Deep Brain Stimulation and Alzheimer's Disease


Introduction

This clip is a video of a TED talk conference on the applications of Deep Brain Stimulation (DBS), a relatively new treatment for Parkinson’s disease, depression, anorexia and dystonia. Andres Lozano, the neurosurgeon who pioneered deep brain stimulation
treatment, explores several cases where DBS was utilised to treat neurological disorders, of which Alzheimer’s disease is one. He talks briefly on how DBS can treat patients with Alzheimer’s and the ongoing research surrounding the possibility of reactivating specific brain regions affected by this medical condition. This conference was held at TEDxCaltech in January 2013 and was posted on TED.com in April 2013. TED.com is a site that focuses on spreading ideas about general topics deemed worthy of media exposure.

We aimed to further explore and elaborate on what Alzheimer’s is and how DBS can be used as a treatment, the effectiveness and hidden (and potentially negative) consequences of undergoing this treatment. As this treatment for Alzheimer’s is relatively new, we found that there has only been one clinical trial thus far. Hence, there is a lack of information surrounding this topic.

We chose to research Alzheimer’s disease as it is a serious and relevant medical issue that affects many Australians. It is an irreversible neurological condition for which, if there is no medical breakthrough, the number of Australians affected could rise from 300 000 to 900 000 in 2050 (fightdementia.org.au, 2013). Furthermore, as Alzheimer’s disease is quite complicated and not well understood, we thought that this medical condition would be surrounded with new and interesting research regarding its causes, effects on neural mechanisms and potential cures. Paired with deep brain stimulation, a frequently mentioned and relatively new treatment, we thought the topic “DBS and Alzheimer’s” would be insightful, useful and informative, not only for neuroscience students, but also the general population.

Alzheimer's disease


What is Alzheimer's disease?

Alzheimer’s disease is a medical condition that is defined through having the symptoms of dementia and the overabundance of amyloid plaques and neurofibrillary tangles within the brain (n.a.d. 2007, s.1). Although there are genetic and environmental factors which influence how severe Alzheimer’s disease is, it is currently considered as an advanced stage of dementia where the affected individual progressively experiences delusions, confusion and mood disruptions. The life expectancy of sufferers from Alzheimer's is approximated at 8.3 years for those at 65 years of age and 3.4 years for those at 90 years of age, an approximate median life span reduction of 67% and 39% respectively (Brookmeyer et al., 2002).

It was first identified by Alois Alzheimer, a German psychiatrist who studied Auguste Deter, a patient suffering from mass delusion and blood and skeletal changes, the first ever recorded case of Alzheimer’s disease. After Auguste Deter’s passing, it was found that she had cerebral atrophy, intraneuronal fibrillar bundles (neurofibrillary triangles) and deposits of amyloid plaques around the cerebral cortex, the symptoms that formed the basis for Alzheimer’s disease, which Emil Kraeplin coined in 1910 (n.a.d, 2007, section 1.1).

Furthermore, distinctions between senile and pre-senile Alzheimer’s patients were made to differentiate between the severities of the illnesses. It was discovered in the mid 1960s that most elderly dementia patients had the same neuropathology as Alzheimer’s disease (Roth et al., 1966). This resulted in the merging of both senile and pre-senile aspects into one syndrome, and what we know today as Alzheimer’s disease.

Figure 1: Alois Alzheimer and Auguste Deter
Figure 1: Alois Alzheimer and Auguste Deter


Causes of Alzheimers disease

The causes of Alzheimer’s is not well understood however research has identified that plaques (beta-amyloid pepties) and tangles (neurofibrillary tangles) both have an impact on developing the symptoms of Alzheimer's, mainly the degeneration of neurons that are vital for cognitive function and retaining short and long term memory (Hardy & Higgens, 1992). The brain uses approximately 20% of the glucose that the body produces. In Alzheimer patients, glucose utilisation in the temporal and parietal lobes are low to non-existent. As a result, action potentials cannot be produced to regulate the neurotransmitters essential for normal bodily functions (such as acetylcholine, dopamine and serotonin).

Alzheimer’s disease is predominantly caused by a deficit in glucose utilisation within the brain. Glucose (C6H12O6) is a monosaccharide, one of the smallest units of carbohydrates utilised in the body, mandatory for metabolism in humans. From a cellular perspective, glucose is transported from the liver through the spinal cord where it is synthesised in the blood brain barrier, providing energy to generate action potentials. In the case of cognitive functioning, glucose reduces the effect of opioid inhibition on acetylcholine (ACTH), a neurotransmitter crucial in learning, which thus enhances cognition (Gold, 1995). A lack of glucose in the medial temporal and frontal cortex leads to neuronal death (figure 1). As a consequence, the function to retain short and long term memories is lost. Recent Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) imaging has demonstrated that the lack of glucose within the parieto-temporal, frontal and posterior cingulate cortices is believed to signal the onset of Alzheimer’s disease (Mosconi, 2005).




Figure 2: Regions within the brain with neuronal death due to a lack of glucose (TED Video) The darkened areas are representative of the lack of neuronal activity in the parietal and temporal lobes, a region crucial for cognition, adaptive functioning and the storage of memories.
Figure 2: Regions within the brain with neuronal death due to a lack of glucose (TED Video) The darkened areas are representative of the lack of neuronal activity in the parietal and temporal lobes, a region crucial for cognition, adaptive functioning and the storage of memories.


Another cause for Alzheimer’s disease is the accumulation of beta-amyloid peptides (Aβ) within the brain which forms amyloid plaques that destroy neurons and their respective synaptic connections. Beta-amyloid peptides are short chained amino acid monomers linked with peptides. These beta-amyloid plaques are formed through the breakdown of the amyloid precursor protein (APP), a protein crucial for neuronal growth, repair and maintenance. Beta-amyloid peptides are formed as a result of this breakdown and are broken into smaller fragments through the process of proteolysis. The peptides clump together and are deposited outside the neurons, forming plaques which causes neuronal degeneration. More recently, it was found that Aβ is formed inside the neuron rather than the outside (Gunnar, Claudia & Reisuke, 2005).

Neurofibrillary tangles are tau proteins that have been hyperphosphorylated, which is the adding of a phosphate group on the end of the tau proteins. Like beta-amyloid peptides, neurofibrillary tangles also contribute to the degradation of neurons within the brain. Not much is known about the neurofibrillary tangles, but there are suggestions that they are created in the neocortex, a region where they cause the amyloid precursor protein (APP) to break down (Arriagada et al., 1992). Neurofibrillary tangles cause the breakdown of APP to produce Aβ, which clumps together to form the Aβ plaque, hence destroying neuronic membrane.

Deep Brain Stimulation


What is Deep Brain Stimulation?

Deep Brain Stimulation (DBS) is a surgical treatment that requires implanting a neurostimulator that allows electrical stimulation (through pulse generation) of specific brain regions involved in symptoms of neurological disorders (Perlmutter & Mink, 2006). The surgery is performed under local or general anaesthesia. Electrodes are inserted into areas of the brain according to the symptoms being treated and accurate placement is ensured through use of magnetic resonance imaging (MRI) during the procedure. Parameters for electrical pulse stimulation are then regulated by a neurologist or trained technician to enhance DBS treatment and minimise side effects.

Deep brain stimulation_no box_small.jpg
Figure 3: How DBS is positioned (bioethics, 2013)
Deep Brain Stimulation on Alzheimer's Disease


electrode positioning.png
Figure 4: Electrode positioning on fornix (Laxton et al., 2010)

In a recent study, Laxton et al. (2010) performed Phase 1 trials on fornix and hypothalamus DBS in patients with mild Alzheimer’s disease. Previously, Hamani et al. (2008) reported memory enhancement in an obese patient following a deep brain stimulation procedure to the fornix and hypothalamus. In Hamani et al.’s study, reversible memory phenomena was triggered using a strong stimulation, and activation in the hippocampal formation and medial temporal lobe could be seen. These brain regions are involved especially in short term and long term memory and the activation was linked to memory improvement. This observation led to the notion that neural elements involved in memory function could be accessible for manipulation through electrical stimulation.

The fornix was chosen as the stimulation point as it plays a vital role in memory function by providing the link between hypothalamus and hippocampus. Figure 4 (Laxton et al. 2010) illustrates the positioning of the electrodes in the fornix. This is supported by the observation that lesions to the fornix produce memory dysfunction in both animals and humans (Powell, Guillery & Cowan, 1957). Laxton et al. (2010) hypothesised that it would be possible for DBS to elicit neural activity in the fornix, and thus, drive medial temporal circuits involved in facilitating memory function, especially for patients with memory impairment.

After the continuous uninterrupted DBS treatment, tests were carried out to examine quantitative effects of DBS on patients’ brain activity and activation. Using Positron Emission Topography (PET), measures of cerebral glucose metabolism were taken (impaired glucose metabolism in brain is linked with Alzheimer’s disease) to determine differences pre- and post-operation with comparison to healthy controls. It was found that one month after DBS procedure, there was an observed increase of glucose metabolism in temporal and parietal cortical areas (especially the posterior cingulate cortex and precuneus, the areas which are most affected in early AD) compared to baseline measurements. However, regions that are relatively unaffected by Alzheimer’s disease also showed increased glucose metabolism. A year following treatment, compared to transient effects of other treatments for AD (such as utilising cholinesterase inhibitors), it was observed that the increase in metabolism was sustained in affected brain regions (Laxton et al., 2010). The increase in glucose metabolism over time due to DBS is illustrated in Figure 5 (Laxton et al., 2010).

Overall, it was found that brain regions which showed most increase in cerebral glucose metabolism were those with excessive amyloid deposits. Amyloid deposits are known to be major causes of Alzheimer’s disease and also a big contributor to impairment of glucose metabolism (Hardy & Selkoe, 2002). Furthermore, DBS produced a sustained increase in metabolism for areas (such as posterior cingulate lobe, parietal lobe) which are normally affected in the early stages of Alzheimer’s disease (Lyketsos, Targum, Pendergrass & Lozanzo, 2012).
increase in glucose.png
Figure 5: Glucose increase comparison (Laxton et al., 2010)

Neural Elements and Mechanisms

Despite therapeutic benefits in memory function, the neural elements and processes involved in effects of DBS on Alzheimer’s are unknown. It is hypothesised that stimulation of the fornix activates the axons of that region which thus immediately activates downstream structures (through poly-synapsing) as a consequence. There are several reasons for using fornix as stimulation point. Firstly, it is thought that the fornix contains axons which are more sensitive, in comparison to neuron cell bodies, when subjected to electrical stimulation. Secondly, when looking at effects of stimulation, electrodes that were located along vertical axis of fornix produced parallel voltage threshold. If the effects of stimulation were controlled by other parts of brain, for example, mammillary bodies, there would be differing current and voltage threshold levels. (Laxton et al., 2010) Moreover, preliminary evidence indicates that stimulation of the Papez circuit (which consists of both fornix and hippocampus) promotes neurogenesis in the hippocampus. Dysfunctional neurogenesis leads to memory impairment and ultimately aggravates Alzheimer’s disease (Toda, Hamani, Fawcett, Hutchison, & Lozano, 2008). Furthermore, past studies have concluded that abnormalities in the fornix are associated with further cognitive decline in individuals with amnestic mild cognitive impairment and hippocampal volume loss. This is a major predictor of AD development and large indicator of eventual cognitive decline (Mielke et al., 2009). Due to the presence of such evidence, the fornix was chosen as an ideal region for electrical stimulation.

Effects of DBS on Alzheimer's patients


DBS seems to have a positive effect on Alzheimer’s patients as evidenced by preliminary findings from the pilot trial conducted by Laxton, etal. (2010). A decrease in glucose metabolism is often associated with memory impairment, which is hailed as the most reliable clinical symptom of Alzheimer’s (Mosconi, 2005). During the pilot trial, functional connectivity analyses revealed increases in glucose metabolism within the temporal and parietal regions of the brain in all patients. This indicated neural activity in areas of the brain which should have been inactive in Alzheimer’s sufferers. Furthermore, it was revealed that the hippocampi of two patients increased by 5% and 8%, an astounding result given the fact that this area of the brain is usually one of the first regions to degenerate in Alzheimer’s sufferers (Gallagher, 2011). The potential of DBS to cause cell growth in the hippocampi region was further investigated in mice, wherein the entorhinal cortex (an important part of the hippocampal memory system) of the mice was stimulated. This resulted in the formation of extra neurons within the hippocampus (Stone, etal. 2011). These findings could have positive implications on Alzheimer’s sufferers due to the critical role the hippocampus plays in the encoding, retrieval and consolidation of declarative memory (Mosconi, 2005).

The efficacy of DBS on clinical measures was tested during the pilot trial through the administration of several tests including the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog) score and Mini Mental State Examination (MMSE). Both these scores revealed DBS caused the rate of decline of the patients to lessen as compared to average Alzheimer sufferers. An example was the mean score for the ADAS-cog test wherein the average score was an increase of 4.2 as compared to an average increase of 6-7 points in Alzheimer patients. However, there did exist great variability in scores between patients, with some showing improvement in condition, whilst others showing regression. This difference may suggest a relationship between the severity of Alzheimer’s and effectiveness of DBS (Laxton, etal. 2010).

Side effects

The pilot trial by Laxton, et al. (2010) was relatively safe, despite several side effects to deep brain stimulation being documented. A decrease in glucose metabolism within the anterior cingulate and medial frontal cortices was recorded in all patients, however this did not seem to have any impact on the participants throughout the duration of the trial. Nevertheless, further tests must be conducted so as to eliminate the possibility of dysfunction within these areas affecting psychomotor and executive processes (Laxton, etal. 2010). Experiential phenomena was also recorded in two patients during surgery, wherein they reported experiencing events that had occurred in the past. Interestingly, those that experienced this phenomena exhibited better results in cognitive assessment scores. As as a result of the relatively limited scope of the study, more work should be conducted to investigate whether any additional side effects exist (Laxton, etal. 2010).

Future of DBS in treating Alzheimer's


With the lack of any long term treatment and the failure of drugs such as Cholinesterase inhibitors (Kaduszkiewicz, Zimmermann, Beck-Bornhodt and van den Bussche, 2005) to adequately treat Alzheimer’s, new methods of treatment must be developed. Whilst the relatively rudimentary nature of the phase 1 trial by Laxton et.al (2010) means no definite conclusions can be drawn as to the efficacy of DBS as a treatment for Alzheimer’s, the preliminary results do suggest DBS as a treatment does warrant further investigation. As a result, a double-blind clinical trial, known as ADvance study, is currently being conducted at several institutions throughout America and Canada, including Toronto Western Hospital, Butler and Rhode Island hospital. The study aims to monitor “safety outcomes and changes in memory, cognition and daily functioning” (ADvance). It is hoped that one day, DBS will become the first successful treatment for Alzheimer’s.

Critical Analysis


The media item was a video of a lecture delivered by Andres Lozano, a pioneer in DBS research. It has been viewed more than 500 000 times and claims DBS may be able to treat Alzheimer’s. It was presented on the TED website, which is well known for spreading new ideas and challenging traditional ways of thinking through mass media through many different languages. Furthermore, Lozano’s sporadic use of scientific jargon demonstrates his intention to present his finding to a layperson audience.

Scientific TED talks are normally given by scholars who have made major contributions to science, therefore their talks are mainly aided by extensive research. Lozano posits the rather incredulous claim that DBS may well be used to treat/cure Alzheimer’s disease. His central role in the DBS project means an element of bias may well be embedded within his rhetoric. This is evident through the lack of mention of any side-effects to the procedure, such as a decrease in glucose metabolism within the anterior cingulate and medial frontal cortices. Moreover, tests administered to test the efficacy of the procedure provided inconclusive results as some patients reported declines in cognitive function.

Whilst Lozano’s talk suffers from the selective exclusion of information, the information that this leading neuroscientist does convey is consistent with neuroscience. He utilises scientific research to demonstrate the recent success of DBS in treating untreatable conditions such as Dystonia. However, scientific jargon was not used extensively and most definitions were explained with simplicity, enabling the layperson to comprehend the talk without difficulty. His analogy of “lights out and power failure” in clarifying brain function failure due to Alzheimer’s was effective in conveying his message to people with a limited/or no understanding of AD. Lozano also thoroughly examined the driving mechanisms behind DBS and linked it to how it can be implemented in the treatment of Alzheimer’s.

Although DBS is a new area of focus within neuroscience, Lozano’s work has immense potential for the future, possibly providing a practical approach to treat Alzheimer patients where medication has failed.

In conclusion, the lecture was presented in a layperson friendly manner to a large audience and uploaded onto the internet for easy access. Jargon was (made easier to understand) and the conference engaged the audience to think and form their opinions on the matter. Therefore, this media item introduced a new and exciting treatment in neuroscience, an area in need for further future research.


Appendix


Search Strategy

In choosing our media item, we had each proposed potential areas of interest. Two of the suggested areas centered around Alzheimer's disease, and as such we chose to look for media items which involved it. Furthermore, we recognised the relevance of this disease due to the burgeoning number of Alzheimer's patients in society. We then set about looking for potential neuroscience topics which involved Alzheimer's, when a member of our group chanced upon a TED talk by Andres Lozano which detailed the possibility of treating Alzheimer's through DBS. Naturally, this topic embodied many areas of neuroscience and as such seemed suitable for our wiki topic. Moreover, the concept of DBS had piqued many of our interests when we first heard it during a lecture on epilepsy. The recency of this finding and it's potential to greatly improve people's lives helped solidify our decision.

We used various search strategies, most pertinent amongst them being Google Scholar which provided us with peer reviewed journal articles detailing such things as the first trial involving DBS on Alzheimer's patients as well as previous research into this topic. We were also able to use Google search engine to locate the website of a current trial involving DBS and Alzheimer's which provided helpful information.

Reviewer comments

We found the reviewer comments to be extremely useful in pointing out the flaws in our work and as such we have added many improvements to our wiki page. Based on the review comments, we alphabetised and made our review list more consistent. Moreover, we added an appendix and labelled our diagrams. We also added a comment describing how electrodes are inserted as well as a diagram demonstrating how electrodes are placed. Another concern that was raised was the long winded nature of our sentences which we addressed by making some sentences more concise. We also explained terms such as entorhinal cortex and hyperphosphorylated. Finally, we fixed up some grammatical errors which were pointed out in the review comments.

Whilst we accepted most of the criticisms, we did dismiss some. One of these was the comment on the use of first person in the introduction. We found this comment to be wrong as the good example from 2010 also used first person in the introduction. Another comment read "why it should be interesting should be in the appendix", however we disagree with this point as the instructions stated the introduction should "explain why it is of interest", hence we did not want to deviate from Dr Vickery's instructions.

Overall, we found the reviewer comments to be highly valuable in allowing us to improve the overall quality of our content.

References



ADvance Study (2013). About ADvance Study. Retrieved from http://www.advancestudy4ad.com/advance.php

Arriagada P.V., Growdon J.H., Hedley-Whyte E.T. and Hyman B.T., (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 42, 631.

Brookmeyer R., Corrada M.M., Curriero F.C. and Kawas C., MD, 2002Survival Following a Diagnosis of Alzheimer Disease, Arch Neurol, ; 59(22), 1764-1767.

Gallagher, J. (2011, November 28). BBC News - Alzheimer's: Deep brain stimulation 'reverses' disease. Retrieved from http://www.bbc.co.uk/news/health-15890749

Gold P.E, 1995, Role of glucose in regulating the brain and cognition. The American Journal of clinical nutrition. 61, no.4, 9875-9955.

Gunnar K. Gouras, Claudia G. Almeida, Reisuke H. Takahashi, 2005, Intraneuronal Aβ accumulation and origin of plaques in Alzheimer's disease. Neurobiology of aging. 26, no. 9, 1235-1244.

Hamani C, McAndrews MP, Cohn M, et al. (2008) Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol. 63(1):119-123.

Hardy J, Selkoe D.J., et al. (2002) The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science’s Compass review: Medicine. 297(7): 353-355.

Kaduszkiewicz, H., Zimmermann, T., & Van den Bussche, H. (2005). Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. British Medical Journal. 331(321), 1-7.

Laxton AW, Tang-Wai DF, McAndrews MP, et al. (2010) A phase 1 trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 68(4):521-534.


Lyketsos CG, Targum SD, Pendergrass JC, Lozano AM, (2012) Deep brain stimulation: A novel strategy for treating Alzheimer’s disease. Innov Clin Neurosci. 9(11-12): 10–17.

Lyons M.K. MP, (2011) Deep brain stimulation: Current and future clinical applications. Mayo Clin Proc. 86(7): 662–672.

Mielke MM, Kozauer NA, Chan KC, et al. (2009) Regionally-specific diffusion tensor imaging in mild cognitive impairment and Alzheimer’s disease. Neuroimage. 46(1):47–55.

Mosconi L., 2005, Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease, European Journal of Nuclear Medicine and Molecular Imaging. 32, no.4, 486-510.

Perlmutter J.S., Mink J.W., (2006) Deep brain stimulation. Annu. Rev. Neurosci. 29:229-57.

Powell TPS, Guillery RW, Cowan WM. (1957) A quantitative study of the fornix-mammillothalamic system. J Anat. 91:419–432.

Roth M., Tomlinson B.E., and Blessed G. 1966. Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects. Nature. 209, 109-10.

Shelley J. Allen, 2007, The neurobiology of Alzheimer’s Disease, sections 1-1.1, (n.a.d, 2007)

Stone, S. S., Teixeira, C. M., DeVito, L. M., Zaslavsky, K., Josselyn, S. A., Lozano, A. M., & Frankland, P. W. (2011). Stimulation of Entorhinal Cortex Promotes Adult Neurogenesis and Facilitates Spatial Memory. The Journal of Neuroscience. 31(38), 13469-13485.

Toda H, Hamani C, Fawcett AP, et al. (2008) The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg. 108:132–138.

Topic: Deep Brain Stimulation and Alzheimer's Disease

Edward Bartolo - z3463282
Geoff Chen - z3466336
Jane Ma - z3466299
Omar Qureshi - z3459183

Video of Ted Talk on DBS


Nice topic - lots of good neuroscience. As I said to one of the other groups doing a TED talk, you probably should weigh up the motivation/benefits to the speaker in terms of self-promotion vs genuine information sharing, and also whether the significance of the work is fairly pitched.

Approved.




Jobs:
Edward: Alzheimer’s: what is it?/Intro/analysis (ideas)
Geoff: Causes of Alzheimer’s/analysis (ideas)/appendix
Jane: Deep brain stimulation/analysis (ideas and type up)
Omar: Effects of DBS and analysis (ideas)/appendix
    • all help out with appendix and analysis

Deadlines:
Research finalised – 17th August
Intro/Neuroscientific context – 29th August
Appendix/Analysis – 6th September

Meetings:
1st meeting: 20130808_124933.jpg
Planning: 11th August
Editing: 7-9th September, 22nd September (final edits)