Auditory Cortex Volume and Gamma Oscillation Abnormalities in Schizophrenia.

We investigated whether the gray matter volume of primary auditory cortex (Heschl's gyrus [HG]) was associated with abnormal patterns of auditory γ activity in schizophrenia, namely impaired γ synchronization in the 40-Hz auditory steady-state response (ASSR) and increased spontaneous broadband γ power. (The γ data were previously reported in Hirano et al, JAMA Psychiatry, 2015;72:813-821). Participants were 24 healthy controls (HC) and 23 individuals with chronic schizophrenia (SZ). The ASSR was obtained from the electroencephalogram to click train stimulation at 20, 30, and 40 Hz rates. Dipole source localization of the ASSR was used to provide a spatial filter of auditory cortex activity, from which ASSR evoked power and phase locking factor (PLF), and induced γ power were computed. HG gray matter volume was derived from structural magnetic resonance imaging at 3 T with manually traced regions of interest. As expected, HG gray matter volume was reduced in SZ compared with HC. In SZ, left hemisphere ASSR PLF and induced γ power during the 40-Hz stimulation condition were positively and negatively correlated with left HG gray matter volume, respectively. These results provide evidence that cortical gray matter structure, possibly resulting from reduced synaptic connectivity at the microcircuit level, is related to impaired γ synchronization and increased spontaneous γ activity in schizophrenia.

Cannabis use correlates with aggressive behavior and long-acting injectable antipsychotic treatment in Asian patients with schizophrenia.

Background: Although cannabis use has been linked with schizophrenia in a dose-response pattern, to our knowledge, the relationship between cannabis and schizophrenia has rarely been reported in Asian population. Aim: We compared the clinical characteristics and psychotropic prescription patterns between cannabis users and non-users among Asian patients with schizophrenia. Moreover, we aimed to identify the independent correlates of cannabis use in these subjects. Methods: We performed the analysis of the data from the Research on Asian Psychotropic Prescription Patterns for Antipsychotics (REAP-AP), a collaborative consortium survey used to collate the prescription patterns for antipsychotic and other psychotropic medications in patients with schizophrenia in Asia. We included 132 schizophrenia patients in the group of lifetime cannabis use and 1756 in the group that had never used cannabis. A binary logistic model was fitted to detect the clinical correlates of lifetime cannabis use. Results: Adjusting for the effects of age, sex, geographical region, income group, duration of untreated psychosis, and Charlson comordity index level, a binary logistic regression model revealed that lifetime cannabis use was independently associated with aggressive behavior [adjusted odds ratio (aOR) = 1.582, 95% confidence interval (CI) = 1.006-2.490, p = .047] and with long-acting injectable antipsychotic treatment (aOR = 1.796, 95% CI = 1.444-2.820, p = .001). Conclusion: Our findings indicate a close link between lifetime cannabis use and aggressive behavior. The use of long-acting, injectable antipsychotics preferentially treats the aggressive behavior cannabis users among patients with schizophrenia in Asia, especially, the South or Southeast Asia.

Phase-Amplitude Coupling of the Electroencephalogram in the Auditory Cortex in Schizophrenia.

BACKGROUND: Cross-frequency interactions may coordinate neural circuits operating at different frequencies. While neural oscillations associated with particular circuits in schizophrenia (SZ) are impaired, few studies have examined cross-frequency interactions. Here we examined phase-amplitude coupling (PAC) in the electroencephalograms of individuals with SZ and healthy control subjects (HCs). We computed PAC during the baseline period of 40-Hz auditory steady-state stimulation and rest. We hypothesized that subjects with SZ would show abnormal theta/gamma coupling during stimulation, especially in the left auditory cortex, and coupling with high frequencies would be higher during stimulation than during rest. METHODS: We reanalyzed data from 18 subjects with SZ and 18 HCs. Auditory cortex electroencephalogram activity was estimated using dipole source localization. PAC was computed using the debiased PAC measure, calculated with the generalized Morse wavelet transform. PAC clusters were identified using cluster-corrected permutation testing and interrogated in analyses of variance with correction for multiple tests. RESULTS: Overall, coupling of high beta and gamma amplitude was higher during the auditory steady-state response, while alpha/beta PAC was higher during rest. Theta/alpha PAC was higher in subjects with SZ than in HCs. Theta/gamma PAC was lateralized to the left hemisphere in HCs but was not lateralized in subjects with SZ. CONCLUSIONS: PAC involving high frequencies was state dependent and not abnormal in SZ. Increased theta/alpha PAC in subjects with SZ was consistent with other evidence of increased low-frequency activity. Hemispheric lateralization of theta/gamma PAC was reduced in subjects with SZ, consistent with evidence for left hemisphere auditory cortex abnormalities in subjects with SZ. PAC may reveal new insights into neural circuitry abnormalities in SZ and other neuropsychiatric disorders.

Increased BOLD Signals Elicited by High Gamma Auditory Stimulation of the Left Auditory Cortex in Acute State Schizophrenia.

Recent MRI studies have shown that schizophrenia is characterized by reductions in brain gray matter, which progress in the acute state of the disease. Cortical circuitry abnormalities in gamma oscillations, such as deficits in the auditory steady state response (ASSR) to gamma frequency (>30-Hz) stimulation, have also been reported in schizophrenia patients. In the current study, we investigated neural responses during click stimulation by BOLD signals. We acquired BOLD responses elicited by click trains of 20, 30, 40 and 80-Hz frequencies from 15 patients with acute episode schizophrenia (AESZ), 14 symptom-severity-matched patients with non-acute episode schizophrenia (NASZ), and 24 healthy controls (HC), assessed via a standard general linear-model-based analysis. The AESZ group showed significantly increased ASSR-BOLD signals to 80-Hz stimuli in the left auditory cortex compared with the HC and NASZ groups. In addition, enhanced 80-Hz ASSR-BOLD signals were associated with more severe auditory hallucination experiences in AESZ participants. The present results indicate that neural over activation occurs during 80-Hz auditory stimulation of the left auditory cortex in individuals with acute state schizophrenia. Given the possible association between abnormal gamma activity and increased glutamate levels, our data may reflect glutamate toxicity in the auditory cortex in the acute state of schizophrenia, which might lead to progressive changes in the left transverse temporal gyrus.

Spontaneous Gamma Activity in Schizophrenia.

IMPORTANCE: A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. OBJECTIVE: To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. MAIN OUTCOMES AND MEASURES: Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. RESULTS: The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30-100 Hz) gamma power was increased in patients with SZ compared with controls during steady-state stimulation (6.579 [3.783] vs 3.984 [1.843]; F1,46 = 9.128 [P = .004]; d = 0.87) but not during rest (0.006 [0.003] vs 0.005 [0.002]; F1,34 = 1.067 [P = .309]; d = 0.35). Induced gamma power in the left hemisphere of the patients with SZ during the 40-Hz stimulation was positively correlated with auditory hallucination symptoms (tangential, ρ = 0.587 [P = .031]; radial, ρ = 0.593 [P = .024]) and negatively correlated with the ASSR phase-locking factor (baseline: ρ = -0.572 [P = .024]; ASSR: ρ = -0.568 [P = .032]). CONCLUSIONS AND RELEVANCE: Spontaneous gamma activity is increased during auditory steady-state stimulation in SZ, reflecting a disruption in the normal balance of excitation and inhibition. This phenomenon interacts with evoked oscillations, possibly contributing to the gamma ASSR deficit found in SZ. The similarity of increased spontaneous gamma power in SZ to the findings of increased spontaneous gamma power in animal models of NMDAR hypofunction suggests that spontaneous gamma power could serve as a biomarker for the integrity of NMDARs on parvalbumin-expressing inhibitory interneurons in humans and in animal models of neuropsychiatric disorders.

Anti-allergic mechanisms of Japanese herbal medicine, yokukansan on mast cells.

We previously reported that the addition of orally administered yokukansan (YKS), a traditional Japanese herbal medicine, to the standard regimen using histamine H1-receptor inhibitors was effective in controlling refractory chronic urticaria, but the mechanism remained unknown. YKS has also been reported to be effective on inhibiting the development of atopic dermatitis-like skin lesions in NC/Nga mice. As known, the release of various chemical mediators including histamine from degranulated mast cells is strongly related to the mechanism of these diseases. Thus the purpose of this study was to examine the mechanisms behind the medicinal effects of YKS on mast cells using an in vitro system and rat basophil leukemia (RBL-2H3) cells. The degree of degranulation was measured by ß-hexosaminidase secretion assay and intracellular calcium influx assay. ELISA for cytokines (TNF-α and IL-4) was also conducted using cell culture media. Furthermore, we investigated the effects of YKS on the expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and cytokine production (IL-8) in human dermal microvascular endothelial cells using gene-transcriptional- and immunohisotoligical analysis. We found that YKS inhibited secretion of ß-hexosaminidase, intracellular calcium increase, production of TNF-α and ICAM-1 expression, and that several YKS ingredients may be the key effectors. In conclusion, YKS may suppress several mast cell functions such as degranulation and calcium increase that eventually inhibits the release of proinflammatory cytokines. Furthermore, YKS suppresses ICAM-1 expression on human microvascular endothelial cells. These findings may promote our understanding of the beneficial effects of YKS on mast cell-associated allergic diseases.

Preattentive dysfunction in patients with bipolar disorder as revealed by the pitch-mismatch negativity: a magnetoencephalography (MEG) study.

OBJECTIVES: Mismatch negativity (MMN) and its magnetic counterpart (MMNm) are thought to reflect an automatic process that detects a difference between an incoming stimulus and the sensory memory trace of preceding stimuli. In patients with schizophrenia, an attenuation of the MMN/MMNm amplitude has been repeatedly reported. Heschl's gyrus (HG) is one of the major generators of MMN and the functional alteration of HG has been reported in patients with bipolar disorder. The present study investigated the pitch-MMNm in patients with bipolar disorder using whole-head 306-ch magnetoencephalography (MEG). METHODS: Twenty-two patients and 22 healthy controls participated in this study. Subjects were presented with two types of auditory stimulus sequences. One consisted of 1,000 Hz standards (probability = 90%) and 1,200 Hz deviants (probability = 10%), and the other consisted of 1,000 Hz standards (90%) and 1,200 Hz deviants (10%). These two tasks were each performed twice. Event-related brain responses to standard tones were subtracted from responses to deviant tones. RESULTS: Patients with bipolar disorder showed a significant bilateral reduction in magnetic global field power (mGFP) amplitudes (p = 0.02) and dipole moments of the MMNm (p = 0.04) compared with healthy controls. Patients with admission experience showed significantly reduced mGFP amplitudes of MMNm compared with patients without admission experience (p = 0.004). Additionally, patients with more severe manic symptoms had smaller mGFP amplitudes of MMNm (ρ = -0.50, p = 0.05). CONCLUSIONS: The results of this study suggest that patients with bipolar disorder may exhibit preattentive auditory dysfunction indexed by reduced pitch-MMNm responses. Pitch-MMNm could be a potential trait marker reflecting the global severity of bipolar disorder.

Reduced high and low frequency gamma synchronization in patients with chronic schizophrenia.

Schizophrenia has been conceptualized by dysfunctional cognition and behavior related to abnormalities in neural circuitry. The functioning of the neural circuitry can be assessed using the auditory steady state response (ASSR). Moreover, in recent years, research on high (>60 Hz) gamma band oscillations has become of increasing interest. The current study used whole-head, 306-channel magnetoencephalography (MEG) and investigated low and high gamma band oscillations with the ASSR. The subjects comprised 17 patients with schizophrenia and 22 controls. The current study investigated the MEG-ASSR elicited by click trains of 20-, 30-, 40- and 80-Hz frequencies, and symptom-ASSR associations in patients with schizophrenia. The mean power, phase-locking factor, dipole moments and source locations of the ASSR were estimated. The main findings were: (1) patients with schizophrenia showed bilaterally reduced ASSR power and dipole moments specific to the 40-Hz and 80-Hz frequencies; (2) patients with schizophrenia showed less right-greater-than-left 40-Hz ASSR power and phase-locking factor compared with healthy subjects, indicating that schizophrenics may be characterized by an abnormal asymmetry of the 40-Hz ASSR; (3) increased severity of global hallucinatory experiences was significantly associated with smaller left 80-Hz MEG-ASSR in patients with schizophrenia. The current study highlights the high and low frequency gamma abnormalities and provides clear evidence that schizophrenia is characterized by abnormalities in neural circuitry.

Development of 2-hour suicide intervention program among medical residents: first pilot trial.

AIM: Suicide is associated not only with primary psychiatric disorders but also with physical disorders. Physicians' education on suicide prevention contributes to reducing suicide. Therefore, medical residents, who contact patients daily and who eventually become primary physicians in each specialty, might be the most appropriate candidates for intervention. In this article, we introduce our newly developed suicide intervention program among medical residents. METHODS: We developed a 2-hour suicide intervention program among medical residents, based on the Mental Health First Aid (MHFA), which had originally been developed for the public. The program contains a 1-hour lecture and a 1-hour role-play session. As the first pilot trial, we conducted the program among 44 first-year medical residents at a university hospital and evaluated its effectiveness. Changes in confidence, attitudes and behavior toward suicidal people were evaluated using self-reported questionnaires before, immediately after, and 6 months after the program. RESULTS: Participants' confidence and attitudes significantly improved after the program. The total mean score (standard deviation) of the Suicide Intervention Response Inventory improved from 18.4 (2.0) before the intervention to 19.4 (2.0) immediately after the intervention. However, the effectiveness was limited after 6 months. In the course of 6 months, the participants learned to apply the MHFA principles in their daily clinical practice. CONCLUSION: Our newly developed brief suicide intervention program demonstrating its effectiveness among medical residents should be modified in order to be more effective in the long term. The next trial with a control group ought to be conducted to evaluate our developed program.

Preattentive visual change detection as reflected by the mismatch negativity (MMN)--evidence for a memory-based process.

The aim of this study was to test the hypothesis that visual mismatch negativity (vMMN) is based on memory trace formation. Special care was taken to distinguish between memory mismatch and rareness effect. Subjects were seated in front of a monitor and asked to listen to a story. The standard sequence block consisted of nine consecutive 24-vane windmill patterns with an 800-ms inter-stimulus interval. The deviant sequence block consisted of one 24-vane pattern with eight six-vane patterns. Inter-train intervals (ITIs) varied among 1, 6, and 12s in the changing ITI experiment, while the deviant stimulus occupied the eighth position in the sequence. In the changing order experiment, the position of the deviant stimulus was varied among the second, fourth and eighth position with a 12-s constant ITI. vMMN was ascertained from the difference in responses to standard and deviant stimulus. vMMN appeared in the occipital region 150-300 ms after stimulus onset. It was significantly modulated by the ITI, and more than four preceding stimuli were needed to reinstate the implicit memory trace. These results suggest that memory-based change detection underlies vMMN. Therefore, vMMN is useful to study visual sensory memory function.

Effect of yokukansan on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer's disease.

OBJECTIVE: The aim of this study was to investigate the effects of yokukansan (YKS) on the behavioral and psychological symptoms of dementia (BPSD) in elderly patients with Alzheimer's disease (AD). METHODS: Fifteen patients with AD (mean age: 80.2+/-4.0 years) participated in the study. The Mini-Mental State Examination (MMSE) was used for the assessment of cognitive function. BPSD were evaluated using the Neuropsychiatric Inventory (NPI). The Barthel Index was used for the assessment for the activities of daily living (ADL). The treatment with YKS along with sulpiride, a dopamine D(2) selective antipsychotic, was performed for 12 weeks. RESULTS: Fourteen patients completed the trial. After the 12 weeks of treatment with YKS, significant improvement of the mean NPI score was observed while no significant improvement was observed in the control group. The average dose of sulpiride at the end of the present study was less in the YKS group than in the control group. The MMSE results did not change either in the YKS group or in the control group. The Barthel Index did not significantly change either in the YKS group or in the control group. No serious adverse effects were noted. CONCLUSIONS: Twelve weeks of the YKS treatment significantly improved BPSD with less antipsychotics in elderly patients with AD. The YKS treatment did not cause any cognitive decline or ADL decline and no serious adverse effects were noted. The present study suggests that YKS is beneficial for the treatment of BPSD and that it can possibly reduce the doses of antipsychotics required for the treatment of BPSD. Further studies with larger patient populations using a double-blind placebo-controlled design should be performed.

Effectiveness of kamishoyosan for premenstrual dysphoric disorder: open-labeled pilot study.

The purpose of the present paper was to investigate the efficacy of kamishoyosan (TJ-24), a traditional Japanese herbal formula (kampo), for outpatients with premenstrual dysphoric disorder (PMDD) as an alternative treatment. Thirty patients with PMDD were treated with TJ-24 for six menstrual cycles. Nineteen patients (63.3%) had >50% improvement in the total score of the Hamilton Depression Rating Scale (HAM-D) Scale (17 items) in the late luteal phase. Fourteen patients (46.7%) went into remission (total HAM-D score <7). In the present study many patients with PMDD were successfully treated with TJ-24.

Effectiveness of herbal medicine (Rokumigan and Hachimijiogan) for fatigue or loss of energy in patients with partial remitted major depressive disorder.

Some patients with major depressive disorder (MDD) do not show remission of their depressive symptomatology. We investigated the efficacy of Rokumigan (TJ-87) and Hachimijiogan (TJ-7) in 20 patients with prolonged partial remitted MDD associated with fatigue or loss of energy. In these 20 patients, TJ-7 or TJ-87 was added to the previous regimen for 4 weeks. Six patients were 'much improved', six were 'minimally improved' (responders), and eight showed 'no change' (non-responders), on the Clinical Global Impression Global Improvement scale. All responders had Shofuku-fujin (tenderness or weakness of the lower abdomen). In conclusion, we experienced 12 outpatients with prolonged partial remitted MDD with fatigue or loss of energy, which was successfully treated with TJ-87 or TJ-7.

Ginseng enhances contextual fear conditioning and neurogenesis in rats.

Panax Ginseng is a commonly used galenical known to have an enhancing effect on learning. Neurogenesis in the hippocampus has been shown to be necessary for hippocampus/amygdala-dependent learning tasks. To investigate the role of Ginseng in neurogenesis and learning of rats, we administered both Ginseng and BrdU for five consecutive days. As a result, Ginseng increased the number of BrdU-positive cells in the dentate gyrus in a dose-dependent manner. Further, we administered one dose of BrdU after Ginseng treatment for five consecutive days, and the number of BrdU-positive cells did not increase significantly. However, when one dose of BrdU was given 1 day before the following five consecutive days of Ginseng treatment, the number of BrdU-positive cells markedly increased in the hippocampus. Therefore, it is likely that Ginseng enhances not proliferation but survival of newly generated neurons in the hippocampus. Second, we administered both Ginseng and BrdU to rats for five consecutive days. One day after the last Ginseng and BrdU co-administration, contextual fear conditioning (CFC) was conducted. Ginseng in a dose-dependent manner increased the % freezing time and the number of BrdU-positive cells in the dentate gyrus of rats that received CFC. Thus, an increase in CFC-related neurogenesis may be one mechanism of Ginseng's properties to enhance learning ability.

Aconiti tuber increases plasma nitrite and nitrate levels in humans.

Some herbal medicines, including Aconiti tuber (Aconitum carmichaeli Debeaux, Ranunculaceae), have been recognized as being effective for the treatment of a "peripheral uncomfortable feeling of cold (hie)". We hypothesized that these compounds affect peripheral vascular function via the nitric oxide (NO) system, which leads to recovery from "hie". To answer this question, we investigated Aconiti tuber-induced changes in plasma levels of nitrite (p-NO2-) and nitrate (p-NO3-), final nitric oxide-oxidation products measurable in vivo. After written informed consent was obtained, patients suffering from "hie" were treated with several kinds of kampo (Japanese traditional herbal medicine), selected on the basis of traditional theory. Twenty-four patients took kampo formulas, some included Aconiti tuber (n=11; A-group) and others did not (n=13; C-group), for 4 weeks. p-NO2- and p-NO3- levels were measured before the start and after 4 weeks of treatment. In the A-group, the p-NO2- plus p-NO3- (p-NOx) level was significantly increased at 4 weeks (p=0.04), while that of the C-group was not. There was a statistically significant increase in the p-NOx level of the A-group as compared to the C-group (d.f.=1,22, F=9.38, p=0.006). The results suggest that Aconiti tuber may increase NO production in humans.

Effectiveness of Gorei-san (TJ-17) for treatment of SSRI-induced nausea and dyspepsia: preliminary observations.

Selective serotonin reuptake inhibitors (SSRIs) are apt to cause gastrointestinal adverse events such as nausea and dyspepsia. Gorei-san (TJ-17), which is composed of five herbs (Alismatis rhizoma, Atractylodis lanceae rhizoma, Polyporus, Hoelen, and Cinnamomi cortex), is a Japanese herbal medicine that has been used to treat nausea, dry mouth, edema, headache, and dizziness. The authors investigated the efficacy of TJ-17 for patients who experienced nausea or dyspepsia induced by SSRIs. Twenty outpatients who experienced nausea or dyspepsia induced by SSRIs were recruited for the study. Seventeen patients were female, three were male, and patient age ranged from 21 to 74 years (49.8 +/- 17.0 years). TJ-17 was added to the previous regimen. Nausea and dyspepsia disappeared completely in nine patients, decreased in four patients, decreased slightly in two patients, and did not change in five patients. No adverse events were associated with the addition of TJ-17 in any patient.

Nitric oxide induced heat shock protein 70 mRNA in rat hypothalamus during acute restraint stress under sucrose diet.

1. Sucrose feeding increases the level of stress-induced heat shock protein 70 mRNA in the rat hypothalamus. However, the mechanism by which a sucrose diet induces mRNA remains unclear. The issues investigated in this study were (1) whether a sucrose diet affects nitric oxide production in the hypothalamus, and (2) whether nitric oxide mediates the sucrose and stress-induced elevation of heat shock protein 70 mRNA. 2. To address the first question, we measured the level of nitrate, a final nitric-oxide-oxidation product measurable in vivo, using a microdialysis method. To address the second question, we administered a nitric oxide synthase inhibitor. NG-nitro-L-arginine methyl ester, prior to stress, then measured the mRNA level of heat shock protein 70 by the reverse transcription-competitive polymerase chain reaction method. 3. After the initiation of restraint stress, rats fed a sucrose-containing diet, unlike those fed standard chow, displayed a transient nitrate elevation. This nitrate elevation was attenuated by pretreatment with NG-nitro-L-arginine methyl ester. The mRNA level increases in rats fed a sucrose diet were dose-dependently attenuated by NG-nitro-L-arginine methyl ester. 4. These data suggest that a sucrose diet induces heat shock protein 70 under stress by enhancing nitric oxide production in the hypothalamus.