I. Introduction

The cerebrum, which is in front or top of the brainstem (as shown in Fig.1), makes up a large portion of the brain. It is the largest and most developed part of the brain's five major divisions in humans. In a phylogenetic sense, the cerebrum is the most recent structure, with mammals having the largest and most developed among all species. It contains the cerebral cortex that develops from the dorsal telencephalon or pallium, and the basal ganglia that develop from the ventral telencephalon, or sub-pallium, in mammals. The cerebral cortex in larger mammals is folded into many gyri and sulci, allowing it to expand in a surface area without taking up much more volume. The cerebrum controls all voluntary actions in the body with the help of the cerebellum.

II. Overview of the cerebrum

i. Cerebral cortex

A large sulcus divides the cortex into two hemispheres, right and left. The corpus callosum, a thick fiber bundle that connects the two hemispheres, allows information to flow from one side to the other. The right hemisphere is in charge of controlling and processing signals from the left side of the body, while the left hemisphere is in charge of controlling and processing signals from the right. Figure 2 shows the internal structure of the cerebral cortex.

ii. The four brain lobes

Each hemisphere of the mammalian cerebral cortex has four functionally and spatially distinct lobes: frontal, parietal, temporal, and occipital (as shown in Fig.3).

The frontal lobe, located at the front of the brain, over the eyes, contains the olfactory bulb. The frontal lobe also houses the motor cortex, which is responsible for movement planning and execution.

Processing somatosensorial (touch sensations such as pressure, pain, heat, and cold) and proprioception are two of the main functions of the parietal lobe (the sense of how parts of the body are oriented in space).

The temporal lobe is near the base of the brain, near the ears. Its primary function is to process and interpret sounds. It also houses the hippocampus, which is in charge of memory formation. The occipital lobe is in the back of the brain. It is mostly concerned with the vision: seeing, recognizing, and identifying the visual world.

iii. Cerebrum function

III. Cerebral lobes

i. The frontal lobe

ii. The parietal lobe

iii. The occipital lobe

iv. The temporal lobe

IV. The white matter of the cerebrum

White matter is one of the two components of the central nervous system (CNS). It is made up primarily of glial cells and myelinated axons, and it makes up the majority of the deep parts of the cerebrum and the superficial parts of the spinal cord (as shown in Fig.5). Because myelin is primarily composed of lipid tissue with capillaries, white matter tissue in a freshly cut brain appears pinkish white to the naked eye.

White matter axons carry nerve impulses between neurons and transmit signals from various grey matter areas (the locations of nerve cell bodies) of the cerebrum to one another. While grey matter is associated with processing and cognition, white matter modulates action potential distribution, acting as a relay and coordinating communication between different brain regions.

V. Conclusion

I. Introduction

Addiction is a chronic disease involving complex interactions among brain circuits, genetics, the environment, and an individual's life experiences. People with addiction use substances such as drugs and engage in compulsive behaviors despite the bad consequences. It starts when a person feels something enjoyable; the reward system in the brain releases dopamine and other chemicals. This action reinforces the brain’s association between certain things and feelings of pleasure, making the person want those things again. The desire to experience these things again grows over time until it becomes a craving. This is the first sign of addiction. Through the continuous use of a substance or engaging in a behavior, the brain produces a large amount of dopamine. The brain’s reward system gets used to this amount and needs it. Then, the person loses interest in things he once enjoyed, because the brain no longer produces much dopamine in response to natural triggers. The addiction develops and the person becomes unable to control his need for substance or behavior, and cannot give up on it [2]. Studies have shown that drug abuse has harmful effects on the metabolic processes in the brain. Health care offers treatment of different types of addiction for those people to increase productivity, as shown in fig1 [3].

II. Mechanism of addiction

A binge/intoxication-related circuit, a withdrawal/negative affect-related circuit, and a preoccupation/anticipation (ie, craving)-related circuit have all been identified as having heuristic value for the study of neurobiological changes associated with the development and persistence of drug dependence (look at fig 2). Such pathways could be important in the treatment of drug addiction with CRF receptor antagonists, corticotropin-releasing factor (CRF) is a 41-amino acid polypeptide that mediates hormonal, autonomic, and behavioral responses to stressors. The acute reinforcing effects of drugs of abuse in the binge/intoxication stage are most likely due to actions involving the ventral striatum and extended amygdala reward system, as well as dopaminergic and opioid inputs from the ventral tegmental area (VTA) and arcuate nucleus of the hypothalamus, respectively [4].

III. Types of addiction

i. Chemical addiction

ii. Behavioral addiction

Although some researchers do not consider behavioral addiction as a real addiction, the Diagnostic and Statistical Manual of Mental Disorders now recognizes two behavioral addictions, which are gambling addiction and internet gaming disorder. However, the general signs of behavioral addiction include spending a lot of time engaging in the behavior, hiding it from other people, feeling anxiety or depression when attempting to quit, and difficulty in avoiding it. Behavioral addiction can be considered under the term “impulse control disorder”. Compulsive shopping, pathologic skin picking, sexual addiction, excessive tanning, video game playing, and internet addiction are among the impulse control disorders, as in fig 3. It's still up for dispute which habits should be classified as behavioral addictions. Behavioral addictions should not include all impulse control disorders or diseases marked by impulsivity. Many impulse control disorders (e.g., pathological gambling) appear to have core characteristics in common with substance addictions [2, 6].

IV. Addiction treatment

The first step in treatment is detoxification. It involves clearing a substance from the body and limiting the reactions. If a person is addicted to more than one substance, they will often need medications to reduce withdrawal symptoms for each. Then, the common treatment is counseling therapies. Counseling helps people change behaviors and attitudes around using a substance, as well as strengthening life skills and supporting other treatments. There are different types of therapies include cognitive-behavioral therapy, multidimensional family therapy, and motivational interviewing. Rehabilitation programs are longer-term treatment programs for substance-related and addictive disorders that can be highly effective and typically focus on remaining drug-free and resuming function within social responsibilities. Self-help groups, shown in fig 4, are where people of the same addiction meet and have conservation that leads to increase the motivation to stop the substance. People most commonly use medications during detoxification to manage withdrawal symptoms. They vary depending on the substance that the person is addicted to. Longer-term use of medications helps to reduce cravings and prevents a return to using the substance after having recovered from addiction. Medication is not a standalone treatment for addiction and should accompany other management methods such as psychotherapy [7].

V. Rat park experiment

In the late 1970s, professor Bruce K. Alexander has performed an experiment called “Rat Park” to determine whether outside factors could influence the potential for addiction. He took two groups of mice and separate them. Half of them were isolated in individual cages. The other half was housed in a giant, open-designed enclosure with walls painted to look like timber and cedar sawdust and dozens of crates for the mice to live and play in, essentially providing everything needed to keep the rats happy. Most importantly, the mice living in this enclosure were able to play and socialize with each other. This enclosure was known as “Rat Park” (fig 5) [8].

VI. Conclusion

I. Introduction

Parkinson’s is a neurodegenerative disease that affects the motor control of our bodies and may has other noncognitive effects. It was first diagnosed in 1817 by James Parkinson. The disease has many subtypes and shares symptoms with other diseases. It can cause cognitive and noncognitive symptoms. It also can result in the development of dementia. Unfortunately, the direct cause behind its pathogenesis is still unknown but there are some present theories that try to connect the dots. The treatments of the disease are all symptomatic, and there aren’t any disease modifying drugs. However, there are promising medications on the way. To understand how the treatments affect the disease, we have to look into its root causes.

II. Causes

There is no doubt that a correlation between loss of dopamine neurons and Parkinson’s disease exists. To understand this correlation, let’s look at the cause of neuronal loss of dopamine neurons. Dopamine neurons in the substantia nigra are lost as we age. About one third of them are lost between the age of 20 and 90 years. The cause behind this is considered to be due to the oxidative stress (reactive oxygen species irregular manifestation). The enzymatic oxidation of dopamine generates hycytotoxic hydroxyl radicals in the presence of iron (Ⅱ) which is rich in the substantia nigra. On the other hand, non-enzymatic oxidation of dopamine yields superoxide, which produces a quinone that binds to a thiol group and denatures active protein. This evidence connects oxidative stress to the deterioration of dopamine [1].

The depletion in dopamine neurons and the clinical features that show up as we age is very similar to what happens in Parkinson’s disease patients. Thus, aging has been considered to play a role in the development of Parkinson’s disease. Parkinson’s was thought to be an accelerated form of aging. However, other processes are considered to be involved in the pathogenesis of Parkinson’s disease as the loss of dopamine neurons is different in aging and Parkinson’s disease. Other evidence supports the notion that neurotoxins are involved in the deterioration of nigra-striatal dopamine system. A neurotoxin called (NM(R)Sal) was found to induce parkinsonism in rats. NM(R)Sal (R refers to R enantiomer) was found in the human brain, cerebrospinal fluid, and intraventricular fluid. (NM(R)Sal) is synthesized by a two-step enzyme reaction from dopamine as shown in Figure 1. (R)Sal is synthesized from dopamine and acetaldehyde by a (R)Salsolinol synthase and turns into (NM(R)Sal) with the addition of an N-methyltransferase [1].

NM(R)Sal is considered to occur in the nigra-striatum due to high activity of N-methyltransferase in this brain region. After its synthesis, NM(R)Sal is oxidized into (DMDHIQ+) by enzymatic or non-enzymatic oxidation that generates hydroxyl radicals. Also, the in vitro and in vivo experiments suggest that the accumulation of (DMDHIQ+) in the substantia nigra is due to the binding of (DMDHIQ+) to neuromelanin (found in large quantities in the substantia nigra). Data suggest that NM(R)Sal synthesized in the striatum is transported by retrograde axonal flow to the substantia nigra and oxidized there or on the way to produce the DMDHIQ+ [1]. It has been proven that the oxidation of (NM(R)Sal) generates hydroxyl radicals and induces the apoptotic death process [5]. In a study with 16 Parkinson’s patients, 12 of the 16 patients’ (NM(R)Sal) level was more than 6 nano molars in the cerebrospinal fluid compared with the control who had a (NM(R)Sal) level lower than 6 nano molars.

III. Motor symptoms

Parkinson’s disease since its discovery was associated with motor symptoms. Afterall, that is how Dr. James Parkinson identified it as shaking then palsy. Parkinson’s disease includes the three most agreed upon symptoms: tremor, rigidity, and bradykinesia (slowness of movement). The onset of Parkinson’s disease may start as early as 12 to 14 years before diagnosis of the disease. Recent data support the fact that Parkinson’s disease start in the peripheral autonomic nervous system and/or olfactory bulb. Then, it spreads through the nervous system, affecting the lower brain stem before reaching the substantia nigra. Clinical diagnosis of Parkinson’s disease depends on the presence of bradykinesia combined with rigidity or a resting tumor. Early symptoms generally show up asymmetrically, with the absence of atypical symptoms (cerebellar signs, early severe autonomic dysfunction, vertical supranuclear palsies, or cortical sensory loss), which would be indicative of an alternative diagnosis (9). In these cases, the asymmetric onset of symptoms and a good response to levodopa support Parkinson’s diagnosis in patients. Also, they are important features to discriminate Parkinson’s disease from other form of Parkinsonism [2]. As the disease progresses, motor symptoms become more severe. Because Parkinson’s is a heterogenous disease, there have been attempts to subclassify it even more. One subclassification based on clinical characteristics suggests two subtypes: a tremor dominant Parkinson’s disease and non-tremor dominant Parkinson’s disease. A patient with tremor dominant disease predominantly lacks other motor symptoms. On the other hand, a patient with a non-tremor dominant disease may have an akinetic rigid syndrome, a postural instability disorder, and increased incidence of non-motor features. The course of the disease differs, and it has been postulated that the various subtypes have different causes and manners of development. With an advanced enough progress of the disease, both motor and non-motor symptoms may become resistant to current medications. Postural instability and freezing of gait may lead to falls and fractures [2].

IV. Non-motor symptoms

Parkinson’s disease has a variety of non-motor symptoms as shown in table 1. The variety of these symptoms resulted in Parkinson’s disease being identified as a neuropsychiatric disorder rather than just a motor disorder. Some recent studies discovered that non-motor symptoms of Parkinson’s disease may precede other motor symptoms of the disease. Identifying these symptoms beforehand can help predict the onset of the disease [3].

i. Neuropsychiatric dysfunction

ii. Sleep disorders

iii. Autonomic dysfunction

iv. Sensory symptoms and pain

V. Treatments

i. Dopamine biosynthesis and metabolism

Dopamine can only be produced in the central nervous system in order to be active in the striatum as it can’t cross the blood-brain barrier. Also, small amounts of it are produced in the medulla of the adrenal glands. Dopamine’s precursor is l-dihydroxyphenylalanine (levodopa or l-DOPA), means that it is in its free form, that is synthesized either directly from tyrosine or indirectly from phenylalanine. After the reuptake of dopamine into dopaminergic neurons or glial cells, it is metabolized. The detailed metabolic pathway is illustrated in Figure 2. Many components of the dopamine pathway were targeted for the treatment of Parkinson’s disease. For example, genes encoding the rate limiting enzymes for dopamine synthesis, TH and DOPA decarboxylase, were part of an experimental gene therapy which has been trailed in PD patients. Levodopa is the basis for most of Parkinson’s disease treatment regimes, with inhibitors of metabolic enzymes MAO-B and COMT being used.

ii. Current treatments

iii. Future treatments

VI. Conclusion

I. Introduction

Parkinson’s disease (PD) is a common neurodegenerative movement disorder. About 0.5- 1% of people aged 65 to 69 suffer from PD, which adds up to more than 10 million people worldwide [1]. The major symptoms of PD include tremors, stiffness of limbs, slowness of movement, and impaired balance. Parkinson’s disease is caused by loss of dopaminergic neurons in a part of the brain called substantia nigra pars compacta, which is responsible for producing dopamine, and accumulation of misfolded alpha-SYN inclusions called Lewy bodies [2]. PD patients also lose the nerve endings that produce norepinephrine, the chemical messenger that is responsible for the sympathetic nervous functions of the body. When missense mutations of the alpha-synuclein gene are introduced, it leads to the familiar forms of PD, which are characterized by increased aggregation of lewy bodies [3]. Research has shown that neuroinflammation processes in the brain play a critical factor in the pathogenesis of PD [4]. This was also evident in a research paper where FK506 had high efficacy in reducing neuroinflammation and neurodegeneration in PD patients [5].

II. Research Aims

Due to the accumulating evidence that the JAK/STAT pathway disrupts the neuroinflammation and causes neurodegeneration of Parkinson’s disease, it was hypothesized that by inhibiting the JAK/STAT pathway in patients, it could help slow the progression of PD. Ruxolitinib will be tested on MPTP mice models of PD to observe their efficacy as they both inhibit protein tyrosine kinases JAK 1 and 2, which could potentially help mitigate the neuroinflammation and increased a-synuclein levels in the brain.

III. Research Hypothesis

Levels of MHC Class II will decline by inhibiting the JAK/STAT pathway using Ruxolitinib, indicating that Parkinson’s disease progression is slowed down.

IV. Methodology

After the treatment period is finished, each animal will be deeply anesthetized using isoflurane. To begin, thirty micrograms of the ventral midbrain, which is shown in figure 2 of the mice will be lysed using ice-cold cell lysis buffer and a homogenizer. To maintain the brain’s state, it would be kept in a tissue collection solution (50% 0.01 moles of cold phosphate-buffered saline and 50% glycerol) and stored -20C for immunoblotting. The immunoblotting process is a technique that will be used for the analysis of the concentration of MHC Class II proteins in the ventral midbrain. It will also be used to measure the concentration of STAT1 and STAT3 using their respective antigens to test that the pathway is inhibited. The sample will be subjected to SDS-polyacrylamide gel electrophoresis to separate the proteins of the cell sample by size using an electroporator with 10% stacking gel solution as shown in figure 3. 140 volts will be applied to the sample to allow efficient separation. The results will be compared to glyceraldehyde 3-phosphate dehydrogenase as it is expressed at all levels in electrophoresis. The slowing down of the progression of Parkinson’s disease will be probed using antibodies of MHC Class II proteins [12].

Correspondingly, the JAK/STAT pathway inhibition will be measured by probing STAT1 and STAT3 using anti-STAT1 and anti-STAT3.

Afterwards, the separated sample will be electro transferred onto a polyvinylidene fluoride (PDVF) membrane by creating a transfer sandwich. The transfer sandwich will be composed of a sponge, 3 filter papers, gel, PVDF membrane, 3 more filter papers in a sandwich structure as shown in figure 4. By placing electrodes on top of the sandwich and applying current, the cell sample on the gel will transfer onto the membrane because it will travel from the cathode to the anode. Lastly, the expression of the MHC Class II will be observed through observing the results in a dark room as the antibodies would be prepared with chemiluminescence.

V. Discussion

In this research proposal, it is suggested to investigate the efficacy of treating Parkinson’s Disease with inhibitors of the JAK/STAT pathway. inson’s disease is a chronic neurodegenerative disorder that is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. In PD patients, inclusions of aggregated a- synuclein (a-SYN) are prominent in dopaminergic neurons. Microglia exhibit pro-inflammatory properties in Parkinson’s Disease. Post-mortem studies of Parkinson’s disease patients have shown a correlation between activated microglia levels and MHC Class II expression levels, which is known to correlate with the level of alpha-synuclein [13]. This observation was evident in many experiments in vivo and vitro. For instance, overexpression of alpha- synuclein in substantia nigra of models for PD, leading to the up-regulation of MHC Class II protein in microglia [14]. Also, known pro-inflammatory cytokines like IL-1β, IFN-y, and TNF-α were detected in the striatum of PD patients as they are known for their role in neuroinflammation.

The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway is a signaling pathway used by cytokines to initiate innate immunity, orchestrate adaptive immune mechanisms, and constrain inflammatory responses. This pathway is made up of three major proteins: cell-surface receptors, JAKs, and STATs. Once a cytokine binds to the pathway receptor, receptor associated JAKs phosphorylate a tyrosine residue in the cytoplasmic domain of the cytokine receptor [15]. This provides a docking site for STATs. After that, two STAT proteins bind to the receptor via its SH2 domains, as shown in figure 5, and are phosphorylated by the SH2-phosphate interactions between JAK and STAT proteins, inducing dimerization. The dimer then translocates from the cytoplasm into the nucleus, binds to specific elements of DNA, and regulates the expression of certain cytokine-responsive genes (16). A summary of this pathway is shown in figure 6. In mammals, four JAKs (JAK1, JAK2, JAK3, and JAK4) and seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) have been identified.

Pre-clinical models have shown that the IFN-γ and IL-6 are elevated in Parkinson’s Disease patients, which are one of the most potent activators of the JAK/STAT pathway [14, 17].This shows the essential link between JAK/STAT pathway, neuroinflammation, and Parkinson’s disease. Thus, the JAK/STAT pathway is an important factor for the development of PD.

Therefore, we propose to test Ruxolitinib as a novel medication for Parkinson’s disease in mice models. Ruxolitinib was chosen specifically because it is an oral JAK inhibitor that binds to protein tyrosine kinases JAK 1 and 2. Furthermore, trials have also shown that Ruxolitinib passes the blood- brain barrier successfully in phase 3 trials of HIV-1 infection [9] and is also FDA-approved for the treatment of myelofibrosis and polycythemia vera [10]. Its mechanism of action in treating Parkinson’s disease patients has not been researched before, but we predict it would be similar to its predicted mechanism of action for myelofibrosis patients.

Ruxolitinib’s chemical formula structure is shown in figure 7. It is predicted to bind to the JAK1 and JAK2 in the JAK/STAT pathway as an ATP-competitive inhibitor, inhibiting its ability to phosphorylate tyrosine residue in the cytoplasmic domain of the cytokine receptor as shown in figure 8. These medications are proposed to be tested on MPTP mice model, which are characterized by abnormal amounts of alpha-synuclein phosphorylated at Ser129 as well as nitrosylated alpha-synuclein. These mice experience 91% destruction of dopaminergic neurons in the substantia nigra pars compacta [18]. MPTP is a lipophilic protoxin that has been shown to pass the blood-brain barrier before [19]. MPTP is converted by Monoamine oxidase B (MAO-B) into an intermediary, and then finally converted into MPP+. Following its release into the extracellular space, MPP+ is taken up into dopaminergic neurons where MPP+ is accumulated in the mitochondria, causing impairing of complex I of the electron transport chain. Consequently, this leads to a reduction of adenosine triphosphate (ATP) production and generation of reactive oxygen species, initiating SNPc degeneration [20].

VI. Expected Results

VII. Conclusion

Acknowledgements

I. Introduction

II. Symptoms

i. Neurologic symptoms

ii. Neuropsychiatric symptoms (NPS) and how they affect the development of dementia

III. Treatments

i. Available treatments

ii. Behavioral and psychological treatments

iii. Disease-modifying treatments

IV. Conclusion

I. Introduction

Alzheimer’s disease (AD) is the world’s most common cause of death after heart disease. Dementia on the other hand is caused by Alzheimer’s disease. Every 3 seconds, someone in the world develops dementia, and there are currently 55 million people living with dementia globally.[1] It begins with a damage in main memory and progresses to difficulty performing even the most basic actions, such as urinating and swallowing. Since AD is the most frequent cause of dementia [1], numerous explanations have been put forth during the past ten years, genetics is the theory that best explains it, although there are other theories such as environment, immunity, or heredity. In Particular, 40 genes are linked to cause AD risks [2], some of the most common are APP, PSEN1, PSEN2. These genes provide the explanation for how Alzheimer's disease arises, although the validity of this idea, known as the beta-amyloid theory (Aβ), is currently being debated by scientists and researchers. According to this theory, a rise in Aβ production triggers a chain of events, also known as a cascade, that eventually leads to neurodegeneration and dementia. Most scientific studies consider the Aβ theory as the primary explanation for the disease and act upon it while trying to design a drug which targets plaques of amyloid; However, it might merely be the initial source of subsequent immunological or physiological processes that result in the well-known symptoms of AD [3].

II. The beta-amyloid hypothesis and its interpretations

These plaques cause substantial disruption to memory formation by blocking the synaptic cleft, a tiny space where neurons communicate electrically and chemically. This space is where these plaques cause damage to neurons. Additionally, these plaques trigger an immunological response with the help of microglia, which are immune cells in the brain. This may result in inflammation and further harm the neurons.

Peptide bond cleavage is carried out by the transmembrane protein known as β-secretase. Scientists conducted preliminary tests on transgenic animal models, or animals whose genomes have been altered for use in gene research, such as mice, to test the validity of this hypothesis. In the case of studying AD, scientists have chosen mice according to some criteria, such as how they identify familial forms of AD. Transgenic mice don’t make the same plaques as humans do; however, they show neuronal degeneration and inflammation due to the toxicity of Aβ. Even the plaques [7] formed in the brains of mice are obvious figure microscopically like humans. (As shown in figure 1). An impairment in spatial learning and memory was seen when the transgenic mice were bred with Tg APP, transgenic amyloid precursor protein, as shown by a water maze test.

These observations imply that cognitive abnormalities seen in other Tg APP animals may also occur prior to A plaque formation like when these mice are assessed at various intervals. [6]

III. Clinical trials that had failed the beta-amyloid hypothesis

i. vaccination:

A pharmaceutical company named Alan has chosen to treat AD by training the immune system to recognise the pathogen, in this case the amyloid plaques, and learn how to eliminate them, acting on the amyloid hypothesis and attempting to target Aβ plaques. To test their vaccine and determine whether it might truly help, they injected mild and moderate AD patients. To create their antigenic components, they created short peptides that mimicked various native Aβ sequences. [8] The ones used in AD vaccinations are only 6 amino acids long, preventing the activation of Aβ-specific auto-reactive T-cells. This makes them exceedingly specific and focuses them solely on Aβ, preventing any cross-reactivity with APP. Unfortunately, this approach was unsuccessful since four patients who were included in the trial's second phase experienced aseptic meningoencephalitis,[10] a type of inflammation brought on by bacterial cultures in the cerebrospinal fluid (CSF). Upon these trials, the corporation suspended the remaining phases after noticing significant side effects. [9]

ii. Solanezumab (synthetics antibody):

An amyloid-targeting antibody called Solanezumab was created in 2006 by the company Lilly, while another antibody called Bapineuzumab was being produced by Johnson & Johnson in collaboration with Pfizer. An antibody is the result of the body's immune response when a pathogen gets in the blood, in this case the blood-brain barrier (BBB). These companies have separately sought out 5000 AD patients in the mild and moderate phases. They both conducted a double-blind, placebo-controlled study in which one group received the actual medication while the other received a placebo. Following that, a test was conducted to see whether there was a relationship between mental state and the deposition of Aβ using florbetapir positron-emission tomography (PET) or an Aβ-42 measurement in CSF. [11] Patients were assigned to be injected with 400 mg of solanezumab or a placebo every four weeks for 76 weeks, using a score range from 0 to 90, with a higher score indicating greater cognitive impairment. According to the results of this trial, solanezumab, which was given to patients with moderate Alzheimer's disease for four weeks, had no noticeable impact on cognitive impairment. According to its claims, Solanezumab was created to accelerate the removal of soluble Aβ from the brain, supporting the Aβ hypothesis of AD, which holds that the condition is brought on by an excess or inadequate removal of Aβ. (or both). The amyloid hypothesis will need to be taken into account in the context of the findings from this trial and other clinical trials of anti-amyloid treatments. They stated: “If amyloid is not the cause of this disease, Solanezumab would not be expected to slow disease progression.” [12]

iii. BACE inhibitors:

The β-secretase enzyme previously stated that cleaves APP and releases C99 fragments that form various species of Aβ peptide is known as BACE, or beta-amyloid cleaving enzyme. In patients with mild and moderate stages of AD, a BACE inhibitor inhibits the first enzymatic step of Aβ production. The inhibitors target these enzymes and stop their work that needs a subsequent course of immunological therapy to remove the amyloid. However, safety concerns persisted as a side effect related with the elimination of Aβ, which was dose-dependent and happened more frequently in ApoE allele 4 carriers than non-carriers. This was demonstrated by monitoring the Aβ levels in the CSF. ApoE, a protein that moves lipids throughout the body, is available in three different forms: e2, e3, and e4. If someone has the e4 allele from either parent, their chance of developing AD is up to 3 or 4 times higher than that of the general population. However, if they have the ApoE 4 allele from both parents, their risk is up to 10 to 14 times higher than that of the general population. [13]

IV. The pathological hypothesis as another suggested theory

V. Conclusion

I. Introduction

As in figure 1, stem cells can replicate themselves and differentiate into other kinds of cells (like neurons, muscle cells, and blood cells) as in figure 1. Stem cell-based therapy is a new kind of treatment that has emerged over the past few decades. The treatment of neurodegenerative diseases is extremely complicated. However, stem cell-based therapy can still give hope. Stem cells that are prepared in labs can substitute the lost nerve and glial cells by simulating the adult central nervous system to form new neurons and glial cells [2].

II. Stem cells strategies

i. Cell Transplantation

Cell transplantation is a well-known technique in stem cell therapies; it is done by inserting stem cells instead of donor organs into the body. It has the potential to treat many diseases by using adult stem cells to replace cells damaged as in leukemia (as in figure 2). After chemotherapy and radiation are complete, stem cells are delivered into the bloodstream through a tube called a central venous catheter. Then, they travel to the bone marrow and restore its function to produce blood cells and platelets [3, 5]. For neurodegenerative diseases, transplanted cells are integrated into host tissue, making synapses reshape the neural networks like the original. But this approach has limited effectiveness due to the problems associated with differentiation, neural network recreation, and subsequent formation of a functional network [6].

ii. Neuroprotection

III. Applications

i. Alzheimer's disease

Alzheimer's disease is characterized by memory loss from neuronal degeneration, cognitive decline, and dementia. It occurs due to the widespread loss of neurons and destruction of synaptic networks throughout the brain cortex, hippocampus, amygdala, and basal forebrain (look at figure 3). Usually, the patient’s brain has pathologic marks, which are beta-amyloid (Aβ) plaque and neurofibrillary tangle. A neurofibrillary tangle is formed by hyperphosphorylation of a microtubule-associated protein known as tau [6].

ii. Parkinson’s disease

Parkinson’s disease results from the progressive loss of dopaminergic neurons in the substantia nigra. Patients suffer from several motor symptoms, including unstable gait and posture, tremors, and muscle rigidity (look at figure 4) [4]. Lewy bodies are the main characteristic of Parkinson’s disease; they are clumps of alpha-synuclein in the midbrain, and the brain stem [6]. Levodopa, a dopamine precursor, neural lesion surgery, and deep brain stimulation are considered current treatments. These treatments are effective early in the disease, but they are symptomatic, which means they have harmful long-term effects [6].

IV. Conclusion

I. Introduction

II. How Brains Process Sound

The main parts that are affected by music are

• Temporal lobe
• Amygdala
• Frontal lobe
• Cerebellum
• Hippocampus

They will be explained in detail in the coming sections.

i. Temporal lobe

The temporal lobe is in the bottom part of the brain, immediately behind the temples within the skull, from where it derives its name. It is also located above the brain stem and the cerebellum. The temporal lobe plays a critical role in establishing and maintaining both conscious and long-term memory. [5] The temporal lobe interprets various frequencies, noises, and pitches received through the ears. As part of this process, the temporal lobe in humans is responsible for selective hearing. Selective hearing aids in filtering superfluous frequencies, allowing a person to focus on the vital noises in their surroundings. As the brain's language centre, the temporal lobe enables song lyrics comprehension. The temporal lobe is always engaged when listening to music, especially songs without lyrics. The temporal lobe is the music processing centre, but two of its subregions allow for more enjoyment of what is heard. [6]

ii. Amygdala

The amygdala is a complex collection of cells located in the brain’s centre, near the hippocampus (associated with memory formation). The amygdala is primarily. While the amygdala might warn of an oncoming ambulance or an aggressive dog, it is also the portion of the brain that makes people happy when hearing a familiar voice or the soothing sounds of rain. [7] The amygdala has a clear relationship to music, and studies suggest that reactions to specific music genres are practically universal. Music may generate the same emotional cues as the noises stated above: a horror film soundtrack can elicit nearly primordial terror, while a soaring war march can inspire enthusiasm. Similarly, meditation music can help relax the mind and the body. And, regardless of the listener's prior mood, catchy pop music might induce an easy smile. The amygdala is responsible for all these physiological reactions to music. [8]

iii. Frontal lobe

The name implies that the frontal lobe is in the front of the brain. The frontal lobe's right hemisphere governs the left side of the body and vice versa. While neurologists do not entirely understand how music influences the frontal lobe, musical interests, perspectives, and preferences for genres and songs are influenced by frontal brain activity. According to research, the frontal brain serves as a centre for how to respond to music. Those are still being researched, although this portion of the brain is a common target for music therapists. [6]

iv. Cerebellum

The cerebellum is a part of the brain located at the back of the brain between the occipital and temporal lobes of the cerebral cortex. Despite accounting for only around 10% of the brain's volume, the cerebellum contains more than 50% of the brain's total number of neurons. [9] The cerebellum does not originate motor signals; it changes motor commands from the descending pathways to make motions more adaptable and accurate. Movement is a typical musical result and is closely related to the cerebellum. The cerebellum is the brain region that prompts and coordinates movement in reaction to (or in rhythm with) music, whether tapping a foot, dancing a jig, or plucking an air guitar. Playing instruments is likewise entirely dependent on this portion of the brain. According to research, even a few weeks of piano training can affect the cerebellum. Those functional alterations aren't limited to performing music; simply listening to music or envisioning playing the piano can have the same effect. The cerebellum is also in charge of muscle memory. While cognitive ability and long-term memory might deteriorate with age, the cerebellum matures differently as a discrete portion of the brain. This has resulted in reports of coma patients reacting to the music, Alzheimer's patients playing instruments, and stroke sufferers rediscovering their voices via singing. As a result, the cerebellum is very useful for various types of music therapy. [10]

v. Hippocampus

The hippocampus is a complicated brain region located deep within the temporal lobe. It serves a crucial role in learning and memory. It is a malleable and fragile structure that many stressors may harm. According to research, it is also impacted by several neurological and mental illnesses. [11] Music does not simply have a momentary influence on the brain; research reveals that hearing or playing music changes brain shape and brain function, especially when the same music is played again. This is because the hippocampus is opposed to the cerebellum.

Scientific research on the hippocampus has revealed a substantial relationship between music listening and long-term and short-term memory. With its themes and phrases, music's repetitive nature stimulates short-term memory while creating long-term memories. That's why individuals may remember a song they heard on the radio the day before but also recall the dress they wore and who else was in the car when they heard that music 30 years later. This impact varies depending on the sort of music being played. This lends credence to the notion that music may strongly influence brain activity. Music may be produced to target different brain areas, eliciting various emotions from the listener. While this enables musicians and composers to create profoundly emotional music works, it also demonstrates that music may be a beneficial tool for healthcare practitioners. [12]

III. Music: A closer look

i. Effect of Music on Dopamine

ii. Music and attention

The result was uneven for people; for some, it was positive for him and increased their production capacity and helped them well, while for others, the music distracted their attention and reduced their productivity in the same period compared to others.

The answer to this problem is that music does not affect people similarly. It differs from one person to another. It may be helpful for people to produce and harmful to others.

When music is helpful for a person while performing his tasks, it will reduce pressure and impressively stimulate him, improve his mood, and help him to focus, memorise and understand well. Still, to be helpful, certain types of music must be listened to because some music may be harmful to them, and the kind of music varies according to the person the listener.

As for the other type of people harmed by listening to music while working, this happens because it reduces their focus, distracts their attention, and makes memorising and understanding complex. Therefore, the matter varies from person to person, and the process is not equal for everyone. The person must try it himself, in the beginning, to determine his condition in this matter. [15]

iii. Music and Memory

After knowing this information, can music help develop memory and help treat Alzheimer's disease?

Research strongly indicates that music significantly improves memory, as music works to reactivate some brain cells responsible for memory.

Music has played a significant role in helping Alzheimer’s disease treatment, as listening to music brings back old memories related to the patient, which allows us to treat him better.

Alive Inside movie tells how music can help restore parts of memory and improve brain health and quality of life for Alzheimer's patients. [16]

IV. Music therapy

Behavioural, biological, developmental, pedagogical, humanistic, adaptive music instruction and other paradigms may be used in music therapy.

Music therapy improves one's quality of life by incorporating interactions between a skilled music therapist and one individual and another, the individual and their family, and the music and the participants. These connections are organised and changed using musical components to create a good atmosphere and set the stage for successful growth. [17]

Music therapy can treat things like

• ASD
• Alzheimer’s disease
• Chronic pain
• Substance abusing

Those things will be discussed in detail in the coming sections.

i. Autism spectrum disorder (ASD)

Autism spectrum disorder encompasses formerly distinct disorders such as autism, Asperger's syndrome, childhood disintegrative disorder, and an unidentified kind of pervasive developmental disability. Some individuals still refer to autism spectrum disorder as "Asperger's syndrome," which is widely regarded at the moderate end of the spectrum. [18]

Autism spectrum condition manifests itself in early infancy and ultimately creates social, academic, and occupational functioning difficulties. Autism symptoms often appear in youngsters during the first year of life. A tiny proportion of children seem to grow normally in the first year but subsequently have regression between 18 and 24 months when they acquire autistic symptoms.

While there is no cure for autism spectrum conditions, early intervention may significantly impact the lives of many children.

Music therapy may assist children with ASD in improving their abilities in main outcome areas such as social interaction, verbal communication, initiating behaviour, and socioemotional reciprocity. Within the treatment framework, music therapy may also assist in improving nonverbal communication abilities. Furthermore, music therapy may enhance social adaption abilities in children with ASD and promote the quality of parent-child interactions in secondary outcome domains.

Children with ASD have the same obstacles in music therapy as in other therapeutic modalities, in school settings, or at home. To date, research has provided some evidence of effectiveness. In secondary and tertiary diagnostic services, child development centres, and clinical and educational settings where music therapy is included as part of the multidisciplinary services, this intervention is most notable in promoting interpersonal communication, reciprocity, and the development of relationship-building skills. [19]

ii. Alzheimer's disease

Alzheimer's disease is a brain illness that progressively deteriorates memory and cognitive functions, as well as the ability to do fundamental tasks. Most people with the disease — those with late-onset symptoms — have symptoms in their mid-60s. Early-onset Alzheimer's disease is uncommon and occurs between 30 and 60. Alzheimer's disease is the most common cause of dementia among the elderly. [20]

Because there is no treatment for the condition, others focus on measures to enhance a patient's quality of life. Music has several advantages for people living with Alzheimer’s at various stages of the illness. Music therapy has been shown in studies to enhance a patient's attention and capacity to interact with people close to them and may reduce their need for psychiatric medicines.

Music has various advantages for people with Alzheimer’s at each stage of the illness. This is particularly true in the latter stages of Alzheimer's disease, when individuals may become disconnected from their surroundings and lose their capacity to interact and connect with people verbally.

When people with Alzheimer’s hear music, they often experience a perceptible shift. They may perk up and become more interested in their environment. They may sing, dance, or clap their hands when they hear music. Responses to rhythm bypass the brain's standard response mechanism. Instead, the brain reacts directly to the music and instructs the body to respond by clapping, swaying, or humming. [21]

Going out dancing or attending a concert may aid patients in the early stages of the condition. Respect their preferences, even music they used to like. Brain alterations may influence their musical perception. Those who used to play an instrument may find it pleasurable to do so again. Note and play precious pieces, such as wedding tunes, to evoke good recollections.

As the condition worsens, listening to music while walking may improve balance. Music may also be utilised to lift a person with Alzheimer's mood, and relaxing music can assist with nocturnal behaviour concerns. Later, while recalling old occurrences, the same favoured bits may spark a person's recollection. Music often stimulates people living with advanced Alzheimer’s to exercise. Relaxing music also relaxes and comforts. [22]

iii. Chronic pain

For years, music has been used to treat acute pain (such as during cancer treatment and before, during, and after surgery) with substantial success. Many studies show that when music therapy is used after surgery, patients take fewer painkillers and have a more positive attitude. [23]

This use of music in acute pain treatment may also be used for chronic pain. In the long run, the same analgesic effect may be obtained, reducing the need for medicines. When combined with other established pain treatment techniques and therapies, patients may have a significant reduction in pain and a notable increase in their levels of functioning.

Studies show that music stimulates parts of the brain that control and decrease pain. This indicates that listening to music may assist the brain in managing and minimise discomfort in the body. Those suffering from chronic pain often feel detached or dissociated from our bodies as a coping mechanism. This may lead to a loss of self-awareness. Patients may benefit from music therapy by being more aware of their bodies and reconnecting with themselves. This understanding may assist patients in learning how to control their symptoms better. [24]

Distraction tactics (such as listening to music) may be helpful in everyday life. Distraction is one of the primary coping mechanisms to deal with chronic pain and bipolar condition. Distracting allows attention to more positive things rather than lingering anxieties or pessimism. Music can greatly assist, whether it's distracting from discomfort during exercise or singing a song to improve mood and re-energize when taking a break from work.

Research on the use of music as a treatment for chronic pain sufferers discovered that those who listened to music had a higher quality of life despite their discomfort. "Music may offer an emotionally engaging diversion capable of lowering both the sense of pain and the associated unpleasant affective experience," they discovered.

Many patients retreat from social events for fear of aggravating their pain or inability to keep up with loved ones. This may lead to loneliness, exacerbating chronic pain symptoms, stress, and destructive emotions. Music therapy may provide a feeling of connection and involvement, mainly when done in a group setting where patients can meet others who are going through similar challenges. [25]

V. Substance abusing

One advantage of music therapy is that it can be utilised in almost any situation. It may be used in intense inpatient treatment programs, outpatient programs, group settings, and any other structured intervention. Music therapy may be used to treat drug use disorders to reduce stress, help people relax, boost focus on recovery, and assist those struggling to adapt to the demands of substance use disorder recovery. When utilised under the supervision of a music therapist, music therapy has defined aims, and its application is employed to achieve these goals. [26]

vdo not need to participate in a structured music therapy intervention program to benefit from the use of music. Music may be used discreetly to improve mood, forget about the stresses of the day, and as a distraction tool to cope with cravings and other challenges typical in recovery. Whether used as a standard form of therapy or as a private method of relaxation and treatment improvement, music is not intended to be a replacement for a professional drug use disorder treatment program. It is intended to boost the effectiveness of these initiatives. [27]

VI. Conclusion

I. Introduction

Disturbance in the FPN function, altering the domain-general neurocognitive feedback system capable of regulating symptoms as they occur, is the primary reason for multiple mental disorders. The FPN is a flexible hub, which means it can quickly modify the functional connections regarding its goals because it has high connectivity across the brain. Individual variations in the overall capacity to control cognition can influence symptoms, according to significant evidence that the FPN functions are domain-general. Depression, schizophrenia, anxiety, attention deficit hyperactivity disorder, and eating disorders have been noticed in patients with disturbances in FPN functional connectivity (FC). In this review, we focused on FC assessed by functional magnetic resonance imaging (fMRI), estimated as the material connection in the blood oxygenation level-dependent (BOLD) signal between brain areas. At the same time, individuals relax in the scanner.

Two studies estimated a summary statistic regarding the level of conductivity of FPN around the brain. However, the relative size of different networks can impact these calculations. For instance, nodes with a smaller network will have fewer connections than the more extensive network. Thus, a study used between-network global connectivity (BGC) to determine how effectively a brain area is connected to its rest.

Patients suffering from severe depression had anomalies in FC patterns in the brain, which involved FPN functional connections. In addition, patients suffering from depression had lower conductivity between FPN areas. A similar result was seen in undiagnosed people with depressive symptoms. Furthermore, according to another research, global brain connectivity was reduced in the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex sections of FPN in individuals with depression. Moreover, A disruption in FC within the DLPFC has been indicated in patients suffering from depression. Also, the same result was found in the default mode network (DMN). Researchers have also sought to categorize depression based on FC patterns. The reduced connectivity in FPN is the most common subtype involving fatigue and anxiety. In addition, when patients are trying to regulate their emotions or being threatened activation in the FPN and changes in FPN FC have been indicated. There is a decline in global brain connectivity in depressed individuals; the FC value for each region's connections has been revealed inside the prefrontal cortex. The loss in global brain connection was saved by using ketamine therapy.

Research on the global connectivity of the front-parietal cognitive control network will be reviewed in this review. It was expected that individual variations in depression symptoms in undiagnosed persons would relate to BGC in the FPN, based on a previously proposed theoretical framework and detected FPN FC changes in patients with severe depression. Support for our theory would give vital evidence for the possibly widespread involvement of global FPN intrinsic FC in controlling mental health symptoms.

II. Major Depressive Disorder

The hippocampus controls the recall and control of emotional memories with the assistance of the amygdala. Hippocampus is a complex brain structure embedded deep into the temporal lobe. Notably, people with depression frequently have reduced hippocampus volume, which correlates with depressive episodes' length and frequency. Major depressive disorder affects several areas of the brain (figure 1). The Monoaminergic neurotransmission influences these brain areas' structure and function by providing the neural basis for mood, motivation, and reward. Consequently, disruptions in the functional connectivity in these neural networks play a vital role in developing severe depression. Three critical hormones are commonly modulated by monoaminergic neurotransmission: serotonin, dopamine, and norepinephrine.

i. Serotonin

Tryptophan depletion

Polymorphisms

Polymorphisms are a group of genes that perform vital processes in the human brain. The number of particular types of neurons and their synaptic connections, the intracellular transduction of neuronal signals, the metabolism of neurotransmitters and their receptors, and the changes in response to environmental stressors are mainly controlled by the polymorphisms. The serotonin transporter gene is the most studied in major depressive disorder. It has a polymorphism that results in two distinct alleles (long and short). The short allele slows down the serotonin transporter's production. Consequently, the rate at which serotonin neurons adjust to changes in their stimulation is considered slowing down. The polymorphism may affect a person's sensitivity to stress since an acute stressor boosts serotonin release. Stress affects the serotonin transporter that carries the short allele, making it very vulnerable

ii. Dopamine

iii. Norepinephrine

The density and sensitivity of 2α-adrenoceptors, which modulate NE release, are altered by increased β-adrenergic receptor binding in the frontal cortex in MDD patients. Additionally, locus coeruleus postmortem tissues from people with significant depression have been shown to have reduced NE transporter binding. All of these alterations are caused by the physiopathology of depression. Regardless of the explanation, these findings suggest that NE plays a significant role in depression. Dare decreased alertness, low energy, issues with inattention, focus, and cognitive function are linked to lower NE neurotransmission.

FPN is a system responsible for the general goal-attaining process, involving regulating the mental disorder symptoms. Thus, the differences in FPN BGC are somehow related to depression symptoms. A study demonstrated a notable correlation between the rate of connection of the FPN to the rest of the brain and the availability of depressive symptoms in persons who have not previously been diagnosed with depression. Using BGC, the results estimated that patients with fewer depression symptoms have an FPN hat is more connected to the brain regions.

III. Between-Network Global Connectivity measures how strongly each brain region is linked to the rest of the brain networks

IV. BGC in the FPN Is Negatively Correlated with Depression Symptoms

Severe depression symptoms can cause an obvious reduced FC between dIPFC and the supramarginal gyrus, instead of decreased levels of connectivity between the superior parietal lobule and the dIPFC. Currently, the found therapies work on treating via modulating the prefrontal cortex FC in depression patients which are expected to develop more in the future and include targeting the treatment of network communication aspects.

V. Methods of Study

i. Demographic Data Analysis

Participants' demographic data were gathered, and they answered 11 questions about their hand use for various tasks, such as writing, throwing, using scissors, holding their toothbrush, striking a match, opening a box, kicking, using a knife, using a spoon, placing one hand on top of another while using a broom, and using which eye when using just one. Each question was answered with one of the following options: always right, often right, no preference often left, or always left. Answers were given a score based on whether they were always right (2), often right (1), no preference (0), often left (-1), or always left (-2). These scores were added up to create the laterality quotient (LQ), which was then divided by the highest possible score of 22. An LQ score of -100 shows a strong preference for the left hand, 0 for no preference, and 100 for a strong preference for the right hand. Right-handedness was self-reported by each participant. One person, however, showed an LQan showing a preference for the left hand. All analyses have taken the person who prefers using their left hand into account. According to studies, the CESD can be divided into one or four variables. Tree factor scores—somatic symptoms, negative affect, and anhedonia—were computed in addition to each participant's raw CESD score, based on a recent study. During the behavior-only session, participants also finished a number of flexible cognition tests. These tests included the culture fair test by Cattell, the goal neglect task by Duncan, and Raven's progressive matrices. 96 people made up the final sample (Table 1)

ii. fMRI Processing and Network Assignment and Analysis

fMRI processing

Network Assignment and Analysis

Briefly, the Generalized Louvain was used to assign each parcel to a network. Using data from the resting state, this process was carried out. Twelve useful networks were discovered. (Figure 2). The major characteristics of various previously published network partitions are replicated by the functional network topology findings. There is a substantial correlation between the degree of BGC and the frequency with which subjects had depressive symptoms. The study was specifically looking for a measure that could quantify the strength of FC for every region compared to every other region in every other network. BGC was determined for each region separately and was established as the mean FC for all connections made outside of the network. All connections from a source region to targets outside the source region's network were referred to as out-of-network connections. Each region of the brain underwent this process in order to obtain a BGC value. To summarize impacts at the network level, the mean BGC value was then determined for each of the functional networks. The relationship between BGC and depression symptoms in all brain networks was tested. The main hypothesis is that BGC in the FPN was correlated with depression symptoms.

VI. VSRAD and MRI

Volume reduced brain areas in patients with major depressive disorder (MDD) were studied through whole-brain analysis using magnetic resonance imaging (MRI) equipped with a Voxel-based Specific Regional analysis system for Alzheimer’s disease (VSRAD). 71 patients with MDD, enrolled in the study, were aged between 54 and 82 years. 44% of the patients experienced complications from panic or anxiety disorders. A healthy control group consisting of 33 individuals, that had no history of having MDD, was also tested for comparison with the MDD patients. VSRAD was used to evaluate the local brain volume of patients through a comparison with visual information gathered from MRI scans of healthy individuals by means of voxel-based morphometry (VBM), an imaging technique that investigates focal differences in brain anatomy. A T1-weighted scan, an MRI modality, of the brain was processed with SPM (Statistical Parametric Mapping) to isolate grey matter. Then, automated statistical analysis of grey matter density for the entire brain was done. The magnitude of grey matter density disparity, standard deviation x n, in individual patients from the healthy individual's means (Z-score) was calculated for each region of the brain. Data from T1 weighted sagittal images were analyzed and the obtained Z score map was checked for the absence/presence of colored areas, which indicates volume reduction. Areas showing volume reduction by Z score ≥2 were colored blue on the obtained brain images.

Of the 71 patients with MDD, volume reduction in the prefrontal cortex, hippocampus, subgenual anterior cingulate cortex (ACC), and amygdala was seen in 20, 35, 66, and 21 patients, respectively. ACC volume reduction appeared more than volume reduction in any other region and had a sensitivity of 93% as an indicator for diagnosing MDD. This provides a means for diagnosing depression using neuroimaging techniques and shows that depression does not affect mental health only, but also has biological effects on the human brain.

VII. Conclusion

I. Introduction

II. METHODS

A. sEMG Signal Processing

Electromyography signals are used to determine the electri- cal activity of muscle fibres during contraction and rest. Two approaches are used to capture these myoelectric signals: inva- sive and noninvasive. Invasive methods use needle electrodes to record the sEMG signal. However, noninvasive is often preferable, since it is positioned right above the skin surface without requiring the electrode to be inserted into the patient’s body. Numerous issues such as motion artefacts, electrode misplacement, and noise interpolation all have an effect on the EMG signal. To extract additional information, signal pro- cessing techniques including as filtering, rectification, baseline drifting, and threshold levelling are used to EMG signals. The block diagram of the EMG signal processing is depicted in (figure 1).

Three pre-gelled surface electrodes are used to capture EMG data for limb rotational movement. Two electrodes are inserted into the limb’s acromial and clavicular portions of the central deltoid muscle (anterior fibers). For efficient grounding, the other portion is equipped with a ground electrode. Surface electrodes are used to detect EMG signals. However, the selected signal has an amplitude of microvolts. Thus, a preamplifier is required to convert the microvoltage EMG signal (µV) to millivoltage (mV). The EMG signal is delivered into the preamplifier directly from the electrode. Using Instrumentation Amplifier (IA) as shown in (fig 2) cause having a high CMRR, a high input impedance, fixed gain for amplification, and high-low pass filtering.

Features : Instrumentation amplifiers are precision, integrated operational amplifiers that have differential input and single- ended or differential output. Some of their key features include very high common mode rejection ratio (CMRR), high open loop gain, low DC offset, low drift, low input impedance, and low noise.

B. High and Low pass filtration

In order to eliminate the high frequency signal, the output of the preamplifier is fed into low pass filter. To design an effective filter, comparison is done with various filter topologies. as shown in (fig 3) that HPF and LPF are critical in filtering pulses that have been amplified. The EMG signals that have been saved are processed. To eliminate motion artefacts and external noise from the collected EMG data, a high pass filter with a cutoff frequency of 20 Hz is used. For stop band attenuation, a fourth order Butterworth high pass filter has been used. When examining muscular contraction, it is recommended to select dominant EMG signals with a frequency range of 20 Hz - 500 Hz. The EMG signals are corrupted by noise.

C. Rectification and Amplification

D. Smoothening

E. Prosthetic Leg Model

Making a prosthetic limb with a high bearing capacity, flexibility, comfort, and shock absorption for long-term usage requires considerable effort. When fabricating a prosthetic limb, it should be lightweight for ease of control and have a good load bearing capability. The prosthetic limb is con- structed from lightweight but robust materials. The limb may or may not have functioning knee and ankle joints, depending on the site of the amputation. The socket is a very accurate cast of your residual limb that fits snugly over it. It assists in the prosthetic leg’s attachment to your body. Suspension systems are used to secure the prosthesis, whether by sleeve suction, vacuum suspension/suction, or distal locking by pin or lanyard. As shown in (fig 4), numbers of models that are created for achieving engineering goals such as high bearing capacity, light, and long-term use.

Following the selection of your prosthetic leg’s components, you will need rehabilitation to strengthen your legs, arms, and cardiovascular system as you learn to walk with your new limb. You’ll work closely with rehabilitation experts, physical therapists, and occupational therapists to develop a rehabilitation plan that is customised to your unique mobility requirements. Maintaining a healthy leg is a critical component of this routine.

Real-life ration modeling for the prosthetic leg with 100 angel of movement as shown in (fig 5).

F. Machine Learning for Amputees

Using canny detection algorithm to detect edge as shown in (fig 6), and it analyzed data:

Finding the Image’s Intensity Gradient: The smoothed picture is then filtered in both the horizontal and vertical directions with a Sobel kernel to obtain the first derivative in both the horizontal (Gy) and vertical (Gx) directions. We can find the edge gradient and direction for each pixel using equation(2).

To estimate the intended joint trajectory, myoelectric signals and a pattern recognition algorithm may be used to forecast the user’s locomotor mode. The intended locomotor activity may be anticipated by recog- nising patterns in the EMG data (i.e., since various locomotor activities can be assessed using distinct joint trajectories). Mechanical signals, in addition to EMG signals, may be analysed and utilised for pattern recognition. To discover patterns in myoelectric data, pattern recognition methods such as linear discriminant analysis and dynamic Bayesian networks have been applied. However, these algorithms may introduce significant delays, particularly when switching between loco- motor activities. Successful intent classifiers have been created employing the forces at the human-socket connection, foot- ground contacts, myoelectric signals, and contralateral limb kinematics. It has been shown that including EMG signals and time history data into the control system considerably reduces classification mistakes during human prosthesis locomotion. Researchers have shown that unilateral transtibial amputees can forecast locomotor activity using myoelectric signals from the undamaged biological knee joint. By collecting signals and identifying the greatest and minimum values for data visualisa- tion, we can foresee the appearance and movement of muscles using the candlestick technique for pattern recognition. As the largest value is considered resistance, while the least value is considered support. Max and Min values are gathered and used as reference points for prediction, as they are included into the formula for prediction:

As data converted from 2d into 1D. Then, The segmented 1D data of the original time series are defined in this equation(3).

As shown in (fig 7), By analyzing data, we can create a candlestick algorithm that predicts and recognizes any pattern. This is for the most exact movements of the bionic limb, since it is an excellent technique to forecast your movement and electrical pulse patterns.

III. Diagnostic Dystonia Using sEMG

Runner’s dystonia (RD) is a task-specific focal dystonia of the lower limbs that occurs when running to diagnostic of dystonia. In this retrospective case series, we present surface electromyography (EMG) and joint kinematic data from thirteen patients who underwent instrumented gait anal- ysis (IGA) at the Functional and Biomechanics Laboratory at the National Institutes of Health [1]. Four cases of RD are described in greater detail to demonstrate the potential utility of EMG with kinematic studies to identify dysto- nia muscle groups in RD. Lateral heel whip, a proposed novel presentation of lower-limb dystonia, is also described. Surface EMG is showing continuous activity in the left ham- strings (b) and early activity in the left tibialis anterior during running (a). Showing how left leg delayed in activation of motor neuron with respect to other leg as shown in (fig 8).

(A) in the time domain and in (B) in the frequency domain. The signal was recorded from the vastus lateralis (VL) muscle during Whole body vibration (WBV) at 30 Hz. While the sEMG signal in the time domain does not highlight any specific characteristics to WBV. The sEMG signal in the fre- quency domain clearly shows excessive spikes at the vibration frequency and at a few multiple harmonics and that means how dystonia is diagnostic obviously. At the same time, and also for preliminary purposes, the electrophysiological signal was recorded from the patella during WBV. Such a signal obtained during WBV at 30 Hz is shown in Figure 9. In the time domain, the patella signal resembles a sinusoidal wave at 30 Hz. In frequency domain, excessive spikes are observed at the vibration frequency and to a lower extent at its multiple harmonics. No myoelectrical activity is shown for all the other frequencies.

A surface electromyography (sEMG) spectrum of the Vastus Lateralis during whole-body vibration at 30 Hz. sEMG signals were processed using the no-filter method (black solid line), linear interpolation (grey solid line), band-stop filter (grey dotted line) and band-pass filter (black dashed line). As shown in Figure 10, The crucial role of filter especially High Pass filtration (HPF) and Low Pass filtration (LPF).

IV. Muscle Re-Innervation Patterns

Strong EMG signals were elicited by the re-innervated ham- string muscles, notably during contractions related to ankle motions. When the patient flexed his knees, he noticed a lot of co-activation of re-innervated muscles (Fig.11). Each attempted move resulted in different EMG signal pat- terns, implying that precise pattern recognition control was possible. With a virtual system configured to regulate ankle plantarflexion and dorsiflexion, as well as knee flexion and extension, the classification accuracy of the patient’s attempted movements was 96.0 percent, and 92.0 percent with a system built to control tibial rotations and femoral rotation. In non- TMR amputees, classification accuracies for these attempted movements were 91.0 ± 4.7% and 86.8 ± 3.0%, Correspond- ingly. This amounts to a 5.0 percent and 5.2 percentage point boost in complete precision, correspondingly. TMR enhances real-time pattern-recognition control by 44 percent and 39 percent, respectively; these data imply that TMR improves real-time pattern-recognition control. Virtual movements were likewise completed more faster by the TMR amputees than by the non-TMR amputees. EMG data from the residual limb and mechanical-sensor data produced a unique stride pattern for each ambulation mode. The inclusion of EMG information increased the accuracy of the control system. With the use of mechanical-sensor data only.

V. Results

For finding the factors that may affect results. It is tested in various conditions. Test on 3 channels of EMG that collect electrical pulses. This shows how movement and shaking of your body affect and make noise in data when it collects. As shown in this graph when there is no cable movement, there is no noise in data. But when slow or fast cable movements, this makes spike, and noise in data. So, by using p300 algorithm, and low-pass filtration, it removes noise and spike to return to original value of it as shown in (Fig. 12).

A. Piezoelectric and Voltage generator

Piezoelectric Effect is the ability of certain materials to gener- ate an electric charge in response to applied mechanical stress. When piezoelectric material is placed under mechanical stress, a shifting of the positive and negative charge centers in the material takes place, which then results in an external electrical field. When reversed, an outer electrical field either stretches or compresses the piezoelectric material. Using piezoelectric devices to recharge batteries. It is necessary to test numerous times to see if it is suitable to be main voltage generator. As demonstrated in the graph, as the load increases, so does the voltage. The output was sufficient for being main voltage generator.

B. Stress Analysis of Presthestic limbs

For Design Prosthetic limb needs to have a high bearing capacity, flexibility, comfort, shock absorption, long-term use. For design, a prosthetic limb needs to have a high bearing capacity, flexibility, comfort, shock absorption, and long-term use.

VI. Conclusion