Brain

Introduction

Deutsch (2012) describes music as an art that entails thinking with sounds. Music is played all over the world in churches, homes, funerals and many other places. It is part of humanity introduced at birth with lullabies and continues throughout the course of life up to death with the funeral march (Hallam, Cross & Thaut, 2016). It is a language that resembles speech in many aspects and has no borders. Sense of sound and rhythm are essential elements of musical functioning (Gruszka, Matthews, & Szymura, 2010). Music is significantly influenced by culture in terms of content and style. As such it evokes the same emotions within members of the same culture. It has two main components (rhythm and pitch) that it uses to pass the intended message and one has to be able to understand the two in order to appreciate music (Jones, Fay & Popper, 2010). Human beings are born with ability to understand and appreciate music and that is why young children appreciate lullabies. However the music potential and preferences vary from one person to the other. People have different musical preferences and this influences the amount of time and resources that they spend listening to music. This study investigates the individual differences in musical functioning with regard to social and biological influences.

Individual differences in Musical Functioning

Individual differences in musical functioning or musicality refer to the differences in the strength of music preference (Kern & Humpal, 2012). These differences are among the most intricate psychological issues in music. An individual may be fine without music while another one may need music so much so that he or she would use huge resources to attend music concerts. The source of such differences is a major concern to psychologists. According to Deutsch (2012), the strength of music preference is a function of the role that music plays in the life of an individual. People use music for different purposes like regulating their mood and emotions, promoting self-awareness, communicating, fostering social relations, distractions, and physiological arousal. Music plays an important role in the lives of many people across the world, and many people depend on music for different purposes. The availability of music on portable devices has increased the use of music with many people making it an ubiquitous companion (Theorell, 2014). Therefore music has a profound effect on the lives of many individuals as it influences their thinking, feelings, behaviour and perception. These factors influence the lives of individuals depending on the level of dependence on music and the specific type of music (Haas & Brandes, 2009). As such it is important to ascertain the factors that influence music preference.

Individual differences in musical functioning belong to an area in psychology that still remains largely unexplored (McPherson, 2016). People like certain artists, tunes, and styles more than the others. The other individuals also have different musical preferences. This is what is termed as style/genre preferences under music preference. In addition to this, individual differences also exist in terms of the extent to which people listen to music. The extent to which people love and enjoy music differs from one individual to the other (Gruszka, Matthews & Szymura, 2010). The knowledge on why people form preferences on certain types of music still remain fragmented partly because music plays different roles in the lives of people (Theorell, 2014). This is what is termed as the strength of preference under musical preference. The major issue of concern to psychologists is the source of these individual differences in strength and genre/style. Strong music preference is an indication that an individual spends a lot of time listening to music, going to concerts and buying music. The decision to invest time and money to listening to music is a sign that music is useful to the lives of these people. Individual differences in musical functioning are a multifaceted phenomenon that has continuously eluded psychologists, researchers and musicologists (McPherson, 2016). However, some factors that affect musical functioning have been identified and they include exposure, musical characteristics, genre and personality. The factors that affect musical preference can be grouped into two broad categories namely extrinsic and intrinsic factors. The intrinsic factors are inherent and they include melody, structure and timbre. The extrinsic factors on the other hand include social influence, personality and emotions.

Social influence on Musical Functioning

Social influence is one of the factors that influence the development of individual preferences in music. This starts at the adolescence stage and continues late into adulthood (Zelazo, 2013). Adolescents often have a strong desire to do the same things that their peers are doing in order to belong. They also tend to dislike the things that their peers dislike. As such they will tend to like the same music that their peers like (Theorell, 2014). They listen to music to create an impression, develop self-image and please their friends. According to McPherson (2016), the teenagers often desire to identify themselves with certain groups that they consider as being “cool” and distance themselves with those that they regard as being “old-fashioned”. Therefore they tend to develop musical preferences that are similar to members of their group and avoid those of the other groups that they regard as “not being cool”. This implies that musical preferences are partly created for the purpose of serving a function of group differentiation (Damon & Lerner, 2006).

According to Juslin & Sloboda (2010), individuals often tend to like the music that was popular during the years that they reached maturity age. The music preference developed at this point is often a function of the songs that are popular among the friends. However, the events that occur in late adolescence and early adulthood often shape the music preference for the rest of adulthood. When individuals first leave home and start being independent, they are often influenced by their peer groups. They spend a lot of time with their peers and tend to like what their peers like and dislike what their peers dislike (Damon & Lerner, 2006). They will like the same songs as they go to concerts together and spend most of their free time doing the same things. For instance the people who fail to acquire higher education tend to like songs that depict a care free attitude to justify their condition. Therefore social perceptions significantly influence the type of music preferred by people. According to the social learning theory, people learn through observation (Lehmann, Sloboda, & Woody, 2007). When people are rewarded for certain behaviours like listening to a certain genre of music, others tend to learn from it and are likely to imitate the behaviour in order to reap the same benefits. People tend to use music socially as a way of reinforcing their self-image. For instance conservative people are more inclined to listen to music that is conventional. Furthermore, people use music to communicate to the world by expressing their ideal self-image. The preferences of society may increase or inhibit the spread of certain music genres thereby influencing their potential to be preferred by individuals (Feezell, 2008 and Gruszka, Matthews & Szymura, 2010). For instance when it was discovered that Mozart music positively affected spatial IQ , more people started listening to classical music. This exposure increase the preference for classical music as it was considered essential for children (Hallam, Cross & Thaut, 2016). This indicates the power of society to influence music perception and preference. Therefore the influence of society is one of the most significant factors that influence individual music preferences. The type of music that people are exposed to from childhood is highly dependent on what the society considers popular and appropriate. For instance the mainstream media may prefer playing certain music over the others thereby influencing the preference of individuals.

Biological influence on Musical Functioning
Music Cognition

A series of processes is often activated when listening to music; these processes include melody recognition, memory of the music, recognising the lyrics and emotional response (Lehmann, Sloboda, & Woody, 2007). These basic processes are often integrated by complex mechanisms in the brain where various neural circuits take part simultaneously and some in succession. Identifying the specific tasks involved in processing music and the various interactions requires theoretical models. According to the functional architecture model proposed by Peretz and Coltheart, perception of monophonic tunes is organised by two independent systems working simultaneously (Sloboda, 2004). The melodic system aids in processing melody whereas the temporal system processes tempo. The melodic system processes all information on melody and differentiates the two main components (i.e. note and intervals). All the perception mechanisms are required for processing melodic contour. Melodic processing is done in right superior temporal gyrus (Lehmann, Sloboda, & Woody, 2007). Both the melodic and temporal systems work in coordination with each other and as such a damaged brain may lose its ability to perceive music.

Both the melodic and temporal systems relay information to musical lexicon to generate musical repertoire. Musical lexicon includes music repertoire and has a perceptual representation of all the things that an individual has be exposed to (Kern & Humpal, 2012). Furthermore, it also contains a memory that stores new music to aid in the recognition of melodies that are both familiar and non-familiar. As such if damage occurs to the musical lexicon, an individual becomes unable to perceive familiar melodies or even record new ones. Information from the musical lexicon is often relayed extemporaneously or immediately after stimulus reception to different areas depending on the required action (Haas & Brandes, 2009). Phonological lexicon is often activated to aid in the retrieval of lyrics, phonological and articulation prepares an individual for singing, motor functions are responsible for producing music, and the multimodal associative memories are used for retrieving information that is not musical (Jones, Fay & Popper, 2010). The perceptual modules are linked to the memory processes and emotional pathways to aid in music recognition and emotional experience. Non emotional processing and emotional processing are independent and as such damage to one may not damage the other. Any impairment to these connections often leads to difficulties in being able to integrate musical processes.

Influence of Biological Factors on Individual Differences

According to Sloboda (2004). , music has rarely been studied from the biological perspective as it is mostly perceived as a function of culture. However, biological factors significantly influence musical preferences (Feezell, 2008). The ability of an individual to process and appreciate music is dependent on cognitive functions. Individual differences in self-perception and personality influence musical preference. Therefore people may opt to like music that will allow them to express themselves to the others on how they would like to be perceived. Moreover, individual differences influence the purpose for which people listen to music (Zelazo, 2013). One of the reasons why people listen to music is to regulate their emotions and help them cope with the daily challenges in life. The differences in musical preference and reasons for listening to music are indications that intelligence and personality partly influence how people use music. Personality and intelligence influence the type of music people listen to, how often they listen to it and the reasons for listening to music (Sloboda, 2004). For instance the intellectuals like those with high IQs are more inclined to like conventional/ reflective music and as such are likely to use it for their intellectual purposes rather than for emotional consumption (Juslin & Sloboda 2010). This is because of their higher cognitive ability. This is clearly noticeable in their preference for jazz or classical music not because they do not elicit emotions but because the complexity of the genre is more inclined to suit the interests of people seeking experiences that are intellectually stimulating. On the other end are extraverts who may rely on music to stimulate their activity level when carrying out monotonous tasks like doing dishes or jogging. This implies that the role music plays in the life of an individual is partly determined by the level of arousal (Lilienfeld, et al 2011). This is particularly evident for those with high or low level of arousal average. The interference caused by background music on cognitive processes is higher in introverts than extraverts (Rickard & McFerran, 2012). Damon & Lerner (2006), claim that the association between musical use and other traits remain largely unexplored although some relationship may be expected. For instance people who suffer from emotional instability and regularly experience negative emotions are more likely to use music to regulate their emotions. Cognitive research has established that these people listen to music more for the purpose of managing their emotions (Rickard & McFerran, 2012). Furthermore, they are more sensitive to the emotions elicited by music and as such find music essential for regulating their emotions. Conscientious people on the other hand react differently to music. Conscientious people are those that have traits which are inversely correlated to psychoticism and creativity (Lilienfeld, et al 2011). Conscientious people are less likely to use music for regulating their emotions as they are likely to use it for other purposes.

Conclusion

The aim of this study was to investigate the influence of biological and social factors on individual musical functioning. The findings show that individual musical preferences and use of music is influenced by both social and biological factors. The social factors mostly influence the type of music people prefer to listen to whereas the biological factors influence the reasons for listening to music. The major social factors that influence the choice of music that people listen to are peers and the society as they determine the kind of music that is played regularly. The biological factors on the other hand influence the purpose for which people listen to music. The purpose for which people listen to music is closely associated with the frequency of listening to music than the choice of music (Hallam, Cross & Thaut, 2016). Therefore biological factors are also responsible for the amount of time and resources people spend to listen to music. However, it is important to note that both the biological and social factors significantly contribute to the individual differences in musical functioning.

References

Damon, W. & Lerner, R. M., (2006). Handbook of child psychology. Hoboken, N.J: John Wiley & Sons.

Deutsch, D. (2012). The psychology of music. London : Academic Press.

Feezell, J. T. (2008). Stereotype: The influence of music preferences on political attitudes and behaviour. Santa Barbara, Calif.: University of California, Santa Barbara.

Gruszka, A., Matthews, G., & Szymura, B. (2010). Handbook of individual differences in cognition: Attention, memory, and executive control. New York: Springer.

Hallam, S., Cross, I., & Thaut, M. (2016). The Oxford handbook of music psychology. Oxford : Oxford University Press

Haas, R., & Brandes, V. (2009). Music that works: Contributions of biology, neurophysiology, psychology, sociology, medicine and musicology. Wien: Springer.

Jones, M. R., Fay, R. R., & Popper, A. N. (2010). Music perception. New York: Springer.

Juslin, P. N., & Sloboda, J. A. (2010). Handbook of music and emotion: Theory, research, applications. Oxford: Oxford University Press.

Kern, P., & Humpal, M. E. (2012). Early childhood music therapy and autism spectrum disorders: Developing potential in young children and their families. London: Jessica Kingsley Publishers

Lehmann, A. C., Sloboda, J. A., & Woody, R. H. (2007). Psychology for musicians: Understanding and acquiring the skills. Oxford: Oxford University Press.

Lilienfeld, S. O., Lynn, S. J., Ruscio, J., & Beyerstein, B. L. (2011). 50 Great Myths of Popular Psychology: Shattering Widespread Misconceptions about Human Behavior. Hoboken: John Wiley & Sons.

McPherson, G. (2016). The child as musician: A handbook of musical development. Oxford : Oxford University Press

Rickard, N. S., & McFerran, K. (2012). Lifelong engagement with music: Benefits for mental health and well-being. Hauppauge, N.Y: Nova Science.

Sloboda, J. (2004). Exploring the musical mind: Cognition, emotion, ability, function. Oxford: Oxford University Press.

Theorell, T. (2014). Psychological health effects of musical experiences: Theories, studies and reflections in music health science. London: Springer

Zelazo, P. D. (2013). The Oxford handbook of developmental psychology. New York, NY: Oxford University Press.

Exposure to diversity is essential for success in our world. While diversity can be anything from ethnicity to economic status to religion to sexuality to shape, our brain has the ability to make connections and discover how differences interact and function in our world. When we give ourselves the opportunity to work with diversity, we learn from one another.

We find so many differences and similarities between each other. Science tells us our brain functions by the transfer and interaction of neurons; in order to remember things, our brains must be exposed to information multiple times. Essentially, learning about and from others benefits us on a worldly scale, but the more new knowledge we retain and the more connections built between exploring differences and similarities, the overall smarter we become.

Though diversity refers to our differences, it also reveals our similarities. Diversity not only helps us to make connections or learn from each other but also makes us think outside of your own perspectives and look at things in different light. Our brain recognizes the difference between us but also recognizes the similarity to past knowledge. As a result, our neurons for this information strengthen their bond and give us a better understanding.

Individual percept things a certain way but interaction with others forces our brain to think outside of the box we look through every day, it helps us understand other people and in some cases even change someone’s views. Sexuality or sexual orientation is becoming increasingly diverse as each day passes by. How do these diverse sexual orientation or sexualities differ within each individual? And more importantly, what did I learn from my Human Sexuality class about my sexuality? How did it changed my perspective about similarities and differences I share with others?

First of all, I will talk about the difference within myself that I wasn’t aware of at first. When I started this class it was pretty clear to me that this class will require some dedication on my part. I was trying my best to keep with my other classes as well when I stumbled upon one of the readings required for Human Sexuality class. The article by Lamaya H is about a Muslim girl and her queerness.

As soon as Lamaya said, “It takes me a while to recognize this as desire. I have no models for these kinds of feelings and it is confusing. I figure I’ll outgrow it.” I took a break from this reading as though it spoke to me. Lamaya H talks about how her experience was and how she tried her best to “crush on boys and (painfully, awkwardly) flirt with them” and that it never got her far because she knew it wasn’t something she wanted. Lamaya talks about the representation of lesbians on media are very limited to naked blonde women kissing each other.

Then moving onto how she got to the word queer and how she found out about Queer Muslim mixers. This way she was able to be who she wanted to be around her friends who would judge her for being queer or Muslim. It was just one sentence to make think about myself. I’ve been so focused on being what people wanted me to be that I completely forgot about what I wanted something else. I knew I had feelings for some of my friends who happened to be girls.

It confused me a lot because I liked boys too. The only option left was me as bisexual. I drowned myself in all the articles and readings online. In my case, it was harder for me to even come out to myself. Some people go through same things, coming out to oneself becomes the hardest part but everyone and every individual is different from one and another. While we do diverse from each other, our brain make connections to things certain things making it easier for us to connect with others.

Moving forward, I will be discussing asexuality and its connection to me or People within LGBTQ community. The first question is; what is asexuality? An asexual person is someone who does not experience sexual attraction. Asexuality just like other sexuality has difference and similarities within itself. One statement can not define everyone’s preferences.

Carrigan, in an article ‘Asexuality’, explains that it can be usefully understood in terms of divergent attitudes towards sexual behavior (positivity, neutrality, repulsion) and romance (aromanticism and romanticism, which can take heteroromantic, homoromantic, biromantic, and panromantic forms). There are many more identifications some of which fall under “Gray-A” commonly known as “Grey Area”.

Carrigan shares some of the statistics that fall within “Gray-A”, “56% of respondents reporting identification as ‘Asexual’, 21% as ‘Gray-asexual’, 21% as ‘Demisexual’, and 2% as ‘None of the above”. Even though not having sexual attractions is not so unknown there are still a lot of confusions or myths about asexuality.

Carrigan talk about one of the most “common confusion is to equate asexuality with celibacy, such that a lack of sexual attraction (asexuality) is conflated with a choice to abstain from sexual acts (celibacy)” Celibacy is a choice to restrain oneself from acting on sexual attractions while asexual person has no sexual attractions (depends on where someone is on gray-A) towards any individual.

As a person who defines herself as demisexual one of the biggest assumption is that everyone is sexually attracted to someone. Demisexuals is a person who does not experience sexual attraction unless they form an emotional connection. Even though demisexuality falls under gray-a, they are sexually attracted to people to they have an emotional connection with but not to everyone as myths suggest. Even within sexuality, people have differences and similarities inwardly within each individual.

Introduction

This study builds on previous research which has investigated the awareness of agency in schizophrenia patients with and without delusions of control. Individuals suffering from schizophrenia can show delusions which cause them to believe that their thoughts and actions are in control of external forces. In such individuals, previous research has shown that there is increased and abnormal activity in certain brain areas when compared to healthy subjects. This fMRI study therefore investigates how these brain areas respond in two different tasks: 1) awareness of action discrepancy, and 2) awareness of action authorship. An experimental paradigm used by Farrer et al (2007) will be replicated, using a manual peg removal task. It is expected that in healthy individuals and schizophrenics without delusions of control will show normal activity in the specified brain areas in both of the studies. However, schizophrenics with delusions of control will show abnormally high activity in both studies, demonstrating an abnormality in brain function.

Scientific Summary (max 200 words):

Currently, there is a wealth of research investigating action authorship in healthy individuals and schizophrenics. These have shown that the rIPL, specifically the Ag, and the TPJ in healthy subjects and schizophrenics without delusions of control show increased BOLD signals to the experience of agency (self or other). However, it has been found that schizophrenics with delusions of control exhibit hyperactivity in these areas, and are more likely to misattribute an action to themselves or an external force. An experimental paradigm used by Farrer et al (2007) will be replicated, using a manual peg removal task – as research is somewhat ambiguous when it comes to brain activity relating to awareness of action discrepancy and awareness of action authorship, the two will be separated into two studies. It is expected that in both studies healthy subjects and schizophrenics without delusions of control will show normal brain function – rIPL activity to detecting a delay in the first study, and TPJ activity to the experience of agency uncertainty. However, the schizophrenics with delusions of control in study 1, will show hyperactivity of the rIPL and TPJ BOLD signals due to their perceived ambiguity of action agency, and study 2, will show similar results as they misattribute the action to external forces more so than the other subjects.

Background of the Project:

Distinguishing oneself from others is something we all take for granted and give the self-other distinction and the source of our perceptions very little explicit thought in everyday life. It seems that the self-other distinction is automatic and operates via non-conscious cognitive processes and aids us in daily social interactions and situations (van den Bos & Jeannerod, 2002). However, this ability is not clear-cut and definite in all individuals as it can be impaired to varying extents in a range of pathological and psychiatric disorders, i.e. schizophrenia.

Schizophrenia is characterised by irregular beliefs, behaviours and experiences. Additionally, patients can typically exhibit symptoms which indicate abnormalities in self-attributing their own actions and thoughts: symptoms such as acoustic or verbal hallucinations and delusions of alien control can all relate to a sense of losing authorship/agency and giving the feeling of being controlled by external forces (Mellor, 1970; Spence et al, 1997). Schneider (1995) classed these as the first-rank symptoms and these were explained by the individuals losing their normal capability to monitor their self-generated intentions and actions (Feinberg, 1978; Frith, 1992).

Before considering where these deficits lie in schizophrenia individuals, it is important to establish how the brain areas of healthy subjects function in response to agency tasks.

Functional neuroimaging has allowed the neural correlates of motor control to be examined in great detail. In healthy subjects, awareness of action has been associated with the right inferior parietal lobule (rIPL) (Frith et al, 2000; Sirgu et al, 2004). Additionally, increased activity has been reported in specifically the right angular gyrus (Ag) of the rIPL when healthy subjects show an awareness that they are not in control of a certain motor action (Farrer & Frith, 2002; Farrer et al, 2007). Further evidence has found that the Ag activity is correlated with the degree of discrepancy between the intended consequence of the action and the actual consequence of the action (Farrer et al, 2003). Other neuroimaging research has demonstrated that when healthy subjects do not feel authorship of an action or when they sensed a discrepancy between predicted and actual movements, activity in the temporo-parietal junction (TPJ) was increased (Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). This suggests that the TPJ has a very important role in whether we feel a sense of authorship of an action or if there is a discrepancy present.

The first model which accounts for the mechanisms underlying the sense of agency is the Predictive Forward Model of motor control (Wolpert et al, 1995; Frith et al, 2000; Haggard, 2005). This model states that when an action is performed, predictions are made about the sensory movement consequences; this is based on the motor efference copy (von Holst & Mittelstaedt, 1950). Next, such predictions are compared with real sensory feedback signals which arise as a consequence of the

movement and these contribute to a sense of agency if no error signals are arise. If the comparison fails, and error signals occur, then the action is experienced as other-generated, or as action failure which can be corrected without conscious awareness (Slachesky et al, 2001).

Now, considering schizophrenia individuals, delusions of control can comprise the belief that one’s actions are being influenced by an external force/agent (e.g. an alien, spirit or machine) (Mellor, 1970). When patients with such delusions are compared to schizophrenics without delusions of control they show impaired motor performance (Mlakar et al,, 1994; Spence et al, 1997). Recently, neuroimaging studies have allowed motor control and any dysfunctions in the neural correlates to be investigated. Firstly, research has shown that like healthy subjects, schizophrenic patients show increased activity in the rIPL when looking at action authorship; however, a different pattern is seen. The spontaneous resting activity of the rIPL is significantly higher than that of healthy subjects (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011) and additionally, this activity is poorly modulated by a discrepancy between predicted movement and actual movement consequences (Farrer et al, 2004). This would suggest that there is a deficit in the parietal mechanism which could be responsible for the impaired sense of agency found in schizophrenia. In relation to the TPJ, there have been anatomo-functional changes which have been reported in schizophrenia (Torrey, 2007; Wible et al, 2009), and sulcal displacements and volume reductions in this region were evidenced in patients who reported delusions of control (Maruff et al, 2005; Plaze et al, 2011).

Previous studies have not been able to disambiguate between brain activity related to awareness of action discrepancy and awareness of action authorship in schizophrenic patients. Therefore, the present study is going to use a slight modification of Farrer et al (2007) experimental paradigm in order to clarify which brain areas are functioning or functioning abnormally in response to the task. It is unclear specifically which process recruits which aforementioned brain regions and this can be achieved by using an experimental design which breaks down the processes into two separate methods. Two fMRI studies will be undertaken and manipulations will include: 1) the awareness of one’s own action being consistent with the predicted action and 2) the experience of being the agent or not being the agent of an action (i.e. authorship/agency).

Study 1 will include delays in visual feedback of actions to manipulate the relationship between predicted and actual sensory consequences of the action. Therefore, brain activity can be monitored to see when subjects are aware vs. unaware of these discrepancies with no bearing on authorship. Uncertainty of authorship will be introduced in study 2 to allow the observation of brain activity in response to manipulations of action authorship.

Questions to be answered:

Will a difference be found in rIPL and TPJ activity of healthy subjects, schizophrenics with delusions of control and schizophrenics without delusions of control in study 1?

Will a difference be found in rIPL and TPJ activity of healthy subjects, schizophrenics with delusions of control and schizophrenics without delusions of control in study 2?

Will there a difference in brain activity between studies 1 and 2?

Plan of Investigation:

Subjects

In accordance with medical research guidelines, after complete description of the study, written informed consent will be obtained from each participant. 12 schizophrenics with delusions of control (6 male, 6 female), and 12 schizophrenics without delusions of control (6 male, 6 female) will be recruited from London teaching hospitals, satisfying the DSM IV-R criteria for schizophrenia. Additionally, 12 healthy subjects (6 male, 6 female) will be used as controls, matched on age, sex and IQ. Each participant will be identified as right hand dominant.

A quantitative assessment of the schizophrenia symptoms will be performed using the PANSS (Kay et al, 1987). Criteria for the schizophrenic patients with delusions of control are that they score 4 or 5 on the “delusions of control” item in the Scale for Assessment of Positive Symptoms (Andreasen, 1984). The criteria for the schizophrenics without delusions of control will be that they have never experienced such delusions.

Exclusion criteria will include any history of substance abuse or dependency, as well as any history of serious head injury or any other neurological or psychiatric disorders.

Stimuli & Procedure

As stated before, the experimental paradigm is very similar to Farrer et al (2007).

Study 1: A manual peg task will be performed with visual feedback delayed by 0, 50, 100, 150, 200, 300 or 300 ms. A board with 33 holes and 25 pegs will be used. For each experimental block the placement of the pegs will be different to avoid any recall of peg positioning. An infrared camera will film the grid and this image will be sent to a delay unit and be delayed for the required time. The feedback image will then be linked to the LCD projector so that the subjects are able to see the delayed action feedback on the rear projection screen at the head of the bore.

Therefore there are 7 conditions: 1 with no delay, and 6 with varying delays. A block design will be used with 8 blocks (20s each); the subjects will have to remove the pegs from the board for the 20s duration – this will then be followed by a rest condition with no action required or stimuli present. Each run involved the 7 conditions in a counterbalanced order. After each block finishes, each subject will be asked to state whether they perceived delays in the visual feedback of their movements: the right hand thumb down for “no” and thumb up for “yes”.

Study 2: The procedure and stimuli will be the same as study 1. However, the subjects will be required to perform index and middle finger alternating actions without pause whilst watching the feedback screen. The delays used will be 800 and 1000ms. Each run will consist of 120s of alternating finger movement, and 30s rest and will be repeated 5 times. The subjects will be told that they can either see their own or another’s movements after the delay, and this would occur randomly. However, in fact subjects will only be able to see their own movements delayed, causing them to switch from self to other. They also will be required to assert whether they think they see themselves or another individual carrying out the action. They will be required to press one of two buttons to show this. To prevent any other source of recognisable information that could give away the authorship of the movement, subjects will be required to wear a snug fitting glove to prevent any recognition cues.

Image Acquisition and Analysis

Studies 1 and 2 used the same functional imaging acquisition procedure. A 1.5-Tesla MRI scanner with a SENSE head coil will be used. For each run an ultrafast echo planar gradient echo imaging (EPI) sequence sensitive to blood oxygenation level-dependent (BOLD) contrast will be used to obtain 25 slices per time repetition, (4.5mm thickness, 1mm gap, in plane resolution, 3.125 x 3.125mm). TR = 2500ms, TE = 35ms. A co-planar, T1-weighted, axial fast spin echo sequence will be used to acquire 25 slices (4.5mm slice thickness with 1mm gap), TE = Min full, TR = 650ms, ET = 2, field of view = 24cm. A whole brain T1-weighted structural image will also be acquired (0.94?0.94?1.2mm) (Farrer et al, 2007). A head restraint will also be used to reduce any head movement during the scan in order to reduce any motion artefact.

Details of Data Analysis:

Both studies 1 and 2 will perform image analyses and statistical analyses using the SPM99 (http://fil.ion.ucl.ac.uk/spm/software/spm99). Functional scans will be realigned, spatially normalised and smoothed using a Gaussian kernel to remove any movement artefacts and to place the data from each subject into a common anatomical frame. The statistical analysis is similar to the analysis carried out by (Farrer et al, 2007).

Study 1: Two statistical analyses of the fMRI data will be performed. Firstly, movement-related activity, a simple contrast between the experimental blocks and the rest blocks. Secondly, delay-detection activity, the subjects’ responses in the detection of the delay will allow the assessment of between trials where subjects did or did not perceived the delay (Farrer et al, 2007).

Study 2: Two statistical comparisons will be performed. Firstly, movement-related activity, the experimental blocks across all conditions for each subject will be grouped and the main effect of task will be created. Secondly, perturbed agency, the subjects’ response to the visual feedback will allow differentiation between trials where the subject experienced self or other action authorship. (Farrer et al, 2007).

For both studies, one-tailed t-tests will be used for each of the contrast images. The set of t-values obtained will constitute a statistical parametric map which will show significant areas of BOLD signals.

Expected Outcomes:

The Expected fMRI Results:

Study 1: Consistent with prior research, it is expected that the healthy subjects will show significant activation in the in the rIPL, specifically the Ag, when detecting a discrepancy (detection of delay) (Frith et al, 2000; Sirgu et al, 2004; Farrer & Frith, 2002; Farrer et al, 2007). No TPJ activity is expected in the healthy subjects as study 1 is not meant to bring about the experience of agency uncertainty; this will be supported by previous research which shows the TPJ to have a role in determining if an action is not ours (Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). Schizophrenics without delusions of control are predicted to show very similar brain activation to the healthy subjects; this can be justified because they have had no prior experience of delusions of control and shouldn’t have any problems with determining action authorship (Spence et al, 1997) – however, this is not entirely certain, and only a prediction. As for the schizophrenics with delusions of control, it is expected that brain activity will be abnormal; the delay detected by the patient could elicit hyperactivation in the rIPL, specifically the Ag,

and the TPJ and give rise to misattribution of agency (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011). Unlike the healthy controls and schizophrenics without delusions of controls, it is predicted that they will be unable to attribute the movement to themselves after the delay.

Study 2:

It is expected that because of the ambiguity of the movement in terms of agency, healthy subjects and schizophrenics without delusions of control will show increased activity in the rIPL, but also in the TPJ due to the uncertainty of agency (Frith et al, 2000; Sirgu et al, 2004; Farrer & Frith, 2002; Farrer et al, 2007; Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). After being told that the action is ambiguous (i.e. self or other) it is predicted that the schizophrenics with delusions of control – similar to study 1 – will be more likely to misattribute the movement to another agent with a greater perturbation of their sense of agency compared to the other subjects. Additionally, the activity in the rIPL and TPJ is expected to show hyperactivation in comparison to the other subjects. (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011). Finally, it is expected that there will be a greater overlap between brain areas active in both studies for the schizophrenics with delusions of control compared to the other subjects.

Details of any difficulties that can be foreseen:

Although the subjects will be paid for their participation in the study, locating both schizophrenics with and without delusions of control may prove to difficult as they must be situated near the fMRI site as it is very unlikely that they will wish to travel long distances due to time and other issues. The criteria provided will narrow down the potential sample further.

When using fMRI, it is important to acknowledge that the BOLD signals are considered to be an indirect measure of brain activity, therefore potentially, all brain responses may not be recorded for each of the stimuli. However, fMRI is viewed as one of the most effective ways to investigate brain activity without invasive procedure in this paradigm. It will be made certain that all precautions are met, and imaging acquisition and analysis are meticulously carried out.

Due to the nature of schizophrenia and the wide variety of symptoms shown, it is possible that during the scanning process, certain subjects might experience symptoms that are debilitating to the scanning process which are out of the control of the experimenter. Medical staff will be on standby in case any violent/aggressive symptoms occur. There is a small chance of such an incident happening, but careful preparation can minimise the risk.

Future purpose and Theoretical Implications:

If the results are as expected, this will have significant implications for several research areas. Firstly, it will add to the abundance of literature on the involvement of the rIPL and TPJ in response to action discrepancy and authorship in healthy individuals (e.g. (Frith et al, 2000; Sirgu et al, 2004; Farrer & Frith, 2002; Farrer et al, 2007; Leube et al, 2003; David et al, 2007; Farrer et al, 2008; Spengler et al, 2009). Furthermore, it will demonstrate that symptoms vary massively across schizophrenia patients – there are deficits in the functioning of neural correlates (i.e. the rIPL and TPJ) between those with and without delusions of control, and will add to the relevant literature (e.g. (Spence et al, 1997; Whalley et al, 2004; Jeannerod, 2009; Jardri et al, 2011).

Future research could delve into the severity of the symptoms of both the schizophrenics with and without delusions of control, and investigate whether it has an effect on subsequent brain activity. If a significant correlation is found it could be used as a “state-marker” of schizophrenia. As Jardri et al (2011) suggested such an increase in activity of the rIPL and TPJ in those with delusions could demonstrate a neuro-physiological signature in those suffering from the disease.

Additionally, it gives further evidence that the deficient parietal mechanism is responsible for the impaired sense of agency demonstrated in schizophrenics with delusions of control. Therefore, as they have problems linking their intentions to their actions, it suggests that for future research the disconnection should not be looked for at the sensorimotor level, but rather, like this experiment, it should be looked for within the cortical network which is known to be responsible for the representations of motor function.

References:

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18. Sirgui, A., Daprati, E., Ciancia, S., Giraux, P., Nighohhossian, N., Posada, A., Haggard, P. (2004). Altered awareness of voluntary action after damange to the parietal cortex. Nat Neurosci, 7, 80-84.
19. Slachevsky, A., Pillon, B., Fourneret, P., Pradat-Diehl, P., Jeannerod, M., Dubois, B. (2001). Preserved adjustment but impaired awareness in sensory-motor conflict following prefrontal lesions. J Cogn Neurosci, 13, 332-340.
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our site – CUSTOM ESSAY WRITING – HEALTH DISSERTATION TOPICS
Abstract

An exploration into Holoprosencephaly, the genetic birth defect; we will observe how it presents itself in su erers- the physical and neurological symptoms, we will brie y try to identify the main candidates that can be linked to its etiology and nally taking the SHH pathway as an example we will explain how a genetic mutation could give rise to the associated symptoms of HPE.

1 HPE

Holoprosencephaly (HPE) is a congenital defect in the nervous system, whereby the developing prosencephalon (or forebrain) fails to bifurcate into left and right hemispheres- typically occurring ve to six weeks into pregnancy (Golden, 1999). It is the most common malformation of the brain- occurring in 1:250 developing embyros, with 1:8,000 live births due to a 3% chance of survival to delivery (Co-hen, 1989). The failure of the cleavage into two bilateral cerebral hemispheres gives rise to a continuum of motor and developmental malformations, the most prominent being craniofacial defects and damaged brain structure. There are four classes of HPE1, varying in the degree of cortical separation and associated severity of symptoms2 (Raam, 2011). The most severe form is Alobar HPE, this is characterised by a complete or near lack of interhemispheric separation and an absence of olfactory bulbs and corpus callosum. This makes up roughly two-thirds of HPE patients (OMIM, 2012), the most extreme grade in this class will have cyclopia: no separation along the midline of the brain, with no sense of chirality in their embryogenesis. In this case the foetus will develop a single, medial eye above the root of the nose- they will rarely survive the perinatal period. The next class is Semilobar HPE, which can be identi ed by a partial posterior cortical separation (but no anterior) with basal hemispheres, the olfac-tory bulbs and corpus callosum are either absent or hypoplastic. In this case the eyes are now slightly separated by proboscis, but the motor skills are still highly impaired. The next form is lobar HPE, this is a milder form of semilobar, di er-entiated by the latter by the presence of a frontal horn in the lateral ventricle. Lobar has an interhemispherical ssure, but there still incomplete separation of the prosencephalon; the corpus callosum is absent in the a ected region and the olfactory bulbs are hypoplastic. There is less severe motor malfunction, and the face can develop closely spaced eyes, at nose and cleft lip. The fourth and mildest form is the Middle Interhemispheric Variant (MIV), where the most a ected regions of nonseparation occur in the posterior frontal and pariental lobes; the corpus callosum is typically absent in the region or hypoplastic. This variant of HPE has mild craniofacial and neurological impairments. All of these deformities can be detected through neuroimaging, and can be discerned by the above phenotypes.

2 Causes

Current research into the causes of HPE is still developing; most sources can-not give exact causes, but there a number of factors that have been linked to the disorder. The most supported model is given by the Multiple Hit Hypothesis which states that HPE derives from a combination of environmental and genetic factors, i.e. it is an autosomal-dominant disease; it is believed that this would explain the heterogeneity of the phenotypes (OMIM, 2012). Teratogens are be-lieved to disturb the development of the normal phenotype: maternal diabetes has been linked to a 200% increased risk of HPE in the foetus( Croen, 2000; Raam, 2011). This along with hypocholesterolemia and the drug cyclopamine are linked to disturbances in cholesterol production, inhibiting the Sonic Hedge-hog (SHH) Signalling Pathway (Cohen, 1989). The fact that the defects occur early in pregnancy implies a gastrulation disorder supporting the theory that infections whilst pregnant and drug taking (alcohol, anti-epileptic medication

1 There is a mild associated form called Microform, with similar craniofacial characteristics, but no sign of nonseparation, as such typically not considered within HPE.

2 A common used term is that “the face predicts the brain”, this is a general correlation that exists between the degree of mental and physical retardation and mortality within the four classes and ethanol for example) are likely environmental causes. The genetic etiology are related to familial occurrences3, genetic syndromes of HPE and non ran-dom chromosomal aberrations- identi ed by high resolution karotype counts, or DNA microarrays. A relatively common cause of HPE-approximately 28%, (Geng, 2009)- has been found to be loss-of-function mutations in the genes: SHH, ZIC2, SIX3 and TGIF- whereby the particular gene product will be un-able to perform its original function. There are ve other genes identi ed with HPE, but these four mutations are the most prevalent and as such are the main roots for DNA sequencing. These genes are related to the Nodal and SHH pathways. De ciency in the Nodal protein results in a failure to form the PrCP gene; this e ects the formation of the primitive streak. The establishment of this structure is important in creating a longitudinal plane of symmetry along the embryonic disk that allows cell migration into the midline to create the mesoderm, the cells of which form a rod called the notochord. The SHH gene is a morphogen that regulates ventral midline structure in the forebrain (Roessler, 2003) and is crucial in formation of the eyes and face. It is a molecule that responds to variations in a concentration gradient within the neural tube by di using Sonic Hedgehog, produced by the signalling centre of the notochord (Placzek, 1999).

3 How the gene leads to the disorder

In order to understand how HPE4 manifests itself through the mutation in this gene we will consider its role in brain embryology (Marieb, 2003). By around the fth day after fertilisation, the blastocyst of the egg is released- this is a sphere composed of trophoblast cells and inner cell mass; this will undergo gastrulation whereby the inner cell mass is converted into the three primary germ layers and the embryonic disk. This disk attens and a primitive streak creates a midline depression along the median. Three weeks into pregnancy the ectoderm thick-ens along the dorsal midline axis of the embryo to form the neural plate, which when folds into the neural tube by the fourth week, the anterior of which expands rapidly to form the three brain ventricles of the prosencephalon along with the middle and the hindbrain; by this time eye rudiments are present. Normally, in the fth week the prosencephalon will bifurcate into the diencephalon and the telencephalon-from the dorsal plate and ventral plate, respectively- connected by the corpus callosum. The telencephalon then “swells” into the cerebral hemi-spheres and by the eighth week all brain exures are formed. The role of the SHH gene is to produce the Sonic Hedgehog protein that signals the activation of the ventral midline of the forebrain. In HPE, with a mutated SHH gene, there is a reduced or no production of this protein and as a result the fore-brain will not split into a left and right (Roessler, 2003). Along with this it secretes the molecule responsible for signalling the division of a single eye eld

3 There are a number of case studies in (OMIM, 2012) on families where HPE is an inherited condition

4 To be exact, this is Holoprosencephaly type 3 into two distinct eyes. Hence, a SHH mutation can lead to a lack of interhemi-spheric separation and merging of the eyes, which would a ect the development of the rest of the face. This shows the symptoms of HPE su erers, suggesting the disorder is a subclass related to the loss-of-function of the SHH signalling pathway. If there was a complete lack of SHH signalling there would be no separation in the telenchephalon, and as such no connecting corpus callosum, the primordial eye eld would not divide into two lateral eye elds, thereby resulting in an embyro with cyclopia from Alobar HPE. Similarly, inactivity of the Nodal signalling pathway causes failure in the formation of the mesendo-derm and axis-asymmetry. As stated before there are a number of genes that are linked to HPE that also regulate organogenesis but the spectrum of the disorder is entirely variable and there are 75% of HPE cases that do not have any of these gene mutations. The most satisfactory hypothesis is the Multi-hit model; there is no single exact cause that could trigger the defect in all of the presented cases and produce the four classes of severity, but it is possible that the pathogenesis must involve some event in the regulatory regions that induces the expression of the four identi ed genes in the forebrain, though the trigger might not necessarily be the same in every instance.

4 References

Cohen, M.M. Jr., Perspectives on holoprosencephaly: Part III. Spectra, distinc-tions, continuities, and discontinuities. Am J Med Genet. 1989; 34: 271-88. Cohen, M & Shiota, K, Teratogenesis of Holoprosencephaly. Amercian Journal of Medical Genetics. 2002; 109: 1-15.

Croen L.A, Shaw G.M & Lammer E.J, Risk factors for cytogenetically normal holoprosencephaly in California: A population-based case-control study. Am J Med Genet. 2000; 90: 320-325.

Geng, X & Oliver, G, Pathogenesis of holoprosencephaly. J Clin Invest. 2009;119(6):14031413 Golden, J.A, Towards a greater understanding of the pathogeneis of holoprosen-

cephaly. Brain & Dev. 1999; 21: 513-521.

Graham, J.M. Jr. & Shaw, G.M, Gene-Environment Interactions in Rare Dis-eases that Include Common Birth Defects. Birth Defects Research. 2005; 73: 865-867.

Marieb, E.N, Human Anatomy and Physiology. California: Benjamin Cum-mings, 1989.

Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Bal-timore, MD. MIM Number: 236100. [Accessed 28/11/2012] World Wide Web URL: http://omim.org/

Placzek, M, The role of the notochord andoor plate in inductive interactions.

Genetics and Development. 1997; 5(4): 499-506.

Raam, M.S, Soloman, B.D & Muenke, M, Holoprosencephaly: A Guide to Di-agnosis and Clinical Management. Indian Pediatrics. 2011; 48: 457-466.

Roessler, E & Muenke, M, How a Hedgehog might see holoprosencephaly. Hu-man Molecular Genetics. 2003; 12(1): R15-R25.

Introduction

Research into the genetic causes of Alzheimer’s disease have progressed considerably and currently at least three different genes are known to be linked with AD pathogenesis. Of these the apolipoprotein gene E (APOE), an amino acid glycoprotein, is one of the main focus of research over the last decade or so and significant associations between one particular isoform of the gene and the onset of AD have been reported. This isomer, referred to as the ApoE 4 allele, has been implicated in AD pathogenesis while other forms of the gene the ApoE 2 and the ApoE 3 have been reported to have a protective effect against the onset of AD. Though research has confirmed this variable effect of the different forms of the ApoE gene, there is still a lack of concrete evidence as to the exact pathway and the mechanism by which ApoE 4 contributes to neurodegeneration in AD patients. A brief review of related research would provide us more insight into the various pathological actions of ApoE 4 and how these multiple factors could lead to a gradual cognitive decline which is symptomatic in Alzheimer’s patients.

The ApoE gene (Physiological Functions)

ApoE is an amino acid glycoprotein that is found mainly in the liver and the brain. In the brain, ApoE is predominantly secreted by the astrocytes. Two other forms of apolipoproteins namely ApoA-1 and ApoJ are also found in the brain. In vitro studies of these two genes have so far suggested that both of them exhibit a neuroprotective effect. Both these proteins bind to A? and therefore are thought to reduce A? aggregation in the brain which is a known marker of AD. However, in vivo studies have not replicated such results and so the protective roles of ApoA-1 and ApoJ are not yet clear. The ApoE supports cholesterol equilibrium by serving as a ligand during endocytosis of lipoprotein particles by LDL receptors. Research is divided in the opinion that the cholesterol released from ApoE mediated endocytosis process is actually used for improving the synaptic connections or the synaptic plasticity. Mice based in vivo studies have not attested to this synaptogenesis. (Kim et.al, 2009)

The ApoE isomers

Three single nucleotide polymorphisms of the ApoE gene are commonly identified in humans. These are the apoE2 (cys112, cys158), apoE3 (cys112, arg158), and apoE4 (arg112, arg158) respectively. (Kim et.al, 2009) The structural and functional aspects of the three isomers of ApoE are totally altered though they differ by only one or two amino acid positions. Studies have reported strong immune-reactivity of the human apoE4 gene on amyloid plagues and the apoE4 isomer has been associated with having a strongest risk factor for AD. Some studies such as (Bertram et al., 2007) and (Bertram et al., 2009) have attested to this role of the apoE4 isomer in AD. Bertram et al., 2009 for instance reported that people with a single copy of the apoE4 gene had a three fold increase in risk for AD, while the risk was 12 fold among those with a dual copy of the ApoE4 gene. The results from studies also suggest the possible role of some environmental factors as research based on some ethnic groups have revealed that the ApoE 4 gene does not have a significant effect on AD.

ApoE & A? Aggregation (Fibrillogenesis)

Several research studies have focused upon the potential role of ApoE 4 in causing A? aggregation and neuronal degeneration. This direct interaction between the ApoE 4 with beta amyloid is attributed in the pathogenesis of the disease. Therefore it was hypothesized that increased levels of ApoE 4 in the brain corresponded to increased formation and thickness of amyloid plaques. The findings from one comprehensive study by Tiraboschi et.al (2004) validated this hypothesis. The researchers in this study confirmed increased plaque density corresponding to increased levels of ApoE 4.

This positive association was again confirmed by a more recent study by Reiman et.al (2009). The researchers of this study used an amyloid detecting agent such as Pittsburgh compound B (PIB) along with positron emission tomography to detect the levels of fibrillar A? in the subjects. The researchers then correlated this information among individuals with varied genetic risks. The results from the study clearly revealed that ApoE 4 homozygotes had the highest risk (91%) for developing AD while ApoE 4 heterozygotes had a moderate risk of 47% and finally ApoE 4 non carriers had only 20% risk of having AD. Furthermore, the mean age of onset of AD was also vastly different with ApoE 4 homozygotes at 64, heterozygotes at 76 and 84 years of age among non carriers. This longitudinal study clearly provides positive evidence connecting the ApoE 4 gene with a high risk for AD. Thus there is enough evidence that ApoE 4 gene may aid in ?brillogenesis and consequent cognitive decline. (Reiman et.al 2009).

A? Clearance by ApoE

Some studies have shown that ApoE by binding with soluble A? promotes the cellular uptake and ingestion of the ApoE –A? complexby endocytosis. However, isomer specific results for this ApoE facilitated cellular uptake of A? are still awaited. Research has also focused on the possible clearance of A? from the brain via the blood brain barrier. However, there is growing evidence that ApoE 4 might actually hinder or reduce this clearance of A?. Deane et.al (2008), a study based on mice reported that the clearance rate of ApoE 4 –A? complex is much lower than that for the ApoE2 and ApoE 3 complexes. Other recent studies such as Bell et.al (2007) and Ito et.al (2007) that focused on studying the A? clearance in humans found that the clearance rate along the Blood Brain Barrier (BBB) was significantly lower for the ApoE 4 –A? complex compared to that of simple A? peptides. These studies offer enough evidence that ApoE 4 might actually increase the fibrillogenesis by directly affecting the A? metabolism in the brain. By reducing the clearance rate and promoting aggregation ApoE 4 gene definitely poses an increased risk factor for AD.

ApoE and Neuronal Inflammation

Several studies have reported that ApoE has marked anti inflammatory properties which explain the surge in their production in the aftermath of an injury. These studies hypothesize that ApoE is needed for maintaining the cholesterol homeostasis, and in particular for increasing the availability of cholesterol for neuronal repair and improving the synaptic plasticity subsequent to brain injury. (Slezak & Pfriege, 2003 ). However studies have also reported differences in neurite growth and synaptic plasticity post neuronal insult in animal studies based on the genotype. One transgenic mice study found that neuronal growth and synaptogenesis were markedly lower among ApoE 4 transgenic mice compared to ApoE3 transgenic mice. (White et.al, 2001) An extensive review of the neuroprotective effects of the various ApoE isomers by (Cambon et al, 2000) clearly showed differential effects between the isomers. Most of the studies reported that ApoE3 promoted synaptic plasticity and neurite growth. However similar positive results were not witnessed in the case of ApoE 4 alleles with some studies even reporting the negative effects of ApoE 4 on synaptic plasticity and neuronal growth. Colton et.al (2004) found that the anti-inflammatory effects vary drastically between the ApoE isomers. The researchers studied this variability in anti-inflammatory response triggered by the ApoE 3 and ApoE4 isomers by using in vivo experiment conducted on ApoE knockin mice. By studying Lipopolysaccharide (LPS) mediated inflammatory responses the researchers observed the differences between the isomers. The inflammatory response was much greater in the ApoE 4 knockin mice when compared to the ApoE3 Knockin mice. These studies suggest that the anti inflammatory response maybe less active in ApoE 4 and this might lead to neuronal damage as witnessed in AD patients.(Kim et.al, 2009)

Conclusion

The review of studies has revealed that the ApoE isomers have differential effects on the A? metabolism in the brain. While the ApoE 2 and ApoE 3 isomers have been reported for their protective effects the ApoE 4 allele clearly seems to contribute to the AD pathogenesis. Results from recent fibrillar PET imaging studies suggest a clear positive correlation between the ApoE 4 allele and the density of amyloid plaque formation. It is clear that by slowing down clearance of A? as well as contributing to its aggregation in the brain, the ApoE 4 allele increases the susceptibility of a person for AD. It is also possible that the ApoE 4 also lowers the protective function by increasing the neuronal inflammatory response and by hindering neurite growth. More studies are necessary to understand the complex relationship between ApoE and A? and the levels of different isomers of ApoE and their corresponding impact on Neuroinflammation and neurotoxicity, etc.

Bibliography

Jungsu Kim, Jacob M. Basak, & David M. Holtzman, (Aug 13th 2009), The Role of Apolipoprotein E in Alzheimer’s disease, Neuron 63.
Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., and Tanzi, R.E. (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39, 17–23.
Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., and Tanzi, R.E. (2009). The AlzGene Database Alzheimer Research Forum available at,
Eric M. Reiman, Kewei Chen,&Xiaofen Liu et.al (Apr 2009), Fibrillar amyloid-? burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease, Proc Natl Acad Sci U S A. ; 106(16): 6820–6825.
Bell, R.D., Sagare, A.P., Friedman, & A.E., Bedi et.al (2007). Transport pathways for clearance of human Alzheimer’s amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J. Cereb. Blood Flow Metab. 27, 909–918.
Ito, S., Ohtsuki, S., Kamiie, J., Nezu, Y., and Terasaki, T. (2007). Cerebral clearance of human amyloid-beta peptide (1-40) across the blood-brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes. J. Neurochem. 103, 2482–2490

Part 2

Fibrillar amyloid-? burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease (Reiman et.al 2009)

This research study by Reiman et.al (2009) hypothesized that fibrillar amyloid accumulation is an early development in the onset of Alzheimer’s disease. The researchers further hypothesized that the fibrillar amyloid accumulation precedes any recognizable symptoms of cognitive decline. Amyloid plaques are a distinct feature of AD as observed from post mortem studies. Given the hypothesis that fibrillar A? accumulation is observed even in healthy, non symptomatic adults, the researchers intended to study the effect of fibrillar A? burden as a predictor of future onset of AD on adults with normal cognitive function using Ante mortem brain imaging studies.

For this study, the researchers used Pittsburgh Compound B (PiB), a radio ligand that binds only with the fibrillar A? species. Earlier studies have also used this PIB for imaging studies of live human brain to observe the formation of fibrillar A? in healthy adults. This study by the authors is aimed to extend the previous studies by providing a genetic risk analysis and to understand the predisposition to AD based on an individuals APOE genotype. The APOE genotypes were identified by using blood sample analysis. The researchers used fluorodeoxyglucose PET, volumetric MRI and neuropsychological tests. Fibrillar imaging was done using 3 dimensional HR+ scanner. The subjects of this study were all cognitively normal and late middle aged people representing a mixture of APOE genotypes. This was a longitudinal study and the subjects were assessed every 2 years.

The researchers observed that cerebral glucose metabolism levels of those subjects carrying dual copy of the ApoE 4 (homozygotes) was significantly lower than that of the heterozygotes and the non carriers. With the PiB Pet images the researchers compared and correlated the fibrillar burden with the genetic risk to understand the predisposition for AD between the various isomers. The average Pittsburgh(PiB) distribution volume rations(DVR), which is a measure of the fibrillar A? accumulation, was on increase in all the three different groups in the 2 years period. One of the homozygote subjects developed mild amnesia and her DVR was close to that of an AD patient. Overall of all the 28 subjects (8 homozygotes, 8 heterozygotes and 12 non carriers), the ROI measurements pertaining to the different brain regions such as temporal, parietal, posterior cingulate-precuneus, basal ganglia, etc, was the highest among the homozygotes.

The researchers used statistical analysis and found that the homozygotes had considerably higher ROI values when compared to the non carriers (P < .05) while the difference between the heterozygotes and the non carriers was not significant (.05 < P < .11). When correlated the APOE4 and Fibrillar A? burden was found to be significant among both homozygotes and heterozygotes compared with the non carriers. The study authors successfully found that even in cognitively normal individuals there is a positive correlation between ApoE 4 and fibrillar A?. The results from the study suggest that the ApoE 4 is clearly associated with increased A? aggregation and decreased A? clearance. The following PET map clearly indicates the various regions of the brain that are affected by A? accumulation.

Group A represents the homozygotes while group B and C represent the heterozygotes and non carriers respectively.

Longitudinal studies are very effective in following the growth of fibrillar A? accumulation as they provide a clear pattern of disease progression even in the asymptomatic stage. People who are in late middle age who are at risk for AD would greatly benefit from a prophylactic intervention based on the brain mapping study and their ApoE genotype. This study clearly contributes to our understanding that the ApoE 4 is directly involved in the A? interaction and the formation of Amyloid Plaques. By considering live brain images for the study the authors were able to clearly confirm the association between the ApoE 4 and A? fibrillar density and predict the increased susceptibility of people with that genotype.

This study has large implications for the treatment of AD. By proving that A? fibrillar formation precedes a perceivable cognitive decline, this study recommends early interventions particularly for people with ApoE 4 genotype, as the current A? modifying treatments would be more effective before extensive A? accumulation has occurred. The researchers advocate the use of brain imaging studies combined with genotype based risk assessment as a potentially powerful tool in preventive therapy for people who are at a genetically high risk for AD. One of the drawbacks of the study is the very small study sample. A large cohort based longitudinal study would have provided more conclusive confirmation of the study results.

Bibliography

Eric M. Reiman, Kewei Chen,&Xiaofen Liu et.al (Apr 2009), Fibrillar amyloid-? burden in cognitively normal people at 3 levels of genetic risk for Alzheimer’s disease, Proc Natl Acad Sci U S A. ; 106(16): 6820–6825.

Neurons are the specialized cells which make up the body’s nervous system. These nerve cells process and transmit information from one part of the body to another. For example, if you were to touch a candle flame for more than an instant, pain nerves also known as receptors that are in your finger would send a message up through your hand and arm to the spinal cord and then to the brain.The brain which in turn records pain and sends the messages back down to various parts of the body. You will the say “ouch” which is then followed by the body or hand jerking away from the flame as pain will be felt as this reaction is caused by the message which was sent through the brain.

This all happens in milliseconds. Much of the brain is made up of highly specialized neurons. They interact to control the five senses, thought, mood and motion.Within the nervous system a process to which the neurons in the body communicate is called Chemical synapses which is a specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands seeing as the flow of information around the brainis achieved by electrical activity. Chemical synapses allow neurons to form circuits within the central nervous system.They play a crucial role to the biological computations that underlie perception and thought as neurons communicate in structures called synapses where neurons send and receive information. The sending neuron is known as the pre-synaptic neuron (which is before the synapse )and the receiving neuron is known as the post-synaptic(after the synapse) which is in the synapse transmission process.

So in other words the synapse consist of two neurons, one of which is sending information to the other. They allow the nervous system to connect to and control other systems of the body. At a chemical synapse, one neuron releases a neurotransmitter into a small space (the synapse) that is adjacent to another neuron. Neurotransmitters must then be cleared out of the synapse efficiently so that the synapse can be ready to function again as soon as possible.

Introduction

Human body consists of different systems among them nervous system is one, it is composed of two parts they are-

The Central nervous system: It is composed of brain and spinal cord; it transmits sensory information to the Central Nervous System from sense organ.

The Peripheral nervous system: It connects the central nervous system to the glands, sensory organs, and muscle through different nerves.

A nerve in our body is covered by a layer of protective sheath it is known as myelin. Myelin is a fatty substance made up of protein it provides protection to the nerves. It helps in the transmission of nerve impulse between the brain and other parts of the body by maintaining the speed of impulses. Each neuron consists of long thread of cytoplasm known as axon; it helps to transport messages from one part of the body to another it is a protected by the sheath of myelin. Axon conducts impulses at a very high rate and allows the transfer of information between neurons to assist motor function and sensory perception. As we know human beings with healthy immune system can fight with disease in proper way in compared with the people whose immune system is weak. Sometime immune system of human beings gets weaker by the different factors such as virus, bacteria, genetic as well as environment. Damage to the immune system causes the white blood cell to attack own healthy tissue and large number of immune cells enter into the central nervous system this is directed against the body’s own tissue it is known as autoimmune disease. Presence of large number of immune cells causes an inflammation this leads to damage of the myelin sheaths that protect the nerves and helps in the transmission of electric impulse in a great speed between the neurons.

Due to the inflammation nerves gets separated from myelin this is known as demyelination then scarring (it is known as sclerosis) occurs at the place where nerves has been separated from myelin. Due to this plaques and inflammation are formed in this place and they vary in number (multi) this is known as multiple sclerosis this cause central nervous system to be affected. As a result delay in transmission of electric impulses between the parts of the body occurs. This leads in slowing day to day activity such as moving, speaking and so on.

Many people gets affected by the multiple sclerosis around 85,000 people are affected by this disease in UK. Symptoms occur between the age of 20 and 40. But this disease has been found in theage of 15 this has been considered as an early age and 60 as later age. Women get affected two or three times more than men as well as their is chance that women get affected in early phase of life in compare to men. This disease can affect white race people in compare to other race. Multiple sclerosis affects Asian, Africanand Hipic people rarely.

Different people face different symptoms it depends on how myelin or axon is damaged thus the symptoms differs from person to person. If a symptom gets more worse it is known as relapse it is not predictable and the symptoms will last minimum for twenty four hours. If the symptoms aren’t seen or gets vanished it is known as remissions. Some common symptoms of this disease are-

Feeling weak- Weakness is the common symptoms in multiple sclerosis, many people face this more time.

Muscular spasms- This is also known as spasticity, in this symptom contraction occur in muscle.

Blurred or double vision- Nerve that controls eye movement is damaged in this symptom. Due to this full range of movement can’t be covered and double vision occurs.

Slurred speech- This is known as dysarthria, in this nerve which controls muscles linked with speaking gets decreased and the patient gets problem related to the speech.

Tremor: In this shaking occurs various part of the body and they aren’t controllable. This is caused by the damage to the different part of the nerve pathways which helps in movement and co-ordination.

Problem related with emotional- People face different problems related with emotion such as depression and anxiety.

Pain- this is divided into two types they are

Neuropathic pain-Nerve fibre gets damaged in this type of pain.

Musculoskeletal pain- Pain occurs in muscle.

Ataxia: Patient can’t control voluntary muscle movement they feel difficult to control the movement. Person feels weak when walking and difficult to manage balance when standing.

Bladder and bowel problems: In this patient face the problem related with overactive bladder or underactive bladder.

Constipation or urgency is the problem connected with the bowel.

Cognitive problem: This is related with the thinking process, patients feel problem with remembering and learning any skilled work.

As many people feel pain due to this disease, use of painkillers would be great help for the people suffering from this disease. If pain occurs due to damage in the nerve fibre then it is known as neuropathic pain. Medicine such as Gabapentin, Pregabalin, Amitriptyline, Imipramine and carbamazepine can be used to treat neuropathic pain.

Gabapentin: Dose for neuropathic pain for adult over 18 years –

300 mg once a day on 1st day and 300 mg twice a day on 2nd day and then 300 mg 3 times daily on 3rd day can be given at the difference of every 8 hours, or 300 mg 3 times daily can be given on 1st day initially, the dose can be increased according to response in steps of 300mg daily (in 3 divided dose) every 2-3 days to max 3.6 gm daily. It is administered orally.

Side effects of this medicine are feeling mouth dry, inflammation of gum, feeling burning like sensation in the mouth, dysarthria (difficult in articulation), nystagmus (involuntary eye movement), tremor, hepatitis, urinary incontinence, ataxia, fatigue, dizziness, blood glucose fluctuations in patients with diabetes, acute renal failure and alopecia (loss of hair).

Gabapentin works by increasing the level of GABA (Gamma Amino Butyric Acid) in the brain and inhibit the Central Nervous System.

Pregablin: Dose for neuropathic pain for the adult over 18 years, 150 mg is given initially in 2-3 divided doses, it can be increased to maximum after 7 days that is 600 mg daily in 2-3 divided doses. It is administered orally.

Side effects of this medicine includes dry mouth, constipation, nausea, vomiting, dizziness, euphoria, thrombocytopenia, swelling in joint, menstrual disturbances, pain in the breast, pancreatitis, change in sexual function and flatulence.

It also works by increasing the level of GABA (Gamma Amino Butyric Acid) in the brain and inhibit the Central Nervous System.

Amytriptyline: for the patient suffering from neuropathic pain initially ( 10- 25) mg daily at night it should be increased to 75 mg daily if necessary, higher dose should be administered under the supervision of specialist. It is administered orally.

Side effects of Amytriptyline are as dry mouth, sedation, vision becomes unclear, constipation, nausea, difficulty in urination, tachycardia and arrhythmias

It works by inhibiting the neuronal reuptake of nor adrenaline in the Central Nervous System; it also inhibits the reuptake of serotonin (5-HT). Prevention of the reuptake of this monoamine neurotransmitter cause to increase nerve impulse outside the brain cells thus increasing the availability of monoamines in the brain inhibits the depression.

Co-codamol 30/500- this is an analgesic medicine this contains 30 mg codeine phosphate and 500 mg paracetamol it is used for severe pain.

Codeine within it binds to the opioid receptors in the Central Nervous System and there is response to painful stimuli and the severity of pain is decreased.

Paracetamol works by inhibiting the prostaglandin synthesis which stimulates pain in the body. Patients feel less pain when prostaglandin synthesis is inhibited.

Dose: 1-2 tablets every 4 hours, maximum 8 tablets daily.

Side effects: feeling dizzy, headache, mouth become dry, feeling pain while urinating, nausea, cramps in the stomach, sore throat

It is administered orally.

Carbamazepine: It is used to treat trigeminal neuralgia the pain in the regions of face. Trigeminal nerve can be found in three areas of the face they are the forehead, cheek and the jaw.

Dose of carbamazepine: initially 100 mg 1-2 times daily should be increased according to response. Usual dose 200 mg 3-4 times daily, up to 1.6 g daily.

Side effects: diplopia, constipation or diarrhoea, anorexia, fever, oedema, arthralgia, leucopoenia, hepatitis, Jaundice, depression, headache, drowsiness

It is administered orally.

Sometimes pain occurs in the body due to stiffness and muscle spasms pain caused by this is known as musculoskeletal pain. For the treatment caused by pain in muscle medicine such as Baclofen, Dantrolene can be used as they are muscle relaxant medicine.

Baclofen: The dose of Baclofen is 5 mg 3 times daily with or after food, it can be increased gradually maximum 100 mg daily (it should be discontinued if benefit is not seen after 6 weeks).

Side effects: dry mouth, hypotension, respiratory or cardiovascular depression, sedation, drowsiness, hallucinations, nightmare, urinary disturbance, nystagmus, abdominal pain and insomnia.

It acts in the spinal cord and reduces nerve impulse from spinal cord to skeletal muscle. As there is decrease in the severity of muscle spasm; due to decrease in the spasms pain is also reduced.

Dantrloene: Dantrolene show its action directly on the muscle, so it is known as direct acting muscle relaxant. It blocks the release of calcium ion from sarcoplasmic reticulum (it is the muscle where calcium is released and stored and it causes muscle to contract and relax.) As the release of calcium ion is blocked contraction of muscle won’t occur.

Dose: Initially 25 mg daily and it may be increased at weekly intervals to max 100 mg 4 times daily; usual dose is 75 mg 3 times daily.

It is administered orally.

Side effects: drowsiness, fatigue, weakness, fatigue, bradycardia, confusion, abdominal pain, nervousness, increased urinary frequency, respiratory depression, fever and disturbance in the visual.

Steroids are the hormone and it occurs naturally in the human beings body. Steroids suppress the immune system of the body and inflammation is reduced in the Central Nervous system. Due to this immune system within the body can’t damage myelin sheath which covers neurons and protect it. Steroids with high dose are prescribed because it increases up the improvement from a relapse. Some commonly used steroids are as follows

Prednisolone: It is given orally initially up to 10-20 mg daily

Methylprednisolone: Orally it is given 2-40 mg daily

By infusion it is given up to 1gm daily for 3 days.

Dexamethasone: Orally it is given usual range of 0.5-10 mg daily for the adult, for the child 10-100 mg/kg daily

Different problem can be seen if a steroid is used for long term, problem such as

Thinning of the skin,

Osteoporosis,

Blood pressure gets increased this can make the condition of diabetes patient make worse

Change in the mood,

Increased in the weight,

Patients feel the taste of metallic in the mouth,

Increased in heart beat,

Ankles gets swollen,

Women will face the problem of irregular menstruation,

Change in sleep style occurs,

Stomach gets upset,

Delay in healing of the wound,

There is more chance of suffering from infections,

Changes occur in the colour of the skin

These can be reduced by carrying some activities in the life such as –

As higher strength drug can cause different problem it should be told to the doctor by the patient so that doctor can prescribe medicine with low dose.

Corticosteroid can be taken alternatively so that there is no need of taking daily, prescriber can prescribe medication which can be used for short time.

As this medication causes increase in weight patient should carry out some exercise daily, patient can deduct the amount of calories they are having and thus change in eating habits.

Osteoporosis is also one of the problems related to the long term use of corticosteroids, patient can take food rich in calcium or vitamin D and they can also have the supplement of calcium or vitamin D so that the bone will be stronger. Prescriber can prescribe the medicine which contains Bisphosphonates such as Alendronic acid it reduces the rate of turnover of the bone which can be the treatment for osteoporosis.

Different symptoms occur in the body due to this disease symptom such as

Overactive bladder- to overcome this problem oxybutynin or toltrerodine can be used. As it is anticholinergic drug, it blocks the release of acetylcholine and the relaxation of smooth muscle of the bladder occurs then the patient won’t have the problem of urinary incontinence.

Urine retention: Patients suffering from urine retention are catheterised normally.

Fatigue and depression- This is also one of the leading problem that the patient of multiple sclerosis are facing.

Medicine such as fluoxetine which is an antidepressant helps in managing the fatigue. As it is antidepressant it blocks up the reuptake of serotonin and raises its level outside the nerve ending. As the level is increased there won’t be any depression and the patient feel excitement which also leads patient to be active and get rid from fatigue.

Sertraline is also given for the patient suffering from mild anxiety it also works by blocking reuptake of serotonin.

Sleep disorder: Modafinal is used to treat the pattern of sleep disorder it also reduces the fatigue. It increases the level of dopamine and norepinephrine by blocking the reuptake of dopamine and by inhibiting the enzyme MAO (Mono Amino Oxidase). This is enzyme it metabolizes neurotransmitters such as dopamine; serotonin and norepinephrine as this medicine inhibit the enzyme MAO, level of serotonin, dopamine and norepinephrine won’t decrease in the body. This leads patient to be free from depression, which then help patient to get rid of excessive sleepiness.

Sexual problem: As neurons get damaged in multiple sclerosis, sexual function gets affected because nerve which send message to the sexual organs don’t function properly and different problems related to sex starts to arise. About 70% women and 90% get affected due to the multiple sclerosis.

For the men

An oral medication Viagra is used, it helps to maintain erection.

Medicine which can be injected: It is injected into the base of the penis and blood flow is increased during sexual intercourse and helps to maintain erection.

Medicine related to relaxant of muscle and pain: It can also be used to treat spasms as well as the pain that occurs during the period of sexual contact.

For the women

Orally Viagra is also given to women.

Vaginal lubricants helps women to get rid from vaginal dryness, this can be bought over the counter such as K-Y jelly.

Constipation: To get rid from the constipation medicine which helps to make the stool softener such as senokot can be used, laxative can also be used.

Vertigo: Medicine such as Prochlorperazine can be used to treat vertigo in multiple sclerosis. As it is anti-emetic it prevents the nausea and vomiting.

Multiple sclerosis can be managed without the medicine as well. Doing regular exercise is beneficial to the people suffering from multiple sclerosis. Spasticity of muscle can be reduced by stretching the muscle and doing different type of exercise. Aerobic exercise such as swimming in cool water, brisk walk helps to reduce fatigue in the people suffering from multiple sclerosis. This exercise helps to get the blood pumping through the heart and it increases pulse and respiration. Having the herbal medicine such as St John’s Wort is also beneficial to the people suffering from multiple sclerosis, this is natural antidepressant. It increases the action of serotonin level in nerve pathways it also inhibits the enzymes which increases depression it also helps to maintain good immune system as it has got anti-inflammatory as well as antiviral properties it helps to the people suffering from multiple sclerosis. Infection of urinary tract can increase the relapse in multiple sclerosis so having cranberry juice would be beneficial. As people suffer from stress in multiple sclerosis it can be reduced by doing the exercise which helps us to relax. Patient should try to be comfortable by slowing down the breathe and inhaling through the nose slowly.

Patient suffering from multiple sclerosis should try to maintain healthy eating habits such as.

They should have 2 litres of water per day, having appropriate amount of green vegetables, drinks which contain caffeine such as coffee, tea etc should be avoided because it increases fatigue in the patient, red meat also should be avoided because it aggravate inflammation. Saturated fats should be avoided by the patient such as cream, margarine because it may increase the symptoms of multiple sclerosis and unsaturated fats such as olives, cornflower oil, sunflower oil and rapeseed oil can be taken by the patient. As people suffer from constipation during the multiple sclerosis, taking the food which is rich in fibre would be beneficial for them.

Disease modifying treatments are also known as immune modulating medications; it changes the activity of the immune system. It reduces the occurrence and severity of relapses as well as it prevents people from being disabled. Different types of drugs were introduced from the research such as-

Interferon beta-1a,

Interferon beta- 1b,

Glatiramer Acetate,

Natalizumb

Where, interferon beta- 1a, 1b aren’t newly modified drug whereas Natalizumb is newly modified drug it was accepted in June 2006.

Interferon beta is used in patients with relapsing, remitting multiple sclerosis. It has been used in a patient who has been suffering from active inflammatory process leading to single demyelinating. It blocks the entry of the harmful immune cells to the blood brain barrier so that harmful immune cells can’t damage the myelin sheath thus it helps to improve the function of the immune system. It is a protein and it occurs in a natural way in the body. It reduces inflammation as well as autoimmune reaction, reduction of this result in stopping of destruction of myelin.

Glatiramer acetate: It is lab made medicine and is the mixture of amino acid (small component of protein). It is used for treating relapsing remitting multiple sclerosis. It stops the entry of T cells that damage the myelin to improve thus reduces the chance of inflammation and protects the sheath of myelin which covers nerve fibres. It is injected under the skin daily.

Natalizumab: This is also disease modifying medicine and it was accepted by the European Union in June 2006. It reduces the inflammation and demyelination by stopping the migration of leucocytes into the central nervous system. It is used in the treatment of relapsing remitting multiple sclerosis. While receiving the treatment it should be supervised by the specialist.

As different research has been carried( under the experiment) out to introduce new disease modified drug some of them are as follows-

Gilenya (Fingolimod).

It is used in those patients who have been suffering from active relapsing-remitting multiple sclerosis and the use of Interferon Beta wasn’t successful. It is taken one capsule once a day, active ingredient within it is fingolimod 0.5 mg.

According to research about 52% patients were recovered from relapse by the use of this medicine incomparision to the patient who are receiving interferon beta.

This medicine works by retaining the lymphocytes in the lymph nodes, in this way the lymphocytes which cause an inflammation can’t reach to the central nervous system and myelin sheath doesn’t separated from myelin.

Cladribine

It is administered orally dosage form is tablet and is undergoing final phase trial iii. According to research by comparing patient taking cladribine and placebo, patient receiving cladribine for a period of two year relapse was reduced by 60% and the patient taking this medicine for more than three months development of disability was reduced by 30%. As this medicine is administered between 8 to 10 days in a year patient can get rid from getting injection as well as intravenous infusion regularly. This medicine wasn’t approved by the European Drug Regulator in September 2010, so this medicine is under the clinical trial it is thought that it would be available by 2012.

This medicine reduces the amount of harmful immune cells getting into the blood, so they can’t reach to the myelin sheath and myelin sheath gets protected.

Liquinimod:

This medicine is under the research for the treatment of patient suffering from relapsing remitting multiple sclerosis. This medicine regulates the entry of harmful immune cells into the central nervous system (brain and spinal cord). It is administered orally dosage form is tablets.

According to clinical trial phase ii this medicine decreases the disease by 30% when the patients were treated with this medicine for more than 6 months and the patient who are at the initial stage of this disease they get it reduced by 40%. Research on second phase iii is still ongoing.

Teriflunomide: According to research 179 people were taken in the clinical trial phase ii it was for more than 36 weeks. A drug with 2 different strength that is 7mg and 14 mg were considered and was compared with placebo. Result shows that higher dose helps to reduce relapse by 67% and lower dose reduce the symptoms by 39%.

Studies related to phase iii shows that it is comparing the benefit of this medicine in relapsing multiple sclerosis in compared to placebo and interferon beta 1a.

As lymphocytes damage myelin sheath and cause multiple sclerosis. This medicine inhibits the division of this cell rapidly and it can’t reach to the blood and inflammation wouldn’t occur.

It is administered orally as a tablet.

BG-12:

This medicine was compared to placebo in those patients suffering from relapsing remittig multiple sclerosis. The study was carried for more than 24 weeks and the data shows that relapse rate was reduced by 32% but it wasn’t considered significant and it is under the experiment phase iii.

It is taken orally as tablets and two or three times a day.

Reference:

Online References:

www.mult-sclerosis.org/howms.html

www.netdoctor.co.uk

www.nhs.uk

www.mstrust.org.uk

www.ukmi.nhs.uk

Book refrences

Flinton Christine C raggs(2006) living with multiple sclerosis, London, Sheldon press.

Sctt N William and Mc Grath Deirdre (2009), made Incredibly Nursing Pharmacology

Martin John (2009) BNF, 57th edition, London, Royal Pharmaceutical Society.