Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network.

BACKGROUND: Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. METHODS: We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. RESULTS: The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume (n = 79; df = 1,75; F = 4.18; p > .04). CONCLUSIONS: Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.     

Basal ganglia abnormalities in tardive dyskinesia

The purpose of the present study was to investigate CT abnormalities in tardive dyskinesia (TD) and to search for possible relationships with clinical data. A group of 30 psychotic patients (15 schizophrenic and 15 affective disorder) with TD was compared to a matched group of 30 psychiatric patients without TD and a matched group of 30 healthy controls. CT data were analyzed using two multivariate statistical methods [multidimensional scaling (MDS) and step-wise discriminant analysis]. MDS clearly separated both TD and non-TD groups from the healthy control group on the basis of CT parameters. Caudate left area reduction and left temporal sulci enlargement were the most important parameters that discriminated TD from non-TD patients. Only in TD-patients did caudate left area reduction and left temporal sulci enlargement correlate significantly with cumulative duration of psychiatric hospitalizations. The data of the present study support the findings of structural abnormalities in the caudate nucleus and in the temporal lobe of patients with TD. These abnormalities were especially marked in the left hemisphere. It is assumed that some factor related to longer psychiatric hospital treatment (e.g. neuroleptic intake) could account for these abnormalities.     

Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex in schizophrenia

Neuropathologic and brain imaging studies have produced evidence of brain abnormalities in schizophrenic patients, often within the cerebrum's limbic lobe, and, less frequently, within basal ganglia. In the present study we used magnetic resonance imaging morphometric techniques to estimate volumes of specific cerebral structures in schizophrenic patients and age- and sex-matched normal controls. Estimates of the volume of mesial temporal lobe structures were reduced and estimates of the volume of the lenticular nucleus were increased in the schizophrenic patients. There was also evidence of reduced cranial volume in some schizophrenics. The magnitude of the lenticular abnormality, but not the temporal lobe abnormality, was associated with age at first psychiatric contact; earlier onset was associated with larger lenticular nuclei. The possible relevance of these results to neurodevelopmental hypotheses about the pathogenesis of schizophrenia is discussed.     

Increased saccadic distractibility in tardive dyskinesia: functional evidence for subcortical GABA dysfunction

In mammals, GABAergic projections from the substantia nigra reticulata to the superior colliculus provide tonic inhibition to tectal neurons involved in the generation of saccades. Dysfunction of this pathway has been shown to produce saccadic "distractibility" in the experimental monkey. In two oculomotor paradigms, control of saccadic eye movements was tested in chronic schizophrenic patients with (n = 18) and without (n = 16) tardive dyskinesia (TD) and normal controls (n = 8). The three groups were matched by mean age; the TD and non-TD patient groups had similar duration of illness, benztropine and chlorpromazine equivalent doses and educational levels. A twofold increase in saccadic distractibility was observed in TD compared to non-TD schizophrenic patients, and both patient groups demonstrated a greater saccadic distractibility than normals. Furthermore, schizophrenic patients (both with and without TD) showed significantly increased latency for "volitional" saccades compared to the normal controls. These findings may provide further evidence for basal ganglia GABA dysfunction in tardive dyskinesia, as well as demonstrate oculomotor abnormalities in schizophrenic individuals.     

Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations.

A role of the caudate nucleus in depression has been suggested from relevant clinical conditions, such as patients with Huntington's disease or caudate infarcts, as well as animal studies. Correlations of caudate nucleus disease with depressive symptoms have been limited to autopsy studies and cases of gross pathological disorder, such as large infarcts. We used serial axial high-field magnetic resonance images and an unbiased stereological technique to estimate the volumes of the caudate nuclei in 50 patients who met DSM-III criteria for major depression (23 men, 48.3 +/- 17 years old) in comparison with 50 age- and gender-matched normal controls free of major neurological and psychiatric disorders. Depressed patients had smaller caudate nucleus volumes (5.2 +/- 1.6 cm3) compared with controls (6.2 +/- 1.7 cm3). Right and left caudate nucleus volumes were smaller in depressed patients compared with controls. Age was negatively correlated with caudate nucleus volumes in depressed patients as well as in controls. Caudate nucleus volumes in depressed patients were inversely correlated with the bicaudate and bifrontal indices. These results may be the first demonstration of diminished caudate nucleus volumes in depression and suggest a role for the caudate nucleus in the pathogenesis of major depression.     

Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings.

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, and negative symptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neuropsychological testing, psychiatric symptom ratings, and most had cerebral computed tomography (CT) scans. Patients with TD significantly differed from controls on only 1 of 23, cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of "organicity." Abnormal movements may result from specific dysfunction within the more purely motor circuits of the basal ganglia without compromising other neural systems involved in cognitive processing.     

Developmental processes and brain imaging studies in Tourette syndrome

OBJECTIVES: It is often difficult to discern how findings of a neuroimaging study relate to the pathophysiology of an illness because imaging correlates may variously represent causes, consequences, or epiphenomena of the condition. The objective of this paper is to exemplify the complexities of interpreting neuroimaging data by reviewing anatomical and functional studies of Tourette syndrome (TS). METHODS: Medline and Psychological Abstracts (PsycInfo) databases were searched for functional and anatomical neuroimaging studies of TS. RESULTS: 9 anatomical and 21 functional cross-sectional imaging studies of TS contributed to this review. Anatomical studies comparing TS patients to age-matched controls have found that lenticular nucleus volumes are reduced in TS adults, while caudate nucleus volumes are reduced in both adults and children with TS. In a study of the cerebral cortex, prefrontal volumes in TS adults were smaller, but in TS children were larger than in those of age-matched controls. Complementing the anatomical findings of reduced volumes of the caudate nucleus in TS, functional studies have suggested that frontal-striatal projections play an important role in the regulation of tic symptoms. The majority of functional studies to date, however, have been limited to the study of adults. These functional studies have yielded variable results that have limited generalizability to the pathophysiology of children with TS. CONCLUSIONS: Although many of the findings in TS imaging may represent pathological causes of the disease, they may also be indicative of compensatory changes in the nervous system of TS subjects. Prospective studies of young children at risk will be necessary to help clarify the relationship between brain abnormalities and the course of the disease.     

Neuropeptides in human brain--postmortem studies

Four neuropeptides (substance P, methionine-enkephalin, neurotensin and cholecystokinin) were measured by radioimmunoassays in a number of brain regions of deceased patients with mental illnesses and controls. The most striking finding in these studies was that methionine-enkephalin concentrations in caudate nuclei of chronic paranoid schizophrenic patients were reduced relative to several control groups. Neuroleptics had no obvious effects on any of the four measured neuropeptides. These findings are not inconsistent with the hypothesis that methionine-enkephalin may be involved in some of the pathology of the schizophrenic syndrome.     

Thalamic and caudate volumes in monozygotic twins discordantfor schizophrenia

OBJECTIVE: The thalamus and caudate nucleus are key subcortical structures in the fronto-striato-thalamic pathways that have been implicated in the pathogenesis of schizophrenia. Previous studies have been inconsistent in identifying structural and functional abnormalities in these structures. However, methodologies in these studies have been unreliable and some have not adequately matched patients and controls. METHODS: Using algebraically-manipulated double-echomagnetic resonance (MR) images, we developed a reliable method to estimate caudate and thalamic volumes in a group of 13 monozygotic(MZ) twins; eight discordant for schizophrenia and five normal.Initially, volumes were measured on four image types: proton density(PD), T2-weighted, summed (PD + T2) and subtracted (PD-T2) to determine the most reliable method. RESULTS: There was a significant method by region interaction, where caudate volumes measured on PD images were significantly larger than those measured on T2-weighted images, while the opposite was found for thalamic volumes. However, there was no interaction of method by diagnosis. Test-retest reliability was highest for the summed images. Using summed images to measure the volumes of the caudate and thalamus in each twin, we found significantly increased caudate volumes in affected twins compared to their unaffected cotwins,but no significant difference in thalamic volume. CONCLUSIONS: Our results in a small sample of MZ twins discordant for schizophrenia do not support the presence of structural abnormalities in the thalamus. The findings in the caudate are consistent with previously reported effects of antipsychotic medication. We also report a reliable method for assessing the volumes of subcortical structures. However, volumetric estimates of brain structures may be dependent on which method is used and the structure being assessed. Such interactions need to be considered in future studies investigating brain structural abnormalities in schizophrenia and other disorders.     

迟发性运动障碍患者超氧化物歧化酶、ATP酶活性改变

目的探讨抗精神病药所致迟发性运动障碍（TD）患者体内自由基代谢状况与TD的关系。方法测定36例TD、36例非TD慢性精神分裂症患者及40名正常人血浆超氧化物歧化酶（SOD）、红细胞ATP酶及丙二醛（MDA）浓度,并进行三组间方差分析;生化指标与异常不自主运动量表（AIMS）总分间的相关性采用直线相关分析。结果对照组血清SOD活性、ATP酶活性均高于TD组及非TD组,对照组MDA浓度低于TD组及非TD组,差异均有统计学意义（均P〈0.05）,TD患者血清SOD活性、ATP酶活性、MDA浓度与非TD组间的差异均有统计学意义（均P〈0.05）。AIMS总分与SOD、ATP酶、MDA均有显著相关（r=-0.225,r=0.225,均P〈0.05）。结论TD患者的血清抗氧化酶、ATP酶活性、脂质过氧化物异常,自由基代谢障碍可能与TD关系密切。     

Decreased plasma brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements

Neurodegenerative processes may be involved in the pathogenesis of tardive dyskinesia (TD). Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) plays a critical role in the maintenance of functional neurons. The present study was to examine plasma BDNF levels and the relationship among BDNF level, psychopathological and tardive dyskinesia symptoms in schizophrenic patients with TD. Eighty schizophrenic patients with TD were compared with 45 schizophrenic patients without TD, as well as with 45 age-, sex-matched normal controls. The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS). The psychopathology of patients was assessed by the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the patients with TD had lower plasma BDNF levels than those without TD, and than that of normal controls. In the patients with TD, plasma BDNF levels was inversely correlated with AIMS total score, and with PANSS negative subscore. Female patients had significantly lower plasma BDNF levels than male TD patients. Our results suggest that decreased BDNF may play an important role in the pathophysiology of TD. There may be a relationship between decreased BDNF levels and dyskinetic movements associated with TD.     

Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.     

Caudate nucleus volume and cognitive performance: Are they related in childhood psychopathology?

BACKGROUND: Impaired neuropsychological test performance, especially on tests of executive function and attention, is often seen in children diagnosed with autism spectrum disorders (ASD). Structures involved in fronto-striatal circuitry, such as the caudate nucleus, may support these cognitive abilities. However, few studies have examined caudate volumes specifically in children with ASD, or correlated caudate volumes to cognitive ability. METHODS: Neuropsychological test scores and caudate volumes of children with ASD were compared to those of children with bipolar disorder (BD) and of typically developing (TD) children. The relationship between test performance and caudate volumes was analyzed. RESULTS: The ASD group displayed larger right and left caudate volumes, and modest executive deficits, compared to TD controls. While caudate volume inversely predicted performance on the Wisconsin Card Sorting Test in all participants, it differentially predicted performance on measures of attention across the ASD, BD and TD groups. CONCLUSIONS: Larger caudate volumes were related to impaired problem solving. On a test of attention, larger left caudate volumes predicted increased impulsivity and more omission errors in the ASD group as compared to the TD group, however smaller volume predicted poorer discriminant responding as compared to the BD group.     

Shape analysis of the middle cranial fossa of schizophrenic patients. A computerized tomographic study

Recent morphometric studies indicate that both right and left temporal lobe volumes are reduced in schizophrenic patients. Subsequent studies suggested that this volumetric reduction is the result of focal or multifocal gray matter abnormalities. Since in early life brain growth or lack thereof influences the overlying skull configuration, we attempted to elucidate the time of onset of the temporal lobe lesion in schizophrenic patients by quantifying both the volume and shape of their middle cranial fossa. Computerized tomographic scans of 17 schizophrenic patients and an equal number of age-matched controls were digitized using a LOATS image analysis system. The middle cranial fossa was manually outlined and software routines allowed the quantification of volume and shape parameters. Our results showed that no significant differences were present between schizophrenic patients and controls. If the bilateral reduction in temporal lobe volumes in schizophrenic patients is the result of an early onset (e.g., developmental) lesion, the resultant foci of gray matter abnormality may occur distant to the base of the skull. Alternatively, tissue loss may be insufficient to alter the development of the overlying skull or to be detected by our methods.     

Synaptic changes in the striatum of schizophrenic cases: A controlled postmortem ultrastructural study

Although studies indicate abnormalities in the striatum of schizophrenic people, little information exists on the synaptic changes that may be present at the ultrastructural level. Autopsy specimens of striatal tissue from people with schizophrenia, normal controls, and psychiatric controls were obtained from the Maryland Brain Collection. Several abnormalities were noted in the schizophrenic group that were not present in the normal or psychiatric controls. In schizophrenic tissue, the density and/or proportion of symmetric synaptic profiles, particularly those ending on spines, were lower in the caudate vs. the putamen, implying an imbalance in inhibitory synaptic transmission between these two structures. The density of perforated synaptic profiles, cortical afferents thought to be involved in synaptic turnover and cognition, was lower in the striatum of the schizophrenic group compared to the control groups. The density of axodendritic synaptic profiles, particularly of the asymmetric type, was decreased in the caudate, but not the putamen, of a subset of schizophrenic cases that were nondyskinetic and off drugs (NDODS). The proportion of asymmetric axospinous synaptic profiles was elevated in the caudate of the NDODS cases in comparison to normal controls. The variety of synapses affected in the schizophrenic group implies the involvement of several neuronal circuits. The alterations observed in the schizophrenic striatum were usually due to changes in the caudate, but not the putamen, which argues against drug-related alterations. Since the striatum, particularly the caudate nucleus, is involved in cognition and emotion, these neuroanatomical changes could underlie, in part, aspects of schizophrenic psychopathology. Synapse 28:125–139, 1998. © 1998 Wiley-Liss, Inc.     

Olanzapine increases grey and white matter volumes in the caudate nucleus of patients with schizophrenia

There are inconsistent reports regarding the caudate nucleus volume in patients with schizophrenia compared with healthy subjects. The reason for this is that neuroleptic medication may affect the volume of the caudate nucleus in schizophrenic patients. To clarify which antipsychotic medication changes the volume of the caudate nucleus in patients with schizophrenia, we measured the volumes of grey and white matter in the caudate nucleus of schizophrenic patients. Ten patients with schizophrenia were examined twice by magnetic resonance imaging (MRI) to measure the grey and white matter volumes in the caudate nucleus. After the first MRI examination, all the patients were treated with olanzapine. The clinical responses were evaluated by the positive and negative rating scale. When the symptoms improved, the patients were examined by a second MRI scan. Ten healthy control subjects also underwent MRI. The schizophrenic patients had reduced volumes of grey and white matter in the caudate nucleus compared to the healthy control subjects. The volumes of grey and white matter in the caudate nucleus of the schizophrenic patients increased after treatment with olanzapine. These findings suggest that treatment with olanzapine may increase the grey and white matter volumes in the caudate nucleus in patients with schizophrenia.     

Blood superoxide dismutase level in schizophrenic patients with tardive dyskinesia: association with dyskinetic movements

Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Superoxide dismutase (SOD), a critical enzyme in the detoxification of superoxide radicals, was found to be abnormal in TD. To examine the blood SOD levels in schizophrenic patients with and without TD, and the relationships between SOD levels and tardive dyskinesia symptoms in TD patients, 45 physically healthy patients with TD who met DSM-III-R criteria for schizophrenia were compared with 45 schizophrenic patients without TD, as well as with 50 age-, sex- and smoking-matched normal controls. The severity of TD was assessed using the abnormal involuntary movement scale (AIMS). The psychopathology of patients were assessed by the Positive and Negative Syndrome Scale (PANSS). Blood SOD levels were measured by radioimmunometric assay (RIA). The results showed that the patients with TD had lower concentrations of blood SOD than those without TD, but had higher blood SOD levels than the normal controls. In the patients with TD, AIMS total score was inversely correlated with SOD levels. Our data support the view that free radicals may be involved in the pathophysiology of TD. There may exist a relationship between the free radical metabolism and the severity of dyskinesia of TD patients.     

Structural brain differences between never-treated patients with schizophrenia, with and without dyskinesia, and normal control subjects: a magnetic resonance imaging study

BACKGROUND: In south India, abnormal movements indistinguishable from tardive dyskinesia have been observed in chronically ill patients with schizophrenia who have never received antipsychotic medication. The present study, using magnetic resonance imaging, examines brain structure in such patients, in those without dyskinesia, and in normal control subjects. METHODS: Chronically ill patients with schizophrenia with and without dyskinesia and controls were identified in villages south of Chennai, India (each group, n = 31). Patients' mental state was assessed by the Positive and Negative Syndrome Scale for schizophrenia, dyskinesia by the Abnormal Involuntary Movements Scale, and parkinsonism by the Simpson and Angus scale. In patients and controls, magnetic resonance imaging measured the volume of the caudate and lentiform nuclei and the lateral ventricle-hemisphere ratio. RESULTS: The left lentiform nucleus was significantly (11%) larger in patients with dyskinesia compared with controls, and the right lateral ventricle-hemisphere ratio was significantly (33%) larger in patients without dyskinesia compared with controls. In all 3 groups, there were significant positive correlations between age and ventricle-hemisphere ratio. In controls, but not in patients, there were significant negative correlations between age and the volume of the caudate and lentiform nuclei. CONCLUSIONS: Never-treated patients with dyskinesia may have striatal pathologic conditions and may represent a subgroup of patients with schizophrenia; in those without abnormal movements, cortical atrophy is more apparent. The schizophrenic process may interfere with normal age-related anatomical changes in the basal ganglia.     

Increased automatic spreading of activation in thought-disordered schizophrenic patients

Previous research on semantic priming in schizophrenia has produced conflicting findings. While several studies provided evidence for an enhanced cognitive spreading of activation in schizophrenia patients with formal thought disorder, other research has failed to replicate. The aim of the present study was to resolve some of the ambiguities in the literature. Thirty-two schizophrenic patients (12 with and 20 without symptoms of formal thought disorder according to the PANADSS) and 65 healthy controls were compared in a semantic priming task using word pronunciation. Irrespective of baseline condition (neutral or unrelated condition) patients with formal thought disorder (TD) exhibited a significantly greater indirect semantic priming effect than both non-TD patients and healthy controls. Known confounding variables such as length of illness, neuroleptic dosage and psychomotor slowness did not moderate priming. Results further strengthen the spreading activation model of formal thought disorder put forward by Maher/Manschreck and Spitzer. Data indicate that hyper-priming is not confined to lexical decision tasks. Possible reasons why several studies have failed to replicate greater priming in TD schizophrenic patients are discussed.     

Corpus callosum area and functioning in schizophrenic patients with auditory--verbal hallucinations

Auditory--verbal hallucinations (AVH) are a characteristic feature of schizophrenia. Patients with AVHs have been found to differ from non-hallucinating patients in volumes of certain asymmetrical brain structures on MRI, and on certain neuropsychological measures. There is also evidence of corpus callosum (CC) abnormalities in schizophrenia, and it has been proposed that abnormalities of inter-hemispheric transmission may underlie hallucinations and other symptoms. The aim of this study was to examine whether patients with AVHs have smaller corpora callosa than those without AVH, and whether CC size is related to performance on neuropsychological tests of functional cerebral asymmetry. Seventy-one DSM-IV male schizophrenics were recruited on the basis of their hallucination history plus 33 matched normal controls. Twenty-nine patients had no history of AVH, and 42 had a strong history of AVH. The mid-sagittal surface area and longitudinal length of the CC were measured from T(1)-weighted spin echo images. Callosal area was divided into four sections. There were no significant differences in any of the measurements between the two patient groups, or between patients with schizophrenia and controls. There was no association between CC measures and handedness, or performance on dichotic listening or finger tapping tasks. The results of this study do not lend support for there being a major morphological abnormality of the corpus callosum in schizophrenic patients, or for a specific relationship to AVH. However, a significant association between CC area and overall grey and white matter volumes was noted in the hallucinating patients and, to a lesser extent, in the non-hallucinators, which may point to differing influences on brain development or degeneration in such patients compared with normal controls.