Hypothalamic deep brain stimulation influences autonomic and limbic circuitry involved in the regulation of aggression and cardiocerebrovascular control in the Göttingen minipig.

BACKGROUND: Deep brain stimulation (DBS) in the ventral tuberal hypothalamus (VTH) is currently under investigation for the treatment of severe obesity. Stimulation impact on a number of closely related hypothalamic neural systems could potentially influence normal hypothalamic function and thereby generate adverse side effects. OBJECTIVE: To assess the feasibility and safety of VTH DBS in a non-primate large animal model. METHODS: In the VTH of 6 Göttingen minipigs, quadropolar leads were implanted bilaterally (n = 2) or unilaterally (n = 4), using optimized MRI sequences allowing identification of major diencephalic landmarks. Heart rate, weight, behavior and nighttime locomotor activity were recorded throughout the study period. Two of the unilaterally implanted minipigs were examined with [15O]H2O positron emission tomography (PET) scans performed in DBS-off and DBS-on mode. RESULTS: VTH DBS elicited an amplitude-dependent increase in heart rate and transient aggressive behavior. PET demonstrated that VTH DBS caused a global increase in cerebral blood flow velocities and decreased mean transit time. CONCLUSIONS: VTH DBS results in behavioral and physiological changes, which may derive from activation of closely related limbic and autonomic networks. Caution and further studies of longer length should be requested before this procedure is used more widely in humans.

Longitudinal MR study of brain structure and hippocampus volume in major depressive disorder.

OBJECTIVE: To determine whether long-term course of treated major depression has an effect on the structure of the brain and the hippocampal volume. METHOD: An 11-year follow-up procedure was used with data collection at baseline and again at follow-up. Tensor-based morphometry (TBM) and automatic hippocampal volume measure was performed on different datasets. The baseline dataset consisted of T1-weighted magnetic resonance images (MRIs) of 24 in-patients suffering from major depression and 33 healthy controls. The second dataset consisted of T1-weighted MRIs of 31 remitted depressive patients and 36 healthy controls. The longitudinal dataset consisted of 19 patients and 19 matched healthy controls present at both the first and the second dataset. Brain segmentation and hippocampal segmentation were fully automated and were based on a spatial normalization to the International Consortium of Brain Mapping (ICBM) non-linear model. RESULTS: Depressed patients were found to have smaller temporal lobes bilaterally, medulla and right hippocampus at baseline. However, these changes were not found at follow-up 11 years later. Moreover, these changes did not significantly correlate with the illness outcome. CONCLUSION: Brain structure changes seem to be state dependent in major depression, only occurring in acute episode of major depression and normalizing after remission.

A deformation-based morphometry study of patients with early-stage Parkinson's disease.

BACKGROUND AND PURPOSE: Previous volumetric magnetic resonance imaging (MRI) studies of Parkinson's disease (PD) utilized primarily voxel-based morphometry (VBM), and investigated mostly patients with moderate- to late-stage disease. We now use deformation-based morphometry (DBM), a method purported to be more sensitive than VBM, to test for atrophy in patients with early-stage PD. METHODS: T1-weighted MRI images from 24 early-stage PD patients and 26 age-matched normal control subjects were compared using DBM. Two separate studies were conducted, where two minimally-biased nonlinear intensity-average were created; one for all subjects and another for just the PD patients. The DBM technique creates an average population-based MRI-average in an iterative hierarchical fashion. The nonlinear transformations estimated to match each subject to the MRI-average were then analysed. RESULTS: The DBM comparison between patients and controls revealed significant contraction in the left cerebellum, and non-significant trends towards frontal, temporal and cingulate sulcal expansions with frontal and temporal white matter contractions. Within the patient group, the unified PD rating scores were highly correlated with local expansions in or near sulci bordering on frontal and temporal cortex. CONCLUSION: Our results suggest that DBM could be a sensitive method for detecting morphological changes in early-stage PD.

Effect of memantine on CBF and CMRO2 in patients with early Parkinson's disease.

OBJECTIVES: Parkinson's disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (rCBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD. METHODS: Quantitative positron emission tomography (PET) recordings were obtained with 15O]water and 15O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg memantine. Dynamic PET data were analyzed using volume of interest and voxel-based approaches. RESULTS: The treatment evoked rCBF decreases in basal ganglia, and in several frontal cortical areas. The regional cerebral metabolic rate of oxygen (rCMRO2) did not decrease in any of the a priori defined regions, and consequently the oxygen extraction fraction was increased in these regions. Two peaks of significantly decreased rCMRO2 were detected near the frontal poles in both hemispheres, using a posteriori voxel-based analysis. CONCLUSIONS: Although we did not find the predicted decrease in basal ganglia oxygen consumption, our data suggest that treatment with memantine actively modulates neuronal activity and/or hemodynamic response in basal ganglia of PD patients. This finding may be relevant to the putative neuroprotective properties of NMDAR antagonists.

The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted to a minipig model of Parkinson's disease: preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers.

A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (approximately 2 ng GDNF/h/10(5) cells). MPTP was administered (1 mg/kg/day, SC) for 7-10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the "Parkinson's score") had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [11C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [11C]raclopride to the dopamine D2-like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.

Formation of homocytotropic antibodies with penicilloyl specificity in the rabbit.

The formation of homocytotropic antibodies (IgE) as determined by immunochemical characteristics against penicilloyl in rabbits was shown. The production of such antibodies to azidocilloyl-human serum albumin (AzO10-HSA) in alum was found optimal using 1 mg of antigen in the tested range of 0.01-8 mg. At the lowest dose (0.01 mg) only haemagglutinating but no IgE antibodies were formed. Immunization with azidocilloyl-bovine gamma-globulin (AzO9-BGG) resulted in a slower increase in antibody levels than was caused by AzO10-HSA. Univalent benzylpenicilloyl-epsilon-aminocaproate or ampicillin given together with the antigen upon immunization decreased the levels of penicllloyl specific IgE and haemagglutinating antibodies, but induced the formation of IgE antibodies against the carrier molecule. Further, the administration of penicilloyl specific IgG antibodies diminished formation of both IgE and haemagglutinating antibodies, but no antibodies specific for the carrier were formed. The usefulness of this animal model for the experimental study of penicillin allergy is discussed.