Brent M. McGrath

Neurobiological findings in bipolar II disorder compared with findings in bipolar I disorder.

Objective: To determine there are consistent neurobiological differences between patients with bipolar I disorder (BD I) and those with bipolar II disorder (BD II). Method: We reviewed the literature in areas where the most consistent neurobiological findings have been reported for bipolar disorder, specifically, neuroimaging and brain metabolism. The imaging studies reviewed, examined structure, using magnetic resonance imaging (MRI), and function, using functional MRI, positron emission tomography, and single photon emission computed tomography. We used magnetic resonance spectroscopy to examine brain chemistry. We reviewed those metabolic studies that examined cell calcium, 3-methoxy-4-hydroxyphenylglycol, and protein kinase C. Results: Some genetic studies suggest that there may be differences between BD II and BD I patients. However, our review of the imaging and metabolic studies identified few studies directly comparing these 2 groups. In those studies, there were few differences, if any, and these were not consistent. Conclusions: While genetic data suggest there may be differences between BD II patients and BD I patients, the neurobiological findings to date do not provide support. However, this may be owing to the small number of studies directly comparing the 2 groups and also to the fact that those carried out have not been adequately powered to detect possible small true differences. This is an important issue because, if there are no neurobiological differences, it would be anticipated that similar treatments would be similarly effective in both groups. Given the importance of understanding whether there are neurochemical differences between these groups, further research in this area is clearly needed.

Lithium and valproate and their possible effects on themyo-inositol second messenger system in healthy volunteers and bipolar patients

Over 25 years ago it was suggested that the mechanism by which lithium was clinically effective may be due to a stabilizing effect on the phosphoinositol second messenger system (PI-cycle), which has multiple effects within cells. It was proposed that lithium, which is an inhibitor of one of the key enzymes in the PI-cycle, acted to lower myo-inositol concentrations; termed the ‘inositol-depletion hypothesis’. Initial animal evidence supported this hypothesis, and also suggested that it was possible that sodium valproate could affect the PI-cycle. Since the first magnetic resonance studies in this area in the early 1990s many studies have examined various aspects of this hypothesis in both healthy volunteers and patients utilizing magnetic resonance spectroscopy (MRS). The present review considers research in this area and concludes that, despite initial promise, current evidence suggests that it is unlikely that either lithium or valproate produce clinically relevant changes in myo-inositol concentrations or the PI-cycle. These findings do not suggest that lithium-induced changes in the PI-cycle are the primary mechanism by which lithium or valproate exert their beneficial clinical effects in bipolar disorder. Nonetheless, given the current technical and clinical limitations of the literature to date, this conclusion cannot be considered completely definitive.

Current Pathophysiological Findings in Bipolar Disorder and in its Subtypes

There have been many studies that have examined various aspects of the pathophysiology of bipolar disorder, with many positive findings in several areas of neuroimaging and metabolic abnormality. These studies might allow some conclusions to be drawn about the underlying pathophysiology. Additionally, it is of significant interest to determine if there are pathophysiological differences between patients with bipolar disorder type I (BPD-I) and those with bipolar disorder type II (BPD-II). The present review examines imaging studies in bipolar patients of possible structural changes (magnetic resonance imaging (MRI)) functional changes (focusing on functional MRI (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT)), and those examining brain chemistry (utilizing magnetic resonance spectroscopy (MRS)). Metabolic studies reviewed were those that examined 3-methoxy-4- hydroxyphenylglycol (MHPG), cellular calcium, and protein kinase C (PKC). The results clearly suggest that BPD patients differ from controls on many of these measures. However, while there is evidence from genetic studies suggesting possible differences between BPD-II patients and BPD-I patients, the neuroimaging and metabolic studies to date do not support this, and there appear to be no consistent pathophysiologica differences between these subtypes from evidence available at present.

Valproate attenuates dextroamphetamine-induced subjective changes more than lithium

Dextroamphetamine administration in healthy controls produces a range of subjective and physiological effects, which have been likened to those occurring during mania. However, it is uncertain if these can be attenuated by lithium since conflicting results have been reported. To date there have been no previous studies examining the effects of valproate on dextroamphetamine-induced mood and physiological changes. The current study was a double-blind, placebo-controlled, study in which volunteers received either 1000 mg sodium valproate (n=12), 900 mg lithium (n=9), or placebo (n=12) pre-treatment for 14 days. Subjective and physiological measures were then obtained prior to administration of a 25 mg dose of dextroamphetamine, and at two time points after administration. Differences in the response to dextroamphetamine were assessed between the three treatment groups. The results of this study show that pre-treatment with lithium only significantly attenuated dextroamphetamine-induced change in happiness, while valproate pre-treatment significantly attenuated the effects of dextroamphetamine on happiness, energy, alertness and on the diastolic blood pressure. These results suggest that lithium and valproate do not have the same mechanism of action on dextroamphetamine-induced changes, and this finding may relate to differences in their mechanism of action in mood disorders.

Carotid artery visualization during anterior skull base surgery: a novel protocol for neuronavigation

Detailed knowledge of the vascular anatomy of the anterior skull base is critical to successful surgery in this area. Whereas conventional neuronavigational approaches combine MRI (± contrast) for tumor visualization and CT (± C) for bony and vascular anatomy, we describe the Canadian and Austrian experiences using a novel protocol integrating MR angiography (MRA) into surgical neuronavigation to provide superior visualization of the carotid arteries. The pre-operative imaging protocol employs a T1-weighted, 3D fast spoiled gradient echo MRI (± C) for soft tissue anatomy, a plain CT for bony anatomy, and a 3D time-of-flight MR angiography for carotid anatomy. The series are imported into the Medtronic StealthStation® TREON® Treatment Guidance System; during intra-operative neuronavigation, each series (MRI, CT, MRA) can be viewed individually, or layered and viewed as a composite image. Our protocol has important advantages. First, it provides detailed tissue, tumor, vascular and bony anatomy. Second, a contrast CT is not necessary; this is important, as numerous reports have highlighted the nephrotoxic nature of radiographic contrast material. Third, visualization of the carotid system is superior than can be obtained from CT angiography. We use this unique imaging protocol routinely for our endoscopic transsphenoidal surgeries to provide superior visualization of the carotid arteries during anterior skull base surgery.

Acute dextro-amphetamine administration does not alter brain myo-inositol levels in humans and animals: MRS investigations at 3 and 18.8 T

The pathophysiological underpinnings of bipolar disorder are not fully understood. However, they may be due in part to changes in the phosphatidylinositol second messenger system (PI-cycle) generally, or changes in myo-inositol concentrations more specifically. Dextro-amphetamine has been used as a model for mania in several human studies as it causes similar subjective and physiological symptoms. We wanted to determine if dextro-amphetamine altered myo-inositol concentrations in vivo as it would clearly define a mechanism linking putative changes in the PI-cycle to the subjective psychological changes seen with dextro-amphetamine administration. Fifteen healthy human volunteers received a baseline scan, followed by second scan 75 min after receiving a 25 mg oral dose of dextro-amphetamine. Stimulated echo proton magnetic resonance spectroscopy (MRS) scans were preformed at 3.0 Tesla (T) in the dorsal medial prefrontal cortex (DMPFC). Metabolite data were adjusted for tissue composition and analyzed using LCModel. Twelve adult male rats were treated acutely with a 5-mg/kg intraperitoneal dose of dextro-amphetamine. After 1 h rats were decapitated and the brains were rapidly removed and frozen until dissection. Rat brains were dissected into frontal, temporal, and occipital cortical areas, as well as hippocampus. Tissue was analyzed using a Varian 18.8 T spectrometer. Metabolites were identified and quantified using Chenomx Profiler software. The main finding in the present study was that myo-inositol concentrations in the DMPFC of human volunteers and in the four rat brain regions were not altered by acute dextro-amphetamine. While it remains possible that the PI-cycle may be involved in the pathophysiology of bipolar disorder, it is not likely that the subjective and physiological of dextro-amphetamine are mediated, directly or indirectly, via alternations in myo-inositol concentrations.

Unlike lithium, anticonvulsants and antidepressants do not alter rat brain myo-inositol.

Lithium is the first-line in bipolar disorder treatment. Lithiums clinical efficacy might be due to its inhibition of myo-inositol turnover in the phosphatidylinositol second messenger system. This study aimed to determine whether this action can extend to antidepressants and anticonvulsants also used to treat bipolar symptoms. Male rats were treated for 2 weeks with an intraperitoneal injection of phenelzine, fluoxetine, desipramine, carbamazepine, lamotrigine, sodium valproate or vehicle. Brains were dissected and myo-inositol concentrations were analyzed using high-field nuclear magnetic resonance spectroscopy at 18.8 T and quantified using Chenomx Profiler software. Brain regions assessed included the prefrontal, temporal and occipital cortical areas as well as the hippocampus. The main finding is that contrary to lithium, the anticonvulsants and antidepressants do not alter brain myo-inositol concentration. This suggests that these agents might work via a mechanism that is not centered on changes in myo-inositol concentration.

Quality of life following coronary artery bypass graft surgery vs. percutaneous coronary intervention in diabetics with multivessel disease: a five-year registry study

Aims The aim of this study is to investigate the long-term relationship between revascularization technique and health status in diabetics with multivessel disease. Methods and results Using the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) registry, we captured 1319 diabetics with multivessel disease requiring revascularization for an acute coronary syndrome (January 2009-December 2012) and reported health status using the Seattle Angina Questionnaire (SAQ) at baseline, 1, 3 and 5-years [599 underwent coronary artery bypass grafting (CABG); 720 underwent percutaneous coronary intervention (PCI)]. Adjusted analyses were performed using a propensity score-matching technique. After adjustment (including baseline SAQ domain scores), 1-year mean (95% CI) SAQ scores (range 0-100 with higher scores reflecting improved health status) were significantly greater in selected domains for CABG compared to PCI (exertional capacity: 81.7 [79.5-84.0] vs. 78.8 [76.5-81.0], P = 0.07; angina stability: 83.1 [80.4-85.9] vs. 75.0 [72.3-77.8], P < 0.001]; angina frequency 93.2 [91.6-95.0] vs. 90.0 [87.8-91.3], P = 0.003; treatment satisfaction: 93.6 [92.2-94.9] vs. 90.8 [89.2-92.0], P = 0.003; quality of life [QOL]: 83.8 [81.7-85.8] vs. 77.2 [75.2-79.2] P < 0.001). At 3-years, these benefits were attenuated (exertional capacity: 79.3 [76.9-81.7] vs. 78.7 [76.3-81.1], P = 0.734; angina stability 79.3 [76.3-82.3] vs. 75.5 [72.5-78.5], P = 0.080; angina frequency: 93.2 [91.3-95.1] vs. 90.9 [89.0-92.8], P = 0.095; treatment satisfaction: 92.5 [91.0-94.0] vs. 91.5 [90.0-93.0] P = 0.382; QOL: 83.2 [81.1-85.2] vs. 80.3 [78.2-82.4], P = 0.057). At 5-years, majority of domains were similar (exertional capacity: 77.8 [75.0-80.6] vs. 76.3 [73.2-79.3], P = 0.482; angina stability: 78.0 [74.8-81.2] vs. 74.8 [71.4-78.2], P = 0.175; angina frequency: 94.2 [92.3-96.0] vs. 90.9 [89.0-92.9], P = 0.018; treatment satisfaction: 93.7 [92.2-95.1] vs. 92.2 [90.6-93.7], P = 0.167; QOL: 84.1 [82.0-86.3] vs. 81.1 [78.8-83.4], P = 0.058). Majority in both groups remained angina-free at 5-years (75.0% vs. 70.3%, P = 0.15). Conclusion Improvements in health status with CABG compared with PCI were not sustained long-term. This temporal sequence should be considered when contemplating a revascularization strategy in diabetics with multivessel disease.

Sgarbossa criteria for acute myocardial infarction

A 63-year-old man presented to the emergency department with a four-hour history of severe central chest pain. He had a history of smoking, hypertension and diabetes mellitus; a single-chamber pacemaker had been implanted for third-degree heart block four years earlier. The baseline