The co-occurrence of zinc deficiency and social isolation has the opposite effects on mood compared with either condition alone due to changes in the central norepinephrine system.

Nutritional and social environmental problems during the early stages of life are closely associated with the pathophysiology of mood disorders such as depression. Disruption or dysfunction of the central norepinephrine (NE) system is also considered to play a role in mood disorders. Therefore, we evaluated the effects of zinc deficiency and/or social isolation on mood and changes in the central NE system using rats. Compared with the controls, the rats subjected to zinc deficiency or social isolation alone exhibited increased anxiety-related behavior in the elevated plus maze and greater depression-like behavior in the forced swim test. However, the co-occurrence of zinc deficiency and social isolation resulted in decreased anxiety-related behavior and control levels of depression-like behavior. Social isolation alone decreased the rats' cerebral NE concentrations. The expression of the NE transporter was not affected by social isolation alone, but its expression in the locus coeruleus was markedly decreased by the co-occurrence of social isolation and zinc deficiency, and this change was accompanied by an increase in the blood concentration of 3-methoxy-4-hydroxyphenylglycol, which is a marker of central NE system activity. These findings suggest that zinc deficiency or social isolation alone induce anxious or depressive symptoms, but the presence of both conditions has anxiolytic or antidepressive effects. Furthermore, these opposing effects of mood-related behaviors were found to be associated with changes in the central NE system.

Mania: not the opposite of depression, but an extension? Neuronal plasticity and polarity.

What underlies bipolar disorder? What pathophysiologic process can produce symptoms that are apparently polar opposites? Recent studies of neuronal plasticity suggest a mechanism. Both zinc deficiency and social isolation impair neuronal plasticity; both are associated with major depression. Yet when zinc deficiency and social isolation occur together, they are associated with aggression, not with depression. On that basis, and according to additional findings in rats reported herein, it was inferred that moderate impairment of neuronal plasticity induces a depressive state, but that further impairment of neuronal plasticity induces not more depression, but a manic state. However, not only neuronal plasticity, but also some kind of load toward neuronal function can influence polarity or symptoms of mood disorder. Our hypothesis is that mania is an extension of depression from the perspective of neuronal plasticity, and that multiaxial evaluation by neuronal plasticity and neuronal load is useful to elucidate the pathophysiology of mood disorder. Using this hypothesis, many clinical aspects that have been heretofore difficult to interpret can be understood. A mood stabilizer or electric convulsive therapy is often used for the treatment of mood disorder, but it has remained unclear why such therapies are useful for both mania and depression. This hypothesis can explain how mood stabilizers or electric convulsive therapy can improve both mania and depression through the recovery of neuronal plasticity. It is difficult to explain the pathophysiology of manic switching by antidepressants solely from the perspective of the impairment of neuronal plasticity. To interpret this phenomenon, the action of antidepressants to neuronal load should be regarded as the other axis from neuronal plasticity. Based on this hypothesis, it is expected that the pathophysiology of mood disorder and clinical mechanism of mood stabilizers and antidepressants can be understood in an integrated manner.

Region-specific causal mechanism in the effects of ammonia on cerebral glucose metabolism in the rat brain.

Ammonia, which is considered to be the main agent responsible for hepatic encephalopathy, inhibits oxidative glucose metabolism in the brain. However, the effects of ammonia on cerebral glucose metabolism in different brain regions remains unclear. To clarify this issue, we added ammonia directly to fresh rat brain slices and measured its effects on glucose metabolism. Dynamic positron autoradiography with [(18)F]2-fluoro-2-deoxy-D-glucose and 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) colorimetric assay revealed that ammonia significantly increased the cerebral glucose metabolic rate and depressed mitochondrial function, as compared to the unloaded control in each of the brain regions examined (cerebral cortex, striatum, and cerebellum), reflecting increased glycolysis that compensates for the decrease in aerobic metabolism. Pre-treatment with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, significantly attenuated these changes induced by ammonia in cerebellum, but not in cerebral cortex or striatum. The addition of ammonia induced an increase in cyclic guanosine monophosphate (cGMP) levels in cerebellum, but not in cerebral cortex or striatum, reflecting the activation of the NMDA receptor-nitric oxide-cGMP pathway. These results suggested that NMDA receptor activation is responsible for the impairment of glucose metabolism induced by ammonia specifically in cerebellum.

Effect of dietary zinc deficiency on ischemic vulnerability of the brain.

Deficiency of zinc, which modulates glutamate release, might increase ischemic vulnerability of the brain. We examined effects of dietary zinc deficiency for 2 weeks on ischemic vulnerability in several brain regions using dynamic positron autoradiography technique and [18F]2-fluoro-2-deoxy-d-glucose with rat brain slices. In the normal diet group, the cerebral glucose metabolic rate (CMRglc) was not significantly different from that of the ischemia-unloaded control even after the loading of ischemia for 45 min. However, in the zinc-deficient diet group, CMRglc was significantly lower than that of the ischemia-unloaded control after loading of ischemia for 45 min. With treatment of MK-801 (NMDA receptor antagonist) from the start of ischemia loading, CMRglc was not significantly different from that of the ischemia-unloaded control. These findings, obtained for all analyzed brain regions, suggest that dietary zinc deficiency increased ischemic vulnerability in the brain, and that glutamate might contribute to this effect through activation of the NMDA receptor.

Effects of antidepressants and mood stabilizers on serum levels of adiponectin.

The effect of antidepressants and mood stabilizers on serum levels of adiponectin was investigated. Fluvoxamine (30 and 50 mg/kg/day) or lithium (40 and 60 mg/kg/day) was dissolved in distilled water and administered orally to rats every day for 4 weeks. Fluvoxamine (50 mg/kg/day) alone significantly elevated the serum level of adiponectin, but no significant difference was found between other drug-treated groups and the control group. This difference of these drugs' effectiveness on serum adiponectin might contribute to their differences of action mechanisms and therapeutic effects.

Switching to aripiprazole in subjects with pervasive developmental disorders showing tolerability issues with risperidone.

BACKGROUND: Subjects with Pervasive Developmental Disorders (PDD) often exhibit behavioral symptoms such as aggressiveness and irritability, which are targets of psychopharmacologic intervention. This retrospective study was designed to examine children and adolescents with PDD experiencing tolerability issues with risperidone treatment, and thereby assess the efficacy and tolerability of switching to aripiprazole. METHODS: This naturalistic study included 23 subjects with PDD (16 males, 7 females, age range 9-24 years, mean age 15.1±3.9 years) diagnosed according to DSM-IV criteria and followed up for 14.9±8.4 weeks after switching to aripiprazole from risperidone. Outcome measures were the Clinical Global Impression-Severity (CGI-S) and CGI Improvement (CGI-I) scales. RESULTS: The mean CGI-S scores of pre-aripiprazole treatment and post-aripiprazole treatment were, respectively 4.7±1.4 and 4.6±1.3. Mean maintenance dosages of risperidone and aripiprazole were, respectively, 0.7±0.5mg/day and 2.8±1.3mg/day. The mean CGI-I score, which shows the difference induced by switching from risperidone to aripiprazole, was 3.4±0.8 for the whole sample, suggesting that the efficacy of risperidone for treating behavioral problems of PDD was maintained by aripiprazole. Some improvement of safety/tolerability issues such as increased appetite, somnolence, hyperprolactinemia, and amenorrhea occurred after switching to aripiprazole. CONCLUSION: Results show that switching to aripiprazole might be generally well tolerated and might constitute an alternative treatment for subjects with PDD who experience tolerability issues with risperidone treatment. Additional long-term controlled studies of PDD subjects should be undertaken to evaluate the efficacy and safety of switching to aripiprazole from other antipsychotics.

Hypomanic switching during influenza infection without intracranial infection in an adolescent patient with bipolar disorder.

Manic switching, which is mood changing from depression to mania, induced by intracranial viral infections have been previously reported. However, manic switching induced by influenza infection without intracranial viral infection in a patient with bipolar disorder (BD), has not been previously reported. We report a patient with adolescent BD who showed a first episode of hypomanic switching during influenza B infection without intracranial viral infection. In addition to neurological monitoring, careful psychiatric interventions for hypomanic state is very important to prevent inappropriate treatment of BD and reduce the risk of suicide attempts in cases presenting with hypomanic symptoms during influenza infection.

Assessment of EEG dynamical complexity in Alzheimer's disease using multiscale entropy.

OBJECTIVE: Multiscale entropy (MSE) is a recently proposed entropy-based index of physiological complexity, evaluating signals at multiple temporal scales. To test this method as an aid to elucidating the pathophysiology of Alzheimer's disease (AD), we examined MSE in resting state EEG activity in comparison with traditional EEG analysis. METHODS: We recorded EEG in medication-free 15 presenile AD patients and 18 age- and sex-matched healthy control (HC) subjects. MSE was calculated for continuous 60-s epochs for each group, concurrently with power analysis. RESULTS: The MSE results from smaller and larger scales were associated with higher and lower frequencies of relative power, respectively. Group analysis demonstrated that the AD group had less complexity at smaller scales in more frontal areas, consistent with previous findings. In contrast, higher complexity at larger scales was observed across brain areas in AD group and this higher complexity was significantly correlated with cognitive decline. CONCLUSIONS: MSE measures identified an abnormal complexity profile across different temporal scales and their relation to the severity of AD. SIGNIFICANCE: These findings indicate that entropy-based analytic methods with applied at temporal scales may serve as a complementary approach for characterizing and understanding abnormal cortical dynamics in AD.

Smaller insula and inferior frontal volumes in young adults with pervasive developmental disorders.

Enlarged head circumference and increased brain weight have been reported in infants with pervasive developmental disorders (PDD), and volumetric studies suggest that children with PDD have abnormally enlarged brain volumes. However, little is known about brain volume abnormalities in young adults with PDD. We explored gray matter (GM) volume in young adults with PDD. T1-weighted volumetric images were acquired with a 3-T magnetic resonance scanner from 32 males with high-functioning PDD (23.8+/-4.2 years; Full Scale Intelligence Quotient [FSIQ]=101.6+/-15.6) and 40 age-matched normal male control subjects (22.5+/-4.3 years; FSIQ=109.7+/-7.9). Regional GM volumes were compared between the two groups using voxel-based morphometry (VBM) with the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL). Compared with the control group, the high-functioning PDD group showed significantly less GM in the right insula, the right inferior frontal gyrus, and the right inferior parietal lobule. A conservative threshold confirmed considerably smaller volumes in the right insula and inferior frontal gyrus. In these areas, negative correlations were found between Autism Spectrum Quotient scores and GM volume, although no significant correlations were found between each subject's FSIQ and GM volume. No regions showed greater GM volumes in the high-functioning PDD group. The insular cortex, which works as a relay area for multiple neurocognitive systems, may be one of the key regions underlying the complex clinical features of PDD. These smaller GM volumes in high-functioning PDD subjects may reflect the clinical features of PDD itself, rather than FSIQ.

Antipsychotics reverse abnormal EEG complexity in drug-naive schizophrenia: a multiscale entropy analysis.

Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naive schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting-state EEG from frontal, temporal, parietal, and occipital regions in drug-naive 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2-8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60-s epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies) than did healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia and elucidating the therapeutic mechanisms of antipsychotics.

Application of a multifractal analysis to study brain white matter abnormalities of schizophrenia on T2-weighted magnetic resonance imaging.

Multifractal analysis provides a precise quantitative description of the structural complexity of white matter (WM) on magnetic resonance imaging (MRI). To test this new technique as an aid to elucidating the pathology of schizophrenia, we examined a multifractal dimension (i.e. Deltaalpha) of WM in schizophrenia patients and their relations to clinical variables. We examined 16 patients with schizophrenia and 16 controls matched for age, sex and handedness. Delta alpha value of WM in the prefrontal and frontoparietal lobes and the corpus callosum (genu and splenium) on T2-weighted MRI was calculated. Delta alpha was not significantly different between groups in either region of interest. However, group-by-side interaction for Deltaalpha was found in the frontoparietal WM; post-hoc analysis revealed normal left dominant asymmetry in Deltaalpha for frontoparietal WM in control subjects, which was absent in schizophrenia patients. Furthermore, the patients with schizophrenia had a lower asymmetry coefficient ([R-L]/[R+L]) for Deltaalpha in frontoparietal WM. Relations to clinical symptoms from the Positive and Negative Syndrome Scale, Deltaalpha in corpus callosum, and the asymmetry coefficient in prefrontal WM were correlated with negative and general psychopathology symptom scores. Our results support the left-sided dysfunction hypothesis of schizophrenia and its relation to schizophrenic symptoms. Multifractal analysis reveals abnormal patterns of WM structures in schizophrenia that could be implicated in the disorder's etiology.

Age-related variation in EEG complexity to photic stimulation: a multiscale entropy analysis.

OBJECTIVE: This study was intended to examine variations in electroencephalographic (EEG) complexity in response to photic stimulation (PS) during aging to test the hypothesis that the aging process reduces physiologic complexity and functional responsiveness. METHODS: Multiscale entropy (MSE), an estimate of time-series signal complexity associated with long-range temporal correlation, is used as a recently proposed method for quantifying EEG complexity with multiple coarse-grained sequences. We recorded EEG in 13 healthy elderly subjects and 12 healthy young subjects during pre-PS and post-PS conditions and estimated their respective MSE values. RESULTS: For the pre-PS condition, no significant complexity difference was found between the groups. However, a significant MSE change (complexity increase) was found post-PS only in young subjects, thereby revealing a power-law scaling property, which means long-range temporal correlation. CONCLUSIONS: Enhancement of long-range temporal correlation in young subjects after PS might reflect a cortical response to stimuli, which was absent in elderly subjects. These results are consistent with the general "loss of complexity/diminished functional response to stimuli" theory of aging. SIGNIFICANCE: Our findings demonstrate that application of MSE analysis to EEG is a powerful approach for studying age-related changes in brain function.

Relationship between plasma leptin level and brain structure in elderly: a voxel-based morphometric study.

BACKGROUND: Recent accumulating lines of evidence reveal that leptin is associated with synaptic plasticity and neuroprotective activity in the brain. METHODS: In this preliminary study with a cross-sectional design, we examined the relationship between plasma leptin level and total or regional gray matter (GM) volume in 34 elderly subjects (mean age 64.5 years) with normal fasting glucose level and without dementia and metabolic syndrome by voxel-based morphometry of magnetic resonance imaging scans. RESULTS: Plasma leptin level showed no significant correlation with total GM volume but showed a significantly positive correlation with GM volumes in the right hippocampus, left parahippocampus, and right cerebellum with adjustments for age, gender, body mass index (BMI), and waist-to-hip ratio (W/H). Also, after adjustments for age, gender, BMI, W/H, and intracranial volume, plasma leptin level significantly positively correlated with GM volumes in the right hippocampus and bilateral cerebella but not with that in the left parahippocampus. CONCLUSIONS: The results of this pilot study would be beneficial for our understanding of the neuroprotective effects of leptin on human brain aging.

The clinical significance of abnormal diurnal blood pressure variation in healthy late middle-aged and older adults.

Objective. A fall in nocturnal blood pressure (BP) is generally observed in normotensive subjects as well as in those with mild to moderate essential hypertension, regardless of the level of daytime BP. Among elderly hypertensive subjects, extreme-dippers with a marked nocturnal fall in BP as well as non-dippers with nocturnal fall absence are at increased risk for cardiovascular and cerebrovascular complications. However, the relationship between these abnormal diurnal BP variation patterns in normotensive elderly subjects has not been investigated. Methods. We classified 45 healthy late middle-aged and older adults into three groups according to the nocturnal systolic BP fall pattern examined by 24-h ambulatory BP monitoring (dipper, non-dipper and extreme-dipper), and compared the parameters of initial atherosclerosis, endothelial function and autonomic function. As a parameter of atherosclerotic factors, the intima-media thickness (IMT) of the carotid artery was examined, and as a parameter of endothelial function, brachial artery endothelium-dependent flow-mediated dilation (FMD) was ultrasonographyically measured. Autonomic function was assessed by power spectral analysis of heart rate variability (HRV). Results. No difference was observed in the severity of IMT between the three groups. The percent change of FMD in subjects in the extreme-dipper group was significantly lower than that of subjects in the dipper group, indicating that extreme-dippers in healthy elderly subjects may be associated with endothelial dysfunction. Also, HRV due to sympathetic modulation of subjects in the extreme-dipper group was significantly higher than that of subjects in the dipper and non-dipper groups, suggesting the activation of sympathetic tone. Conclusion. In healthy elderly subjects, the extreme-dipper type may reflect a decrease in endothelial function, i.e. initial stage atherosclerosis, rather than the dipper type.