Oscillatory network markers of subcallosal cingulate deep brain stimulation for depression.

Identifying functional biomarkers related to treatment success can aid in expediting therapy optimization, as well as contribute to a better understanding of the neural mechanisms of the treatment-resistant depression (TRD) and subcallosal cingulate deep brain stimulation (SCC-DBS). Magnetoencephalography data were obtained from 16 individuals with SCC-DBS for TRD and 25 healthy subjects. The first objective of the study was to identify region-specific oscillatory modulations that both (i) discriminate individuals with TRD (with SCC-DBS OFF) from healthy controls, and (ii) discriminate TRD treatment responders from non-responders (with SCC-DBS ON). The second objective of this work was to further explore the effects of stimulation intensity and frequency on oscillatory activity in the identified brain regions of interest. Oscillatory power analyses led to the identification of brain regions that differentiated responders from non-responders based on modulations of increased alpha (8-12 Hz) and decreased gamma (32-116 Hz) power within nodes of the default mode, central executive, and somatomotor networks, Broca's area, and lingual gyrus. Within these nodes, it was also found that low stimulation frequency had stronger effects on oscillatory modulation than increased stimulation intensity. The identified functional network biomarkers implicate modulation of TRD-related activity in brain regions involved in emotional control/processing, motor control, and the interaction between speech, vision, and memory, which have all been implicated in depression. These electrophysiological biomarkers have the potential to be used as functional proxies for therapy optimization. Additional stimulation parameter analyses revealed that oscillatory modulations can be strengthened by increasing stimulation intensity or reducing frequency, which may represent potential avenues of direction in non-responders.

Induction of anti-GM1 ganglioside antibodies by Campylobacter jejuni lipopolysaccharides.

A frequent association exists between acute motor neuropathy, antecedent Campylobacter jejuni (CJ) and anti-GM ganglioside antibodies. Despite the chemical and immunological similarity between CJ lipopolysaccharides (LPS) and GM1, the mechanism of induction of anti-GM1 antibodies is still unclear. We used CJ LPS to immunize rats, mice and immunodeficient mice lacking in NK, CD8+ or T-cell populations. None of these animals developed significant anti-GM1 titers. However, rats immunized with keyhole limpet hemocyanin which contains the cross-reactive sugar epitope Gal(beta1-3)GalNAc developed high titers of IgM anti-GM1 antibodies. This occurred only after these rats were given an intraperitoneal injection of CJ LPS. These results suggest that a glycoprotein antigenic stimulus can induce B-cells which are autoreactive to ganglioside but which remain anergic. A second stimulus with a cross-reactive LPS can then overcome the anergy to induce autoantibody production. A similar mechanism may explain the occurrence of GM1 antibodies in patients after CJ enteritis.

Keyhole limpet hemocyanin contains Gal(beta 1-3)-GalNAc determinants that are cross-reactive with the T antigen.

Keyhole limpet hemocyanin (KLH) is widely used as a carrier molecule to enhance immune responses to administered antigens, and for immunotherapy of bladder and renal carcinoma. In the present study we show, using lectin and antibody binding studies, that native KLH contains Gal(beta 1-3)GalNAc-bearing oligosaccharides, and that immunization with KLH in Lewis rats induces the production of anti-Gal(beta 1-3) GalNAc antibodies. This might explain the beneficial effect of KLH in bladder cancers that express cross-reactive Gal(beta 1-3)GalNAc determinants or the T antigen.

Monoclonal IgM antibodies to GM1 and asialo-GM1 in chronic neuropathies cross-react with Campylobacter jejuni lipopolysaccharides.

We tested monoclonal IgM anti-GM1 and asialo-GM1 antibodies from 6 patients with chronic motor neuropathies for binding to lipopolysaccharides (LPS) from three stains of Campylobacter jejuni. Four of the 6 patients showed strong reactivity with LPS from at least one of the three C. jejuni strains tested as shown by enzyme-linked immunosorbent assay or western blot. Preabsorption with GM1 or asialo-GM1, or blocking with cholera toxin, prevented antibody binding to LPS. These studies indicate that human anti-GM1 or anti-asialo-GM1 antibodies cross-react with LPS from certain strains of C. jejuni, and that bacterial LPS might provide antigenic stimuli for the activation of B cells expressing anti-GM1 antibodies.

Identification of Gal(beta 1-3)GalNAc bearing glycoproteins at the nodes of Ranvier in peripheral nerve.

A subset of human anti-GM1 ganglioside antibodies cross-reacts with Gal(beta 1-3)GalNAc bearing glycoproteins in peripheral nerve and spinal cord. The same oligosaccharide determinant is recognized by the lectin peanut agglutinin (PNA) which binds at the nodes of Ranvier in intact peripheral nerve. The Gal(beta 1-3)GalNAc bearing glycoproteins were isolated using PNA lectin affinity chromatography followed by separation on Western blot, and the proteins were subjected to partial amino acid sequence analysis. Two major PNA binding glycoproteins were identified in peripheral nerve and spinal cord; one had an approximate molecular weight of 120 kD and had sequence homology to the oligodendrocyte-myelin glycoprotein (OMgp). The other migrated between 70 and 80 kD and had sequence homology to the hyaluronate binding domain of versican, which has been reported to share sequence homology with the 70 kD proteins hyaluronectin and the glial hyaluronic acid binding protein (GHAP). By immunocytochemistry, OMgp was localized to the paranodal region of myelin, and the protein homologous to the hyaluronate binding domain of versican was localized to the nodal gap in peripheral nerve. These PNA binding glycoproteins might be target antigens for autoantibodies in peripheral nerve.