The basic research and teaching missions of Cingulum NeuroSciences Institute produce numerous new strategies for interceding in brain function to alter activity of cingulate cortex. Cingulate NeuroTherapeutics (CNT) was established to implement these new strategies for brain therapy through both non-invasive psychotherapies and drug therapeutics. Thus, CNT is the clinical research and development arm of the company. It currently provides diagnostic imaging and imaging for CNS drug development services. It is involved in a number of clinical research projects that seek to demonstrate the functional efficacy of pharmacological and cognitive therapeutics in a broad range of neuropsychiatric conditions, including chronic pain, anxiety, depression, and aging related disorders. Both business units contribute to a Clinical Research Training program for Medical Residents. CNT provides imaging and clinical technology expertise in CNS drug research and development programs for pharmaceutical corporations.
Non-invasive imaging methods have become established tools in the modern drug research and development process. CNT provides imaging expertise and consulting services to pharmaceutical companies including development of clinical imaging localization technologies for drug research and development, which fit specific company needs. We work closely with clinical program directors and discovery scientists in finding appropriate external imaging facilities and imaging scientists to test new compounds and drugs. We educate company personnel in localization imaging technologies and drug development through seminar presentations and consulting. Specific areas of expertise include the following:
We do not seek to replicate the services of neuroradiology departments. Our expertise is in the high-resolution localization of any signal or signal change in the brains of either human or monkey species. This includes changes in fluorodeoxy-glucose (PET), regional cerebral blood flow (PET), ligand binding (PET), and functional activation (fMRI). This can involve assessing images provided from the primary data and/or reanalyzing the data with different planes of sections, statistical thresholds, or other analytical modifications. We also consider the normal and impaired functions of regions of interest from a physiological and receptor function point of view that is not part of routine neuroradiological assessments.
For example, where most studies of opiate binding present binding to medial cortex, our assessments emphasize different densities of binding (volumes of distribution; VDtot) in highly defined subregions including divisions of anterior cingulate cortex on the gyral surface and sulcal depths. PET co-registered to MRI were used to define 37 regions of interest on the medial surface for assessing VDtot of [11C]diprenorphine binding and these calculations were converted to three ranges of binding, color coded, and plotted onto the medial surface MRI for these cases (Vogt et al., 1995; Human Brain Mapping 3:1-12; "Topography of diprenorphine binding in human cingulate gyrus and adjacent cortex derived from coregistered PET and MR Images"). The resulting plots are shown below and were further analyzed in flat map representations of the medial cortex. No higher resolution methodology has even been applied to the in vivo localization of ligand binding in human brain. In this figure, highest binding is in the circle in perigenual anterior cingulate cortex (pACC). In contrast, binding in the cingulate sulcas in midcingulate cortex (MCC, CS) is very low.
In another example of localization of binding and second messenger formation, the photographs below are from Leslie Vogt et al. (2001; J Pharmacol Exper Ther 299:840-848, "Colocalization of m-opioid receptors and activated G-proteins in rat cingulate cortex"). They show localization of the mu-selective ligand binding of Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO) and its stimulation of [35S]GTPgS binding in sections of anterior cingulate cortex. The binding and G-protein stimulation are localized to areas and layers in adjacent sections stained with the Nissl stain thionin. Also, notice that the right hemisphere has an undercut lesion that removed all inputs to anterior cingulate cortex without destroying the cortical neurons themselves. In this instance, there was a massive reduction in binding and stimulated G-protein activity in most layers. There was, however, some binding and activity left in layer I. With the use of a neurotoxin that kills noradrenergic neurons in the locus coeruleus, it was shown that these mu opioid receptors are localized to noradrengeric inputs to layer I of anterior cingulate cortex.
Thus, by "high-resolution localization techniques" we refer to a range of strategies to localize receptors, functions, and alterations associated with neurological and psychiatric diseases in human as well as non-human primate and other animal models.
- Morphometric MRI
- Functional MRI
- PET and MicroPET
Human Imaging Analysis
Beth Krauss provides statistical analysis of imaging data with FSL, SPM, and other software packages.