Integration of electrical neuroimaging with other functional imaging methods

Integrating evidence from different imaging modalities is important to overcome specific limitations of any given imaging method, such as insensitivity of the EEG to unsynchronized neural events, or the lack of fMRI sensitivity to events of low metabolic demand. Processes that are visible in one modality may be related in a nontrivial way to other processes visible in another modality and insight may only be obtained by integrating both methods through a common analysis. For example, brain activity at rest seems to be at least partly determined by an interaction of cortical rhythms (visible to EEG but not to fMRI) with sub-cortical activity (visible to fMRI, but usually not to EEG without averaging). A combination of EEG and fMRI data during rest may thus be more informative than the sum of two separate analyses in both modalities. Integration is also an important source of converging evidence about specific aspects and general principles of neural functions and their dysfunctions in certain pathologies. This is because not only electrical, but also energetic, biochemical, hemodynamic and metabolic processes characterize neural states and functions, and because brain structure provides crucial constraints upon neural functions. Focusing on multimodal integration of functional data should not distract from the privileged status of the electric field as the primary direct, noninvasive real-time measure of neural transmission. The preceding chapters illustrate how electrical neuroimaging has turned scalp EEG into an imaging modality which directly captures the full temporal dynamics of neural activity in the brain.

Effect of IGF-I therapy on VLDL apolipoprotein B100 metabolism in type 1 diabetes mellitus

Abnormal lipid metabolism may be related to the increased cardiovascular risk in type 1 diabetes. Secretion and clearance rates of very low density lipoprotein (VLDL) apolipoprotein B100 (apoB) determine plasma lipid concentrations. Type 1 diabetes is characterized by increased growth hormone (GH) secretion and decreased insulin-like growth factor (IGF) I concentrations. High-dose IGF-I therapy improves the lipid profile in type 1 diabetes. This study examined the effect of low-dose (40 microg.kg(-1).day(-1)) IGF-I therapy on VLDL apoB metabolism, VLDL composition, and the GH-IGF-I axis during euglycemia in type 1 diabetes. Using a stable isotope technique, VLDL apoB kinetics were estimated before and after 1 wk of IGF-I therapy in 12 patients with type 1 diabetes in a double-blind, placebo-controlled trial. Fasting plasma triglyceride (P < 0.03), VLDL-triglyceride concentrations (P < 0.05), and the VLDL-triglyceride-to-VLDL apoB ratio (P < 0.002) significantly decreased after IGF-I therapy, whereas VLDL apoB kinetics were not significantly affected by IGF-I therapy. IGF-I therapy resulted in a significant increase in IGF-I and a significant reduction in GH concentrations. The mean overnight insulin concentrations during euglycemia decreased by 25% after IGF-I therapy. These results indicate that low-dose IGF-I therapy restores the GH-IGF-I axis in type 1 diabetes. IGF-I therapy changes fasting triglyceride concentrations and VLDL composition probably because of an increase in insulin sensitivity.

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp

Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 microg x kg(-1) x day(-1)) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1-13C]leucine and [6-6-2H2]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26+/-0.07 vs. 0.17+/-0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (approximately 67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37+/-6 vs. 52+/-10 micromol x kg(-1) x min(-1), P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (approximately 28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17+/-0.03 vs. -0.10+/-0.02, P < 0.01, and 0.25+/-0.08 vs. 0.40+/-0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulin-stimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes.

Growth hormone replacement in adults with growth hormone deficiency: assessment of current knowledge

The recent availability of recombinant human growth hormone (GH) has led to intense investigation of the consequences of adult GH deficiency (GHD) and the effects of GH replacement. These studies have led to the identification of a characteristic syndrome of GHD consisting of decreased mood and well-being, with alterations in body composition and substrate metabolism. In both placebo-controlled and open studies, GH replacement therapy has consistently been shown to reverse or correct these features. Whether long-term GH replacement will result in a reduction of osteoporotic fractures, cardiovascular morbidity and mortality is not yet known. To date, no permanent serious adverse effects have been associated with GH replacement in GHD, and although currently expensive, it is anticipated that GH replacement will become routine in the treatment of the severely hypopituitary adult.

The identification of cerebral volume changes in treated growth hormone-deficient adults using serial 3D MR image processing

A pilot study to detect volume changes of cerebral structures in growth hormone (GH)-deficient adults treated with GH using serial 3D MR image processing and to assess need for segmentation prior to registration was conducted.

Growth hormone replacement therapy in adults with growth hormone deficiency improves vascular reactivity

Patients with adult growth hormone (GH) deficiency are thought to be of increased risk of cardiovascular disease. Impaired vascular reactivity to endothelium derived nitric oxid (NO) is an early event in the development of atherosclerosis. In order to detect a possible effect of GH on vascular endothelium we examined forearm vasodilator responses in 8 patients with adult GH-deficiency before and after 3 months GH replacement therapy.

Dynamics of lipoprotein metabolism in adult growth hormone deficiency

Dyslipidaemia is often associated with adult growth hormone (GH) deficiency. Reduced removal of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apo B-100) can, in part, explain the "unfavourable" lipid profile of these patients. By modifying VLDL composition and through its action on low-density lipoprotein (LDL) receptors, GH may improve the lipid profile by increasing direct hepatic uptake of VLDL apo B-100, thereby decreasing conversion to LDL. Although GH stimulates VLDL apo B-100 secretion, this is exceeded by its effects in upregulating LDL receptors and modifying VLDL composition. We hypothesize that the improved lipid profile, in particular the decrease in cholesterol-rich VLDL particles, may contribute to a possible antiatherogenic action of GH. GH appears to have an important role in hepatic apo B-100 metabolism. However, we are just at the beginning of understanding the underlying mechanism. Further studies are required to investigate the effect of GH on other lipoprotein classes, in particular VLDL subfractions, intermediate-density lipoprotein, LDL and high-density lipoprotein. The key question, however, remains as to whether GH replacement therapy can reduce cardiovascular mortality. Long-term studies with sufficient numbers of patients are required to answer this question.

The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with growth hormone deficiency

Total body water (TBW) is reduced in adult GH deficiency (GHD) largely due to a reduction of extracellular water. It is unknown whether total blood volume (TBV) contributes to the reduced extracellular water in GHD. GH and insulin-like growth factor I (IGF-I) have been demonstrated to stimulate erythropoiesis in vitro, in animal models, and in growing children. Whether GH has a regulatory effect on red cell mass (RCM) in adults is not known. We analyzed body composition by bioelectrical impedance and used standard radionuclide dilution methods to measure RCM and plasma volume (PV) along with measuring full blood count, ferritin, vitamin B12, red cell folate, IGF-I, IGF-binding protein-3, and erythropoietin in 13 adult patients with GHD as part of a 3-month, double blind, placebo-controlled trial of GH (0.036 U/kg.day). TBW and lean body mass significantly increased by 2.5 +/- 0.53 kg (mean +/- SEM; P < 0.004) and 3.4 +/- 0.73 kg (P < 0.004), respectively, and fat mass significantly decreased by 2.4 +/- 0.32 kg (P < 0.001) in the GH-treated group. The baseline RCM of all patients with GHD was lower than the predicted normal values (1635 +/- 108 vs. 1850 +/- 104 mL; P < 0.002). GH significantly increased RCM, PV, and TBV by 183 +/- 43 (P < 0.006), 350 +/- 117 (P < 0.03), and 515 +/- 109 (P < 0.004) mL, respectively. The red cell count increased by 0.36 +/- 0.116 x 10(12)/L (P < 0.03) with a decrease in ferritin levels by 39.1 +/- 4.84 micrograms/L (P < 0.001) after GH treatment. Serum IGF-I and IGF-binding protein-3 concentrations increased by 3.0 +/- 0.43 (P < 0.001) and 1.3 +/- 0.15 (P < 0.001) SD, respectively, but the erythropoietin concentration was unchanged after GH treatment. No significant changes in body composition or blood volume were recorded in the placebo group. Significant positive correlations could be established between changes in TBW and TBV, lean body mass and TBV (r = 0.78; P < 0.04 and r = 0.77; P < 0.04, respectively), and a significant negative correlation existed between changes in fat mass and changes in TBV in the GH-treated group (r = -0.95; P < 0.02). We conclude that 1) erythropoiesis is impaired in GHD; 2) GH stimulates erythropoiesis in adult GHD; and 3) GH increases PV and TBV, which may contribute to the increased exercise performance seen in these patients.

The consequences of growth hormone deficiency in adulthood, and the effects of growth hormone replacement

The availability of recombinant human growth hormone (GH) has resulted in investigation of the role of GH in adulthood and the effects of GH replacement in the GH-deficient adult. These studies have led to the recognition of a specific syndrome of GH-deficiency, characterized by symptoms, signs and investigative findings. Adults with long-standing growth hormone deficiency are often overweight, have altered body composition, with reduced lean body mass (LBM), increased fat mass (FM), reduced total body water and reduced bone mass. In addition, there is reduced physical and cardiac performance, altered substrate metabolism and an abnormal lipid profile predisposing to the development of cardiovascular disease. Adults with GH deficiency report reduced psychological well-being and quality of life. These changes may contribute to the morbidity and premature mortality observed in hypopituitary adults on conventional replacement therapy. GH treatment restores LBM, reduces FM, increases total body water and increases bone mass. Following GH therapy, increases are recorded in exercise capacity and protein synthesis, and "favourable" alterations occur in plasma lipids. In addition, psychological well-being and quality of life improve with replacement therapy. GH is well tolerated; adverse effects are largely related to fluid retention and respond to dose adjustment. It is likely that GH replacement will become standard therapy for the hypopituitary adult in the near future. The benefits of GH replacement in the GH-deficient adult have been unequivocally demonstrated in studies lasting up to 3 years. The results of longer term studies are awaited to determine whether these benefits are sustained over a lifetime.

Abnormalities of very low density lipoprotein apolipoprotein B-100 metabolism contribute to the dyslipidaemia of adult growth hormone deficiency

Increased cardiovascular mortality in adult growth hormone deficiency (GHD) may be, in part, explained by the dyslipidaemia associated with this condition. It is possible that abnormalities of very low density lipoprotein apolipoprotein B-100 (VLDL apoB) metabolism contribute to this dyslipidaemia. To test this hypothesis, we measured VLDL apoB kinetics in adult GH deficient patients (4 females, 3 males; age 50.1 +/- 4.7 yr (mean +/- SEM); BMI 28.2 +/- 1.1 kg/m2; total cholesterol (TC) 6.6 +/- 0.3 mmol/l; triglyceride (TG) 2.8 +/- 0.6 mmol/l; HDL cholesterol 1.1 +/- 0.1 mmol/l) and in control subjects (4 females, 3 male; age 47.0 +/- 4.7 yr; BMI 27.0 +/- 2.6 kg/m2; TC 5.0 +/- 0.4 mmol/l; TG 0.9 +/- 0.2 mmol/l; HDL cholesterol 1.4 +/- 0.1 mmol/l). [1-(13)C] leucine was administered by a primed (1 mg/kg), constant intravenous infusion (1 mg/kg/hr) and VLDL apoB enrichment with 13C leucine was determined using gas-chromatography mass-spectrometry. The GHD patients had a significantly higher hepatic secretion rate of VLDL apoB (15.5 +/- 1.8 mg/kg/day vs 9.4 +/- 0.6 mg/kg/day p = 0.007) and reduced catabolism ofVLDL apoB (metabolic clearance rate; 12.3 +/- 1.7 ml/min vs 24.3 +/- 4.8 ml/min p < 0.05) compared with control subjects. These findings suggest that GH is integrally involved in the regulation of VLDL apoB metabolism.