior temporal electrodes (placed 1 cm above one third the distance from the external auditory meatus to the external canthus) are also useful for demonstrating epileptiform discharges (ED) from the temporal lobe and the yield appears comparable to that from sphenoidal electrodes (Krauss et al, 1992) [7].

**Figure 1.** Figure of 10x20 system, 10x10, 10x5; neonatal-10-20, 10-5 placement

**Figure 2.** Measurement landmarks10-20 landmarks, measurements, deformity adjustment

#### **3.2. Digital EEG**

**◦** Differential diagnosis of paroxysmal neurological events

**◦** Assessing risk of recurrence after an unprovoked seizure

**◦** Likelihood of seizure relapse if medication is withdrawn

**◦** Identification of epileptogenic region in epilepsy surgery candidates

Although the diagnosis of seizures and epileptic syndromes is primarily made from careful history and examination, the EEG remains an important investigative tool. The EEG often provides supportive evidence of seizure disorder and assists with classification of seizures and epilepsy. Moreover, EEG findings are important for determination of seizure focus and may

The international ten-twenty system of electrode placement, originally proposed in 1958 (Jasper, 1958) [3], is now widely used and is the recommended standard method for recording scalp EEG. The American EEG Society has recently advocated slight modifications to the original alphanumeric nomenclature (American EEG Society) [4] The original T3, T4, T5 and T6 are now referred to as T7, T8, P7 and P8 respectively. This modification allows standardized extension of electrode placement in the sub-temporal region (e.g., F9, T9, P9, F10, T10, P10) and designates named electrode positions in the intermediate coronal lines between the standard coronal lines (e.g., AF7, AF3, FT9, FT7, FC5, FC3, FC1, TP9, TP7, CP5, CP3, CP1, PO7, PO3 and so on). Additional and more closely spaced scalp electrodes placed midway between the standard electrodes of the 10-20 system often provide further localization of epileptiform discharges in patients with partial seizures (Morris et al, 1987) [5]. Several electrodes are available for demonstrating temporal lobe activity. Sphenoidal electrodes are particularly useful for detecting mediobasal temporal discharges and are inserted under the mandibular notch (app. 2.5 to 3 cm anterior to the tragus) and directed posterosuperiorly towards the foramen ovale (Rovit et al, 1961). [6] Anterior "cheek" electrodes (placed on the maxilla

also help with prognosis under certain circumstances. (Sundaram M et al, 1999) [2]

**◦** Identification of syndrome specific changes

**◦** Recognition of photosensitivity

**◦** Selection of antiepileptic treatment

**◦** Investigation of cognitive decline **◦** Detection of non-convulsive status

**◦** Monitoring in convulsive status

**3. Technical considerations**

**3.1. Electrodes**

**•** Management of epilepsy

16 Epilepsy Topics

**◦** Distinction between a focal and generalised seizure disorder

Digital recording machines are rapidly replacing the traditional "paper" systems.

#### Advantages:

**•** Digital EEG is particularly useful for detecting and analyzing ED as the waveforms in question can be reformatted in various montages after the recording is completed.

Photic stimulation is particularly useful in primary generalized epilepsy and ED may occur during PS in up to 40% of these patients (Gastaut et al, 1958) [12]. Recent evidence indicates that approximately a quarter to a third of EEGs with photic related ED also contain sponta‐ neous focal or generalized ED elsewhere in the records (Gilliam and Chiappa, 1995) [13].

Role of EEG in Epilepsy

19

http://dx.doi.org/10.5772/57430

When the first EEG fails to show ED in patients with epilepsy, sleep deprived recording often helps. Several studies have convincingly documented that the chances of finding ED increase with sleep deprived recordings in both partial and generalized seizure patients of all ages (Degan, 1980) [14]. Epileptiform discharges following sleep deprivation occur both in the awake and sleep portions of the EEG. Moreover, Rowan and co-workers (1982) [15] have shown that EEGs following sleep deprivation are more likely to contain ED than the recordings

**4. Clinical Significance of Interictal Epileptiform Discharges (ED)**

Although the presence of interictal ED generally supports the diagnosis of seizure disorder, caution is necessary in interpreting the clinical significance as ED may occur in subjects without seizures. Among healthy adults without seizure history, the frequency of ED is approximately 0.5% (Robin et al, 1978) [16]. Practically none of these healthy subjects subsequently develops seizures. "Incidental" ED occur slightly more often (app. 2%) in subjects with a history of previous neurological insults such as trauma, stroke, craniotomy, infections, cerebral palsy or during migraine (Zivin et al, 1968) [17]. Up to 14% of these patients subsequently develop seizures. In children without prior seizures, ED may occur in up to 5% and this may be as high as 8% if adequate sleep is recorded (Okubo et al, 1994) [18]; these tend to be benign rolandic or occipital spikes or generalized 3 Hz spike-wave discharges and likely represent incidental genetic trait. Risk of subsequent seizures in these children is around 6% (Cavazzuti et al, 1980) [19]. Certain EEG patterns, however, almost always indicate associated clinical seizures and

these include hypsarrhythmia and 1 or 2 Hz generalized slow spike-wave complexes.

First standard EEGs in patients with a reasonably certain diagnosis of seizure disorder contain ED in approximately 50% (Ajmone-Marsan et al, 1970) [20]. Yield from the first EEG in children with absence seizures, however, is higher, around 75% (Goodin and Aminoff, 1984) [21]. Apart from sleep, several other factors have been shown to increase the likelihood of ED and these include i) recording within 48 hours of a seizure and ii) ongoing seizure frequency of at least one attack per month (Sundaram et al, 1990) [22]. The yield, however, is not significantly altered by neurological status, etiology of seizures, age of the patient and anti-epileptic drug therapy

*3.3.3. Sleep Deprivation (SD)*

of similar length done following sedation.

**4.1. ED in nonepileptic subjects**

**4.2. ED in the first and serial EEGs**

(Sundaram et al, 1990) [22].


Disadvantages:


#### **3.3. Activation procedures**

#### *3.3.1. Hyperventilation*

Forster [9], in 1924, first demonstrated that hyperventilation (HV) may precipitate absence seizures in children and this method of activation has since become routine during EEG recordings. Although HV is particularly useful for demonstrating generalized epileptiform discharges, it may also activate focal epileptiform discharges in up to 10% of patients with partial epilepsies (Miley and Forster, 1977) [10]. The neuronal irritability during HV is considered to be due to brainstem mediated cerebral vasoconstriction induced by hypocapnia.

Hyperventilation should be avoided in patients with potential for brain damage from further vasoconstriction, e.g. malignant hypertension, subarachnoid hemorrhage, sickle cell disease or trait.

#### *3.3.2. Photic stimulation*

Photic stimulation (PS) is useful for activation of generalized epileptiform discharges. Testing is generally done with stepwise increase of frequencies up to 30 Hz with a strobe light at a distance of 20 to 30 cm from the eyes. At low frequencies, PS is recommended with eyes open and then closed. At medium and higher frequencies, stimulation should start with the eyes open, and the patient is asked to close the eyes during PS, thereby continuing with PS for a few more seconds with the eyes remaining closed. Eye closure during PS is particularly useful for augmenting ED and should routinely be used. ED outlasting PS strongly suggest general‐ ized seizure disorder, whereas those confined to the train of PS may be an incidental finding in nonepileptic subjects, especially in the setting of drug withdrawal or toxic metabolic encephalopathy, or simply represent a genetic trait (Newmark and Penry, 1979) [11].

Photic stimulation is particularly useful in primary generalized epilepsy and ED may occur during PS in up to 40% of these patients (Gastaut et al, 1958) [12]. Recent evidence indicates that approximately a quarter to a third of EEGs with photic related ED also contain sponta‐ neous focal or generalized ED elsewhere in the records (Gilliam and Chiappa, 1995) [13].

#### *3.3.3. Sleep Deprivation (SD)*

Advantages:

18 Epilepsy Topics

Disadvantages:

**3.3. Activation procedures**

*3.3.1. Hyperventilation*

*3.3.2. Photic stimulation*

or trait.

**•** Digital EEG is particularly useful for detecting and analyzing ED as the waveforms in question can be reformatted in various montages after the recording is completed.

**•** Very little storage space requirement, elimination of paper costs, automatic event detection

**•** Filter and paper speed settings with digital recordings are accurate and automatic, thereby

**•** Problems due to pen alignment and curvilinear effect are not seen with digital systems.

**•** The incompatibility of systems made by different vendors, often forcing one to resort to

**•** Comparing two separate epochs is somewhat cumbersome, as only limited data can be

Forster [9], in 1924, first demonstrated that hyperventilation (HV) may precipitate absence seizures in children and this method of activation has since become routine during EEG recordings. Although HV is particularly useful for demonstrating generalized epileptiform discharges, it may also activate focal epileptiform discharges in up to 10% of patients with partial epilepsies (Miley and Forster, 1977) [10]. The neuronal irritability during HV is considered to be due to brainstem mediated cerebral vasoconstriction induced by hypocapnia.

Hyperventilation should be avoided in patients with potential for brain damage from further vasoconstriction, e.g. malignant hypertension, subarachnoid hemorrhage, sickle cell disease

Photic stimulation (PS) is useful for activation of generalized epileptiform discharges. Testing is generally done with stepwise increase of frequencies up to 30 Hz with a strobe light at a distance of 20 to 30 cm from the eyes. At low frequencies, PS is recommended with eyes open and then closed. At medium and higher frequencies, stimulation should start with the eyes open, and the patient is asked to close the eyes during PS, thereby continuing with PS for a few more seconds with the eyes remaining closed. Eye closure during PS is particularly useful for augmenting ED and should routinely be used. ED outlasting PS strongly suggest general‐ ized seizure disorder, whereas those confined to the train of PS may be an incidental finding in nonepileptic subjects, especially in the setting of drug withdrawal or toxic metabolic

encephalopathy, or simply represent a genetic trait (Newmark and Penry, 1979) [11].

paper printouts for transmission of EEG data between two centers.

observed simultaneously on the monitor (Gorney, 1992) [8].

and the ability to network different recording stations.

avoiding technician oversight.

When the first EEG fails to show ED in patients with epilepsy, sleep deprived recording often helps. Several studies have convincingly documented that the chances of finding ED increase with sleep deprived recordings in both partial and generalized seizure patients of all ages (Degan, 1980) [14]. Epileptiform discharges following sleep deprivation occur both in the awake and sleep portions of the EEG. Moreover, Rowan and co-workers (1982) [15] have shown that EEGs following sleep deprivation are more likely to contain ED than the recordings of similar length done following sedation.

#### **4. Clinical Significance of Interictal Epileptiform Discharges (ED)**

#### **4.1. ED in nonepileptic subjects**

Although the presence of interictal ED generally supports the diagnosis of seizure disorder, caution is necessary in interpreting the clinical significance as ED may occur in subjects without seizures. Among healthy adults without seizure history, the frequency of ED is approximately 0.5% (Robin et al, 1978) [16]. Practically none of these healthy subjects subsequently develops seizures. "Incidental" ED occur slightly more often (app. 2%) in subjects with a history of previous neurological insults such as trauma, stroke, craniotomy, infections, cerebral palsy or during migraine (Zivin et al, 1968) [17]. Up to 14% of these patients subsequently develop seizures. In children without prior seizures, ED may occur in up to 5% and this may be as high as 8% if adequate sleep is recorded (Okubo et al, 1994) [18]; these tend to be benign rolandic or occipital spikes or generalized 3 Hz spike-wave discharges and likely represent incidental genetic trait. Risk of subsequent seizures in these children is around 6% (Cavazzuti et al, 1980) [19]. Certain EEG patterns, however, almost always indicate associated clinical seizures and these include hypsarrhythmia and 1 or 2 Hz generalized slow spike-wave complexes.

#### **4.2. ED in the first and serial EEGs**

First standard EEGs in patients with a reasonably certain diagnosis of seizure disorder contain ED in approximately 50% (Ajmone-Marsan et al, 1970) [20]. Yield from the first EEG in children with absence seizures, however, is higher, around 75% (Goodin and Aminoff, 1984) [21]. Apart from sleep, several other factors have been shown to increase the likelihood of ED and these include i) recording within 48 hours of a seizure and ii) ongoing seizure frequency of at least one attack per month (Sundaram et al, 1990) [22]. The yield, however, is not significantly altered by neurological status, etiology of seizures, age of the patient and anti-epileptic drug therapy (Sundaram et al, 1990) [22].

Serial EEGs are often necessary for demonstrating ED. Most patients who eventually show ED do so by the fourth EEG. Recordings are persistently negative in only 8% of epileptics although there is evidence that a higher proportion of patients with partial seizures may have persis‐ tently negative serial EEGs (Sundaram et al, 1990) [22].

**5.2. Generalized seizures**

Typical absence seizures are characterized by isomorphic and stereotyped patterns that do not evolve as partial seizures. However, the spike-wave discharges may change from 3.5 or 4 Hz at the onset to 2 or 3 Hz as the seizure progresses. Also, the spike amplitude may decrease during the later part of the seizure. Atypical absence attacks frequently show gradual onset

Role of EEG in Epilepsy

21

http://dx.doi.org/10.5772/57430

Generalized tonic-clonic seizures may be preceded by diffuse polyspike-wave complexes. Ictal recordings during the tonic phase typically shows generalized attenuation with or without high frequency rhythmic waves that gradually increase in voltage ("epileptic recruiting rhythm") and evolve into polyspikes. The clonic phase is characterized by paroxysmal spike activity mixed with slow waves and the post-ictal period shows generalized attenuation

Myoclonic seizures are associated with 10 to 15 Hz polyspikes with or without slow waves, whereas tonic seizures show generalized paroxysmal fast activity or diffuse voltage attenua‐ tion preceded or followed by sharp and slow wave complexes. Generalized atonic seizures may show 2-3 Hz spike-wave discharges or may not be associated with any scalp EEG change.

Although PLEDs have traditionally been considered "interictal" (Young et al, 1988) [29], there is some evidence that this pattern in some patients may be "ictal" in nature, especially when seen following traditional ictal patterns (Handforth et al, 1994) [30]. Moreover, Reiher and coworkers (1991) [31] reported that the "PLEDs plus pattern", consisting of periodic epileptiform activity closely followed by brief, low amplitude, stereotyped rhythmic discharges, is often associated with clinical seizures and may indeed be a foreteller of imminent seizures. However, whether the PLEDs or PLEDs plus pattern requires aggressive treatment similar to status

and offset with spike-wave discharges occurring at frequencies less than 3 Hz.

followed by gradual recovery of rhythms (Gastaut et al, 1972) [28].

**5.3. PLEDs (Periodic lateralized epileptiform discharges)**

epilepticus remains unclear (Treiman, 1995) [32].

**i.** assisting in epilepsy syndrome classification,

**ii.** predicting recurrence after the first seizure and

Routine EEG is useful for prognostic purposes in at least three situations:

**iii.** providing information on seizure relapse after anticonvulsant withdrawal.

The EEG provides important information for classification of various epileptic syndromes and thereby assists in predicting the natural history of the syndrome. For example, a child with

**6. Prognosis of epilepsy**

**6.1. Classification of epilepsy**

The above observations suggest that –


### **5. Ictal EEG**

While interictal ED generally provides support for the diagnosis of seizure disorder, electro‐ graphic or clinical seizures during EEG confirm seizures. The scalp EEG may not reflect all of the ictal activity as this depends on –


#### **5.1. Partial seizures**

Partial seizures, in scalp EEGs, are metamorphic, i.e., they show two or more distinct phases (Sharbrough, 1993) [23]. The most common patterns consist of a series of rhythmic waves, sequential spikes/sharp waves, a mixture of spikes and rhythmic waves or regional voltage attenuation. Most often the initial frequency of temporal lobe seizures is in the alpha or theta range with slower frequencies occurring in a lesser proportion (Geiger and Harner, 1978) [24]. Extra temporal seizures, however, often start in the beta frequencies rather than slower frequencies. With scalp EEG, the frequency may diminish or augment, but as the seizure ends, rhythmic waves or sequential spikes change to a slow spike-wave pattern that gradually decreases in frequency. Focal electrodecremental events are of excellent localizing value, reflecting intense neuronal depolarization or high frequency firing (Sharbrough, 1993) [23]. Following metamorphic seizures, there is often postictal delta slowing, suppression or activation of focal spikes. These postictal changes also have good localizing value for seizure origin and should be carefully sought (Kaibara and Blume, 1988) [25].

It is important to recognize that simple partial seizures, especially those with sensory rather than motor symptoms, may not be associated with discernable changes in routine scalp EEG in up to 80% of seizures (Devinsky et al, 1988) [26]. However, the yield in these patients may be augmented by using additional closely spaced electrodes (Bare et al, 1994) [27].

#### **5.2. Generalized seizures**

Serial EEGs are often necessary for demonstrating ED. Most patients who eventually show ED do so by the fourth EEG. Recordings are persistently negative in only 8% of epileptics although there is evidence that a higher proportion of patients with partial seizures may have persis‐

**ii.** one should consider long-term monitoring if four routine recordings have remained

While interictal ED generally provides support for the diagnosis of seizure disorder, electro‐ graphic or clinical seizures during EEG confirm seizures. The scalp EEG may not reflect all of

**iii.** the surface area of the focus with respect to the recording electrode. In spite of these

Partial seizures, in scalp EEGs, are metamorphic, i.e., they show two or more distinct phases (Sharbrough, 1993) [23]. The most common patterns consist of a series of rhythmic waves, sequential spikes/sharp waves, a mixture of spikes and rhythmic waves or regional voltage attenuation. Most often the initial frequency of temporal lobe seizures is in the alpha or theta range with slower frequencies occurring in a lesser proportion (Geiger and Harner, 1978) [24]. Extra temporal seizures, however, often start in the beta frequencies rather than slower frequencies. With scalp EEG, the frequency may diminish or augment, but as the seizure ends, rhythmic waves or sequential spikes change to a slow spike-wave pattern that gradually decreases in frequency. Focal electrodecremental events are of excellent localizing value, reflecting intense neuronal depolarization or high frequency firing (Sharbrough, 1993) [23]. Following metamorphic seizures, there is often postictal delta slowing, suppression or activation of focal spikes. These postictal changes also have good localizing value for seizure

It is important to recognize that simple partial seizures, especially those with sensory rather than motor symptoms, may not be associated with discernable changes in routine scalp EEG in up to 80% of seizures (Devinsky et al, 1988) [26]. However, the yield in these patients may

be augmented by using additional closely spaced electrodes (Bare et al, 1994) [27].

limitations, scalp recorded seizures provide valuable information regarding the

**ii.** the distance and orientation of the focus from the recording electrode and,

**i.** the ideal time for obtaining an EEG is the first day or two after a seizure,

tently negative serial EEGs (Sundaram et al, 1990) [22].

negative in patients with ongoing "seizures".

**i.** the frequency-filtering properties of the skull and scalp,

origin and should be carefully sought (Kaibara and Blume, 1988) [25].

The above observations suggest that –

the ictal activity as this depends on –

seizure type and focus.

**5. Ictal EEG**

20 Epilepsy Topics

**5.1. Partial seizures**

Typical absence seizures are characterized by isomorphic and stereotyped patterns that do not evolve as partial seizures. However, the spike-wave discharges may change from 3.5 or 4 Hz at the onset to 2 or 3 Hz as the seizure progresses. Also, the spike amplitude may decrease during the later part of the seizure. Atypical absence attacks frequently show gradual onset and offset with spike-wave discharges occurring at frequencies less than 3 Hz.

Generalized tonic-clonic seizures may be preceded by diffuse polyspike-wave complexes. Ictal recordings during the tonic phase typically shows generalized attenuation with or without high frequency rhythmic waves that gradually increase in voltage ("epileptic recruiting rhythm") and evolve into polyspikes. The clonic phase is characterized by paroxysmal spike activity mixed with slow waves and the post-ictal period shows generalized attenuation followed by gradual recovery of rhythms (Gastaut et al, 1972) [28].

Myoclonic seizures are associated with 10 to 15 Hz polyspikes with or without slow waves, whereas tonic seizures show generalized paroxysmal fast activity or diffuse voltage attenua‐ tion preceded or followed by sharp and slow wave complexes. Generalized atonic seizures may show 2-3 Hz spike-wave discharges or may not be associated with any scalp EEG change.

#### **5.3. PLEDs (Periodic lateralized epileptiform discharges)**

Although PLEDs have traditionally been considered "interictal" (Young et al, 1988) [29], there is some evidence that this pattern in some patients may be "ictal" in nature, especially when seen following traditional ictal patterns (Handforth et al, 1994) [30]. Moreover, Reiher and coworkers (1991) [31] reported that the "PLEDs plus pattern", consisting of periodic epileptiform activity closely followed by brief, low amplitude, stereotyped rhythmic discharges, is often associated with clinical seizures and may indeed be a foreteller of imminent seizures. However, whether the PLEDs or PLEDs plus pattern requires aggressive treatment similar to status epilepticus remains unclear (Treiman, 1995) [32].

#### **6. Prognosis of epilepsy**

Routine EEG is useful for prognostic purposes in at least three situations:


#### **6.1. Classification of epilepsy**

The EEG provides important information for classification of various epileptic syndromes and thereby assists in predicting the natural history of the syndrome. For example, a child with normal neurological examination and rolandic spikes in EEG has a high probability of "outgrowing" seizures and may not even need treatment following isolated, infrequent seizures. Similarly, generalized 4-6 Hz spike-wave and polyspike discharges in an adolescent with seizures suggest juvenile myoclonic epilepsy of Janz: a condition with a high response rate to valproic acid.

exact seizure focus cannot be ascertained with several routine EEGs, telemetry monitoring often provides necessary additional information. With current telemetry systems, EEG data may be collected continuously for several days or even weeks. This may be done as an inpatient procedure using VEEG or at home/work environment with ambulatory EEG. The equipment also has video capability and provides an opportunity to analyze physical changes during the ictus. Most of the equipment available today is highly sophisticated and digitised and portable.

Role of EEG in Epilepsy

23

http://dx.doi.org/10.5772/57430

**i.** for confirming the nature of epileptic attacks and nonepileptic events such as pseudoseizure, paroxysmal movement disorders, and sleep disorders

**ii.** for determination of seizure focus in patients with atypical features (e.g. frontal lobe

**v.** for research purposes, e.g. analysis of the relationship between the quantity of

Video telemetry is generally indicated when visual analysis of physical changes during the event is necessary as in pseudoseizure, frontal lobe seizures, and paroxysmal movement disorders. Ambulatory monitoring without video may be sufficient for confirming the nature of events such as syncope or absence attacks. VEEG is a labour intensive and costly method of investigating patients with difficult to control epilepsy. It involves continuous video and synchronised EEG recording done over many hours usually more than 24 hrs with documen‐ tation of at least 3 events or more (specially if discordant). The VEEG is also used in the differential diagnosis of the epilepsy specially when nonepileptic events are suspected. A short term VEEG (3-6 hrs) may be performed in patients where psychogenic non epileptiform events

All procedures should be carried out ONLY by trained technicians and Neurologists trained in epilepsy and epilepsy monitoring. Since VEEG does carry a risk a standard operating

are suspected. It is also useful when the number of episodes are several in a day.

Often the more the number of EEGs more the chance of picking up an abnormality.

The yield inceases with performing an EEG with both sleep and awake state.

An abnormal EEG should be interpreted according to the clinical situation.

procedure and manual should be available in all centres carrying this out.

A normal EEG does not rule out the diagnosis of epilepsy.

seizures, gelastic seizures), and for presurgical evaluation

**iii.** for exact classification of seizures prior to appropriate therapy

**iv.** for assessing the response to anticonvulsant therapy, and

interictal spikes and clinical seizures, sleep etc.

VEEG monitoring is useful:

**Pearl**

#### **6.2. First seizure**

Prediction of recurrence after a single seizure is clinically important and many studies have addressed this question. However, differences in methodology make comparison of these studies difficult and the results still remain somewhat controversial. A meta analysis of sixteen published reports suggests that EEG abnormalities may increase the risk of recurrence after first seizure (Berg and Shinnar, 1991) [33].

A recent large prospective study of children with single unprovoked seizure (Shinnar et al, 1994) [34] showed that, in those without obvious etiology ("idiopathic"), the presence of epileptiform discharges in the EEG was associated with a recurrence rate of 54% whereas the rate was only 25% when the first EEG was normal. In the above study, the EEG was not of any predictive value in children with remote symptomatic seizures.

Several recent prospective studies suggest that the EEG is useful in adults with first seizure, especially among those with idiopathic seizures (Van Donselaar et al, 1992) [35]. The Dutch workers (Van Donselaar et al, 1992) [35] showed that when two EEGs (one baseline and one sleep deprived recording) are normal, the recurrence rate was 12% at two years, whereas in those with one or both EEGs containing ED, recurrence rate increased to 83%. The Italian first seizure trial group (1993) [36] also showed a 1.7 fold increase in seizure recurrence when the EEG contained ED. Some controversy still exists in this area as some authors maintain that the EEG findings are of no predictive value after first seizure (Hopkins et al, 1988) [37].

#### **6.3. Anti-epileptic drug withdrawal**

The role of EEG in predicting relapses after anti-epileptic drug withdrawal remains more controversial. A recent meta analysis discussing in depth various factors in predicting relapses after anti-epileptic drug withdrawal indicates that any EEG abnormality (epileptiform activity or slowing) is associated with a relative relapse risk of 1.45 (Berg and Shinnar, 1994) [38]. Other factors found to increase the relapse rate in the above meta analysis were adolescent or adult epilepsy onset (rather than childhood onset) and known remote etiology.

#### **7. Video EEG monitoring**

Although the EEG remains the gold standard for confirming seizures, an actual attack or event is rare during a standard 20 to 30 minute recording. Even serial EEGs may fail to reveal ED in up to 10% of epileptics (Ajmone-Marsan et al, 1970) [20]. When the nature of attacks or the exact seizure focus cannot be ascertained with several routine EEGs, telemetry monitoring often provides necessary additional information. With current telemetry systems, EEG data may be collected continuously for several days or even weeks. This may be done as an inpatient procedure using VEEG or at home/work environment with ambulatory EEG. The equipment also has video capability and provides an opportunity to analyze physical changes during the ictus. Most of the equipment available today is highly sophisticated and digitised and portable.

VEEG monitoring is useful:

normal neurological examination and rolandic spikes in EEG has a high probability of "outgrowing" seizures and may not even need treatment following isolated, infrequent seizures. Similarly, generalized 4-6 Hz spike-wave and polyspike discharges in an adolescent with seizures suggest juvenile myoclonic epilepsy of Janz: a condition with a high response

Prediction of recurrence after a single seizure is clinically important and many studies have addressed this question. However, differences in methodology make comparison of these studies difficult and the results still remain somewhat controversial. A meta analysis of sixteen published reports suggests that EEG abnormalities may increase the risk of recurrence after

A recent large prospective study of children with single unprovoked seizure (Shinnar et al, 1994) [34] showed that, in those without obvious etiology ("idiopathic"), the presence of epileptiform discharges in the EEG was associated with a recurrence rate of 54% whereas the rate was only 25% when the first EEG was normal. In the above study, the EEG was not of any

Several recent prospective studies suggest that the EEG is useful in adults with first seizure, especially among those with idiopathic seizures (Van Donselaar et al, 1992) [35]. The Dutch workers (Van Donselaar et al, 1992) [35] showed that when two EEGs (one baseline and one sleep deprived recording) are normal, the recurrence rate was 12% at two years, whereas in those with one or both EEGs containing ED, recurrence rate increased to 83%. The Italian first seizure trial group (1993) [36] also showed a 1.7 fold increase in seizure recurrence when the EEG contained ED. Some controversy still exists in this area as some authors maintain that the

The role of EEG in predicting relapses after anti-epileptic drug withdrawal remains more controversial. A recent meta analysis discussing in depth various factors in predicting relapses after anti-epileptic drug withdrawal indicates that any EEG abnormality (epileptiform activity or slowing) is associated with a relative relapse risk of 1.45 (Berg and Shinnar, 1994) [38]. Other factors found to increase the relapse rate in the above meta analysis were adolescent or adult

Although the EEG remains the gold standard for confirming seizures, an actual attack or event is rare during a standard 20 to 30 minute recording. Even serial EEGs may fail to reveal ED in up to 10% of epileptics (Ajmone-Marsan et al, 1970) [20]. When the nature of attacks or the

EEG findings are of no predictive value after first seizure (Hopkins et al, 1988) [37].

epilepsy onset (rather than childhood onset) and known remote etiology.

rate to valproic acid.

first seizure (Berg and Shinnar, 1991) [33].

**6.3. Anti-epileptic drug withdrawal**

**7. Video EEG monitoring**

predictive value in children with remote symptomatic seizures.

**6.2. First seizure**

22 Epilepsy Topics


Video telemetry is generally indicated when visual analysis of physical changes during the event is necessary as in pseudoseizure, frontal lobe seizures, and paroxysmal movement disorders. Ambulatory monitoring without video may be sufficient for confirming the nature of events such as syncope or absence attacks. VEEG is a labour intensive and costly method of investigating patients with difficult to control epilepsy. It involves continuous video and synchronised EEG recording done over many hours usually more than 24 hrs with documen‐ tation of at least 3 events or more (specially if discordant). The VEEG is also used in the differential diagnosis of the epilepsy specially when nonepileptic events are suspected. A short term VEEG (3-6 hrs) may be performed in patients where psychogenic non epileptiform events are suspected. It is also useful when the number of episodes are several in a day.

All procedures should be carried out ONLY by trained technicians and Neurologists trained in epilepsy and epilepsy monitoring. Since VEEG does carry a risk a standard operating procedure and manual should be available in all centres carrying this out.

#### **Pearl**

A normal EEG does not rule out the diagnosis of epilepsy.

Often the more the number of EEGs more the chance of picking up an abnormality.

The yield inceases with performing an EEG with both sleep and awake state.

An abnormal EEG should be interpreted according to the clinical situation.

**Figure 3.** Documentation before recording: Patient demographic details such as name, age, clinical diagnosis or indi‐ cation for EEG, state of the patient, medication details, test number and comments have to be entered.

13

**References**

[1] Smith S J M. EEG in the diagnosis, classification, and management of patients with

Role of EEG in Epilepsy

25

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[2] Sundaram M, Sadler RM, Young GB, Pillay N. EEG in Epilepsy: Current Perspec‐

[3] Jasper H. Report of committee on methods of clinical exam in EEG. Electroencepha‐

[4] American EEG Society. Guidelines for standard electrode position nomenclature. J

[5] Morris HH, Luders HL, Lesser RP, Dinner DS, Wyllie E. Value of closely spaced elec‐ trodes in the localization of epileptiform foci: a study of 26 patients with complex

[6] Rovit RL, Gloor P, Rassmussen T. Sphenoidal electrodes in the electrographic study

[7] Krauss GL, Lesser RP, Fisher RS, Arroyo S. Anterior "cheek" electrodes are compara‐ ble to sphenoidal electrodes for the identification of ictal activity. Electroencephalogr

[8] Gorney DS. The practical guide to digital EEG. Am J EEG Technol 1992; 32:260-289.

[10] Miley CE, Forster FM. Activation of partial complex seizures by hyperventilation.

[11] Newmark ME, Penry JK. Photosensitivity and Epilepsy: A Review. 1979; New York:

[12] Gastaut H, Trevisan C, Naquet R. Diagnostic value of electroencephalographic ab‐ normalities provoked by intermittent photic stimulation. Electroencephalogr Clin

[13] Gilliam FG, Chiappa KH. Significance of spontaneous epileptiform abnormalities as‐

[14] Degan R. A study of the diagnostic value of waking and sleep EEGs after sleep depri‐ vation in epileptic patients on anticonvulsive therapy. Electroencephalogr Clin Neu‐

[15] Rowan J, Veldhuisen RJ, Nagelkerke NJD. Comparative evolution of sleep depriva‐ tion and sedated sleep EEGs as diagnostic aids in epilepsy. Electroencephalogr Clin

sociated with a photoparoxysmal response. Neurology 1995; 45:453-456.

[9] Forster O. Hyperventilations epilepsie Dtsch Z. Nervenheilkd 1924; 83:347-356.

partial seizures. Electroencephalogr Clin Neurophysiol 1987; 63:107-11.

of patients with temporal lobe epilepsy. J Neurosurg 1961; 18:151-158.

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tives. Can. J. Neurol. Sci. 1999; 26: 255-262

logr Clin Neurophysiol 1958; 10:370-375.

Clin Neurophysiol 1991; 8:200-2.

Clin Neurophysiol 1992; 83:333-338.

Arch Neurol 1977; 34:371-373.

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Neurophysiol 1982; 54:357-364.

Raven Press.

#### **Author details** Documentation before recording: Patient demographic details such as name, age, clinical diagnosis or indication for EEG, state of the patient, medication details,

Manjari Tripathi1\* and Man Mohan Mehendiratta2

\*Address all correspondence to: manjari.tripathi@gmail.com

test number and comments have to be entered.

1 Neurology, Neurosciences Centre, AIIMS, New Delhi, India

2 Neurology, GB Pant Hospital, Delhi, India

#### **References**

**Author details**

24 Epilepsy Topics

Manjari Tripathi1\* and Man Mohan Mehendiratta2

EEG normal Judge clinical situation followup

2 Neurology, GB Pant Hospital, Delhi, India

\*Address all correspondence to: manjari.tripathi@gmail.com

test number and comments have to be entered.

cation for EEG, state of the patient, medication details, test number and comments have to be entered.

1 Neurology, Neurosciences Centre, AIIMS, New Delhi, India

13

EEG abnormal EEG identifies seizure syndrome or discharge type Manage patient according to guidelines

Seizures continue despite 2 appropriately chosen and dosed AEDs plan VEEG and special electrode EEG.

Documentation before recording: Patient demographic details such as name, age, clinical diagnosis or indication for EEG, state of the patient, medication details,

**Figure 3.** Documentation before recording: Patient demographic details such as name, age, clinical diagnosis or indi‐

Report by experienced/trained neurologist/pediatric neurologist

Perform EEG with procedures which increase the yield of EEG- both awake and sleep and sleep deprived Along with CT or MRI

First unprovoked seizure


[16] Robin JJ, Tolan GD, Arnold JW. Ten year experience with abnormal EEGs in asymp‐ tomatic adult males. Aviation Space Env Med 1978; 49: 732-736.

[31] Reiher J, Rivest J, Grand'Maison F, Leduc CP. Periodic lateralized epileptiform dis‐ charges with transitional rhythmic discharges: association with Seizures. Electroence‐

Role of EEG in Epilepsy

27

http://dx.doi.org/10.5772/57430

[32] Treiman DM. Electroclinical features of status epilepticus. J Clin Neurophysiol 1995;

[33] Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seiz‐

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**Chapter 3**

**Nonlinear Epilepsy Forewarning by Support Vector**

Epilepsy is a neurological disorder that changes the observable behavior of an individual to the point of inducing complete loss of consciousness. Pharmaceutical drugs may reduce or eliminate the problems of epilepsy, but not all people respond to pharmaceuticals favorably, and some may find the side effects undesirable. EEG-based epilepsy prediction may offer an acceptable alternative or complementary treatment to pharmaceuticals. Invasive, intra-cranial EEG provides signals that are directly from the brain, without the muscular activity that infests non-invasive, scalp EEG. However, intra-cranial EEG requires surgery, which increases risk and cost of health care, while reducing the number of people able to receive medical attention. Algorithms to predict the seizure event—the ictal state—may lead to new treatments for chronic epilepsy. Finding solutions that involve non-invasive procedures may result in

Epilepsy prediction is greater than 1 minute of forewarning before there is any visible indication that a seizure will occur. The physician does not label the pre-ictal periods that precede the seizure—states that may indicate a seizure is near. Event characterization only labels the start time of the seizure. Consequently, labeled data for the pre-ictal state is nonexistent, but is necessary to train a Support Vector Machine (SVM). Other researchers address this problem by assuming that the pre-ictal phase occurs immediately prior to a seizure [1];

> © 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

W.S. Ashbee, L.M. Hively and J.T. McDonald

Additional information is available at the end of the chapter

treatments for the largest section of the population.

**Machines**

http://dx.doi.org/10.5772/57438

**1. Introduction**

**2. Background**

see Figure 1 for an example.
