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Magnetic Resonance Imaging of the Thalamic Mediodorsal Nucleus and Pulvinar in Schizophrenia and Schizotypal Personality Disorder
William Byne, MD, PhD;
Monte S. Buchsbaum, MD;
Eileen Kemether, MD;
Erin A. Hazlett, PhD;
Akbar Shinwari, MD;
Vivian Mitropoulou, MA;
Larry J. Siever, MD
Arch Gen Psychiatry. 2001;58:133-140.
ABSTRACT
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Background The importance of neuronal interactions in development, the cortical
dependence of many thalamic nuclei, and the phenomenon of transsynaptic degeneration
suggest possible abnormalities in thalamic nuclei with connections to other
brain regions implicated in schizophrenia. Because frontal and temporal lobe
volumes are diminished in schizophrenia, volume loss could characterize their
primary thalamic relay nuclei (mediodorsal nucleus [MDN] and pulvinar).
Methods Tracers delineated the thalamus, MDN, and pulvinar on contiguous 1.2-mm
magnetic resonance images in 12 schizophrenic patients, 12 with schizotypal
personality disorder (SPD), and 12 normal control subjects. The MDN and pulvinar
were rendered visible by means of a Sobel intensity-gradient filter.
Results Pixel overlap for delineation of all structures by independent tracers
was at least 80%; intraclass correlations were r
= 0.78 for MDN and r = 0.83 for pulvinar. Pulvinar
volume was smaller in schizophrenic (1.22 ± 0.24 cm3) and
SPD (1.20 ± 0.23 cm3) patients than controls (1.37 ±
0.25 cm3). Differences for MDN were not statistically significant;
however, when expressed as percentage of total brain volume, pulvinar and
MDN together were reduced in SPD (0.14%) and schizophrenic (0.15%) patients
vs controls (0.16%). Reductions were more prominent in the left hemisphere,
with MDN reduced only in the schizophrenic group, and pulvinar in both patient
groups. Total thalamic volume did not differ among the 3 groups.
Conclusions Measurement of MDN and pulvinar in magnetic resonance images is feasible
and reproducible. Schizophrenic and SPD patients have volume reduction in
the pulvinar, but only schizophrenic patients show reduction relative to brain
volume in MDN.
INTRODUCTION
SCHIZOPHRENIA involves impairments in multiple brain circuits that synaptically
gate or relay information through the thalamus. Consequently, the thalamus
is being scrutinized as a site of schizophrenia-related abnormalities. Postmortem
studies of schizophrenia have revealed synaptic degeneration and volumetric
loss in thalamic subdivisions.1, 2, 3, 4
Neuroimaging studies have also detected schizophrenia-associated thalamic
abnormalities5, 6, 7, 8, 9
but have not localized changes to anatomically defined thalamic subdivisions.
Instead, they have described changes in size, shape, or function of broadly
delimited thalamic regions or within the entire thalamus.
Because each thalamic subdivision has a unique set of efferent and afferent
projections, localization of schizophrenia-associated changes could advance
understanding of neuronal-circuitry impairments. The importance of neuronal
interactions in brain development,10 the phenomenon
of transsynaptic degeneration,11 and activity-related
neuronal plasticity12, 13 suggest
mechanisms by which an abnormality in one brain region could induce abnormalities
in others. Volume loss or other abnormalities in thalamic subdivisions may
relate to abnormalities in their efferent and afferent fields. The fact that
some thalamic nuclei remain cortically dependent (ie, exhibit degenerative
changes when their cortical fields are damaged) into adulthood14
suggests that this expectation would hold whether the primary lesion occurred
in early development or much later. Two macroscopically visible thalamic nuclei,
the mediodorsal nucleus (MDN) and the pulvinar, are seen on magnetic resonance
imaging (MRI) and appear salient to schizophrenia because of their connections
with 2 regions implicated by neuroanatomical theories, ie, prefrontal and
temporal cortex.
Prefrontal cortex (PFC), regionally defined by some researchers on the
basis of MDN projections,15 may have volumetric
and functional loss in schizophrenia.16, 17, 18, 19, 20
Volume loss in PFC could cause MDN shrinkage; alternatively, volume loss in
MDN could cause volume loss in PFC.
Attentional disturbances in schizophrenia have been linked to sensory-perceptual
dysfunction by theories postulating disturbed stimulus selection or filtering.
Some researchers, emphasizing strategic planning, future orientation, and
executive function deficits, have posited PFC dysfunction21, 22, 23, 24
or failure of thalamofrontal connectivity.25
Others, influenced by sensory hyperactivity in schizophrenia, have invoked
the temporal lobe as a site of cerebral failure. Studies have found frontal
and temporal size reductions on MRI,16, 26
gray matter heterotopias in frontal and temporal white matter,27
and frontal and temporal deficits on functional imaging.17, 19
Complex deficits in sensory and perceptual processing in schizophrenia could
suggest disturbances in frontal and temporal lobe linkages with other brain
areas, eg, the thalamus.28 Volume and neuronal
loss in MDN, as described in postmortem studies,2, 3, 4, 29, 30
might account for decreased thalamic metabolism in schizophrenia detected
in positron emission tomographic (PET) studies,6, 7, 8, 9
as well as for the functional19, 20, 21, 22
and anatomical changes31 that have been described
in its terminal fields in PFC.32 Schizophrenia-associated
neuronal loss has also been described in the pulvinar.33
The schizophrenia-associated abnormalities of MDN and pulvinar found
in postmortem studies2, 3, 4, 33
have yet to be demonstrated in vivo. They have not been examined in schizotypal
personality disorder (SPD), which has genetic-phenomenological links to schizophrenia34, 35, 36, 37 (2 MRI
studies reported thalamic volume reductions in relatives of schizophrenic
patients7, 38). Shared brain abnormalities
might account for the common deficits that characterize schizophrenia-spectrum
disorders, whereas differences might explain the diminished severity of psychosis
that distinguishes SPD from schizophrenia. Our objective was to compare the
size of the MDN and pulvinar in patients with schizophrenia and SPD with findings
in normal control subjects. Our hypothesis was as follows: (1) schizophrenic
patients would have a smaller volume of the MDN than controls, and (2) both
major association nuclei of the thalamus (MDN and pulvinar) would show smaller
volumes in schizophrenic than SPD patients, who in turn would show smaller
volumes than controls.
SUBJECTS AND METHODS
SUBJECTS
Schizotypal Personality Disorder
Twelve SPD patients (11 men; 1 woman; mean age, 42.7 years; SD, 14.1
years; 11 right-handed) met DSM-IV39
diagnostic criteria based on interviews using the Schedule for Schizophrenia
and Affective Disorders40 and the Structured
Interview for DSM-III Personality Disorders.41 Their mean Brief Psychiatric Rating Scale42 score was 37.5 (SD, 6.20; range, 28-46). Ten patients
were recruited from clinics at Mt Sinai Hospital, New York, NY, and Bronx
Veterans Affairs Hospital, Bronx, NY, and from community psychiatrists; 2,
from newspaper advertisements for people with loneliness and trouble with
relationships. Seven of the 12 patients had never received neuroleptics, and
all were free of medication for at least 2 weeks. Interrater reliability for
SPD diagnosis was assessed on 56 individuals with 4 raters (2 for each subject); 
values for each criterion ranged from 0.86 for magical thinking to 0.60 for
suspiciousness (average, = 0.73). For SPD vs other personality disorders,
= 0.90. Median educational level was 14 years. Illness onset was gradual and
not precisely determined.
Schizophrenia
Twelve schizophrenic patients (11 men; 1 woman; mean age, 43.7 years;
SD, 13.2 years; 11 right-handed), all recruited from the clinics at Mt Sinai
Hospital and Bronx Veterans Affairs Hospital, underwent evaluation using the
Comprehensive Assessment of Symptoms and History43
and diagnosis according to DSM-IV.39
Patients were neuroleptic naive (n = 9) or neuroleptic free (median, 3 weeks;
shortest washout, 12 days; next shortest, 14 days; longest, 3 years); none
had taken depot neuroleptics. Medians for educational level, age at onset
of illness, and illness duration were 14 years, 23 years, and 20 years, respectively.
Total Brief Psychiatric Rating Scale scores were obtained at the time of PET
and MRI studies (mean, 55.2; SD, 14.2; minimum possible rating, 18).
Subjects with SPD underwent assessment using the Schedule for Affective
Disorders and Schizophrenia because it extensively covers depressive symptoms,
the most common comorbidity in SPD, whereas the Comprehensive Assessment of
Symptoms and History was administered to schizophrenic patients because it
is oriented toward a detailed evaluation of psychotic symptoms.
Controls
Twelve normal controls (11 men; 1 woman; mean age, 42.2 years; SD, 12.4
years) received the Comprehensive Assessment of Symptoms and History to exclude
psychiatric illness in themselves or first-degree relatives and the Structured
Interview for DSM-III Personality Disorders, modified
for administration to normal controls, to screen out personality disorders.
The controls, recruited from community newspaper advertisements and bulletin-board
postings, underwent screening as described elsewhere, and were age- and sex-matched
to the experimental subjects.44 Median educational
level was 16 years. Median socioeconomic status level in controls was 3, the
same as in the patient groups.
Subjects described herein are a subsample of those described in an earlier,
less anatomically detailed PET and MRI report.8
After complete description of the study, subjects provided written informed
consent.
MRI ACQUISITION
The same 1.5-T MRI scanner (LX Horizon; GE, Milwaukee, Wis) was used
throughout (repetition time, 24 milliseconds; echo time, 5 milliseconds; flip
angle, 40°; contiguous 1.2-mm thick axial slices; pixel matrix, 256 x
256; field of view, 23 cm). Images were coded, intermixed, and screened by
neuroradiologists for white matter hyperintensities or other evidence of vascular
or neoplastic abnormality. Inhomogeneities of the field main magnetic field
were monitored monthly and compensated for with shims in the hardware. Radiofrequency
field inhomogeneities were monitored using a cylindrical water-filled phantom;
after a 1-pass gaussian filter was applied, the histogram was less than 10
U wide, and differences in signal-intensity values on the x- and y-axis 5
cm from the center would not be expected to exceed 1 U in 256. Image geometric
linearity was monitored with a 100-mm square-cross phantom; current data showed
a 1.6% difference between the vertical and horizontal scales, well within
measurement error. Details of image acquisition were kept uniform throughout
the study, and regularly obtained phantoms ensured consistency. Brain volume
was determined by visual placement of points on the cortical rim and fitting
a spline curve45 through the points on 16 to
20 planes spaced 6.5 mm apart from the highest plane with gray matter to the
lowest plane in which frontal and temporal lobes were contiguous to match
previously reported PET data.8 The intraclass
correlation coefficient (ICC) for 2 raters, 10 brains, was 0.98.
REGIONAL ASSESSMENT AND MORPHOMETRY
The MDN and pulvinar were delineated in serial slices proceeding dorsally
and then ventrally (typically 8-11 slices), beginning with the level at which
the structure was most clearly demarcated (see Figure 1 for approximate level). For MDN and pulvinar, spline points
were placed on lines of demarcation established by a Sobel intensity-gradient
filter. A 3 x 3 maximizing function (ie, local search in the 3 x
3 pixel vicinity for maximum value) was applied to pull the spline line to
the contour of maximal contrast.8
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Figure 1. A, Gross specimen of the thalamus
viewed from top looking down, showing surface contour of nuclei. Arrow indicates
lateral inflection. B, Microscopic atlas14 showing
MDN and internal medullary lamina (IML) in axial section (arrowhead). C, Typical
axial magnetic resonance image (MRI) at this level of normal control with
nuclear regions visible. D, Application of gradient filter to MRI enhances
IML markedly. CCT indicates corticotectal tract. E, The MDN traced as described
in text. Before delineation of regions of interest using a spline function,
serial slices through the entire dorsal-to-ventral extent of the thalamus
were viewed on a 53-cm workstation. The region of the thalamus was enlarged
(original magnification x4). An identical enlarged image was displayed
in an adjacent window of the same dimensions. The Sobel gradient filter was
applied6 to this second window. A gray scale
window range and axial position were chosen in which the IML was most distinct
in the original enlarged image and in which lines defined by the Sobel filter
most completely circumscribed the MDN and the PUL. In all cases, this level
corresponded closely to the following brain atlas levels: Talairach and Tournoux46 for z= 8-12; level 8 of Matsui and Hirano.47
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Mediodorsal Nucleus
The medial border is defined by the interface of brain matter with cerebrospinal
fluid; lateral and posterior borders, by the internal medullary lamina. Anteriorly,
the lamina is heavily myelinated, in sharp contrast with surrounding gray
matter. More posteriorly, the lamina appears less heavily myelinated, and
contrast to surrounding thalamus is partly based on the extremely rich vascular
supply running within the lamina. Multiple Sobel filter lines were sometimes
seen in this region. Fortunately, a conspicuous anatomical feature allows
a reliable caudomedial border to be established. The pulvinar (derived from pulvinus, Latin for "cushion") forms a cushionlike eminence
that protrudes into the ventricle. The point at which the ventricular wall
abruptly deviates medially to form that eminence establishes the pulvinar's
rostromedial extent (Figure 1). This
point (usually lying on the line established by the Sobel filter) defined
the border between the MDN and the pulvinar on the medial aspect of the thalamus.
The dorsal extent of the nucleus was taken as the most dorsal level at which
the Sobel filter circumscribed an ovoid structure situated medially within
the thalamus and lying primarily posterior to the level of the mammillothalamic
tract. The MDN's ventral extent was taken as the most ventral level at which
the Sobel filter circumscribed an ovoid structure that appeared to be continuous
with the MDN as delineated in the more dorsal sections. This generally corresponded
to 1 MRI slice above the plane in which the superior colliculus appeared,
in agreement with our observations of the ventral extent of the nucleus in
histological sections.
Pulvinar
Medial and posterior borders were unambiguously defined by their interface
with cerebrospinal fluid. The lateral border was established by the internal
capsule. Medially, the anterior border was defined by the posterior border
of the MDN. More laterally, the anterior border was defined by the corticotectal
tract, a myelinated band of fibers extending from the lateral extent of the
thalamus to join the internal medullary lamina at the MDN's posteromedial
edge. The ventral extent of the pulvinar merges imperceptibly with the pretectum
and was taken as the most ventral level at which the Sobel filter circumscribed
a structure that appeared continuous with that identified as the pulvinar
in more dorsal sections. This usually occurred at or slightly above the level
of the superior colliculus. The dorsal extreme of the pulvinar coincides approximately
with the dorsal extreme of the MDN. It was defined as the most dorsal level
at which the Sobel filter circumscribed a structure extending to the posterior
extent of the thalamus and continuous with profiles identified as pulvinar
in more ventral sections (Figure 2). Figure 3 shows the entire thalamus reconstructed
in 1 subject.
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Figure 2. Four typical subjects with tracing
of mediodorsal nucleus (MDN) and pulvinar (PUL). Rows show unprocessed magnetic
resonance imaging with midline (A), gradient-filtered image (B), MDN tracing
(C), and PUL tracing (D). First column is at smaller magnification for orientation.
B, Arrows point to internal medullary lamina.
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Figure 3. Volume rendering in 3 dimensions
of thalamus viewed looking down from the top with mediodorsal nucleus in red
and pulvinar in blue. Orientation is the same as in Figure 1.
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RELIABILITY
Two tracers independently outlined the whole thalamus (W.B. and E.K.),
the MDN (W.B. and E.K.), and the pulvinar (W.B. and A.S.) on 8 subjects. The
ICC48 and the proportion of overlapping pixels
between the tracers (pixels common to traced outlines divided by number of
pixels included by either tracer) were computed. The ICC for whole thalamus
volume between 2 tracers was 0.90; percentage of pixel overlap between tracers
1 and 2 was 95.2%, and that between tracers 2 and 1 was 93.8%. Tracing of
individual nuclei had acceptable reliability (79.6% and 90.4% pixel overlap
for the MDN; 90.6% and 90.1% for the pulvinar). The ICCs for the MDN and the
pulvinar were r = 0.78 and r
= 0.83, respectively.
STATISTICAL ANALYSIS
Data were expressed in cubic centimeters for each region of interest
(ROI). Variance of the diagnostic groups for both nuclei did not differ significantly
(Levene F test for variability). Volumes of the nuclei were normally distributed,
and the Kolmogorov-Smirnov test for both nuclei did not reject a nonnormal
distribution (P = .29). Multivariate analysis of
variance for volume used a 3-group (controls and schizophrenic and SPD patients)
x 2-nuclei (MDN and pulvinar) x 2-hemispheres (right and left)
mixed-factorial design. A 3 x 2 mixed-factorial design was used for
the whole-thalamus volume analysis. The first variable consisted of the 3
groups; the second, the 2 hemispheres. Separate analyses of variance (ANOVAs)
were performed for each ROI (including total thalamus), ROI/(thalamic volume -
ROI), and ROI/brain volume. Our statistical approach allowed (1) specific
a priori hypothesis testing with a single F (main effect of group indicating
bilateral nuclear effects) to moderate type I error within the MRI-based outline
of the thalamus and (2) assessment of the specificity of findings for an individual
ROI (group x structure x hemisphere). Follow-up 2-tailed t tests ( level, P<.05)
examined specific contrasts suggested by the literature. Strictly speaking,
it could be argued that we should use 1-tailed tests for smaller schizophrenic
MDN, since that was our hypothesis based on findings in postmortem material
in several studies. However, specification of the number of tails and exact P value permits the reader to interpret the findings.
RESULTS
BRAIN AND THALAMIC VOLUME
Mean total brain volume was not significantly different in the schizophrenic
(1272 cm3; SD, 134 cm3) or SPD (1392 cm3;
SD, 210 cm3) group compared with controls (1341 cm3;
SD, 68 cm3). Average thalamic volume across right and left hemispheres
did not significantly differ in the schizophrenic (4.43 cm3; SD,
0.35 cm3) and SPD (4.58 cm3; SD, 0.42 cm3)
groups vs controls (4.68 cm3; SD, 0.40 cm3; F2,33 = 1.39; P = .26), and follow-up group differences
were not statistically significant when tested 2-tailed (control vs schizophrenic
groups, t22 = 2.06; P = .05). At the observed effect size of 0.67 for thalamic volume,
45 subjects per group would be required to detect a significant control vs
schizophrenic group difference with power of 0.90.
THALAMIC NUCLEI
When pulvinar and MDN were analyzed together in a 3-way ANOVA, there
was a significant main effect of patient group for nuclear size relative to
brain volume (F2,33 = 3.35; P = .047),
but the effect of patient group for nuclear size ((F2,33 = 3.09; P = .06) and a group x nuclear size interaction did
not reach statistical significance (F2,33 = 2.94; P = .07).
PULVINAR
Volume of the pulvinar was significantly smaller in the SPD and schizophrenic
groups than in controls (Table 1).
With correction for brain size, the relative volume of the pulvinar was also
significantly reduced (Table 1).
For volume and relative volume, there was no significant group x hemisphere
interaction. However, because the size difference across groups was so marked
(14.9% across all groups; main effect of hemisphere, F1,33 = 29.7; P<.001), right and left hemispheres were examined separately
(Table 2), revealing that the major
size reductions were in the left thalamus. The t
tests examining right minus left difference scores for volume data revealed
significant asymmetry (right>left) in schizophrenic and SPD patients (t11 = 3.09 and t11 = 3.65, respectively; P<.01) but not
controls (t11 = 2.01; P<.10). There were no significant differences in asymmetry when
difference scores for schizophrenic and SPD groups were compared separately
with control scores (t22 = -0.45
vs t22 = -0.77; P = .65; the effect size of 0.18 for control vs schizophrenic group
is small, and the effect size of 0.32 for control vs SPD group would require
n = 150 for 80% power).
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Table 1. Volume and Relative Size of Thalamic Mediodorsal Nucleus and
Pulvinar in Schizophrenia and Schizotypal Personality Disorder*
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Table 2. Hemispheric Asymmetry in Thalamic Volume*
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MEDIODORSAL NUCLEUS
Volume of the MDN was smaller in the SPD and schizophrenic groups than
in controls, but in the same statistical contrasts as performed for the pulvinar,
group differences were not statistically significant (n = 52 needed for 80%
power). There were no significant group or group x hemisphere effects.
Compared with normal values, the only statistically significant MDN volume
loss was for the schizophrenic group, only in the left hemisphere (Table 2 and Figure 4). The t tests examining right
minus left difference scores revealed significant asymmetry (right>left) in
the schizophrenic (t11 = 2.89; P<.01) but not control (t = 0.24; P = .58) groups, whereas the greater asymmetry in patient
groups than in controls was not significant (t22 = 1.75; P = .10; effect size, 0.71; n =
30 in each group for 80% power).
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Figure 4. Scatterplot of left mediodorsal
nucleus (MDN) volume in control, schizophrenic, and schizotypal personality
disorder (SPD) groups. Frequency histogram and fitted normal distribution
are shown to the right with number of subjects (0-8) on the x-axis.
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COMMENT
Previous studies of anatomically delineated thalamic divisions in schizophrenia
have relied on postmortem material and have been mainly restricted to the
MDN.2, 3 Our study examined the MDN
and the pulvinar in living subjects. Evidence was obtained of a reduction
in the volume and relative size of the pulvinar in both schizophrenia and
SPD. The MDN was also reduced in volume, but this reduction was statistically
significant only for the left hemisphere and only in schizophrenia. Since
the volume of the whole thalamus or whole brain was not significantly reduced
in schizophrenia or SPD, the reductions observed in the nuclei cannot be attributed
to generalized brain-size reduction. Failure to detect significant volume
loss in the whole thalamus is consistent with most8, 49, 50, 51, 52
but not all7 studies.
An interesting implication of the present study is that of a common
neurologic substrate (pulvinar volume loss) in 2 schizophrenia-spectrum disorders
(schizophrenia and SPD). In contrast, MDN volume loss appears specific to
schizophrenia. The widespread connections of the pulvinar with temporal association
and sensory cortices53 suggest that associational
and perceptual disturbances may be linked to abnormalities in the pulvinar.
On the other hand, although patients with SPD manifest some peculiarities
of thinking and associations, they do not show the severe formal thought disorder
(eg, frequent derailment or incoherence) of schizophrenia. The MDN, via its
projection from the dentate of the cerebellum, has been proposed as a potential
substrate for schizophrenic thought disorder.5
That proposal is based on analogy to the motor system in which complex movements
are conceptualized as being built up from simple movements (ie, modules) that
are assembled into meaningful sequences by the cerebellum.54, 55, 56
Complex thoughts may be similarly constructed from modules (ie, partial thoughts)
that are sequenced by the cerebellum. Work based on the transsynaptic transport
of herpesvirus in monkeys has demonstrated that MDN neurons that receive cerebellar
input project to the PFC.57, 58 In
addition to the assembly of complex thoughts from modules, communication among
MDN, PFC, and cerebellum may play a role in working memory and the integration
of complete thoughts. Abnormality of the MDN might result in the assembly
of partial thoughts that are not only inappropriately sequenced (ie, incoherence)
but out of context (ie, loosening of associations).
Consistent with our hypothesis of abnormalities in efferent and afferent
fields of abnormal thalamic divisions, schizophrenia-associated anatomical
anomalies have been described for the following 2 projection fields of the
MDN: the PFC and the cerebellar dentate.59 The
abnormalities of the PFC have been hypothesized to be atrophic changes due
to a loss of excitatory glutamatergic input, such as that supplied by the
MDN. Loss of volume and cells within the MDN could reflect a loss of excitatory
input to the PFC. If there is indeed an etiologic link between the schizophrenia-associated
changes described for MDN and PFC, one might propose a corresponding link
between PFC abnormalities and volume loss in the pulvinar, since the medial
pulvinar and the MDN have similar connections with the PFC.60
We are examining postmortem histological sections to determine whether the
MRI-detected volume loss is distributed throughout all divisions of the pulvinar
or restricted to its medial division.
Changes in the MDN might instead be secondary to abnormalities that
have been described in its cortical fields. Although auditory, visual, and
somatosensory pathways primarily pass through the ventral posterior and geniculate
nuclei, the complex associational thalamocorticothalamic loop of the lateral
orbitofrontal and dorsolateral PFC independently involves anterior and mediodorsal
regions of the thalamus. The sensory information processed in the PFC is probably
derived primarily from corticocortical connections. The proposal61, 62
that schizophrenia involves faulty filtering of sensory signals from input
to the cortex via the thalamus is consistent with our observation of a loss
of the normal correlation between glucose metabolism in the thalamus and PFC
in PET studies.25
Temporothalamic interactions also merit consideration for their potential
role in schizophrenia-related disturbances. The important interactions between
the pulvinar and the occipital and temporal lobes53—areas
of visual and auditory processing—suggest the pulvinar as another site
for interregional communication failure. The pulvinar, which is absent in
rodents, increases in size and complexity from monkeys to apes to humans,
in which it is the largest thalamic nucleus.63
Lateral regions of the pulvinar have widespread projections, including connections
to temporal association and visual and auditory cortices.53
These connections suggest a potential role for the pulvinar in the unusual
associations and sensory disturbances of schizophrenia. Moreover, the role
of the left pulvinar in language and the association of dominant left-lateral
pulvinar lesions with "semantic paraphasias sometimes deteriorating into jargon"64, 65 suggest the pulvinar's potential importance
in schizophrenic speech disturbance. The pulvinar (especially medial regions)
also has reciprocal connections with the PFC,24
suggesting a possible link between the pulvinar and prefrontal abnormalities
of schizophrenia.
Although loss of excitatory projection neurons to the PFC might account
for schizophrenia-associated volume loss in MDN and pulvinar, a loss of interneurons
must also be considered. Both nuclei are believed to contain some neurons
of telencephalic origin.63 Because these neurons
migrate into the diencephalon through the gangliothalamic body after most
thalamocortical connections have been established, they are likely to be interneurons.63 Disruption of the telencephalic germinal zone or of
the migration of neurons into the diencephalon might produce cell and volume
loss in both MDN and pulvinar. One study described a schizophrenia-associated
loss in the pulvinar of small neurons that were hypothesized to be interneurons.33
Our study is limited by several considerations. First, the sample size
of 36 (12 in each group) limited power to detect small total thalamic volume
decreases. Indeed, a meta-analysis of 14 MRI studies that measured the thalamus
in schizophrenia suggested "a statistically significant, small-to-moderate
effect size for thalamic size reduction in schizophrenia."66
Second, the extent to which structures identified as MDN and pulvinar on MRI
overlap with those identified in histological sections is unknown; however,
the lines established on MRI scans by the intensity-gradient filter are consistent
from one brain to the next and allow subregions of the thalamus to be identified
reliably. Nevertheless, current MRI resolution did not permit assessment of
thalamic nuclei in addition to the MDN and pulvinar. Thus, it is not yet possible
to determine whether thalamic volume changes in schizophrenia and SPD are
restricted to those nuclei or involve additional nuclei. Finally, in the absence
of significant clinical correlations, the functional significance of the observed
volume changes remains speculative.
Postmortem histological work is necessary to determine the exact units
of thalamic cytoarchitecture and the neuronal phenotypes affected in schizophrenia,
but such studies are extremely laborious and can only be performed on relatively
small samples of brains, typically from older individuals. Moreover, diagnostic
information, postmortem intervals, and tissue fixation are often less than
optimal for autopsy specimens. Partly for these reasons, the specificity of
thalamic abnormalities to schizophrenia as opposed to other chronic psychiatric
conditions has been explored inadequately. Although neuroimaging lacks the
fine-grained resolution of histological work, and the exact correspondence
between histologically defined nuclei and gradient-filter MRI borders remains
to be established, in vivo studies allow many more subjects to be examined,
provide greater diagnostic precision, allow both hemispheres of the brain
to be assessed, and avoid uncertainties introduced by artifacts of tissue
fixation and other histological procedures. In addition to providing information
on brain function in living subjects, neuroimaging studies promise to increase
the efficiency of labor-intensive postmortem studies by identifying thalamic
regions that are most affected in schizophrenia and the schizophrenic subgroups
that exhibit the greatest structural abnormalities. Postmortem studies then
may be able to target specific brain regions and patient populations to clarify
the precise units of cytoarchitecture that are affected and to characterize
the nature of the abnormalities at cellular and molecular levels.
AUTHOR INFORMATION
Accepted for publication October 10, 2000.
This project was supported by grants MH40071, MH60023 (Dr Buchsbaum),
MH55989 (Dr Byne), MH42827 (Dr Siever), and MH56460 (Dr Hazlett) from the
National Institute of Mental Health. The VISN-3 Mental Illness Research Education
and Clinical Center (Bronx, NY) also provided support, with young investigator
awards from the National Alliance for Research on Schizophrenia and Depression
(Great Neck, NY) (Drs Byne and Hazlett), a Veterans Affairs (Washington, DC)
Merit Review grant (Dr Siever), the Charles A. Dana Foundation (New York,
NY), and the private contribution of Mrs Grace De Wolff (Dr Kemether).
Craig Geneve, Bradley R. Buchsbaum, and Rayzel Kinderlehrer provided
technical assistance.
From the Mount Sinai School of Medicine, New York, NY (Drs Byne, Buchsbaum,
Kemether, Hazlett, Shinwari, and Siever); the Bronx Veterans Affairs Medical
Center, Bronx, NY (Drs Byne and Siever and Ms Mitropoulou); and Pilgrim Psychiatric
Center, West Brentwood, NY (Dr Byne).
Corresponding author and reprints: William Byne, MD, PhD, Veterans
Affairs Medical Center, Department of Psychiatry (1F-29), 130 W Kingsbridge
Rd, Bronx, NY 10468 (e-mail: byne{at}mindspring.com).
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