Faculty Bibliography

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!

Calcium mobilization in cerebellar Purkinje cell (PC) of CD38 knockout mouse was imaged using two photon microscopy. CD38 is a homolog of ADP-ribosyl cyclase which activates Cyclic ADP-ribose, an endogenous Calcium Induced Calcium Release (CICR)regulator (Lee, 2001 ). In the CD38 knockout mouse (CD38(-/-)), which showed no phenotypic motor abnormalities, whole cerebellar cyclic ADP-ribose (cADPR) was reduced to a quarter of that in a wild control (CD38(+/+)). In addition caffeine treated CD38(-/-) PC dendrite showed a markedly reduced calcium response to a test depolarizing pulse most probably related to the reduced CICR. Cerebellar long-term depression (LTD) induced by the parallel fiber (PF) -climbing fiber (CF) conjunctional stimulation was absent in CD38(-/-) PC. However, during very prolonged direct depolarization of Purkinje cell somata, or when the test (PF) stimulation was quite close to the cell body during direct somatic depolarization, LTD could be induced in CD38(-/-) PC by the PF/depolarizing pulse conjunction. Overall, the CD38/cADPR system seems to be sensing/regulating intradendritic calcium levels. This seems to be an important modulator of the integrative properties of Purkinje cell activity. It seems clear that if (Ca)i becomes high enough to be deleterious to neuronal viability such system must be down regulated via LTD as a neuroprotective response to reduce further calcium increase. Immuno-staining study with a polyclonal CD38 antibody is presently in progress which is expected to find different levels of CD38 on the Purkinje cell soma, dendrites and spines of wild type mouse (CD38(+/+)) vs CD38 knockout cerebella

Thalamic relay cells occupy a pivotal position in cerebral architecture, and characterizing the manner in which they integrate ascending and descending input is a requisite for understanding cortical function. It was demonstrated by McCormick and Huguenard in the early 1990's that the relay and low threshold burst modes of intrinsic response can be readily modeled using a single somatic compartment with an appropriate set of voltage and calcium concentration-gated currents. However, the study of synaptic integration in model cells requires simulations incorporating the dendritic tree. Destexhe, Huguenard and coworkers have decribed a relay cell model including a dendritic tree (Destexhe et al 1998) which concluded a predominantly distal T-channel density distribution, primarily constrained by recordings from acutely dissociated cells. There is however another intrinsic electrophysiological characteristic of relay cells which models have not yet accounted for: at holding potentials near spike threshold, relay cells produce a waxing and waning subthreshold oscillation observable at the soma (Pedroarena and Llinas 1996). Here we present the development of a new model of the thalamic relay cell, guided by the simultaneous constraints that it must produce the relay and low threshold burst modes which characterize these cells, as well as the ripple occurring at near-threshold holding potentials. We arrive at a model cell which is capable of the production isolated fast Ca2+ spikes in distal branch segments, driven by a rapidly inactivating high threshold channel. The model reproduces the low threshold spike behavior of the relay cell without requiring high T current density in the distal dendritic segments, and thus presents an alternative picture of the dendritic tree of relay cells, in which fast high threshold Ca2+ events occur distally, and slower T channel-driven spikes are primarily proximally driven. If borne out by direct experimental evidence, this model would have implications for the integration of descending and ascending inputs

The olivo-cerebellar network plays a key role in the organization of vertebrate motor control. The oscillatory properties of inferior olive (IO) neurons have been shown to provide timing signals for motor coordination in which spatio-temporal coherent oscillatory neuronal clusters control movement dynamics. Based on the neuronal connectivity and electrophysiology of the olivo-cerebellar network we have developed a general-purpose control approach, which we refer to as a universal control system (UCS), capable of dealing with a large number of actuator parameters in real time. In this UCS, the imposed goal and the resultant feedback from the actuators specify system properties. The goal is realized through implementing an architecture that can regulate a large number of parameters simultaneously by providing stimuli-modulated spatio-temporal cluster dynamics

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