**3. Introduction of hexagonal boron nitride**

hBN is structurally similar to graphite and has hardness comparable to graphite. Since hBN is the isoelectric analog of graphite structure and shares very similar structural characteristics and many physical properties, is so-called white graphite. It is not present in nature and is synthesized.

Due to its unique properties, including high resistance to oxidation, high thermal conductivity, good thermal insulation, chemical inertness, excellent lubrication, non-toxicity, and environmental friendliness, hBN has diverse industrial applications in surface coatings, composites, lubricants, and insulators. Due to the impressive properties of nanoscale materials and the development of the application of nanomaterials in the industry, ongoing research is carried to develop new methods for synthesis of nanomaterials. However, until now, there is no ensured large-scale and high yield method to achieve a significant amount of boron nitride nanosheets (BNNSs).

Although researches on 2D nanomaterials have been began several decades ago, the wave of interest and attention to these materials get started in 2004 when Novoselov discovered single-layer graphene with superb electronic properties [1]. Many efforts have been made to achieve 2D materials including graphene, boron nitride, and several dichalcogenides. Boron nitride (BN) is one of the most promising systems ever to be the lightest compound of the three and four groups in the periodic table. BN is composed of equal numbers of N and B atoms, which are configured in hexagonal arrange, similar to carbon atoms in graphene. For naming, the term "single-layer BN" is used for monolayer of BN, and in the case of multilayers, is called BNNSs.

#### *Nanostructures*

As shown in **Figure 4**, single-layer BN has honeycomb structure consisting of isoelectric borazine rings and benzene structures. B▬N bonds have a covalent nature, but due to the electronegativity difference, these bonds have ionic properties with a length of 1.45 Å. The distance between the two centers of the borazine rings is 2.54 Å (compared with 2.46 Å for graphene). The edges of the plates could be zigzagged (boron or nitrogen on the edges) or armchair (nitrogen-boron on the edge) [37].

The lateral dimension of BNNSs is in range from several hundred nanometers to several 10 micrometers [39, 40]. The dimensions of the nanosheets are different depending on the synthesis method. **Figure 5** shows a transmission electron microscopy (TEM) micrograph possessing boron nitride plates, with a lateral dimension of 600 nm.

The single layers of BN can be placed on each other to form few-layer BNNSs. The vdW interaction between layers holds BN layers together, so that the distance between these sheets is 0.333 nm, while the layer's distance in carbon structures is about 0.337 nm [37].

The inorganic analog of graphene, sometimes assigned white graphene, is isoelectronic similar to graphene. However, due to electronegativity differences between the boron and the nitrogen atoms, π electrons are shifted into nitrogen atomic centers, forming the insulating materials [42, 43].

The arrangement of atomic layers in BN and its nanosheets differs with graphite and graphene. The arrangement in the graphene is called AB stacking mode, so that each carbon atom is located at the top of the center of the neighboring layer benzene ring. While in the layers of BN, the stacking mode is AA, and each atom at the upper and lower layers has nitrogen atoms due to polar-polar or electrostatic interactions [6]. Although the AA stacking mode is always observed in nanosheets obtained from the top-down approaches, this order is not always seen in bottomup synthetic techniques [39, 40]. In addition, the calculations show that the B–N layers have relative displacement from AA to AB stacking mode, along the favorable energy [44].

Duo to the difference in electronegativity, B▬N bonds have ionic characteristic which is compared to covalent C▬C bonds in graphene. This can lead to lip-lip interactions between the layers, i.e., chemical interactions as bridges or spotwelds. This phenomenon helps to reduce energy and then stabilize the formation

**27**

*Two-Dimensional Nanomaterials*

**3.1 The preparation of BNNSs**

**Figure 5.**

*middle [41].*

the exfoliation process.

[58–61] are based on the later approach.

**3.2 The properties and applications of BNNSs**

also have special properties due to high surface area.

*DOI: http://dx.doi.org/10.5772/intechopen.85263*

of few-layered BNNSs by reducing the number of dangling bonds at the edges, as well as reduction of frustration effect (forming B▬B and N▬N bonds instead of favorable B▬N bonds) [45, 46]. Interestingly, such a strong interaction has only a negligible effect on the distance between the BN layers compared to graphene [6].

*The transmission electron microscope image of two relatively large BNNSs, which have been overlapped in the*

2D nanosheets can be synthesized with two bottom-up and top-down approaches that relate to the synthesis of sheets from boron and nitrogen precursor [47, 48] and also the separation of layers. Chemical reaction [49] and CVD [39, 40, 50]

are based on the former and micromechanical cleavage [51, 52], high-energy

are always disadvantages in any way. In synthesis processes, a great amount of effort was put into preventing the formation of a strong chemical bond between the substrate and nanosheets. The crystallization process time, the nucleation on the substrate and the low density of critical nuclei are the important factors in synthetic methods. On the other hand, in the top-down view, exfoliation of layers is used. Nanosheets obtained from exfoliation usually have a higher crystallinity, but their lateral dimensions are limited by the material used. Also, due to lip-lip interactions between sheets, exfoliation of layers to isolate them is difficult. Therefore, the production of single layer is associated with a lot of problems. But in the bottomup approach, there is a lot of control over the supply of thin nanosheets with high lateral dimensions. However, the crystallinity of obtained nanosheets is less than

electron beam [53, 54], ball milling [55], and chemical [49, 56, 57]/liquid exfoliation

Each technique has unique advantages for a specific application; however, there

hBN has attracted many attentions due to its low density, high thermal conductivity, electrical insulation, high resistance to oxidation, low chemical efficiency, and low refractive index. BNNSs also inherit these properties, and in addition, they

**Figure 4.** *Structural view of 2D BNNSs [38].*

#### **Figure 5.**

*Nanostructures*

dimension of 600 nm.

about 0.337 nm [37].

able energy [44].

As shown in **Figure 4**, single-layer BN has honeycomb structure consisting of isoelectric borazine rings and benzene structures. B▬N bonds have a covalent nature, but due to the electronegativity difference, these bonds have ionic properties with a length of 1.45 Å. The distance between the two centers of the borazine rings is 2.54 Å (compared with 2.46 Å for graphene). The edges of the plates could be zigzagged (boron or nitrogen on the edges) or armchair (nitrogen-boron on the edge) [37]. The lateral dimension of BNNSs is in range from several hundred nanometers to several 10 micrometers [39, 40]. The dimensions of the nanosheets are different depending on the synthesis method. **Figure 5** shows a transmission electron microscopy (TEM) micrograph possessing boron nitride plates, with a lateral

The single layers of BN can be placed on each other to form few-layer BNNSs. The vdW interaction between layers holds BN layers together, so that the distance between these sheets is 0.333 nm, while the layer's distance in carbon structures is

The inorganic analog of graphene, sometimes assigned white graphene, is isoelectronic similar to graphene. However, due to electronegativity differences between the boron and the nitrogen atoms, π electrons are shifted into nitrogen

The arrangement of atomic layers in BN and its nanosheets differs with graphite and graphene. The arrangement in the graphene is called AB stacking mode, so that each carbon atom is located at the top of the center of the neighboring layer benzene ring. While in the layers of BN, the stacking mode is AA, and each atom at the upper and lower layers has nitrogen atoms due to polar-polar or electrostatic interactions [6]. Although the AA stacking mode is always observed in nanosheets obtained from the top-down approaches, this order is not always seen in bottomup synthetic techniques [39, 40]. In addition, the calculations show that the B–N layers have relative displacement from AA to AB stacking mode, along the favor-

Duo to the difference in electronegativity, B▬N bonds have ionic characteristic which is compared to covalent C▬C bonds in graphene. This can lead to lip-lip interactions between the layers, i.e., chemical interactions as bridges or spotwelds. This phenomenon helps to reduce energy and then stabilize the formation

atomic centers, forming the insulating materials [42, 43].

**26**

**Figure 4.**

*Structural view of 2D BNNSs [38].*

*The transmission electron microscope image of two relatively large BNNSs, which have been overlapped in the middle [41].*

of few-layered BNNSs by reducing the number of dangling bonds at the edges, as well as reduction of frustration effect (forming B▬B and N▬N bonds instead of favorable B▬N bonds) [45, 46]. Interestingly, such a strong interaction has only a negligible effect on the distance between the BN layers compared to graphene [6].


**4. Approach and Discussion**

An Ecological Genomics approach would satisfy the need for experimental and molecular genetics to evaluate the hypothesis in several of the predictions. Ecological Genomics (EG) is an interdisciplinary approach in the biological sciences that seeks to find the genes underlying species interactions in natural habitats and to study the evolutionary forces that have shaped these genes, their expression patterns, and the phenotypes that they encode [22-26]. As such, nucleic acid sequencing, forward and reverse genetic tools, comparative methods, and other molecular techniques are required to find the relevant genes, to establish databases of candi‐ date genes, and to study their expression patterns and allelic variants.

tolerance. Candidate genes in Arabidopsis for the evolutionary constraint include specific TFs that are involved in gene regulation within and among signaling pathways (Figure 1). For example, if there exists genetic variation in TFs MYC2 or AF2 that natural or artificial selection could act upon to increase drought stress tolerance traits for more stable expression, we predict that [1] a glucosinolate defense response would also change because these TFs help to regulate

**1.** Defense and stress tolerance phenotypes will be genetically correlated in family structured

**2.** Genetically diverged populations from different elevations will also be diverged for defense and abiotic stress tolerance traits; neither population will have high values of both

**3.** Defense allocation and stress tolerance phenotypes will not segregate independently from

**4.** Defense and stress tolerance genetic covariation will be associated with markers linked to candidate transcription factors (TFs) that regulate both defense and drought tolerance pathways (AtMYC2 [At1g32640], AtMYB2 [At2g47190], and a NAC TF AtAF2

**5.** DNA sequence variation of candidate regulatory genes (TFs) implicated in prediction #3 will also correlate with the defense and stress tolerance tradeoff in (a) the segregating crosses and in (b) unrelated individuals (linkage disequilibrium association analysis). Comparison of DNA sequence of coding regions will also show molecular evidence for

**6.** There may be other regions of the genome besides those containing the candidate TFs that also simultaneously affect defense and stress tolerance phenotypes and thus would also provide molecular evidence for the tradeoff. For whole genome marker analysis away from candidate TFs, defense and stress tolerance phenotypes will either co-locate in

**7.** Gene expression of candidate genes in genetically diverged populations will reflect the evolution of more stable expression of defense and stress tolerance response pathways.

An Ecological Genomics approach would satisfy the need for experimental and molecular genetics to evaluate the hypothesis in several of the predictions. Ecological Genomics (EG) is an interdisciplinary approach in the biological sciences that seeks to find the genes underlying

one another in extended generation crosses between diverged populations.

evolution (McDonald-Kreitman Test and dS/dN ratios).

linkage mapping or their QTL will show negative epistasis.

both pathways, and [2] other pleiotropic or epistatic effects would reduce fitness.

**3. Predictions**

common garden experiments.

692 Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives

traits simultaneously.

[At5g08790]).

**4. Approach and Discussion**

Although many model species (species whose genomes have been completely sequenced and that have broad interest from molecular biologists) meet and exceed these molecular criteria, often they lack the attributes for ecological studies. For example, the natural distribution of *A. thaliana* is in Eurasia, making it difficult for study by North American researchers. Further‐ more, there are still relatively few model species. With the advent of affordable high-through‐ put next-generation sequencing (NGS), however, sequence information is becoming available for more species and populations. As of June 2015, for example, there were 6,653 completely sequenced genomes, but only a small fraction of these are eukaryotes (http://www.genome‐ sonline.org). The GOLD website also listed 60,631 genome sequencing projects (June, 2015), but only 9,059 or 15% were eukaryotes. Thus, although NGS is helping the field of EG to move away from model species, especially, for example, in evolutionary studies [27], there is still a need to understand the attributes that constitute an ideal model organism for EG studies.

Feder and Mitchell-Olds [22] listed the criteria for an ideal model species in Evolutionary and Ecological Functional Genomics (EEFG), which is synonymous with EG. The criteria stated that there needs to be: (1) a co-operative community of researchers from different disciplines that share resources and information; (2) the tools to find genes and study their variation within and among species; (3) natural, undisturbed habitats such that genetically diverged popula‐ tions can be studied for local adaptation; (4) molecular data on sequences and chromosomal maps for marker development and mapping, cis and trans regulatory regions identified, and gene function and its fitness consequences known under natural conditions; and, finally, (5) the ability to study the ecological consequences of natural genetic sequence variation in the genes for evolutionary inferences. Thus, access to NGS alone does not necessarily make a species ideally suited for EG study.

*Boechera stricta*, a close wild relative of Arabidopsis, satisfies many of these criteria and is an emerging ecological model species that inhabits environments that differ substantially in drought stress, herbivore community, and other abiotic and biotic conditions [28]. The selfing rate of *B. stricta* in the northern portion of its geographic range is 0.95 [29], enabling the creation of experimental advanced generation hybrids for forward ecological genetic studies (e.g., [30]). The genome of *B. stricta* has also been recently sequenced (http://phytozome.jgi.doe.gov/pz/ portal.html#!info?alias=Org\_Bstricta).

Forward genetics for finding candidate genes in ecology include population genomics, association mapping, linkage mapping, and transcriptomics [31, 32]. Population genomics identifies outlier marker loci in the statistical analysis of population genetic parameters, but there is no knowledge of associated phenotypes. Association and linkage mapping both include measurement of phenotypes, but a distinct advantage of association mapping is that no pedigree is required and that allelic variants representative of naturally occurring popula‐ tions can be used in analyses [26, 33]. Association mapping can be conducted on unrelated individuals because it is based on general inherent linkage disequilibrium (LD). When markers for association analysis are developed from candidate genes, significant associations may actually identify relevant genes. We assume that candidate genes in Arabidopsis could often be studied with success under natural conditions in close relatives in the genus *Boechera*. Unidentified causal genes in LD with significant candidate markers are unlikely in *B. stricta* where LD decays rapidly, within 10 kb [34]. If present, population substructure (i.e., stratifi‐ cation, admixture, or inbreeding) must be controlled for genetic association analyses because of confounding effects on LD that can lead to false positives [33].

#### **4.1. Tests of prediction #1**

Using family structured quantitative genetic analyses, previous studies have examined the genetic correlation between defense and stress tolerance of prediction #1. This work has been conducted on a close wild relative of Arabidopsis in the genus *Boechera*. *Boechera stricta* is a genetically diverse, diploid, predominantly self-fertilizing species that occurs at higher elevations throughout western North America in natural habitats [29, 34]. The phenotype of an individual of any species is determined by genetic and environmental factors (P = G + E), and these factors and thus the phenotypes vary among individuals within populations (VP = VG + VE). If the phenotypes are measured from in a common garden experiment, environmental variation is eliminated so that the phenotypic and genetic variations are equal (VP = VG). Among full-siblings of clonal or self-fertilizing species such as *B. stricta*, the genetic variation (VG) measured from a common environment can be used for evolutionary inferences because all allele combinations within and among loci are inherited without change. In accordance with prediction #1, the negative genetic correlation between glucosinolate (GS) toxin defense allocation and stress tolerance associated with range limits of *B. stricta* has been observed using these methods in the field and lab five times previously [2, 35-37]. Stressors involved in the tradeoff have included drought, nutrient deficiency, and change in plant community structure across the range boundary (suggesting competition) and the multivariate stress of the range boundary itself. In these studies, it was hypothesized that these tradeoffs occurred because of antagonistic crosstalk between abscisic acid (ABA) stress tolerance and jasmonic acid/ethylene (JA/ET) or salicylic acid (SA) defense-signaling pathways. Circumstantial evidence implicating the pathways in the tradeoff comes from experimental ABA soil inoculations that depended on endogenous GS level [35]. These conclusions are based mainly on correlative methods and circumstantial evidence. Experimental and molecular genetics and more direct measures of pathway components are needed.

#### **4.2. Tests of prediction #2**

For gene mapping in *B. stricta*, a replicated cross has been conducted between populations from the Big Horn Mountains, Wyoming, and the Black Hills, South Dakota. These are geographically isolated and genetically diverged populations [36, 38]. The populations are located at different ends of the altitudinal range of *B. stricta* (Big Horns 3,000 m, Black Hills 1,700m) and thus the sites differ by several environmental factors. The populations have diverged for glucosinolate content and stress tolerance traits such as root:shoot ratio as predicted; neither population had high values of both traits (Figure 2).

**Figure 2.** Genetic variation in GS levels (F18, 701 = 7.101, P < 0.001) (left) and root:shoot ratios (F5, 251 = 3.576, P = 0.004) (right) between genetically diverged populations. Data are from a growth chamber experiment. Residuals controlled for plant size, thus GS levels reflect content.

#### **4.3. Tests of prediction #3**

individuals because it is based on general inherent linkage disequilibrium (LD). When markers for association analysis are developed from candidate genes, significant associations may actually identify relevant genes. We assume that candidate genes in Arabidopsis could often be studied with success under natural conditions in close relatives in the genus *Boechera*. Unidentified causal genes in LD with significant candidate markers are unlikely in *B. stricta* where LD decays rapidly, within 10 kb [34]. If present, population substructure (i.e., stratifi‐ cation, admixture, or inbreeding) must be controlled for genetic association analyses because

Using family structured quantitative genetic analyses, previous studies have examined the genetic correlation between defense and stress tolerance of prediction #1. This work has been conducted on a close wild relative of Arabidopsis in the genus *Boechera*. *Boechera stricta* is a genetically diverse, diploid, predominantly self-fertilizing species that occurs at higher elevations throughout western North America in natural habitats [29, 34]. The phenotype of an individual of any species is determined by genetic and environmental factors (P = G + E), and these factors and thus the phenotypes vary among individuals within populations (VP = VG + VE). If the phenotypes are measured from in a common garden experiment, environmental variation is eliminated so that the phenotypic and genetic variations are equal (VP = VG). Among full-siblings of clonal or self-fertilizing species such as *B. stricta*, the genetic variation (VG) measured from a common environment can be used for evolutionary inferences because all allele combinations within and among loci are inherited without change. In accordance with prediction #1, the negative genetic correlation between glucosinolate (GS) toxin defense allocation and stress tolerance associated with range limits of *B. stricta* has been observed using these methods in the field and lab five times previously [2, 35-37]. Stressors involved in the tradeoff have included drought, nutrient deficiency, and change in plant community structure across the range boundary (suggesting competition) and the multivariate stress of the range boundary itself. In these studies, it was hypothesized that these tradeoffs occurred because of antagonistic crosstalk between abscisic acid (ABA) stress tolerance and jasmonic acid/ethylene (JA/ET) or salicylic acid (SA) defense-signaling pathways. Circumstantial evidence implicating the pathways in the tradeoff comes from experimental ABA soil inoculations that depended on endogenous GS level [35]. These conclusions are based mainly on correlative methods and circumstantial evidence. Experimental and molecular genetics and more direct measures of

For gene mapping in *B. stricta*, a replicated cross has been conducted between populations from the Big Horn Mountains, Wyoming, and the Black Hills, South Dakota. These are geographically isolated and genetically diverged populations [36, 38]. The populations are located at different ends of the altitudinal range of *B. stricta* (Big Horns 3,000 m, Black Hills 1,700m) and thus the sites differ by several environmental factors. The populations have diverged for glucosinolate content and stress tolerance traits such as root:shoot ratio as

predicted; neither population had high values of both traits (Figure 2).

of confounding effects on LD that can lead to false positives [33].

694 Abiotic and Biotic Stress in Plants - Recent Advances and Future Perspectives

**4.1. Tests of prediction #1**

pathway components are needed.

**4.2. Tests of prediction #2**

The segregating F2 populations from the crosses can be used to test prediction #3 that the defense and stress tolerance traits will not be inherited independently of one another. F2s from more than one cross allow for broader inference and increased statistical power [39]. Because each genotype in the F2 segregating generation cannot be replicated, drought treatments in the lab would need to be imposed on all plants after the plants were first monitored for performance (e.g., growth) under controlled watering conditions. Measures of drought tolerance could include relative growth (before and after drought treatments), leaf mass area (LMA), water use efficiency (carbon isotope ratio), and root:shoot ratio. Several measures of stress tolerance increase the probability of detecting the tradeoff, and provide a general assessment of stress tolerance [40]. Glucosinolate analysis should be conducted on leaf tissue at the time of drought stress.

Of course, the goal should be to test for the tradeoff in the field across the low-elevation range boundary using the segregating generation of the experimental crosses. However, this requires replication of each F2 genotype that could be compared within and just outside the range boundary. In the F3 generation, there is replication of each F2 lineage. Common garden experiments of F3 families could be established within and across low-elevation range boundaries. Previous field transplant experiments [2, 35, 36] have established the areas just across the low-elevation range boundary as stressful in terms of several correlated abiotic and biotic stressors, which manifest as slower growth and survivorship. Large sample sizes would guarantee the detection of effects if they exist, and would also allow for assessment across multiple years and the possibility of ecological gradient manipulations. For example, removal treatments of candidate competitors, such as *Lithophragma* parviflorum [36], could be included within and outside the range. Competitive interactions also induces ABA [36] and therefore might also induce the tradeoff.


**3. Primary care, mental health and telemedicine**

#### **3.1. Mental health services in primary care**

Primary care medicine is crucial to mental health care delivery in the United States, for over half of those suffering from mental disorders (Regier et al 1978), particularly in rural areas where access to specialists is a greater problem. This lack of mental health services leads to poor outcomes, such as higher rates of homicide and suicide, as well as increased use of emergency services, hospitalizations, and placement in mental health institutions (Lishner et al 1995; Health Data Summaries 2000). Primary Care Providers (PCPs) in rural areas also report having inadequate skills to manage mental health issues, and they would benefit from assistance (Geller and Muus 2002; Geller 1999). However, rural areas inherently have provider shortages, particularly with regard to consultation-liaison psychiatrists.

Health providers use a number of psychiatric, health service and disease management models to reach primary care patients, predominantly in suburban and urban locales (Katon et al 1995; Pincus 1987; Strathdee 1987). The traditional referral or replacement model uses the psychiatrist as the principal provider of mental health services. The consultation care model includes the PCP as the principal provider of mental health services, after a psychiatric consultation. The collaborative care model involves mental health services jointly provided by the PCP and psychiatrist, including frequent communication between providers. Variations on these models also include use of mental health extenders and a stepped care to judiciously use scarce psychiatric resources (Katon et al 1997). Quality improvement programs also improve treatment rates and outcomes for depressed patients with comorbid medical illness in primary care (Koike et al 2002) and are cost-effective, too (Wells et al 2001).

These models have been evaluated both in the United States and Great Britain. In Great Britain, the majority of psychiatrists function in the traditional referral model (Strathdee 1987). The majority of PCPs, though, favored the collaborative care model, as having the psychiatrist located in the primary care clinic setting versus an offsite mental health clinic greatly improved the consultation process (Katon et al 1995; Bailey et al 1994). Such research shows that those PCPs patients are more likely to receive adequate doses of antidepressants and recover from depression (Simon et al 2000). But in rural areas, there is a dearth of specialists (Off Tech Assessment 1990), resulting in travel for patients or providers. In addition, some rural sites have unique needs and issues (e.g., high rates of substance disorders and few treatment options at an Native American reservation; enmeshed small communities, wherein patients want an objective person from the outside).

#### **3.2. Telemedicine history**

Population dispersion of tribal groups in California makes it unlikely that a hospital-based service program will develop or support the members, meaning many rural and even some urban clinics depend on specialists outside the IHS. High costs associated with distance, time, and a shortage of primary care physicians in rural areas put Native Americans at high risk for suicide, trauma, and diabetes. Native Americans often do not obtain treatment due to barriers to care, differences in help-seeking behaviors, and higher dropout rate for mental health

A few studies have been completed regarding substance issues in Native Americans. A previously mentioned study that examined the relationship of substance abuse and psychiatric disorders among family members (Robin et al 1997) also considered their use of mental health services. Of those with a mental disorder, only 32% had received mental health or substance abuse services. The AI-SUPERPFP showed that Native American men were more likely than those in NCS to seek help for substance use problems from specialty providers; Native American women were less likely to talk to nonspecialty providers about emotional problems (Beals et al 2005b). Help-seeking from traditional healers was common in both Native Amer‐

There are many serious manifestations of untreated mental illness in Native Americans, particularly in rural areas. The prevalence rate of suicide for Native Americans is 1.5 times the national rate, particularly higher rates for males aged 15-24 and women aged 25-44 (U.S. HHS 2004; National Women's Health Information Center 2006). More Native Americans live in rural areas compared to Caucasians (42% to 23%) (U.S. HHS 2004). These areas have a shortage of mental health services and inadequate treatment (e.g., 70% of patients have an inadequate antidepressant dose for depression) (Unutzer et al 2002), and rural depressed patients have three times more hospitalizations and higher suicide rates than suburban patients (Rost et al 1999; Rost et al 1998). On the whole, rural communities are experiencing an acute shortage of adult, adolescent, and child psychiatric providers and those skilled in culturally appropriate

Primary care medicine is crucial to mental health care delivery in the United States, for over half of those suffering from mental disorders (Regier et al 1978), particularly in rural areas where access to specialists is a greater problem. This lack of mental health services leads to poor outcomes, such as higher rates of homicide and suicide, as well as increased use of emergency services, hospitalizations, and placement in mental health institutions (Lishner et al 1995; Health Data Summaries 2000). Primary Care Providers (PCPs) in rural areas also report having inadequate skills to manage mental health issues, and they would benefit from

outpatient services than Caucasians (Weinick et al 2000).

ican populations and was especially common in the Southwest.

care (Am Acad Child Adol Psychiatry 2004; Martinez 1993).

**3. Primary care, mental health and telemedicine**

**3.1. Mental health services in primary care**

**2.1. Substance, rural health and Native Americans**

78 Telemedicine

Telemedicine, defined as the use of technology to deliver health care (usually through videoconferencing), is one strategy to improve the accessibility of mental health care, partic‐ ularly to areas underserved by physicians (Preston et al 1992; Hilty et al 2004a; Hilty et al 2013a). Telecommunications technology has been used to link specialists at academic health centers with health care professionals in rural areas for the management of patients (Hilty et al 1999). Videoconferencing, telephone and computer-based (e.g., e-mail) connect specialists with PCPs for patient care (Nesbitt et al 2000; Levine and Gorman 1999; Dick et al 1999; Hilty et al 2004b).

Medical home, home health and other mobile technology methods are in development and need to be better studied, although costs are dramatically decreasing. The patient-centered medical home (PCMH) is a concept founded on the presence of inadequate treatment in primary care and/or an inability to access needed services (Rosenthal 2008). PCMH allows telepsychiatric input at home, still under the general purview of the primary care provider, and it has been shown to improve patient care and health (Hollingsworth et al 2011). Deskmounted video systems offer great convenience for therapy to cancer patients to avoid travel, but the cost used to be prohibitive for most consumers (Cluvey et al 2005). Internet-based video technology via personal computers and mobile devices must be HIPAA-adherent. Use of these technologies is increasingly becoming available, and will support the move of telepsychiatry to the home, such as programs that are now being implemented by the Veteran's Health Administration (Shore 2011).

referral. The average duration of consultation was 47 minutes, and the consultation was accompanied with a 4-page summary/case for the referring physician. The top three services requested for consultation were psychiatry (e.g., management of behavioral disturbance), medical genetics (e.g., diagnosis), and gastroenterology. PCPs rated items baseline satisfaction on a 7-point Likert scale: 1) pre-existing local services at 3.37; 2) timeliness of the PACT Net consultation at 5.45; 3) quality of the communication at 6.3; and 4) overall quality and utility of the consultation at 6.2. Specialists rated the quality of the communication at 6.45, and the ease of the service at 6.46. While phone and e-mail consultation was effective, it was not used

Mental Health Services for California Native Americans — Usual Service Options and a Description…

http://dx.doi.org/10.5772/56569

81

**Model 3:** An integrated program of mental health screening, therapy on site, and telepsychi‐ atric (video, phone, e-mail) consultation to rural primary care. The UCDHS and Northern Sierra Rural Health Network collaborated to develop a program for rural Northeastern California, funded by the California Endowment. Over a three-year period, 10 rural sites learned how to utilize screening instruments for multiple disorders (e.g., depression, alcohol‐ ism, and anxiety disorders), and collect basic outcome measures for depression at regular intervals, in concert with telepsychiatric consultations and on site therapy visits. The number of consultations per year increased by 120%. Continuing medical education (CME) was provided annually for PCPs and other providers. Services included a telepsychiatric consul‐ tant / therapist on site 25% for specific brief therapy and integrated planning meetings between rural primary and mental health care staff. Outcomes were that most children were seen only once, but a statistically significant improvement between initial evaluation and three-month follow-up in the convenience sample was seen in the Affect and Oppositional domains of the Child Behavioral Checklist (CBCL) for girls and boys, respectively; incorporating standardized checklists, may assist in diagnosis and treatment of rural children (Neufeld et al 2007).

**Model 4:** Cultural consultation to rural primary care using telemedicine. Early in the telepsy‐ chiatry service of UC Davis Department of Psychiatry and Behavioral Sciences in 1996, culturally informed consultation became incorporated into the telemedicine rural primary care collaboration. Some rural patients faced language and cultural barriers to seeking and receiving care from their local primary care physician. For example, a 56 year-old Mexican American female who became depressed following the sudden death of her husband of thirty years, was diagnosed with major depression, and started on an antidepressant but did not improve despite 4 months of treatment (Cerda et al 1999). She did not take medication as recommended and did not communicate concerns to the PCP because of the stigma and cultural reasons. A 60-minute telepsychiatric evaluation was conducted by a Mexican Amer‐ ican psychiatrist, who met with the PCP and patient. At follow-up the patient reported daily compliance with medication thereafter, the depression had remitted and the frequency of medical visits decreased from one-to-two times per month over a one-year period to only a

**Model 5:** Collaborative care via telepsychiatry. This model is co-provision of medication for primary care patients by the telepsychiatrist and primary care provider in rural communities, based on the earlier models of in-person care to achieve national standards of antidepressant prescriptions (Fortney et al 2013; Katon et al 1997).This model is often integrated with stepped

single visit in the six months since the consultation.

as much as expected.

Telemedicine was first used for medical purposes for psychiatric consultation (i.e. telepsy‐ chiatry) in the 1950's and 1960's to help the Nebraska Psychiatric Institute provide education, patient care, and consultation to a variety of sites (Wittson et al 1961). In the 1960s, telemedicine was also used to connect academic centers with urban populations (Straker et al 1976). Over the past several decades, academic health systems consisting solely of the medical center, are reaching out with telemedicine to rural clinics by using a consultation model of care. The University of California Davis Health System (UCDHS) connects the Medical Center with approximately 50 suburban and rural primary care clinics, up to 300 miles away, with telepsychiatric care (Nesbitt et al 2013; Hilty et al 2004a).

Telepsychiatry, in the form of consultation to primary care, and psychiatric management, has been well-received, enables valid and reliable evaluations, has good (preliminary) outcomes, and empowers parties using it (Hilty et al 2004a). PCPs in rural areas also have reported inadequate skills to manage mental health issues, and benefit from assistance (Geller 1999; Geller and Muus 2002). Telemedicine has been shown to improve medication adherence, depression severity, mental health status, health-related quality of life, and satisfaction for patients being treated for mental illnesses in primary care practices lacking on-site psychiatrists (Hilty et al 2006a; Hilty et al 2007a). The American Telemedicine Association has published telemental health practice guidelines (Yellowlees et al 2010) as has the American Association of Child and Adolescent Psychiatry (AACAP 2007).

#### **3.3. Models of care for rural populations (Hilty et al 2006b)**

**Model 1:** Randomized controlled trial (RCT) for depression in adults. A RCT recruited depression patients through self-report and structured psychiatric interviews (Hilty et al 2007b). Subjects were randomized to: 1) usual care with a disease management module (DMM) using telephone and self-report questionnaires; or 2) a DMM using telephone, questionnaires, and repeated televideo psychiatric consultation coupled with training of the PCP. Subjects' depressive symptoms, health status, and satisfaction with care were tabulated at 3, 6, and 12 months after study entry. There was significant clinical improvement for depression in both groups, with a trend toward significance in the more intensive module. Satisfaction and retention were statistically superior in the intensive group; there was no change in overall health functioning.

**Model 2:** Formal, multi-specialty phone and email physician-to-physician consultation. The UCDHS and California Department of Developmental Services (CDDS) developed the Physician Assistance, Consultation and Training Network (PACT Net) to assist PCPs in the treatment of patients with developmental disabilities in rural California (Hilty et al 2004b). PACT Net was a 24-hour warm-line in design and was funded from CDDS at approximately \$450,000 over three years. Thirty consultations were completed: 28 by telephone and 2 by email; 24 of those consultations were able to be responded to within one business day of the referral. The average duration of consultation was 47 minutes, and the consultation was accompanied with a 4-page summary/case for the referring physician. The top three services requested for consultation were psychiatry (e.g., management of behavioral disturbance), medical genetics (e.g., diagnosis), and gastroenterology. PCPs rated items baseline satisfaction on a 7-point Likert scale: 1) pre-existing local services at 3.37; 2) timeliness of the PACT Net consultation at 5.45; 3) quality of the communication at 6.3; and 4) overall quality and utility of the consultation at 6.2. Specialists rated the quality of the communication at 6.45, and the ease of the service at 6.46. While phone and e-mail consultation was effective, it was not used as much as expected.

technology via personal computers and mobile devices must be HIPAA-adherent. Use of these technologies is increasingly becoming available, and will support the move of telepsychiatry to the home, such as programs that are now being implemented by the Veteran's Health

Telemedicine was first used for medical purposes for psychiatric consultation (i.e. telepsy‐ chiatry) in the 1950's and 1960's to help the Nebraska Psychiatric Institute provide education, patient care, and consultation to a variety of sites (Wittson et al 1961). In the 1960s, telemedicine was also used to connect academic centers with urban populations (Straker et al 1976). Over the past several decades, academic health systems consisting solely of the medical center, are reaching out with telemedicine to rural clinics by using a consultation model of care. The University of California Davis Health System (UCDHS) connects the Medical Center with approximately 50 suburban and rural primary care clinics, up to 300 miles away, with

Telepsychiatry, in the form of consultation to primary care, and psychiatric management, has been well-received, enables valid and reliable evaluations, has good (preliminary) outcomes, and empowers parties using it (Hilty et al 2004a). PCPs in rural areas also have reported inadequate skills to manage mental health issues, and benefit from assistance (Geller 1999; Geller and Muus 2002). Telemedicine has been shown to improve medication adherence, depression severity, mental health status, health-related quality of life, and satisfaction for patients being treated for mental illnesses in primary care practices lacking on-site psychiatrists (Hilty et al 2006a; Hilty et al 2007a). The American Telemedicine Association has published telemental health practice guidelines (Yellowlees et al 2010) as has the American Association

**Model 1:** Randomized controlled trial (RCT) for depression in adults. A RCT recruited depression patients through self-report and structured psychiatric interviews (Hilty et al 2007b). Subjects were randomized to: 1) usual care with a disease management module (DMM) using telephone and self-report questionnaires; or 2) a DMM using telephone, questionnaires, and repeated televideo psychiatric consultation coupled with training of the PCP. Subjects' depressive symptoms, health status, and satisfaction with care were tabulated at 3, 6, and 12 months after study entry. There was significant clinical improvement for depression in both groups, with a trend toward significance in the more intensive module. Satisfaction and retention were statistically superior in the intensive group; there was no change in overall

**Model 2:** Formal, multi-specialty phone and email physician-to-physician consultation. The UCDHS and California Department of Developmental Services (CDDS) developed the Physician Assistance, Consultation and Training Network (PACT Net) to assist PCPs in the treatment of patients with developmental disabilities in rural California (Hilty et al 2004b). PACT Net was a 24-hour warm-line in design and was funded from CDDS at approximately \$450,000 over three years. Thirty consultations were completed: 28 by telephone and 2 by email; 24 of those consultations were able to be responded to within one business day of the

Administration (Shore 2011).

80 Telemedicine

telepsychiatric care (Nesbitt et al 2013; Hilty et al 2004a).

of Child and Adolescent Psychiatry (AACAP 2007).

health functioning.

**3.3. Models of care for rural populations (Hilty et al 2006b)**

**Model 3:** An integrated program of mental health screening, therapy on site, and telepsychi‐ atric (video, phone, e-mail) consultation to rural primary care. The UCDHS and Northern Sierra Rural Health Network collaborated to develop a program for rural Northeastern California, funded by the California Endowment. Over a three-year period, 10 rural sites learned how to utilize screening instruments for multiple disorders (e.g., depression, alcohol‐ ism, and anxiety disorders), and collect basic outcome measures for depression at regular intervals, in concert with telepsychiatric consultations and on site therapy visits. The number of consultations per year increased by 120%. Continuing medical education (CME) was provided annually for PCPs and other providers. Services included a telepsychiatric consul‐ tant / therapist on site 25% for specific brief therapy and integrated planning meetings between rural primary and mental health care staff. Outcomes were that most children were seen only once, but a statistically significant improvement between initial evaluation and three-month follow-up in the convenience sample was seen in the Affect and Oppositional domains of the Child Behavioral Checklist (CBCL) for girls and boys, respectively; incorporating standardized checklists, may assist in diagnosis and treatment of rural children (Neufeld et al 2007).

**Model 4:** Cultural consultation to rural primary care using telemedicine. Early in the telepsy‐ chiatry service of UC Davis Department of Psychiatry and Behavioral Sciences in 1996, culturally informed consultation became incorporated into the telemedicine rural primary care collaboration. Some rural patients faced language and cultural barriers to seeking and receiving care from their local primary care physician. For example, a 56 year-old Mexican American female who became depressed following the sudden death of her husband of thirty years, was diagnosed with major depression, and started on an antidepressant but did not improve despite 4 months of treatment (Cerda et al 1999). She did not take medication as recommended and did not communicate concerns to the PCP because of the stigma and cultural reasons. A 60-minute telepsychiatric evaluation was conducted by a Mexican Amer‐ ican psychiatrist, who met with the PCP and patient. At follow-up the patient reported daily compliance with medication thereafter, the depression had remitted and the frequency of medical visits decreased from one-to-two times per month over a one-year period to only a single visit in the six months since the consultation.

**Model 5:** Collaborative care via telepsychiatry. This model is co-provision of medication for primary care patients by the telepsychiatrist and primary care provider in rural communities, based on the earlier models of in-person care to achieve national standards of antidepressant prescriptions (Fortney et al 2013; Katon et al 1997).This model is often integrated with stepped models of care, which similar to above use 'less intensive or expensive interventions' first then if patients fail to improve, 'step it up' to more intensive services, and

2012a). These services have occurred in a number of Western States (Alaska, Colorado, Montana, New Mexico, South Dakota, Wyoming), involved both consultative and direct service models in a range of settings (community clinics, hospitals) and spanned age ranges from children and adolescents to geriatric population. These services have helped to demon‐ strate the feasibility of telepsychiatry with native populations, various models of clinical

Mental Health Services for California Native Americans — Usual Service Options and a Description…

http://dx.doi.org/10.5772/56569

83

A recent review (Shore et al 2012a) summarizes 10 years of CAIANH work with rural Native Veterans, of rural American Indian Veterans who serve at the highest rate per capita in the military, and who have the highest rates of posttraumatic stress disorder and substance abuse related to their military service. These clinics represent a unique multi-organizational collab‐ oration between the Department of Veterans Affairs, the Indian Health Service, the University of Colorado and Tribal partners. Outcomes provide strong evidence of the positive impact of improved access and quality of care to rural Native veterans. For example a recent published report described the increase in service utilization and appropriate medications for patient in these clinics (Shore et al 2012b). The clinics utilize a model that includes culturally knowl‐ edgeable providers, onsite clinic tribal outreach workers and collaboration with local services including as appropriate traditional medicine. This work strongly suggests the importance of the development and use of an appropriate telepsychiatry clinic model for Native patients that accommodates cultural issues, maintains overall fidelity of approach but can be adapted to

This article is a description of the patients seen from three California Native American IHS sites using a telepsychiatric consultation program from the academic medical center. Its objectives were to: a) describe the population's demographics and illnesses, b) identify needs of patients and physicians, c) report the services delivered to this patient population, and d) examine the quality of psychopharmacologic services. Patient, clinic, and system factors related to telepsychiatric consultation, which have important implications for federal health

The University of California Davis Health System (UCDHS) is based in Sacramento, California, and serves a 33-county area to the Oregon state border. Since 1995, UCDHS has provided telemedical consultations since 1995 in 28 specialties to 42 clinics (26 rural, 16 prisons) between 100 and 350 miles away (Nesbitt et al 2013). The telepsychiatry service has provided over 4,000

structure and integration and the importance of cultural adaptation.

**4. UC Davis telepsychiatric Native American study**

policy toward Native Americans, will be noted (Dixon 2001).

consultations, using a variety of models (Hilty et al 2006b).

best fit local services and culture.

**4.1. Overview**

**4.2. Methods**

**Model 6:** Asynchronous telepsychiatry. Traditionally, there have been two main types of telemedicine: *synchronous*, which typically relies on live, two-way interactive video to a remote area, and *asynchronous* (store-and-forward), which transmits clinical information via email or web applications for later review by a specialist. Broadly speaking, synchronous communica‐ tion by phone or with video allows synthesis of information and easy exchange of information, with in -the-moment questions by PCPs. *Asynchronous* telemedicine has been commonly used and well-received for pathology, cardiology, radiology, dermatology and other fields. A study of synchronous telepsychiatry, including Native American patients, revealed that PCPs are highly satisfied with the service, with 100% of the respondents noting the consultation as fast as from a regular face-to-face visit, was able to meet their patient's needs and lead to an improvement in the management of their patient; 64% thought the ATP consultant was able to completely meet their patient's needs and the feedback they received over ATP was as good as from a regular face-to-face visit (Yellowlees et al 2010; Butler and Yellowlees 2012).

#### **3.4. Telepsychiatry and cultural populations**

Ethnicity, culture and language issues affect health (Office of Surgeon General, 2001) and there is often inadequate access to specialists (Moreno et al 2012) —inroads to patient needs and preferences that can be met by telemental health are progressing. A recent study of nearly 40 rural health clinics compared impressions of 25 primary care providers and 32 staff impres‐ sions of factors important to care: using providers who value differences (5.4/7.0), quality of the provider's care (4.9/7.0), access to care in general (4.5/7.0) and availability of trained interpreters for use with patients (4.4/7.0) (Hilty et al 2013). Others are studying the specific needs of Hispanics/Latinos (Moreno et al 2012; Nieves et al 2007, Chong et al 2012), Asians (Ye et al 2011), Native Americans (Weiner et al 2005, Shore et al 2007, Shore et al 2008), Eastern Europeans (Mucic, 2004), and those using sign language (Lopez et al 2004) —all using telepsychiatry for service provision. With patients of different cultural backgrounds, using the patients' primary language allows for a more comfortable atmosphere where they may express their genuine feelings and emotions.

#### **3.5. Telepsychiatry to Native Americans**

Northern Plains Native Americans were very satisfied and comfortable with telepsychiatric treatment for post traumatic stress disorder (Shore and Manson 2004a; Shore and Manson 2004b; Shore et al 2006). In fact, location, communication, trust, and confidentiality were equally satisfactory for treatment in-person versus videoconferencing. Even Native American children and families are receptive to telepsychiatric consultation (Savin et al 2006).

#### **U. Colorado.**

Over the past decade the University of Colorado's Center for American Indian and Alaska Native Health (CAIANH) has collaborated on multiple telepsychiatry services targeted at American Indian and Alaska Native populations (Shore et al 2006; Savin et al 2006; Shore et al 2012a). These services have occurred in a number of Western States (Alaska, Colorado, Montana, New Mexico, South Dakota, Wyoming), involved both consultative and direct service models in a range of settings (community clinics, hospitals) and spanned age ranges from children and adolescents to geriatric population. These services have helped to demon‐ strate the feasibility of telepsychiatry with native populations, various models of clinical structure and integration and the importance of cultural adaptation.

A recent review (Shore et al 2012a) summarizes 10 years of CAIANH work with rural Native Veterans, of rural American Indian Veterans who serve at the highest rate per capita in the military, and who have the highest rates of posttraumatic stress disorder and substance abuse related to their military service. These clinics represent a unique multi-organizational collab‐ oration between the Department of Veterans Affairs, the Indian Health Service, the University of Colorado and Tribal partners. Outcomes provide strong evidence of the positive impact of improved access and quality of care to rural Native veterans. For example a recent published report described the increase in service utilization and appropriate medications for patient in these clinics (Shore et al 2012b). The clinics utilize a model that includes culturally knowl‐ edgeable providers, onsite clinic tribal outreach workers and collaboration with local services including as appropriate traditional medicine. This work strongly suggests the importance of the development and use of an appropriate telepsychiatry clinic model for Native patients that accommodates cultural issues, maintains overall fidelity of approach but can be adapted to best fit local services and culture.


*3.1. Pretreatment of Bacteria Cellulose*

The overview of pathway to fabricate the porous bacteria cellulose/poly Schiff base was described in Scheme 1. Bacteria cellulose was saturated with the sodium silicate solution (alkaline). Then, HCl acid reacted with sodium silicate to produce SiO2 aggregation. The formation of SiO2 could enlarge the inner space of bacteria cellulose and disassemble the large bacteria cellulose fiber bundles into much thinner fibers. The SiO2 was removed by NaOH solution and the pure modified bacteria cellulose was obtained by water rinse and subsequent freeze-drying. After the pretreatment, the bacteria cellulose was still macro-scale monolith. As shown in Figure 1a,b, the smooth surface of pristine bacteria cellulose consisted of compact fibers. In contrast, the pretreated bacteria cellulose had many macroscopic holes (Figure 1e), which should be generated by the SiO2 formation. The photograph and high-magnification images of bacteria cellulose/SiO2 composites can verify this (Figure 1c,d). More interestingly, the original bacteria cellulose fibers with diameter 400 nm was decreased to 30 nm (Figure 1f). The small nanofibers were most possibly free from the aggregated cellulose fibers by alkaline treatment. Moreover, the SiO2 formation within the gap or pores in the aggregated fiber bundles would also produce small nanofibers.

**Scheme 1.** The pathway of porous bacteria cellulose/poly Schiff base fabrication.

**Figure 1.** The photograph and of SEM images of bacteria cellulose (**a**,**b**), bacteria cellulose/SiO2 (**c**,**d**) and pBC (**e**,**f**); the photograph of adsorbent with ultra-low density (**g**) and the content of poly Schiff base in pBC-Polym-0.08 and BC-Polym-0.08 with various reaction time (**h**).

XRD was used to validate the variation of bacteria cellulose before and after pretreatment. As seen in Figure 2a, the raw bacteria cellulose exhibited characteristic of typical cellulose I by diffraction peaks at 14.3◦ and 22.6◦ [30–32]. Noticeably, after the pretreatment, the peak intensity at 14.3◦ and 22.6◦ attenuated obviously, which indicated the decrease of crystallinity. On the other hand, the relative intensity of 16.4◦ increases. Moreover, a small peak located at 20.0◦ appeared, indexed as the (110) of cellulose II. It inferred that the structure of semi-crystalline region and amorphous region was altered via pretreatment. This can be explained by the separation of small cellulose nanofibers from original fiber bundles, which inevitably exposed new facet. It must be mentioned that in the raw cellulose the H bonding (by –OH) pushed the formation of cellulose crystal. The decrease of crystallinity of bacteria cellulose demonstrated the breaking of H bonding, which signified that the –OH is free from the crystal. This is conducive to increasing its affinity toward aqueous solution, which can promote the mass transfer within the body of bacteria cellulose.

**Figure 2.** (**a**) XRD patterns of raw bacteria cellulose and pretreated bacteria cellulose. (**b**) FTIR spectra of pBC, pBC-Polym-0.02, pBC-Polym-0.04 and pBC-Polym-0.08 and (**c**) magnified graph in the range of 1750 to 1450 cm<sup>−</sup>1.


**6. Palliative treatment**

#### **6.1 Corpus callosotomy**

This is a palliative interhemispheric surgical approach for PR patients, which consists of surgical disconnection of the corpus callosum to disrupt synchronization of epileptiform discharges between both brain hemispheres. It is indicated in multifocal

#### *Recent Advances in Epilepsy Surgery DOI: http://dx.doi.org/10.5772/intechopen.107856*

ictal onset where seizures emanate from bilateral cortical foci at different frequency. Indication could also include failed or poor response with VNS implantation [62].

Concerning the outcome, several studies have suggested that complete corpus callosotomy is more effective, and its efficacy is sustainable with less relapse rates compared with anterior 2/3 corpus callosotomy (88% versus 58% in pediatric patients, [63]. Drop attacks improved from corpus callosotomy more than other generalized seizure types. Transient disconnection syndrome was significantly more likely in total corpus callosotomy than in anterior 2/3 corpus callosotomy [63, 64].

The decision whether to perform anterior 2/3 corpus callosotomy versus complete/ total corpus callosotomy is based on the degree of cognitive impairment and developmental delay and is also guided intraoperatively in some subjects by the presence of EEG activity desynchronization or transformation of generalized epileptiform

#### **Figure 5.**

*Corpus callosotomy; (a); brain MRI, coronal section T1 weighted, showing the disconnection of the corpus callosum (one row), (b); brain MRI sagittal section T2-weighted showing anterior 2/3 of the disconnection of the corpus callosum (2 rows).*

#### **Figure 6.**

*Vagus nerve insertion, a: Vagus nerve dissection, b: Electrode insertion, around the VNS, c: The lead of the device fixed to the muscle, and introduced subcutaneous to the infrascapular area, d: Intraoperative cheek of the stimulator, before subcutaneous insertion.*

discharges to asynchronized (lateralized) epileptiform discharges during the surgical course of the corpus callosotomy procedure (**Figure 5**) [64].

### **6.2 Vagus nerve stimulation**

This is a type of stimulation of the vagus nerve on a set schedule. It is a well-established palliative treatment although it seems that VNS is unlikely to offer a substantial advance in epilepsy surgery. Current evidence points toward a deactivation of the nucleus of the solitary tract with widespread projections to the dorsal raphe nucleus, locus coerules, thalamus, hypothalamus, amygdala, and hippocampus [18]. A metanalysis has demonstrated a 44.1% decrease in seizure frequency with a follow-up of more than 3 years (**Figure 6**) [65].

### **6.3 Responsive neuro-stimulator (RNS)**

RNS is a programmable neurostimulator, which is cranially implanted and connected to one or two depth and/or subdural cortical strip electrodes to detect the onset of seizure and stop it as it occurs. It is now gaining a major position in the USA as a new device with closed-loop system [66]. It is more effective in focal onset seizure, with 75% of seizure reduction [67].