White matter abnormalities in schizophrenia patients with tardive dyskinesia: A diffusion tensor image study

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Abstract

Objective

Tardive dyskinesia (TD) is a severe side effect of antipsychotics. While increasing evidence suggests that damaged brain microcircuitry of white matter (WM) is responsible for the clinical symptoms in schizophrenia, no reports of WM abnormality associated with TD were noted.

Method

Brain white matter abnormalities were investigated among 20 schizophrenia patients with TD (Schizophrenia with TD group), 20 age-, gender-, and handedness-matched schizophrenic patients without TD (Schizophrenia without TD group), and 20 matched healthy subjects with magnetic resonance imaging and diffusion tensor imaging analysis. Voxel-wise analysis was used to compare fractional anisotropy (FA) maps of the white matter following intersubject registration to Talairach space. Clinical ratings included the Positive and Negative Symptoms Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Scale (SAS).

Results

The study subjects were 75% female with average of 40.1Ā Ā±Ā 9. 8Ā years. The Schizophrenia with TD group had significantly higher PANSS total scores (pĀ =Ā 0.024), PANSS negative score (pĀ =Ā 0.001), SAS (pĀ <Ā 0.001) and AIMS (pĀ <Ā 0.001) scores; and demonstrated more widespread FA decreases than the Schizophrenia without TD group, especially over the inferior frontal gyrus, temporal sublobar extranuclear WM (around the basal ganglion), parietal precuneus gyrus WM (around somatosensory cortex), and medial frontal gyrus WM (around dorsolateral prefrontal cortex). The AIMS (pĀ <Ā 0.01) and SAS (pĀ <Ā 0.01) score positively correlated with decreased FA over these areas, and PANSS negative score positively correlated with FA decrease over medial frontal gyrus WM (pĀ <Ā 0.01).

Conclusions

More widespread abnormality of white matter was noted among schizophrenia patients than those without, especially involved cortico-basal ganglion circuits with clinical symptom correlation of involuntary movements and negative symptoms. Further studies with larger sample size are required to validate the findings.

Introduction

Tardive dyskinesia (TD), a severe and disabling side effect of antipsychotics, is characterized by late-onset, repetitive, involuntary choreiform movements, tics and grimaces of the orofacial muscles, and dyskinesia of the distal limbs, paraspinal muscles, and diaphragm (Miller et al., 2005). Schizophrenic patients with TD have an unusually high incidence of cognitive impairment and negative symptoms (Berry et al., 2007). These symptoms frequently continue and may become permanent even after antipsychotics are discontinued (Bai et al., 2003). A recent report showed that the annualized incidence of TD was 5.5% with first-generation antipsychotics, and 3.9% with second-generation antipsychotics (Correll and Schenk, 2008). This incidence of TD with atypical antipsychotics was higher than expected, and underscores the fact that TD is still a significant clinical problem (Chouinard, 2006).

It has been hypothesized that schizophrenic patients with TD have more neurodevelopmental disturbances, particularly minor physical anomalies in association with cognitive dysfunction and cerebral abnormalities (Waddington et al., 1995). Researchers have sought evidence of structural neuropathological alterations related to TD using several neuronimaging techniques. First, using CT, Bartels et al. found patients with TD were with significantly greater width of the third ventricle, greater bicaudate distance, smaller areas of caudate nucleus head and lenticular nucleus, compared with age- and sex-matched controls. They suggested that structural abnormalities, primarily in the basal ganglia system, are present in TD patients (Bartels and Themelis, 1983). Ueyama et al. also found a low density rate in the basal nucleus of a group of TD patients, which was significantly higher than that of non-TD patients (Ueyama et al., 1993). Similarly, Gold et al. found patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls, and suggested that the abnormal movements of TD may result from specific dysfunction within the motor circuits of the basal ganglia (Gold et al., 1991). Dalgalarrondo et al. also found that caudate left area reduction and left temporal sulci enlargement were the most important parameters that discriminated patients with TD from non-TD patients. In that study, caudate left area reduction and left temporal sulci enlargement correlated significantly with cumulative duration of psychiatric hospitalizations only among patients with TD. Dalgalarrondo et al. concluded that structural abnormalities in the caudate nucleus and temporal lobes of patients with TD were related to longer treatment with antipsychotics (Dalgalarrondo and Gattaz, 1994).

Similar findings have been reported with magnetic resonance imaging (MRI). Bartzokis et al. found that schizophrenia patients with TD had significantly shortened left caudate T2 relaxation times, compared to patients without TD. They suggested that T2 relaxation time shortening in the basal ganglia may be helpful for predicting the risk for TD (Bartzokis et al., 1990). In another study, the volumes of the caudate nuclei of patients with TD were significantly smaller than those of patients without TD and normal controls (Mion et al., 1991). Granholm et al. also showed that increased severity of TD was associated with shortened caudate T2 relaxation time, and motor-learning scores correlated with caudate T2 relaxation time (Granholm et al., 1993). However, other MRI studies showed negative results. Elkashef et al. reported that schizophrenic patients had significantly larger right and left globus pallidus and right putamen volumes than did comparison subjects; but without significant differences in the volume of these structures between patients with and without persistent TD (Elkashef et al., 1994). In a study by Buckley et al., schizophrenic patients showed prolonged T2 relaxation times in the right putamen and globus pallidus than did control subjects, but no significant difference in T2 values was found between patients with and without TD (Buckley et al., 1995). In Harvey's study, neither significant differences in T1 relaxation time of the basal ganglia (putamen, globus pallidus and the head of the caudate) were found between schizophrenic patients with and without TD (Harvey et al., 1991). Thus, the result of neuronimaging for TD is still controversial, and the specific pathophysiologic processes underlying movement disorders are still not completely understood (Casey, 2004).

Increasing evidence suggests that a disturbance in connections between different brain regions, rather than abnormalities within the separate regions themselves, is responsible for the clinical symptoms and cognitive dysfunctions observed in schizophrenia (Volkow et al., 1988). Impaired neuropsychological performance and related functional imaging and electrophysiological findings in patients with schizophrenia are considered as expressions of disturbed functional connectivity of microcircuits throughout the brain (Stephan et al., 2006), and most frequently reported for the frontotemporal, frontoparietal, corticothalamic, interhemispheric, and corticocerebellar circuits (Hanson and Gottesman, 2005, Winterer and Weinberger, 2004). This disturbed connectivity is related to alterations in the numbers, distribution, and ultrastructural integrity of oligodendrocytes of white matter (Hanson and Gottesman, 2005). Postmortem studies also identified abnormalities in the myelin sheath (Uranova et al., 2004), oligodendroglia (Hof et al., 2003), and interstitial neurons (Akbarian et al., 1996) in schizophrenic patients compared with healthy volunteers. Thus, new attention is turning to white matter (WM) fiber tracts, which subserve anatomical connections between distant, as well as proximal, regions of the brain (Kubicki et al., 2007).

Diffusion tensor imaging (DTI) is a useful tool for examining and quantifying the microstructure of WM, and provides information about its integrity by exploring water molecular anisotropy within each MRI voxel (Garver et al., 2007). In coherent fiber structure, diffusion of water is greater parallel to, rather than perpendicular to, axonal tracts and is termed ā€œanisotropy.ā€ In general, water molecules are more restricted perpendicularly, and the anisotropy is high, with greater WM integrity. Fractional anisotropy (FA) is a normalized DTI index ranging from 0 (completely random) to 1 (completely unidirectional) (Lim and Helpern, 2002). Previous DTI studies have shown that schizophrenia is associated with significant FA reduction in the frontal thalamic cerebellar circuit (Okugawa et al., 2006), the left internal capsule, the left-hemisphere WM of posterior superior temporal gyrus (Szeszko et al., 2005), corpus callosum (Agartz et al., 2001) and middle cerebellar peduncle (Okugawa et al., 2005). The results supported that damaged brain microcircuitry might contribute to the pathophysiology of schizophrenia. However, although many reports have shown abnormal WM among schizophrenia patients, none has investigated WM abnormality among patients with TD, who had involuntary movement and unusually high incidence of negative symptoms (Berry et al., 2007). Previous report showed progressive decrement in frontal lobe white matter volume were associated with greater negative symptom severity (Ho et al., 2003).

We designed the study to investigate WM abnormalities in patients with TD using DTI among 20 schizophrenia patients with TD (Schizophrenia with TD group), 20 age-, gender- and handedness-matched schizophrenic patients without TD (Schizophrenia without TD group), and 20 matched healthy subjects. We hypothesized that more prominent reduction in FA will be found in schizophrenic patients with TD for white matter circuit involved in movement control and negative symptoms.

Section snippets

Patients

The study was conducted in a Medical Center, Taipei Veterans General hospital in Taiwan. The study subjects were enrolled from patients in psychiatric department outpatient clinic and Day care unit. Twenty schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, fourth edition, or DSM-IV, criteria) patients with TD (Schizophrenia with TD group), 20 schizophrenia patients without TD (Schizophrenia without TD group), and 20 matched healthy subjects (normal control group) were

Results

The study subjects were 20 schizophrenia patients with TD (Schizophrenia with TD group), 20 age-gender- and all right-handedness matched schizophrenia patients without TD (Schizophrenia without TD group), and 20 healthy subjects (normal control group). No significant difference in the age at onset of illness, duration of illness, antipsychotic chlorpromazine (CPZ) equivalent dose, or class of antipsychotics were noted between the Schizophrenia with and without TD groups (Table 1). All patients

Discussion

Our study results showed that schizophrenia patients without TD had significantly lower FA over temporal subcortical WM, parietal postcentral gyrus WM and frontal subgyral WM compared with normal controls. The result was consistent with previous results (Okugawa et al., 2006, Szeszko et al., 2005), and supported the hypothesis that damaged brain microcircuits of WM might contribute to the pathophysiology of schizophrenia. Our results further demonstrated that the Schizophrenia with TD group had

Role of the funding source

Funding for this study was provided by National Science Council, Taiwan and Taipei Veterans General Hospital, Taiwan; the National Science Council and Taipei Veterans General Hospital had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors

Dr. Ya Mei Bai: collect the subjects and clinical rating, wrote the protocol, conducted the analysis and wrote the article.

Mr. Kun-Hsien Chou, and Miss I-Yun Chen: conducted the MRI procedures for all subjects and analyzed the data of Diffusion Tensor Image.

Dr. Cheng-Ta Li, and Dr. Kai Chun Yang: collected the subjects, reference search and gave the idea for study design.

Dr. Yuan-Hwa Chou: gave the critical comment for the study design.

Professor Tung-Ping Su and Dr: coordinate the clinical

Conflict of interest

None.

Acknowledgements

The study was supported by grants from the National Science Council, Taiwan (NSC 96-2314-B-075-009 and NSC 97-2752-B-075-001-PAE), and Taipei Veterans General Hospital (V97C1-061 and V97ER1-003).

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