Aberrant brain activation following motor skill learning in schizophrenic patients as shown by functional magnetic resonance imaging.

BACKGROUND: Motor skill learning may be impaired in schizophrenia. While functional brain imaging studies have shown reduced activation during motor task performance in schizophrenic patients, brain activity changes with motor skill learning in these patients have not been studied by functional imaging. METHODS: A sequential complex motor task involving the right hand was performed by nine medicated schizophrenic patients and 10 age-matched healthy controls. Functional magnetic resonance images were obtained using a gradient echo, echoplanar imaging (EPI) pulse sequence before and after 1 week of training in performing the task. RESULTS: Bilaterally, patients showed significantly less blood oxygenation level-dependent (BOLD) signal response in the premotor area (PMA) before beginning motor training than controls. BOLD signal response increased in the left PMA of schizophrenic patients after 1 week of motor training; in contrast, the signal decreased in the left PMA of control subjects. Training effects concerning the number of finger movement sequences achieved did not differ between groups. Daily neuroleptic dose did not significantly affect changes with training in BOLD signal response in the PMA. CONCLUSIONS: These preliminary results suggest that schizophrenic patients have dysfunction of neural networks in areas including the PMA that are involved in executing a complex motor task. In terms of brain activity, motor learning may be less efficient or slower in the patients than in healthy subjects.

c-Fos expression in rat brain after repetitive transcranial magnetic stimulation.

We investigated neuronal response to repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) in terms of c-Fos expression. In rats at postnatal day 49, six rTMS sessions induced widespread nuclear c-Fos-like immunoreactivity in frontal cortex, lateral orbital cortex, striatum, lateral septal nucleus, piriform cortex, dentate gyrus, Ammon's horn, cingulate cortex, parietal cortex, thalamus, occipital cortex, and amygdala; this reactivity was greater than with two sessions of rTMS or sham rTMS. ECS produced even stronger c-Fos expression than six sessions of rTMS in all regions except thalamus (no difference) and striatum (stronger with rTMS). Thus, functional modification of neuroanatomic substrates as demonstrated by c-Fos expression may partially differ between rTMS and ECS.

Comparisons of event-related potentials after repetitive transcranial magnetic stimulation.

Effects of repetitive transcranial magnetic stimulation (rTMS) on the human cognitive process were investigated by examining auditory event-related potentials (ERPs) in 15 healthy subjects. Two rTMS trains were delivered over the left frontal area, with 30 pulses in each train. ERPs were recorded at 14 electrode sites on the scalp using a typical oddball protocol before and after rTMS. Tone stimuli (20% target and 80% standard) were delivered through earphones. Latency and amplitude of N100, P200, N200 and P300 were measured and compared during the study. To observe information flow between two electrode sites, directed coherence (DCOH) was calculated on the ERPs. Our results show that the effect of rTMS differs in the various ERPs components (P < 0.001). The latency of P300 significantly increased after stimulation, and the increase was more obvious in the frontal (18.6 ms) and central (15.8 ms) areas. The latency of P200 decreased in all areas. The amplitude of component N100 in the frontal and central areas decreased after rTMS. DCOH from the central area to the temporal area and DCOH from the parietal area to the temporal area were significantly higher than the DCOH between other areas (P < 0.01), and these properties were not affected by rTMS (P > 0.05). Information flow was driven from the frontal area to the parietal area after stimulation. Our results suggest that rTMS can suppress cognitive activities, showing an inhibitory effect on neurophysiological processes in the human brain. Since the temporal area is located at the terminus of the propagation pathways, it plays important roles in processing information in cognitive activities.

Effects of high frequency repetitive transcranial magnetic stimulation on P(300) event-related potentials.

OBJECTIVE: Auditory event-related potentials (P(300)-ERPs) were analyzed before and after repetitive transcranial magnetic stimulation (rTMS). METHODS: Two rTMS trains (10 Hz, 3 s, 100% motor threshold and 5 min interval) were delivered over the left frontal area in healthy subjects. P(300)-ERPs were recorded at 14 electrode sites on the scalp using a typical oddball paradigm before and after rTMS. The latencies and amplitudes of N(100), P(200), N(200) and P(300) were measured and compared. The directed coherence (DCOH) was estimated to demonstrate information flow between different cortical areas. RESULTS: rTMS significantly influenced P(300)-ERPs. The effects differed on the different components (P<0.001). The latency of P(300) significantly increased after stimulation, which was more obvious in the frontal and central areas. The changes in P(300) amplitude were not significant (P>0.05). The DCOH from the frontal, central, parietal and occipital areas to the temporal area was significantly higher than the DCOH from the temporal area to the former 4 areas (P<0.01). CONCLUSIONS: rTMS with the present parameters can affect P(300)-ERPs, leading to a delayed P(300) component and changes in information connections around the stimulated site. Our data suggest that rTMS may postpone neuronal activities related to cognitive processing.

Neurochemical investigation of the schizophrenic brain by in vivo phosphorus magnetic resonance spectroscopy.

Abnormal phospholipid metabolisms may play important roles in the pathophysiology of schizophrenia. Phosphorus magnetic resonance spectroscopy (31P-MRS) offers a new method for studying phosphorus-related metabolism in vivo. A decrease in the level of phosphomonoesters (PME) and an increase in the level of phosphodiesters (PDE) has been demonstrated in the prefrontal lobe of neuroleptic-naive schizophrenic patients. Most of the studies in medicated schizophrenic patients have shown decreased PME and/or increased PDE. The decreased PME in the frontal lobe appears to be associated with negative symptoms and poor working memory performance. 1H-decoupled 31P-MRS revealed a reduction in the phosphocholine element of PME and an elevation in the mobile phospholipids of PDE in the prefrontal region of medicated schizophrenic patients. PDE were elevated in the temporal lobes of neuroleptic-naive schizophrenic patients, and this increase was partially normalized by haloperidol administration. Data about the temporal lobes of medicated schizophrenic patients have not been consistent. Except for the reduction in the adenosine triphosphate (ATP) in the basal ganglia and the correlation between the increase in the frontal lobe phosphocreatine (PCr) and negative symptomatology, data related to changes in high-energy phosphates are contradictory. No consensus on the effect of neuroleptics on phosphorus metabolites has been achieved. Methodological problems inherent in 31P-MRS may have contributed to the confusion in understanding available data. Future directions of MRS studies are suggested in the last section of the paper.

Heritability heightens brain metabolite differences in schizophrenia.

Single-voxel proton magnetic resonance spectroscopy was performed in 64 medicated schizophrenic patients and 51 healthy subjects. Spectra were obtained from a voxel in the left medial temporal lobe by using a 2.0-tesla whole-body magnetic resonance imaging system. Schizophrenic patients showed a lower N-acetylaspartate/ creatine-phosphocreatine ratio than did healthy subjects, and this reduction was greater in 13 patients with a family history of psychotic disorders.

Haloperidol improves membrane phospholipid abnormalities in temporal lobes of schizophrenic patients.

Using 31P magnetic resonance spectroscopy, we examined changes in the levels of phosphorus metabolites in the temporal lobes of 13 schizophrenic patients before and 12 weeks after initiating haloperidol treatment. Spectra were obtained from a volume of interest positioned in each temporal lobe. Findings were compared with those in 13 age- and gender-matched healthy subjects. Prior to treatment the patients showed higher levels of phosphodiesters (PDE) in both temporal lobes than healthy subjects. Haloperidol administration significantly reduced the excess of PDE in the left temporal lobe, although the PDE concentration remained somewhat higher bilaterally than in controls. Treatment was associated with a decline in the total symptom score according to the Brief Psychiatric Rating Scale and the score for positive symptoms showed a relatively high correlation with reduction in PDE level in the left temporal lobe. These preliminary results suggest that haloperidol may partially normalize disturbed metabolism or abnormalities in components of membrane phospholipids in the left temporal lobe of untreated schizophrenic patients, paralleling symptom alleviation.

Changes in levels of phosphorus metabolites in temporal lobes of drug-naive schizophrenic patients.

OBJECTIVE: The authors examined phospholipids and high-energy phosphorus metabolism in the temporal lobes of drug-naive schizophrenic patients. METHOD: In vivo 31P magnetic resonance spectroscopy was performed on 17 first-episode, drug-naive schizophrenic patients and 17 age- and gender-matched healthy subjects. RESULTS: Patients showed higher levels of phosphodiesters and lower levels of phosphomonoesters than the comparison group. Phosphocreatine levels were increased in the left temporal lobes of patients. CONCLUSIONS: The results suggest disturbed membrane phospholipid metabolism in both temporal lobes and decreased energy demands in the left temporal lobes of drug-naive schizophrenic patients.

Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats.

To clarify the involvement of D1 and D2 dopamine systems in intracranial self-stimulation (ICSS) and locomotor activity in rats, we studied the acute effects of cocaine and the interaction between cocaine and dopamine antagonists with respect to these behaviors. Although cocaine (5.0, 10.0, or 20.0 mg/kg) dose-dependently increased locomotor activity, it augmented the rate of ICSS only at 5.0 mg/kg. The failure of high doses of cocaine to augment purpose-oriented behavior such as ICSS may result from its induction of a manic-like state. The D1 dopamine receptor antagonist SCH23390 (0.02, 0.1, or 0.5 mg/kg) or the D2 antagonist nemonapride (0.04, 0.2, or 1.0 mg/kg) significantly decreased cocaine augmentation of ICSS. The higher two doses of either antagonist also produced a significant decrease in cocaine-induced locomotor activity. We therefore suspect that cocaine's augmentative effect on those behaviors, especially ICSS, requires activation of both D1 and D2 dopamine receptors.

P300 event-related potentials in probable dissociative generalized amnesia.

1. To investigate whether abnormalities in objective neurophysiologic measures are observable in patients with probable dissociative generalized amnesia, the P300 and N100 event-related potentials were evaluated in six such patients in both acute stage and after recovery from amnesia. Findings were compared with those in 12 age- and gender-matched healthy subjects. 2. While latencies did not differ from those of control subjects, P300 amplitudes in acute-stage recordings were lower than those in controls. Repeated recordings in the patients showed a significant increase in P300 amplitude after recovery from amnesia. 3. Amplitude and latency of N100 did not differ between the patient and control groups, nor changed significantly after retrieval of memory. 4. These findings suggest that some unknown biological and/or psychologic mechanisms that cause retrograde autobiographic amnesia may impair cognitive function as reflected in an objective neurophysiologic measure such as the P300.

Subtype-associated metabolite differences in the temporal lobe in schizophrenia detected by proton magnetic resonance spectroscopy.

Brain imaging studies have indicated that the medial temporal lobe functions aberrantly in schizophrenic patients. Both diagnostic subtype and gender may affect functional and morphologic abnormalities in this region. We investigated subtype- and gender-associated differences in metabolites in the left medial temporal lobe in 40 medicated schizophrenic patients by proton magnetic resonance spectroscopy and compared findings with those in 40 healthy control subjects. Peaks corresponding to N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine-phosphocreatine (Cr), and inositol were measured. Schizophrenic patients showed a decrease in the NAA/Cr ratio in the left medial temporal lobe, and patients with the disorganized subtype of illness showed significantly lower NAA/Cr and Cho/Cr ratios than those with paranoid schizophrenia. The NAA/Cr ratio in patients with the undifferentiated subtype also was significantly lower than in the paranoid subtype. No significant associations were observed between metabolite ratios and clinical symptom scores, age at onset of illness, or gender. These findings suggest that patients with the disorganized and undifferentiated subtypes have greater impairments in neuronal integrity or function in the left medial temporal lobe than patients with other subtypes of schizophrenia.

Metabolite changes with age measured by proton magnetic resonance spectroscopy in normal subjects.

To determine whether there are metabolite changes in the left medial temporal and frontal lobes with aging, we performed proton magnetic resonance spectroscopy in 36 normal subjects. The N-acetylaspartate/creatine-phosphocreatine ratio in the medial temporal lobe tended to be decreased in subjects over 60 years of age. The ratio decrease in the frontal lobe related to aging was lower than that in the medial temporal lobe. There were no significant differences in the metabolite ratios between males and females. These findings suggest that structures in the medial temporal lobe may be more susceptible to neuronal dysfunction associated with aging than those in the frontal lobe.

Hippocampal volume asymmetry and age at illness onset in males with schizophrenia.

To determine whether there are disturbances of hippocampal volume asymmetry in schizophrenic patients, we obtained contiguous, 1-mm-thick magnetic resonance images in 28 males with chronic schizophrenia and in 28 age-matched healthy males. The schizophrenic patients showed a bilateral reduction in volume of the hippocampal formation (HF; left 7.0%; right 8.7%). This reduction was significantly associated with the severity of disorganization syndrome (P < 0.0005). A significant asymmetry in the HF volume was found in the control subjects (P = 0.006), but not in the patients (P = 0.40). There was a significant positive correlation between the asymmetry index and the patient's age at the onset of schizophrenia (r = 0.46, P = 0.01). Results indicate that a disturbance in the normal asymmetry of the HF may be a characteristic in schizophrenia, particularly in patients with an early onset of the illness.

Reduction in hippocampal formation volume is caused mainly by its shortening in chronic schizophrenia: assessment by MRI.

We performed contiguous, 1 mm thick, magnetic resonance imaging scans in 18 men with chronic schizophrenia and in 18 age-matched healthy subjects to test in living patients the findings of a previous postmortem study. The schizophrenic patients showed bilaterally shortening (left, -6%; right, -9%) and volume reduction (left, -9%; right, -11%) of the hippocampal formation (HF). Volumes of HF correlated positively with HF length in the schizophrenic patients. The reduction in bilateral HF volumes was small after controlling for HF lengths (left, -3%; right, -3%). In schizophrenic patients, significant negative correlations were found bilaterally between the length of HFs and the scores for attention, bizarre behavior, and positive formal thought disorder. The results suggest that the volume reduction seen in the HFs of schizophrenic patients was caused mainly by a shortening of the HF and that these clinical symptoms may be associated with shorter HF length.

Cavum septum pellucidum in schizophrenia: a magnetic resonance imaging study.

In order to determine if cavum septum pellucidum (CSP) is more prevalent in schizophrenic patients, we studied 72 Japanese patients who fulfilled the DSM-III-R criteria for schizophrenia and 41 normal controls. Sagittal, 1 mm thick magnetic resonance imaging slices of the entire cranium were obtained using a gradient-echo pulse sequence, and coronal and axial images were reconstructed for assessment. A CSP was observed in 34 patients (47.2%) and in 16 controls (38.0%). Although the CSP appeared to be more prevalent in schizophrenic patients, this difference was not statistically significant. However, schizophrenic patients with a history of long-term institutionalization had a higher incidence of CSP compared with patients who had not been admitted to hospital for more than 3 years (68.2 vs 38.0%). These results suggest that the CSP may be a pathophysiology that characterizes schizophrenic patients with poor prognoses.

Phosphorus magnetic resonance spectroscopy in schizophrenia: correlation between membrane phospholipid metabolism in the temporal lobe and positive symptoms.

1. To determine any correlations between phosphorus metabolites in the temporal lobes and clinical symptoms in schizophrenic patients, the authors performed 31phosphorus magnetic resonance spectroscopy in 31 medicated patients and age- and sex- matched normal subjects. 2. Schizophrenic patients demonstrated an increased level of phosphodiesters (PDE) in the temporal lobes bilaterally and a decreased level of beta-adenosine triphosphate (beta-ATP) in the left temporal lobe. 3. A significant positive correlation was observed between the level of PDE in the left temporal lobe and the score of positive symptoms on the Brief Psychiatric Rating Scale. 4. These results suggest that altered membrane phospholipid metabolism in the left temporal lobe is associated with neuroleptic-resistant positive symptoms in schizophrenic patients.

Argyria and convulsive seizures caused by ingestion of silver in a patient with schizophrenia.

The case study of a schizophrenic patient with argyria which resulted from the chronic and excessive ingestion of antismoking pills contain silver, is presented. Convulsive seizures developed after the patient had been addicted to the pills for 40 years. An extremely high concentration of silver was detected in serum. This case provides support for the hypothesis that silver may cause convulsive seizures as a result of systemic poisoning.

EEG analysis of epilepsy by directed coherence method. A data processing approach.

Directed coherence (DCOH) was proposed in our previous work as a measure of the correlation between the EEGs of different sites of human brain. In the present research, we applied this method to the interpretation of intrahemispheric information flow in the EEGs of thirteen epileptic patients. This paper discusses the bidirectional communication pattern with DCOH between the frontal and the occipital cortex in the EEGs of epileptics. Comparing with the high values in the alpha-band for the controls, significantly (P < 0.001) small DCOH values were found in the thirteen epileptic patients. The DCOH values of epileptic patients were scattered over the beta-, theta- and delta-bands. This may suggest that the dysfunction of the epileptic brain may be due to an abnormality of the neural networks in the brain.

Proton magnetic resonance spectroscopy of the left medial temporal and frontal lobes in chronic schizophrenia: preliminary report.

Proton magnetic resonance spectroscopy (MRS) was performed in 30 medicated schizophrenic patients and 30 normal subjects. Two groups, each containing 15 schizophrenic patients and 15 age-and sex-matched normal subjects, received MRS examinations for different volumes of interest, either the frontal lobe or the medial temporal lobe. Schizophrenic patients showed a decrease in the ratios of N-acetylaspartate (NAA)/choline-containing compounds (Cho) and NAA/creatine-phosphocreatine (Cr). The patients also showed an increase in the ratio of Cho/Cr in the left medial temporal lobe but not in the left frontal lobe. The age at onset of illness correlated positively with the ratios of NAA/Cho and NAA/Cr in the medial temporal lobe. No significant correlation was observed between the ratios of NAA/Cho, NAA/Cr, or Cho/Cr in the left medial temporal and frontal lobes and clinical symptomatology as assessed by the Scale for the Assessment of Negative Symptoms and the Positive and Negative Syndrome Scale.