Human Brain Disorders: A Review

The brain is the command center of the Central Nervous System (CNS) made up of a large mass of nerve cells, protected in the skull [1 3]. It has three main parts i.e. the cerebrum, the brainstem, and the cerebellum. It controls the intellectual activities of the body, like processing, integrating, and coordinating the information received from the sensory organs. It is a jelly-like mass of tissue, weighing about 1.4 kg, and containing 86 billion nerve cells [4 7]. The cerebrum is connected to the brainstem, which, on the other end, connects to the spinal cord. The brainstem consists of three parts, namely the midbrain, the pons, and the medulla oblongata. Underneath the cerebral cortex, there are several brain structures, namely the thalamus, the pineal gland, the hypothalamus, the pituitary gland, the amygdala and the hippocampus. The cross-section of each cerebral hemisphere shows a ventricle cavity where the cerebrospinal fluid is produced and circulated. Below the corpus callosum is the septum pellucidum, a membrane that separates the lateral ventricles [8, 9]. The cerebrum is the largest part of the human


INTRODUCTION
The brain is the command center of the Central Nervous System (CNS) made up of a large mass of nerve cells, protected in the skull [1 -3]. It has three main parts i.e. the cerebrum, the brainstem, and the cerebellum. It controls the intellectual activities of the body, like processing, integrating, and coordinating the information received from the sensory organs. It is a jelly-like mass of tissue, weighing about 1.4 kg, and containing 86 billion nerve cells [4 -7]. The cerebrum is connected to the brainstem, which, on the other end, connects to the spinal cord. The brainstem consists of three parts, namely the midbrain, the pons, and the medulla oblongata. Underneath the cerebral cortex, there are several brain structures, namely the thalamus, the pineal gland, the hypothalamus, the pituitary gland, the amygdala and the hippocampus. The cross-section of each cerebral hemisphere shows a ventricle cavity where the cerebrospinal fluid is produced and circulated. Below the corpus callosum is the septum pellucidum, a membrane that separates the lateral ventricles [8,9]. The cerebrum is the largest part of the human adult human brain contains approximately 86 billion neurons. It was suggested by many researchers that both neurons and glial cells are necessary for the proper functioning of the brain. Neurons in the brain are responsible for sending and receiving electrical and biochemical signals [17]. The neuron is made up of three basic parts: the cell body or soma, branching dendrites, and the axon. They are building blocks of the brain and transmit information to other neurons, muscles and tissues throughout the body.
Neurons help to think, feel, move, and comprehend the world around us. Glia cells are also very important cells of the nervous system. The name "glia" is the Latin word for "glue" [18]. The glial cells actively participate in brain signaling and are necessary for the healthy functioning of neurons. There are many types of glial cells in the brain. The three important types of glial cell are Oligodendrocytes: which help in insulating the axons and to pass the electrical signals properly at incredible speed over long distances; Microglia: also known as immune cells of the CNS, move around within the brain and constantly communicate with other glia cells; Astrocytes: These are starshaped cells supporting to the Blood-Brain Barrier (BBB), provide nutrients to the neurons, repair the nervous tissue, and facilitate neurotransmission [19 -21].

BLOOD BRAIN BARRIER (BBB)
Blood vessels are critical in delivering oxygen and nutrients to all the tissues and organs throughout the body. The blood vessels system of CNS is unique, constituting the BBB, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain [22]. The purpose of the BBB is to protect it against circulating toxins or pathogens, while at the same time allowing the vital nutrients to reach the brain. BBB is formed by the brain capillary endothelium [23]. It also maintains the level of hormones, nutrients and water in the finely tuned brain environment [24]. The delivery of therapeutic agents to the specific regions of the brain is a major challenge in the treatment of almost all types of brain disorders. The BBB hampers the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and antibodies that might otherwise be effective in therapy do not cross the BBB in sufficient amount [25].

BRAIN DISORDERS
Any deformities, dysfunction and disease condition in the brain affect the whole body. The brain is susceptible to neuronal disease and neurons or tissue infection. Damage can be caused by trauma (psychiatric condition), or a loss of blood supply (accidental or environmental factors) known as a stroke. In brain injury, the degeneration of brain cells occurs [26,27]. It depends upon a wide range of internal as well as external factors. Brain damage due to trauma is induced by personal factors or mentally unstable conditions, while neurotoxicity refers to chemically induced neuronal damage [26]. Broadly human brain disorders are divided into two categories namely, Neurodegenerative diseases and Neuropsychiatric disorders (Fig. 1). Both are tough to understand and incurable, but there are medicines, surgery and physical therapies applied for the treatment or to suppress the symptoms of the diseases (Table 1) [28 -124].

Brain cells
Fatigue, fever, joint pain, stiffness and swelling, butterflyshaped rash on the face, skin lesions, fingers toes turn white or blue when exposed to cold or during stress, shortness of breath, chest pain and dry eyes.
[ Headache, fever, aches in muscles or joints, fatigue or weakness, confusion, agitation or hallucinations, seizures, loss of sensation or paralysis in certain areas of the face or body, muscle weakness, problems with speech or hearing and loss of consciousness.

Brainabscess Fungal and viral infection in brain
Differences in mental processes, such as increased confusion, decreased responsiveness, and irritability, speech, sensation, decreased movement due to the loss of muscle function, changes in vision, changes in personality or behavior, vomiting, fever, chills, neck stiffness, especially when it occurs with fever and chills, sensitivity to light.
Antibiotic medications and surgery. [

Nerve cells and basal ganglia
Involuntary jerking or writhing movements, muscle problems, such as rigidity or muscle contracture, slow or abnormal eye movements, impaired gait, posture and balance, difficulty in speech or swallowing.
Multiple System Atrophy (MSA) Cerebellum, basal ganglia and brainstem Impaired movement and coordination, such as unsteady gait and loss of balance, slurred, visual disturbances, difficulty swallowing (dysphagia) or chewing, constipation, agitated sleep due to "acting out" dreams, abnormal breathing at night, inability to achieve or maintain an erection, loss of libido, irregular heartbeat and difficulty in controlling emotions.
[70, 71]. (Table )  Muscle weakness and twitching, difficulty in breathing and swallowing, changes in the shape of the limbs, spine, and chest due to muscle weakness, difficulty in standing and walking.

Neurodegenerative Diseases
Neurodegenerative Diseases are a composite form of disorders characterized by progressive loss of neurons, which hamper the function of the Central Nervous System (CNS) as well as Peripheral Nervous System (PNS). These diseases show their impact on both mental as well as and physical activity of the human body such as, movement, speech, memory, intelligence and coordination. The causes of these diseases are not specific due to the similarity in symptoms. Some common neurodegenerative diseases are Alzheimer's Disease (AD), Parkinson's Disease (PD), Prion disease, Huntington's Disease (HD), Spino-Cerebellar Ataxia (SCA) and Spinal Muscular Atrophy (SMA) [125]. In AD, neuron death has been reported amygdala, cortex, and hippocampal region of the brain [126]; while in PD, substantia nigra pars compacta shows neuronal death that leads to the deficiency of dopamine [127].
Alzheimer's Disease (AD) is the most prevalent and mainly affects the population of above 60 years. It was first described in 1906 by German Physician Alois Alzheimer on the basis of a medical case of Auguste D, a patient who showed symptoms of memory loss and some psychological changes like mood swing and unresponsive behavior. AD was named after German Doctor Alois Alzheimer by Emil Kraepelin, who was the colleague of Dr. Alzheimer. In 1910, he mentioned for the first time this disease as "Alzheimer's disease" in his medical book named 'Psychiatrie' [128,129]. It is characterized by progressive memory loss and cognitive impairments. Mainly two proteins are responsible for causing this disease i.e., beta-amyloid (β) and tau protein which show a high amount of accumulation in the brain. Both proteins may lead to the degeneration of neurons [126]. The pathological hallmark of AD includes, the presence of extracellular amyloid β plaques and formation of intracellular neurofibrillary tangles that leads to synaptic dysfunction, neuronal loss, and brain atrophy [130].
Parkinson's Disease (PD) is the second most common neurodegenerative disease after AD. It is a progressive CNS disorder that affects mainly the movement of the body. It affects both motor as well as non-motor functions. The causes of PD are still unknown, but the involvement of both genetic and environmental factors considered to be responsible for the progression of the disease. It was described by Dr. James Parkinson (1817) in his monograph entitled "An Essay on the Shaking Palsy" [131,132]. It is characterized by the loss of dopaminergic neurons and the accumulation of Lewy bodies in the substantia nigra pars compacta of the mid brain. Clinical symptoms mainly involves rigidity, akinesia, tremors, postural instability, and non-motor symptoms [133].
In 1920, Neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob describe prion disease as a human neurological disorder. Prion disease is also known as Transmissible Spongiform Encephalopathies (TSEs) and is characterized as rare progressive neurodegenerative disorders which not only affect humans but also animals [134]. In this disease a normal cell surface glycoprotein (PrP C ) is converted into conformational altered isoform i.e. (PrP Sc ) . PrP SC is responsible for the neurological disorder [135]. The most common form of prion disease that affects human is Creutzfeldt-Jakob Disease (CJD) and animal (cows) bovine spongiform encephalopathy (BSE or 'mad cow' disease). Prions are protein that are misfolded and also have the property to propagate [136,137].
Huntington's Disease (HD) is also known as Huntington's chorea. It results due to the progressive degeneration of neuronal cells in the brain. George Huntington, described it in 1872 as a hereditary neurodegenerative disease [138]. It is an autosomal-dominant neurodegenerative disease which results from the unstable trinucleotide repetition of Cytosine-Adenine-Guanine (CAG). It is clinically characterized by involuntary movements, cognitive decline, and behavioral changes [139].

Neuropsychiatry Disorders/Conditions
Neuropsychiatry is a kind of disorder or conditions that deals with mental disruption which results due to the improper functioning of the brain. It is defined as mental disorders or disorders of the brain [140]. According to Berrios and Markova,, neuropsychiatry explains about brain having some lesions that disfigured the brain leading to mental disorder [141]. Neuropsychiatric disorders severely affect the wellbeing of a person with a negative impact on general health. It hampers the ability of learning (childhood) and inability of focusing or concentrating in work (adulthood) [141,142]. They are complex and hard to understand because of the similarity in symptoms. Some common neuropsychiatric disorders are seizures, attention or cognitive deficit disorders, uncontrollable anger, migraine headaches, addictions, eating disorders, depression and anxiety. The person suffering from neuropsychiatry disorders shows changes in behavior i.e. aggression, violence, criminal activity, antisocial personality disorder, psychopathy, impulse control disorders and episodic dyscontrol [143,144]. The causes of brain disorders are still unclear, but some genetic as well as environmental factors are responsible for the diseased condition. These disorders have a relatively high prevalence and show early onset (autism in childhood and schizophrenia in adulthood) [145,146]. Table 1 summarizes the different categories of brain disorders with their symptoms and preventions.

CAUSES OF NEURODEGENERATIVE DISEASES AND NEUROPSYCHIATRY DISORDERS
The role of genes and the environment for the progression of neurological disease/disorders cannot be ignored. Any damage to the CNS leads to cell death which leads to the loss of function [147]. The brain disorders hampered the normal functioning of the brain and lead to the progressive decline or sudden complete loss of brain functions (sensory, motor, and cognitive) [148]. There are some neurodegenerative diseases which are characterized by the abnormal accumulation of the protein in the brain tissue i.e. Tau protein, β-amyloid (accumulation of plaques in the form of neurofibrillary tangles) in AD, misfolded Huntingtin protein in HD, aggregation of ubiquitinated proteins in ALS, α-synuclein accumulation in PD, and cell surface glycoprotein accumulation in prion disease [149 -152]. Some studies have suggested that the mutation in genes leads to the accumulation of misfolded protein. Physical injury to the brain may lead to synaptic insufficiency, massive cell death and inflammation that may lead to temporary or permanent loss of various bodily actions like coordination in the movement (ataxias) and different cognitive functions like memory, learning, decision-making skills, talking and dementia. There is no permanent treatment for neurodegenerative diseases. In advanced stages of the diseases, DBS and cell transplantation therapies are used for controlling/reducing the physiological as well as cognitive deficits [153 -155].
In AD, aggregation of β-amyloid protein accelerates the formation of neurofibrillary tangles which leads to synaptopathy in the form of glial inflammation and neuronal cell death in the cerebral cortex, sub-cortical regions, temporal lobes, parietal lobes, and cingulate gyrus in brain [156]. In PD the depletion of dopamine producing neurons in substantia nigra is accelerated by the intracellular accumulation of protein α-synuclein bound to ubiquitin complex. These protein aggregates form cytoplasmic inclusions in the form of Lewy bodies, which play a significant role in familial as well as sporadic cases of PD [133]. Similarly, HD is also caused by the intracellular accumulation of Huntingtin protein. The mutation in huntingtin (gene) results in the death of cells in the striatum region of the brain [138]. Multiple Sclerosis (MS) is a glial disorder. It involves massive damage to myelinated fibers through autoimmune reaction, causing axonal injury and further loss of neuronal communication mostly in the white matter tracts, the basal ganglia, and the brain stem [157]. It has been reported that the genetic factors responsible for AD ranges from 49-79% [156]. Similarly, for PD it ranges from 5-10% [156]. While, HD is considered as a pure genetic disorder which is caused by tri-nucleotide repeat expansions (CAG) nucleotides [138]. The whole genome sequence may help both researchers as well as clinicians to understand the genetic factors that play an important role in health, disease, and drug response [158]. The interplay of genetic and environmental factors that hampers the brain function is difficult to understand [159]. It was studied that in schizophrenia and bipolar disorders, genetic factors play a huge role in the development of disease. In a twin study, it ranges from 70-80%. Similarly, in depression, the genetic factors showed significant increment of 38% to 75% [160,161]. In dementia cases, 1 in 4 person aged above 55 has a family history of dementia [162].
Dementia is an umbrella term used to demonstrate a group of symptoms in neurodegenerative diseases. The late stages of the neurodegenerative diseases lead to significant cognitive dysfunctions that are enough to affect a routine life. The symptoms of Dementia shows deficits in memory and learning, impairment in visual, loss of attentive function, as well as behavioral disturbances [162]. Epigenetic factors also play an important role in aggravating the symptoms or enhancing the disease like symptoms. Some metals have been reported to contribute for the progression of AD and PD i.e. lead (Pb), Mercury (Hg), Arsenic (As), Cadmium (Cd), Almuniun [163,164]. Pesticides also play an important role in neurological disorders like Paraquat (PQ) and 1-methy l-4 phenyl l-1, 2, 3, 6-tetrahydropyridine (MPTP) [165]. Rotenone, like Trichloroethylene (TCE) and toxic nanoparticles have also been shown to cause neuronal cell damage and improper functioning of the CNS [166,167].

DATABASE FOR NEURODEGENERATIVE DISEASES
Due to the complex pathophysiology and overlapping of symptoms in various neurodegenerative diseases it is the need of the hour to build a database for neurodegenerative diseases. Researchers have developed an online web database (DND: Database of neurodegenerative disorders) that contains more than 100 neuro related disease concepts having the information of all related genes, their products, pathophysiological pathways and treatment strategies [168]. It provides enormous data related to almost every aspect of neurodegenerative disorders for better understanding of molecular and genetic pathways involved in the progression as well as treatment of the disease [168] BD gene is another database that was designed to address the genetic complexities of Bipolar Disorder (BD) and its overlapping with Schizophrenia as well as Major Depressive Disorder (MDD) [173]. It is freely available for the researchers. It provides not only a detailed review of research but also provides details for high confidence candidate genes and pathways for better understanding the pathology of the disease [173].

MODELS TO STUDY BRAIN DISORDERS
A number of animal model such as Caenorhabditis elegans, Drosophila melanogaster (fruitfly), Musca domestica (house fly), Danio rerio (zebra fish), pig and monkeys are used for understanding molecular pathways involved in various categories of brain disorders/diseases [175]. Cell lines are also used to explore the molecular pathways involved in the progression of brain diseases/disorders. Recent studies have revealed a great similarity between monkey and human brain (both in structure as well as in organization). It is expected that it will help a lot in understanding human brain diseases/disorders [176]. However, the selection of the model depends on the nature of the biological questions to be answered [176]. C. elegans has been used as a model organism for studying various aspects of neurodegenerative diseases like PD [177], AD [178], and HD [179], due to the conserved counterparts in C. elegans. The improved transgenic technology has led Drosophila as a model for number of neurodegenerative disorders such as AD, taupathies, PD, amyotrophic sclerosis, hereditary spastic paraplegia and various polyglutamine diseases [180 -182]. Zebra fish genes and their human homologues have conserved functions with respect to the etiology of neurodegenerative diseases including PD, HD and AD [183]. The larvae of Zebrafish display neuropathological and behavioral phenotypes that are quantifiable and comparable to humans [184]. By using genetic manipulation techniques, transgenic mice and rats have been developed to understand the pathophysiology of autism, Fragile X syndrome (FXS) and other neuropsychiatric disorders [185 -187]. The cerebral cortex of pig, unlike that of mice or rat, has cerebral convolution (gyri and sulci) similar to human neocortex and thus is expected to yield high translational value [188]. The use of pig in neuroscience for the modeling of human brain disorders has been extensively reviewed by Lind et al. [189]. Pigs are more similar to humans than mice in anatomy, physiology and genome, hence genetically modified pigs are also being used to study various neurological disorders [190]. Neurological disorders have also been studied in transgenic monkeys [191]. Due to the highest similarity with humans, monkeys are preferred for understanding the pathways involved in the progression of PD [191], microcephaly [192], AD [193], and sleep disorders [194]. The brain neurons lack the potential of regeneration; hence, the aging degeneration leads to severe consequences of brain dysfunctions. The neurodegenerative diseases/disorders are characterized by slow progression at an early stage. These diseases affect elderly persons especially in developed countries where the life expectancy is high [195]. These diseases include Parkinson's Disease (PD), Progressive Supranuclear Palsy (PSP), Multi-System Atrophy (MSA), Alzheimer's Disease (AD), Fronto-Temporal Dementia (FTD), and Dementia with Lewy Bodies (DLB). PD is a progressive neurodegenerative disorder that causes slowness of movement and rigidity in the body. It is characterized by neuronal loss in the substantia nigra and the other brain regions. It is associated with the formation of intracellular protein inclusions known as Lewy bodies (LBs) in the neurons [196,197].
Nanotechnology has provided a platform for the transfer of drugs across the BBB. Researchers are trying to build liposomes, loaded with nanoparticles to gain access through the BBB [198,199]. More research is required to determine effective strategies for the improvement of patients with brain disorders. Delivering drugs across the BBB is one of the most promising application of nanotechnology in the field of clinical neuroscience. Nanoparticles may potentially carry out multiple tasks in a pre-defined sequence, which may be important for the delivery of drugs across the BBB [200 -204].

CONCLUSION
Due to the involvement of non-genetic factors in the progression of human brain disorders, the research has been focused more on the study of epigenetic factors. In this context the data available from the GWAS and the databases developed for neurodegenerative diseases have proven a great boon in the area. Although there are several models to study the neurodegenerative disease but still there is a need for other specialized techniques, especially for neuropsychiatric disorders due to the overlapping of symptoms. BD gene has attempted not only to address the genetic complexities of bipolar disorders but also overlapping symptoms of both schizophrenia and Major Depressive Disorders (MDD).

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