Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia.

AIM: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). METHODS: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. RESULTS: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. CONCLUSION: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.

Comparison between a real sequential finger and imagery movements: an FMRI study revisited.

Recently, much discussion has been centered on the brain networks of recall, memory, and execution. This study utilized functional magnetic resonance imaging to compare activation between a simple sequential finger movement (real task) and recalling the same task (imagery task) in 15 right-handed normal subjects. The results demonstrated a greater activation in the contralateral motor and somatosensory cortex during the real task, and a higher activation in the contralateral inferior frontal cortex, ipsilateral motor, somatosensory cortex, and midbrain during the imagery task. These real task-specific areas and imagery-specific areas, including the ipsilateral motor and somatosensory cortex, are consistent with recent studies. However, this is the first report to demonstrate that the imagery-specific regions involve the ipsilateral inferior frontal cortex and midbrain. Directly comparing the activation between real and imagery tasks demonstrated the inferior frontal cortex and midbrain to therefore play important roles in cognitive feedback.

Exploratory eye movement dysfunction as a discriminator for schizophrenia : a large sample study using a newly developed digital computerized system.

In our previous studies, we identified that exploratory eye movement (EEM) dysfunction appears to be specific to schizophrenia. The availability of a biological marker specific to schizophrenia would be useful for clinical diagnosis of schizophrenia. Consequently, we performed the discriminant analysis between schizophrenics and non-schizophrenics on a large sample using the EEM test data and examined an application of the EEM for clinical diagnosis of schizophrenia. EEM performances were recorded in 251 schizophrenics and 389 non-schizophrenics (111 patients with mood disorders, 28 patients with neurotic disorders and 250 normal controls). The patients were recruited from eight university hospitals and three affiliated hospitals. For this study with a large sample, we developed a new digital computerized version of the EEM test, which automatically handled large amounts of data. We measured four parameters: number of eye fixations (NEF), total eye scanning length (TESL), mean eye scanning length (MESL) and responsive search score (RSS). These parameters of schizophrenics differed significantly from those of the other three groups. The stepwise regression analysis selected the TESL and the RSS as the valid parameters for discriminating between schizophrenics and non-schizophrenics. In the discriminant analysis using the RSS and TESL as prediction parameters, 184 of the 251 clinically diagnosed schizophrenics were discriminated as having schizophrenia (sensitivity 73.3%); and 308 of the 389 clinically diagnosed non-schizophrenic subjects were discriminated as non-schizophrenics (specificity 79.2%). Based on our findings we believe that the EEM measures may be useful for the clinical diagnosis of schizophrenia.

Characteristics of left and right scanning in schizophrenia patients using exploratory eye movements: comparison with healthy subjects.

To characterize the left and right scanning function and the effect of affection in schizophrenia patients exploratory eye movements as biologic markers were recorded in 44 schizophrenia patients and 72 age-matched healthy controls. The total eye scanning length (TESL) and total number of gaze points (TNGP) in the left and right visual fields were calculated as subjects viewed neutral or affectively charged pictures. TESL of patients was shorter than that of controls when viewing pictures of smiling babies and open circles. TESL of patients was shorter for smiling faces than for crying babies, but TESL of controls was longer for smiling faces than for crying babies. Left TNGP for smiling faces and circles was lower in patients than in controls. In patients, left TNGP for crying babies was higher than for either smiling babies or circles. In controls, left TNGP for smiling babies was higher than crying babies. In patients, left TNGP for smiling babies and circles was smaller than the right TNGP. In controls, left TNGP was larger for smiling than for crying babies. When viewing smiling babies, both TESL and TNGP were negatively correlated with negative symptom scores in patients. Patients' eye movements in the left visual field were clearly different from controls', suggesting that visual cognitive function is impaired in schizophrenia patients. Exploratory eye movements are a useful marker of visual cognitive function, and are a useful tool to evaluate the influence of affection in schizophrenia patients.

Sleep findings in young adult patients with posttraumatic stress disorder.

BACKGROUND: Laboratory sleep studies in posttraumatic stress disorder (PTSD) have not provided consistent evidence of sleep disturbance, despite apparent sleep complaints. Most of these studies have investigated middle-aged chronic PTSD subjects with a high prevalence of comorbidities such as substance dependence and/or personality disorder. METHODS: Ten young adult PTSD patients (aged 23.4 +/- 6.1 years) without comorbidities of substance dependence and/or personality disorder underwent 2-night polysomnographic recordings. These sleep measures were compared with those of normal control subjects and were correlated with PTSD symptoms. RESULTS: Posttraumatic stress disorder patients demonstrated significantly poorer sleep, reduced sleep efficiency caused by increased wake time after sleep onset, and increased awakening from rapid eye movement (REM) sleep (REM interruption). We found significant positive correlations between the severity of trauma-related nightmare complaints and the percentage of REM interruption, as well as wake time after sleep onset. CONCLUSIONS: The results indicate that trauma-related nightmares are an important factor resulting in increased REM interruptions and wake time after sleep onset in PTSD.

The dopamine D1 receptor agonist, but not the D2 receptor agonist, induces gene expression of Homer 1a in rat striatum and nucleus accumbens.

Stimulation of dopamine receptors may induce striatal Homer 1a, an immediate-early gene (IEG) that is involved in the molecular mechanism for the signaling pathway of the group I metabotropic glutamate receptors. This study examined the effects of the agonists for dopamine D(1)-like and D(2)-like receptors on gene expression of Homer 1a, in comparison with the IEG c-fos expression, in the discrete brain regions of rats. The D(1)-like agonist SKF38393 (20 mg/kg, s.c.) significantly increased the mRNA levels of Homer 1a in the striatum and nucleus accumbens, but not in the medial prefrontal cortex or hippocampus, 2 h after injection, whereas the D(2)-like agonist quinpirole (1 mg/kg, s.c.) had no significant effect on Homer 1a mRNA levels in any brain region examined. Co-administration of SKF38393 and quinpirole significantly increased Homer 1a mRNA levels in the striatum, nucleus accumbens and hippocampus, while this effect was not significantly greater than that of SKF38393 alone. Any treatment did not affect the mRNA levels of other splicing variants, Homer 1b or 1c. In contrast, combination of both dopamine agonists produced a greater increase than SKF38393 did in the mRNA levels of c-fos in the nucleus accumbens, striatum and substantia nigra. These results suggest that stimulation of D(1)-like receptors, but not D(2)-like receptors, may induce gene expression of Homer 1a in the striatum and nucleus accumbens. However, in contrast to c-fos expression, it is unlikely that co-activation of both D(1)-like and D(2)-like receptors exerts a synergic action on Homer 1a expression in these regions.

Effect of zolpidem on sleep architecture and its next-morning residual effect in insomniac patients: a randomized crossover comparative study with brotizolam.

This study was conducted to determine the effect of zolpidem (ZOL) 10 mg orally on the sleep architecture and the next-morning residual effect in patients with non-organic insomnia (ICD-10) as compared to the effect of brotizolam (BTM) 0.25 mg orally, a widely used short-acting benzodiazepine (BZD) hypnotic in Japan, in a randomized, crossover comparative study. Fourteen patients with non-organic insomnia (3 males and 11 females; mean age of 54.9+/-S.D. 8.9 years). First three nights with placebo, middle three nights with either ZOL 10 mg or BTM 0.25 mg, and last three nights again with placebo in each session (a total of two sessions). Primary endpoints were polysomnography findings of sleep stages, sleep parameters, and sleep latency (SL) in the morning to examine calculable sleepiness as a residual effect. Secondary endpoint was sleep quality assessed by self-assessment questionnaire. At 150 min after Tmax, both ZOL and BTM significantly increased stage 2 (S2), and ZOL showed significantly longer slow wave sleep (SWS; stage 3+4) as compared to BTM. Stage wake was significantly increased by ZOL at the first withdrawal night and by BTM at the second withdrawal night. ZOL did not affect SL after rising, whereas BTM showed significantly shorter SL. Both drugs reduced the number of nocturnal awakenings and improved subjective sleep quality. The common adverse drug reaction (ADR) was sleepiness (3 patients) in each treatment. All events were mild. No serious adverse events occurred. ZOL is as effective as BTM in improving subjective sleep quality in patients with psychophysiological insomnia (PPI). ZOL has advantages over BTM in having a unique profile of increasing SWS with less next-morning residual effect.

Regulation of spinophilin Ser94 phosphorylation in neostriatal neurons involves both DARPP-32-dependent and independent pathways.

Spinophilin is a protein phosphatase-1 (PP-1)- and actin-binding protein that is enriched in dendritic spines. Phosphorylation of the actin-binding domain of rat spinophilin at one or more sites by protein kinase A (PKA) inhibits actin binding. Here, we investigated the regulation of mouse spinophilin that contains only a single PKA-site (Ser94) within its actin-binding domain. In vitro phosphorylation of Ser94 resulted in the dissociation of spinophilin from actin filaments. In mouse neostriatal slices, phospho-Ser94 (p-Ser94) was dephosphorylated mainly by PP-1 and also by PP-2A. Activation of dopamine D1 receptors in striatonigral medium spiny neurons, and of adenosine A 2A receptors in striatopallidal medium spiny neurons increased, whereas activation of dopamine D2 receptors in striatopallidal neurons decreased, spinophilin Ser94 phosphorylation. In neostriatal slices from DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) knockout mice, the effects of D1, D2 and A 2A receptors were largely attenuated. Activation of NMDA receptors decreased Ser94 phosphorylation in a PP-2A-dependent, but DARPP-32-independent, manner. These results suggest that PKA-dependent phosphorylation of spinophilin at Ser94 in both striatonigral and striatopallidal neurons requires synergistic contributions from the PKA and DARPP-32/PP-1 pathways. In addition, PP-2A plays a role in Ser94 dephosphorylation in response to activation of both D2 and NMDA receptors.

An open study of risperidone liquid in the acute phase of schizophrenia.

An open-label study was performed to investigate the clinical efficacy and mechanisms of risperidone liquid in ameliorating positive symptoms in the acute phase of schizophrenia. Eighty-eight patients (M/F: 50/38; age: 18-74 years;, mean +/- SD =32 +/- 16 years) meeting DSM-IV criteria for schizophrenia and treated with risperidone liquid (14 patients also used lorazepam) were evaluated with regard to their clinical improvement and extrapyramidal side effects using the positive and negative syndrome scale (PANSS) and the Simpson and Angus scale (SAS), while plasma concentrations of HVA and MHPG were analysed by HPLC-ECD before and 4 weeks after risperidone liquid administration. Patients showing a 50% or greater improvement in PANSS scores were defined as responders. An improvement in the PANSS scores related to excitement, hostility and poor impulse control was seen within 7 days after administration of risperidone liquid, and an improvement with regard to hallucinatory behaviour and uncooperativeness was seen within 14 days after its administration. Finally, 68% of patients were classified as responders 4 weeks after risperidone liquid administration. The scores of SAS were not changed after risperidone liquid administration. Pretreatment plasma homovanillic acid (HVA) levels in the responders (8.1 +/- 2.9 ng/ml) were higher than those in nonresponders (5.9 +/- 1.9 ng/ml). In addition, a negative correlation was seen between the changes in plasma HVA levels and the percentage of improvement in PANSS scores. On the other hand, there were no differences between pretreatment plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and those of nonresponders. These results suggest that risperidone liquid is effective and well tolerated for the treatment of acute phase schizophrenic patients, and that efficacy is related to its affects on dopaminergic activity, not noradrenergic activity.

Recognition of facial expression and visual P300 in schizophrenic patients: differences between paranoid type patients and non-paranoid patients.

This study compared the effects of facial affective stimuli on visual event-related potentials (ERP) in schizophrenic patients and healthy subjects using photographs of babies depicting sadness (crying face), neutrality (neutral face), and pleasure (smiling face). Visual ERP were recorded using an oddball paradigm in 32 schizophrenic patients (16 paranoid type and 16 non-paranoid patients) and 32 age-matched healthy subjects. The P300 amplitude, latency, and the subject's reaction time were recorded. The P300 amplitude when viewing a photograph of a smiling baby was the smallest registered of three photographs for healthy subjects and paranoid type patients with successively greater amplitudes for neutrality and sadness. However, the P300 amplitude was the smallest while viewing crying photographs and was the largest while viewing a smiling photograph for non-paranoid patients. These results suggest that the P300 amplitude is influenced by viewing emotionally moving facial expressions and that the effect is different for different subtypes of schizophrenia. These differences may reflect differences in information processing resulted from emotional influences caused by visual-affective stimuli.

Gender difference in QTc prolongation of people with mental disorders.

BACKGROUND: We examined gender difference in QTc interval distribution and its related factors in people with mental disorders. METHODS: We retrospectively reviewed medical charts of patients discharged from a university psychiatric unit between November 1997 and December 2000. Subjects were 328 patients (145 males and 183 females) taking psychotropics at their admission. We examined patient characteristics, medical history, diagnosis, and medication before admission. RESULTS: Mean QTc interval was 0.408 (SD = 0.036). QTc intervals in females were significantly longer than those in males. QTc of females without comorbidity was significantly longer than that of males. CONCLUSION: The influence of gender difference on QTc prolongation in people with mental disorders merits further research.

The nucleus accumbens unit activities related to the emotional significance of complex environmental stimuli in freely moving cats.

To establish the functional role of the nucleus accumbens (ACC) in emotionally motivated behaviors, extracellular single or multiple units were recorded from the ACC under an unanesthetized, freely moving non-operant condition in 43 cats. Then neuronal and behavioral responses to stimuli such as tones, live small animals, a human, air puffs and so on were analyzed using a videotape monitoring method. A total of 98 units were recorded from the ACC, and 34 (34.7%) of them responded to some of the stimuli. Of the 34 responded units, 5 (15%) units responded to quiet approach-provoking stimuli (appetitive stimuli), and 29 (85%) units responded to escape- or defensive attack-provoking stimuli (aversive stimuli). Although most of the units responded in an individual item-specific manner, there was no unit reacted to both the appetitive and aversive stimuli. The neuronal responses were not related to any movement or locomotion. The results were compared with those with the amygdala, and their neuronal responsiveness were shown to be quite different from each other. Although the ACC appears to be involved in the central processing of emotional behavior in some way, the role was suggested to be entirely different from that of the amygdala.

Improvement of exploratory eye movements in schizophrenic patients during recovery period.

In the present paper exploratory eye movements were examined as biologic markers in both acute schizophrenic patients (acute patients discharged after approximately 3 months and treated as outpatients, n = 8; acute patients who were still in hospital after 6 months, n = 8) and chronic schizophrenic patients (hospital stay >5 years, n = 15) in comparison with age-matched healthy subjects (n = 30). Using an eye-mark recorder, exploratory eye movements were analyzed for mean gazing time (MGT), and total eye scanning length (TESL) as subjects viewed six simple pictures in preparation for copying them. In acute schizophrenic patients discharged after 6 months (DP), MGT became significantly shorter and TESL became longer after 3 or 6 months treatment. In acute schizophrenic patients during admission after 6 months, TESL became longer after 3 or 6 months of treatment. However, no significant changes were observed in chronic patients in these measures. In schizophrenic patients, negative symptom scores were positively correlated with MGT (r = 0.43; P < 0.001), and negatively correlated with TESL (r = -45; P < 0.001). These findings suggest that exploratory eye movements are a biologic state and trait marker useful for evaluation of schizophrenia.

Effects of aroma on sleep and biological rhythms.

The polysomnogram (PSG), blood melatonin concentration, rectal temperature, and answers to a self-evaluation questionnaire about the effects of agarwood (jinkoh in Japanese), which has been reported to have sleep-promoting effects were examined. The subjects tested were male medical students, who were free of otorhinolaryngological diseases and were non-smokers. The results of sleep stage and other sleep variables, and those of rectal temperature rhythm and blood melatonin concentrations showed no significant differences between the baseline nights, experimental nights, and recovery nights.

Neurotensin regulates DARPP-32 thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors.

Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cAMP-dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP 1). Here, we examined the effect of neurotensin on DARPP-32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP-32 Thr34 phosphorylation by 4-7-fold with a K(0.5) of approximately 50 nM. The effect of neurotensin was antagonized by a combined neurotensin receptor type-1 (NTR1)/type-2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor- and AMPA receptor-dependent manner, leading to the increase in DARPP-32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild-type mice but not in DARPP-32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1-receptor/cAMP/PKA/DARPP-32/PP 1 cascade.