German Journal of Psychiatry
SPECT and PET studies have provided evidence suggesting that
the orbitofrontal gyrus, the cingulate gyrus and the striatum
are part of the functional neuroanatomy of obsessive compulsive
disorder (OCD). Structural deficits may account for abnormal brain
activation, but cranial computed tomography and nuclear magnetic
resonance studies have produced contradictory results to date.
Lower N-acetyl aspartate (NAA) was described in the right striatum
of OCD patients in a 1H proton magnetic resonance spectroscopy
study. We therefore compared the right striatum of 10 drug-naive
patients suffering from OCD with 10 controls, matched for sex,
age, and education, using 1H magnetic resonance spectroscopy.
The relative NAA levels in the right striatum of OCD patients
were 7% lower, but there was no significant difference to the
controls. It is concluded that basal ganglia pathology may define
only a subgroup of OCD patient (German J Psychiat 1998;1(2):53-61)..
Key words: Nuclear magnetic resonance tomography - magnetic
resonance spectroscopy - obsessive-compulsive disorder - anxiety
disorders - n-acetyl-aspartate - brain imaging
The study was supported by DFG Eb144/2-1
SPECT and PET studies have provided evidence that the orbitofrontal gyrus, the cingulate gyrus and the striatum may be part of the functional neuroanatomy of obsessive compulsive disorder (OCD). In these regions a pattern of symptom-related functional hyperactivity has been shown (Baxter 1995). Inadequate sensory information gating in the basal ganglia is believed to allow cortical inputs to capture and drive a self-sustaining loop. Therefore, it has been hypothesized that neuronal loss in one of the inhibitory pathways, e.g. the striatum, might account for the functional hyperactivity in the cortico-limbic loop.
C-CT (cranial computed tomography), NMR (nuclear magnetic resonance) and MRS (1H proton magnetic resonance spectroscopy) studies have produced contradictory results in regard to the involvement of the striatum in the pathophysiology of OCD. Using C-CT or NMR, Luxenburg et al. (1988) and Robinson et al. (1995) reported reduced caudate volumes. Kellner et al. (1991), Calabrese et al. (1993), Aylward et al. (1996) and Stein et al. (1993, 1997) did not find significant differences between OCD patients and controls, and Scarone et al. (1992) even found increased caudate volumes. A morphometric NMR study conducted by Jenike et al. (1996) revealed widely distributed brain abnormalities which were pronounced in the striatum. However, comparison of OCD versus controls was not significantly different in the striatum. Ebert et al. (1997) described lower N-acetyl aspartate (NAA) in the right striatum in 12 OCD patients compared to 6 controls. It has been suggested that NAA is a neuronal marker, although its exact role in neuronal biochemistry is not known. NAA is reduced in disease states that involve tissue reduction, neuronal loss, damage or destruction. There is also evidence that reversible changes occur in NAA and that this reversibility depends on the extent of the neuronal damage (Birken and Oldendorf 1989; Maier 1995). The differences between the studies are not the result of differences in statistical power, since the sample sizes of confirming and non-confirming studies are similar.
This study attempted to replicate the results of the first MRS
study (Ebert et al. 1997) by comparing the right striatum of 10
OCD patients with 10 age and sex matched controls using 1H
All experiments were performed on a 2 T whole body system (Bruker S 200F) with actively shielded gradients.
Each scanning procedure consisted of three steps: In the first step, anatomical slices were made, in which the voxel had to be positioned; the second step involved positioning the voxel in the striatum; in the third step acquisition of the proton spectra within the positioned voxel was performed.
For anatomical assessment, a standard T2 -weighted NMR sequence was used that contained 16 parallel transversal sections, starting from the intercommisural line, and 16 sagittal slices centered on the midline, slice thickness=5mm, interslice distance=2mm. We used the localization technique of image-selected in-vivo spectroscopy. The anatomical position of the voxel was drawn in advance from a standard brain atlas (Tailarach et al., 1988), outlining the right striatum. The voxel of 2cm x 2cm x 2cm was positioned in the transversal slice fitting to the Tailarach coordinates and was positioned by hand to fit the anatomical region. Afterwards the voxel was readjusted to the anatomical region according to the position in the sagittal slices. The placement of the voxel was performed by one experienced rater who was blind to the diagnoses. The voxels of all patients and all probands were always placed in the same slice level. The striatal region comprised the N. caudatus and the putamen. Parts of the ventricles and the pallidum were included according to the voxel size of 8 cubic centimeters.
After placement of the voxel the spectra were acquired using the PRESS-technique with an echo time of 30ms and a repetition time of 1500ms in a voxel of 2cm x 2cm x 2cm. The sweep width was 1000 Hz and 1k datapoints were acquired with 256 averages.
Spectra were processed using eddy current correction calculated from a reference water FID, and signal intensities were determined with the LC-model fitting package. The N-acetyl-aspartate (NAA)/creatinine+phosphocreatinine ratios were calculated as areas under the curve. The evaluation of the spectra was performed by one rater who was blind to the diagnoses.
The in-plane resolution was approximately 1mm. In pre-studies the intraindividual variance was approximately 2-5%.
The analysis was restricted to the NAA ratio of one voxel in the right striatum to minimize long scanning times and movement artefacts and to confirm the previous MRS results.
A spectrum and a localization scout of the striatal voxel are
presented in figure 1.
10 patients fulfilling DSM-IV criteria for OCD and 10 healthy controls without a current or past history of a DSM-IV diagnosis were entered into the study. The study criteria excluded patients with a significant medical illness, current and past alcohol or psychoactive substance abuse, and DSM-IV defined dementia, delirium, schizophrenia, or schizoaffective disorder. The controls were matched for age, sex and education.
All patients were drug-naive. The clinical data are presented
in table 1.
|Outcome, % mprovement after 8 weeks therapy|
Table 1: Demographic and clinical data
The spectra were compared by an ANOVA with the independent factors
being group, sex and education, with age and Y-BOCS-scores (Yale
Brown Obsessive-Compulsive Symptom Scale) as covariates. The covariates
were entered since previous studies found negative correlations
of age and severity to striatal NAA or striatal volume. Pearson
correlations were calculated for the assessment of correlations
between the NAA ratios and age, severity of illness or improvement
after therapy (outcome).
The ratios of the striatal NAA spectra are presented in table
ANOVA: no significant group effect (OCD versus controls),
df=1, F=2.8, p<0.12; no significant sex effect, df=1, F=0.13,
p<0.72; no significant 2-way interaction group/sex, df=1, F=0.02,
Table 2: Comparison of the NAA proton spectra of OCD patients
and healthy controls and females and males. The calculated ratios
are relative to creatinine+phosphocreatinine. Means and standard
deviations are reported.
The relative NAA values in the right striatum were about 7% lower in the OCD group compared to the control group, a difference similar to a previous MRS study. Using an ANOVA, this difference was not significant, with an effect size of 0.35. Men and women were not significantly different. NAA ratios did not significantly correlate with age (r=-0.39), severity of illness (r=-0.47) or improvement after therapy (r = 0.47).
The relative choline values were 0.24+/-0.03 in OCD versus 0.25+/-0.03
in controls, the relative glutamate values were 0.57+/-0.12 in
OCD versus 0.62+/-0.18 in controls, the relative myoinositol values
were 0.52+/-0.17 in OCD versus 0.46+/-0.05 in controls. The differences
were not statistically significant.
Figure 1: Localization scouts of voxels and the corresponding proton spectra
(upper left: striatal voxel and corresponding striatal
We could not replicate a previous finding of significantly lower NAA levels in the right striatum of OCD patients (Ebert et al. 1997), though we found a similar NAA reduction of approximately 7%.
In the first study (Ebert et al 1997) the groups were not matched, as they showed unequal sex and age distribution, and some male OCD patients had excessively low striatal NAA levels, leading to a significant group difference in a multivariate ANOVA. In this study patients and controls were carefully matched for age, sex and education.
Both studies had some methodological limitations: Single voxel techniques were applied, with an increased risk of partial volume effects and missing the exact anatomical boundaries. No segmentation was performed, and, though water was suppressed, liquor and tissue differ in their NAA content. Finally, we did not obtain absolute values, but restricted our analysis to relative NAA values.
Although disappointing, the failure to find group differences here is consistent with previous research, which has shown contradictory results as mentioned in the introduction. In our opinion, three explanations can be postulated for this variance of research on striatal pathology:
The first possibility is that no real group differences exist, and that positive results are an effect of chance or insufficient matching.
The second possibility is that small, not easily detectable differences exist. This was corroborated by our power analysis using the results of the presented study, which revealed that we would have to go on investigating more than 70 persons in each group to have an 80% chance of finding significant striatal differences.
The third possibility is that abnormalities in the striatum of OCD patients may not be homogeneous. Subgroups may exist, making OCD an inhomogeneous disease. Different pathogenic mechanisms may differentially affect caudate size or cell content. In this respect, it is of interest that two patients in our study, but none of the controls, had NAA levels less than two standard deviations below the mean. One of them had increased neuropsychological dysfunction. Accordingly, Stein et al. (1993) found differences between OCD patients with high neurological soft signs and OCD patients with low neurological soft signs in a sample of only 24 patients. Furthermore, Stein et al. (1997) described a correlation of increased neuropsychological dysfunction and neurological soft signs with low left caudate volume in OCD.
Due to the fact that OCD-control comparisons are less likely to
provide consistent results, we recommend that subgroups of OCD
patients be defined for further research in striatal pathology.
These could be differentiated, for example, according to the prevalence
of hyperkinetic disorders or neurological soft signs.
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