Shock Therapy Treatment in Alzheimer's Disease

Shock Therapy
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Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by loss of neurons in several brain regions, including the hippocampusand prefrontal cortex [1] . This deterioration of memory pathways and regions results in the disease’s defining symptom of memory loss. Recent leading research has shown that shock therapy treatment in Alzheimer and non-Alzheimer’s patients has been demonstrated to improve memory, brain cognition and stimulate regrowth of brain regions affected by the disease [1][2]. This treatment method has also been successful in improving both Parkinson's disease, and Major Depressive disorders . Although shock therapy has a negative connotation from its history of misuse to treat psychiatric patients, the methods used today are modernized and safe. Electrodes are inserted into the brain inducing deep brain stimulation with low electrical currents, targeting specific brain regions [1]. While shock therapy treatment is still in the trial phase for Alzheimer’s disease, it is proving to have significant potential as a treatment. With further research, shock therapy can be a possible cure for Alzheimer’s disease.

Impact of Alzheimer’s Disease on neurophysiology

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The adult Brain contains over 100 billion neurons that form branching networks of synaptic connections[9]. The signals that travel through these networks form the basis of our everyday motor movement, memories, thoughts and feelings. Alzheimer's Disease (AD) is a neurodegenerative disease, which over time results in the deterioration of these neurons and the disruption of the synaptic connections. It causes nerve cell death and tissue loss throughout the entire brain, causing dramatic brain shrinkage and affecting nearly all of its functioning. The most common affects of AD on the structural brain are a significant decrease in the Cortex and the Hippocampus, and enlarged brain ventricles[9]. The cortex and Hippocampus are responsible for thinking and planning, and memory, respectively, hence decrease in these masses results in the loss those functions as well as further behavioral changes that include but are not limited to: loss of judgment, impaired language, emotional outbursts, and general agitated state[9].
At the microscopic level, protein from fatty nerve cell surroundings break down and clump together forming Beta-Amyloid laques[9]. These plaques build up between nerve cells and block cell-to-cell signalling at nerve synapses. Nerve cell death can be attributed to intracellular neurofibrillary tangles[9]. In neurons, a cell transport system that provides nourishment throughout the entire cell is organized into parallel strands by a protein called tau[9]. In AD, tau proteins collapse, resulting in the parallel strand arrangements to entangle and disintegrate[9]. The cell no longer has a system to provide it with nourishment, resulting in cell death.

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Modernized Methods of shock therapy

Electroconvulsive Therapy (ECT)

Electroconvulsive therapyis a procedure in which electric currents are passed bilaterally through the brain[16]. This elicits an intentional seizure that produces the therapeutic effects for the symptoms in which the patient is being treated for[16]. ECT is a beneficial treatment because it often works in treatment resistant patients. Modernized ECT is safe because the patients are put under a general anesthesia[16]. It can have some side effects, such as the loss of memories, however patients are passive to the memory loss when they experience the amazing relief that ECT brings them.

Magnetic Seizure Therapy

Magnetic Seizure Therapy is a new method to replace ECT in the treatment of depression[18]. ECT is known to cause memory loss in some patients, however magnetic seizure therapy provides the same benefits as ECT but without the memory loss. The procedure involves magnetic coils that are placed on the patients head, sending a magnetic pulse into select regions of the brain[18].

Deep Brain Stimulation (DBS)

Deep-brain stimulation is a technique used to treat neurologic and neuropsychiatric disorders[2]. It achieves this by implanting electrodes and stimulating specific sites in the brain to achieve desired functional brain modifications[17]. The electrodes produce electrical impulses (volts) that are given in timed pulses at a certain frequency. This eliciting of stimulation is controlled by a pacemaker that is surgically placed under the skin of the upper chest area in the patient. A wire travels from this pace maker connecting it to the electrodes[17]. Because of its site-specific stimulation, DBS is effective in treating Parkinson’s disease, dystonia depression and obsessive-compulsive disorderobsessive-compulsive disorder[2].

Results of shock therapy on Alzheimer’s patients

Alzheimer’s disease is known to influence structural changes in the brain’s entorhinal cortex and hippocampus, as well as functional changes, which is seen in the decrease in utilization of glucose
in the temporal lobe and posterior cingulate area[1]. In a study by Laxton et al, the researchers did a safety trial of deep brain stimulation on the fornix to see if they could activate and regulate the memory circuits in patients with Alzheimer’s disease. The subjects were 6 patients with early to mild Alzheimer’s disease. Deep Brain Stimulation electrodes were implanted 2mm anterior and parallel to the vertical portion of the fornix within the hypothalamus[1]. All patients received stimulation at 3.0 to 3.5 volts with the frequency set at 130 Hz and the pulse width at 90 microseconds for 12 months, and they received follow-ups at 1,6 and 12 months following electrode the implants[1]. Both sLORETA and PET scans were done for baseline references. sLORETA images would be used to identify brain areas showing change in activity in response to the EEG stimulation at 6 and 12 months. PET scans would be used to measure regional cerebral glucose metabolism levels at 1 and 12 months.

Insertion of Electrodes near Fornix
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sLORETA found that stimulation of the fornix lead to downstream activation of other structures, more specifically, the stimulation produced localized changes in the activity of the ipsilateral mesial temporal lobe structures[1]. At short latencies after stimulation, activation was localized to the hippocampus and parahippocampal gyrus[1]. At long latencies after stimulation, a significant activation of the cingulate gyrus was seen[1]. Hence, sLORETA demonstrated that DBS produced strong ipsilateral activation in the hippocampus and mesial temporal lobe, both structures that are strongly involved in memory function. Patients with a milder case of AD were seen in sLORETA to have responded best, which can be attributed to the fact that better preserved memory circuitry responds better to DBS.

PET scans at 1 year relative to 1 month revealed increased metabolism in the anterior and subcortical regions[1]. The brain regions that were found to have the greatest increase in metabolism were those with large accumulations of amyloid deposits. The deep brain stimulation produced long-lasting effects of glucose metabolism increase as well. Hence, through PET it was observed that DBS reversed the reduced glucose metabolism in the AD patients.

Overall the study demonstrated that DBS led to reactivation of memory circuits and increased glucose metabolism in brain regions where glucose metabolism is low or has even diminished. As well, the study established that the DBS approach is safe. The safety and amazing biological effects it has produced are sufficient enough to continue further research of this treatment method, which is currently being followed up by Dr. Andres Lozano and his research team at Toronto western Hospital Krembil Research Institute.

Results of Shock Therapy on Memory in non-Alzheimer’s patients

DBS to Treat Morbid Obesity was found to Elicit Autobiographical Memories

sLORETA Hypothalamic Stimulation
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Hypothalamic Stimulation lead to significant activity changes of the Ipsilateral Mesial Temporal Lobe.
Retrieved From:http://www.societyns.org/runn/2008/265-Memory%20enhancement%20induced%20by%20hypothalamic-fornix.pdf

A study done by Hamani et al used deep brain stimulation to treat a patient with morbid obesity. The 50-year-old man had life-long obesity and was not responding to dietary or medication treatments. Hypothalamic stimulation was taken as a new approach. This neurosurgical treatment was proposed based on studies of appetite control in animals, and previous use as a treatment for obesity in humans[3]. Deep Brain stimulation electrodes were implanted bilaterally in the ventral hypothalamus of the patient’s cranium[3]. While testing specific stimulation points to suppress appetite, the stimulation unexpectedly evoked a “déjà vu” sensation from the patient, who was under local anesthesia without sedation. At the original stimulation of 3.0 volts, the patient described himself observing a memory scene in the park from his younger years of 20. The memory was in color, and he could describe identifiable clothes that his friends in the memory were wearing. When the researchers increased the stimulation intensity from 3.0 to 5.0 volts, the patient reported the details in the memory becoming more vivid. These autobiographical memories could be elicited with stimulation of either the left or right most ventral electrodes. As researchers further tested out stimulation points, they found that contacts that most readily produced these “déjà vu” experiences were located in the thalamus. They estimated that these contacts were in the areas that are in close association to the fornix. Researchers looked further into the memory potential of the deep brain stimulation in this specific area and had the patient perform memory evaluation tasks. Each task was performed twice, once with stimulation and once without. In the first task, the patient was presented with a series of 80 word-pairs. After a ten minute break the patient underwent a recognition task where he had to identify whether the test pairs presented were the same as the ones he was previously presented, recombined, or new. 12 months later, he participated in a second task where 120 word pairs were presented and he had to generate a sentence containing the two words. After three months of DBS, the patient was found to have significant improvement in verbal and spatial learning tasks as opposed to pre-operational[3]. From the patient’s performance results from the two tasks, he was more likely to provide a “remember” response as opposed to “recognize” response of the stimulus pairs in the “on” stimulation condition (70%) then the “off” stimulation (43%)[3]. When his results were compared to that those of a healthy control group, his improvement in recollection with “on” stimulation in both tasks far exceeded the control groups. sLORETA was done 1 month after DBS and determined that there was a significant increase in the activity in ipsilateral mesial temporal lobe structures, mainly the hippocampus and the parahippocampal gyrus region[3].

DBS to Identify Seizure Onset Zones for Epilepsy Surgery Also Enhance Memory of Spatial Learning

In a study by Suthana et al, intracranial electrodes were implanted to identify seizure onset zones in epilepsy patients. However the researchers also investigated if DBS of the hippocampus or entorhinal cortex alters memory performance. Intracranial depth electrodes were implanted in seven patients. Of the seven, six subjects had entorhinal electrodes, five had at least one hippocampal electrode and four had both entorhinal and hippocampal electrodes. The electrodes elicited a voltage of up to 3.0 V at a pulse width of 450 microseconds and a frequency of 130 Hz[2]. The subjects completed a spatial learning task that involved them being taxi drivers in a virtual world. They had to learn their destinations via landmarks and pick up and deliver passengers to stores. During half of the trials, electrical stimulation was given. It was found that direct hippocampal stimulation had no effect on the subjects performance[2]. However, when entorhinal stimulation was given while the subjects were learning their virtual surroundings, it enhanced their memory of the environment[2]. This was measured by the fact that subjects reached passenger destinations more quickly and by shorter routes, as compared to locations learned without stimulation. Hence, the study found that spatial learning in humans can be enhanced by electrical stimulation in the entorhinal region, which is a prime gateway into the hippocampus.

Parkinson's Disease

Parkinson's Disease (PD) is a neurodegenerative disease affecting the cells in the substantia nigra of the brain, causing significant disability in people as the disease progresses [4]. The loss of cells in this part of the brain results in the blockage of neural messages within the brain that control the body’s movements. Other symptoms include slowed body movements, loss of posture or balance, difficulty talking, depression and lack of facial emotions [4]. PD affects about five million people worldwide [8], of which 100,000 are Canadians, with 10-20 per 100, 000 people being newly diagnosed every year in Canada [4]. Of those diagnosed, 85% are above the age of 65 years old [4]. While there is no cure, there is dopamine-enhancing medication and therapy based treatments to help with the severity of the symptoms.

ECT has been shown to have significant effects in the improvement of PD patients. Through research studies, it has been hypothesized that the effects of ECT in PD are beneficial as it enhances dopamine transmission and increases the sensitivity of dopamine receptors [8]. As well, these beneficial effects persist for periods after the ECT treatment [8]. In a study by Fall P.A et al. ECT was given to 16 patients with advanced Parkinson’s disease. An Anti-Parkinson effect was seen in all of the patients and lasted for as long as 18 months in one of the patients, and a couple of weeks to five months in eight other patients [5]. A significant increased level of homovanillic acid in cerebrospinal fluid was also observed in the patients [5]. Homovanillic acid is a metabolite of dopamine [5], hence increased resulted in increased levels of Dopamine. Cells in the substantia nigra, which are affected by degeneration in PD, are responsible for the production of Dopamine, resulting in the loss limbic motor movement. Hence, the increased levels of homovanillic acid resulted in long lasting motor improvement. In another study, an elderly man with Drug Induced parkinsinism (DIP) was treated with 8 treatments of bilateral ECT [7]. Drug induced Parkinsonism is the onset of Parkinsonism with the treatment use of particular medications [6]. These medications are usually dopamine inhibitors. This results in many of the same symptoms as Parkinson’s disease, such as slowed body movement, expressionless face and speech difficulties [6]. His symptoms improved and maintained for 6 months despite stopping the treatment [7].

Major Depressive Disorder

Depression can severely impact almost all aspects of a person’s life. It leads to no motivation, feeling helpless, empty and worthless, even to the point of suicidal thoughts. Depression is common as it can impact anyone such as children, mothers with post-partum depression, and even an everyday person in the workplace. With a significant portion of the population struggling with depression, more treatments need to be made. ECT is an effective treatment because it provides significant reliefs of depressive symptoms in patients, helping patients get back to their daily lives. ECT is one of the treatments showing major results in patients with depression as well as treatment-resistant depression patients. Patients that are treatment resistant have been observed to have a metabolically overactive Brodmann area 25, which is the subgenual cingulate region of the brain[12]. A study done by Mayberg, H.S. et al. found that using ECT in the adjacent white matter tracts to the subgenual cingulate gyrus can reduce the high metabolic activity, as it resulted in sustained reduction of depression. This shows that ECT can effectively reverse symptoms in otherwise treatment-resistant depression.

ECT is useful because it is safe to elicit to those of older aged groups that have medical conditions[11]. It is also beneficial because it can be a long-term treatment for patients that need maintenance as opposed to those that recover after a series of treatments [10]. Unfortunately for those that need continued maintenance, there is no solution to the common depression relapse that happens in 50% of patients within six to twelve months of discontinuing ECT treatments[11].

Obsessive Compulsive Disorder

Obsessive Compulsive Disorder is an anxiety disorder that is characterized by obsessive thoughts, which result in performing compulsive rituals[13]. These compulsive actions, however, only provide temporary relief from the anxiety. Hence a person with OCD struggles with these rituals, which can easily dominate and prevent them from living a normal life. An example of a common OCD obsession involves the extreme fear of germs and contamination. This disorder can occur in people of all ages, but usually the general onset is before forty years of age[13].

ECT is an effective treatment as it improves and can even resolve the symptoms of OCD as demonstrated in the following studies. In the study done by Alpak, G et al. ECT was used as a treatment in a patient with Bipolar Disorder accompanied by OCD. The treatment was elicited during a depressive episode of the bipolar disorder. Both the depressive and OCD symptoms were resolved and sustained with ECT treatments[14]. However the symptoms reoccurred once the treatment was discontinued. In another study by Makhinson, M et al. ECT was given to a patient for treatment of co-occurring Catatonia and OCD. The catatonia was treated medically and the OCD was treated with ECT simultaneously. Both disorder symptoms improved in the patient[15]. Hence, OCD symptoms can be affectively treated with ECT, however the benefits of the treatment stop if treatment discontinues.

Bibliography
1. Laxton et al. A Phase I Trial of Deep Brain Stimulation of Memory Circuits in Alzheimer’s Disease. American Neurological Association 00;1-13.(2010)
2. Suthana et al. Memory Enhancment and Deep-Brain Stimulation of the Entorhinal Area. The New England Journal of Medicine 366;502-510 (2012)
3. Hamani et al. Memory Enhancement Induced by Hypothalamic/Fornix Deep Brain Stimulation. Annals of Neurology 63; 119-123. (2008)
5. Fall P.A. et al. ECT in Parkinson's disease. Changes in motor symptoms, monoamine metabolites and neuropeptides. J Neural Transm Park Dis Dement Sect.;10(2-3):129-40 (1995)
6. Parkinson’s Disease Society. (2008). Retrieved from:http://www.parkinsons.org.uk/PDF/FS38_druginducedparkinsonism.pdf
7. Sadananda, S.K. et al. Effectiveness of electroconvulsive therapy for drug-induced parkinsonism in the elderly. J ECT. (1):e6-7. (2013)
8. Popeo, D. et al. ECT for Parkinson’s disease. Medical Hypotheses. Volume 73, Issue 4, Pages 468–469 (2009)
9. Alzheimer's Association. (2011). Retrieved from: http://www.alz.org/braintour/3_main_parts.asp
10. Sidney, H. et al. Deep Brain Stimulation for Treatment-Resistant Depression: Follow-Up After 3 to 6 Years. Am J Psychiatry;168:502-510. (2011)
11. Flint, A.J. et al. Effective use of electroconvulsive therapy in late-life depression. Can J Psychiatry;47(8):734-41.(2002)
12. Mayberg, H.S et al.Deep brain stimulation for treatment-resistant depression. Neuron.3;45(5):651-60.(2005)
13. Canadian Mental Health Association.(2013). Retrieved from: http://www.cmha.ca/mental_health/obsessive-compulsive-disorder/#.UVplkc3P0hQ
14. Alpak, G. et al. Maintenance Therapy With Electroconvulsive Therapy in a Patient With a Codiagnosis of Bipolar Disorder and Obsessive-Compulsive Disorder. J ECT (2013)
15. Makhinson, M. et al. Successful treatment of co-occurring catatonia and obsessive-compulsive disorder with concurrent electroconvulsive therapy and benzodiazepine administration. J ECT.(3):e35-6 (2012)
16. Mayo Clinic. Electroconvulsive Therapy. (2012)Retrieved from:http://www.mayoclinic.com/health/electroconvulsive-therapy/MY00129
17. Mayo Clinic. Deep Brain Stimulation. (2013) Retrieved from:http://www.mayoclinic.com/health/deep-brain-stimulation/MY00184
18. CTV News. Canadian researchers study alternative therapy for hard-to-treat depression. Retrieved from :http://www.ctvnews.ca/health/canadian-researchers-study-alternative-therapy-for-hard-to-treat-depression-1.1035803#ixzz2PHcANJMh

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