Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons.

Corticotropin releasing factor in concentrations of 15 to 250 nanomoles per liter increased the spontaneous discharge frequency and decreased the size of hyperpolarizations after burst discharges in CA1 and CA3 pyramidal neurons of rat hippocampal slices. Concentrations greater than 250 nanomoles per liter also depolarized the cells. These excitatory actions of corticotropin releasing factor may involve a novel calcium-dependent process.

The calcium response of human T lymphocytes is decreased in aging but increased in Alzheimer's dementia.

BACKGROUND: A significant increase in the [Ca2+]i response of single T lymphocytes to mitogenic stimulation with phytohemagglutinin is reported for 27 Alzheimer patients compared with 27 healthy gender- and age-matched control subjects, regardless of gender. METHODS: The [Ca2+]i signals of T lymphocytes were assessed using the Fura-2-AM method. RESULTS: In Alzheimer's disease (AD) the reaction pattern is similar to that seen in a group of 27 young healthy control subjects who exhibited a marked [Ca2+]i rise after stimulation. During normal aging the reaction pattern of T cells is significantly attenuated in comparison to that found in young subjects. In healthy control subjects differences in age-related changes in calcium homeostasis are highly significant among women, young women showing the most intense cell response. CONCLUSIONS: The elevation of [Ca2+]i appears to be a prerequisite for apoptosis, which is suggested to be involved in the neuronal death occurring in AD. An increased [Ca2+]i in AD is consistent with processes leading to neurodegeneration in AD.

A nonlinear approach to brain function: deterministic chaos and sleep EEG.

In order to perform a nonlinear dimensional analysis of the sleep electroencephalogram (EEG), we applied an algorithm proposed by Grassberger and Procaccia to calculate the correlation dimension D2 of different sleep stages under Lorazepam medication versus placebo. This correlation dimension characterizes the dynamics of the sleep EEG and it estimates the degrees of freedom of the signal under study. We demonstrate that slow-wave sleep depicts a much smaller dimensionality than light or rapid eye movement (REM) sleep, and that Lorazepam does not alter the EEG's dimensionality except in stage II and REM.

Does corticotropin releasing factor act via a calcium-dependent mechanism?

The widespread distribution of CRF in the brain suggests a possible role of this peptide as a neuromodulator. An interaction with calcium-dependent conductances, as observed in hippocampal slices, could explain the action of CRF in different brain structures. In the present study, the calcium antagonist, verapamil, was found to block the excitatory action of CRF on neuronal discharge activity. This supports the hypothesis that CRF blocks a calcium-dependent potassium conductance, which represents a resting component of neuronal activity, thereby enhancing ion fluxes into the cell.

The effects of verapamil on the locomotor-activating properties of corticotropin releasing factor (CRF) in the rat.

CRF was administered to rats following intracerebroventricular administration of the calcium antagonist verapamil. Treatment with verapamil elicited biphasic dose-response effects on rat locomotor activity: doses equimolar to CRF treatment slightly increased CRF-stimulated locomotion, while doses of verapamil ten times greater slightly depressed CRF-stimulated locomotion. These results suggest that CRF-stimulated locomotion, unlike other effects of CRF, is not mediated in a simple way by processes dependent on neuronal calcium influx.

Nimodipine in acute alcohol withdrawal state.

The effect of the calcium channel blocker, nimodipine, in acute alcohol withdrawal was investigated in a randomized, placebo controlled, double blind study. Thirty-two male patients with a history of alcohol dependence according to DSM-III criteria, but no other substance abuse, were included. A new rating instrument which fulfilled theoretical test criteria was applied to determine the severity of the alcohol withdrawal state. The patients received nimodipine or a placebo on four separate occasions (4 x 60 mg) and, in addition, clomethiazole, according to a standardized procedure. Our investigation has shown that, in the first 48-72 h of alcohol withdrawal, both groups consumed similar amounts of additional clomethiazole medication. Thus, no significant effect of nimodipine on the acute alcohol withdrawal state could be demonstrated. There was some tendency for nimodipine to ameliorate psychosensory dysfunction.

Altered Ca(2+)-homeostasis in single T-lymphocytes of depressed patients.

After stimulation of T-lymphocytes from healthy volunteers with the mitogen phytohemagglutinin (PHA) 40% of the cells exhibit an oscillatory increase in intracellular calcium concentration ([Ca2+]i). During depression the number of cells responding to PHA is reduced to 20%. These cells show a marked decrease in [Ca2+]i-reaction to stimulation and flattened oscillations. This reduction of mitogen-induced Ca2+ signals in T-cells of depressed patients appears to be a reliable state marker in depressive illness and is reversed upon successful treatment with interpersonal psychotherapy (IPT).

Reduced olfactory performance in patients with major depression.

The aim of the present study is to investigate olfactory sensitivity and odor evaluations in a homogeneous sample of unipolar depressive patients using pure olfactory odors. Twenty-four in-patients with major depressive disorder (MDD) were investigated during their acute depressive phase. Eighteen of them participated a second time after successful treatment. A group of healthy subjects, matched by age, sex, and smoking behavior, served as a control. Olfactory sensitivity, as measured by threshold tests, was strongly reduced in patients with severe depression. Additional correlative analyses revealed that the lowered sensitivity could partly be predicted by high depression scores. After successful medical treatment, these sensitivity differences were reduced and did not reach the significance level. The subjective odor evaluations (valence and intensity ratings) were not markedly changed in general. The results reveal that olfactory performance in MDD patients is reduced at an early perceptional level of stimulus processing. It is discussed whether this effect can be attributed to the close functional connection between the main olfactory bulb and the amygdala.

Stimulation of a sodium influx by cAMP in Helix neurons.

Brief pressure injections of aqueous solutions of cAMP in identified neurons of Helix pomatia caused depolarizations which lasted for tens of seconds. In voltage-clamped neurons an inward current of similar duration was induced which saturated at 10 microA/cm2 cell surface. In the range of negative membrane potentials with little voltage-dependent activation, this current was not accompanied by a change in membrane conductance. The inward current was not produced by injection of ATP, ADP, adenosine, inosine or cGMP. cAMP derivatives produced longer-lasting effects. Prolongation of the inward current was also observed after inhibition of the phosphodiesterase by IBMX. Drugs which block active transport had no effect on the response to cAMP injection. The inward current depended on extracellular sodium, and was maximal when all other mono- and divalent cations were replaced by Na+. The cAMP-induced current was accompanied by a transient increase in [Na+]i, but there was no change in [Cl-]i. Li+ could largely substitute for Na+; Ca2+ was less effective. Addition of Mg2+ or Ca2+ to solutions containing a high Na+-concentration inhibited the response. Internal acidification with HCl reversibly enhanced the inward current. These data indicate that the depolarizing effect of cAMP can be accounted for by an inward movement of Na-ions, and that the effect is augmented by H+-ions.

Lithium slows neuronal calcium regulation in the snail Helix pomatia.

Steady-state and transient changes in intracellular calcium concentrations ([Ca2+]i) of snail neurons (Helix pomatia) were measured by the Ca2+ indicator Arsenazo(III) following manipulation of the extracellular concentration of lithium chloride (LiCl). Application of LiCl in concentrations equivalent to those used in the treatment of manic-depressive illness produces slowing in Ca2+ reequilibration after Ca2+-influx during depolarization, concomitantly with steady-state elevation of [Ca2+]i of about 100 nM, suggesting a change in Ca2+ reequilibration as a prominent action of LiCl. This mechanism may be relevant to the therapeutic effects of LiCl.

K+ currents of human T-lymphocytes are unaffected by Alzheimer's disease and amyloid beta protein.

Alterations of Ca2+ homeostasis have been reported for both fibroblasts and T-lymphocytes of patients with Alzheimer's disease (AD). Considering the importance of K+ conductances for the cellular Ca2+ regulation and the recently reported absence of a K+ channel in Alzheimer fibroblasts, we investigated K+ currents in T-lymphocytes of patients with AD. In addition, the finding that amyloid beta protein affects the Ca2+ signal of T-lymphocytes and the function of K+ channels in fibroblasts prompted us to study a possible influence of amyloid beta protein fragments on K+ channels of T-lymphocytes. Our data, obtained by means of the whole-cell patch-clamp configuration on freshly isolated T-lymphocytes, indicate that K+ channels of these cells do not present any functional deficit in AD, and amyloid beta protein does not mediate an alteration of their currents.

Mitogen stimulated rise of intracellular calcium concentration in single T lymphocytes from patients with major depression is reduced.

1. The authors investigated the signal transduction in T-lymphocytes as a peripheral model for central neurons. 2. Intracellular free calcium concentration [Ca2+]i was measured using fura 2 in T-lymphocytes from 6 patients with major depression during and after depression and from 6 healthy controls. Patients were treated with interpersonal therapy (IPT) but not with psychotropic medication. 3. Phytohemagglutinin (PHA) triggers an oscillatory [Ca2+]i signal in human T-lymphocytes. This implies two mechanisms for [Ca2+]i regulation: inositol phophate (IP) mediated release from intracellular stores and [Ca2+]i influx from the extracellular medium. 4. PHA stimulates 49% of T cells from controls but only 17% of T cells from depressed patients. This finding explains previous results from cells in suspension indicating that [Ca2+]i signals after PHA-stimulation are reduced in cells from depressed patients. 5. Cells from depressed patients show less [Ca2+]i oscillations. Normal oscillation patterns are restored after clinical recovery from depression. 6. Thus altered [Ca2+]i oscillations in T-lymphocytes are a state phenomenon and may give us clues where to search for altered cellular mechanisms during depression.

The influence of lorazepam medication upon the transfer properties of the brain during sleep in man.

In order to get better insight into the principles of information processing by the brain during sleep and its alterations under the influence of drugs we applied some tools from linear system theory to sleep EEG data. We investigated late components of auditory and visually evoked potentials (AEPs and VEPs) during different sleep stages and calculated from these the so-called amplitude-frequency characteristics (AFC). The main advantage of this analysis is that it enables one to detect functional differences during different sleep stages. This information can hardly be obtained by conventional spectral analysis. The result of our investigation was that the transfer properties of the brain during sleep were extremely different and that lorazepam medication not only resulted in quantitative alterations of the sleep profile but mainly in highly significant alterations of the functional properties of sleep.

Functional properties of the brain during sleep under subchronic zopiclone administration in man.

Zopiclone, a non-benzodiazepine, has been shown to be efficient in the treatment of transient, short-term or chronic sleep disorders. Apart from its hypnotic effects zopiclone has anxiolytic, anticonvulsant and myorelaxant properties and is therefore hardly distinguishable from benzodiazepines. Dependence liability and discontinuation effects have been reported to be less pronounced. Therefore zopiclone seems to be a hypnotic drug which may cause fewer side effects than conventional benzodiazepines. From the electrophysiological point of view one requires from a hypnotic drug the induction of a physiological sleep pattern as well as no alterations of information processing by the brain. The aim of the present study was to investigate the subchronic effect of zopiclone medication on some functional properties of the sleep EEG in healthy subjects. In order to get better insight into the principles of information processing by the brain during sleep and its alterations under the influence of zopiclone we applied some tools from linear system theory to sleep EEG data. For this purpose we investigated late components of auditory and visual evoked potentials during different sleep stages and calculated from these the so-called amplitude-frequency characteristic of the brain. This function describes the relationship between an input and the output of the investigated system. The main advantage of this kind of analysis is that it enables one to detect functional differences during sleep stages. This information can hardly be obtained from conventional spectral analysis. As a result we could demonstrate that under subchronic zopiclone medication no quantitative or qualitative alterations of the functional sleep EEG properties concerning the transfer properties of the brain under auditory and visual stimulation were detectable.

Regional cerebral blood flow in depression: associations with psychopathology.

Regional cerebral blood flow (rCBF) was measured during rest and cognitive activation in 21 patients with a major depressive episode and 21 healthy subjects. Depressive patients had significantly lower rCBF during rest in the right global, frontal, parietal, occipital and temporal regions and in the left global and frontal regions. During mental activation patients showed significantly lower values in all right and left parietal regions. rCBF was correlated with the scores of the Brief Psychiatric Rating Scale (BPRS), the parietal regions. rCBF was correlated with the scores of the Brief Psychiatric Rating Scale (BPRS), the Bech-Rafaelsen Melancholia Scale (BRMS), the Hamilton Depression Scale (HAM-D) and the Hamilton Anxiety Scale (HAM-A). The most significant negative correlations were obtained with the BPRS. Correlation analyses between each single item of the BPRS and CBF values revealed the strongest associations between emotional withdrawal and decreased CBF. Patients with 'reactive' features had higher CBF than patients without 'reactive' symptoms. Only patients without 'reactive' symptoms had a lower CBF than controls. 'Endogenous' features had no impact on CBF.

Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep.

Evidence from animal experiments has suggested that the triggering and maintenance of rapid eye movement (REM) sleep is mainly under the control of cholinergic neurons in the brain stem. Correspondingly, studies in humans have demonstrated that the application of cholinergic agonists or cholinesterase inhibitors provokes an earlier onset of REM sleep. The present study investigated the influence of galanthamine hydrobromide, a reversible cholinesterase inhibitor, on REM sleep regulation in 18 healthy volunteers. After an adaptation night, the subjects were given two doses of galanthamine (10 mg and 15 mg) or placebo at 10 p.m. in a randomized double-blind design. Both doses of galanthamine shortened REM latency (with statistical significance depending on the definition of REM latency used), increased REM density, and reduced slow wave sleep mainly in the first non-REM cycle. Higher doses of galanthamine (15 mg) seem to be accompanied by unwanted side effects that warrant the application of a peripheral antidote. These results are comparable to those for other cholinomimetics and stress the usefulness of galanthamine for pharmacological challenge studies in healthy subjects and depressed patients.

Computed tomography in depression: association between ventricular size and psychopathology.

The relationship between psychopathology and brain alterations, measured by computed tomography (CT), was investigated in 44 depressed patients. Comparisons of ventricle-brain ratio (VBR) between "endogenous" vs. "nonendogenous" subgroups, classified by six distinct diagnostic systems, revealed no significant differences. The VBR and the width of the third ventricle correlated significantly with scores on the Brief Psychiatric Rating Scale, the Global Assessment Scale, the Bech-Rafaelsen Melancholia Scale, the Rating for Emotional Blunting, and the Scale for the Assessment of Negative Symptoms, but not with scores on the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety. Item analyses of the Bech-Rafaelsen Melancholia Scale revealed that retardation-related items were most significantly correlated with ventricular size. The wider diameter of the third ventricle in psychotic patients was associated with higher scores on retardation in the psychotic subgroup, whereas the greater distances of both Sylvian fissures showed no relationship to psychomotor retardation. No significant correlations were found between CT values and anxiety, suicidal impulses, somatic complaints, and sleep disturbances.

Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy.

BACKGROUND: The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep-wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy. METHODS: In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography. RESULTS: Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions. CONCLUSION: In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.