Article

Anterior limb of the internal capsule in schizophrenia: A diffusion tensor tractography study

Psychiatry Neuroimaging Laboratory, Department of Psychiatry and Radiology, Brigham and Women's Hospital, Harvard Medical School, 1249 Boylston Street, Boston, MA 02215, USA.
Brain Imaging and Behavior (Impact Factor: 4.6). 03/2012; 6(3):417-25. DOI: 10.1007/s11682-012-9152-9
Source: PubMed

ABSTRACT

Thalamo-cortical feedback loops play a key role in the processing and coordination of processing and integration of perceptual inputs and outputs, and disruption in this connection has long been hypothesized to contribute significantly to neuropsychological disturbances in schizophrenia. To test this hypothesis, we applied diffusion tensor tractography to 18 patients suffering schizophrenia and 20 control subjects. Fractional anisotropy (FA) was evaluated in the bilateral anterior and posterior limbs of the internal capsule, and correlated with clinical and neurocognitive measures. Patients diagnosed with schizophrenia showed significantly reduced FA bilaterally in the anterior but not the posterior limb of the internal capsule, compared with healthy control subjects. Lower FA correlated with lower scores on tests of declarative episodic memory in the patient group only. These findings suggest that disruptions, bilaterally, in thalamo-cortical connections in schizophrenia may contribute to disease-related impairment in the coordination of mnemonic processes of encoding and retrieval that are vital for efficient learning of new information.

Full-text

Available from: Martha E Shenton, Dec 19, 2013
Anterior limb of the internal capsule in schizophrenia:
a diffusion tensor tractography study
Gudrun Rosenberger & Paul G. Nestor & Jungsu S. Oh &
James J. Levitt & Gordon Kindleman & Sylvain Bouix &
Jennifer Fitzsimmons & Margaret Niznikiewicz &
Carl-Fredrik Westin & Ron Kikinis &
Robert W. McCarley & Martha E. Shenton &
Marek Kubicki
#
Springer Science+Business Media, LLC 2012
Abstract Thalamo-cortical feedback loops play a key role in
the processing and coordination of processing and integration
of perceptual inputs and outputs, and disruption in this con-
nection has long been hypothesized to contribute significantly
to neuropsychological disturbances in schizophrenia. To test
this hypothesis, we applied diffusion tensor tractography to 18
patients suffering schizophrenia and 20 control subjects. Frac-
tional anisotropy (FA) was evaluated in the bilateral anterior
and posterior limbs of the internal capsule, and correlated with
clinical and neurocognitive measures. Patients diagnosed with
schizophrenia showed significantly reduced FA bilaterally in
the anterior but not the posterior limb of the internal capsule,
compared with healthy control subjects. Lower FA corr elated
with lower scores on tests of declarative episodic memory in the
patient group only. These findings suggest that disruptions,
bilaterally, in thalamo-cortical connections in schizophrenia
may contribute to disease-related impairment in the coordina-
tion of mnemonic processes of encoding and retrieval that are
vital for efficient learning of new information.
Keywords Schizophrenia
.
Disconnection
.
MRI
.
Cognitive
neuropsychology
Introduction
Neuropsychiatric symptoms of schizop hrenia have been
thought by some to reflect a disruption of limbic and
sensory feedback loops (e.g., Friston and Frith 1995;Liu
et al. 2008). Thalamo-cortical projections play a key role
G. Rosenberger
:
J. S. Oh
:
J. J. Levitt
:
M. E. Shenton
:
M. Kubicki (*)
Psychiatry Neuroimaging Laboratory,
Department of Psychiatry and Radiology,
Brigham and Womens Hospital, Harvard Medical School,
1249 Boylston Street,
Boston, MA 02215, USA
e-mail: Kubicki@bwh.harvard.edu
G. Rosenberger
Department of General Psychiatry, Medical University Innsbruck,
Innsbruck, Austria
P. G. Nestor
:
J. J. Levitt
:
S. Bouix
:
M. Niznikiewicz
:
R. W. McCarley
:
M. E. Shenton
:
M. Kubicki
Clinical Neuroscience Division, Laboratory of Neuroscience,
Boston VA Healthcare System-Brockton Division,
Department of Psychiatry, Harvard Medical School,
Brockton, MA, USA
J. S. Oh
Department of Nuclear Medicine,
Asan Medical Center,
Seoul 138-736, South Korea
G. Kindleman
:
C.-F. Westin
Laboratory of Mathematic Imaging, Department of Radiology,
Brigham and Womens Hospital, Harvard Medical School,
Boston, MA, USA
S. Bouix
:
J. Fitzsimmons
Psychiatry Neuroimaging Laboratory, Department of Psychiatry,
Brigham and Womens Hospital, Harvard Medical School,
1249 Boylston Street,
Boston, MA 02215, USA
R. Kikinis
:
M. E. Shenton
Surgical Planning Laboratory, Department of Radiology,
Brigham and Womens Hospital, Harvard Medical School,
Boston, MA, USA
Brain Imaging and Behavior
DOI 10.1007/s11682-012-9152-9
Page 1
in this circuitry, as the thalamus filters sensory and
higher order inputs, before its further transmission to
the cortex (Schlos ser et al. 2003). Disconnectivity in the
thalamo-cortical loop might especially be involved in the
pathophysiological development of cognitive dysfunctions
observed in schizophren ic patients. Of note, the dorso-
medial nucleus (DMA) projects to the dorsolateral prefrontal
cortex (DLPFC) (Giguere and Goldman-Rakic 1988)andis
involved in the coordinatio nofattentionalprocesses
(Hazlett et al. 2001). Disruptions in attention (Heinrichs
and Zakzanis 1998)andrelatedexecutivefunctionsof
planning, organization and goal-directed action (Weickert
et al. 2000)areamongthecorecognitiveimpairmentsin
schizophrenia.
From an ana tomical perspective, the internal capsule
represents the intercept point in the course of these projec-
tion fibers. Further, anatomically, the internal capsule is
subdivided into anterior and posterior limbs. The anterior
limb (AL) contains fibers reciprocally connecting the thala-
mus with the frontal lobe (Parent 1996), also the cortico-
pontine fibers, and to a lesser extent caudate/pallidum fibers
(Axer and Keyserlingk 2000). The posterior limb contains
cortico-spinal, cortico-bulbal, and cortico-cerebellar fibers.
Loss of neurons in the mediodorsal (MD) nucleus of the
thalamus (Byne et al. 2002; Popken et al. 2000; Young et al.
2000), in the thalamic subnucleus, and in the anterior nuclei
(Young et al. 2000), has been reported in postmortem stud-
ies of schizophrenia. In addition, reduced volume of prefrontal
cortex has been found (Rajkowska et al. 1998), suggesting
reduced connectivity in schizophrenic patients in regions con-
necting the thalamus to the prefrontal cortex through the
anterior limb of the internal capsule (AL-IC).
The AL-IC has also been an area of kee n interest in
understanding the pathophysiology of schizophrenia (see
review in Shenton et al. 2001). From a structural ana-
tomical perspective, the anterior and posterior limbs of
the internal capsule are not clearly discernible, and fibers
from both limbs intercept with the other, complicating
dissociation. A functional analysis of the fibers of interest is
only possible if fibers of the posterior limb are excluded and
separately investigated. This is made possible by fiber
tractography, which we use in this study.
Thus far, Magnetic Resonance Imaging (MRI) has been
successful in detecting in-vivo structural alterations in
patients with schizophrenia in the prefrontal cortex (PFC)
(see review in Shenton et al. 2001), basal ganglia, and
thalamus (e.g., Young et al. 2000). These findings suggest
that white matter interconnec ting these brain regions may
be disrupted. Of further note, basal ganglia and thalamo-
cortical feedb ack loops ha ve reciprocal f ibers that a re
projected through the internal capsule from the thalamus
to the prefrontal cortex. In recent structural imaging
studies, AL-IC volume has also been shown to be decreased
in patients with schizophrenia (Brickman et al. 2006;Langet
al. 2006;Zhou et al. 2003). A major concern in the
analysis of conventional s tructural images, however, is
that they do not carry information regarding the integrity
of the fibers. In this regard, diffusion tensor imaging
(DTI) has emerged as an MRI-technique that provides
detailed informati on about fiber integrity. That is, DTI,
unlike conventional MRI, contains information about the
direction and intensity of water flow in each voxel. One
important parameter is fractional a nis o tr o py (FA ), whic h
is a scalar val ue characterizi ng the deviation from isotro-
pic diffusion. Beaulieu suggested that FA might correlate
with high density, diameter, degree of organization, and
myelinat
ion of axons (Beaulieu 2002). This information
can be useful in characterizing the integrity of white
matter (WM) brain tissue, since it predominantly contains
myelinated axons. Furthermore, tractography is a rela-
tively new method for analyzing DTI data. Its advantage
over ROI methods is that it enables analyzing specific
fiber tracts throughout their course until they reach the
cortical rim.
Reduced white matter integrity of the AL-IC may also
underlie some of the neuropsychological disturbances
observed in schizophrenia. (Kubicki et al. 2005;Zouet
al. 2008). One of the theories linking AL-IC and schizo-
phrenia symptoms involves the introduction of a cogni-
tive syndrome called cognitive dysmetria (Andreasen et
al. 1996). Cognitive dysmetria refers to difficulty in
coordinating and monitoring the process of receiving,
processing, and expressing logically linked information
(Andreasen et al. 1996). Moreover, Andreasen postulated
that neuropsyc hol ogi ca l measu res of decl arat ive -ep iso dic
memory, such as narrative recall not only requires the
patient to learn and recall logi cally linked information,
but also to monitor this process while they do so. In this
model, timing or sequencing the flow of information is
required during normal thought and speech, and these
functions are often disrupted in schizophrenia. As
Andreasen et al. (1996)suggested,theabilitytocoordi-
nate and sequence multiple inputs and outputs may be
examined by using the WMS-III Logical Memory subt-
ests, which require the subject to orally rec al l c ompl ex
narrative material.
While the notion of cognitive dysmetria is speculative,
and cognitive d eficits postulated by this m odel can arise
from abnormalities within any parts of the network,
including AL-IC itself, the focus o f the current study is
in investigating the integrity of thalamo-cortical and
cortico-thalamic fiber tractsrunningthroughtheAL-IC,
their disruptions, and its cognitive consequences (including
measures suggested by Andreasen et al. 1996). We chose the
cortico-spinal tract passing through the posterior limb of the
internal capsule (PL-IC) as a control region, hypothesizing
Brain Imaging and Behavior
Page 2
that these fibers, involving mostly sensory and motor axons,
would not show differences between patients and controls.
In a ddit ion, we assessed mnemoni c functions requirin g
monitoring of encoding and retrieval as well as expres-
sion of remem ber ed inform at io n with story re cal l tasks of
the Wechsler Memory Scale (WMS-III) (measures sug-
gested by Andreasen et al., to be best related to schizo-
phrenia symptomatology and thalamo-cortical
connections ), where we hypothesized we would find
correlations with FA in thalamo-cortical tracts in patients
with schiz oph ren ia.
Methods
Subjects
This study included 18 patients with chronic schizophrenia,
and 20 age-matched normal controls. These subjects
overlapped with subjects from two prior studies, which
addressed different questions (Levitt et a l. 2004;Ohet
al. 20 09). Patients were recruited from inpatient, day
treatment, outpatient, and foster care programs at the
VA B ro c k t o n H o s p i t a l , M a s s . D S M - I V d i a g n o s i s w a s
assessed using the Structured Clinical Interview for
DSM-IV-patient Version (SCID), and from information
in the medical records. The 23 normal comparison sub-
jects completed the non-patient edition of the SCID to
rule out any psychiatric illness after having been
recruited in r espo ns e to l ocal advertis em ent or b y word
of mouth. Controls were matched to patients by age,
gender, handedness, and parental socio-economic status.
The inclusion criteria for all subjects were IQ above 75,
negative history of seizures, negative history of head
trauma with loss of consciousness o r neurological disor-
der, and no history of alcohol or other drug dependence
in the last 5 years a nd an ability and desire to cooperate
with the procedures as evidenced by written informed
consent. Comparison subjects also underwent screening
to exclude individuals who had a first-degree relative
with an axis I disorder. Afteracompletedescriptionof
the study, writ ten informed consent was obtain ed from
each subject. The study was approved by the VA Human
Subjects Comm ittee, as well as by the Institutional Re-
view Board at Brigham and WomensHospital.
All subjects underwent neuropsychological tests, which
were carefully selected according to functions that we
thought were especially related to the AL-IC function To
investigate concept formation, abstraction, and mental flex-
ibility, subjects completed the Wechsler Memory Scale-3rd
Edition (WMS-III) (Wechsler 1997). This test measures
immediate memory, visual immediate m emory, auditory
delayed memory, visual delayed memory, general-delayed
memory, auditory recognition delayed memory, and work-
ing memory. The logical memory is a subtest of the WMS-
III and assesses verbal memory, demanding recall of two
stories consecutively after an oral presentation (Part I) and
again after a 30-min delay (Part II).
MRI methods
Image acquisition and post-processing
Line-scan diffusion tensor images were acquired for all
subjects. Images were obtained using a quadrature head coil
on a 1.5-Tesla GE Echospeed system (General Electric
Medical Systems, Milwaukee, Wisconsin), on which maxi-
mum gradient amplitudes of 40 mT/m can be achieve d.
First, we started off with a set of three orthogonal T1-
weighted (T1W) images (sagittal, axial oblique aligned to
the anterior commissure-posterior commissure (AC-PC) line
and another sagittal oblique aligned to the interhemispheric
fissure) which were used as localizers. The LSDI sequence
in the coronal orientation from the last sagittal T1-weighted
image was then aligned to the ACPC line. Six images with
high (1 000 sec/mm) diffusion-weighting along six non-
collinear directions, and two images for low (5 sec/mm)
diffusion-weighting were collected for each line. The fol-
lowing scan parameters were used: 128×128 scan matrix
(256×256 image matrix) field of view (FOV); slice thick-
ness 4 mm; inter-slice distance 1 mm; receiver bandwidth
4kHz;echotime64msec;effectiverepetitiontime
2592 m sec; scan time 60 sec/slice section . We acquired
3135 coronal slices covering the entire brain, depending
on brain size. The total scan time was 3135 min. After
reconstruction, the diffusion-weighted images were trans-
ferred to a LINUX workstation, where the label-maps were
drawn in slicer (www.slicer.org).
Manual segmentation: internal capsule anatomical
landmarks
ROI (Region of interest) All ROIs were drawn on the FA
(fractional anisotropy) map. A single rater (G.R.), blind to
diagnosis, gender and age, drew regions of interest (ROIs)
for the whole internal capsule (anterior and posterior limb,
as well as genu). The borders were placed generously,
including tissue surrounding the internal capsule (IC), in
order to include all fibers passing through the capsule. This
was possible, since second and third ROIs were drawn to
eventually exclude extraneous fibers. From the resulting
bulky fiber bundle, the fibers connecting the internal capsule
and the frontal lobe were extracted. This was done by
drawing a second ROI (ROI 2) in the coronal plane anterior
to the most anterior slice where the corpus callosum was
visible as an area including the frontal lobe. The third ROI
Brain Imaging and Behavior
Page 3
was drawn to eliminate extraneous fibers and was placed at
the first axia l plane beneath the internal capsule ROI 1.
Calculation of diverse scal ar values, i.e., FA , linear,
spherical, and mode within these fi ber s w as performed
using MATLAB software (Figs. 1 and 2).
Image analysis
In the present study, open source in-house s oftware, 3D
Slicer (www.slicer.org) was used for diffusion tensor trac-
tography based on whole-white matter seeding. The detailed
methodology is described elsewhere (Oh et al. 2009;Ohet
al. 2007). In brief, once the diffusion tenso rs were estimated,
fiber seeds were placed (one seed per voxel) throughout the
entire brain in locations were FA > 0.1. Fibers were then
traced (using in-house software- slicer3D, that utilizes
streamline tractography algorithm usingafourthorder
RungeKutta solver, introduced in Basser et al. 2000) until
a curvature angle threshold of 80°/mm was reached to avoid
rapid change of direction or the FA was lower than 0.1. To
create fronto-subcortical fiber tracts (i.e., those connecting
anterior limb of the internal capsule and frontal lobe, but not
extending to the spinal cord) we used predefined ROIs - as
described earlier ROI 1 representing the AL-IC and ROI 2
representing the posterior most coronal slice of the frontal
lobe. To exclude fibers extend ing to the spinal cord, we used
ROI 3 as an exclusion ROI. For assessing spinal cord fiber
tracts we used the internal capsule ROI 1 and the spinal cord
ROI 3, and we used ROI 2 as exclusion ROI to avoid
including frontal fibers (Figs. 1 and 2). We then recon-
structed a volumetric mask of the fiber tracts and compu ted
averages across all voxels within this mask to avoid double
counting due to several fibers traveling through the same
voxel (Fig. 1).
Statistical analysis
Statistical analysis was done using the Statistical Package
for Social Sciences (SPSS v.15.0). To test for specificity in
group differences in FA within the anterior and posterior
limbs of the internal capsule, analysis of covariance
(ANCOVA) was performed, with region (anterior and pos-
terior) and side (left and right) as the within-subject factors,
group as the between-subject factor, and age as a covariate.
This was followed by separate ANCOVAs for each tract
(AL-IC and PL-IC). Finally, protected post-hoc independent
sample t-tests were used to evaluate differences between
groups on the left and on the right side.
Results
Groups did not differ in age at time of scan (P
(1,36)
0 0.253,
t0 1.6), in handedness (P
(1,33)
0 0.826, t0 0.22) or in gender
(all males). Additional demographic data are included in
Table 1. Schizophrenics, had fewer years of education and
lower SES than controls, but had comparable parental
socioeconomic status, i.e., PSES, with controls (P
(1,33)
0
0.12, t0 1.6). A pre-morbid measure of W RAT-3 full-
scale IQ, indicated that schizophrenics and contr ol s di d
not differ s ignificantly from each other on a measure of
premorbid IQ (P
(1,20)
0 .593, t 0 0.544) Schizophrenics
were all chronically ill, with a mean duration of illness
at 16.9 years (SD0 9.4 years), and all were medicated,
with a mean Chlorpr omazine (CPZ) equ ivalent of
450 mg per day (SD0 345 mg) (Stoll 2001). There were
no statistically significant correlations between diffusion
measures and IQ, PSES, age or handedness for neither
Fig. 1 ROIs used to extract the anterior limb of the internal capsule
Fig. 2 ROIs used for extraction of anterior, as well as posterior limbs
of the internal capsule (the pink fiber bundle demonstrates the fronto-
thalamic fibers passing through the anterior limb of the internal
capsule)
Brain Imaging and Behavior
Page 4
group, nor were there any statistical ly significant c orre-
lations between the diffusionmeasuresandageofonset
or medication in the schizophrenia group. To make sure
that the fiber tractography threshold criteria did not in-
troduce any systematic bias towards one of the groups,
we per formed t-tests comparing the number of fibers,
mean length and mean angle for each of the four fiber
tracts that we compared (i.e., left AL-IC, right AL-IC, left
PL-IC and right PL-IC). No differences were observed for any
of these variables for any fiber tract.
ANCOVA demonstrated tract by age (F0 7.97; df0 1,35;
p0 .008), and tract by diagnosis (F0 7.21; df0 1,35; p0 .011)
interactions. Other interactions, including side, side by age,
side by group, tract, side by tract, side by tract by age and
side by tract by group were all non-significant. Repeated
Measures ANCOVA for the AL-IC revealed a main effect
for group (F0 7.21; df0 1,35; p0 .011) but not for side by
group (F0 0.69; df0 1,35; p0 .41), or side by age interaction
(F0 1.22; df0 1,35; p0 .27). Repeated measures ANOVA for
the PL-IC revealed no statistically significant group (F0.685;
df0 1,35; p0 .414), side by group (F0 .05; df0 1,35; p0 .823),
nor side by age (F0 .156; df0 1,35; p0 .219) interactions.
Post-hoc t-test using independent samples t-statistics (see
Table 2)revealedthatmeanFAforschizophrenicswas
significantly lower in the left ( P
(1,36)
0 0.046), and right
(P
(1,36)
0 0.007) anterior limbs of the internal capsules than
was FA for control subjects (Fig. 3). As expected, both left
and right posterior limbs of the internal capsules did not
show significant FA reductions in schizophrenics vs. con-
trols (Fig. 4).
We next examined Spearman-rank correlation of FA and
WMS-III subtests of recall and recognition for the patient
and control groups. In the correlational analyses, summa-
rized in Table 3, statistically significant associ ations were
found between averaged FA values for AL-IC in schizo-
phrenics in WMS-III immediate (Logical Memory-I) and
delayed (Logical Memory-II) recall of stories (see Table 3)
These correlations pointed to statist ically significantly cor-
relations of FA AL-IC with narrative recall. In addition,
WMS-III LMII delayed recognition total score was positive-
ly correlated with left and right AL-IC FA. Also of note,
reduced left and right AL-IC was associated with lower
values in the WMS-III family pictures I recall unit and also
in the family pictures II recall unit bilaterally. No correla-
tions between WMS scores and AL-IC were found for
control subjects.
Discussion
Results from this study strongly suggest bilateral disruption
in the integrity of white matter fibers passing through the
Table 1 Demographic
characteristics for Chronic
Schizophrenic and
Normal Comparison Subjects
Schizophrenic Subjects Comparison Subjects Students's t-test (two tailed)
N0 18 N0 20
Characteristic Mean SD Mean SD t df p
Age (years) 39.2 9.0 42.1 6.5 1.2 36 .253
Education (years)
a
13.4 1.9 15.4 2.2 2.8 33 .007
WAIS-iii IQ
b
94.5 13.1 107.7 12.8 2.79 28 .009
WRAT3 RS
c
51.0 4.76 49.9 4.6 0.54 20 0.59
SES
a, e
3.8 1.2 2.3 1.1 3.7 34 0.001
Parental SES
d,e
2.9 1.0 2.3 1.2 1.6 33 .35
handedness
a
.8 .17 .81 .13 0.22 33 .826
Table 2 Values of Mean FA
of Internal Capsule Regions
of Interest In Chronic
Schizophrenic and Normal
Comparison Subjects
Schizophrenic Comparison Students's t-test
N0 18 N0 20 Significance (two tailed)
Mean SD Mean SD t df p
Anterior limb of IC left (FA) .28 .019 .29 .015 2.06 36 .046
Anterior limb of IC right (FA) .28 .015 .29 .014 2.86 36 .007
Posterior limb of IC left (FA) .30 .030 .30 .020 -.25 36 .806
Posterior limb of IC right (FA) .30 .019 .30 .026 -.25 36 .806
Brain Imaging and Behavior
Page 5
anterior limb of the internal capsule, but not for those fibers
traveling through the posterior limb of the internal capsule,
in patients with chronic schizophrenia. Additionally, statis-
tically significant associations were found between disrup-
ted integrity in the anterior limb fiber tract measures and
neurocognitive functioning in schizophrenia, which was not
observed in control subjects. More specifically, cognitive
dysfunctions associated with fiber disruption involved mne-
monic functions requiring monitoring of encoding and re-
trieval a s well as expression of re membered information
with story recall tasks of the Wechsler Memory Scale
(WMS-III) (measures suggested by Andreasen et al., to be
best related to schizophrenia symptomatology (Andrease n et
al. 1998).
Clinical and cognitive correlates of AL-IC in schizophre-
nia have been found in previ ous studies (Honey et al. 2005;
Mendrek et al. 2004). Andreasen et al. (Andreasen et al.
1998), in fact, have proposed a disease model for schizo-
phrenia called cogni t iv e dysm et r ia.Findingsfromthe
current study demonstrate a reduction in white matter integ-
rity in the thalamic-cortical pathway, which correlate with
worse performance in the recall of na rrative material in
patients with schizophrenia but not in normal controls.
In a recent study we observed patients with schizophrenia
to show a significant decline in FA with age in the cingulum
and uncina te fasciculus (Rosenberger et al. 2008), but not in
the occipito-frontal fasciculus. In this study we did not find
a statistically signi ficant correlation between age and AL-
IC. Previous studies of normal healthy aging have shown a
decrease of FA in white matter correlating with age espe-
cially in prefrontal, temporal and parietal areas of the
brain (Salat et al. 2005). In a region of interest study,
Schneiderman et al. (2009) found that first episode adoles-
cent patients differed significantly in their pattern of fractional
anisotropy in the internal capsule from adults with chronic
schizophrenia and that this pattern deviated from the normal
pattern of anisotropy change seen with age as demonstrated by
age matched controls. These findings, taken together, under-
score the importance of understanding local and regional
patterns of interactions between age and WM integrity in
controls, and abnormalities in such patterns in schizophrenia
subjects.
In a previous study by our group, Levitt et al. (Levitt et
al. 2004) found no significant FA decrease, but did find a
significant vo lume reduction in AL-IC in schizophrenia.
The difference between findings from the current study
and those reported by Levitt et al. may be explained by the
fact that they used an ROI approach and measured FA only
within the region of the AL-IC, whereas we measured FA
using tractography measures along the entire course of the
fibers passing through the internal capsule. In addition, in
the current study fibers running to the prefrontal cortex were
examined, whereas in the previous study, other fibers may
have been included. The focus exclusively on fibers running
to the prefrontal cortex thus eliminated the analysis of
contaminating fibers running to other areas of the brain
(i.e. brainstem). Of note, both studies reported no differ-
ences in the PL-IC, which served as a control region. These
results thus suggest involvement of AL-IC in schizophrenia
pathology, but not PL-IC.
Reduced white mat ter integrity of the AL-IC, which can
be expressed as reduced FA, may also underlie some of the
neuropsychological disturbanc es observed in schizophrenia.
Other DTI studies have recently been employed to measure
AL-IC integrity in schizophrenia. For example, a reduction
in FA in schizophrenia in the AL-IC was report ed by Jeong
et al. (Jeong et al. 2009) using tract-based spatial statistics,
by Kubicki et al. (2005) and Sussmann et al. (2009) using
voxel-based morphometry, by Mitelman et al. (Mitelman et
al. 2007) using an automated stereotactic ROI approach.
Fig. 3 Mean FA values for fronto-thalamic connections passing
through the anterior limbs of the internal capsule
Fig. 4 Mean FA values for the fibers passing through the posterior
limbs of the internal capsule
Brain Imaging and Behavior
Page 6
Zou et al. (Zou et al. 2008) also reported reduced FA in both
AL-IC in neuroleptic-naïve schizophreni c patients using an
ROI-based DTI approach. Mamah et al. (Mamah et al. 2010)
showed reduced FA in the right AL-IC, which also correlat-
ed with executive function and working memory. The only
other tractography studies focusing on anterior thalamo-
frontal projections, but did not focus on the association with
neurocognitive functions, have been published by Oh et al.
(2009) and by Buchsbaum et al. (2006). Other diffusion
tensor imaging studies have also investigated the internal
capsule in patients with schizophrenia. An earlier diffusion
tensor fiber tractography study (Buchsbaum et al. 2006)
found no FA differences in the AL-IC. However, these
investigators did find significantly shorter tracts in this fiber
bundle. Because Buchsbaum et al. ( 2006) chose a different
approach defining the stopping criteria, they may have ef-
fectively excluded voxels that represent parts of the fiber
tract potentially causing FA decrease in our study. In Buchs-
baum's paper, the investigators introduced a measure of
relative FA, or a certain percentage drop of FA along the
tract, as a stopping criterion. This method makes
tractography extremely sensitive to even small artifact,
where even a few noisy voxels, not necessarily related to
crossing fibers, can term inate tracts prematurely. Our trac-
tography method, on the other hand, takes into account
small artifacts by incorporating tract regularization
(smoothi ng along the bundle). Here, tracts are measured
until FA falls and stays below a certain value, which makes
tractography less sensitive to noise. Regardless of the method,
both findings shorter tracts when more stringent stopping
criteria are used, or lower FA when stopping criteria are set
lower may suggest the same underlying abnormality: de-
creased FA within frontal WM in schizophrenia.
Suggestions about the possible significance of these find-
ings comes from a previous publication from our group (Oh
et al. 2009) where a different method was used for tract
selection and termination (i.e., th e internal capsul e was
used as the initial ROI, but it was excluded from the
analysis, and tracts were terminated at the boundary of
gray matter), as well as parameterization along the white
matter connections between the thalamus and frontal Brod-
mann areas (BA 9, 10, 11, 32, 44, 45, 46, and 47). Using
Table 3 Correlations between FA measures of AL-IC and neurocognitive measures of recall and recognition
Clinical/Cognitive Measures DTI measures SZ Group NC Group
ρ pnρ pn
WMS-III LM-II Recall total score Left AL-IC FA .65 .009 15 -.18 .523 15
Right AL-IC FA .73 .002 15 -.3 .3 15
WMS-III LM-II Recognition Total Score Left AL-IC FA .69 .005 15 -.21 .45 15
Right AL-IC FA .65 .009 15 -.48 .07 15
WMS-III LM-II Story A Recall Unit Score Left AL-IC FA .65 .009 15 -.33 .227 15
Right AL-IC FA .66 .007 15 -.61 .015 15
WMS-III LM-II Story B recall unit score Left AL-IC FA .54 .037 15 -.00 .99 15
Right AL-IC FA .67 .007 15 .05 .849 15
WMS-III Family Pictures II Recall total score Left AL-IC FA .61 .015 15 -.17 .545 15
Right AL-IC FA .54 .036 15 -.01 .978 15
WMS-III family pictures I recall total score Left AL-IC FA .66 .007 15 -.33 .229 15
Right AL-IC FA .53 .041 15 -.01 .966 15
WMS-III LM-I recall total score Left AL-IC FA .55 .034 15 -.23 .404 15
Right AL-IC FA .57 .025 15 -.1 .728 15
WMS-III LM-I story B-2nd recall unit score Left AL-IC FA .57 .027 15 -.23 .412 15
Right AL-IC FA .6 .017 15 -.23 .412 15
WMS-III auditory recognition delayed scaled score Left AL-IC FA .63 .011 15 -.283 .308 15
Right AL-IC FA .56 .029 15 -.461 .084 15
WAIS-III matrix reasoning total raw score Left AL-IC FA .53 .036 16 N/A
Right AL-IC FA .54 .03 16 N/A
CPZ dosage equivalent Left AL-IC FA -.12 .638 17 N/A
Right AL-IC FA .03 .925 17 N/A
Duration of illness Left AL-IC FA -.3 .227 18 N/A
Right AL-IC FA -.33 .187 18 N/A
Brain Imaging and Behavior
Page 7
this method Oh et al. showed FA abnormalities in chronic
schizophrenics in several projections (DLPFC, ACC, BA
44/45, frontal pole, OFC and IPFC), but they did not
include the entire bundle trajectories, as was done in the
current study.
There are few methodological issues, which need to be
mentioned with respect to limitations of the study. First, we
used anisotropic, relatively thick diffusion data, character-
ized by partial volume effects. These artifacts were, howev-
er, somewhat minimized by the fact that the images were
acquired perpendicular (coronal) to the main fiber tract
direction, thus enabling relatively good tracking results.
We used relatively anisotropic, thick diffusion data, which
are characterized by significant partial volume effects. For-
tunately, partial volume effects were somewhat limited in
our investigation due to the fact that the acquisition plane
(coronal) was perpendicular to the main fiber tract direction,
thus giving us relatively good tracking results. In addition,
tensors were calculated along the tract at very small steps
(1 mm), and the tracking algorithm uses a regularization
method along the tract, which limits the influence of thick
slices and gaps between slices on data results. Second, the
patients tested suffered from chronic schizophrenia and had
been medicated for many years. Although CPZ dosage did
not correlate with FA measures, cumulative medication
effects cannot be entirely ruled out. Third, although compa-
rable to those reported in previously published studies, the
sample size is small. Small sample sizes are related to
another limitation of our study- that is, even though
AL-IC disruptions in patients with schizophrenia were quite
strongly correlated with deterioration in their cognitive func-
tions, especially those related to immediate and delayed rec-
ognition, and those functions were not significantly correlated
with PL-IC integrity, we were not able to demonstrate signif-
icant differences between those correlations (using Fisher
exact tests). Fourth, and also of note, possible differences in
gender could not be accounted for, since we only had male
subjects in our cohorts. We thus acknowledge these results as
exploratory, and suggest to treat them with caution.
We also note a limitation of tract-tracing, which neces-
sitates setting FA at a certain threshold for stopping criteri-
on. This limits the possibility of measuring voxels below a
certain FA value. It has, however, been shown by Kanaan
and colleagues (Kanaan et al. 2006) that FA differences
between schizophrenia patients and controls fall above 0.2
FA values. We chose to set the threshold at 0.1, likely
allowing voxels of significant change in schizophrenia to
be included in our investigation.
In conclusion, we found DTI tractography to be a useful
tool to investigate disturbances in fronto-thalamic circuitry in
schizophrenia. Our results show bilateral white matter integ-
rity disruption within the anterior but not posterior limb of the
internal capsule in schizophrenia, as well as a statistically
significant relationship between these abnormalities and poor
memory performance. This study broadens our understanding
of cognitive malfunctioning in schizophrenia and its associa-
tion with cortico-thalamic circuitry abnormalities.
Acknowledgements The authors would like to thank Nancy Maxwell
and Jennifer Goodrich for administrative support; and Georgia Bushell,
B.A., Kate Smith, B.A., Jorge Alvarado, B.A., and Usman Khan, B.A.
for their support as research assistants. Additionally, we gratefully ac-
knowledge the support of the National Institute of Health (K05
MH070047 and R01 MH 50740 to MES, R01 MH 40799 to RWM and
R01MH 074794, P41RR013218 and P41EB015902 to CFW, P50MH
080272 to RWM, MES), the Department of Veterans Affairs Merit
Awards (MES, RWM), and the VA Schizophrenia Center Grant (RWM/
MES), Neuroimage Analysis Center, NAC (NIH P41RR013218) to
CFW and RK. This work is also part of the National Alliance for Medical
Image Computing (NAMIC), funded by the National Institutes of Health
through the NIH Roadmap for Medical Research, Grant U54 EB005149
(MK, RK, MES).
Competing interest None declared.
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    • "These findings suggest that researchers should select appropriate DKI parameters to sensitively detect diffusion changes in specific white matter regions in schizophrenia. In the current study, schizophrenia patients demonstrated lower DTI_FA in widespread white matter regions, especially the temporal and frontal lobes, CC, ALIC and fornix, which are consistent with previous DTI studies (Rahman et al., 2011; Ellison-Wright et al., 2014; Ellison-Wright and Bullmore, 2009; Kunimatsu et al., 2012; Kyriakopoulos et al., 2008; Rosenberger et al., 2012). Decreased MK and FA in the white matter of the prefrontal cortex in schizophrenia patients observed in this study are in line with a pioneer study using a histogram analysis approach (Ramani et al., 2007). "
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    • "White matter abnormalities in the anterior thalamic radiation have not been previously shown in CD, but are consistently identified correlates of schizophrenia and bipolar disorder (Sussmann et al., 2009; Mamah et al., 2010). White matter abnormalities in the cerebrospinal tract/ALIC have not previously been linked to CD, but are associated with depression and schizophrenia (Rosenberger et al., 2012; Zhang et al., 2013). It is now clear that the cerebellum plays a role in the modulation of cognitive , emotional, and social processes, and an intact cerebellar vermis is essential for providing neocortical regulation of the limbic system (Villanueva, 2012). "
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    • "Internal capsule VBM Kubicki et al., 2005; Buchsbaum et al., 2006; Munoz Maniega et al., 2008; Skelly et al., 2008; Sussmann et al., 2009; Nakamura et al., 2012; Levitt et al., 2012 Tractography Oh et al., 2009; Rosenberger et al., 2012 TBSS Seal et al., 2008; Knochel et al., 2012 Cortico-spinal tract TBSS Knochel et al., 2012 Tractography de Weijer et al., 2011 Corona radiata VBM Cui et al., 2011 TBSS Fujino et al., 2014 Middle cerebellar peduncles VBM Okugawa et al., 2004 tracts being affected, there is more likely an array of subtly altered networks distributed throughout the brain. Nevertheless, it could also be argued that the data suggest that the connectivity of frontal regions is particularly affected. "
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