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European Review for Medical and Pharmacological Sciences 2014; 18: 3354-3367

Cingulate Cortex in Schizophrenia: its relation


with negative symptoms and psychotic onset.
A review study
F.S. BERSANI1, A. MINICHINO1, M. FOJANESI1, M. GALLO1, G. MAGLIO1,
G. VALERIANI1, M. BIONDI1, P.B. FITZGERALD2
1
Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy
2
Monash Alfred Psychiatry Research Centre, The Alfred and Central Clinical School, Monash
University, Melbourne, Australia

Abstract. OBJECTIVE: The cingulate cortex verse cognitive and emotional processes that sup-
is a functionally heterogeneous region involved port goal-directed behaviour and it is involved in
in diverse cognitive and emotional processes. It motivation, memory and attention1. The cingu-
is a region of special interest to investigate the
neurological substrate of schizophrenia. The
late cortex has, therefore, come under scrutiny as
aim of this paper is to review all the studies that a region of special interest to those investigating
investigated the relation between the cingulate the neurological substrate of schizophrenia.
cortex and two of the most important and little It is anatomically divided into anterior and pos-
known areas of this disease: the psychotic on- terior portions; the anterior cingulate cortex
set and the negative symptoms. (ACC) seems to be involved in the pathogenesis
MATERIALS AND METHODS: Relevant litera-
ture was identified through a search in PubMed, of negative-type processes both in neuropsychi-
Web of Science, and Cochrane database. Search atric patients2 and in healthy populations3. Locat-
terms included negative symptoms, cingulate ed bilaterally in the medial frontal lobes, the ACC
cortex, cingulate gyrus, schizophrenia, PET, comprises the cytoarchitectonic areas 24/24 and
SPECT, MRI, fMRI, BOLD, deficit schizophrenia, 32/32, with area 25, commonly called the sub-
early-onset schizophrenia, psychotic onset, psy-
chosis.
genual cingulate4, located posterior to the subcal-
RESULTS: 9 studies evidenced a link between losal extension of area 24,ventral to the genu. Ar-
negative symptoms and hypoactivity of cingu- eas 24/32 are located dorsal to the corpus callo-
late cortex, whereas 7 studies did not. A positive sum, while areas 24/32 occupy a pregenual posi-
relationship between anterior cingulate cortex tion5. Areas 32 and 32 have been termed transi-
gray matter thinning and high risk for schizo- tion cortex because they possess cytoarchitectonic
phrenia is well characterized in literature.
CONCLUSIONS: In a large portion of patients
features common to areas 24/24 and adjacent
hypoactivity of cingulate cortex underlie the pres- frontal regions5. Other authors have labeled areas
ence of negative symptoms. In particular, ACC 32/32 as paralimbic, or paracingulate, cortex and
(anterior cingulated cortex) thinning seems to be areas 24/24 as limbic ACC due to the latters
related to the increasing social withdrawal that is denser connections with emotional centres6,7.
characteristic of the psychosis prodrome. New Given the possible complex involvement of
therapies focused on the brain stimulation of the
cingulate cortex could represent an important aid the cingulate cortex in the pathogenesis of schiz-
for patients with this kind of symptoms. ophrenia, the aim of this paper is to review all
the studies that investigated the relation between
Key Words:
the cingulate cortex and two of the most impor-
tant and little known areas of this disease: the
Negative symptoms, Psychotic onset, Schizophre-

psychotic onset and the negative symptoms.


nia, Cingulate cortex.

Negative symptoms are a cluster of symptoms


generally characterized by the absence of normal
levels of activation, initiative, and affect8. The
Introduction
The cingulate cortex is part of the limbic sys- negative symptom constellation in schizophrenia
tem and has extensive reciprocal connections includes psychomotor retardation, avolition, bio-
with cortical and sub-cortical structures. It is a rythm disturbances, apathy, neurological soft
functionally heterogeneous region involved in di- signs, anhedonia, attention impairment and de-

3354 Corresponding Author: Amedeo Minichino, MD; e-mail: amedeominichino@yahoo.it


Cingulate Cortex in Schizophrenia

creased emotional expression9-12. These symptoms late gyrus, negative symptoms, schizophrenia,
are associated with poor premorbid function, the PET, SPECT, MRI, fMRI, BOLD, deficit schizo-
male sex and a low IQ13 and are correlated with phrenia, early-onset schizophrenia, psychotic on-
poor outcome14. Controversy surrounds whether set, psychosis. We searched the references of all
second generation antipsychotics are more effec- included articles. This strategy yielded more than
tive than first generation antipsychotics in the 200 studies. Two independent reviewers extracted
treatment of negative symptoms; undisputed, data and assessed the quality of methodological
however, is that negative symptoms persist in reporting of selected studies using data extractions
many cases despite pharmacological treatment15-19. forms. We considered only those studies investi-
Moreover, it has become clear that it is the nega- gating in several different ways the relation of cin-
tive symptoms (more than the positive symptoms) gulate cortex with negative symptoms and psy-
that account for much of the functional disability chotic onset. Only clinical trials were included in
of schizophrenia20,21. Accordingly, the develop- this review. We excluded single case reports, dis-
ment of effective treatments for this kind of symp- sertations, and meeting abstracts. In section 3 and
toms has the potential to remediate the often sub- section 4 of this paper we summarize the most im-
stantial functional disability associated with schiz- portant outcomes achieved.
ophrenia. Because of the importance of negative
symptoms in schizophrenia, deficit schizophrenia Anterior Cingulate Cortex Abnormalities
(DS) has been proposed as a putative disease sub- and Psychotic Onset
type defined by prominent, primary negative Mounting neuropathologic and magnetic reso-
symptoms that endure as trait-like features during nance imaging (MRI) evidences support a prima-
periods of clinical stability22. Although negative ry role for abnormalities of the ACC in the
symptoms are considered an important feature of pathogenesis of psychotic disorders32, but it re-
schizophrenia, they are not pathognomic of it. mains unclear whether these abnormalities pre-
Negative symptoms of schizophrenia have gener- cede or follow psychosis onset. Establishing the
ally been found in association with organic lesions timing of such neuroanatomic changes is critical
and altered functioning in several cerebral regions, to determine whether they represent a risk mark-
such as ventricles, prefrontal cortex and cingulate er for illness onset or a secondary manifestation
cortex 23-28 and they often represent one of the of the disease process. To determine whether
most characterizing symptom of the first phases of neuroanatomic differences represent risk mark-
schizophrenia. ers, it is necessary to identify and follow-up indi-
In addition to negative symptoms, we found viduals at elevated risk for psychosis to charac-
that a consistent feature of psychosis prodromes terize diagnostic outcomes. In recent years opera-
is the presence of attenuated or subthreshold tionalised criteria have been developed that iden-
psychotic features. These differ from frank psy- tify individuals in the prodrome to the first psy-
chotic symptoms in their intensity, frequency chotic episode. These criteria require the recent
and/or duration. It is likely that not all people onset of specific symptoms or clinical features,
with subthreshold forms of psychotic symptoms termed an at risk mental state (ARMS), and are
and syndromes will develop a full-blown psy- associated with functional impairment. Individu-
chotic disorder. However, a combination of these als with an ARMS display a need for care33 and
subthreshold syndromes with other risk factors have an ultra high risk of developing a psychotic
for psychotic disorder may increase the likeli- disorder, predominantly schizophrenia, within
hood of imminent onset of psychotic disorder in two years. Diffusion Tensor Imaging (DTI) stud-
an individual. Many authors recently used such ies have provided evidence of disruption in white
an approach for identifying a group said to be at matter tracts in first-episode psychosis patients in
ultra high risk (UHR) for psychotic disorder (i.e. comparison to age matched controls, which indi-
putatively prodromal)29-31. cates that abnormalities in structural connectivity
are present at illness onset and are not a sec-
ondary consequence of medication, or illness du-
ration34. Similar abnormalities have also been re-
ported in ARMS subjects35.
Materials and Methods

We searched PubMed, Web of Science, and the In a study conducted by Lord et al36, function-
Cochrane database of systematic reviews. We used al MRI and graph theoretical analysis were used
the following keywords: cingulate cortex, cingu- to characterize the organization of a functional

3355
F.S. Bersani, A. Minichino, M. Fojanesi, M. Gallo, G. Maglio, G. Valeriani, M. Biondi, P.B. Fitzgerald

brain network in at-risk mental state patients NP individuals displayed a relative thickening of
with varying symptoms assessed with the Posi- dorsal and rostral limbic areas that was correlat-
tive and Negative Syndrome Scale (PANSS) and ed with anxiety ratings. An intriguing possibility
healthy volunteers during performance of a ver- arising from these data is that abnormal thicken-
bal fluency task known to recruit frontal lobe ing in the UHR-NP group confers increased re-
networks and to be impaired in psychosis. They silience against transition to psychosis, although
first examined between-groups differences in to- the positive correlation observed between thick-
tal network connectivity and global network ness and anxiety levels suggest that it predispos-
compactness/efficiency and then addressed the es to other psychopathology. Comparison be-
role of specific brain regions in the network or- tween UHR-P and UHR-NP individuals indicated
ganization by calculating the node-specific be- that changes in the rostral limbic-ACC and, to a
tweeness centrality, degree centrality and lo- lesser extent, the rostral paralimbic and limbic
cal average path length metrics; different ways and paralimbic subcallosal regions, differentiated
of assessing a regions importance in a network. between the two groups. These thickness differ-
They focused their analysis on the ACC. Al- ences predicted time to psychosis onset indepen-
though global network connectivity and efficien- dently of any correlations with baseline symptom
cy were maintained in at-risk patients relative to ratings. With their findings Fornito et al41 demon-
the controls, they reported a significant decrease strated that anatomic changes in the ACC are ap-
in the contribution of the ACC to task-relevant parent before the onset of frank psychosis, distin-
network organization in at risk subjects with ele- guish between UHR individuals who subsequent-
vated symptoms (PANSS 45) relative to both ly do and do not develop a psychotic episode and
the controls and the less symptomatic at-risk sub- are relatively specific to individuals who develop
jects, as reflected by a reduction in the topologi- a schizophrenia spectrum disorder. The differ-
cal centrality of the ACC. ences between the UHR-P and UHR-NP groups
Two studies37-38 have investigated individuals are unlikely to be due to variations in their base-
at UHR for psychosis identified using state and line clinical characteristics, given that ACC mea-
trait criteria. Both the studies reported reduced sures predicted time to psychosis onset indepen-
ACC gray matter in UHR individuals who subse- dently of any shared variance with symptom
quently developed psychosis (UHR-P) compared measures. The two groups were well-matched
with those who did not (UHR-NP). demographically, and while a small proportion of
Job et al39-40 found reduced ACC gray matter in UHR individuals were also enrolled in an inter-
individuals at genetic high risk for schizophrenia vention trial, the relative proportions in each
compared with healthy control subjects, but these group receiving each intervention type were sim-
reductions were no more severe in those high-risk ilar. Moreover, the dissociation observed with re-
individuals who eventually developed schizo- spect to correlations between regional ACC ab-
phrenia or subthreshold psychotic symptoms. normalities and symptom measures in the two
In a study of Fornito et al41, using the Compre- groups suggests that the anatomic changes are re-
hensive Assessment of At-Risk Mental States lated to distinct pathophysiologic processes relat-
(CAARMS)42, a structured clinical interview de- ed to their divergent psychiatric outcomes.
signed to assess prodromal symptomatology and The localization of changes individuated by
risk for psychosis, were recruited 103 partici- Fornito et al is interesting in light of a recent
pants. The UHR cohort was regularly monitored work demonstrating bilateral thinning of the par-
over a minimum 12-month period (mean=13; alimbic region in first episode schizophrenia, and
maximum=44 months). Participants were then longitudinal research in childhood-onset schizo-
divided into UHR-P and UHR-NP groups using phrenia suggesting the earliest post-onset
operational criteria for determining psychosis on- changes appear in paralimbic regions and spread
set43. Baseline ACC morphometry was then com- to engulf the limbic ACC over a 5-year period.
pared between UHR individuals who developed A longitudinal gray matter reduction in dorsal
psychosis (UHR-P; n=35), those who did not paralimbic regions of ACC (ACCp) during the
(UHR-NP; n = 35), and healthy control subjects transition to psychosis was also demonstrated.
(n = 33). Relative to control subjects, UHR-P in- Together these findings suggest a timetable for
dividuals displayed bilateral thinning of a rostral the progression of ACC abnormalities in schizo-
paralimbic ACC region that was negatively cor- phrenia, whereby the earliest reductions emerge
related with negative symptoms, whereas UHR- in the rostral paralimbic region during the pro-

3356
Cingulate Cortex in Schizophrenia

drome, extend across the dorsal and subcallosal sociated with a specific pattern of ACC abnor-
paralimbic regions following psychosis onset, malities that cannot be attributed to variations in
and spread to encompass limbic regions with sulcal and gyral morphology. The absence of
continued illness duration. grey matter volume differences described is like-
Evidence that the rostral-ACCp plays an im- ly explained by the fact that patients showed a si-
portant role in social cognitive processing, partic- multaneous decrease in thickness and increase in
ularly mentalizing others intentions44, suggests surface area; that is, the different direction of
abnormalities in the area lead to difficulties inter- these changes are likely to have cancelled each
acting with others. This may underlie the increas- other out when combined in the summary volu-
ing social withdrawal that is characteristic of the metric measure41.
psychosis prodrome45. The combined decrease in ACC cortical thick-
Recent data suggest46 that high-risk relatives ness and increase in surface area provides some
of individuals with schizophrenia displaying sub- clues regarding the underlying pathophysiology
threshold psychotic symptoms show poorer per- causing the change. Similar changes are also
formances on theory of mind (ToM) tasks than seen during normal adolescent (and early adult)
those without such symptoms. This finding was brain maturation, to the extent that continued
confirmed by a neuroimaging study47 of the same brain growth is accompanied by a reduction in
research team. cortical grey matter, the changes being particu-
In a parallel study, Fornito et al48 used a novel larly protracted in frontal regions50. In this re-
surface-based protocol for parcellating the ACC gard, decreased thickness coupled with increased
into functionally relevant regions, while account- surface area may reflect an exaggeration of nor-
ing for individual variations in sulcal anatomy. mal neurodevelopmental processes. The speci-
The approach enabled calculation of multiple in- ficity of the thickness reduction to paralimbic,
dices of anatomical change, including regional but not limbic, areas in their sample (which con-
grey matter volume, surface area, cortical thick- trasts the surface area expansion of both) may re-
ness, and sulcal depth and curvature with submil- flect a regionally specific pathology that spreads
limeter precision. By focusing on a sample of pa- from the paralimbic ACC to the limbic ACC with
tients experiencing their first episode of schizo- illness progression.
phrenia, they minimized the potential confound- Kuperberg et al51 have reported thickness re-
ing influences associated with prolonged illness ductions in both the limbic and paralimbic
and treatment effects49. Importantly, they individ- ACC of patients with established schizophre-
ually matched patients and healthy controls for nia, but with more prominent differences occur-
age, sex, and paracingulate sulcus (PCS) mor- ring in the latter. By way of speculation, the
phology to ensure that any identified changes gradual progression of anatomical abnormali-
could not be attributed to group differences in ties from paralimbic to limbic regions may rep-
cortical folding patterns. In this study they ap- resent a pathophysiological basis for the in-
plied a surface-based protocol to T1-weighted creasing prominence of negative symptoms in
scans acquired from 40 first episode schizophre- the clinical presentation of patients with pro-
nia patients and 40 healthy controls individually longed illness, consistent with reports of limbic
matched for age, sex, and morphology of the ACC involvement in motivational function 3
PCS, a major anatomical variation that has been and evidence that lesions in the area can lead to
shown to affect morphometric estimates in the apathy and/or akinetic mutism52.
region. The surface-based approach enabled cal- The earlier involvement of paralimbic regions
culation of regional grey matter volume, surface may be associated with the deficits in executive
area and curvature, cortical thickness, and depth function and social cognition known to occur
of the cingulate sulcus, with sub-millimeter pre- from the outset of the illness and even prior to
cision. Relative to controls, schizophrenia pa- psychosis onset53, consistent with evidence that
tients displayed a bilateral reduction in thickness the ACCp is critically involved in these
of paralimbic regions of the ACC, along with a functions 44 , and functional imaging studies
concomitant increase in surface area of both the demonstrating abnormal ACCp activation in
limbic and paralimbic ACC. No differences were schizophrenia patients performing such tasks54.
identified for regional grey matter volume, sur- The cortical grey matter reduction seen in MRI
face curvature, or CS depth. These findings indi- studies of normal adolescent development is
cate that the early stages of schizophrenia are as- thought to reflect partial volume effects caused

3357
F.S. Bersani, A. Minichino, M. Fojanesi, M. Gallo, G. Maglio, G. Valeriani, M. Biondi, P.B. Fitzgerald

by ongoing myelination of fibers penetrating the Alzheimers disease 58. Moreover, VENs have
cortical mantle, rather than overt neuronal loss3. been found to be selectively reduced in fron-
Postmortem studies have found increased ax- totemporal dementia59, in cases with agenesis of
onal input into the limbic ACC of patients with the corpus callosum60, and it has also been spec-
schizophrenia55, suggesting that myelination of ulated that VENs may play a role in the patho-
these excess fibers in early illness stages may physiology of autism. VEN comprise an inter-
contribute to a thinning of the cortical ribbon esting population of neurons that could be af-
(Table I). fected in complex diseases, such as schizophre-
nia in which both neurodevelopmental and neu-
Von economo Neurons, Anterior rodegenerative alterations occur12,61.
Cingulate Cortex and Brune et al 62 tested the hypothesis that the
Early-Onset Schizophrenia density of VENs is reduced in a neurodevelop-
The human ACC comprises an extraordinary mental subtype of schizophrenia, defined by an
spindle-shaped bipolar neuron in layer V, first early onset of the disorder. The density of VENs
discovered by Betz, later studied in detail by was estimated in layer V of Brodmanns area 24
von Economo and Koskinas, and hence referred in 20 subjects diagnosed with schizophrenia.
to as von Economo neurons (VENs), a label The results were compared with 19 specimens
that is less ambiguous than the wide-spread use from patients with bipolar disorder as a clinical
of the term spindle cells. The density of control and 22 non-psychiatric samples. The
VENs in humans reaches the adult figure density of VENs did not differ between the
around 4 years of age, suggesting a role in three groups. However, the VEN density in the
functional domains that mature slowly, such as right ACC correlated with the age at onset, and
emotion regulation, motor control56, and eco- inversely with the duration of the illness in
nomic decision-making57. In support of this as- schizophrenia, but not in bipolar disorder. Thus,
sumption, VENs have been found to be rich in patients with early onset schizophrenia (and
vasopressin, dopamine, and serotonin recep- longer duration of illness) had a reduced VEN
tors. These neurotransmitters are known to be density. Age, sex, postmortem interval, brain
critically involved in the regulation of reward weight, and cortical thickness had no significant
and complex social behaviours. impact on the results. These findings suggest
With regard to pathological conditions, VENs that VENs in the ACC are involved in neurode-
contain a high amount of neurofilament, which velopmental and perhaps neurodegenerative
is why they are assumed to be affected in processes specific to schizophrenia.

Table I. Resume of the studies investigating the ACC abnormalities in relation with the psychotic onset.

Study Acc abnormalities and psychotic onset

Gasparotti et al, 2009; Bloemen et al, 2009 Disruption in white matter tracts in first-episode psychosis patients in
comparison to age matched controls
Pantelis et al, 2003; Borgwardt et al, 2007 Reduced ACC gray matter in UHR individuals who subsequently de-
veloped psychosis compared with those who did not
Job et al, 2003; Job et al, 2005 Reduced ACC gray matter in individuals at genetic high risk for schiz-
ophrenia compared with healthy control subjects
Fornito et al, 2008 ACC thickness differences predicted time to psychosis onset indepen-
dently of any correlations with baseline symptom ratings, also these
differences are relatively specific to individuals who develop a schizo-
phrenia spectrum disorder
Fornito et al, 2008 Bilateral thinning of the ACC paralimbic region in first episode schizo-
phrenia
Fornito et al, 2008 The early stages of schizophrenia are associated with a specific pattern
of ACC abnormalities: combined decrease in AC cortical thickness and
increase in surface area.
Lord et al, 2011 Significant decrease in the contribution of the ACC to task-relevant
network organization in at risk subjects with elevated symptoms rela-
tive to both the controls and the less symptomatic at-risk subjects

3358
Cingulate Cortex in Schizophrenia

mild and severe negative symptoms, and to de-


termine whether the degree of severity can be re-
Cingulate Cortex Abnormalities and

lated to specific dysfunctional areas of the brain.


Negative Symptoms

Single Photon Emission Computed The PANSS was used to form two groups of pa-
Tomography (SPECT) and Positron tients (n=14) with prevalence of negative symp-
Emission Tomography (PET) Studies toms: Mildly Affected (MA), and Severely Af-
Since 1981, more than 100 articles on func- fected (SA). Brain PETs were obtained in resting
tional brain imaging in schizophrenia have been conditions and Statistical Parametric Mapping
published. PET and SPECT, which measure re- was used to perform statistical comparisons. It
gional cerebral blood flow (rCBF) and or metab- was not highlighted any correlation between neg-
olism, reveal a number of abnormalities and defi- ative symptoms and ACC both in MA and in SA
ciencies in people with schizophrenia compared group; on the other hand, the MA-group showed
with healthy subjects63. increased activity in posterior cingulate gyrus.
Sabri et al in 199764 performed a study in which Lahti et al in 200668 reported the correlations
24 drug-naive acute patients with a first manifesta- between whole brain rCBF and the positive and
tion of schizophrenia and 20 control subjects were negative symptoms of schizophrenia in two co-
examined with technetium-99m-labeled hexam- horts of patients who were scanned while free of
ethylpropyleneamine oxime (99mTc-HMPAO) antipsychotic medication. Both cohorts of pa-
brain SPECT. The patients with schizophrenia tients with schizophrenia (Cohort 1: n=32; Co-
were also assessed according to PANSS. The re- hort 2: n=23) were scanned using PET with
sults of this study showed that all negative symp- H2(15)O while free of antipsychotic medication
toms had a negative correlation to bifrontal, bitem- for an average of 21 and 15 days, respectively.
poral, cingulate, basal ganglia and thalamic rCBF. Both groups were scanned during a resting state.
Ashton et al in 200065 presented a SPECT study Negative symptoms correlated inversely with
involving 39 exclusively neuroleptic naive schizo- rCBF in frontal and parietal regions, but not in
phrenic patients and a tightly selected control cingulate cortex (Table II).
group (n=39). Imaging was performed on a high
resolution SPECT scanner with the perfusion trac- Magnetic Resonance Spectroscopy
er 99mTc-HMPAO and the PANSS was used for (H-MRS) Studies
the psychopathological assessment. A verbal flu- Magnetic resonance spectroscopy (H-MRS)
ency task66 was used to produce a degree of stan- allows in vivo measurement of several metabo-
dardisation of the cognitive state of subjects dur- lites critically important for brain function, in-
ing the period of fixation of the tracer and to ac- cluding N-acetylaspartate (NAA), an amino acid
centuate task related group differences. They considered a marker of neuronal integrity69-71,
found an association between negative PANSS glutamate (Glu), an amino acid involved in exci-
scores and decreased rCBF in the cingulate gyrus. tatory neurotransmission72 and metabolism73,74 ,
Potkin et al in 200263 used PET to compare cere- and choline-containing compounds (Cho), that
bral metabolic patterns in schizophrenic subjects reflect primarily the constituents of cell mem-
with predominantly negative or positive symp- branes, phosphocholine and lycerophospho-
toms. 14 right-handed male subjects with DSM-IV choline, that increase with accelerated turnover
schizophrenia were assigned to groups with pre- or loss of membrane phospholipids75.
dominantly negative or predominantly positive In the study performed by Yamasue et al in
symptoms on the basis of their post-drug-washout 200276 schizophrenic (n=15) and normal control
scores on the PANSS. The patients were compared (n=13) subjects were examined using both H-mag-
to 7 age- and gender-matched normal volunteers. netic resonance spectroscopy (MRS) and MRI, in
PET scans with 18-F-fluorodeoxyglucose were ob- order to accurately assess the partial volume within
tained during a degraded Continuous Performance the spectroscopic volume of interest (VOI) in the
Task to measure absolute glucose metabolic rates. anterior cingulate cortex. The gray matter volume
The results showed that negative symptom subjects within VOI correlated positively with the NAA to
had a lower glucose metabolic rate in several sec- Cho ratio in patients with schizophrenia only, not in
tions of the right hemisphere including posterior controls. The results of the study showed that there
cingulate cortex. was a significant negative correlation between the
Galeno et al in 200467 performed a study to NAA/Cho ratio and the severity of blunted affect
compare the cerebral regions that are involved in symptom in patients with schizophrenia.

3359
F.S. Bersani, A. Minichino, M. Fojanesi, M. Gallo, G. Maglio, G. Valeriani, M. Biondi, P.B. Fitzgerald

Table II. Studies investigating the relation between negative symptoms and hypoactivity of cingulate cortex.

Relation between
Neuroimaging negative symptoms and
Study technique Patients hypoactivity of
cingulate cortex

Sabri et al 1997 SPECT/99mTc-HMPAO 24 drug-naive first-episode Yes


schizophrenia patients.
20 healthy control subjects.
Ashton et al 2000 SPECT/99mTc-HMPAO 39 drug-nave patients with Yes
schizophrenia
39 healthy control subjects
Sigmundsson et al 2001 MRI 27 patients with schizophrenia and Yes
predominant negative symptoms
27 healthy control subjects
Potkin et al 2002 PET/18-F- 14 patients with schizophrenia Yes
fluorodeoxyglucose 7 healthy control subjects
Yamasue et al 2002 H-MRS/ NAA, Cho, Cr 15 patients with schizophrenia
13 healthy control subjects Yes
Galeno et al 2004 PET/18-F- 10 patients with schizophrenia and No
fluorodeoxyglucose low negative symptoms
4 patients with schizophrenia and
high negative symptoms
6 healthy control subjects
Lahti et al 2006 PET/H2(15)O 55 patients with schizophrenia No
Wood et al 2007 H-MRS/NAA, Glx 15 patients with schizophrenia No
14 healthy control subjects
Calabrese et al 2008 MRI 28 patients with schizophrenia and Yes
their non-psychotic siblings.
38 healthy control subjects and
their siblings.
Galderisi et al 2008 MRI 34 patients with schizophrenia and No
predominant negative symptoms
32 patients with schizophrenia
31 healthy control subjects
Lui et al 2009 MRI 68 antipsychotic-naive first-episode No
schizophrenia patients
68 healthy control subjects
Preuss et al 2010 MRI 50 patients with schizophrenia. Yes
50 healthy control subjects.
Makris et al 2010 MRI 88 patients with schizophrenia and No
predominant negative symptoms
40 healthy control subjects
Cascella et al 2010 MRI 19 patients with schizophrenia and Yes
predominant negative symptoms.
31 patients with schizophrenia.
90 healthy control subjects
Berge et al 2010 MRI 21 drug-naive first-episode No
schizophrenia patients
20 healthy control subjects
Reid et al 2010 H-MRS/ NAA, 26 patients with schizophrenia Yes
Cho, Cr, Glx 23 healthy control subjects

In the study performed by Wood et al in 200777 concentrations throughout the dorsal and rostral
15 male patients with schizophrenia and 14 male portions of the anterior cingulate and in both
controls were assessed using H-MRS, with re- hemispheres, but showed no changes in Glx. Pa-
gions of interest placed in the right and left dor- tients were administered the PANSS to assess
sal and rostral cingulate. The metabolites of in- general psychopathology. A significant positive
terest were NAA and glutamate + glutamine correlations was found between right rostral
(Glx). Schizophrenia patients had lower NAA NAA and the Negative Syndrome factor.

3360
Cingulate Cortex in Schizophrenia

In 2010 Reid et al78 used H-MRS acquired in the study showed that subjects with schizophrenia and
dorsal anterior cingulate cortex and fMRI during their non-psychotic siblings had similar reductions
performance of a Stroop color-naming task79 to in- of gray matter volume (approximately 10%) in the
vestigate the neurochemistry and functional re- posterior cingulate cortex (PCC) compared to
sponse of the anterior cingulate cortex/medial healthy control subjects and their siblings; in the
frontal cortex in 26 stable, medicated subjects with combined group of schizophrenia subjects and their
schizophrenia and 23 matched healthy control sub- siblings, an inverse correlation between left PCC
jects. They observed a significant negative correla- volume and negative symptoms, such that a larger
tion between Glx (glutamate+glutamine)/Cr levels left PCC volume was associated with fewer nega-
and negative symptoms in the group of medicated tive symptoms, was found; there was no significant
subjects. Because of this correlation, this study as- effect of group on ACC volume, thickness, or area.
sessed the relation between the deficit of integrity Galderisi et al in 200882 performed a study in-
of ACC and negative symptoms in patients with cluding 34 patients with Deficit Schizophrenia
schizophrenia (Table II). (DS), 32 with nondeficit schizophrenia (NDS),
and 31 healthy comparison subjects. The schedule
MRI Studies for the Deficit Syndrome was used to categorize
Structural MRI studies have used 2 approaches patients as DS or NDS patients. The 2 patient
to investigating neuroanatomical changes in pa- groups were matched on age and gender and did
tients with schizophrenia. One, the region-of- not differ on clinical variables, except for higher
interest (ROI) method, involves manual delin- scores on the negative dimension and more im-
eation of the ACC on each scan, with morphomet- paired interpersonal relationships in DS than in
ric parameters such as gray matter volume calcu- NDS subjects. This study found that the cingulate
lated secondarily. The second, commonly termed gyri volume was smaller in NDS but not in DS pa-
voxel-based morphometry (VBM), is an automat- tients as compared with healthy subjects.
ed technique that involves spatial normalization of Lui et al in 200983 used MRI optimized voxel-
each participants scan to a common stereotactic based morphometry and resting state functional
space, followed by voxelwise statistical compari- connectivity analysis to characterize the associa-
son of group differences in gray matter measures. tion between clinical symptoms and anatomical
This has provided an attractive alternative to the cerebral deficits in a large sample of antipsychot-
ROI methodology because it affords a relatively ic-naive first-episode schizophrenia patients. The
unbiased assessment of gray matter changes participants of the study were 68 antipsychotic-
across the entire brain, although errors in spatial naive first-episode schizophrenia patients and 68
normalization, particularly in morphologically matched healthy comparison subjects. Both pa-
variable regions such as the ACC, can complicate tients and healthy comparison subjects were
interpretation of findings7. scanned using a volumetric three-dimensional
Sigmundsson et al in 200180 performed a study spoiled gradient recall sequence and a gradient-
involving 27 right-handed patients who met echo echo-planar imaging sequence. They used
DSM-IV criteria for schizophrenia with enduring the PANSS84 to assess the psychopathological
negative symptoms and 27 healthy comparison status. Optimized voxel-based morphometry was
subjects. All these patients received dual echo used to characterize gray matter deficits in schiz-
MRI. Significant deficits of gray and white mat- ophrenia patients. The clinical significance of re-
ter volume in the patient group were found at the gional volume reduction was investigated by ex-
ACC and medial frontal gyri. amining its association with symptoms in pa-
To investigate whether the decrease in the gray tients with first-episode schizophrenia and with
matter volume of the cingulate gyrus in subjects alterations in resting state functional connectivity
with schizophrenia might be related to heritable in- when brain regions with gray matter volume re-
fluences Calabrese et al in 200881 used high-resolu- duction were used as seed areas. Significantly
tion MRI and labeled cortical mantle distance map- decreased gray matter volume was observed in
ping to measure gray matter volume, as well as schizophrenia patients in the right anterior cingu-
thickness and the area of the gray/white interface, late gyrus but not related with the severity of
in the anterior and posterior segments of the cingu- negative-type processes.
late gyrus in 28 subjects with schizophrenia and In the MRI study performed by Makris et al in
their non-psychotic siblings, and in 38 healthy con- 201085, the researchers compared the volume of
trol subjects and their siblings. The results of the all brain fiber systems between chronic patients

3361
F.S. Bersani, A. Minichino, M. Fojanesi, M. Gallo, G. Maglio, G. Valeriani, M. Biondi, P.B. Fitzgerald

with DSM-III-R schizophrenia (n=88) and be enduring and less reactive to medication,
matched healthy community controls (n=40). other concomitant therapies that are focused on
They found that a set of a priori white matter re- the brain stimulation of the cingulate cortex
gions of local and distal associative fiber systems could represent an important aid for patients
was significantly different in patients with schiz- with this kind of symptoms. In fact recent tech-
ophrenia. They found a positive correlations be- nologies as the H-coil for the Transcranial Mag-
tween volumes (larger) in anterior callosal, cin- netic Stimulation (deep TMS)89 and the surgical
gulate and temporal deep WM regions. Deep Brain Stimulation90 offer the opportunity
Preuss et al in 201086 examined a large sample to stimulate specific brain regions91. In particu-
of schizophrenic inpatients and controls in order lar we think that deep TMS, as it is a totally
to assess the potential relationship between ante- non-invasive and well tolerated procedure,
rior cingulate cortex volumes and P300 charac- could easily be used in schizophrenic patients
teristics in patients with more pronounced nega- with pharmaco-resistant negative symptoms92,93
tive symptoms. They obtained auditory P300 and as well as in patients with other psychopatho-
structural magnetic resonance imaging volume logical problems94-96.
measurements of the ACC in 50 male schizo- Over recent years, the concept of negative
phrenic patients and 50 matched controls. Pa- symptoms has also been described as a promi-
tients negative symptoms were assessed using nent feature in other neurological and psychiatric
the PANSS. The results of the study showed that disorders including mood disorders97-98, Parkin-
volumetry of ACC subregions revealed a volume sons disease99-100, Conversion disorder101, sub-
reduction in patients with schizophrenia com- stance abuse 102, Alzheimers disease 103-104 and
pared with controls in right hemispheric rostral Epilepsy 105 . In particular, in patients with
ACC subregions that were most pronounced in Alzheimers disease negative symptoms were
more negative schizophrenia patients. correlated with a significantly lower rCBF in cin-
In 2010, Cascella et al87 performed a study gulate cortex106.
were they acquired MRI of the whole brain in 19 Some of the studies we reviewed used the
outpatients with Deficit Schizofrenia, 31 with PANSS to evaluate negative symptoms; this fact
Non Deficit Schizofrenia, and 90 healthy adults. represent a limit of the specificity of the clinical
The results of the study showed that regions in evaluation of patients because the items of the
which Gray Matter Volume reductions best dis- PANSS for negative symptoms are also symp-
tinguished negative symptoms patients from non toms and signs sometimes found in MDD; blunt-
negative symptoms patients included the left an- ed affect, emotional withdrawal, poor rapport,
terior cingulate cortex. social withdrawal, difficulty in abstract thinking,
Berge et al in 201088 tried to determine brain lack of spontaneity and flow of conversation and
areas reduced in first episode of psychotic sub- stereotyped thinking. This could mean that nega-
jects and its association with lack of insight and tive symptoms could just reflect depressed mood
negative symptoms. In their study 21 drug naive at the time of assessment107.
first-episode subjects and 20 controls underwent The studies we reviewed also found that cin-
a structural MRI scan and were clinically as- gulate hypoactivity was often connected with hy-
sessed. Optimized voxel-based-morphometry po or hyper functionality of other brain regions
analysis was implemented to find between-group such as dorsolateral prefrontal cortex, left anteri-
differences and correlations between GMV vol- or temporal cortex, posterior inferior frontal
ume and lack of insight and negative symptoms. gyrus, transcortical speech area, retrosplenial
Negative symptoms correlated with decreased cortex, lingual gyrus, occitotemporal conver-
GMV volume at cerebellum and frontal inferior gence, middle temporal gyrus, inferior temporal
regions, but not at cingulate cortex (Table II). gyrus, superior temporal gyrus, premotor cortex
and deep cerebellar nuclei. This point reflects
that cingulate cortex has large anatomical con-
nections and that negative symptoms are com-
plex and cannot be associated with only one
Discussion
The data we presented suggest that there is a brain area, but rather with neuron networks that
large portion of patients where hypoactivity of involve all the brain.
cingulate cortex underlie the presence of nega- From a clinical point of view, this wide
tive symptoms. As negative symptoms tend to spread of connections could also explain the

3362
Cingulate Cortex in Schizophrenia

role of the anterior cingulate in cognitive func-


tions. In fact, studies using fMRI 108-109 and
Conclusions

PET110-111 have shown that the anterior cingulate Our review evidences that cingulate cortex
and/or the pre-motor areas are activated in nor- dysfunction may underlie negative symptoms
mal control subjects when performing a verbal and that there is a relation between a gray mat-
fluency test. In particular, three of these studies ter thinning of ACC and high risk for schizo-
showed activation of both the anterior cingulate phrenia. For these reasons, therapies focused on
and premotor areas in normal subjects with ver- the stimulation of this area should be further in-
bal fluency tests, some of which involved a vestigated.
memory component in addition to free recall.
Fletcher et al. extended their results using con- -
nectivity theory112 to suggest that the anterior
cingulate with the premotor areas form part of a
Conflict of Interest
All authors of this paper have no relevant affiliations or fi-
network of interconnected regions involved in nancial involvement with any organization or entity with a
cognitive functions that may be disrupted in financial interest in, or financial conflict with the subject
schizophrenia107. matter or materials discussed in the manuscript. This in-
cludes employment, consultancies, honoraria, stock owner-
The data we presented also offer other sugges- ship or options, expert testimony, grants or patents received
tions: a change in cingulate function could be a or pending, or royalties. All authors acknowledge that the
useful objective biological marker in the assess- conflict of interest disclosures are complete for both them-
ment of neuroleptic medication on negative selves and their co-authors, to the best of their knowledge.
symptoms.
It is also true that recognizing the prodrome of
a first psychotic episode prospectively creates the
opportunity of intervention, which could delay,
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