Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction

Objectives:  Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD.
Methods:  Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls.
Results:  Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses.
Conclusions:  These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.     

Endothelial progenitor cells stimulate cerebrovascular production of prostacyclin by paracrine activation of cyclooxygenase-2

In the present study we hypothesized that endothelial progenitor cells (EPCs) enhance production of vasoprotective substances in cerebral arteries. Isolated mononuclear cells from rabbit peripheral blood were cultured in endothelial growth medium (EGM-2) for 7 days to yield EPCs. Rabbit basilar arteries were exposed to autologous EPCs ( approximately 5x10(5) cells) in vitro or in vivo. Twenty-four hours after intracisternal delivery of autologous EPCs, basilar arteries were isolated and expression of vasoregulatory proteins, production of prostacyclin (PGI(2)), and cAMP were determined. Arteries transplanted with EPCs demonstrated increased protein expression of cyclooxygenase-2 and PGI(2) in adventitia, media, and endothelium. Furthermore, production of PGI(2) and arterial content of cAMP, second messenger for PGI(2), were significantly augmented after transplantation of EPCs. In contrast, production of thromboxane A(2) was significantly reduced, whereas production of prostaglandin E(2) remained unchanged. The increased production of PGI(2) and arterial content of cAMP were inhibited only by a selective cyclooxygenase-2 inhibitor, NS-398. In vitro or in vivo treatment of basilar artery with conditioned media from EPCs also caused increase in cyclooxygenase-2 and PGI(2) synthase protein expression associated with elevation of cAMP. Our results suggest that in cerebral arteries, paracrine effect of EPCs promotes vasoprotection by increasing PGI(2) production and intracellular concentration of cAMP. This effect appears to be mediated by activation of arachidonic acid metabolism via stimulation of cyclooxygenase-2/PGI(2) synthase pathway.     

Glia mechanisms in mood regulation: a novel model of mood disorders

Introduction Recent evidence in clinical and preclinical studies has implicated glutamate neurotransmissions in pathophysiology of mood disorders. The regulation of amino acid neurotransmission, i.e., glutamate and gamma-aminobutyric acid (GABA) involves coordinated mechanisms of uptake and transport within a tripartite synaptic system that includes neurons and glia. Newly appreciated role of the glia, more specifically astrocytes on neuronal functions combined with reported postmortem abnormalities of glia in patients with mood disorders further supports the role of glia in mood disorders. Materials and methods This report presents some of our preliminary results utilizing glia-selective toxins and other pharmacological tools to suppress glial function within the limbic system to study the resulting behavioral abnormalities, and thus, elucidate glial involvement in the development of mood disorders. Results and discussion We demonstrate that chronic blockade of glutamate uptake by a glial/neuronal transporter antagonist l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) within the amygdala, a key area implicated in mood regulation, results in dose-dependent reduction in social exploratory behavior and disrupts circadian activity patterns consistent with symptoms of mood disorders. Similarly, the selective astrocytic glutamate transporter type 1 (GLT-1) blocker dihydrokainic acid (DHK) injected into the amygdala also results in reduced social interaction that is blocked by selective glutamate N-methyl-d-aspartate (NMDA) type receptor antagonist AP5. The results are discussed in the context of glial and glutamate mechanisms in mood disorders and potential therapeutic avenues to address these mechanisms.     

Changes in Central Sodium and not Osmolarity or Lactate Induce Panic-Like Responses in a Model of Panic Disorder

Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar -mannitol, increased ‘anxiety'' (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or -mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.     

Does hemorrhagic presentation in cerebral arteriovenous malformations affect obliteration rate after gamma knife radiosurgery?

OBJECTIVES: Radiosurgery has been widely adopted for the treatment of cerebral AVMs. However radiosurgical treatment of patients with hemorrhagic presentation is fraught with risk of rebleed during latency period. The present study intends to analyze the obliteration rate, time to obliteration and chances of rebleed in patients with hemorrhagic versus non-hemorrhagic clinical presentation in cerebral arteriovenous malformations (AVMs) treated with gamma knife radiosurgery (GKS). PATIENTS AND METHODS: Of all the patients with cerebral AVMs treated from May 1997 to Jun 2006, 157 patients with neuroimaging follow up with digital subtraction angiography harboring 160 AVM nidii formed the study group. The mean age of presentation was 28 years (range, 6-58 years); mean nidus volume being 3.64cm(3) (range, 0.011-36.6cm(3)). The mean follow up period was 70 months (range, 13-121 months). All the patients were treated predominantly by primary GKS with use of adjunctive pre-GKS embolization in selected patients. RESULTS: A total of 103 (64%) patients presented with hemorrhage. There was no difference in the obliteration rate (69% versus 67%, p=0.672), mean latency period to obliteration (30 months versus 32 months, p=0.1989) and chances of hemorrhage (4.8% versus 3.5%, p=0.690) in patients with hemorrhagic as compared to non-hemorrhagic presentation. CONCLUSION: Prior hemorrhage does not affect the outcome after GKS in terms of obliteration rate, latency to obliteration as well as chances of hemorrhage during latency period. Gamma knife appears equally efficacious irrespective of the mode of clinical presentation in the management of cerebral AVMs; a concomitant use of pre-GKS embolization/surgery may be needed in patients with hemorrhagic presentation in selected cases, however.     

Eumycetoma presenting as a cerebellopontine angle mass lesion

Eumycetoma in the cerebellopontine angle region is extremely uncommon with no case being reported as per an extensive review of the literature by the authors. The authors report a case of cerebellopontine angle eumycetoma in a young female managed by subtotal decompression and antifungal treatment. The pre-operative diagnosis of eumycetoma in this location is extremely difficult and the role of histopathology is very important to characterize this uncommon lesion. The prognosis of this bizarre pathology is dismal despite all treatment modalities as compared to the usual tumors of the cerebellopontine angle that generally have a favorable outcome.     

Prefrontal cortex and insight in schizophrenia: a volumetric MRI study

Previous studies have suggested a relationship between frontal lobe-based neuropsychological functions and insight in schizophrenia. There is some evidence linking both smaller whole brain volume and frontal cortical atrophy to poor insight in this population. We investigated the relationship between total as well as specific prefrontal regional volumes and insight in schizophrenia. Twenty-eight stable outpatients with schizophrenia underwent magnetic resonance imaging scanning and assessment for insight. Insight was measured using the Birchwood self-report Insight Scale and the Expanded Schedule of Assessment of Insight. The whole brain and prefrontal regional (superior frontal, middle frontal, inferior frontal and orbitofrontal) volumes were then manually measured using the Cavalieri method and established criteria. Twenty healthy subjects were also scanned to provide control data for volumetric assessments. Smaller total prefrontal grey matter volume was moderately associated with a lower level of insight into the presence of illness. At the prefrontal sub-regional level, volumes of the superior, inferior and orbitofrontal regions contributed to this relationship, especially in males. It is concluded that smaller prefrontal grey matter volume is associated with poor insight into the presence of illness in stable schizophrenia patients. Future research should examine the association of specific dimensions of insight with frontal as well as non-frontal regional brain volumes.     

The anxiogenic drug FG-7142 increases serotonin metabolism in the rat medial prefrontal cortex

The neural mechanisms underlying anxiety states are believed to involve interactions among forebrain limbic circuits and brainstem serotonergic systems. Consistent with this hypothesis, FG-7142, a partial inverse agonist at the benzodiazepine allosteric site of the GABAA receptor, increases c-Fos expression within a subpopulation of brainstem serotonergic neurons. Paradoxically, FG-7142 has no effect on extracellular serotonin concentrations, as measured using in vivo microdialysis, in certain anxiety-related brain structures. This study tested the hypothesis that FG-7142 alters serotonin metabolism within one or more nodes of a defined anxiety-related forebrain circuit. Rats received one of four treatments (vehicle, 1.9, 3.8, or 7.5 mg/kg FG-7142, i.p.) and brains were collected 1 h following treatment. Thirteen forebrain regions were microdissected and analyzed for l-tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations using high pressure liquid chromatography with electrochemical detection. FG-7142 (7.5 mg/kg) increased l-tryptophan, serotonin, and 5-hydroxyindoleacetic acid concentrations in the prelimbic cortex but not in several other regions studied including subdivisions of the amygdala and bed nucleus of the stria terminalis. These data demonstrate that FG-7142 alters brain tryptophan concentrations and serotonin metabolism in specific components of an anxiety-related forebrain circuit including the medial prefrontal cortex, an important structure involved in executive function and the regulation of emotional behavior.