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Context: Insula, which is a vital brain region for self-awareness, empathy, and sensory stimuli processing, is critically implicated in schizophrenia pathogenesis. Existing studies on insula volume abnormalities report inconsistent findings potentially due to the evaluation of 'antipsychotic-treated' schizophrenia patients as well as suboptimal methodology. Aim: To understand the role of insula in schizophrenia. Materials and methods: In this first-time 3-T magnetic resonance imaging study, we examined antipsychotic-naive schizophrenic patients (N=30) and age-, sex-, handedness- and education-matched healthy controls (N=28). Positive and negative symptoms were scored with good interrater reliability (intraclass correlation coefficient (ICC)>0.9) by using the scales for negative and positive symptoms. Gray matter volume of insula and its anterior/posterior subregions were measured by using a three-dimensional, interactive, semiautomated software based on the valid method with good interrater reliability (ICC>0.85). Intracranial volume was automatically measured by using the FreeSurfer software. Results: Patients had significantly deficient gray matter volumes of left (F=33.4; P<0.00001) and right (F=11.9; P=0.001) insula after controlling for the effects of age, sex, and intracranial volume. Patients with predominantly negative symptoms had a significantly deficient right posterior insula volume than those with predominantly positive symptoms (F=6.3; P=0.02). Asymmetry index analysis revealed anterior insular asymmetry to be significantly reversed (right>left) in male patients in comparison with male controls (left>right) (t=2.7; P=0.01). Conclusions: Robust insular volume deficits in antipsychotic-naive schizophrenia support intrinsic role for insula in pathogenesis of this disorder. The first-time demonstration of a relationship between right posterior insular deficit and negative symptoms is in tune with the background neurobiological literature. Another novel observation of sex-specific anterior insular asymmetry reversal in patients supports evolutionary postulates of schizophrenia pathogenesis.
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Indian Journal of Psychological Medicine | Apr - Jun 2012 | Vol 34 | Issue 2 133
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
Address for correspondence: Dr. Harve Shanmugam Virupaksha
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore, Karnataka 570 029, India.
E‑mail: virupaksha.hs@gmail.com
INTRODUCTION
Schizophrenia is among the most severe neuropsychiatric
disorders that has been associated with deficits involving
various brain regions.
[1]
The defining features of
schizophrenia involve disturbances in self-awareness,
empathy, and sensory processing.
[2]
Interestingly, insula –
an important brain region in the limbic neuroanatomical
Access this article online
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DOI:
10.4103/0253-7176.101778
Context: Insula, which is a vital brain region for self-awareness, empathy, and sensory stimuli processing, is critically
implicated in schizophrenia pathogenesis. Existing studies on insula volume abnormalities report inconsistent findings
potentially due to the evaluation of ‘antipsychotic-treated’ schizophrenia patients as well as suboptimal methodology.
Aim: To understand the role of insula in schizophrenia. Materials and Methods: In this first-time 3-T magnetic
resonance imaging study, we examined antipsychotic-naive schizophrenic patients (
N
=30) and age-, sex-, handedness-
and education-matched healthy controls (
N
=28). Positive and negative symptoms were scored with good interrater
reliability (intraclass correlation coefficient (ICC)>0.9) by using the scales for negative and positive symptoms. Gray
matter volume of insula and its anterior/posterior subregions were measured by using a three-dimensional, interactive,
semiautomated software based on the valid method with good interrater reliability (ICC>0.85). Intracranial volume
was automatically measured by using the FreeSurfer software. Results: Patients had significantly deficient gray matter
volumes of left (
F
=33.4;
P
<0.00001) and right (
F
=11.9;
P
=0.001) insula after controlling for the effects of age, sex,
and intracranial volume. Patients with predominantly negative symptoms had a significantly deficient right posterior
insula volume than those with predominantly positive symptoms (
F
=6.3;
P
=0.02). Asymmetry index analysis revealed
anterior insular asymmetry to be significantly reversed (right>left) in male patients in comparison with male controls
(left>right) (
t
=2.7;
P
=0.01). Conclusions: Robust insular volume deficits in antipsychotic-naive schizophrenia support
intrinsic role for insula in pathogenesis of this disorder. The first-time demonstration of a relationship between right
posterior insular deficit and negative symptoms is in tune with the background neurobiological literature. Another
novel observation of sex-specific anterior insular asymmetry reversal in patients supports evolutionary postulates of
schizophrenia pathogenesis.
Key words: Insula, schizophrenia, volumetry
Volume and Asymmetry Abnormalities of Insula
in Antipsychotic-Naive Schizophrenia: A 3-Tesla
Magnetic Resonance Imaging Study
Harve Shanmugam Virupaksha, Sunil V. Kalmady, Venkataram Shivakumar, Rashmi Arasappa,
Ganesan Venkatasubramanian, Bangalore N. Gangadhar
ABSTRACT
Original Arcle
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134 Indian Journal of Psychological Medicine | Apr - Jun 2012 | Vol 34 | Issue 2
circuit – is critically implicated to subserve self-
awareness,
[3]
empathy
[4]
and sensory stimuli processing.
[5]
It is divided into the anterior insula and the posterior
insula with a central insular sulcus dividing the both.
Both the anterior insula and the posterior insula have
different cytoarchitectural appearance as well as function.
The anterior insula is made of agranular region with an
adjacent dysgranular area. It has extensive connections
with the limbic system and higher order visual areas.
Functionally, it specializes in emotional processing
of the interoceptive awareness,
[3]
anticipation, and
the evaluation of the emotional stimuli
[5]
and self-
awareness.
[6]
The neurons in the anterior insula almost
function like mirror neurons,
[7]
which generate empathy
and identification of the boundaries. The posterior
insula encompasses granular region with the adjacent
dysgranular area. It has an extensive connection with
the higher order visual areas, auditory processing, and
somatosensary areas.
[8,9]
It specializes in the function
of the directly experienced, multimodal sensory
processing.
[4,5,10]
It is reasonable to hypothesize that the
many of the functional and the behavioral deficits that we
observe in schizophrenia may involve insula considering
its function and the connections with other areas.
Gray matter volume abnormalities of insula in
schizophrenia have been examined by previous
magentic resonance imaging (MRI) studies with
disparate findings. Some studies have noted that there
is an overall decrease in the gray matter of insula.
[11-20]
Similarly, deficits in gray matter specific to the anterior
[17]
or posterior
[18]
insula were also noted in schizophrenia.
Among high-risk subjects, the insular volume is lower
in people who develop psychosis subsequently;
[21,22]
compared to people who did not develop schizophrenia.
Negative correlation of insular volume with the positive
symptoms has been reported,
[23-25]
which could not
be replicated in other studies;
[20,26]
Hallucinations in
schizophrenia were associated with a bilateral decrease
in the insular volume.
[27]
The inconsistent findings in
the existing studies are potentially due to the evaluation
of ‘antipsychotic-treated’ schizophrenic patients as
well as suboptimal methodology. The need to look
into the relationship between the insular volume
and schizophrenia – especially in antipsychotic-naive
patients – is very apt to the current context.
In this present study, to the best of our knowledge,
we describe, for the first time, the 3-T MRI evaluation
of insular gray matter volume with its subregions in
antipsychotic-naive schizophrenia patients (
N
=30) in
comparison with matched healthy controls (
N
=28). On
the basis of background studies (as reviewed above), we
hypothesized that the patients will have significantly
deficient gray matter volume of insula.
MATERIALS AND METHODS
Subjects
The study sample consisted of 30 antipsychotic-
naive schizophrenic patients and 28 age-, sex-,
handedness-matched healthy controls. Patients
meeting the Diagnostic and Statistical Manual of
mental disorders – IV (DSM-IV) diagnostic criteria
for schizophrenia were recruited from the clinical
services of National Institute of Mental Health and
Neurosciences (NIMHANS), Bangalore, Karnataka,
India. Diagnosis was established by applying Mini
International Neuropsychiatric Interview–Plus
(MINI-Plus)
[28]
and it was confirmed by another
experienced psychiatrist through an independent
clinical interview. The details related to the illness
onset and antipsychotic-naive status were carefully
ascertained by reliable information obtained from
at least one first-degree relative. None of the
patients were ever treated with any psychotropic
medications including antipsychotics. Also, none had
received electroconvulsive therapy previously. The
psychopathology was assessed by using the Scale for
the Assessment of Positive Symptoms (SAPS)
[29]
and
the Scale for the Assessment of Negative Symptoms
(SANS)
[30]
with good interrater reliability as assessed
by the intraclass correlation coefficients greater
than 0.9.
Healthy comparison subjects (
n
=28) were recruited
with the contact help of friends and volunteers through
word of mouth’. Through these contacts, the healthy
controls were chosen from different backgrounds to suit
the varying sociodemographic status of the patients.
Healthy controls were evaluated in detail to rule out
history suggestive of psychiatric illness and were also
screened by using MINI-Plus
[28]
and comprehensive
mental status examination. None of the control subjects
had a family history of psychosis in any of their first-
degree relatives.
Only right-handed subjects were included in the
study and the left-handed subjects were excluded
as ascertained by the Annett’s questionnaire.
[31]
None of the subjects had any contraindication to
MRI. None had any neurological/systemic illness,
seizure disorder, and history suggestive of delayed
developmental milestones or history of significant head
injury. Neither the patients nor the controls had any
clinically significant nutritionally deprived state. The
substance-use history was carefully ascertained from the
subject with corroboration by at least one first-degree
relative. Patients and controls did not have current or
past history of alcohol abuse or dependence. None
used cannabis, opiates, stimulants, or any other illicit
drugsofabuse.Femalesubjectsneitherwerepregnant
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nor were within the postpartum period. None of the
subjects had dyskinesia [as assessed using the Abnormal
Involuntary Movements Scale
[32]
or parkinsonism [as
assessed using the Simpson and Angus Scale.
[33]
Clinical
assessments and MRI acquisition were performed on
the same day before starting antipsychotics. After a
complete description of the study to the subjects (and
care givers of patients), written informed consent was
obtained. The institute’s ethics committee approved
the study.
MRI scanning protocol
MRI was done with a 3.0-T scanner. T1-weighted images
(with capability for three-dimensional reconstruction)
were acquired by using the following parameters:
(repetition time) TR=8.1 ms, (echo time) TE=3.7
ms,nutationangle=8º,(fieldofview)FOV=256mm,
slice thickness=1 mm without interslice gap,(number
ofexcitationpulses)NEX=1,matrix=256×256.The
images were transferred onto a personal computer
platform. The images were randomly coded and stored
with coded identification to prevent any bias during
the study.
Semiautomated volumetry of insula
Insula is a triangular structure folded deep in the lateral
sulcus between the temporal and the frontal lobe
covered by opercula. Circular sulcus outlines the insula.
The apex of the insula is pointed toward anterior and
inferior sides and the base of the triangle toward the
superiorside.Eachinsulaisdividedintotheanterior
insula and the posterior insula by the central insular
sulcus.
[34]
The specific guidelines for insula volume measurement
were compiled by the first author (H.S.V.) after
exhaustive literature search to arrive at a set of validated
steps that are described as below. The insula of both
sides were measured with the open-source software
3D slicer (http://www.slicer.org/) by using methods
followed previously.
[35]
The tracing was done manually.
The central insular sulcus was marked in the most
prominently appearing slice by using the fiducial points
in the sagittal section. The anterior and posterior points
werealsomarkedbyusingthefiducialpoints[Figure1].
Thetracingwasdoneincoronalslices[Figure2].The
most rostral slice containing the insular cortex and the
slice containing the fusion of the superior and inferior
insular sulcus were taken as the anterior and the
posterior boundaries, respectively, following methods
used previously.
[22]
All four subregions (right anterior insula, right posterior
insula, left anterior insula, and left posterior insula)
were traced separately and labeled. The tracing was
checked and confirmed by viewing in the sagittal
section for accuracy. The intracranial volume, which
was used as a covariate in statistical analyses to control
for the potential confounding effect of the global brain
size, was automatically computed by using established
methodswiththeFreeSurfersoftware.
The first author (H.S.V.) was trained for the tracing and
the use of software by researchers with experience in
neuroimaging research (G.V.S. and S.V.K.). The volume
was measured by the first author by using coded MRI
images; this ensured methodological rigorosity by keeping
the rater blind to the subject status. The reliability of
insular volume measurement was established by the
first author along with another researcher, tracing
five subjects with excellent concurrence as measured
bytheintraclasscorrelation(ICC).Fivesubjectswere
randomly chosen and traced by two raters (H.S.V. and
V.S.) for interrater reliability (ICC>0.85).
Figure 1: Sagittal section of MRI showing the 3D reconstruction of
the anterior (blue) and posterior (green) subregions of insula, with the
central insular sulcus dividing them
Figure 2: Coronal section of MRI showing the tracings of all four
subregions of insula
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Statistical analysis
The statistical analysis was performed by using the
statistical package for social sciences, version 15.0.
The sociodemographic data were analyzed by using
the independent samples
t
test and the chi-square
test. In addition to comparative analyses for volume
deficits using the analysis of covariance (controlling
for the potential confounding effects of age, sex, and
intracranial volume), we performed two analyses
examining (a) asymmetry of insula and (b) effect of
predominant symptom status.
[36]
For the analysis of insula asymmetry, the insula
asymmetry index was calculated separately for the
anterior and posterior subregions by using the following
formula:
Left-side volume – Right-side volume
--------------------------------------------------------
Left-side volume + Right-side volume
The insula asymmetry index was subsequently
compared between patients and controls by using the
independent samples
t
test.
For the analysis of the effect of predominant
symptom status, a ratio was obtained by dividing
the total positive syndrome score by the total
negative syndrome score with a priori definition of
predominantly positive syndrome as having a ratio of
>1 and predominantly negative syndrome having a
ratio of <1.
[36]
A comparative evaluation of the effect
of predominant symptom status was done within
the patients’ group by using analysis of covariance
controlling for the potential confounding effects of age
and intracranial volume. Correlational analyses were
performed to examine for any potential relationship
between various clinical parameters (age at onset,
duration of untreated psychosis, and symptom scores)
and volumes of insular subregions.
RESULTS
Patients and controls were not significantly different
in age and sex ratio [Table 1]. The clinical profile of
patients (age at onset, duration of untreated psychosis,
and symptom scores) is given in Table 1.
Insular volume analyses
Patients had significantly deficient gray matter volumes
of the left insula (
F
=33.4;
P
<0.00001) as well as
the right insula (
F
=11.9;
P
=0.001) than do healthy
controls[Table2,Figures3and4].Thesignificance
of deficits persisted in the left insula even in subregion
analyses, whereas that in the right insula did not
[Table 3].
Asymmetry index analysis
Asymmetry index analysis revealed anterior insular
asymmetry to be significantly reversed (right>left) in
male patients (-0.01±0.03) in comparison with male
controls (0.03±0.05) (left>right) (
t
=2.7;
P
=0.01).
Table 1: Clinical characteristics of study subjects
Variable Patients
(n=30)
Controls
(n=28)
c
2
/t*
P
Age (years) 29.7±7.3 27.5±7.1
t
=1.1 0.6
Sex ratio (males/females) 16:14 14:14
χ
2
=0.7 0.8
Age at onset (years) 27.7±6.5
Duration of untreated psychosis
(months)
38.1±34.6
Positive syndrome score 21.5±6.6
Negative syndrome score 27.1±15.9
* c
2
, chi-squared test;
t
, independent sample
t
-test
Table 2: Comparisons of insular volume (in milliliters)
between patients and controls
Brain region Status Mean ± SD F* P
Left insula Patient 4.5±0.5 33.4 0.00001
Control 4.9±0.6
Right insula Patient 4.6±0.5 11.9 0.001
Control 4.9±0.7
*ANCOVA: a statistic controlling the potential confounding effects of
age, sex, and intracranial volume
Table 3: Volume (in milliliters) of insular subregions in
patients and controls
Brain region Mean±SD F* P
Patients (n=30) Controls (n=28)
Left anterior insula 3.0±0.42 3.4±0.52 6.4 0.014
Left posterior insula 1.4±0.22 1.6±0.25 6.1 0.017
Right anterior insula 3.1±0.41 3.3±0.55 2.0 0.162
Right posterior insula 1.5±0.32 1.7±0.32 3.6 0.065
*ANCOVA: a statistic controlling the potential confounding effects of
age, sex, and intracranial volume
Figure 3: Left insular volume between patients and controls
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Effect of predominant symptom status
Schizophrenic patients with predominantly negative
symptoms (
N
=21) (1.5±0.3) had significantly
deficient gray matter volume of the right posterior
insula in comparison with those of predominantly
positive symptoms (
N
=9) (1.6±0.2) (
F
=6.3;
P
=0.02)
whereas other insular subregions did not differ
significantly[Figure5].
Wedidnotobserveanysignificantcorrelationbetween
clinical parameters (age at onset, duration of untreated
psychosis, and symptom scores) and volumes of insular
subregions.
DISCUSSION
To the best of our knowledge, this is the first
study to apply the high-resolution 3-T MRI to
examine insular volumetry in antipsychotic-naive
schizophrenic patients. Our study found statistically
significant volumetric deficits in insula in patients with
schizophrenia when compared to healthy controls.
Patients with predominantly negative symptoms had
significantly deficient right posterior insular volume
than those with predominantly positive symptoms.
Asymmetry index analysis revealed anterior insular
asymmetry to be significantly reversed (right>left)
in male patients in comparison with male controls
(left>right).
As explained earlier, insula is a vital structure for
processing the emotional stimuli, empathy, self-
awareness, and identification of boundaries. It is
essential that the insular volume is intact for the normal
processing of the emotional and the sensory stimuli. It
has been observed earlier that the left insula has larger
volumethandoestherightinsula.Withineachinsula,
the anterior insula has larger volume compared to the
posterior insula. There has been a difference in the
volume of the insula in men and women, with insula
in men being larger in volume.
This study observed a significant volume deficit of
insula in schizophrenic patients. This might also explain
the various symptom profiles of patients and the
psychopathology, such as the loss of boundaries, lack of
emotional reactivity, and poor empathy. The functions
of the insula and the deficits in schizophrenia correlate
well. This supports the earlier findings of insular volume
deficits in patients with schizophrenia.
[11,12,19,37]
The
left-side involvement appears to be more severe than
the right side; this finding in our study supports the
earlier studies which have explained a similar trend.
[38]
Wewereabletodemonstrateforthefirsttimethatright
posterior insular volume had an inverse relation with
negative symptoms, although no statistically significant
relation was found between positive symptoms and
insular volume. This novel finding of ours has not been
evaluated in the previous studies even though there
has been evidence regarding the association of the
right posterior insula with poor insight.
[39]
Any loss of
gray matter volume in insula will lead to disturbance
in its functions as explained earlier. It is reasonable to
hypothesize that the loss in volume may lead to the
genesis of negative symptoms; hence, the more the
negative symptoms, the more is the loss of gray matter
volume. Specifically, we were able to demonstrate
significant volume deficits in right posterior insula
in patients with predominantly negative symptoms
[Table 2]. The role of the right posterior insula and its
association with negative symptoms of schizophrenia
needs further systematic exploration in future studies.
Another novel finding in our study is the reversal of
Figure 4: Right insular volume between patients and controls Figure 5: Right posterior insular volume comparision between
predominantly postive, negative syndrome patients
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138 Indian Journal of Psychological Medicine | Apr - Jun 2012 | Vol 34 | Issue 2
the asymmetry in the right–left insula in male patients.
Male patients had larger right insular volume compared
to left insular volume, which is contrary to the fact that
the left insula is larger than the right insula in normal
individuals.
The above reversal is not noted in female patients.
Reversal has been explained to be a process of brain
evolution where there has been a significant difference in
themaleandfemalebrainarchitecture.Femalesociality
is more closely related to neocortex volume, but male
sociality, which is more competitive and combative, is
more closely related to subcortical units, notably those
associated with emotional responses.
[40,41]
Insula being
the structure to process the emotional stimuli and
also considered to be a part of the limbic system has a
significant role in etiopathogenesis of schizophrenia. The
left-sided insular volume deficits in male patients than in
controls lead to the reversal of asymmetry. The reversal
has also been noted in other brain structures in relation
to schizophrenia and attributed to the anomalous brain
asymmetry as an evolutionary concept.
[42,43]
Methodological issues
This is the first study to examine antipsychotic-naive
schizophrenic patients for neuroanatomical correlates
of symptoms in schizophrenia and its association with
insular volume by using 3-T MRI scans. Some of the
other methodological advantages of the study include
the following: (1) antipsychotic-naive status of the
patients during the assessments; (2) MINI-Plus to
establish the diagnosis of the patients; (3) independent
confirmation of the diagnosis by an experienced
psychiatrist; (4) reliable methodology – good interrater
reliability for insular cortex volume measurements;
(5) measurements of subregions of insula; (6) age-, sex-,
and handedness- matched controls; (7) use of 1-mm
MRI slices with no interslice gap; and (8) first-time use
of 3-T MRI scan in drug-naive patients.
Implications
The findings of our study points toward the potential
neural basis involving insula in the pathogenesis of
schizophrenia. In addition to the previous evidences
for the involvement of insula in schizophrenia, the
association of the negative symptoms with more
volume deficits in right posterior insula specifically
emphasizes the need to look at the particular area in
the insula in schizophrenia and its various symptom
dimensions. This approach can potentially lead to better
understanding of the biological basis of schizophrenia
and its etiopathogenesis. Asymmetry is noted and
this might point toward the evolutionary perspective
and explain the origins of schizophrenia from a ‘distal
etiological model’. The above findings can also be used
to study the high-risk subjects for schizophrenia that
can be used in predicting the onset and progression as
well as understanding its neurobiology.
CONCLUSION
Insular volume is significantly deficient in patients with
schizophrenia, and especially right posterior volume
deficits are noted in patients of schizophrenia with
predominantly negative symptoms. Asymmetry of the
insula on the right side, especially in men, is noted.
The findings of our study support the involvement of
the insula in schizophrenia and shed more light on the
involvement of specific areas in negative symptoms that
needs to be systematically studied in the future studies.
ACKNOWLEDGMENT
This work is supported by the Innovative Young Biotechnologist
Award Research Grant to Dr. G. Venkatasubramanian by the
Department of Biotechnology, Government of India.
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How to cite this article: Virupaksha HS, Kalmady SV, Shivakumar
V, Arasappa R, Venkatasubramanian G, Gangadhar BN. Volume and
asymmetry abnormalities of insula in antipsychotic-naive schizophrenia:
A 3-Tesla magnetic resonance imaging study. Indian J Psychol Med
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Source of Support: Nil, Conict of Interest: None.
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... Patients with predominantly negative symptoms had significant volume reduction in right posterior insula compared to those with predominantly positive symptoms. Virupaksha et al. [81] conclude that insular volume deficits in antipsychotic-naive SZ patients, support intrinsic role for the insula in the pathogenesis of this disorder. Gong et al. reported reductions in the gray matter volume of the right anterior insula in SZ patients as compared to controls, describing their finding as "a neuroanatomical signature" [82]. ...
... Deficit in right posterior insula volume in those with negative symptoms, 3T MRI study [81]. ...
... Third and lateral ventricles Enlargement [130] Mediodorsal thalamic nuclei Reduction in total neuron number [26] Anterior cingulate cortex Gray matter reduction [84] Spindle neurons reduction in the right side [138] Right insula Deficit in right anterior insula volume [82] Deficit in right posterior insula volume [81] Left prefrontal cortex Lower thalamocortical connectivity [25] Right prefrontal cortex (anterior) (middle and inferior) ...
... Insula L > R (Biduła and Króliczak, 2015;Virupaksha et al., 2012) No effects Esteves et al., 2019) No effects Esteves et al., 2019) L > R volume associated with L > R activation of supramarginal gyrus and Broca's area during gesture planning and silent word generation respectively (Biduła and Króliczak, 2015). Side-independent volumetric asymmetry correlated with improved depressive mood . ...
... Insula. Also the insula has shown a leftward volumetric bias (Biduła and Króliczak, 2015;Virupaksha et al., 2012). Such (leftward) asymmetry has been demonstrated to be positively correlated with leftward biased activation of the supramarginal gyrus during gesture planning and Broca's area during silent word generation (Biduła and Króliczak, 2015). ...
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The pioneer works of Marc Dax and Paul Broca on the association between left hemisphere injuries and speech impairments, revealed one of the most intriguing properties of the brain – asymmetry. Since then, lateralized features have been observed in virtually all phylogenetic branches, suggesting evolutionary conservation, although its adaptive role is still not clear. In humans, the field remains greatly shaped by early observations on language, but the advent of brain imaging revealed that functional and structural laterality is not only widespread, extending to memory, decision-making and emotion, but also that it is plastic. In this review, we systematize information regarding structural and functional hemispheric asymmetries of the healthy brain and their associations with cognition and behavior. We briefly explore evolutionary theories and the pathways for asymmetry development, but mostly we focus on central nervous system asymmetries of the adult human, bridging towards the laboratory rodent for mechanistic explanations.
... While Bora et al reported insula GMV reduction only in chronic patients (Bora et al., 2011). Our results in line with previous reports that selective GMV reduction in left insula in chronic DS patients relative to both NDS patients and healthy controls (Cascella et al., 2010), and primarily in line with volumetric study which found a significantly deficient right posterior insula volume in drug naïve patients with predominantly negative symptoms than those with predominantly positive symptoms (Virupaksha et al., 2012). Together, these results suggested that GMV loss in left insula at the early period of illness might be characteristic to DS patients. ...
... Also, GMV in left insula was associated with negative symptoms in a recent meta-analysis (Bora et al., 2011). Less GMV in insula was consistently found in patients with predominantly negative symptoms, both at first-episode (Virupaksha et al., 2012) and chronic stage (Sigmundsson et al., 2001). In a recent follow-up MRI study, the GMV reduction of bilateral insula was also associated with negative symptoms (Takahashi et al., 2009). ...
... One way to exclude this confounding factor is to compare the medication-naïve patients to the healthy controls. To our knowledge, there were a few DTI studies investigating the integrity of WM [19,[35][36][37][38][39][40] and some morphometric studies [39][40][41][42] in medicationnaïve schizophrenia patients. ...
... One way to exclude this confounding factor is to compare the medication-naïve patients to the healthy controls. To our knowledge, there were a few DTI studies investigating the integrity of WM [19,[35][36][37][38][39][40] and some morphometric studies [39][40][41][42] in medicationnaïve schizophrenia patients. ...
... Several findings of our study are supported by previous works [15], [16] and also consistent with our previous work [1]. For the asymmetric performance, the subcortical area [17] and insula [18] showed abnormal asymmetries in brain volume in SZ, which give further insight on the functional asymmetric performance. Functionally, decreased intra-and interhemisphere asymmetry have been detected in SZ [19], [20]. ...
... The spatial allocation of these regions extended from the ventral anterior, dorsal anterior to posterior insula, which corresponded to the known cytoarchitectonic patterns (Augustine, 1996) and functional profiles (Kurth et al., 2010) in the insula. The decreased functional connection between the bilateral insula of patients in the current study was consistent with the structural abnormality of the insula in schizophrenia patients identified in previous studies (Shepherd et al., 2012;Virupaksha et al., 2012). Schizophrenia is associated with difficulties to discriminate self-generated sensory stimuli from externally generated stimuli, resulting in a broad range of symptoms (Waters and Badcock, 2010). ...
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The insula is involved in detecting the salience of internal and external stimuli, and it plays a critical role in psychosis. Previous studies have demonstrated the structural and functional alterations of the insula in schizophrenia. To acquire a full picture of the functional alterations of the insula in schizophrenia, the resting-state fMRI data of 46 patients with schizophrenia and 46 healthy control subjects were collected. We used clustering analysis to divide the insula into three subregions: the dorsal anterior insula (dAI), ventral anterior insula (vAI) and posterior insula (PI). Then, whole-brain functional connectivity analysis was conducted based on these subregions. The results showed that the right dAI and PI in patients exhibited altered functional connections with the primary sensorimotor area. In addition, the right PI of the patients exhibited increased functional correlations with the thalamus. More importantly, the altered functional properties of the right PI were significantly correlated with the severity of the delusion and poor insight in schizophrenia. The results suggested that the right PI might play an important role in self-experience processing in schizophrenia. Accordingly, the right PI should be considered very important in the pathological mechanism of schizophrenia.
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