Faculty Bibliography

This paper represents an effort to review the history of the various conceptualizations of schizophrenia as a mental disorder, and to summarize issues concerning diagnosis and etiology. The question of biologically based diagnosis is considered

Clearly, more clinical experience must be amassed to define in detail the possibilities of this surgical approach in disabling neuropsychiatric disorders. We propose, however, that the evidence for benign and efficient surgical intervention against the neuropsychiatric TCD syndrome is already compelling. The potential appearance of strong postoperative reactive manifestations requires a close association between surgery and psychotherapy, with the latter providing support for the integration of the new situation as well as the resolution of old unresolved issues

Ongoing studies indicate that the conjunction of spontaneous thalamocortical activity, at low-(theta; 4-8Hz) and high-(gamma; 25-50Hz) frequencies serves as the physiological basis for a set of disorders we have termed the thalamocortical dysrhythmia syndromes (TCD). Elements in this set are proposed to include Parkinson's disease, tinnitus, central pain, OCD, depression and schizoaffective (SA) disorder. The common denominator is a prominent theta-range oscillation underlying negative symptoms, in temporal coherence with gamma band activity relating to positive symptoms. Results demonstrate that localization of TCD activity is possible and add a more direct functional dimension to results obtained with other imaging techniques.Continuous neuromagnetic activity was recorded with whole-head MEG (4D Neuroimaging) from 6 subjects with SA disorder and 8 healthy controls. Multitaper spectral estimation was used to calculate frequency spectra, and independent components (ICs) were derived with EEGlab software. Selected ICs were localized in a probabilistic sourcespace. A recursive weighted minimum norm algorithm was used to calculate solutions for current density localization.Power spectra from controls demonstrated typical occipital alpha rhythm, while spectra from SA subjects showed an increase in theta power localized in mediofrontal supraorbital and temporal areas. These results support a model in which deinactivation of thalamic T-type Ca++ currents leads to localized oscillatory changes. The presence of both frontal and temporal activity in individual ICs suggests functional synchronization between these areas in SA disorder and corroborates findings of low-frequency oscillation with metabolic hypofrontality in PET studies.It is concluded that ICA may identify and localize abnormal TC dynamics in SA disorder and that MEG represents an important tool in the investigation of TCD patients

Neuropsychiatric surgery has had a long and complex history with examples of less than optimal surgical procedures implemented in wrong settings. Such past errors have raised important philosophical and ethical issues that remain with us for good reasons. However, the existence of enormous suffering due to chronic therapy-resistant disabling neuropsychiatric disorders compels a search for alternative surgical approaches based on a sound understanding of the underlying physiopathological mechanisms. We bring evidence, from single cell physiology and magnetoencephalography, for the existence of a set of neuropsychiatric disorders characterized by localized and protracted low frequency spontaneous recurrent activation of the thalamocortical system. This condition, labeled thalamocortical dysrhythmia, underlies certain chronic psychotic, affective, obsessive compulsive, anxiety and impulse control disorders. Considering the central role of recurrent oscillatory thalamocortical properties in the generation of normal hemispheric functions, we propose a surgical approach that provides a reestablishment of normal thalamocortical oscillations without reduction of cortical tissue and its specific thalamic connectivity. It consists of small strategically placed pallidal and medial thalamic lesions that serve to make subcritical the increased low frequency thalamocortical recurrent network activity. This result is attained via reduction of both thalamic overinhibition and low frequency oversynchronization. Thalamic disinhibition is obtained by a lesion in the anterior medial paralimbic pallidum. The medial thalamic lesion is localized in the posterior part of the central lateral nucleus, where a large majority of cells have been shown to be locked in low frequency production and to have lost their normal activation patterns. We present here our experience with 11 patients, including clinical follow ups and pre- and postsurgical magnetoencephalographic studies. The evidence speaks (1) for a benign and effic!

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

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

BACKGROUND:A portion of the genetic risk factors for the personality trait neuroticism (N) may also increase risk for major depression (MD). Females have both higher levels of N and higher rates of MD than males, suggesting that these traits may be more genetically correlated in females. METHODS:Structured interviews, including a lifetime assessment for MD by DSM-III-R criteria, were administered to 863 male-male MZ (monozygotic), 649 male-male DZ (dizygotic), 506 female-female MZ, 345 female-female DZ, and 1,408 opposite-sex twin pairs. N was assessed using the short-form of the Eysenck Personality Questionnaire. A sex-limited Cholesky model was fitted which allowed us to decompose into additive genetic, common environmental, and individual-specific environmental components two main classes of correlations: within-sex between-variable and between-sex within-variable. RESULTS:Our best-fitting model contained only additive genetic and individual-specific environmental factors for both N and MD. The within-sex genetic correlations between N and MD were estimated at +0.68 in men and +0.49 in women. This model fitted only slightly better than one in which the N-MD within-sex genetic correlation was constrained to be equal across the sexes, and estimated at +0.55. There may be sex-specific genes influencing both N and MD. CONCLUSION/CONCLUSIONS:Our best-fitting model failed to establish a significant sex difference in the genetic correlation between N and MD. These results, as well as evidence for sex-specific genetic factors for both traits, have implications for the diagnosis, classification, and treatment of the affective disorders, and molecular genetic approaches to the study of these traits.