• Users Online: 556
  • Home
  • Print this page
  • Email this page
Home Current issue Archives Ahead of print Search Subscribe Instructions Submit article About us Editorial board Contacts Login 

 Table of Contents  
Year : 2014  |  Volume : 35  |  Issue : 1  |  Page : 1-13

Caudate nucleus volume in schizophrenia, bipolar, and depressive psychosis

1 Department of Psychiatry, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo, Egypt
3 Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
4 FRCR, Department of MRI, Hadi Hospital, Kuwait

Date of Submission11-Jan-2012
Date of Acceptance17-Mar-2012
Date of Web Publication18-Feb-2014

Correspondence Address:
Maha ELTayebani
Department of Psychiatry, Faculty of Medicine, Cairo University, Cairo
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-1105.127264

Rights and Permissions

The caudate nucleus (CN) is a crucial component of the ventral striatum and part of the striatal-thalamic circuits that is modulated by limbic structure to subserve emotional processing. MRI studies examining the CN have yielded equivocal, mixed results. We aimed to examine the CN size and its clinical, cognitive correlates in drug-naive patients with first-episode psychosis.
Materials and methods
(i) The CN was manually traced on MRI scans from 49 schizophrenic patients, 21 bipolar patients, and 20 patients with depressive psychosis as well as 23 healthy control individuals both at baseline and after 2 years. (ii) Structured SCID interviews of DSM-IV, HDRS, YMRS as well as PANSS were conducted. (iii) WMS-III and WAIS were used to test cognitive function and finally, the Simpson-Angus Scale for extrapyramidal Parkinson features.
(i) CN size was significantly more reduced in bipolar patients than in healthy controls with a magnitude of around 18.5%. (ii) Schizophrenic and depressive patients showed a modest volume reduction in CN (8.5 and 12.5%, respectively). (iii) Only bipolar patients showed cognitive dysfunction associated with a 1% progressive reduction in CN size after 2 years of follow-up. Clinical importance was unclear for depressive and schizophrenia patients.
Conclusion and recommendation
CN volume reduction in bipolar psychotic patients may reflect part of the pathophysiology of the illness, but it is unclear whether it is primary or secondary to other structural changes. Study of the shape, functional changes in CN as well as areas connected to it may uncover the primary mechanisms of bipolar psychosis.

Keywords: Bipolar disorder, caudate volume, cognition, MRI, psychotic depression, schizophrenia

How to cite this article:
ELTayebani M, ElGamal M, Gado O, Abdelaal MS. Caudate nucleus volume in schizophrenia, bipolar, and depressive psychosis. Egypt J Psychiatr 2014;35:1-13

How to cite this URL:
ELTayebani M, ElGamal M, Gado O, Abdelaal MS. Caudate nucleus volume in schizophrenia, bipolar, and depressive psychosis. Egypt J Psychiatr [serial online] 2014 [cited 2024 Mar 5];35:1-13. Available from: https://new.ejpsy.eg.net//text.asp?2014/35/1/1/127264

  Introduction Top

The basal ganglia (BG) are a paired group of nuclei interconnected with the cerebral cortex, thalamus, and brainstem. They have been implicated in a variety of processes, including associative, cognitive, mnemonic, and motor functions (Slaght et al., 2002).

More recently, understanding of the complexity in structure, neurochemical interaction, and anatomical inter-relationships with the thalamus and cortex has led to an understanding of its influence on executive function, emotion, and cognitive behaviors (Alexander and Crutcher, 1990). Within this, the caudate nucleus (CN) is known for its role in higher-order motor control, and more recently, learning and memory, particularly feedback processing (Packard and Knowlton, 2002).

Mounting evidence suggests that emotional processing is linked to anatomically defined networks consisting of limbic structures that modulate iterative prefrontal striatal-thalamic circuits (Szily and Keri, 2008). The ventral striatum, which includes the CN, is known to play a crucial role in this network (Lehericy et al., 2004).

Studies investigating minimally medicated and antipsychotic-naive schizophrenia patients have often focused on the striatum, which consists of the CN, putamen, and nucleus accumbens (Glenthoj et al., 2007).

Striatal volume reductions are not consistently found in medicated first-episode patients, likely because treatment in itself can induce alterations in the striatum (Scherk and Falkai, 2006). Nevertheless, a recent meta-analysis of voxel-based structural MRI studies in first-episode patients found the presence of CN reductions compared with chronic schizophrenia patients (Ellison-Wright et al., 2008). Moreover, nonpsychotic children of individuals with psychosis have been shown to have smaller CN (Rajarethinam et al., 2007).

Bipolar affective disorder (BAD) is a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) axis-I mood disorder that confers considerable individual and societal morbidity and cost (Gardner et al., 2006). A significant body of evidence suggests that BAD has a strong neurobiological basis that involves dysfunction of the anterior limbic brain networks, which include the BG (Strakowaski et al., 2005). Specifically, metabolic (Baxter et al., 1985; O'Connell et al., 1995; Blumberg et al., 2000) and monoaminergic receptor (Pearlson et al., 1995) changes have been identified in the BG of BAD patients, and medications routinely used to treat the illness, such as lithium and valproate, have been shown to alter the anatomy of the limbic system (Foland et al., 2007; Yucel et al., 2008). Antipsychotic medications, also used in the treatment of BAD, block dopamine receptors in the BG (Miklowitz and Johnson, 2006), and are known to affect the size of structures within the BG (Chakos et al., 1994; Gur et al., 1998). However, the findings from these studies have been marked by a huge degree of heterogeneity, as a result of small sample sizes, cross-sectional design, and differing mood states in patients at the time of assessment (Langan and McDonald, 2009). Structural MRI studies have been increasingly utilized to characterize in-vivo brain changes in bipolar patients (Strakowski et al., 1999; Malhi et al., 2004; Strakowaski et al., 2005), albeit with similarly heterogeneous results (Arnone et al., 2009).

A recent summary of functional and structural studies in BAD reported that bipolar disorder is generally associated with striatal overactivity at a functional level, whereas structural findings are mixed and that the most likely reason for this variability is the use of antipsychotic medication, which affect striatal volume (Marchand and Yurgelun-Todd, 2010).

We aimed to expand the results on the size of the CN by examining patients with first-episode psychosis including the schizophrenia spectrum, and bipolar and depressive psychosis when antipsychotic free and when medicated after 2 years, using an established caudate tracing protocol. The clinical correlates of CN volume were also examined.

  Materials and methods Top

Place and participants

All patients had been selected among drug-naive first-contact patients admitted from outpatient facilities, or referred to causality or inpatient facilities of the Psychological Medicine Hospital, Kuwait, the only formal center for admission and treatment of psychotic patients in Kuwait, over a period of 2 years (from 1 January 2008 to 31 December 2009).

Approval for the study was obtained from the hospital research and ethics committee.

Written informed consent was a prerequisite for participation.

The inclusion criteria for patients were as follows:

  1. First-ever psychiatric treatment in the public sector because of this disorder.
  2. Right-handed patients.
  3. Age 18-65 years, of both sexes.

    1. Kuwaiti patients, residence in Kuwait (two million inhabitants).

The exclusion criteria were as follows:

  1. History of previous neuroleptic or electroconvulsive therapy treatment.
  2. Patients with any neurological disorders, epilepsy, organic brain syndrome, mental abnormality, or a history of head trauma with loss of consciousness for more than 10 min.
  3. History of or current substance abuse or dependence.
  4. Metallic implants or pacemaker.
  5. Claustrophobia.

Control participants

Using normative data from the radiology department, control participants were recruited after obtaining informed consent. An attempt was made to match healthy control participants with patients for age, sex, and IQ.


The study was carried out over 4 years, divided as follows:

Baseline assessment (2 years)

All patients with first-contact psychosis admitted from January 2008 to December 2009 were assessed by clinical, psychometric, and MRI studies.

Follow-up (2 years)

Patients who continued 2-year follow-up were reassessed by all clinical, psychometric, and MRI studies used at baseline. The study was terminated at the end of 2011.


At the end of the recruitment study, we had 176 patients with first-episode psychoses; only 139 patients were Kuwaiti. Eighteen of them did not fulfill the inclusion criteria and 11 refused to participate in the study. A total of 110 patients completed the baseline study. On follow-up, 90 patients completed the entire study and accordingly they were compared with 23 control participants.

Consensus diagnosis was made by members from the clinical and research team using the structured clinical interview of DSM-IV (First et al., 1998), and all available collateral information from families and/or previous caregivers, medical records, and information provided from the clinical and research team. This information generally included not only initial symptoms but also direct and ancillary information over the course of 6-8 weeks of the initial treatment. Repeated clinical assessments every 6 months or at the time of rehospitalizations were performed.

Of 90 study-eligible patients, 49 patients (54.4%) were diagnosed with schizophrenia spectrum disorders (schizophrenia, n = 44; schizoaffective disorder, n = 5); 21 patients with bipolar disorder; and 20 patients with unipolar depression with psychosis.

The medications used during the 2-year follow-up period were as follows:

Antipsychotic drugs were mainly atypical, risperidone (17.78%), olanzapine (36.67%), quetiapine (34.45%), and haloperidol (8.89%), and only two patients were receiving sulpride (2.2%). Only one patient was prescribed benzotropine for extrapyramidal symptoms, but he did not differ cognitively from the rest of the patient sample.

Three patients in the affective group were prescribed low doses of lorazepam (1-2 mg) just on admission and were discontinued at least 3 days before baseline assessments. Bipolar patients used valproic acid or carbamazepine as mood stabilizers; none of them received lithium. Depressed patients received serotonin-specific reuptake inhibitors (90%); only two patients (10%) were treated using tricyclic antidepressants. Those medications were tapered gradually and discontinued 3 days before follow-up reassessment.


Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987)

PANSS items are scored along a continuum of severity between 1 (asymptomatic) and 7 (extreme symptom severity).

Analysis was carried out both on the total scale and the subscale (positive, negative, and general psychopathology) scores.

Hamilton Depression Rating Scales (HDRS) (Hamilton, 1960; Hamilton, 1967)

The original version includes 17 items (HDRS 17) pertaining to symptoms of depression experienced over the past week; a score of 0.7 is generally considered to be within the normal range (or in clinical remission), 8-13 as mild depression severity, 19-22 as moderate severity, and more than 23 as very severe degree of depression.

Young Mania Rating Scale (YMRS) (Young et al., 1978)

YMRS is an 11-item clinician-rated scale designed to assess the severity of manic symptoms over the previous 48 h before each assessment.

Four of the YMRS items were scored on a 0-8 scale, with the remaining five items being rated on a 0-4 scale. A score of 12 or less indicates remission of symptoms.

Cognitive tests

A standardized cognitive battery was completed by all participants, tested and scored by one of the trained researchers not involved in the treatment of the individuals at both the baseline assessment and at the end of the 2-year follow-up. Cognitive ability was examined by dividing various neuropsychological tests into six domains following the recommendation of the National Institute of Mental Health-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) (Neuchterlein et al., 2004, 2008; Kern et al., 2004, 2008).

The following domains were derived:

  1. Working memory: from spatial span subtests of the Wechsler Memory Scale, 3rd ed. (WMS-III) (Wechsler, 1997) and the digit span subtests of the Wechsler Adult Intelligence Scale, 3rd ed. (WAIS-III) (Wechsler, 1997).
  2. Verbal learning and memory: from logical memory subtest of WMS-III.
  3. Visual learning and memory: from the visual reproduction subtest of WMS-III.
  4. Speed and processing: from the trail-making test A (completion time) (Reitan, 1992) and the digit-symbol subtest of WAIS-III.
  5. Reasoning and problem solving: from the trail-making test B and the block design subtest of WAIS-III.
  6. Attention: from the spatial span and digit span forward subtest of WAIS-III.
  7. Intellectual ability using the two-subtest version of WAIS (verbal and performance subtest as well as the total score). It was measured both at baseline and at the end of the 2-year follow-up.

Duration of untreated psychosis (DUP) was defined as the number of weeks between the first expression of psychosis and the start of study recruitment.

Duration of untreated illness (DUI) was defined as the number of weeks between the start of any behavioral changes and/or pathological change and start of study recruitment.

Simpson-Angus extrapyramidal side effect scale (Simpson and Angus, 1970)

A score below or equal to 3 is considered normal; that is, without Parkinsonian features. The scale is composed of 10 items scored from 0 to 4. Patients were examined during walking in normal rhythms and each side of the body was examined separately.

Magnetic resonance imaging study

All participants were examined using an MRI study at baseline and at the end of the 2-year follow-up. The patients at baseline were examined according to schedule after patients were assessed clinically and were stable.

Imagining protocol and volume measurements

Left and right caudate perimeters were traced manually on each contiguous 1.0 mm thick coronal slice. The slices were aligned with the plane perpendicular to the line between the anterior and the posterior commissure. The lateral ventricle was used to define the anterior, posterior, medial, and superior boundaries of the CN. Dorsally, the caudate is easily demarcated from the white matter that surrounds it - as such, the traces continued posteriorly and anteriorly until the caudate was no longer visible in the slice. Inferiorly, the caudate was no longer visible in the slice. Inferiorly, the caudate shares borders with the stria-terminals and the nucleus accumbens. The caudate has been shown to play distinct functional roles and have different neuroconnectivity from the nucleus accumbens (Parent and Hazrati, 1995); thus, it was important to exclude it in the traces. For tracing purposes, the nucleus accumbens was demarcated by a line connecting the inferior margin of the lateral ventricle with the inferior border of the internal capsule, bordering with the caudate from the slice most anterior where the putamen appeared as a distinct entity to the slice most posterior where the internal capsule extends past the inferior point of the lateral ventricle. There are cell bridges between the putamen and the caudate; these were traced to their midpoint when the voxel resolution allowed.

Magnetic resonance image acquisition and processing

MRI was obtained using single 1.5-TS cameras (Monterial, Quebec, Canada) (Sigma Horizon General Electronic Medical System). Head positioning was strategized using canthometal landmarks; head movements were minimized by foam padding and straps across the forehead and chin.

An eight-channel high-resolution head coil was used. A three-dimensional volumetric spoiled gradient-recalled echo in the steady-state sequence generated 60 contiguous 3 mm coronal oblique slices perpendicular to CN TR9, TE2ET0, matrix 320 × 256, for 24 cm, and axial T2 Fsetr7000Te88eT25 5 mm thick with a 1.5 spacing matrix of 512 × 256 for 24 cm to exclude organic lesions and other pathologies. MRI data were transferred to a work station (advantage windows V4.1) and analyzed.

CN volume was estimated using manual tracing after delineation of their anatomical boundaries. One rater performed all tracings included in the analysis. One limitation of our study in comparison with published articles discussing the same subject was that we did not correlate CN volume with the whole-brain volume; yet, the advantage of the current studies over others is the use of three dimentional thinner slices perpendicular to the anatomical area of study (Caudate).

Statistical methodology

Data were collected and coded, and then entered into an IBM-compatible computer using SPSS version 17 for windows (SPSS Inc., Chicago, Illinois, USA). Entered data were checked for accuracy and then for normality using the Kolmogorov-Smir test.

Qualitative variables were expressed as numbers and percentage whereas quantitative variables were expressed as means (X) and SD. The arithmetic mean (X) was used as a measure of central tendency whereas the SD was used as a measure of dispersion.

The following statistical tests were used:

Independent-samples t-test was used as a parametric test of significance for comparison between two sample means after carrying out Levene's test for equality of variances.

Independent-samples Mann-Whitney U-test (or Z-test) was used as a nonparametric test of significance for comparison between two sample medians.

The χ2 -test (or likelihood ratio) was used as a nonparametric test of significance for comparison between the distribution of the two qualitative variables.

The Kruskal-Wallis test was used as a nonparametric test of significance for one-way comparison between more than two sample means when the one-way ANOVA test was not appropriate.

Spearman's rank correlation coefficient (r) was used as a nonparametric measure of the mutual relationship between two non-normally distributed quantitative or ordinal variables.

A 5% level was chosen as a level of significance in all statistical significance tests.

  Results Top

As shown in [Table 1] and [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5] and [Figure 6], group comparison of different diagnoses of first-episode psychosis patients (schizophrenia spectrum, n = 49; bipolar psychoses, n = 21; depressive psychoses, n = 20; and the control group, n = 23) showed that there was a highly significant difference in CN size, whereas the control group showed the largest size in the right (RT) side (CN) (F = 9.80, P < 0.001) and left (LT) side (CN) (F = 10.66, P < 0.001), whereas patients with bipolar psychoses showed the smallest size, followed by depressed patients and then the schizophrenia spectrum group (i.e. control > schizophrenia > depression > bipolar) both at baseline and after the 2-year follow-up assessment.
Figure 1:

Click here to view
Figure 2:

Click here to view
Figure 3:

Click here to view
Figure 4:

Click here to view
Figure 5:

Click here to view
Figure 6:

Click here to view
Table 1: Group comparison of caudate nucleus size and clinical characteristics for schizophrenia, bipolar, and depressive psychosis patients and the control group

Click here to view

In terms of clinical characteristics, there was a highly significant difference in age (F = 17.49, P < 0.001), where patients with affective psychoses were older than the patients in the schizophrenia and control group by 3-5 years. Regarding gender, 79.59% of schizophrenia patients were men (d.f. = 3, P = 0.03), where as both the affective patients and the control subjects were matched.

The bipolar psychosis group showed the shortest DUP (F = 18.6, P < 0.0001) among others, whereas patients with depressive psychosis had delayed age at onset (F = 537.20, P < 0.001), longer DUI (F = 11.6, P < 0.001), and higher rate of hospitalization (F = 13.5, P < 0.0001) than bipolar and schizophrenia patients.

In terms of the medications used to treat the individuals studied, neither the medication type nor the doses were found to be related to caudate size in the three groups of patients studied.

As antipsychotic medications can block the dopaminergic transmission, which is the basis of extrapyramidal symptoms, measurement of the Parkinson features was fundamental. According to the Simpson-Angus extrapyramidal rating scale, none of the individuals studied presented with extrapyramidal side effects after 2 years of treatment. Perhaps, this may have been because the majority of patients (86%) were receiving atypical antipsychotics, which do not seem to alter CN volume in drug-naive patients (Scherk and Falkai, 2006), may be because of its transient blockade of D2 receptors.

Clinical symptoms

As expected, patients with depressive psychoses showed a more severe degree of depression (HDRS mean score = 19.40 ± 3.79) than schizophrenia and bipolar groups, whereas bipolar patients showed higher YMRS mean score = 46.38 ± 5.72 and positive psychotic symptoms (positive PANSS mean score = 35.29 ± 4.11) than schizophrenia and depressive ones.

Patients with first-episode psychosis diagnosed as the schizophrenia spectrum group had higher negative symptoms (negative mean scores of PANSS = 26.98 ± 6.79) and higher general psychopathological symptoms (mean score = 54.63 ± 8.7). Their total PANSS mean score (108 ± 13.2) was high, followed by that of bipolar patients and finally, the mean scores of depressive patients [Table 2].
Table 2: Mean scores of HDRS, YMRS, PANSS in schizophrenia, bipolar, and depressive psychoses at baseline and after 2 years of follow-up

Click here to view

Cognitive function

[Table 3] shows that patients with first-episode psychosis had lower mean scores of cognitive functions and intellectual abilities scales than the control group both at baseline and even after improvement on treatment with antipsychotics after 2 years of follow-up.
Table 3: Cognitive function tests at baseline and after 2 years in different diagnostic groups of first-episode psychosis

Click here to view

  1. Among patients with first-episode psychosis, the schizophrenia group had lower mean scores of all cognitive functions measured by (WMS-III) including working memory, visual memory, verbal memory, attention, and executive functions (speed and processing, reasoning and problem solving) as well as baseline intellectual abilities (WAIS) scores compared to bipolar psychosis patients, whereas depressed patients had higher scores, but generally less than the control group [Table 3], [Figure 7] and [Figure 8]).
  2. Despite improvement in cognition and intellectual abilities after 2 years of treatment, all patients had lower scores compared to the control group. Patients with schizophrenia showed the lowest mean scores in all cognitive functions and intellectual abilities [Table 3].
Figure 7:

Click here to view
Figure 8:

Click here to view

Caudate nucleus correlates

  1. In terms of clinical characteristics, the significant correlates between CN volume and clinical characteristics were very limited. On baseline assessment, there was a negative correlation between CN size (RT, LT, overall) with current age, age at onset as well as DUI (P < 0.001), significant only in the schizophrenia spectrum group. This means that in first-episode psychosis, among patients who were diagnosed with schizophrenia, the younger the age, the earlier the age at onset, and the longer the duration of untreatment, the larger the size of the CN.
  2. On assessment after 2 years of follow-up, CN size was found to be negatively correlated with age, age at onset as well as severity of depression in the schizophrenia group. Therefore, patients with schizophrenia who experienced more severe degrees of depression showed greater reduction in CN size.
  3. There was no significant correlation between CN size and other clinical characteristics (rehospitalization rate, DUP, YMRS all PANSS scores) in the schizophrenia group.
  4. Another interesting finding was the highly significant sex difference in CN size in patients with schizophrenia, where men had a larger CN size than women in RT, LT, and overall size. RT side (F = 3.367, P = 0.002), LT side (F = 3.357, P = 0.002), and overall size (F = 3.383, P = 0.001).
  5. In contrast, sex had no impact on CN volume in patients with bipolar and depressive psychoses at baseline.
  6. After 2 years, an MRI volumetric study of CN showed comparable percent change between men and women in all diagnostic groups of first-episode psychotic patients.
  7. No significant correlation was observed between CN size and all clinical characteristics in bipolar and depressive psychosis.
  8. There was no significant impact for age or sex in the control healthy groups (P > 0.05).

Cognitive functions

Schizophrenia group

Patients diagnosed with schizophrenia showed a positive significant correlation between total CN size and the executive function test (digit-symbol subtest) at baseline and a negative correlation between the left CN size with the trail-making test B subtest at the 2-year follow-up assessment; this means that the higher the scores of executive function, the larger the size of the CN.

In addition, the total mean scores of the WAIS test correlated positively with the RT CN size (P = 0.01). This means that the larger the size of CN, the higher the basic intellectual abilities.

No other significant correlation was observed between the rest of the cognitive functions and CN size in the schizophrenia group.

Depressive psychosis group

There was no significant correlation between CN size and all cognitive functions (working, verbal, visual memory, attention, executive functions as well as baseline intellectual abilities) in patients with depressive psychosis at baseline.

After 2 years of follow-up, a significant negative correlation between (RT, LT, and overall) CN size and the mean scores of verbal memory (logic memory immediate subtest) was observed. This means that after 2 years of treatment, with more improved verbal memory, the CN size was smaller.

No other correlation for other cognitive functions with the CN was found.

Bipolar group

At baseline

There were significant positive correlations between CN size and verbal memory (logic memory immediate subtest) (P = 0.02), verbal WAIS mean scores (P = 0.001), and the total WAIS mean score (P = 0.04).

In contrast, significant negative correlations were evident between (RT, LT, and overall) CN size and the mean scores of both attention [spatial span forward (SSF), P = 0.05] and executive function (digital symbol, P = 0.03). This finding indicates that the higher the verbal memory and intellectual ability scores, the larger the CN.

No other significant associations were found between CN size and other tests of cognition.

Assessments after 2 years of treatment

It was found that the percent change of the mean scores of visual memory (visual reproduction immediate subtest, P < 0.001, visual reproduction recognition subtest scores, P < 0.001), attention (SSF, P < 0.05), performance, and total intellectual function (WAIS) (P < 0.05) were all negatively correlated with (RT, LT, and overall) CN size.

In other words, the greater the improvement in cognitive functions, the more the CN is reduced in size.

A significant positive correlation was also found between the percent charge of working memory (spatial back subtest score) (P ≤ 0.05) and CN size [Table 4].
Table 4: Relation between cognitive functions and caudate nucleus size in bipolar patients at baseline and after 2 years of follow-up

Click here to view

  Discussion Top

On studying CN size in drug-naive patients with first-episode psychosis diagnosed with schizophrenia, bipolar, and depressive psychosis and healthy controls using a manual tracing protocol, a highly significant difference in CN size was found among the patient groups and the healthy controls.

The significant difference in size was mainly found in patients with bipolar psychosis, whereas patients with schizophrenia or depression had a modest reduction in CN volume.

On follow up (after 2 years of initial assessments), MRI scans showed a progressive reduction in CN volume in patients with bipolar disorder but not in other patient groups or healthy controls.

The reduced volume of CN was around 8.5% for patients with schizophrenia and around 12.5% in depressive patients, whereas the highest reduction was in the bipolar psychosis group (>18%) in comparison with the healthy control individuals.

Our finding of reduced CN volume in first-episode schizophrenia patients is in agreement with studies reporting an absolute or a significant CN reduction in antipsychotic-naive schizophrenic patients (Keshavan et al., 1998; Shihabuddin et al., 1998; Corson et al., 1999; Salgado-Pineela et al., 2003; Ettinger et al., 2004; Chua et al., 2007; Glenthoj et al., 2007). Some consider that CN reductions as a key structure in the pathology of schizophrenia (Abi-Dargham et al., 1998) may be attributed to decreased metabolic rates in the basal gangalia (Buchsbaum and Hazlett, 1998).

The magnitude of reduction in CN size of this study 8.5% in first-episode schizophrenia was comparable with the result of Ebdrup et al. (2010) and Glenthoj et al. (2007), who reported a 5% reduction in CN volume. The slight difference can be attributed to the differences in sample characteristics, with younger age and early age at onset in our sample in comparison with the above-mentioned study.

The highly significant reduction in CN size in bipolar psychoses (∼18.5%) at baseline assessment with a progressive reduction in the short-term period (2 years) in comparison with schizophrenia and depressive patients may highlight the importance of the CN in the pathophysiology of bipolar psychoses than other patient groups, and can be considered a morphological trait.

The smaller CN volume was consistent with the finding of Beyer et al. (2004), Foland et al. (2007), Hwang et al. (2006), and Wilke et al. (2004), who reported reduced volume of CN in drug-naive bipolar patients; also, Strakowski et al. (2002) suggested that lateral ventricle enlargement in bipolar patients may be a result of periventricular atrophy of structures such as CN.

Most early studies have failed to find a difference between BAD patients and controls (Swayze et al., 1992; Strakowski et al., 1993; Brambilla et al., 2001). Aylward et al. (1994) found bilateral larger caudate volumes in male bipolar patients, but could not rule out the effects of comorbidity or medication. Strakowski et al. (1999) reported striatal enlargement in BAD patients compared with controls, with no association between medication exposure and enlargement. More recent studies have yielded mixed results, with some suggesting increases in CN size (Noga et al., 2001; Strakowski et al., 2002; DelBello et al., 2004), but others found no differences between patients with bipolar affective disorder and controls (Sax et al., 1999; Beyer et al., 2004; Chang et al., 2005a; Sanches et al., 2005).

The mixed results reported above may be because of different sample sizes, inclusion criteria, MRI acquisition, and slice thinning. This may highlight the importance of microscopic changes that may appear on localized regional reduction more than that in a macroscopic volumetric study.

Rajkowska et al. (2001) reported reductions in both glial and neuronal density in dorsolateral prefrontal cortex bipolar patients. Woo et al. (2004); Pantazopoulos et al. (2007) found a reduction in GABAergic neurons in entorhinal and anterior cingulated cortex. Such microscopic changes lead to changes in shape more than volumetric loss.

The trend toward a significant increase in the left caudate head in psychotic bipolar patients compared with nonpsychotic patients raises the question of how psychosis may result in gray matter increase; reports on the effects of psychosis are controversial. Fornito et al. (2009) reported an increase and Koo et al. (2008) reported a decrease in gray matter of CN.

It is difficult to determine whether microscopic (shape) or macroscopic changes (size) can be considered the primary pathology in the caudate or secondary to changes elsewhere in frontal subcortical loops (Marchand and Yurgelun Todd, 2010).

Clinical and cognitive correlates

Other than an inverse relation of CN size in first-episode schizophrenia with sex, age, age of onset, and DUI, there were no significant clinical correlations between severity of symptoms (HDRS, YMRS, PANSS) and CN size in schizophrenia, bipolar, and depressive psychosis both at baseline and at the short-term follow-up.

The above results are in agreement with those of Ebdrup et al. (2010), who reported no or inconsistent results for CN size with clinical variables in patients with first-episode psychosis of different diagnostic entities; this inconsistency may reflect the heterogeneity of psychoses. Associations between structural abnormalities and clinical variables presumably reflect underlying pathophysiologic disturbances in neurotransmission, metabolism, and genetic various as well as different mechanisms that may underlie positive, negative, and affective symptoms.

The significant correlation between cognitive functions and CN size in the first-episode schizophrenia and the depressed group was minimal and of no clinical value both at baseline and at follow-up; this indicates that reduced CN size in depression and schizophrenia (which is modest) may reflect the involvement of other areas in the pathophysiology such as the hippocampus and frontotemporal areas. It may also raise the hypothesis that such modest changes in the size of CN may be secondary to other structural change in other areas at a microscopic or a macroscopic level.

At baseline, reduced CN volume in bipolar psychotic patients was correlated with lower verbal memory scores (logic memory recall subtest) and with lower IQ (WAIS) scores in addition to an inverse relation with attention (spatial spam forward subtest) as well as executive function (digit-symbol subtest) scores.

After 2 years of assessment, the progressive reduced CN volume was significantly correlated with lower working memory (spatial back subtest) scores, in contrast to higher visual memory (visual reproduction immediate and visual reproduction recognition subtest) attention (SSF subtest) and executive function (block design (BD subtest and trail-making test B).

Bondar et al. (2008) have reported similar results. In their study, working memory and verbal memory were significantly compromised in first-episode schizophrenia and nonschizophrenia patients and this reflected a poor outcome.

On the basis of the above results, it appears that reduced CN size may reflect some cognitive dysfunction in bipolar patients in verbal and working memory. These specific cognitive tests may be more sensitive in predicting the short-term outcome compared with other tests. Despite the above data, there still remains an inconsistency, which points to the presence of other shared areas of importance in bipolar psychopathology or the presence of localized regional microscopic subtle changes, which could be confirmed by studying the shape and functional state of CN (Strakowaski et al., 2005).

  Conclusion and recommendations Top

Reduced CN size was evident in bipolar psychoses with a modest change in schizophrenia and depressed patients at their first contact.

The clinical and cognitive importance of CN volume change is limited and cannot be understood without the study of other areas such as the hippocampus.

Despite insights from functional receptor and genetic studies, the pathophysiology of first-episode psychosis patients with different diagnostic entities is still largely incomplete.

Studies focusing on the determination of symptoms and syndrome with interacting clinical, biochemical, structural, and functional measures may help to determine the pathophysiology of patients with first-episode psychoses.

MRI studies with new technology combining size, shape, and microscopic changes may be valuable to determine the importance of CN and other straital areas.

Strenghtens of the study

The study included drug-naive, first-contact psychosis patients.

  1. This was a 2-year prospective study.
  2. Clinical and cognitive correlates of CN volume reduction were examined in different patient groups.
  3. The use of manual tracing, high resolution with thin slice MRI acquisition, perpendicular to the CN was a good choice for better measurements.


The current study focused on volume but not the shape of CN.

CN size was not correlated with whole-brain volume.

The current study lacks information about other areas of structural importance in first-episode psychosis; for example, the prefrontal context, and other BG structures.[67]

  Acknowledgements Top

Conflicts of interest

There are no conflicts of interest.

  References Top

1.Abi-Dargham A, Gil R, Krystal J, Baldwin R, Seibyl J, Bowers M, van Dyck C, Dennis S, Charney D, et al. (1998). Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761-767.  Back to cited text no. 1
2.Alexander GE, Crutcher MD (1990). Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 13:266-271.  Back to cited text no. 2
3.Arnone D, Cavanagh J, Gerber D, Lawrie SM, Ebmeier KP, McIntosh AM (2009). Magnetic resonance imaging studies in bipolar disorder and schizophrenia: a meta-analysis. Br J Psychiatry 195:194-201.  Back to cited text no. 3
4.Aylward E, Roberts Twillie J, Barta P (1994). Basal ganglia volumes and white matter hyperintensities in patients with bipolar disorder. Am J Psychiatry 151:687-693.  Back to cited text no. 4
5.Baxter LR, Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE, Sumida RM (1985). Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry 42:441-447.  Back to cited text no. 5
6.Beyer J, Kuchibhatla M, Payne M, Moo-Young M, Cassidy F, MacFall J, Krishnan KR (2004). Caudate volume measurement in older adults with bipolar disorder. Int J Geriatr Psychiatry 19:109-114.  Back to cited text no. 6
7.Blumberg H, Stem E, Martinez D, Ricketts S, de Assis J, White T, et al. (2000). Increased anterior cingulated and caudate activity in bipolar mania. Biol Psychiatry 48:1045-1052.  Back to cited text no. 7
8.Bondar M, Malla A, Joober R, Lepage M (2008). Cognitive markers of short-term clinical outcome in first-episode psychosis. Br J Psychiatry 193:297-304.  Back to cited text no. 8
9.Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC (2001). Differential effects of age on brain gray matter in bipolar patients and healthy individuals. Neuropsychobiology 43:242-247.  Back to cited text no. 9
10.Buchsbaum MS, Hazlett EA (1998). Positron emission tomography studies of abnormal glucose metabolism in schizophrenia. Schizophr Bull 24:343-364.  Back to cited text no. 10
11.Chakos MH, Lieberman JA, Bilder RM, Borenstein M, Lerner G, Bogerts B, et al. (1994). Increase in caudate nuclei volumes of first-episode schizophrenic patients, taking antipsychotic drugs. Am J Psychiatry 151:1430-1436.  Back to cited text no. 11
12.Chang K, Barnea-Goraly N, Karchemskiy A, Simeonova DI, Barnes P, Ketter T, Reiss AL (2005a). Cortical magnetic resonance imaging findings in familial pediatric bipolar disorder. Biol Psychiatry 58:197-203.  Back to cited text no. 12
13.Chua SE, Cheung C, Cheung V, Tsang JT, Chen EY, Wong JC, et al. (2007). Cerebral grey, white matter and CSF in never-medicated, first-episode schizophrenia. Schizophr Res 89:12-21.  Back to cited text no. 13
14.Corson PW, Nopoulos P, Andreasen NC, Heckel D, Arndt S (1999). Caudate size in first episode neuroleptic naive schizophrenic patients measured using an artificial neuaral network. Biol Psychiatry 46:712-720.  Back to cited text no. 14
15.DelBello MP, Zimmerman ME, Mills NP, Getz GE, Strakowski SM (2004). Magnetic resonance imaging analysis of amygdale and other subcortical brain regions in adolescents with bipolar disorder. Bipolar Disord 6:43-52.  Back to cited text no. 15
16.Ebdrup BH, Glenthoj B, Rasmussen H, Aggernaes B, Langkilde AR, Paulson OB, et al. (2010). Hippocampal and caudate volume reduction in antipsychotic-naive first episode schizophrenia. J Psychiatry Neurosci 35:95-104.  Back to cited text no. 16
17.Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore ED (2008). The anatomy of first episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry 165:1015-1023.  Back to cited text no. 17
18.Ettinger U, Kumari V, Chitnis XA, Corr PJ, Crawford TJ, Fannon DG, et al. (2004). Volumetric neural correlates of antisaccade eye movements in first-episode psychosis. Am J Psychiatry 161:1918-1921.  Back to cited text no. 18
19.First MB, Spitzer RL, Gibbon M, Williams JBW (1996). Structured clinical interview for DSM-IV. Washington, DC: American Psychiatric Press.  Back to cited text no. 19
20.Foland LC, Altshuler LL, Sugar CA, Lee AD, Leow AD, Townsend J, et al. (2008). Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport 19:221-224.  Back to cited text no. 20
21.Fornito A, Yucel M, Wood SJ, Bechdolf A, Carter S, Adamson C, et al. (2009b). Anterior cingulate cortex abnormalities associated with a first psychotic episode in bipolar disorder. Brit J Psychiat 94:426-433.  Back to cited text no. 21
22.Gardner HH, Kleinmann NL, Brook RA, Rajagopalan K, Brizee TJ, Smeeding JE (2006). The economic impact of bipolar disorder in an employed population from an employer perspective. J Clin Psychiatry 67:121-1209.  Back to cited text no. 22
23.Glenthoj A, Glenthoj BY, Mackeprang T, Pagsberg AK, Hemmingsen RP, Jernigan TL, Baaré WF (2007). Basal ganglia volumes drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug. Psychiatry Res 154:199-208.  Back to cited text no. 23
24.Gur RE, Maany V, Mozley D, Swanson C, Bilker W, Gur RC (1998). Subcortical magnetic resonance imaging volumes in neuroleptic-naive and treated patients with schizophrenia. Am J Psychiatry 155:1711-1717.  Back to cited text no. 24
25.Hamilton M (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-82.  Back to cited text no. 25
26.Hamilton M (1967). Development of rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278-296.  Back to cited text no. 26
27.Hwang J, Lyoo IK, Dager SR, Friedman SD, Su Oh J, Lee JY, et al. (2006). Basal ganglia shape alterations in bipolar disorder. Am J Psychiatry 163:276-285.  Back to cited text no. 27
28.Kay SR, Fiszbein A, Opler I (1987). The positive and negative syndrome scale (PANSS)for schizophrenia. Schizophr Bull 2:261-276.  Back to cited text no. 28
29.Kern RS, Green MF, Nuechterlein KH, Deng BH (2004). NIMH-MATRICS survey on assessment of neurocognition in schizophrenia. Schizophr Res 72:11-9.  Back to cited text no. 29
30.Kern RS, Nuechterlein KH, Green MF (2008). The MATRICS consensus cognitive battery, Part 2: Co- Norming and standardization.  Back to cited text no. 30
31.Keshavan MS, Rosenberg D, Sweeney JA, Pettegrew JW (1998). Decreased caudate volume in neuroleptic naive psychotic patients. Am J Psychiatry 155:774-778.  Back to cited text no. 31
32.Koo MS, Levitt JJ, Salisbury DF, Nakamura M, Shenton ME, McCarley RW (2008). A cross-sectional and longitudinal magnetic resonance imaging study of cingulated gyrus gray matter volume abnormalities in first-episode schizophrenia and first-episode affective psychosis. Arch Gen Psychiatry 65:746-760.  Back to cited text no. 32
33.Langan C, McDonald C (2009). Neurobiological trait abnormalities in bipolar disorder. Mol Psychiatry 14:833-846.  Back to cited text no. 33
34.Lehericy S, Ducros M, Van de Moortele PF, Francois C, Thivard L, Poupon C, et al. (2004). Diffusiontensor fiber tracking shows distinct corticostriatal circuits in humans. Ann Neurol 55:522-529.  Back to cited text no. 34
35.Malhi GS, Valenzuela M, Wen W, Sachdev P (2002). Magnetic resonance spectroscopy and its applications in psychiatry. Aust N Z J Psychiatry 36:31-43.  Back to cited text no. 35
36.Marchand WR, Yurgelun Todd D (2010). Striatal structure and function in mood disorders: a comprehensive review. Bipolar Disord 12:764-785.  Back to cited text no. 36
37.Miklowitz DJ, Johnson SL (2006). The psychopathology and treatment of bipolar disorder. Annu Rev Clin Psychol 2:199-235.  Back to cited text no. 37
38.Neuchterlein KH, Barch DM, Gold JM, Goldberg TE, Green MF, Healton RK (2004). Identification of separable cognitive factors in schizophrenia. Schizophr Res 72:29-39.  Back to cited text no. 38
39.Neuchterlein KH, Green MF, Kern RS (2008). The MATRICS consensus cognitive battery, Part 1: Test selection ,reliability, and validity. Am J Psychiatry 165:203-213.  Back to cited text no. 39
40.Noga JT, Vladar K, Torrey EF (2001). A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder. Psychiatry Res 106:25-34.  Back to cited text no. 40
41.O'Connell RA, Van Heertum RL, Luck D, Yudd AP, Cueva JE, Billick SB, et al. (1995). Single photon emission computed tomography of the brain in acute mania and schizophrenia. J Neuroimaging 5:101-104.  Back to cited text no. 41
42.Packard MG, Knowlton BJ (2002). Learning and memory functions of the basal ganglia. Annu Rev Neurosci 25:563-593.  Back to cited text no. 42
43.Pantazopoulos H, Lange N, Baldessarini RJ, Berretta S (2007). Parvalbumin neurons in the entorhinal cortex of subjects diagnosed with bipolar disorder or schizophrenia. Biol Psychiatry 61:640-652.  Back to cited text no. 43
44.Parent A, Hazrati LN (1995). Functional anatomy of the basal ganglia. 1. The cortico-basal ganglia-thalamo-cortical loop. Brain Res Rev 20:91-127.  Back to cited text no. 44
45.Pearlson GD, Wong DF, Tune LE, Ross CA, Chase GA, Links JM, et al. (1995). In vivo D2 dopamine, receptor density in psychotic and nonpsychotic patients with bipolar disorder. Arch Gen Psychiatry 52:471-477.  Back to cited text no. 45
46.Rajarethinam R, Upadhyaya A, Tsou P, Upadhyaya M, Keshavan MS (2007). Caudate volume in off spring of patients with schizophrenia. Br J Psychiatry 191:258-259.  Back to cited text no. 46
47.Rajkowska G, Halaris A, Selemon LD (2001). Reductions in neuronal and glial density characterize the dorsolateral frontal cortex in bipolar disorder. Biol Psychiatry 49:741-752.  Back to cited text no. 47
48.Reitan RM (1992). Trail making test: manual for administration and scoring Reitan Neuropsychology Laboratory.  Back to cited text no. 48
49.Salgado-Pineela P, Baeza I, Pérez Gómez M, Vendrell P, Junqué C, Bargalló N, et al. (2003). Sustained attention impairment correlates to gray matter disease in first episode neuroleptic-naive schizophrenia patients. Neuroimage 19:365-375.  Back to cited text no. 49
50.Sanches M, Roberts RL, Sassi RB, Axelson D, Nicoletti M, Brambilla P, et al. (2005). Developmental abnormalities in striatum in young bipolar patients: a preliminary study. Bipolar Disord 7:153-158.  Back to cited text no. 50
51.Sax KW, Strakowski SM, Zimmerman ME, DelBello MP, Keck PE Jr, Hawkins JM (1999). Frontosubcortical neuroanatomy and the continuous performance test in mania. Am J Psychiatry 156:139-141.  Back to cited text no. 51
52.Scherk H, Falkai P (2006). Effects of antipsychotics on brain structure. Curr Opin Psychiatry 19:145-150.  Back to cited text no. 52
53.Shihabuddin L, Buchsabaum MS, Hazlett EA, Haznedar MM, Harvey PD, Newman A, et al. (1998). Dorsal striata size, shape and metabolic rate in never-medicated and previously medicated schizophrenics performing overhaul learning task. Arch Gen Psychiatry 55:235-243.  Back to cited text no. 53
54.Simpson GM, Angus JWS (1970). A rating scale for extra pyramidal side effects. Acta Psychiatr Scand Suppl 212:11-19.  Back to cited text no. 54
55.Slaght SJ, Paz T, Mahon S, Maurice N, Charpier S, Deniau JM (2002). Functional organization of the circuits connecting the cerebral cortex and the basal ganglia: implications for the role of the basal ganglia in epilepsy. Epileptic Disord 4 (Suppl 3): s9-s22.  Back to cited text no. 55
56.Strakowaski SM, Deibello MP, Adler CM (2005). The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 10:105-116.  Back to cited text no. 56
57.Strakowski SM, Woods BT, Tohen M, Wilson DR, Douglass AW, Stoll AL (1993). Structural brain abnormalities in first-episode mania. Biol Psychiatry 33:602-609.  Back to cited text no. 57
58.Strakowski SM, DelBello MP, Sax KW, Zimmerman ME, Shear PK, Hawkins JM, Larson ER (1999). Brain magnetic resonance imaging of structural abnormalities in bipolar disorder. Arch Gen Psychiatry 56:254-260.  Back to cited text no. 58
59.Strakowski SM, DelBello MP, Zimmerman ME, Getz GE, Mills NP, Ret J, et al. (2002). Ventricular and periventricular structural volumes in first-versus multiple-episode bipolar disorder. Am J Psychiatry 159:1841-1847.  Back to cited text no. 59
60.Swayze VW 2nd, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC (1992). Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study. Biol Psychiatry 11:221-240.  Back to cited text no. 60
61.Szily E, Keri S (2008). Emotion-related brain regions. Ideggyogy Sz 61:77-86.  Back to cited text no. 61
62.Wechsler D (1997). Wechsler adult intelligence scale. 3rd ed. San Antonio, TX, USA: The Psychological Corporation.  Back to cited text no. 62
63.Wechsler D (1997). Wechsler memory scale. 3rd ed. San Antonio, TX, USA: The Psychological Corporation.  Back to cited text no. 63
64.Wilke M, Kowatch RA, DelBello MP, Mills NP, Holland SK (2004). Voxel-based morphometryin adolescents with bipolar disorder: first results. Psychiat Res 131:57-69.  Back to cited text no. 64
65.Woo TU, Walsh JP, Benes FM (2004). Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-d-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch Gen Psychiatry 61:649-657.  Back to cited text no. 65
66.Young RC, Bigg SJT, Zeigler VE, Meyer DA (1978). A rating scale for mania: reliability validity and sensitivity. Br J Psychiatry 133:429-435.  Back to cited text no. 66
67.Yucel K, Taylor VH, McKinnon MC, et al. (2008). Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 33:361-367.Caudate nucleus volume in schizophrenia, bipolar, and depressive psychosis  Back to cited text no. 67


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1], [Table 2], [Table 3], [Table 4]

This article has been cited by
1 The prevalence of physical multimorbidity among people with non-affective psychotic disorders 10 years after first diagnosis: a matched retrospective cohort study
Myanca Rodrigues,Saverio Stranges,Bridget L. Ryan,Kelly K. Anderson
Social Psychiatry and Psychiatric Epidemiology. 2021;
[Pubmed] | [DOI]
2 Grey and white matter alteration in euthymic children with bipolar disorder: a combined source-based morphometry (SBM) and voxel-based morphometry (VBM) study
Anshita Singh,Amit Arya,Vivek Agarwal,Raj Shree,Uttam Kumar
Brain Imaging and Behavior. 2021;
[Pubmed] | [DOI]
3 Sparse Representation and Dictionary Learning Model Incorporating Group Sparsity and Incoherence to Extract Abnormal Brain Regions Associated With Schizophrenia
Peng Peng,Yongfeng Ju,Yipu Zhang,Kaiming Wang,Suying Jiang,Yuping Wang
IEEE Access. 2020; 8: 104396
[Pubmed] | [DOI]
4 The rise and fall of MRI studies in major depressive disorder
Chuanjun Zhuo,Gongying Li,Xiaodong Lin,Deguo Jiang,Yong Xu,Hongjun Tian,Wenqiang Wang,Xueqin Song
Translational Psychiatry. 2019; 9(1)
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Materials and me...
Conclusion and r...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded262    
    Comments [Add]    
    Cited by others 4    

Recommend this journal