Advancement in utilization of magnetic resonance imaging and biomarkers in the understanding of schizophrenia

Abstract

Historically, psychiatric diagnoses have been made based on patient’s reported symptoms applying the criteria from diagnostic and statistical manual of mental disorders. The utilization of neuroimaging or biomarkers to make the diagnosis and manage psychiatric disorders remains a distant goal. There have been several studies that examine brain imaging in psychiatric disorders, but more work is needed to elucidate the complexities of the human brain. In this editorial, we examine two articles by Xu et al and Stoyanov et al, that show developments in the direction of using neuroimaging to examine the brains of people with schizophrenia and depression. Xu et al used magnetic resonance imaging to examine the brain structure of patients with schizophrenia, in addition to examining neurotransmitter levels as biomarkers. Stoyanov et al used functional magnetic resonance imaging to look at modulation of different neural circuits by diagnostic-specific scales in patients with schizophrenia and depression. These two studies provide crucial evidence in advancing our understanding of the brain in prevalent psychiatric disorders.

Key Words: Schizophrenia; Magnetic resonance imaging; Biomarkers; Neurotransmitters; Psychiatric disorders

Core Tip: Schizophrenia is a serious psychiatric condition that has life-long implications for the individual as well as their family. The underlying psychopathology is still unclear and evolving. With advancements in the field of neuroimaging and neurotransmitters the understanding of the disorder is gradually improving, however, a lot of work is still needed in this area. In this editorial article we briefly discuss what we already know and how recently published articles help to advance our knowledge about schizophrenia.

INTRODUCTION

Schizophrenia is a complex neuropsychiatric condition that has a long-lasting impact on an individual’s functioning in all areas. Schizophrenia is associated with high unemployment rates, poor dietary habits, increased rates of smoking, and comorbid substance use that contribute to a reduced life expectancy of 13-15 years[1]. Our understanding of schizophrenia has come a long way from Emil Kraepelin’s distinguishment of dementia praecox (schizophrenia) to manic-depressive psychosis in 1893, to Eugen Bleuler coining the term schizophrenia (previously known as dementia praecox) in 1908, to the current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classification in 2013. The DSM-5 criteria for schizophrenia include positive symptoms such as delusions, hallucinations; disorganized speech, grossly disorganized or catatonic behavior and negative symptoms such as decreased motivation and diminished expressiveness; two or more of these must persist for a period of one month or longer[1]. Additionally, cognitive symptoms of schizophrenia include deficits in working memory, executive function, and information processing.

NEUROIMAGING AND NEUROTRANSMITTERS IMPLICATED IN SCHIZOPHRENIA

During Kraepelin and Bleuler’s time, they did not have access to our current capabilities of the neuroimaging modalities. However, even with today’s imaging tools for exploring the brain, the underlying psychopathology of schizophrenia is still not fully understood. Structural alterations associated with schizophrenia have been examined widely. Some of the consistent findings across various studies include smaller total brain volume, enlarged ventricles, and reduced hippocampal and thalamic volumes[2]. A meta-analysis utilizing magnetic resonance imaging (MRI) of over 4000 patients determined that patients with schizophrenia had widespread thinner cortex and smaller brain surface area[3]. Another meta-analysis of 317 studies inclusive of over 18000 patients, compared medicated and non-medicated individuals and determined that medicated schizophrenia patients had decreased intracranial and total brain volume, while medication-naive patients had increased volume reductions in the caudate nucleus and thalamus[4]. They also found that advanced gray matter reduction was associated with a longer duration of illness and a higher dose of antipsychotic medication at the time of scanning[4]. In addition to structural changes in schizophrenia, researchers have also used functional MRIs to show support for both hypofrontality, decreased prefrontal cortex activity, and hyperfrontality, increased prefrontal cortex activity[5,6]. Patients with hypofrontality were more likely to experience negative symptoms of schizophrenia, while patients with hyperfrontality were more likely to experience positive symptoms[6,7].

The two main neurotransmitters implicated in schizophrenia are dopamine and glutamate. Dopamine was first suspected to play a role in schizophrenia after recreational amphetamines induced psychotic symptoms that had similarities to schizophrenia[8]. Numerous methods including animal studies, post-mortem research, clinical effects of drugs that either block or accentuate dopaminergic neurotransmission, and positive emission tomography studies all show indirect evidence that increased dopamine signaling is associated with schizophrenia[9]. A meta-analysis of 21 studies found that patients with schizophrenia had greater elevation of dopaminergic functioning in the dorsal striatum when compared with controls[10]. However, antipsychotics that block dopamine receptors effectively treat the positive symptoms of schizophrenia, but are not nearly as effective at treating the negative symptoms[8]. Further research is needed to elucidate the psychopathology behind the negative symptoms of schizophrenia to provide more effective treatment.

Glutamate is an excitatory neurotransmitter which has 2 receptors- ionotropic and metabotropic. Ionotropic N-methyl-D-aspartate (NMDA) receptors have been the primary focus of the underlying role of glutamatergic transmission in schizophrenia. Various animal models have shown that administration of NMDA antagonists such as ketamine and phencyclidine can induce symptoms of schizophrenia[9,11]. Several post-mortem studies targeting structural alterations of glutamate neurons have found reductions in dendrite arborization, spine density, and synaptophysin expression across frontal and temporal regions suggesting indirect evidence of role of glutamate in schizophrenia[9]. Moreover, recent research has shown evidence suggesting that the glutamatergic projections from the cortical brainstem communicate with the dopaminergic pathways and are associated with the positive symptoms of schizophrenia. Hypofunctional NMDA receptors can cause inhibition of the mesocortical dopamine pathway which may result in limited dopamine release in the prefrontal cortex with subsequent development of negative and cognitive symptoms[9]. One study showed that the results of the Positive and Negative Syndrome Scale (PANSS) were not associated with glutamine variability in the medial frontal cortex or glutamate variability in the basal ganglia[12].

Although extensive research has been conducted on the dopamine and glutamate systems independently of one another, neither one alone explains the full spectrum of schizophrenia. It is theorized that schizophrenia may be caused by the interactions of the dopamine and glutamate systems and therefore the most effective treatments will target both[13].

REVIEW OF THE STUDIES

In this article we review 2 studies published in the journal by Xu et al[14] and Stoyanov et al[15] that look at interdisciplinary connectivity and validation of schizophrenia. The studies focus on imaging modalities and quantitative measurements of neurotransmitters to show how the brain reacts and responds to certain stimuli in individuals diagnosed with schizophrenia. With improvements in imaging modalities, there continues to be an evolving understanding of the brain that spans all the way from neurotransmitters to the gyri.

In one of the studies that this article reviews, Xu et al[14] enrolled 97 patients with schizophrenia and 100 control patients to examine brain anatomical and neurotransmitter differences. This study aims to fill the gap in the understanding of the biological and anatomical differences between positive and negative symptoms of schizophrenia. First, fasting venous blood was drawn from subjects to examine the levels of dopamine, glutamate, and Gamma-aminobutyric acid (GABA). MRIs of patient’s brains examined several craniocerebral measurements which included the distance between the midline of the brain to the inferior fornix, the vertical and horizontal distance between the corpus callosum and the inferior part of the fornix, the distance between the middle fornix, and the area of the ventricles. They further divided the case group into positive or negative symptom groups based on the results of the PANSS. They examined neurotransmitter levels and craniocerebral measurements between patients with positive or negative symptoms of schizophrenia.

There were many significant findings in this study. In terms of neurotransmitters, the patients in the case group had significantly higher dopamine levels and significantly lower glutamate and GABA levels compared to patients in the control group. Additionally, patients with positive schizophrenia symptoms had significantly higher levels of dopamine, glutamate, and GABA than those with negative symptoms. In terms of the MRI results examining brain anatomical characteristics, patients in the case group had significantly greater vertical and horizontal distances between the corpus callosum and the inferior part of the fornix and a larger ventricle area than patients in the control group. There were no significant differences in brain structural characteristics between the positive and negative symptom groups. Unfortunately, this study is limited by the number of participants and would have benefited from examining other neurotransmitters such as serotonin and acetylcholine.

Increased dopamine levels contributing to the pathology of schizophrenia has been a long-supported theory. Additionally, some studies support that patients with schizophrenia have differences in brain anatomy compared to healthy controls when analyzed at the group level[16]. It is well known that antipsychotics are less effective for patients with negative symptoms of schizophrenia, however, the biological differences between the negative and positive symptoms of schizophrenia must be further investigated[17]. The results of Xu et al[14] provide possible targets to develop improved treatment methods for the negative symptoms of schizophrenia.

In the other study, Stoyanov et al[15] looked at various brain networks that were activated during responses to various items in 27 patients with Schizophrenia and 33 patients with major depressive disorder (MDD). As per this study, clinical diagnostic scales identified five independent brain signals displayed on the functional magnetic resonance imaging paradigm. These components included specific locations of the brain that are activated and utilized in patients with schizophrenia and MDD. Research is still ongoing to examine the active brain regions in patients with Schizophrenia. MRI continues to be utilized in this growing field as we know that diminished brain volume occurs with the first break. The study consisted of three distinct conditions with depressive, paranoid, and neutral items and a resting condition representing a standard block. Every block contained four textual statements, paranoid and depressive sections stemming from von Zerssen subscales of depression and paranoia, whereas the neutral section was based on a general questionnaire of likes and interests.

The study by Stoyanov et al[15] displayed several significant findings in the two groups of patients while they performed the task with depressive, paranoia-specific, and neutral stimuli. One significant finding is that the component (C) 14 area in the brain within the right superior and middle temporal gyri, left middle and inferior frontal gyri, and right anterior insula was shared between all three groups of patients. Therefore, C14 is limited in the differential diagnostic algorithm between schizophrenia and MDD. The frontal motor/Language and parietal areas of the brain were shared between the MDD and schizophrenic patient groups. One specific component, C38, which entails the brain's prefrontal region, was linked to the paranoid-specific section. C22 and C36, which included areas within the posterior cingulate and precuneus, lingual and fusiform gyrus, and parahippocampal gyrus, are linked to the depression-specific items in schizophrenia as compared to the MDD patients. This study furthers our understanding of the anatomical validation between neuroimaging, neuroanatomy, and neurophysiology for common psychiatric disorders affecting our population. Another recent study by Iliuta et al[18] showed a reduction in brain volume in patients with schizophrenia. Still, it did not demonstrate specific connectivity to brain regions like Stoyanov et al[15] showed, especially in paranoid schizophrenia.

CONCLUSION

These two studies encourage clinicians in psychiatry to go beyond the traditional methods and to provide objective measures in the understanding of schizophrenia. They provide future directions for distinguishing the biological differences between positive and negative symptoms of schizophrenia. However, we are not yet able to use imaging or neurotransmitters to assess diagnoses, prognosis, or which treatment may be most effective on an individual level. The differences in brain anatomy can overlap between patients with schizophrenia and controls, so we cannot yet rely on MRI findings alone to diagnose schizophrenia. These studies have certain limitations, including but not limited to the number of participants and the question of other confounding factors. The presence of other neurotransmitter involvement, such as the serotonin and cholinergic systems in schizophrenia are still evolving and warrants further investigation. There were also specific items used to assess the responses in patients, which is another limitation. These items are not standardized tools that have been seen used more broadly in psychiatry outside of the focus of these studies. It would be beneficial to use more standardized items and protocols with questionnaires to show better replicability of the results.