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[Preface] "A stroke (cerebrovascular accident, CVA) is the rapidly developing loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood)."

1. Why was 'handedness' assessed, and only right handed subjects included in the study? Explain their theory of transcallosal disinhibition with regards to rTMS treatment.

2. Referencing Figure 1, patients A and B suffered varied degrees of lesion severity. Which subject would you expect to exhibit more linguistic impairment? Do you think they should have narrowed the range of lesion size in their included subjects?

3. The study assessed non-fluent speech production/execution before and after treatment - why not the comprehension or CONTENT of speech? Where would you expect a lesion to be that would produce these symptoms?

4. What are the current treatments for stroke (these are a serious emergency and must be treated immediately!)? Can you think of any procedures/drugs that might help (look at the current research)

I thought that the article brought up a number of interesting points, primarily in its conclusion that TMS can confer a significant improvement on those suffering from non-fluent aphasia following a stroke. Strokes are a major cause of a number of brain disorders and while treatments certainly do exist, they are dependent upon being issued in a timely manner so as to limit the amount of time certain areas of the brain are starved of blood. Following the stroke, in order to repair at least some motor or cognitive functions, rehabilitation in the form of physical therapy or speech therapy is required. The TMS in the study is interesting since it offers another avenue of improvement in function. In the study they mentioned the patients examined had their strokes many years previously (with a mean of about 3). It is my understanding that most traditional rehabilitation must occur immediately and continuously for several months, after which improvement drastically falls off in effectiveness, but the TMS in the study appears to be able to treat patients long after opening the door for further improvements even in those that were still significantly impaired after treatment.

The reason the study did not examine the comprehension or content of speech is due to the nature of non-fluent or expressive aphasia. Had they instead chosen to study receptive aphasia, then measuring comprehension and content would indeed have been a good methodology, however; non-fluent aphasia is not characterized by deficits in either comprehension or content, but instead includes difficulties in initiating fluid speech and difficulty naming various objects. The non-fluent speech is thought to be caused primarily by lesions in Broca?s area (inferior frontal gyrus). That being said, from the research I did, it looks clear that aphasia is a remarkably diverse disorder and there are a number of different models to categorize the various subtypes, and in all the models there are at least some patients that do not fit any one category, due to the vast differences observed in severity and specificity of lesions or other brain damage.

This diversity in people with aphasia is clearly evident in figure 1, with patient a displaying very severe lesions, and consequently a much more severe aphasia in comparison to patient b whose lesion is much more moderate, leading to a mild or moderate aphasia. I think it would have been ideal if the researchers could have refined their study more to find subjects with similar sized lesions, since it is possible that TMS might be more or less helpful depending upon the severity of impairment. I do think that lesions of assorted severity should be studied, since as I mentioned, aphasia appears to be a very diverse disorder but I think they should be compared to lesions of a similar nature to ensure that the effect ascribed to TMS is in fact real.

The fact that the study chose to only include right-handed subjects can be attributed to brain lateralization. The majority of humans have their speech and language centers specialized in the left hemisphere. However, not all do. It?s been found that a person?s handedness is correlated to which side of the brain we see this specialization occur on. Approximately 95% of those with right-handedness have their language centers in their left hemispheres. However, over 18% of people who are left-handed have specialized language centers on the right side of their brains. Thus, Barwood et al. induced a control of only including right-handers in an effort to make sure that the rTMS was being applied to the homologous language-related site in the contralateral hemisphere, not to the primary language site itself (i.e. Broca?s area).

You see, they believed that the overactive homologue of Broca?s area inhibited patient recovery due to the healthy right hemisphere hogging remaining neural resources, so to speak. rTMS repetitively depolarizes neurons via a weak electrical current which can produce a long-term depression of neural activity. Thus, researchers in this study theorized that rTMS would inhibit the overactive homologue contralateral to Broca?s Area, allowing more resources to be directed transcallosally to the damaged area in the left hemisphere, hence ?transcallosal disinhibition? theory.

With respect to their experimental design, it was also very wise of the researcher to concentrate on assessing non-fluent speech. rTMS was applied to Broca?s area homologue. Broca?s area is responsible for speech production/execution. Hence, speech comprehension would most likely go unaffected in the ?Real group? as its processing is centered in Wernicke?s Area. A lesion there would more likely produce problems with understanding speech content.

I agree with Drew that the article was very interesting in proving that TMS can offer help to those who have suffered from a stroke. On the topic of handedness it makes sense to pick all right handed subjects. The lesions that were inflicted all occurred in the left hemisphere of the brain, the area where language is located. Aphasia can be defined as "speechless, is an acquired language disorder in which there is an impairment of any language modality. This may include difficulty in producing or comprehending spoken or written language." Clearly the affects of aphasia would mainly be caused by disruption in the left hemisphere. The majority of the population is right handed and have associated language centers in the contralateral hemisphere of the brain, the left side. This is the main reason that handedness was a factor in choosing subjects for this experiment.

It is clear in the diagram above that figure a has a much more severe lesion in the brain, while figure b is far less severe in comparison. It is expected that figure a will have had more brain damage and lead to a more intense case of aphasia. I think that having a more similar group of subjects would have helped narrow down results and produce a more precise study pool. While results from the normal test show important changes between the two, it could be helpful to see similar lesion sizes compared.

As of now, there are not many immediate cures/treatments for stroke. The few options that people have now are surgery, medication, and rehabilitation, none of which guarantee recovery. One option that is available to those who suffer from a ruptured aneurysm is reconstructive surgery where they repair the blood vessels in the brain. As for an ischemic stroke, caused by a blood clot, they aim to dissolve the clot via intravenous TPAs which flow to clot and break it apart. These are some of the few available treatment options. One particular group of research at Massachusetts General Hospital is currently researching anticoagulants, though there is the problem of increasing intracerebral hemorrhage when using said anticoagulants.

Since most of the population is right handed, most of the association speech area is in the Broca?s area of the left hemisphere. Patients with lesions in that area will develop speech impairment, but recover slowly as the speech translocate to the homologous area of the right hemisphere due to the injury of the left hemisphere as demonstrated by another study done by Thiel et. al. This study uses rTMS to treat the homologous language centers on the right side of the brain based on the idea that post-stroke patients after 2-6 years will have sufficiently recovered the most amount of speech they can. Their being right handed rules out the possibility that they?re applying the rTMS on the wrong side of the brain.

I do think that they should have limited the size of the lesions in their patients. The first set of images showed significantly larger portion of brain death than the second. I wonder if that degree of damage to the cortex, and what seems to be even some midbrain could have added some intrinsic discrepancies in the results they obtained. A set of psych evaluation could be applied to make sure they have a certain range of functionality of their brain.

Current treatments for stroke is to minimize the damage to the brain. This means they will have to remove the blood clot in the fastest way possible. They can do this surgically, perform angioplasty, or use pills to dissolve the clot under careful monitoring to make sure there is no hemorrhaging. Current methods that are being employed is to cool the patient in ice cold water in order to slow down the damage of the stroke and increase recovery. There is research being done on neuroprotective agents, and calcium channel (NMDA) inhibitors to prevent the effects of excitotoxicity. There?s also a drug called Zendra that?s in phase III of testing, it?s a GABA receptor agonist.

Just as Caley said, the reason handedness was assessed by this experiment was to assure that the patients being treated had interruptions in their primary language and speech centers in the left hemisphere. When using patients with damage to the left hemisphere who are left handed, there is a much higher chance that the rTMS would be applied to the primary language center. Also a higher proportion of left handed people have bilateral language functions. Producing positive results from patients who are not screened for handedness would not support the theory of transcallosal disinhibition, because this would not prove that because the functional side is taking an uneven amount of resources, language recovery is affected. However, I think that this experiment should be done with people with bilateral hemispheric language function or left handed people with similar deficits. Perhaps, even though it seems unlikely, that transcallosal disinhibiton is not the reason why we are seeing recovery.
Like other people said, you would expect more impairment from patient A due to the large size of the lesion. However, I think that the large range of lesions is beneficial, as long as the lesion size average is the same among the control and experimental groups. The varying sizes gives strength to the results of similar improvements. This experimental question is not hindered by the varying sizes of the lesions, this experiment is trying to support the use of rTMS. However, for future experiments it would be beneficial to use patients with lesions in similar areas and of similar sizes. Multiple similar experiments with varying sizes could allow us to observe the affect that the size of the lesion has on the chances of improvement.
This experiment studied the BA analogue in humans, not Wernicke's Area. Assessing the comprehension of speech would involve this area. Therefore assessing the content of speech would involve Wernicke's Area.
For stroke treatment, tissue plasminogen activators (tPA's) are commonly used for ischemic stroke and transient ischemic attack (TIA's). Both of these are caused by blood clots in the brain blocking blood flow to certain areas, however TIA's are generally less severe. These drugs are only effective for a short time following the onset of a stroke and for about 85% of strokes. The other 15% are hemorrhagic strokes, resulting from blood loss from a blood vessel in the brain. Of the 85% there is a huge problem with identifying the risks associated with the use of certain drugs and the speed at which they must be administered. For example tPA's Need to be administered within 3 hours to be effective. Recently the development of the Alberta Stroke Program Early CT Score or ASPECTS has become useful for allowing doctors to identify the risks of using several types of drugs for patients with ischemic strokes and TIA based off a CT scan, including with the implementation of thrombolysis for acute ischemic stroke.

The above study was selective for right-handed participants. This was because in around 95% of right-handed people. the dominant hemisphere of their brain is the left one, meaning that their language centers (such as Broca's and Wernicke's areas) will also exist within that hemisphere of their brain. This being said, it would make sense for them to look for people who had suffered a stroke who were also right-handed to assess their speech capabilities after the CVA. It also may have been the case that some of the individuals were unaware of what side their stroke had occurred on, and during recruitment of subjects, simply specifying "right-handed" would eliminate the possibility of having anybody with a dominant right hemisphere interested in participating. As far as the transcallosal disinhibition theory, the thought is that stimulating an area with rTMS in the right hemisphere of the brain that is in the same area as Broca's area (pars triangularis) in the left side of the brain, via connections in the corpus callosum, will work to inhibit extraneous activity in homologous language centers and allow the left hemisphere to take more control over language production again instead of other language centers, some in the right hemisphere.

Personally, I would expect patient A to exhibit much more linguistic impairment that patient B simply due to the size of the lesion. In patient A, the lesion has effectively destroyed around 1/2 to 3/4 of the left hemisphere, rendering significant damage to not only Broca's area but many other parts of the brain, as well. Patient B's lesion, while still significant, is much smaller and much more localized, so although speech was affected, it seems to me as if not much besides that would have been affected (not nearly to the extent of patient A, anyway). Narrowing the lesion sizes allowed in the study may have improved results or provided a more accurate data set regarding rTMS therapy in speech-affected stroke patients, but honestly, I feel like since they were only studying speech impairment and its subsequent improvement with therapy, other damage does not play into the experiment much. This isn't to say that these brain areas are not also involved with speech, and indeed, since localization of function only extends so far in any area of the brain, it is entirely possible that the major destruction of the left hemisphere could contribute to language deficiency in different ways than simply lesioning primary language areas (such as Broca's and Wernicke's), but in my estimation, lesion size probably did not have much of a noticeable effect on the data set.

The reason this study did not look at the comprehension or content of speech is because these aspects of speech are more associated with Wernicke's area than Broca's. While Broca's area is associated with speech production and the use of content words, Wernicke's area is associated with speech comprehension. After what we've learned in class and what I've found in my studies about Broca's and Wernicke's areas, assessing the patients' speech as was done in the study seems to me to have been entirely appropriate, since assessing the use of content words and the comprehension of speech would fall more within the realm of studies looking at Wernicke's area and the role it plays in language. While Wernicke's area is important to language, it has to do with these particular aspects, and in this particular study, the researchers were interested more in speech production, which falls under the domain of Broca's area.

As far as emergency treatment of stroke, as an EMT, I can tell you that a suspected stroke is assessed immediately using the Cincinnati Pre-Hospital Stroke Scale, which consists of three tests: the "smile test," wherein the stroke patient may exhibit one-sided facial weakness/drooping; the falling arm test, where the patient is asked to raise both arms to shoulder height in front of them and close their eyes, and if one of the arms falls at this point, the opposite side of the brain is affected by stroke; and the speech test, where the patient is asked to repeat the phrase "The sky is blue in Cincinnati" or "You can't teach an old dog new tricks," and if the speech is slurred, the patient is suspected of having suffered a stroke. These tests are simple and can be performed by anyone, and in the pre-hospital setting, positive findings for any of these tests necessitates immediate transport to a hospital where the patient can receive further treatment. Once in the hospital, imaging is often the first step for a suspected stroke patient so that the affected area may be identified. If a blood clot or a bleed is found in the brain, immediate steps are taken to preserve the most neural tissue possible. In the case of a blood clot, thrombolytic (clot-busting) drugs are often administered if the patient has been assessed in the proper time span and meets a slew of criteria assuring that they will not be harmed by the drug rather than helped. In the case of a hemorrhagic stroke, steps must be taken to relieve pressure on the brain, cauterize the bleeding vessel, and restore blood flow to the area affected. Clot-busting drugs are contraindicated in this situation due to the stroke being caused by active bleeding into the brain, thereby depriving the brain of oxygen and nutrients, rather than a clot keeping blood from reaching the brain.