A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression.

Target identification and contact selection are known contributors to variability in efficacy across different clinical indications of deep brain stimulation surgery. A retrospective analysis of responders to subcallosal cingulate deep brain stimulation (SCC DBS) for depression demonstrated the common impact of the electrical stimulation on a stereotypic connectome of converging white matter bundles (forceps minor, uncinate fasciculus, cingulum and fronto-striatal fibers). To test the utility of a prospective connectomic approach for SCC DBS surgery, this pilot study used the four-bundle tractography 'connectome blueprint' to plan surgical targeting in 11 participants with treatment-resistant depression. Before surgery, targets were selected individually using deterministic tractography. Selection of contacts for chronic stimulation was made by matching the post-operative probabilistic tractography map to the pre-surgical deterministic tractography map for each subject. Intraoperative behavioral responses were used as a secondary verification of location. A probabilistic tract map of all participants demonstrated inclusion of the four bundles as intended, matching the connectome blueprint previously defined. Eight of 11 patients (72.7%) were responders and 5 were remitters after 6 months of open-label stimulation. At one year, 9 of 11 patients (81.8%) were responders, with 6 of them in remission. These results support the utility of a group probabilistic tractography map as a connectome blueprint for individualized, patient-specific, deterministic tractography targeting, confirming retrospective findings previously published. This new method represents a connectomic approach to guide future SCC DBS studies.

Targeting synapses and myelin in the prevention of schizophrenia.

Many of the functions that are mediated by the prefrontal cortex (PFC) are severely impaired in schizophrenia. The maturation of these functions takes place during late adolescence and early adulthood, which coincides with the period of time when overt symptomatology of schizophrenia most commonly emerges. Two developmental processes occurring during the periadolescence period appear to mediate the functional maturation of the PFC: pruning of exuberant synapses and myelination of axons. It has long been speculated in the literature that disturbances of these processes may result in dysfunction of the PFC and thereby trigger the emergence of symptoms and deficits of schizophrenia. Alternatively, but not mutually exclusively, it has also been suggested that these late developmental processes may not be aberrant but they "unmask" preexisting deficits in the PFC, resulting in the onset of symptoms. The important implication of both of these scenarios is that in either case the emergence of PFC functional disturbances and the onset of symptoms and deficits of schizophrenia would in theory be preventable by pharmacologic manipulation of the synaptic pruning and/or axonal myelination processes. Thus, better understanding of the cellular and molecular mechanisms that mediate these processes will provide truly novel insight into the therapeutics and prevention of schizophrenia.

Stereoselective bimolecular phenoxy radical coupling by an auxiliary (dirigent) protein without an active center.

The regio- and stereospecificity of bimolecular phenoxy radical coupling reactions, of especial importance in lignin and lignan biosynthesis, are clearly controlled in some manner in vivo; yet in vitro coupling by oxidases, such as laccases, only produce racemic products. In other words, laccases, peroxidases, and comparable oxidases are unable to control regio- or stereospecificity by themselves and thus some other agent must exist. A 78-kilodalton protein has been isolated that, in the presence of an oxidase or one electron oxidant, effects stereoselective bimolecular phenoxy radical coupling in vitro. Itself lacking a catalytically active (oxidative) center, its mechanism of action is presumed to involve capture of E-coniferyl alcohol-derived free-radical intermediates, with consequent stereoselective coupling to give (+)-pinoresinol.