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ORIGINAL ARTICLE
Year : 2022  |  Volume : 31  |  Issue : 2  |  Page : 282-292  Table of Contents     

Clinical correlates of regional gray matter volumes in schizophrenia: A structural magnetic resonance imaging study


1 Department of Psychiatry, M. S. Ramaiah Medical College, Bengaluru, Karnataka, India
2 Department of Psychiatry, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India

Date of Submission12-May-2021
Date of Acceptance12-Oct-2021
Date of Web Publication08-Aug-2022

Correspondence Address:
Dr. Shailaja B
Department of Psychiatry, M. S. Ramaiah Medical College, M. S. Ramaiah Nagar, MSRIT Post, Bengaluru - 560 054, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipj.ipj_104_21

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   Abstract 


Objectives: The objective of this study is to investigate the correlation between the regional gray matter volumes and length of Para Cingulate Sulcus (PCS) with the clinical profile of patients with schizophrenia. Materials and Methods: In this hospital-based, cross-sectional study, thirty consecutive in-patients diagnosed with schizophrenia and equal number of healthy volunteers matched for age- and sex- were recruited as controls. Detailed clinical assessment and magnetic resonance imaging (MRI) of the brain were carried out within 2 days for controls and within 2 weeks of hospitalization for patients. The Positive and Negative Syndrome Scale and Montreal Cognitive Assessment were applied to schizophrenia patients to assess symptoms and cognitive function, respectively. Results: Schizophrenia patients had significant volume deficit in bilateral amygdalae, bilateral superior temporal gyri, anterior cingulate cortex and bilateral hippocampi, along with a highly significant reduction in the length of right PCS. Schizophrenia patients with the duration of untreated psychosis (DUP) of 6–12 months showed a significantly greater volume of the right superior temporal gyrus (STG). First-episode schizophrenia patients had a significant reduction in the length of the left PCS. The volume of bilateral superior temporal gyri in schizophrenia patients showed a significant direct correlation with positive symptoms and an inverse correlation with negative symptoms. Conclusion: Schizophrenia patients have significant volume deficit in some brain regions. DUP of 6–12 months is associated with significantly greater volume of the right STG. First-episode schizophrenia patients have a significant reduction in the length of the left PCS. In schizophrenia patients, the volume of bilateral superior temporal gyri showed a significant direct correlation with the positive symptoms and an inverse correlation with the negative symptoms.

Keywords: Negative symptoms, paracingulate sulcus, positive symptoms, Schizophrenia, superior temporal gyrus


How to cite this article:
Shailaja B, Javadekar A, Chaudhury S, Saldanha D. Clinical correlates of regional gray matter volumes in schizophrenia: A structural magnetic resonance imaging study. Ind Psychiatry J 2022;31:282-92

How to cite this URL:
Shailaja B, Javadekar A, Chaudhury S, Saldanha D. Clinical correlates of regional gray matter volumes in schizophrenia: A structural magnetic resonance imaging study. Ind Psychiatry J [serial online] 2022 [cited 2022 Dec 6];31:282-92. Available from: https://www.industrialpsychiatry.org/text.asp?2022/31/2/282/338008



Schizophrenia is a chronic brain disorder manifesting with the signs and syamptoms involving thought, perception, emotions, cognition, movements, and behavior.[1] The vast nature, fluctuation, and differential expression of the symptoms in schizophrenia suggest dysfunction of multiple brain processes.[2] Intense neuroimaging research has provided compelling evidence in support to the current view.[3] Many studies comparing between the patients with the first episode and chronic schizophrenia have shown that similar structural brain abnormalities already exist by the first episode in patients. The brain abnormalities are even detectable in the prodrome of the disorder or in individuals with the genetic loading of schizophrenia.[4] Studies have shown greater gray matter volume loss associated with factors such as genetic loading, symptom severity, treatment with first-generation antipsychotics, duration of relapse, length of hospitalization, and poor social functioning.[5],[6],[7],[8] Due to early age at the onset of schizophrenia in males than in females, the impact of early insults may have differential consequences on the brain structures. The factors such as poorer premorbid adjustment, predominant negative symptoms, and inadequate response to treatment in male patients may contribute to the sex-specific difference of the structural brain abnormalities.[9] Schizophrenia patients with a family history have an early age of onset, greater severity of negative symptoms, poorer outcome, and a higher re-hospitalization rate than sporadic patients.[10] Few studies have established similar but subtler structural brain abnormalities in individuals with high risk of schizophrenia when compared with patients.[11]

Duration of untreated psychosis (DUP) is the time between the onset of the frank psychotic symptoms and the initiation of adequate treatment. It is indeed tough to test the association between untreated psychosis and the structural brain abnormalities owing to the presence of confounding factors, such as substance use which also imply volumetric abnormalities of the brain.[12],[13] Several studies investigating the association of DUP with structural brain changes yielded equivocal results. However, studies with large sample size and better methodologies have produced positive findings.[12] Alternatively, two researchers have suggested the possibility of the brain abnormalities being the marker for poor premorbid functioning or insidious onset of illness leading to the delayed initial presentation to the psychiatric services.[14],[15]

Neuroimaging of the patients with first-episode schizophrenia provides a golden opportunity to examine the effects of the disease process on the brain morphology without the confounders like chronicity of disease and neuroleptic exposure. Several studies have shown that similar but subtler morphological brain abnormalities compared to chronic patients with schizophrenia are present at the onset of illness, suggesting a neurodevelopmental influence. Temporal lobe structures like superior temporal gyrus (STG), Heschl's gyrus, and left planum temporale, amygdala and hippocampus volume deficits have been well documented in first-episode patients with schizophrenia compared to healthy controls.[5],[16] Numerous studies have shown a relationship between the structural brain abnormalities and symptoms of Schizophrenia. The timing of scan plays a crucial role here as the symptoms wax and wane with time. Positive symptoms predominate in the acute phase, and the negative symptoms are seen mostly in the chronic stage. Positive symptoms fluctuate more than the negative symptoms. Furthermore, antipsychotic medication is highly effective in alleviating positive symptoms but has minimal effect on the negative symptom.[17] Many studies have shown a direct association between the STG gray matter loss and the positive symptom severity, few have observed no or an inverse association.[18],[19],[20],[21] A study inferred that the left anterior cingulate cortex (ACC) volume deficit best-distinguished deficit symptoms patients from nondeficit symptoms patients compared to the rest of the regions with volume deficit.[22]

Schizophrenia is characterized by progressive clinical and cognitive decline; structural brain abnormalities also are progressive in nature. Major longitudinal MRI studies on first-episode schizophrenia patients have substantiated the same.[23],[24] As the follow-up studies are limited to the early course of illness, and also treatment with antipsychotic medications confounds for the effects of disease process on the brain structures over time, it is difficult to demonstrate the effect of duration of illness.[25],[26] Cognitive impairment is one of the core features of schizophrenia. Patients with schizophrenia exhibit moderate-to-severe deficits in attention, working memory, processing speed, problem-solving, planning, and other executive functions. These deficits predate the onset and persist throughout the course of illness. Furthermore, cognitive impairment can predict functional disability in these patients.[27],[28] Hallucination, one of the core symptoms of schizophrenia is often a result of impaired reality testing. Reality monitoring has been linked to a structure of the medical prefrontal cortex namely Para cingulate sulcus (PCS). It is one of the last sulci to develop in utero, showing significant inter-individual variation. It is absent in 12%–27% healthy individuals. Accuracy of reality monitoring is reduced in individuals with absent PCS than the individuals with a visible PCS in one or both hemispheres of the brain.[29] One study concluded that 1 cm reduction in sulcal length increases the likelihood of hallucinations by 19.9%, regardless of the sensory modality in which they were experienced.[30] In view of paucity of Indian studies in this area, we tried exploring the correlation between the gray matter volumes of amygdala, hippocampus, STG, ACC and the sociodemographic and clinical profile of the patients, and the association between the length of PCS and auditory hallucination in patients with Schizophrenia.


   Materials And Methods Top


This cross-sectional study was conducted in a tertiary care hospital affiliated to a medical college in Maharashtra. Institutional Ethics Committee clearance was obtained before starting the study. A written informed consent was obtained from each participant. Thirty consecutive inpatients with Schizophrenia consenting for the study were included. Thirty healthy volunteers matched for age-and sex-were recruited as controls. Detailed clinical assessment and magnetic resonance imaging (MRI) of brain were carried out within 2 days for controls and within 2 weeks of hospitalization for patients.

Inclusion criteria

  1. Patients aged 15–64 years of either sex diagnosed with Schizophrenia by two qualified Psychiatrists as per the ICD 10 Classification of Mental and Behavioural Disorders Diagnostic criteria for research,[31] after screening for Psychiatric comorbidities using the Mini-International Neuropsychiatric Interview (MINI)
  2. Age-and sex-matched healthy controls after screening for Psychiatric disorders using the MINI.


Exclusion criteria

  1. Schizophrenia patients with other psychiatric comorbidities
  2. Patients/controlswith head injury/organic brain disease/epilepsy/major medical illness/intellectual disability, substance use and with absolute/relative contraindication for MRI.


Two patients were excluded from the study as one of them had a sutured wound over scalp which was an artifact for imaging, another patient felt claustrophobic inside the MRI chamber.

Tools

A semi-structured proforma

This was designed to record sociodemographic and clinical profile.

The mini-international neuropsychiatric interview

The MINI was used to screen thePsychiatric co morbidities in patients and controls. It is designed to diagnose DSM 5 and ICD-10 Psychiatric disorders. It has good validity and reliability and compares well as a diagnostic instrument with the Composite International Diagnostic Interview and theStructured Clinical Interview for DSM-IV.[32]

The positive and negative syndrome scale

The positive and negative syndrome scale is 30 items scale; 7 itemsmeasuring negative, 7 itemspositive and 16 itemsgeneral psychopathology symptoms. Each item is offered a score of 1 (absent) to 7 (extreme). Summation of the score of each item gives the final score. It has a Cronbach's alpha of 0.73, 0.83, and 0.79 (P < 0.001) for the positive, negative, and general psychopathology scales, respectively.[33]

The montreal cognitive assessment

The montreal cognitive assessment (MoCA) helps to detect mild cognitive impairment. It is a 30-points test which takes around 10 min. The cut-off points to determine cognitive impairment is >26 points. It has a Cronbach's alpha of 0.71. We have used Marathi, Hindi and English versions of this test for accurate understanding and convenience of patients.[34]

Magnetic resonance imaging acquisition

MRI were acquired on a Siemens Magnetom Avanto MRI (1.5 Tesla) scanner. The images were analyzed using the Osirix DICOM software. The Regions of Interest (ROIs) were manually traced in the 1-mm axial, coronal and sagittal views on the T1-weighted Three-Dimensional Magnetization Prepared Rapid Acquisition Gradient Echo sequence. ROI volume analyzer automatically calculated the volumes of ROIs on simultaneous sections.

Manual tracing and computation of the regions of interest

The amygdala and hippocampus

The axial slices superior to the parahippocampal gyrus were used to draw the amygdala and the hippocampus. The amygdala and hippocampus were traced manually on both the left and right hemispheres, and volume was calculated.[35],[36],[37],[38],[39]

The superior temporal gyrus

The anterior boundary of the anterior STG is the first slice showing the white matter tract connecting the temporal lobe with the base of the brain. The last slice before the appearance of the mammillary bodies forms the posterior boundary of the anterior STG. The first slice on which the mammillary bodies appeared is the anterior boundary of the posterior STG. The slice where the fibers of the crux of the fornix last appeared marks the posterior boundary of the posterior STG. The whole STG was then traced manually, and the volume was calculated automatically using the ROI volume analyzer.[40],[41],[42],[43]

The para cingulate sulcus and anterior cingulate cortex

On a sagittal slice, 4 mm to the left or right of the medial line, the cingulate sulcus was identified dorsal to the corpus callosum as the first major sulcus running anteroposteriorly. The para cingulatesulcus lying dorsally and running in parallel with the cingulate sulcus was then identified. The cingulate sulcus and PCS are visible for five or more and three or more sagittal slices measured from the medial plane respectively. The PCS was then manually traced from anteroposterior direction, and the length was automatically calculated. The boundaries of the ACC were traced manually on sagittal sections, and volume was calculated.[44],[45],[46]

The above ROIs were manually traced in all the patients by a single radiologist who was blinded with respect to two groups. The unit of volume and length are in cubic centimetres (cc) and centimetres (cm) respectively.

Statistical analysis

The data wereanalyzed using software SPSS-18 (IBM, Chicago, Illinois, USA). Descriptive statistics were summarised in terms of percentage. The volume of brain structures was summarised asmedian with inter-quartile range. To compare two groups Mann–Whitney U-test was used. For the comparison of more than two independent groups, Kruskal Wallis test was used. Spearman correlation coefficient was used to find the relationship between the volume of brain structures and MoCA scores.


   Results Top


Sociodemographic and clinical profile

The mean + standard deviation age of the patients was 29.67 + 9.83, and the age range was 15–54 years. Among 30 patients, 17 patients (56.7%) were males, and 13 patients (43.3%) were females; 10 patients (33.3%) had a family history of Schizophrenia and the rest were sporadic. The DUP was <6 months in 17 patients (56.7%), 6 months to 1 year in 6 patients (20%), and more than a year in 7 patients (23.3%). Six patients (20%) had First-Episode Schizophrenia, and 24 patients (80%) had chronic Schizophrenia. The majority, i.e., 25 patients (83.3%) had positive symptom predominance, and 5 patients (16.7%) had predominantly negative symptoms. Duration of illness was <5 years in 17 patients (56.67%), 5–10 years in 6 patients (20%) and more than 10 years in 7 patients (23.33%).

Volumetric analysis of regions of interest in patients with schizophrenia compared to controls

Schizophrenia patients had a highly significant volume deficit in bilateral amygdalae, bilateral superior temporal gyri and ACC. A highly significant reduction in the length of right PCS was observed in the patients. The volume of bilateral hippocampi was significantly reduced in the patients than controls. There was no significant difference in the length of left PCS between the patients and controls [Table 1], [Figure 1]. Illustrations of the manually drawn outline of the ROIs on sagittal/coronal MR images along with the brief description of the structural change between the Schizophrenia patients and controls are given in [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10].
Table 1: The comparison of the volume of brain structures between the patients and matched controls

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Figure 1: Box plot showing the volumes of the right and left amygdala in the patient and control groups

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Figure 2: T1 three-dimensional magnetization prepared rapid acquisition gradient echo sequence, 1-mm coronal slice showing the manual tracing of the right amygdala in (a) Patient with Schizophrenia, and (b) Matched control. In the patient, there is volume loss of amygdala with no difference in signal intensity. Furthermore, prominent cortical sulci and gyral atrophy are evident in patients compared to control

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Figure 3: Box plot showing the volumes of the right and left hippocampus in the patient and control groups

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Figure 4: T1 three-dimensional magnetization prepared rapid acquisition gradient echo sequence, 1-mm coronal slice showing the manual tracing of the right hippocampus in (a) patient with schizophrenia, and (b) Matched control. In patient, there is volume loss in hippocampus with prominent cortical sulci and gyral atrophy compared to control. (b) Control subject

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Figure 5: Box plot showing the volumes of the right and left Superior Temporal Gyrus in the patient and control groups

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Figure 6: T1 three-dimensional magnetization prepared rapid acquisition gradient echo sequence, 1-mm sagittal slice showing the manual tracing of the right Superior Temporal Gyrus in (a) patient with Schizophrenia and (b) Matched control. There is volume loss in the right superior temporal gyrus of the patient with no difference in sulci and gyri compared to control

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Figure 7: Box plot showing the volume of the anterior cingulate cortex in the patient and control groups

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Figure 8: Box plot showing the length of the right and left Para-Cingulate Sulcus in the patient and control groups

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Figure 9: T1 three-dimensional magnetization prepared rapid acquisition gradient echo sequence, 1-mm sagittal slice showing the manual tracing of anterior cingulate cortex in (a) Patient with schizophrenia and (b) Matched control. There is volume loss in the anterior cingulate cortex with prominent cortical sulci and gyral atrophy in the patient

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Figure 10: T1 three-dimensional magnetization prepared rapid acquisition gradient echo sequence, 1-mm sagittal slice showing the manual tracing of right paracingulate sulcus in (a) Patient with Schizophrenia and (b) Matched control. Smaller para-cingulate sulcal length and generalized cortical atrophy is evident in the patient

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The correlation of the volume of brain structures with the clinical variables

Sex of the patient

The study did not find an association between the volume of different brain structures examined and the sex of the patients [Table 2].
Table 2: The correlation between volume the brain structures and the sex of the patient

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Family history of schizophrenia

The study did establish correlation between the volume of different brain structures examined and the family history of Schizophrenia [Table 3].
Table 3: The correlation between the volume of brain structures and the family history of schizophrenia

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Duration of untreated psychosis

A statistically significant relationship between the volume of the right STG and the three groups of the DUP was seen. The volume of right STG was significantly higher in the patient group with the DUP in the range of 6–12 months compared to other groups [Table 4]a and [Table 4]b.


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Stage of schizophrenia

First-episode Schizophrenia patients had a significant reduction in the length of left PCS compared to the patients with chronic Schizophrenia. No other brain structural volumes varied significantly with the stage of Schizophrenia [Table 5].
Table 5: The correlation between the volume of brain structures and the stage of schizophrenia

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Predominant symptom of schizophrenia

The study showed a significant direct correlation between the volume of bilateral superior temporal gyri and the positive symptom. Also, a significant inverse correlation between the volume of bilateral superior temporal gyri and the negative symptom was observed. The volume of no other brain structure showed correlation with the symptom [Table 6].
Table 6: The correlation between the volume of brain structures and the predominant symptom of schizophrenia

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Duration of schizophrenia

A significant correlation between the volume of different brain structures of patients and the duration of Schizophrenia was not found [Table 7].
Table 7: The correlation between the volume of brain structures and the duration of schizophrenia

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Montreal cognitive assessment score

The study did not find a significant correlation between the volume of brain structures and the MoCA scores [Table 8].
Table 8: The correlation between the volume of brain structures and the montreal cognitive assessment score

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Para cingulate sulcus and auditory hallucination

There was no association between the length of the PCS and the auditory hallucination [Table 9].
Table 9: The association between the length of para cingulate sulcus and auditory hallucination in the patients

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   Discussion Top


The present study compared the grey matter volumes of brain areas of interest in patients with schizophrenia and controls and explored the clinical correlates of gray matter volume of the chosen brain areas of interest in patients with schizophrenia.

Volumetric analysis of regions of interest in patients with schizophrenia compared to controls

Significant volume deficits in bilateral amygdalae, bilateral hippocampi and bilateral superior temporal gyri found in patients compared to controls in the study is in line with conclusion of major reviews.[5],[47] The ACC volume deficit found in the study in agreement with the conclusion drawn in a meta-analysis and review of studies on ACC.[48] Right paracingulate sulcus was shorter in patients compared to controls. This finding is the replication of the findings of two studies.[29],[30] Length of left PCS did not vary significantly between the patients and controls with is in contrast to the findings of two studies.[29],[30]

Sex of the patient

The finding of lack of correlation between the volume of brain structures and the sex of the patient is in line with the conclusion of two meta-analyses.[47],[49] However, the finding is in contrast to the study by Gur et al.[50] showing that the male schizophrenia patients had an increased volume deficit of amygdala along with a generalized gray matter loss of temporal lobe.

Family history of schizophrenia

This study did not note a statistically significant correlation between the volume of brain structures in patients and the family history of Schizophrenia. As compared to sporadic, the familial patients had a greater deficit of prefrontal cortex was seen in the study by Ananth et al.[51] The ROIs in the present study was different than the regions chosen by the studies showing correlation with the family history.

Duration of untreated psychosis

In the present study, patients with the DUP in the range of 6–12 months had a greater volume of the right STG than the patients with the DUP of <6 months or more than 12 months. No other brain structures showed an association with the DUP. Further investigation is needed as no firm conclusion about the association between the DUP, and the volume of brain structures could be drawn on the basis of this finding. A systematic review could not draw a firm conclusion on the association of DUP and volume of brain structures in Schizophrenia.[52] However, few studies have demonstrated a negative correlation between the DUP and brain volume changes in Schizophrenia patients.[13],[53],[54]

Stage of schizophrenia

No difference in the volume of brain structures between the first-episode Schizophrenia patients and patients with chronic Schizophrenia except for the length of the left PCS showing a significant reduction in the patients with first-episode Schizophrenia was observed. Further investigations are needed to interpret this finding. This study finding of hippocampal volume showing no difference between the two patient subgroups is in concordance with the conclusion of review and meta-analysis.[55]

Symptoms of schizophrenia

The volume of bilateral superior temporal gyri in the patients with Schizophrenia showed a direct correlation with the positive symptoms and an inverse correlation with the negative symptoms in teh present study. The volume of other brain structures studied did not show any association with symptoms. The study finding is in contrast to two studies showing a negative correlation between the volume of STG and the positive symptoms[19],[20] and another in which volume of left STG correlated inversely with positive symptoms.[21]

Duration of schizophrenia

The lack of a significant association between the volume of brain structures studied and the duration of Schizophrenia in the present study is in line with two follow up studies[56],[57] in which the progressive nature of the cortical and hippocampal volumes deficits was not evident. Our finding is in contrast to the study by Tanskanen et al.[58] showing a direct correlation between the volume deficits of brain structures and the duration.

Cognitive functions

The present study did not find a significant correlation between the volume of brain structures and the cognitive functions scored by the MoCA. Further investigations are needed to draw a firm conclusion. Our finding is in contrast to one study showing that the volume of the hippocampus and the cognitive functioning share a direct correlation[49] and to another study in which the fronto-temporo-parietal cortex volume loss had a positive correlation with cognitive impairment of patients.[59]

Para cingulate sulcus and auditory hallucination

Lack of a statistically significant association between the length of PCS and auditory hallucination is in contrast to the findings of two earlier studies in which an inverse correlation was evident.[29],[30] This discrepant finding may be due to the difference in the samples under study.

Strenghts

This is the first Indian study to evaluate the length of PCS in patients with Schizophrenia and to study its association with auditory hallucination. Also, the first study in India to evaluate the association of the volume of brain structures of interest in patients with Schizophrenia with the family history of Schizophrenia and the DUP.

Limitations

The present study was hospital-based, cross-sectional; a community-based, longitudinal study would have been superior. The ROIs -analysisutilized in the study limited the number of brain regions assessed. Voxel-Based Morphometry would have been superior in providing the structural brain abnormalities of the whole brain.


   Conclusion Top


Schizophrenia patients have significant volume deficit in some brain regions. DUP of 6–12 months in Schizophrenia patients is associated with significantly greater volume of the right STG. First-episode Schizophrenia patients have a significant reduction in the length of the left PCS. The volume of bilateral superior temporal gyri in Schizophrenia patients showed a significant direct correlation with the positive symptoms and an inverse correlation with the negative symptoms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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