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Brain Farts
Solidsquid
Okay, I have some old Q&As over brain development, anatomy and physiology. So I figured I’d share that knowledge here with any interested. If anyone wants to know a bit more about what is posted, just let me know and I’ll do what I can to further explain things.

Describe the involvement of axon growth and guidance, target selection or apoptosis in a clinical condition, citing relevant literature.


Apoptosis is Greek which means, “falling from” or “falling away” and is defined by Wolf and Green (2002) as “a conserved cellular suicide program that eradicates excess or potentially dangerous cells”. This necessary program for suicide in cells can also contribute to the progression of some diseases and disorders. One particular disease in which this has become a salient point is Alzheimer’s disease, amongst a list of other disorders and diseases (Chamond, Anon, Aguilar and Pasadas, 1999).

Detection of cell cycle proteins have been found in human and rat models of Alzheimer’s in several studies (Guo et al., 1998; Gibson, 2001). It has also been substantiated through detection of DNA replication that an ectopic cell cycle is involved which precedes neuronal death (Yang et al., 2001; Herrup et al., 2004) which can lead to apoptosis. The pattern of the cell death itself occurs in such a fashion that it is consistent with apoptosis due to the fact that the cells do not lie together but individually (Siegel et al., 2006).

For apoptotic cell death, one would expect to find apoptotic proteins increased – which is exactly what has been found. Guo et al. showd that the Par-4 (Prostate Apoptosis Response-4) protein expression is increased in neurons that are “vulnerable”. Later, Guo et al. (2001) showed that their earlier findings to be substantiated. They found that Par-4 increases the secretion of the amyloid β peptide 42 via a caspase-dependent pathway. It was found that inhibition of caspase activity by a broad spectrum inhibitor weakened the Par-4 induced peptide production. Also, implicated is p53 (Cellular tumor antigen p53) protein which is involved in regulation of the cell cycle, DNA repair and can initiate apoptosis. Ohyagi et al. (2005) found that Aβ 42 activates the p53 promoter subsequently leading to p53 induced apoptosis. All these activities interact within the brain of Alzheimer’s patients – specifically the hippocampus to produce the cognitive deficits we see as a result and “support a role for apoptosis” (Siegel et al., 2006).

References

Chamond, R., Anon, J., Aguilar, C. and Pasadas, F. (1999). Apoptosis and disease. Alergologia e Immunologia Clinica, 14, 367-374.

Gibson, R. (2001). Does apoptosis have a role in neurodegeneration? British Medical Journal, 322, 1539-1540.

Guo, Q., Fu, W., Xie, J., Luo, H., Sells, S., Geddes, J. et al. (1998). Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nature Medicine, 4, 957-962.

Guo, Q., Xie, J., Chang, X. and Du, H. (2001). Prostate apoptosis response-4 enhances secretion of amyloid β peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway. Journal of Biological Chemistry, 276, 16040-16044.

Herrup, K., Neve, R., Ackerman, S. and Copani, A. (2004). Divide and die: Cell cycle events as triggers of nerve cell death. Journal of Neuroscience, 24, 9232-9239.

Ohyagi, Y., Asahara, H., Chui, D., Tsuruta, Y., Sakae, N., Miyoshi, K. et al. (2005). Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB Journal, 19, 255-257.

Siegel, G., Albers, R., Brady, S. and Price, D. (2006). Basic Neurochemistry: Molecular, Cellular and Medical Aspects. (7th ed.). London: Elsevier Academic Press.

Wolf, B. and Green, D. (2002). Apoptosis: Letting slip the dogs of war. Current Biology, 12, R177-R179.

Yang, Y., Geldmacher, D. and Herrup, K. (2001). DNA replication precedes neuronal cell death in Alzheimer’s disease. Journal of Neuroscience, 21, 2661-2668.


More to come later, I promise!
 
Skeeve
I had forgotten how easy it was for solidsquid to give me a headache. Wink
"The world is my country, and do good is my religion." - Thomas Paine
 
seeker
I see how this describes a mechanism that would contribute to some diseases but is this a symptom of the disease or a cause of the disease
 
Hypatia
Since my husband and I take care of his 92 year old mother, who has Alzheimer's disease, I'm somewhat familiar with amyloid peptides, and maybe another thing or two from the article (doesn't mean I understand it well though), but otherwise I'm sharing in Skeeve's headache.

But I'll try to keep up, because it's interesting none the less.

 
Solidsquid
seeker wrote:
I see how this describes a mechanism that would contribute to some diseases but is this a symptom of the disease or a cause of the disease


That's one of the questions that's being attempted to be answered - is the ectopic cell cycling a consequence of the disease or a contributor? Some lean toward it being a contributor to the disease and others think it may be a consequence. Only further research may be able to answer that question and give us 50 more to answer. Such is the nature of science.
Edited by Solidsquid on 08/18/2008 14:14
 
seeker
That's kind of what I thought, we can see the process but really don't know what stage of the process we are seeing.
 
Hypatia
Solidsquid wrote:
seeker wrote:
I see how this describes a mechanism that would contribute to some diseases but is this a symptom of the disease or a cause of the disease


That's one of the questions that's being attempted to be answered - is the ectopic cell cycling a consequence of the disease or a contributor? Some lean toward it being a contributor to the disease and others think it may be a consequence. Only further research may be able to answer that question and give us 50 more to answer. Such is the nature of science.


Oy. Ain't that the truth. We've come so far, yet we're still so far away.
 
Solidsquid
Some more for everyone's reading pleasure:

How do researchers determine if a region of tissue is specified to become a particular cell type? Describe 3 different approaches.


Researchers utilize several methods for determining if tissue will be a specific cell type. One way researchers can determine what a tissue is fated to become is through the use of cell cultures. A progenitor cell is placed in isolation in a culture dish and different signal molecules are utilized to determine how they influence the fate of that progenitor cell (Sanes et al., 2006). Mouse embryonic stem cells (ES) have been utilized in cultures to examine differentiations through this method. As an example, Watt (1991) describes using mouse ES to examine the regulation of differentiation by exogenous signals (pp. 288). Watt describes also having the ability to introduce genes into the cells or to knock specific genes in order to examine the impact they will have upon the cell.

Another technique is transplantation of cells. One example given by Sanes et al. (2006) is the work of Le Douarin in transplanting neural crest cells between a chick and a quail. The work showed how environmental context played a role in the differentiation of the cells. Cells which usually form specifically in one area of the quail adopted the fate of the new environment in the chick and vice-versa. This is not a phenomenon restricted to the nervous system either as was shown in work done transplanting pancreatic progenitor cells into the liver of a rat. The work done by Dabeva et al. (1997) showed that the pancreatic cells transplanted into the liver differentiated into hepatocytes, experessed liver proteins and were fully integrated into the environment (pp. 7356). The evidence tells us that environmental context is of great importance in cell differentiation.

A third technique is the use of genetic screening models. Two options are available in so far as method is concerned forward and reverse genetic screening. Reverse screening involves the use of knockout models to knockout or overexpress particular genes (Sanes et al., 2006). This allows researchers to create mice that may lack a particular gene or have an over-expression thereof. Newer methods are currently being developed in utilizing RNA interference to silence genes (Lykke-Anderson, 2006). This is what is termed reverse genetics. Forward genetics would involve the induction of mutation to identify new genes. An example of how this works I breeding of mice which express mutant alleles of particular genes. Utilizing such a technique Garcia-Garcia et al. (2005) were able to identify 38 mutations which had not previously shown to affect embryonic development (pp. 5916).

References:

Dabeva, M., Hwang, S., Vasa, S., Hurston, E., Novikoff, P., Hixson, D. et al. (1997). Differentiation of pancreatic epithelial progenitor cells into hepatocytes following transplantation into rat liver. Proceedings of the National Academy of Sciences, 94, 7356-7361.

Garcia-Garcia, M., Eggenschwiler, J., Caspary, T., Alcorn, H., Wyler, M., Huangfu, D. et al. (2005). Analysis of mouse embryonic patterning and morphogenesis by forward genetics. Proceedings of the National Academy of Sciences, 102, 5913-5919.

Lykkes-Anderson, K. (2006). Regulation of gene expression in mouse embryos and its embryonic cells through RNAi. Molecular Biotechnology, 34, 271-278.

Sanes, D., Reh, T., and Harris, W. (2006). Development of the Nervous System. (2nd ed.). London: Elsevier Academic Press.

Watt, F. (1991). Cell culture models of differentiation. The FASEB Journal, 5, 287-294.
 
Solidsquid
Tourettes Syndrome: An Overview of Etiology and Treatments

In 1825, the first case of what was to be called Tourette's Syndrome was reported by French physician Jean Marc Gaspard Itard. Itard reported the case of an aristocrat woman named Marquise de Dampierre. Dampierre sufferred from childhood until her death in 1884 and exhibited convulsive tics and cursing called coprolalia. The name the disorder carries, however, is that of Georges Albert douard Brutus Gilles de la Tourette who reported a case of nine individuals in 1885. It was the physician Jean-Martin Charcot who suggested that the syndrome carry Tourettes name. Although it carries Tourettes name, the description of the primary symptoms of Tourette's Syndrome is thought to go back to the 15th century and found in the Malleus Malefacarum, a treatise on witchcraft (Martin, 2002). The passage referred to describes the case of a priest who is thought to be possessed:

when he passed any church, and genuflected in honour of the Glorious Virgin, the devil made him thrust his tongue far out of his mouth; and when he was asked whether he could not restrain himself from doing this, he answered: I cannot help myself at all, for so he uses all my limbs and organs, my neck, my tongue, and my lungs, whenever he pleases, causing me to speak or to cry out; and I hear the words as if they were spoken by myself, but I am altogether unable to restrain them; and when I try to engage in prayer he attacks me more violently, thrusting out my tongue. (Kramer and Sprenger, 1486/1971, pp. 131)


The syndrome is also referred to as Tourette's disorder, Gilles de la Tourette syndrome and abbreviated as either TS or GTS. TS is considered a neurological disorder with a strong biological components contrary to some early etiological speculations that it arose as the result of deep psychological problems or emotional conflicts (De Lange, Oliver and Meyer, 2003).

TS is characterized by what are referred to as tics. The diagnosis of TS must meet several criteria. Those criteria are: multiple motor tics and one or more vocal tics which must occur many times a day for more than one year and not disappear for longer than 3 consecutive months. They may be present many times a day and persist everyday or intermittently for longer than one year (APA, 2000). Motor tics might include or take the form of simple tics which are brief, rapid movements involving only one muscle group. Complex motor tics are sudden and involve more coordinated movements or a cluster of muscle group such as hitting, biting, smelling, jumping et cetera. Other criteria include an onset of the disorder before age 18 and tics that are not due to direct physiological effects of substance abuse or a general medical condition such as Huntingtons disease or post viral encephalitis. The disorder usually begins in childhood between the ages of 3 and 8 (Leckman, 2002).

Tourettes is often accompanied by secondary clinical features such as scholastic problems, anxiety attacks, depression, alcoholism, phobias, sleeping disturbances, and stuttering. It is also not uncommon to be found co-morbid with other clinical disorders such as ADHD and OCD (De Lange et al., 2003). Tourettes is estimated to occur in 10 out of every 1000 children and adolescents and is more common in males. The most commonly thought of aspect of Tourettes is coprolalia (involuntary cursing or speaking of obscene words) but is only seen in a small percentage (about 10%) of Tourettes cases (Singer, 2005).

The causative agents for TS have been under much scrutiny over the past several decades. With advances in neuroscience and neurology, much has been learned yet it also gives rise to many more questions. This disorder once thought of as rare might still turn out to be largely undiagnosed among the population today (Leckman, 2002).

Tourettes has been shown to manifest in several specific brain regions. The most focused on area is the basal ganglia for its role in the control of movement and participation in habit formation (Albin and Mink, 2006). The basal ganglia includes the striatum, putamen, caudate nucleus, nucleus accumbens, substantia nigra and subthalamic nuclei. It receives input primarily from the cortex and sends output to the brainstem via the thalamus and is in large portion governed by the motor areas of the prefrontal cortex (Martin, 1996; Kandel, Schwartz and Jessell, 2000). Imaging of anatomical areas has shown mixed results. Albin and Mink (2006) chalk these variable results up to problems such a small studies, mixing of adults and children, mixing of TS only with co-morbid individuals et cetera.

In investigating the clinical characteristics of TS, Chang et al. (2004) studied a group of adolescents in Taiwan with a mean age of 14.6 years. Utilizing a four part questionnaire consisting of a self report demographic form, the Family APGAR, Symptom Checklist-90-R and a Tic Symptoms questionnaire, they measured the tic symptoms of two groups one younger than 15 years and one 15 years and older. Their findings indicated "less impact of TS symptoms on the psychopathology as patients matured, or as tic symptoms declined around young adulthood" (p. 356).

The findings of Chang et al. allude to a possible developmental situation in which maturity seems to curtail the symptoms. One possible explanation for this is put forth by Plessen et al. (2004). Their research focused on the corpus collosum citing findings which report that "the corpus collosum helps to support the lateralization of brain function by segregating and integrating function across the cerebral hemispheres, disturbances in corpus collosum morphology have been postulated to contribute to the presumed aberrant cerebral lateralization in subjects with Tourette's disorder" (p. 2028). Their study included 158 subjects with TS and 121 control subjects for comparison. Using MRI scans and analysis, they found that the younger individuals with TS had smaller corpus collosums compared to the controls. However, larger corpus collosum sizes were found in adults with TS. Although the adults in this study were "highly symptomatic" and could interfere with interpretations since tic symptoms tend to improve as a person grows into young adulthood. However, the morphology of the corpus collosum is thought to not be a causative agent of tics but a consequence of a mediation effect. The sizes of the corpus collosums of the subject correlated inversely with the size of prefrontal regions and positively with premotor regions in both the TS and control groups. This has led the team to reason that "the size of the anterior corpus collosum and the volumes of prefrontal cortices may represent compensatory responses that help to attenuate the severity of tic symptoms" (p. 2034). The team concluded that the smaller size of the corpus collosum in subject with TS is a response to tics and may enhance prefrontal function to better control tic behaviors because of the reduced "interhemispheric inhibition of prefrontal control" (p. 2035).

Findings pointing to problems of the executive function were also found by Channon et al. (2003). Their study consisted of twenty-nine participants who met the criteria for TS as outlined by the DSM-IV-TR. The ages ranged from 9 to 18 years. While the study found no impairment in aspects of memory and learning, their TS-alone group (a group that did not have a co-morbid diagnosis) show impairment on the Hayling test which was utilized to assess inhibition. This study shows that deficits in the executive function of the prefrontal cortices and lends credence to view that TS "is associated with basal ganglia abnormalities leading to disruption of dopaminergic fronto-subcortical circuits" (p. 252).

Genetic components have been alluded to through twin studies finding a high correlation between monozygotic twins showing an 86% condcordance in monozygotic twins as opposed to only 20% in dizygotic twins (Martin, 1996). The specific gene or genes is still not known but some paths for further research have been found. A study of 108 extended families of patients diagnosed with TS was analyzed using a variant of the S.A.G.E. program concluded that pattern of TS in the data sample was not consistent with Mendelian inheritance (Seuchter et al., 2000). Genetic linkage studies, however, have implicated several chromosomes and loci including Chromosomes 2, 4, 5, 7, 8, 10, 11, 13, 17, and 19 with variable loci proposed in different studies (Singer, 2005). Also, Cuker et al. (2004) reported the case of a 14 year old female co-morbid for TS and OCD with no familial history of the disorders. They found a translocation between chromosomes 2 and 18. This coincides with the implication of previous studies of the same area on chromosome 18.

Lit et al. (2007) utilized genomic of peripheral blood to investigate genetic components involved in TS. They tested 32 participants with familial TS and matched against controls with headache, neurofibromitosis, Parkinsons Disease, pediatric epilepsy, and a healthy individual. Their results implicated gene expression profiles for 14 genes including the Natural Killer cell cytotoxic response, antigen presentation, and immune response.

Abelson et al. (2005) found an allele of SLITRK1 (Slit and Trk-like 1 gene) to be implicated in TS. The allele they investigated is a mutant form created by a truncating frame-shift mutation. A patient was identified who presented with TS and ADHD he was carrying a de novo chromosome 13 inversion. 174 individuals were then screened, looking at SLITRK1. Only one proband exhibited a mutant SLITRK1 form a base deletion leading to a frame-shift mutation and was also found in the patients mother who suffered from Trichotillomania (TTM) - TTM being an impulse control disorder with the urge to rip out body hair. A certain sequence variant (var321) was found in two non-related individuals with TS and OCD and not found in any of their 4296 control chromosomes nor was the mutant SLITRK1 found in any of 3600 control chromosomes. The implication for this mutation and variation are suggested to promote dendritic growth and the frameshift may result in the loss of function. The slit gene produces a protein that is important for axon growth during development in vertebrates. The slit protein secreted by glial cells and aids in cell migration, axonal guidance and axonal branching (Brose et al., 1999; Grados and Walkup, 2006). Trk encodes a receptor for NGF (nerve growth factor) (Cordon-Cardo et al., 1991). The SLITRK family is homologous to SLIT and TRK and is known to modulate neurite development and is expressed in areas such as the putamen, globus pallidus and thalamus. (Aruga, Yokota, and Mikoshiba, 2003). While the mutant SLITRK1 gene is not the sole cause of TS, it provides a reference point for further research. As Grados et al. (2006) note, rare mutations in small subsets of patients with complex disorders can identify pathways for disease pathogenesis (pp. 292).

Genes for various dopamine receptors, the dopamine transporter as well as serotonergic and noradrenergic genes have been focused on. Several studies have identified dysfuntion in dopaminergic receptors and transporters in TS. The role of dopamine in the control of motor movements is an obvious starting point since its implications are heavy in diseases such as Parkinsons which is the result of a loss of dopamine-secreting cells within the basal ganglia.

A 2004 study by Diaz-Anzaldua et al. found several genes implicated in TS from samples of 110 unrelated patients. The D4 receptor gene was found to have a 7 repeat allele in patients with TS which showed a specific linkage to TS. The number of repeats in the polymorphism affects the amino acid sequence and the structure of the receptor. MAO-A was also implicated where two common haplotypes were observed in the mothers of TS patients. However, the preferential transmission of one particular haplotype is considered to confer high activity. High activity of MAO-A would lead to a high rate of degradation of dopamine. DRD3 and DRD2 were examined and implicated as contributors as well, especially urging focus on the DRD2 since it is the target for neuroleptic drugs.

Diaz-Anzaldua et al. (2004b), based upon previous genetic work, focused on chromosome 7 for a gene which lends to a predisposition to TS. The participants were 258 individuals from a French Canadian population. TS was associated with two markers at the 7q31 region. The highest associated marker was located closely to IMMP2L (inner mitochondrial membrane peptidase 2 like) gene.

Dopamine alterations in D3 receptors have been implicated. Schirmer, Nobrega, Harrison, and Loscher (2007) described a circling rat (ci) which displayed abnormal lateralized circling behavior. Circling rats are prone to bursts of circling behavior and locomotor hyperactivity a proposed animal model for TS. This circling rat was discovered in normal litter. The mutant was bred to produce 14 males and 11 female ci3 rats. The mutant rats have behavioral similarities to mutant mice lacking functional D3 receptors in that both are hyperactive, particularly in novel environments. In the mutant, a decrease in dopamine D3 receptor binding was found in the islands of Calleja (a small groups of cells located in the basal forebrain and contain many D3 receptors) and the shell region of the nucleus accumbens. Although the differences were small, they were still statistically significant.

Dopamine transporter genes and their proteins have been looked at as well. Dopamine transporters are proteins which are responsible for the reuptake of dopamine from the synapse. Rowe et al. (1998) and Yoon et al. (2006) both focused on polymorphisms in the DAT1 gene in association with TS. It was found that the VNTR polymorphism, specifically a 10 repeat allele, was associated with TS as well as other internalizing disorders such as OCD and generalized anxiety. The DAT1 Ddel polymorphism was implicated in TS without ADHD. The Ddel mutation is generally regarded as silent.

Muller-Vahl et al. (2000) focused on D2 receptor binding (in the striatal-to-frontal cortex) in an imaging study to test the hypothesis that TS is related to change in receptor binding capacity. The study did not find any support for the variable binding hypothesis which claims that spontaneous recovery of tics in adulthood is due to the diminished binding capacity of postsynaptic D2 receptors. However, the study did find that the results, fit the assumption that TS is associated with an increased dopamine transporter activity.

Gilbert et al. (2006) also focused on D2 receptor binding but in extrastriatal structures such as the orbitofrontal cortex and the hippocampus. Reduced D2 binding was found in all areas in the TS patient compared to the controls. However, the sample size was small and focused only on adult males.

Minzer et al. (2004) examined postmortem frontal cortex and striatum of patient who had TS. Of note are the higher densities of DAT and D2 receptors as well as higher norepinephrine in the prefrontal cortex which was not a predicted outcome.

Ozbay et al. (2006) examined the role of Dopamine Beta Hydroxylase in TS. They examined 71 nuclear families and 5 multi-generational families from two samples originating in Canada and Turkey. The focus was on the DBH (dopamine beta hydroxylase) gene. There was no evidence found for any linkage to TS. However, in the Turkish sample, a linkage was found involving a 19 bp marker for an indel (insertion/deletion). Yet the finding may be the result of a false positive finding, the authors admit. They concluded that they could not find any significant linkage between polymorphisms in the DBH gene and TS.

Some studies have evidence a role for serotonin in TS. Some research has found lower levels of 5-HT and its metabolites in sub-cortical areas of patients with TS (Cavallini, Di Bella, Catalano and Bellodi, 2000). Therefore Cavallini et al. set out to focus on the possible role of the serotonin transporter and its gene as well as COMT. TS is often found co-morbid with OCD and SSRIs are effective in treating OCD, thus the focus on the 5-HTT. COMT is an enzyme that inactivates adrenaline, noradrenaline as well as dopamine and levodopa which is implicated in Parkinsons. They studied 52 patients 30 male and 22 female of which 53.84% has a co-diagnosis of OCD. Genomic DNA was extracted from anti-coagulated blood to examine for polymorphisms in those genes. COMT showed no statistically significant deviation from that of controls. 5-HTTLPR also showed no statistically significant deviation from the controls. The authors conclude that although there was no link found, TS has been proposed by many to be a polygenic disorder and therefore there may still be a role played by 5-HT.

Muller-Vahl et al. (2005) decided to look at serotonin transporter binding in TS patients. Patients examined were 12 TS patients with varying degrees of OCB (obsessive-compulsive behavior) and 16 healthy controls using SPECT scans. All 12 TS patients were men. Ages range from 24-64. Of the TS patients two were taking SSRIs, two were taking dopamine blockers, two had combined therapy (SSRI, NL) and six were drug free for 5 months. Binding ratios for the SSRI free patients was lower than controls (2.770.18, range, 2.583.09, versus 3.150.30, range, 2.743.82, p = 0.003). Binding ratios for the patients on SSRIs was signficantly lower than the SSRI-free patients (2.480.17, range, 2.272.67, versus 2.77, p = 0.023) and the controls (2.48 versus 3.15, p = 0.0005). In the control patients, it was found that 5-HTT (or SERT) binding was negatively correlated with age and no difference was found between males and females. The authors conclude that serotonin can indeed play a role in TS especially when co-morbid with OCD or OCD-like behavior.

Streptococcal infection has also been proposed to play a role in TS. It is thought that an infection causes an immune response which damages parts of the brain. With this in mind Muller et al. (2000) examined the titers of two antibodies antistreptolysin (ASL) antiDNase B in children and adults. a unit of detection of the amount of antibodies in blood. ASL and antiDNase B are both antistrep antibodies. They examine two groups of TS patients one of children and adolescents (age range 9-15 years; 4 female, 9 male) and of adults (age range 21-55; 7 female, 16 male). A group of 17 schizophrenic patients was also included ( 9 male and 8 female). The TS child group showed higher titers of antistrep antibodies than controls and the adults showed higher titers of anitbodies than the controls or the schizophrenia comparison group. The authors conclude that this confirms a role for streptococcal infection in TS as this is in line with other streptococcal-associated autoimmune neuropsychiatric disorders (PANDAS). PANDAS is diagnosed according to several criteria the diagnosis of OCD or a tic disorder, pediatric onset, an episodic course of the symptom severity, association with a GABHS (Group A Beta-Hemolytic Streptococci) infection, and an association with neurobiological abnormalities. According to a review of the hypothesis by Kurlan and Kaplan (2004), PANDAS should be considered only as a yet-unproved hypothesis.
Such conclusions are in line with the findings of Singer et al. (2005). Singer et al. compared antineuronal antibodies in patients with TS and PANDAS to controls. 48 children fitting a PANDAS diagnosis 46 with TS were had single-point-in-time serum examined for antineuronal antibodies. The results did not find any significant differences between PANDAS, TS patients and controls lending further support to Kurlan and Kaplans conclusion.

Other findings have appeared in the research some anomalous and some needing further research for substantiation. Leckman et al. (2005) found increased serum levels of Interleukin-12 and Tumor Necrosis Factor-Alpha in patients with TS that was elevated significantly higher than age-matched controls. Interleukin-12 plays a role in the activity of lymphocytes and natural killer cells. Necrosis Factor Alpha is involved in inflammation as well as causing apoptosis it is the inflammatory response which is implicated in autoimmune disorders.
Other intriguing avenues for inquiry into the causative agents of TS have been reported. For example, a case study by Sedel et al. (2006) found an 18 year old patient who suffered from TS and was found to have two novel mutations on the β-Mannosidase gene which caused a deficiency in β-mannosidase activity. Beta Mannosidase is a lysosomal enzyme that plays a role in the last step of oligosaccharide breakdown. Its deficiency leads to the pathological accumulation of disaccharides composed of mannose and N-acetylglucosamine. Which in turn lead to various outcomes such as mental retardation and behavioral disturbances.

Cosentino and Torres (2000) reported a case of an 11 year old boy who met the criteria for a diagnosis of TS which also had neurofribomatosis type 1. An MRI revealed bilateral pallidal hyperintensities. The authors conclude (however call for more research to be done) that the TS might be a result of the NF-1 or simply a possible co-morbidity. A report by Kumar (2005) reported a similar finding in a 12 year old boy in India.
An interesting study reported by Kessler (2002) looked at body temperature dysregulation associated with TS. In this interesting study, Kessler studied 50 patients who met the DSM-IV criteria for TS, with an age range from 8 to 36 years. The group showed abnormal body temperatures, in both males and females. Their temperatures ranged from 33.3 C (91.94 F) to 37.9 C (100.2 F). In normal conditions and normal individuals there is only small amount of temperature fluctuation, however, the subjects with TS showed fluctuation values of up to 4.6 C where the normal fluctuation is about 0.5 C. One patient showed that their body temperature fluctuations predicted the severity of their tics. Because of the findings in body temperature, Kessler points to the involvement of the hypothalamus which regulates temperature perception and body temperature. Specifically he names the calcium channel activity and points to calcium channel antagonists which have shown to have beneficial effects for those with TS.
Kurup & Kurup (2002) focused on hypothalamic digoxin - a glycoside which has been shown to modulate neurotransmitter transport. Their study included 15 patients diagnosed with TS. A downregulation of the isoprenoid pathway, which synthesizes digoxin, was found. This leads to a decrease in the endogenous digoxin and a rise in membrane Na+-K+ ATPase. This causes a decrease in intracellular calcium which increases magnesium that leads to an increase in mitochondrial ATP and thereby causes further stimulation of Na+-K+ ATPase. This process, as they state, "appears to be crucial to the pathophysiology of OCD/TS cases" (pp. 808). The study also found increased dopamine and morphine due to increased tyrosine synthesis. Morphine has the ability to increase the sensitivity of dopamine receptors. The authors conclude that "the neurotransmitter changes producing TS can be attributed to digoxin induced upregulation of tyrosine transport and increased tyrosine synthesis" (p. 809). Another salient finding is that morphine can have an immunosuppressive function which can contribute to increased respiratory infections including streptococcal, which has been implicated in the possibility of brain damage resulting in TS, as noted earlier.

Although there has not been any etiological smoking gun per se, these studies do open up new possibilities for research into the pathology of TS. While the exact underlying causes of the disorder may still be somewhat elusive, many treatments are available for those suffering from TS. They range from standard medications already in use for other disorders to neurosurgical implants. Unfortunately, there is no standardized treatment for TS, however, some have shown promise.

Varying medication is utilized in patients with TS depending on the severity of their tics and whether or not and with what a co-morbid diagnosis is made. Antipsychotics are often prescribed for TS patients, one such medication is Risperidone. Risperidone has a high affinity for 5-HT2A and D2 receptors for which it is an antagonist for both. Studies indicate it to occupy 75-80% of striatal D2 receptors at 6mg/day and 78-88% of cortical 5-HT2A receptors (Tasman, Kay and Lieberman, 2003). Clozapine is another antipsychotic which is sometimes utilized and has the same action as Risperidone but has a lower receptor affinity. Other antidopaminergic medications are often prescribed as well. For management of OCD symptoms, SSRIs are often prescribed such as fluoxetine and Paroxetine (Prozac and Paxil). SSRIs block the reuptake of serotonin from the synaptic cleft.

For those with ADHD psychostimulants can be useful but are not recommended (Jimenez-Jimenez and Garcia-Ruiz, 2001). Baclofen, a GABA analogue which binds to GABAB receptors and impedes the release of glutamate and aspartate has shown some usefulness (Singer, Wendlandt, Krieger and Giuliano, 2001).

Davies et al. (2006) described the case of 11 patients which were administered between 10 and 20mg of aripiprazole to treat their tic symptoms. Only one patient showed no response and was only treated for 1 month with a low (5mg) dose. The other 10 patients showed improvement which was sustained. 5 showed dramatic improvement and the remaining 5 was not as marked but improvement did occur. Aripiprazole is an atypical neuroleptic medication which acts as a partial agonist for dopamine D2 receptors, serotonin 5-HT1A and 2A receptors. It was originally approved to treat schizophrenia.

In a randomized, placebo-controlled, double-blind, crossover study, Smith-Hicks et al. (2007) report the use of Levetiracetam in the treatment 22 child patients with TS. Previous studies had reported a 100% suppression of tics, however, this study found no significant difference between the drug and placebo effects on the patients. Levetiracetam is a broad spectrum anti-epileptic medication. It has been suggested that it binds to SV2a which is a synaptic vesicle protein and enhances chloride ion influx at the GABA-A receptor complex.
A variety of other medications are utilized depending on the severity of the symptoms exhibited. However, because of the waxing and waning of the course of the disorder and the high frequency of medication side effects, pharmacological treatment is recommended to be used sparingly (De Lange, Oliver and Meyer, 2003).

Some non-pharmacological treatments are utilized as well such as behavior modification which has had some limited success (Stoudemire, 1998). Other, more eclectic, treatments have also been evaluated such as the use of repetitive trans-cranial stimulation (rTMS). rTMS utilizes small magnetic fields in a noninvasive fashion. Munchau et al. (2002) reported using rTMS on 16 TS patients. Unfortunately the rTMS did not show any improvement in any of the patients symptoms.

More invasive methods have been utilized in some patients for which medication and all other forms of treatment have failed to control their tics. For some, surgery was the only option left. For those who have only this option left, deep brain stimulation has shown promising results in many case studies.

Bajwa et al. (2007) reported a case of a 48 year old male with severe TS upon whom deep brain stimulation (specifically bilateral thalamic stimulation) was performed. Two electrodes were placed in the patients brain. One electrode was 5mm lateral of the midline of the brain and another was 4mm behind the midcommisural plane. 2 years after the surgery, the patient reported a 95% improvement in tic occurrence going from > 1,000 per day to only 16-25. The stimulator settings were found to be optimal in this case at a low level of 2 2.2 volts and a frequency of 130Hz. The surgery is thought to work due to the abnormalities in functioning of the striatal fast-spike neurons which receive direct input from TANs (tonically active neurons). The TANs receive afferent signals from the midline thalamic nuclei. Problems can lead to thalamocortical dsyrhythmias.

Ackersman et al. (2006) reported the cases of two who underwent surgery for DBS. A 45 year old man had electrodes placed bilaterally in the thalamus 5 mm lateral to the AC-PC line and 4 mm posterior to the midcommisural point. A 27 year old man had 2 electrodes placed in the thalamic nuclei (same as the other patient) and also 2 placed posteroventrolateral GPi (globus pallidus interna). Both patients had their major tics disappear. In a 1 year follow-up Patient 1s tics reduced from 20 to 3 tics/min and Patient 2s reduced from 28 to 2 tics/min.
Diederich et al. (2005) reported the case of a 27 year old man who also underwent surgery for DBS. Electrodes were inserted bilaterally into the globus pallidus internus (GPi). The mans tics were reduced by a mean of 73% after the operation. This lends further evidence to problems in the GPi relating to tics.

Much research has been done that supports genetic factors as well as brain structure abnormalities and neurotransmitter-receptor dysfunction involved in TS. Strong support has been found for these but exact mechanisms have left room for much debate although there is no shortage of data from which to draw. TS is a complex disorder and not one that seems to be reducible to a singular cause. The evidence presented displays the complexity and many agents involved in the formation of TS. However, all the evidence shows that TS has a biological basis and cannot be attributed to items such as emotional conflicts or poor parenting which were speculated causes in the past.

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