Open Journal of Psychiatry, 2012, 2, 253-257 OJPsych Published Online October 2012 (
The subgenual cingulate gyrus exhibits lower rates of
bifurcation in schizophrenia than in controls, bipolar
disorder and depression
Matthew R. Williams1,2*, Ronald K. B. Pearce2, Steven R. Hirsch2, Olaf Ansorge3, Maria Thom4,
Michael Maier5
1King’s College London, Institute of Psychiatry, De Crespigny Park, London, UK
2Neuropathology Unit, Department of Clinical Neuroscience, Division of Neuroscience & Mental Health, Imperial College London,
Charing Cross Hospital, London, UK
3Department of Neuropathology, The Radcliffe Infirmary, Oxford, UK
4Institute of Neurology, UCL, London, UK
5Trust HQ, West London Mental Health NHS Trust, Middlesex, UK
Email: *
Received 23 August 2012; revised 25 September 2012; accepted 5 October 2012
The subgenual cingulate cortex has been found to be
different in structure and function in mood and affec-
tive disorders compared to healthy individuals. Im-
aging studies have shown a decrease in function of the
subgenual region in bipolar disorder and depression,
with overall glial number shown to be decreased in
these disorders. Decreases in subgenual grey matter
in SZ have been observed also. In this neuropatho-
logical study upon formalin-fixed coronal brain sec-
tions we describe the morphological finding of de-
creased frequency of subgenual cingulate crown bi-
furcation (p = 0.02) as compared to control, bipolar
and depression cases. This suggests that the cingulate
cortex in schizophrenia may be morphologically dis-
tinct in utero formation, potentially enabling an early
identification of high-risk individuals.
Keywords: Neuropathology; Schizophrenia; Cortical;
The subgenual cingulate cortex (SCC), part of Brodmann
area 24a, is a region of interest in schizophrenia (SZ) and
bipolar disorder (BPD). The anterior cingulate cortex
(ACC) lies on the medial surface of the cerebral hemi-
sphere, covering the anterior part of the corpus callosum.
It is defined as Broadmann area 24a. The ACC extends
from the subgenual ventral terminus and continues rostal
to the genu of the corpus callosum following the dorsal
The ACC has been implicated in regulation of emotional
tional states, and in cognitive and attentional processes
[1-5]. Projections travel directly from the SCC cortical
grey matter to the corpus callosum. DTI studies have
demonstrated decreased anisotropy in this cingulum
bundle in patients with chronic SZ [6,7]. MRI imaging
studies have shown a decrease in SCC grey matter vo-
lume with decreased thickness in first episode schizo-
phrenic patients [8,9] and in chronic disease and that the
extent of thinning is related to illness duration [10-12]
and a decrease in overall anterior cingulate volume [13].
Meta-analysis has suggested that the ACC in SZ has
slightly decreased overall volume in SZ compared to
controls, although there is significant heterogeneity in
published articles [14]. Decreased ACC volume has also
been observed in BPD in SCC cortical grey and white
matter [15,16]. Smaller subgenual volumes have also
been reported in unmedicated recurrent depressive dis-
order (RDD) [17] and decreased ACC volume has been
shown to correlate inversely with good clinical outcome
Whilst stereological examination shows no change in
overall volume in frontal cortices in schizophrenia [19,
20], cortical thinning has been observed in area 24a in
both SZ and BPD [15,21], and a decrease in the grey mat-
ter density in schizophrenia has also been reported in the
orbitofrontal, cingulate and supramarginal cortices [22].
Some studies have suggested that in schizophrenia this
thinning is more pronounced in the left side of the SCC
[23,24], and also a tendency to thicker SCC cortical grey
matter in major depression. In addition, there has been
reported a decrease anterior cingulate white matter integ-
rity in schizophrenia [25,26], suggesting a widespread
*Corresponding author.
M. R. Williams et al. / Open Journal of Psychiatry 2 (2012) 253-257
issue with the morphology of anterior cingulate in these
In this study we have taken coronal sections through
the SCC in cases of SZ, BPD and RDD and control cases
to examine the prevalence of cortical bifurcation. The size
of the bifurcation within a gyrus means it is not visible by
imaging and therefore requires a microscopic methodol-
ogy. As the extent of folding of the cortex increases its
surface area within a given gyral volume, potentially re-
flecting the number of cortical neurons, this pattern of
morphology may reflect a smaller cortical volume present
from initial neurodevelopment of the cingulate.
A cohort of cases obtained from the Corsellis brain col-
lection was used in neuropathological investigation of
the cingulate in a series of studies (Williams, 2012). De-
tails of the diagnostic groups are shown in Table 1. A
total of 68 age and post-mortem interval (PMI) matched
cases were used, with 20 control cases with no psychia-
tric disorder (NPD), 12 SZ cases, 16 BPD cases and 20
cases of RDD.
All cases underwent full neuropsychiatric review and
were subject to full neuropathological screening. Cases
involving heavy alcohol or drug use and those exhibiting
significant pathology such as neurodegenerative disease,
cerebral vascular disease, ischemic brain damage, CNS
infections and traumatic brain injury were excluded from
the study. The majority of samples come from the county
of Essex but a smaller number came from national refer-
rals [27]. Medical notes were reviewed by a consultant
psychiatrist and patients were selected on fulfilment of
the ICD-10 criteria for SZ and MDD, for robustness of
diagnosis the brains of the three diagnostic groups all
suffered from chronic illness. Assessment for any neu-
rodegenerative, neurovascular or infectious pathology,
including Parkinson’s disease, was undertaken by a
consultant neuropathologist and affected patients ex-
cluded. Patients with any recorded history of alcohol or
drug abuse were also excluded. In SZ selection the
presence of first-rank symptoms was a necessity, and
cases with onset younger than 20 and older than 30
were excluded.
Bilateral SCC and adjacent corpus callosum were dis-
sected from formalin-fixed coronal blocks by a consult-
ant neuropathologist and immersed in 10% formalin (4%
formaldehyde v/v) until processing. Processing involved
serial immersion in formalin, alcohols, methanol and
xylene overnight. Tissue blocks were then embedded in
paraffin wax and stored at 4˚C. Paraffin-embedded blocks
were serially sectioned in the coronal plane at 10 µm and
mounted on 25 × 75 mm electrostatic glass slides. Slides
were blinded by an investigator not involved with the
project before measurement. Sections from within 100
μm each case were stained with hematoxylin and eosin
(H & E) and cresyl-violet (CV) for accurate examination
of the anatomy of the structures. Sections for H & E stain
were submerged in xylene for 30 minutes and serially
placed in troughs of 2 × 100%, 90%, 70% ethanol (EtOH)
and pure distilled water, each for 2 minutes. Slides were
immersed in Mayer’s haematoxylin stain for 5 minutes
and subsequently washed in distilled water. Specimens
were placed in differentiating agent acid-alcohol (1%
HCl/70% EtOH) for 10 seconds and into distilled water
for 2 minutes. Sections were then immersed in 1% eosin
stain for 5 minutes and washed in distilled water. Finally,
specimens were dehydrated in serial baths of 70%, 90%
and 2 × 100% IMS for 2 minutes each and submerged in
xylene for 20 minutes before cover slips were fixed using
DPX. Sections for CV stain were immersed in xylene for
30 minutes, incubated in 100%, 90% and then 70% al-
cohol for 10 minutes each, before immersion in ultra-
pure water. Sections were immersed in cresyl-violet stain
for 5 minutes before washing in ultra-pure water and
differentiation in 95% alcohol/ethanoic acid. After wash-
ing in ultra-pure water sections were dehydrated in se-
rial alcohols, immersed in xylene and mounted with
Images of both H & E and CV stained coronal sections
were taken using an Olympus microscope at 40× total
magnification and captured at 2096 × 1536 resolution
covering 2200 × 1600 µm area. Image analysis was per-
formed using Image Pro Plus software (Media Cybernet-
ics, US), calibrated using an optical graticule. In total for
regions were measured in each case, both left and right
SCC in H & E and CV sections. H & E sections were
consulted to define the limits of the SCC grey matter.
Measures were taken in CV and H & E stained sections
Table 1. Summary group data. NPDNo Psychiatric Disorder; SZSchizophrenia; BPDBipolar Disorder; RDDRecurrent
Depressive Disorder. Age, PM delay and fixation time shown as means with SEM in brackets.
Diagnosis n Age/y Sex ratio M/F PM Delay/h Fixation time/y
NPD 20 65.5(2.34) 12/8 44.2(7.38) 10.2(0.52)
SZ 12 58(6.44) 6/6 47.8(10.5) 11.1(1.30)
BPD 16 56.1(5.21) 7/9 50.5(7.46) 19.4(2.02)
RDD 20 47.6(3.12) 6/14 37.3(5.62) 10.4(0.88)
Copyright © 2012 SciRes. OPEN ACCESS
M. R. Williams et al. / Open Journal of Psychiatry 2 (2012) 253-257 255
by a scoring of incidence of bifurcation in the SCC from
both hemispheres from each case, after comparable mea-
sures were taken from adjacent sulci and from the level
of the crown. Bifurcation was defined as the existence of
a sulcal-type projection into the crown of the primary
SCC that were less than 50% the depth of both the cal-
losal-cingulate sulcus and the primary cingulate sulcus,
shown in Figure 1. Scoring of bifurcation of was taken
from both left and right primary SCC in both CV and H &
E slides, totalling two measures per hemisphere and four
measures per case. Bifurcation had to be present in both
CV and H & E slides for inclusion.
Measures were performed blind to diagnosis and were
unblinded by an investigator not involved with the pro-
ject before analysis using Image Pro Plus. Multiple com-
parisons of confounding variables were performed using
the general linear model univariate analysis using SPSS
v16.0 statistical software (SPSS, USA). Direct analysis
of the incidence of bifurcation was performed using Pear-
sons Chi-Square test (SPSS, USA).
The MDD group had a significantly lower age of death
as compared to controls (p = 0.038, 1-way ANOVA). The
MDD group (n = 20) contained 11 confirmed cases of
suicide. The other disease groups also showed instances
of suicide, which may contribute toward the non-signifi-
cant trend downward in age in SZ (1 suicide, n = 12) and
BPD (3 suicides, n = 16). The brain tissue of the BPD
group was in formalin significantly longer than the other
groups (Mean fixation time: NPD 11.3 yr vs. BPD 19.7
yr, p = 0.0004; NPD vs. SZ. 11.6 yr, p = 0.074; NPD vs.
RDD. 11.8 yr, p = 0.59, ANOVA). There was no effect of
sex, age, PM delay, incidence of suicide, fixation time or
hemisphere on the incidence of bifurcation.
The incidence of bifurcation was 11/20 NPD cases (55%),
2/12 SZ cases (17%), 9/16 BPD cases (56%) and 11/20
RDD cases (55%), shown in Figure 2. The SZ group
showed a significantly lower incidence of bifurcation
than the controls or other diagnostic groups (p = 0.02,
Pearsons Chi-Square test, SPSS v16.0).
The results suggest that SCC bifurcation is less common
in schizophrenia than in either controls, BPD or RDD.
Whether this bifurcation is related to changed numbers
of neuron or glial cells, or the function of the SCC, are
unknown. Future neuropathological studies will be re-
quired to elicit further information of the cellular changes
associated with altered cortical folding. Due to the nature
of neuropathological studies it is not possible to measure
total SCC volume using this type of study.
The cases of bipolar disorder had a longer mean PM
Figure 1. Schematic illustrating the measurement of the
primary subgenual cingulate sulcus depth and a bifurca-
tion in the SCC in the coronal plane.
Percentage incidence of bifurcation
Figure 2. Incidence of bifurcation of the subgenual cingulate
cortex as a percentage of cases. NPD—No Psychiatric Disorder;
SZ—Schizophrenia; BPD—Bipolar Disorder; RDD—Recur-
rent Depressive Disorder.
delay than the cases from the other diagnostic groups.
This was predominantly due to three male bipolar cases,
numbers 32 (89 h), 34 (91 h) and 45 (100 h). The RDD
group showed a reduced age of death, which may reflect
a higher number of suicides amongst this group. Simi-
larly male schizophrenia cases showed a younger age of
death than female schizophrenia cases which was likely
related to a higher number of suicides. Additionally the
BPD cohort has a longer period of fixation, due to the
lower number of BPD cases in the tissue bank, requiring
tissue from earlier donations to be included. However
these variables had no effect on the occurrence of bifur-
cation, or previous variables measured in the cingulate of
these cases [21,28]. We did not have data on the illness
duration. However as a requirement for inclusion was
symptom onset between 20 - 30 yr this strongly corre-
lated age, which had no effect on incidence of bifurca-
Although the measures were collected from slides
within 100 μm of one another bifurcation was a gross
Copyright © 2012 SciRes. OPEN ACCESS
M. R. Williams et al. / Open Journal of Psychiatry 2 (2012) 253-257
anatomical occurrence and was easily visible with the
naked eye on the blocks. Ideally the full volume of the
SCC could be estimated by many serial sections, but this
would require many blocks along the entire structure and
this amount of tissue was not available. Also there would
be errors involved due to the tissue shrinkage during
fixation and processing. If these technical issues could be
overcome then a volumetric study would be extremely
useful as the measurements could be performed with far
greater accuracy than in imaging.
Cortical folding changes in length and depth of tem-
poral and frontal lobes have been reported in schizophre-
nia [29]. These changes been shown to be present before
disease onset. Patients with adolescent onset schizo-
phrenia have significantly more flattened curvature in the
sulci and more steeped or peaked curvature in the gyri
[30], and increased cortical folding in the superior frontal
cortex and in gyral and sucal folding in temporal lobe of
first episode schizophrenia [31,32]. High risk individuals
have been observed to have altered cortical folding in the
prefrontal cortex [33]. Examination of bifurcation may
give additional information of changes in the cortex in
schizophrenia between the scales of neuropathological
reports of cell density and morphometry and the imaging
data showing larger scale trends across cortical regions.
As gyral morphology is created in utero during the ini-
tial folding of the cortex, this suggests that morphologi-
cal changes in schizophrenia may be hardwired early in
life. If these can be identified then they may help with
the early identification of high-risk individuals. Whilst
large-scale changes in gyral folding may only be detect-
able in detailed analysis of the whole brain surface this
study suggests that by looking at regions of high vulner-
ability signs of this change may be measurable at the
microscopic level.
The authors are grateful to Prof. Federico Turkheimer for statistical
advice. This was supported by funding from the Stanley and Starr
foundations, and MRC-UK PET Methodology Programme Grant
G1100809/1. This project was conducted under ethical permission
granted by the London south west local ethics committee reference
WL/02/12 (2002), and amendment WL/02/12/AM01, granted by the
Ealing and WLMHT local research ethics committee (2006).
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