Imaging of thalamocortical dysrhythmia in neuropsychiatry.

Abnormal brain activity dynamics, in the sense of a thalamocortical dysrhythmia (TCD), has been proposed as the underlying mechanism for a subset of disorders that bridge the traditional delineations of neurology and neuropsychiatry. In order to test this proposal from a psychiatric perspective, a study using magnetoencephalography (MEG) was implemented in subjects with schizophrenic spectrum disorder (n = 14), obsessive-compulsive disorder (n = 10), or depressive disorder (n = 5) and in control individuals (n = 18). Detailed CNS electrophysiological analysis of these patients, using MEG, revealed the presence of abnormal theta range spectral power with typical TCD characteristics, in all cases. The use of independent component analysis and minimum-norm-based methods localized such TCD to ventromedial prefrontal and temporal cortices. The observed mode of oscillation was spectrally equivalent but spatially distinct from that of TCD observed in other related disorders, including Parkinson's disease, central tinnitus, neuropathic pain, and autism. The present results indicate that the functional basis for much of these pathologies may relate most fundamentally to the category of calcium channelopathies and serve as a model for the cellular substrate for low-frequency oscillations present in these psychiatric disorders, providing a basis for therapeutic strategies.

Differential regulation of catechol-O-methyltransferase expression in a mouse model of aggression.

This study was designed to understand molecular and cellular mechanisms underlying aggressive behaviors in mice exposed to repeated interactions in their homecage with conspecifics. A resident-intruder procedure was employed whereby two males were allowed to interact for 10 min trials, and aggressive and/or submissive behaviors (e.g., degree of attacking, biting, chasing, grooming, rearing, or upright posture) were assessed. Following 10 days of behavioral trials, brains were removed and dissected into specific regions including the cerebellum, frontal cortex, hippocampus, midbrain, pons, and striatum. Gene expression analysis was performed using real-time quantitative polymerase-chain reaction (qPCR) for catechol-O-methyltransferase (COMT) and tyrosine hydroxylase (TH). Compared to naive control mice, significant up regulation of COMT expression of residents was observed in the cerebellum, frontal cortex, hippocampus, midbrain, and striatum; in all of these brain regions the COMT expression of residents was also significantly higher than that of intruders. The intruders also had a significant down regulation (compared to naive control mice) within the hippocampus, indicating a selective decrease in COMT expression in the hippocampus of submissive subjects. Immunoblot analysis confirmed COMT up regulation in the midbrain and hippocampus of residents and down regulation in intruders. qPCR analysis of TH expression indicated significant up regulation in the midbrain of residents and concomitant down regulation in intruders. These findings implicate regionally- and behaviorally-specific regulation of COMT and TH expression in aggressive and submissive behaviors. Additional molecular and cellular characterization of COMT, TH, and other potential targets is warranted within this animal model of aggression.

Predictors of aggression on the psychiatric inpatient service.

Patients with severe mental illness are at increased risk to commit acts of aggression in the inpatient hospital setting. Aggressive behaviors have severe negative consequences for the patient, victims, clinical staff, and the therapeutic community as a whole. While risk factors of community and inpatient aggression overlap, many predictive factors diverge between the two settings. For example, while medication noncompliance has been a robust predictor of community aggression, this factor has little predictive value for inpatient settings where patients' pharmacotherapy is closely monitored. Relatively fewer investigators have examined a wide range of predictive factors associated with aggressive acts committed on the psychiatry inpatient service, often with conflicting results. The present study examined demographic, clinical, and neurocognitive performance predictors of self, other, object, and verbal aggressiveness in 118 acute inpatients. Results revealed that the arrival status at the hospital (voluntary vs involuntary), female gender, and substance abuse diagnosis were predictors of verbal aggression and aggression against others. Impaired memory functioning also predicted object aggression. Fewer symptoms, combined with higher cognition functioning, however, were significant predictors of self-aggressive acts committed on the inpatient service. The need for relating predictors of specific types of aggressiveness in schizophrenia is discussed.

Cocaine craving and attentional bias in cocaine-dependent schizophrenic patients.

Cocaine craving has been implicated as a major factor underlying addiction and drug relapse. From a cognitive viewpoint, craving may reflect, in part, attentional processing biased in favor of drug-related cues and stimuli. Schizophrenic individuals (SZ), however, abuse cocaine in high numbers but typically manifest baseline cognitive deficits that impair their ability to selectively allocate their attentional resources. In this study, we examined the relationship between attentional bias and craving in patients with cocaine dependence (COC; n=20), schizophrenic patients comorbid for cocaine dependence (COC+SZ; n=23), as well as two other comparison groups using a modified version of the Stroop test to include cocaine-relevant words. Results revealed that only the COC patients demonstrated Stroop interference on the cocaine-related words. Moreover, COC patients' attentional processing biases were significantly associated with their cocaine craving severity ratings. COC+SZ patients, in contrast, did not demonstrate Stroop interference and manifested significantly fewer craving symptoms than their COC counterparts. These results suggest that COC+SZ patients' inability to selectively encode their drug-use experience may limit and shape their subjective experience of craving cocaine and motivation for cocaine use.

A molecular basis of the therapeutic and psychoactive properties of cannabis (delta9-tetrahydrocannabinol).

All of the therapeutic properties of marihuana (analgesic, antiemetic, appetite stimulant, antiglaucoma) have been duplicated by the tetrahydrocannabinol (THC) molecule or its synthetic derivatives. Today, the molecular mechanisms of action of these compounds have led to a general understanding of the pharmacological effects of marihuana and of its therapeutic properties. These mechanisms involve the specific binding of THC to the 7-transmembrane (7TM) domain G protein-linked receptor, a molecular switch which regulates signal transduction in the cell membrane. The natural ligand of the 7TM receptor is an eicosanoid, arachidonylethanolamide (AEA), generated in the membrane and derived from arachidonic acid. THC acts as a substitute ligand to the 7TM receptor site of AEA. THC would deregulate the physiological function of the 7TM receptor and of its ligand AEA. As a result, the therapeutic effects of the drug may not be separated from its adverse psychoactive and cardiovascular effects. The binding of THC to the 7TM receptor site of AEA induces allosteric changes in the receptor sites of neurotransmitter and opiates resulting in variable interactions and pharmacological responses. The pharmacokinetics of THC with its prolonged storage in fat and its slow release result in variable and delayed pharmacological response, which precludes precise dosing to achieve timely therapeutic effects. The experimental use of THC and of its synthetic analogues, agonists, and antagonists has provided novel information in the nature of molecular signaling in the cell membrane. As a result, the relationships between allosteric receptor responsiveness, molecular configuration of proteins, and physiological regulation of cellular and organ function may be further investigated.

Subtyping of psychiatric disorders: implications for drug development.

Psychiatric diagnosis suffers from being based on phenomenology and not on pathophysiology. Data are presented showing that psychiatric patients reveal consistent quantitative electroencephalographic abnormalities, such that they can be separated from normals and from each other. Clustering these pathophysiological groupings reveals an underlying variability, which permits useful subtyping. Data are presented relating subtyping to pharmacological treatment.