Parkinson's disease, also known as shaking palsy, is a degenerative disorder of the central nervous system that mainly affects the motor system. Symptoms start slowly at the onset of the disease, the most noticeable being tremors, contractions, decreased movement and gait abnormalities. Problems with thinking and behavior may also occur. Dementia becomes common in the later stages of the disease. Depression and anxiety are also common symptoms, occurring in more than a third of people with Parkinson's disease. Sensory symptoms include sleep disturbances and emotional problems. The main motor symptoms are collectively called "parkinsonism", or "parkinsonian syndrome". The cause of Parkinson's disease is generally unknown, but is thought to involve genetic and environmental factors. There is also an increased risk in people exposed to certain pesticides and among those who have had head injuries, while there is a lower risk in tobacco smokers and those who drink coffee or tea. The motor symptoms of the disease result from cell death in the substantia nigra, an area of the midbrain. This leads to insufficient dopamine in these areas. The cause of cell death is not understood, but it involves the accumulation of proteins in the bodies of the brain. Lewy in neurons. Diagnosis of typical cases is based mainly on symptoms, with tests such as neuroimaging used to rule out other diseases. There is no cure for Parkinson's disease. Initial treatment is usually the antiparkinsonian drug levodopa with a dopamine agonist. As the disease progresses, neurons continue to be lost, so these drugs become less effective. Diet and some forms of rehabilitation have shown some effectiveness in improving symptoms. Neurosurgery to place microelectrodes to stimulate the brain has been used to reduce motor symptoms in severe cases when drugs are ineffective. In 2015, Parkinson's disease affected 6.2 million people and resulted in about 117,400 deaths worldwide. Parkinson's disease usually occurs in people over the age of 60. Males are more affected than females. When the disease affects people under the age of 50, it is called juvenile Parkinson's disease. The average life expectancy after diagnosis of Parkinson's disease is between 7 and 14 years. The disease was discovered by the English physician James Parkinson, who published the first detailed description in a paper on shaking palsy, in 1817. Public awareness campaigns include World Parkinson's Day and the use of a red tulip as a symbol for the disease. People who have suffered from Parkinson's disease and have helped raise public awareness of the condition include actor Michael J. Fox, Olympic cyclist Davis Finney, and the late boxer Muhammad Ali. The movement difficulties found in Parkinson's disease are called "parkinsonism." The motor symptoms of "parkinsonism" are bradykinesia (slowness in initiating voluntary movements, with a gradual decrease in speed), plus one of three other physical signs: muscle rigidity, tremor, and postural instability. Parkinson's disease is sometimes called "idiopathic Parkinsonism," because no specific cause is known. Identifiable causes of Parkinson's disease include toxins, infections, drug side effects, metabolic deterioration, and brain lesions such as strokes. Several neurological disorders can also occur with Parkinsonism, sometimes referred to as "atypical Parkinsonism" or "Parkinsonism plus." They include multiple system atrophy, progressive supracentral palsy, Cortical degeneration, dementia and Lewy body disease. Scientists sometimes refer to Parkinson's disease as a synucleinopathy to distinguish it from other neurodegenerative diseases, such as Alzheimer's disease, in which the protein tau accumulates in the brain. There is considerable clinical and pathological overlap between tonopathies and synucleinopathies. In contrast to Parkinson's disease, Alzheimer's disease is most commonly associated with memory loss, and the cardinal signs of Parkinson's disease are not typical features of Alzheimer's disease. Dementia and Lewy body disease are closely related to Parkinson's disease. The relationship between Parkinson's disease and Lewy body disease is quite complex. They may represent parts of a continuum with distinct clinical and pathological features or may prove to be separate diseases. The most characteristic symptom of Parkinson's disease is difficulty with movement. Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems, sensory and sleep difficulties, are also common. Some of these non-motor symptoms may be present at the time of diagnosis. The four cardinal motor symptoms in Parkinson's disease are tremor, decreased The most common motor symptom in Parkinson's disease is a slow tremor of the hand that disappears during voluntary movement of the affected arm and in the stages of deep sleep. This tremor usually occurs in one hand, but the other hand eventually becomes affected as the disease progresses. The tremor frequency in Parkinson's disease is between 4 and 6 hertz per second. A characteristic of the hand tremor is the tendency of the index finger and thumb to touch each other and make a circular motion. Hypokinesia is present in all cases of Parkinson's disease, and is due to disturbances in the motor planning of movement initiation, and is associated with difficulties along the movement process, from planning to initiation to execution of a movement. Motor performance is impaired. Bradykinesia is the most disabling symptom of Parkinson's disease, leading to difficulties in daily tasks such as dressing, feeding, and bathing. It leads to particular difficulty in performing two independent motor activities at the same time, and can be worsened by psychological stress or concurrent illnesses. Ironically, patients with Parkinson's disease can often ride a bicycle or climb a mountain. Stairs are easier to climb than walking. While most doctors may easily notice slowness of movement, a formal evaluation requires the patient to make repetitive movements of the fingers and toes. Rigidity is a symptom of Parkinson's disease and is a stiffness and resistance to movement of the limbs caused by increased muscle tone and excessive and persistent muscle contraction. Rigidity is a combination of tremor and increased muscle tone at the same time. Rigidity may be associated with joint pain. This pain is a frequent initial manifestation of the disease. In the early stages of Parkinson's disease, rigidity is often asymmetrical and tends to affect the neck and shoulder muscles before the face and limbs. As the disease progresses, rigidity usually affects the entire body and reduces the ability to move. Postural instability is common in the later stages of Parkinson's disease, leading to poor balance and frequent falls that can lead to bone fractures, loss of confidence, and decreased mobility. Instability is often absent in the early stages, especially in young people, especially before the onset of bilateral symptoms. Up to 40% of people diagnosed with Parkinson's disease fall to the ground frequently. Other recognized signs and symptoms include The symptoms that affect the patient's motor system are: , and also signs: quiet voice, a face that does not move, and the patient's handwriting becomes noticeably smaller over time. Parkinson's disease can cause neuropsychiatric disorders, which can range from mild to severe disorders. These include disorders of perception, mood, behavior, and thought. Cognitive disorders can occur in the early stages of the disease and sometimes before diagnosis, and these disorders increase with increasing age of the patient and the progression of the disease stages. The most common cognitive deficit in Parkinson's disease is impaired execution and planning, which can include problems with planning, cognitive flexibility, abstract thinking, inhibiting inappropriate actions, initiating appropriate actions, and working memory. Other cognitive difficulties include slow cognitive processing speed, decreased neurotransmission, poor perception, and time estimation. Vision problems are also part of the disease, for example, when an individual is asked to perform facial recognition tests and perceive the direction of drawn lines, they cannot easily determine this. A person with Parkinson's disease has two to six times the risk of dementia compared to the general population. The prevalence of dementia increases with age and the length of the disease. Dementia is associated with With a reduced quality of life for people with Parkinson's disease and their caregivers, the patient is more likely to require home nursing care. Behavior and mood changes are more common in Parkinson's patients without cognitive impairment than in healthy people, and behavioral and mood changes are often associated with dementia. The most common mood problems are depression, apathy, and anxiety. Diagnosing depression is complicated by the fact that the body language of depression can masquerade as Parkinson's disease, such as a sad, expressionless face, slow movements, and a quiet, broken voice - all of which could be Parkinson's disease or just depression, and thus distinguishing between them using these symptoms alone is very difficult. Up to 30% of people with Parkinson's disease may have symptoms of anxiety, ranging from generalized anxiety disorder to social anxiety disorder, panic disorder, and obsessive-compulsive disorder. Dissociative identity disorder, in which repetitive, purposeless, stereotyped behaviors occur only for a few hours, is another disorder caused by anti-Parkinson's medication. Hallucinations or delusions occur in about 50% of people with Parkinson's disease over the course of the disease, and can be a sign of Dementia. These range from minor hallucinations—“feeling like you’re passing by” or “feeling like you’re there”—to visual hallucinations and paranoid thoughts. Auditory hallucinations are uncommon in Parkinson’s disease, and are rarely described as voices. Psychosis is now thought to be an integral part of the disease. Psychosis with associated delusions and delirium is a recognized complication of anti-Parkinson’s therapy and can also be caused by urinary tract infections, but drugs and infections are not the only factors behind the pathology or changes in neurotransmitters or their receptors are thought to play a role in psychosis in Parkinson’s disease. In addition to neuropsychiatric and motor symptoms, Parkinson’s disease can be compounded by problems with other systems. Sleep problems are a feature of the disease and can be exacerbated by medications. Symptoms can include daytime sleepiness, sleep disturbances, or insomnia. Rapid eye movement (REM) sleep, where the patient acts as if they are dreaming, and sometimes injures themselves or their bed partner, may begin many years before the motor system or cognitive features of Parkinson’s disease develop. Changes in the autonomic nervous system can lead to orthostatic hypotension, seborrheic dermatitis, excessive sweating, urinary incontinence, and altered sexual function. Constipation and stomach weakness can be severe enough to cause discomfort and even endanger health. Changes in cognition may include a poor sense of smell, blurred vision, and pain. All of these symptoms can occur years before the disease is diagnosed. Exposure to pesticides and head injury have been linked to Parkinson's disease, but the risk is relatively low. People who have never smoked cigarettes have an increased risk of Parkinson's disease and moderate consumption of caffeinated beverages increases the risk of the disease. Low serum concentrations of urate may increase the risk of Parkinson's disease. Parkinson's disease is presumed to be a non-inherited disorder, but it appears to be the product of a complex interaction of genetic and environmental factors. About 15% of individuals who have a close relative with the disease also have the disease, and 5-10% of people with Parkinson's disease may be caused by a mutation in one of several specific genes. These gene mutations lead to the disease, and they put an individual at increased risk, often in combination with other risk factors, but in most cases, people with these mutations will develop Parkinson's disease. The genes involved in the development of Parkinson's disease are: alpha-synuclein, LRRK2, GBA, PRKN, PINK1, PARK7, VPS35, EIF4G1, DNAJC13 and CCHHD2. SNCA gene mutations are important in Parkinson's disease because the protein the gene encodes, alpha-synuclein, is a major component of Lewy bodies that accumulate in people's brains. Mutations in certain genes, including SNCA, LRRK2, and GBA, have been found to be risk factors. Mutations in the LRRK2 gene are the most common cause of Parkinson's disease, accounting for about 5% of individuals with a family history of the disease and 3% of sporadic cases. A mutation in GBA greatly predisposes a person to the development of Parkinson's disease. Several genes associated with the disease are involved. Parkinson's disease in lysosomal function. It has been suggested that some cases of Parkinson's disease may be caused by lysosomal dysfunctions that reduce the cells' ability to break down alpha-synuclein. The main pathology of Parkinson's disease is cell death in the basal ganglia of the brain as well as in many of the remaining neurons. This is accompanied by neuronal loss, astrocyte death, and a significant increase in the number of microglia in the substantia nigra. There are five major pathways in the brain that connect other brain regions to the basal ganglia. These are known as the motor cortex, oculo-motor cortex, temporal cortex, limbic system, and orbitofrontal cortex. All of them are affected in Parkinson's disease, and disruption of these brain regions explains many of the symptoms of the disease, because these circuits are involved in a wide range of functions, including movement, attention, and learning. There is a particular conceptual model of the motor system and its alteration in Parkinson's disease that has been influential since the 1980s, although some limitations have led to some modifications. In this model, the basal ganglia typically exert a persistent inhibitory influence on a wide range of systems. Motor, preventing them from becoming active at inappropriate times. When a decision is made to perform a certain action, the inhibition of the required motor system is reduced, thus releasing it for activation. Dopamine acts to facilitate this release from the motor system, so high levels of dopamine tend to promote motor activity, which is what happens in Parkinson's disease where the patient requires more effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, a general decrease in motor output. Drugs used to treat Parkinson's disease may work by increasing dopamine, allowing motor systems to be activated. There are several mechanisms by which brain cells can be lost. One mechanism consists of an abnormal accumulation of the ubiquitin-bound protein alpha-synuclein in damaged cells. This insoluble protein accumulates within neurons forming derivatives called Lewy bodies. According to Braak, the disease is classified on the basis of pathological findings. Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum. Individuals at this stage may be asymmetrical or may have They have early non-motor symptoms. As the disease progresses, Lewy bodies develop in the substantia nigra, areas of the midbrain and basal forebrain, and finally, the neocortex. These sites in the brain are the main sites of neuronal degeneration in Parkinson's disease. However, Lewy bodies may not cause cell death and may be protective. Other forms of alpha-synuclein that do not aggregate into Lewy bodies while Lewy neurites are toxic forms of the protein. In people with dementia, Lewy bodies are common in cortical areas. Neurofibrillary tangles and senile plaques, which are characteristic of Alzheimer's disease, are not common unless the person is demented. Other mechanisms of cell death include dysfunction of the proteasomal and lysosomal systems and reduced mitochondrial activity. Iron accumulation in the substantia nigra is often seen in conjunction with protein inclusions. It may be related to oxidative stress, protein aggregation, and neuronal death, but the mechanisms are not fully understood. The physician initially evaluates Parkinson's disease with a history Careful medical and neurological examination. The patient may be given levodopa, and any resulting improvement in motor system dysfunction helps to confirm the diagnosis of Parkinson's disease. The finding of Lewy bodies in the midbrain on autopsy is usually considered definitive evidence that the person has had Parkinson's disease. The clinical course of the disease over time may reveal it is not Parkinson's disease, requiring periodic review of the clinical presentation to confirm the diagnosis. Other causes that can secondarily resemble Parkinson's disease are stroke and drugs. Progressive suprarenal palsy and multiple system atrophy should be excluded. Antiparkinsonian drugs are usually less effective in controlling symptoms in Parkinson's plus syndromes. Rates of progression, early cognitive impairment, or postural instability may initially indicate Parkinson's disease. Genetic forms with an autosomal or recessive pattern of inheritance are sometimes referred to as familial Parkinson's disease. Medical organizations have developed diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely recognized criteria come from the British Neurological Disorders Bank and the National Institute of American Neurological Association and Stroke. The Kingdom criteria require bradykinesia plus either rigidity, tremor, or postural instability. Other possible causes of these symptoms need to be ruled out. Finally, three or more of the following supporting features are required during the onset or progression of the disease: disease on only one side of the body, tremor at rest, asymmetry of motor symptoms, and response to levodopa therapy for at least five years. When diagnoses of Parkinson's disease are examined by autopsy, movement disorders are found to be an average of 79.6% accurate at initial assessment and 83.9% accurate after their diagnosis has been refined at follow-up examination. When clinical diagnoses performed primarily by nonpsychologists are examined by autopsy, average accuracy is 73.8% and 82.7% of diagnoses using brain bank criteria. A task force of the International Parkinson's and Movement Disorders Society has proposed diagnostic criteria for Parkinson's disease, as well as research criteria for the diagnosis of prodromal disease, but they require validation of the more established criteria. Computed tomography is usually It appears normal in people with Parkinson's disease, and MRI has become more accurate in diagnosing the disease over time, specifically iron-sensitive T2* and magnetization-weighted MRI at at least 3T, both of which can show the absence of the characteristic "swallow tail" imaging pattern in the dorsolateral substantia nigra. In a meta-analysis, the absence of this pattern was 98% and 95% specific for this disease. Diffusion MR imaging shows the potential to differentiate between Parkinsonism and Parkinson's plus syndrome, although its diagnostic value is still under investigation. CT and MRI are also used to rule out other diseases that can be secondary causes of parkinsonism, most commonly encephalitis and chronic brain insults, as well as less common entities such as basal ganglia tumors and hydrocephalus. Dopamine-related activity in the basal ganglia can be measured directly with PET and SPECT scans. The detection of decreased dopamine-related activity in the basal ganglia can rule out drug-induced parkinsonism, but decreased dopamine-related activity Basal ganglia dopamine in both Parkinson's and Parkinson's Plus disorders is not reliable in distinguishing Parkinson's disease from other disorders. Exercising in middle age may reduce the risk of Parkinson's disease later in life. Caffeine also appears to be protective against Parkinson's disease and shows a greater reduction in risk than occurs with a higher intake of caffeinated beverages such as coffee. People who smoke cigarettes or use smokeless tobacco are less likely than nonsmokers to develop Parkinson's disease, and the more tobacco they use, the less likely they are to develop it. It is not known what underlies this effect. Tobacco use may actually protect against Parkinson's disease. Antioxidants, such as vitamin C and vitamin E, have been suggested to protect against the disease, but study results have been inconsistent and no positive effect has been demonstrated. Results regarding fatty acids have been inconsistent, with studies reporting different protective effects and increased risk effects. There have been preliminary indications that the use of anti-inflammatory drugs and calcium channel blockers may be protective. A 2010 analysis found that nonsteroidal anti-inflammatory drugs, NSAIDs, were associated with a 15 percent At least reduce the incidence of Parkinson's disease progression. There is no cure for Parkinson's disease, but medications, surgery and physical therapy can provide relief to patients and are much more effective than treatments available for other neurological disorders such as Alzheimer's disease, motor neuron disease, Parkinson's syndrome and multiple sclerosis. The main families of medications useful for treating motor symptoms are levodopa, dopamine agonists and MAO-B inhibitors. The stage of the disease and age at onset of the disease determine which group is most useful. Three stages can be distinguished: an initial stage where the individual with the disease has developed some disability requiring drug therapy, a second stage associated with the development of complications related to the use of levodopa, and a third stage with symptoms unrelated to dopamine or levodopa deficiency. Treatment in the first stage aims at an optimal trade-off between symptom control and treatment of side effects. Levodopa can be delayed initially by using other medications such as MAO-B inhibitors and dopamine agonists instead of levodopa itself, in the hope of delaying the onset of complications due to the use of levodopa. However, levodopa remains the most effective treatment for motor symptoms and should not be delayed in patients whose quality of life is impaired by those symptoms. Dysfunction is associated with Levodopa is more potent with the duration and severity of the disease, so delaying this treatment is not the best solution in this case. In the second stage, the goal is to reduce the symptoms of Parkinson's disease while controlling fluctuations in the drug's effect. Abrupt withdrawals from the drug or overuse must be managed. Oral medications are not sufficient to control symptoms and therefore surgery, deep brain stimulation, subcutaneous injections of apomorphine and intestinal dopa pumps can be of benefit. The third stage presents many difficult problems requiring a variety of treatments for psychological symptoms, orthostatic hypotension, bladder dysfunction, etc. In the final stages of the disease, care is provided to improve the quality of life. Levodopa has been the most widely used treatment for more than 30 years. L-DOPA is converted to dopamine in neurons by dopa-decarboxylase. Since motor symptoms result from a lack of dopamine in the substantia nigra, the use of L-DOPA temporarily reduces motor symptoms. Only 5-10% of L-DOPA crosses the blood-brain barrier. The rest is often converted to Dopamine elsewhere, causing a wide range of side effects including nausea, dyskinesia. Carbidopa and benserazide are dopa decarboxylase inhibitors that inhibit the formation of dopamine elsewhere, thereby minimizing the side effects of treatment as much as possible. They inhibit the metabolism of L-DOPA elsewhere, thereby increasing the delivery of levodopa to the central nervous system. Current inhibitors are carbidopa/levodopa and benserazide/levodopa. Tolcapone inhibits the enzyme catechol-O-methyltransferase, which degrades dopamine and levodopa, thereby prolonging the therapeutic effects of levodopa. Tolcapone is used, in combination with peripheral dopa decarboxylase inhibitors, to increase the therapeutic potency of L-DOPA. However, this treatment is limited, due to its potential side effects such as liver failure. A similar drug, entacapone, has not been shown to cause significant changes in liver function and maintains adequate COMT inhibition over time. Entacapone can be used as a treatment or in combination Along with carbidopa and levodopa, the results of using levodopa work to reduce the body's own formation of L-DOPA, in the long term treatment can cause the development of motor complications characterized by involuntary movements, motor dysfunction, and fluctuations in response to medications. When this happens, a Parkinson's patient goes from a patient who responds very well to treatment and has a noticeable improvement in the disappearance of symptoms of the disease to a patient who does not respond at all to treatment and the appearance of the disease symptoms in a bad way. For this reason, Parkinson's patients are given as low doses of levodopa as possible to reduce this problem. Delaying the initiation of drug treatment, rather than using alternatives for some time, is also common to avoid this problem. The previous strategy to reduce motor complications was to withdraw L-DOPA from patients for some time. But it was a bad thing because it could bring serious side effects such as the syndrome. Most patients eventually need levodopa and later on motor complications will appear. The phenomenon of pathological complications due to the use of treatment is called in English and is an almost constant result of sustained levodopa treatment in patients with Parkinson's disease. Stages Immobility and disability associated with depression. All of these symptoms are responsible for the treatment, and despite all the problems caused by pharmacological agents in Parkinson's patients, evidence is presented to indicate the importance of treating with levodopa. Redistributing the doses of levodopa to smaller and more frequent doses may be useful in controlling oscillations in some patients. Restricting dietary protein and using selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. A new approach to treatment involves the use of apomorphine subcutaneously, and the release of small amounts of levodopa with a peripheral dopa decarboxylase inhibitor. This helps reduce complications resulting from the use of L-DOPA. The dopamine agonist has a similar effect to levodopa because it binds to dopamine receptors in the brain. Dopamine agonists were initially used for patients with L-DOPA treatment problems and dyskinesia as an adjunct to levodopa, but are now used mainly on their own as a first-line treatment for motor symptoms with the aim of delaying motor complications. Dopamine agonists include: bromocriptine, Pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride. Dopamine agonists have many side effects, albeit mild, such as drowsiness, hallucinations, insomnia, nausea, constipation. Sometimes, side effects occur even at the lowest clinically effective dose, leading the physician to look for a different agonist. Compared to levodopa, dopamine agonists delay motor complications, and control symptoms worse than levodopa. However, they are usually effective enough to manage symptoms in the early years. Dopamine agonists are also more expensive. Dopamine agonists at high doses cause impulse control disorders. Dyskinesias with dopamine agonists are rare in younger patients, and more common in older patients. All of this illustrates the importance of dopamine agonists as a first-line treatment for Parkinson's disease over levodopa. Apomorphine, a dopamine agonist that is not taken orally, can be used to reduce motor loss in the later stages of the disease. Since secondary effects such as confusion Hallucinations are not uncommon with apomorphine treatment, and patients should be closely monitored. Apomorphine can be administered by subcutaneous injection using a small pump carried by the patient. A low dose is administered automatically throughout the day, thus limiting fluctuations in motor symptoms by providing consistent doses of dopamine agonists. When using an apomorphine pump, the injection site should be changed daily to avoid nodules forming. Apomorphine is also available in large doses as an autoinjector pen used for emergency dosing such as falls or first thing in the morning. Nausea and vomiting are common with apomorphine, and may require domperidone. In a study evaluating the efficacy of dopamine agonists compared to levodopa, the results showed that patients who took dopamine agonists were less likely to develop dyskinesia, dystonia, and movement fluctuations, although they were more likely to discontinue treatment due to negative side effects such as nausea, constipation, etc. MAOIs work by increasing the level of dopamine in the basal ganglia. They inhibit monoamine oxidase-B, which By breaking down dopamine released from neurons. Therefore, reducing MAO-B leads to higher amounts of L-DOPA. Like dopamine agonists, MAO-B inhibitors improve motor symptoms and delay the need to take levodopa as a monotherapy in the early stages of the disease, but these inhibitors produce more negative effects and are less effective than levodopa. Their effectiveness in the advanced stage of the disease is also poor. The metabolites of selegiline include: L-amphetamine and L-methamphetamine. This may lead to side effects such as insomnia. Another side effect can be inflammation of the mouth. Unlike other monoamine oxidase inhibitors, foods containing tyramine do not cause hypertensive crisis. Some evidence suggests that other drugs such as amantadine and anticholinergics may be useful as treatments for motor symptoms in early and late Parkinson's disease, but these drugs are not considered the first-line treatment for the disease. In addition to motor symptoms, Parkinson's disease is accompanied by a range of different symptoms and different compounds are used to improve some of these problems. An example of this is the use of clozapine For psychosis, cholinesterase inhibitors for dementia, and modafinil for drowsiness. A preliminary study suggests that taking donepezil may help prevent falls in Parkinson's patients. Donepezil boosts levels of the neurotransmitter acetylcholine, and is currently the approved treatment for the cognitive symptoms of Alzheimer's disease. The introduction of clozapine represents a major breakthrough in the treatment of psychotic symptoms of Parkinson's disease. Before the introduction of clozapine, treatment of psychotic symptoms relied on dopamine reduction therapy or treatment with first-generation antipsychotics, all of which were detrimental to motor function in patients. Atypical antipsychotics useful in treatment include quetiapine, ziprasidone, aripiprazole, and paliperidone. Clozapine is thought to have the highest efficacy and fewest side effects. Parkinson's disease used to be treated with surgery, but after the discovery of levodopa, surgery was limited to only a small number of cases. Studies in the past few decades have led to significant improvements in surgical techniques, and surgery is being used again in people with advanced Parkinson's symptoms who are no longer treated. Medication is sufficient for them. Less than 10% of Parkinson's patients qualify as suitable candidates for surgical response. Three different mechanisms of surgical response for Parkinson's disease are: , deep brain stimulation, or restorative surgery. Target areas for deep brain stimulation include the thalamus, globus pallidus, or subthalamic nucleus. The neuronal lesion is destroyed by heat, and parts of the brain associated with producing parkinsonian neurological symptoms are destroyed. Procedures generally involve thalamotomy and/or globus pallidus. For the thalamus, a portion of it is destroyed, particularly the ventromedial thalamic nucleus (nucleus pallidus), to suppress tremor in 80-90% of patients. If akinesia is evident, the site of ablation is the subthalamic nucleus. In patients with akinesia or