A Concise Study of Schizophrenia and Resting-state fMRI data analysis

Schizophrenia is a severe mental illness in which people experience hallucinations and delusions. Reasons for happening schizophrenia are genetics, occur in a family, and it is heritable. It can happen due to the brain's inappropriate development due to complications at the time of birth due to the intake of drugs and an increase in the environment's stress level. Diagnosing critical psychological disorders like schizophrenia, functional magnetic resonance imaging (fMRI) has always been proved its beneficial usage. This technique measures the indirect neural activity of the brain tracing the oxygenation level of the blood flow. Resting-state fMRI measures the same in the rest condition of the patient while doing no cognitive task. In this review article, we first describe schizophrenia and a brief description of its occurrence, cause, symptoms, and treatment. Secondly, we describe the fMRI technology followed by the resting-state analysis, and finally, we describe the methods of data analysis briefly to diagnose schizophrenia with resting-state fMRI. This review article may act like a start-up for the research in this domain.


Schizophrenia
Schizophrenia is a chronic, severe mental disorder in which people live in delusions and hallucinations [1] [2] . The person starts losing its real-world connections. Although it is not a common disorder, it is the most chronic and disabling. It generally origins in childhood and is experienced again and reinforced later in life [3] . It can happen, including: Genetics (heredity) [4] Qeios, CC-BY 4.0 · Article, November 5, 2020 Qeios ID: 599711.2 · https://doi.org/10.32388/599711. 2 1/12 Brain chemistry and circuits Brain abnormality

Environment
There are no laboratory tests to precisely diagnose schizophrenia. Whenever there are the below-mentioned symptoms present in the persons, then they can be diagnosed by it [5] : Delusions Hallucinations Disorganized speech Disorganized or catatonic behavior Addressing schizophrenia involves the development of a stress-free environment, a sense of hope, self-reliance, and a personalized awareness of current strengths and challenges [6] .

Occurrence of schizophrenia
Schizophrenia is a severe mental illness that affects a considerable amount of the population worldwide [7] . The prevalence of the disorder is growing high. Around 1% of the global population is being affected by schizophrenia. It is affected by people regardless of race, ethnicity, geographical location, etc. In 2000, the World Health Organization (WHO) found that the illness's prevalence and incidence are similar across the globe. According to a recent survey, it is found that around 1.2% of Americans are affected by schizophrenia#. According to the data released for schizophrenia by WHO in 2004, it was found that the age-standardized DALY (disability-adjusted life-years) rate of India was 286.903 per 100,000 inhabitants.
Schizophrenia can occur in people throughout their lifetime, but new instances of the illness are most likely to happen in early adulthood. It occurs mostly in the late adolescent years (the early twenties) to early adulthood (early thirties). People with schizophrenia starts experiencing the primary symptoms during the 16 to 25 years of age. It was found that the men tend to develop the condition for the disorder earlier than the women, i.e., early diagnosis is more frequent in males than females. The onset of the illness is rare in the older population, as in childhood. Researchers have identified 108 genes that are someway associated with the risk of schizophrenia. Most of the identified genes are dopamine receptors, glutamate transmission, immune system, and synaptic plasticity. It was also found that it is twin concordance, i.e., if one of the identical twins has schizophrenia, the other will have a 50% chance of developing the disorder, even if the children are raised separately. However, the genetic factor is not only the reason behind the illness.

Development of the brain
When studied on people with schizophrenia, the differences in the brain structure suggest that the illness may also occur due to additional development of the brain. But the developmental changes may be noticed in people without any mental illness.

Neurotransmitters
Neurotransmitters are endogenous chemicals that help in the neurotransmission of information. It is found that the drugs that change the level of neurotransmitters often diminish some symptoms of schizophrenia. It shows that the neurotransmitters may have some connections with the illness. An alteration may cause schizophrenia in the level of dopamine and serotonin, or sometimes may be caused due to an imbalance of these two neurotransmitters.

Birth time complications
Research suggests that experiencing birth time complications may affect the person to develop the condition for schizophrenia. Before birth, complications such as low birth weight, premature labor, and asphyxia during birth, are more likely to affect their brain development.

Social and personal triggers
Triggers are the different factors that are mostly responsible for the cause of schizophrenia. The triggers include stress such as in job and relationship, emotional, physical, and sexual abuse. These stressful situations are not necessarily causing schizophrenia but can trigger their development.

Drug Intake
Studies show different drugs such as cannabis, cocaine, or LSD may affect the human brain to trigger mental illness development. However, medicines don't cause schizophrenia directly.

Types of Schizophrenia
In recent days, schizophrenia is considered a neurodevelopmental disorder. In this mental illness, the patients suffer from various symptoms. According to DSM-5 criteria [8] , if two of the following five main symptoms persist, they are said to Delusions are false beliefs out of reality. The patient thinks several fake thoughts are being harmed or harassed; he gains sudden exceptional fame; some catastrophe may happen. It is ubiquitous in schizophrenia.

Hallucinations:
Hallucinations can be visual or auditory. In auditory hallucination, the patient use to listen to individual, indistinct voices, noise, someone's cry or call for him, which do not exist in actuality. Visual hallucinations cause the patient to see unwanted things, some known/ unknown person who does not live. The person with schizophrenia has a full force in these beliefs.

Disorganized thinking (speech):
Disorganized thinking is also a common symptom in schizophrenia. It is basically inferred from disorganized speech. The patient suffers from the illness experience the impaired ability of effective communication. In rare cases, the patient uses a combination of meaningless words that may not be understood.

Disorganized or abnormal motor behavior:
In some schizophrenia cases, the patient shows an abnormality in their motor behavior in several ways, such as childlike silliness, resistance to instructions, inappropriate postures, and unresponsiveness to queries.

Negative symptoms:
Negative symptoms lead to an inability to function in daily life properly. The patients suffering from negative symptoms show a lack of interest in daily activities, withdraw themselves from society and social gatherings, show a lack of emotions, and even show negligence to personal hygiene. Negative symptoms often are seen much before the occurrence of positive signs.

Early symptoms or prodrome of Schizophrenia
Most patients with schizophrenia (around 80 % -90 %) have a prodrome characterized by some attenuated or subthreshold symptoms appear along with the delusion and hallucination [9] . The primary prodromal symptoms include perplexity, diminished understanding, hearing a few indistinct noises, highly unusual beliefs, guardedness, etc.
According to some studies, the prodromal phase can vary from person to person, but it stays for almost one year for each patient. Most of the schizophrenic patients sought help and seemed to be distressed while in Clinical High Risk (CHR) state.
Bleuler made the primary classification of schizophrenia. He recognized two significant classes of the symptoms, viz. positive and negative symptoms. In 1980, Crow suggested that schizophrenia can be classified into two types, referred to as type-1 and type-2.
The Characteristics of type-1 Schizophrenia: Positive Symptoms Normal brain structure Comparatively good response to treatment Dopamine was assumed to be responsible for the neurochemical process that governed the disease.
The Characteristics of type-2 Schizophrenia: Negative symptoms Some abnormalities in brain structure were observed on the Computed Tomography scan.
Relatively low responses to the treatment Impaired cognitive function The type-1 schizophrenia with positive symptoms was named Positive Schizophrenia, and the type-2 with negative symptoms was named Negative Schizophrenia. In 1982, Andreasen suggested [10] that some of people have both positive and negative schizophrenic symptoms. Based on that, She added one more type, i.e., mixed type, along with the previous two.
The symptoms that mainly lie in the two types of schizophrenia are: Positive Schizophrenia: -At least one of the below was present: 1. Hallucinations (auditory, visual, haptic, or olfactory) [10] 2. Delusions 3. Positive formal thought disorder 4. The repeated occurrence of disorganized behavior.
5. Alogia (e.g., poverty of speech, low content of speech) [10] ; Mixed Schizophrenia: This category incorporated patients who show both positive and negative symptoms or did not fulfill the criteria for either one.
1.1.5 Treatments of Schizophrenia: As Schizophrenia was considered a brain disease or a set of diseases due to transmission of genetic or prenatal or perinatal insult, the assumption was made that psychological interventions can't treat this disorder. Most of the patients are still untreated due to unawareness.
Treatment is sometimes misguided due to the manifestation of similar symptoms in psychosis. But psychosis is not associated with only schizophrenia but also with other disorders such as dementia, Parkinson's disease, stroke, brain tumors, drug abuse, and alcohol usage. Schizophrenia is a psychosis primarily associated with delusion and hallucinations.
Schizophrenia patients have premature death around 14.5 years lesser than the average mortal age of the normal population. It is found that 40% of premature deaths are due to suicides-the mean age of hospitalization.

The process of treatment:
The treatment goals of schizophrenia patients mainly aim to reduce the symptoms, prevent the relapse of the symptoms, and enhance the basic functionality, helping the patients live everyday social life.
Till the mid-1900s, no drugs for schizophrenia were available. The treatment was mostly like confining the patients in asylums, and potent doses of sedative drugs were administered to suppress the behavioral changes. The electric shock treatment, also known as electro-convulsive therapy (ECT), was widespread to control the depression and psychotic abnormal behaviors. The application of ECT is still controversial and used today for serious psychotic administration.
The treatment of schizophrenia can be broadly categorized into two types, namely non-pharmacological therapy and pharmacological therapy. Pharmacotherapy being the necessary thing in treating schizophrenia, the residual symptoms still may remain active. Thus, non-pharmacotherapy, like psychotherapy, is essential. Psychotherapy may be again categorized into three, namely, Other psychotherapies include social skills training, rehabilitation, family education, joining self-help groups.

Pharmacological therapy
Pharmacotherapy involves the administration of medicine. Medication is the most vital form of treating schizophrenia.
Antipsychotic medications are the common drugs prescribed to schizophrenia patients. They can control and reduce the symptoms like hallucinations and delusions by affecting the brain neurotransmitters. The dosage and selection of the drug is a very crucial task in antipsychotic medication. It is always targeted to manage the illness with the lowest possible dose.
It usually takes 1-2 weeks to start working.
As the medicines for schizophrenia have serious side-effects, patients sometimes become hesitant to take it. Thus, it is also essential to support and help the patients bring their willingness to cooperate with the treatment process. Recently, a new treatment option is an available alternative to oral medication in the form of injection. It is called long-acting treatment (LAT) or long-acting injectable (LAI), which can be administered once every few weeks to once every few months, depending on the severity providing long-term effects on the body.
There are mostly two types of antipsychotic medicines, first-generation and second-generation*. The first-generation drugs show frequent and potential side effects in the brain, sometimes causing temporary or permanent motion disorder.

Perphenazine
These drugs are comparatively cheaper than the second generation. Thus, these drugs may be administered to patients when long-term treatment is needed.
The second-generation antipsychotics are generally recommended and prescribed due to its fewer side-effects in the brain. Second-generation antipsychotics include [11]  While a massive number of schizophrenia patients are still untreated due to social exclusion and stigma having negative stereotypes, lifelong treatment, including medication and psychotherapy, is required in schizophrenia, even after subsiding of symptoms. Proper dosage of medications and psychosocial therapy can help in the management of the disorder.

FMRI (Functional Magnetic Resonance Imaging)
fMRI stands for functional magnetic resonance imaging. It is an imaging technique used to identify the functional activations across different brain [13] . The fMRI data are 4-D data, which consist of 3-Dimensional images over time [14] . A 3-D data is a sequence of 2-Dimensional images (or slices) over the entire brain. Each slice consists of brain volume small units, which are called a voxel. Therefore, a specific spot of the brain is represented by voxel [15] . So, by comparing the fMRI data of schizophrenia patients and healthy control, we can diagnose the disease by detecting the active regions during a particular task in schizophrenia patients and healthy controls [15] .

Principal of FMRI
When neurons get activated, they are supplied with raised cerebral blood flow, and the oxygen supply is usually more than the adjacent capillaries require them by the hemodynamic response process. They do not have any internal set aside of energy, neither in the form of oxygen nor glucose. Based on their distinctive magnetic susceptibilities, MRI detects the activations by measuring the ratio of oxyhemoglobin and deoxyhemoglobin levels. This technique is called blood oxygen level-dependent (BOLD) imaging. According to recent researches, BOLD signals intent by arteries partial pressure of both O2 and CO2. These BOLD signals are the main foundation of fMRI. We can construct maps of active brain regions active during a particular task or react to a detectable change in the neural activity at a low frequency (0.01-0.01Hz) [16] [17] .

Why do we use fMRI
Because of its excellent spatial resolution, we use fMRI, from which we can detect the regions of the brain which are active during the tasks [18] .

Resting-state fMRI (rs-fMRI)
Resting-state fMRI is widely used for mental, neurological, neuropsychiatric disorders. Unlike task-based fMRI, rs-fMRI does not prescribe subjects to do any cognitive (mental, emotional) task. The spontaneous neural activities can be related by low-frequency oscillations (0.01Hz -0.1Hz) of rs-fMRI.
We can perform rs-fMRI data analysis in many ways, with popularly known ICA and seed-based analysis techniques.
Before that, we have to do preprocessing of data by reorganizing and eliminating the confounding artifacts. Moreover, rs-fMRI data requires correction of slice-timing, spatial filtering, motion compensation, and normalization in these preprocessing steps.

Challenges of rs-fMRI
The removal of noise, i.e., temporal filtering, must be done carefully so that there is no removal of appropriate or closely connected low-frequency resting-state signals. Noise levels from movement and physiological (like breathing) needs in rs-fMRI are very high. There are less than 5% of the total signals that derive from neurological activity. The main problems for rs-fMRI studies are the frequencies of cardiac and respiratory pulsations close to the resting state networks [4] .

Methods of analysis of rs-fMRI data
A large amount of rs-fMRI data can be easily compared with the help of graphs and maps. Different methods can analyze rs-fMRI data and models, like Amplitude of Low-Frequency Fluctuations (ALFF), fractional ALFF, Regional Homogeneity (ReHo), Functional connectivity Density, Seed-Based Functional connectivity Analysis or ROI-based FC, Independent Component Analysis (ICA) [1] [15] .
The ALFF methods measure the strength of the BOLD signals within a low-frequency range between 0.01Hz and 0.1Hz.
Both fractional-ALFF and ALFF reveal the densities of the active brain regions. Both of them do not provide details about the functional connectivity within areas of the brain. These methods are known for their simplicity of analysis without any hypothesis. Both of them give long-term test-retest reliability and high temporal stability.
ReHo analysis is a voxel-based method with providing information about the different features of regional neurological activity. It finds the correlation between the BOLD signal of a given voxel and its close-by neighbors. It is calculated by the Kendall Coefficient of corresponding BOLD signals. The higher value of ReHo represents centrality and higher coherence of regional brain activity.
Seed based Functional connectivity is also called ROI-based functional connectivity. It finds the regions which are active at the same time when the seed region is active. It visualizes the correlation between seed and the rest of the brain regions by the connectivity matrix, which shows all connections' strength. These regions may not be directly connected, yet the coupling of activation of different brain regions shows their involvement in the same functional process and indicates that they are functionally connected.
Independent component analysis (ICA) [19] is used to separate spatially independent figures [20] from their unswerving mixed blood-oxygen-level-dependent (BOLD) signals in the form of spatial maps, which are temporally correlated [21] .

Need rs-fMRI
Infants, neuropsychiatric disordered patients cannot able to perform the task in task-based fMRI. rs-fMRI possesses no burden on them to perform any task.
They provide information about the neural activities or active regions, free from demanding external stimuli.
The rs-fMRI can find a marker to distinguish an individual with major depressive disorder (MDD) from a healthy control.

Advantages of rs-fMRI
Unlike task-based fMRI, rs-fMRI can be easily performed by infants, young children, and a person suffering from neurological and psychiatric diseases. Resting-state functional connectivity determines the brain's tightly coupled functional networks by using spontaneous synchronized fluctuations in the BOLD signal. These random fluctuations are postulated to coordinate, organize, and maintain functional brain systems [22] . The rs-fMRI is placing a minimum mental burden on the participants and taking a little time of a few minutes only.

Conclusions and future scope
In this article, we have discussed the first schizophrenia, its symptoms, causes, and treatments. Secondly, about fMRI followed by the rs-fMRI, we have finally described the data analysis methods of rs-fMRI and its advantages over taskbased fMRI. This paper throws light on the applicability of rs-fMRI for the diagnosis of schizophrenia. As a future work scope, the researcher may study the different pathophysiological aspects of schizophrenia using rs-fMRI after gaining basic knowledge of the disorder and fMRI.

Correspondence
For any kind of correspondence and query regarding the study, one may contact the corresponding author Dr. Indranath