Adrian Carpenter

The relationship between motor deficit and hemisphere activation balance after stroke: A 3T fMRI study.

Functional imaging during movement of the hand affected by a stroke has shown excess activation of the contralesional motor network, implying less physiological hemisphere activation balance. Although this may be adaptive, the relationship between the severity of motor deficit and the hemisphere activation balance for the four major cortical motor areas has not been systematically studied. We prospectively studied 19 right-handed patients with first-ever stroke (age range 61+/-10 years) in the stable phase of recovery (>3 months after onset), using auditory-paced index-thumb (IT) tapping of the affected hand at 1.25 Hz as the fMRI paradigm. The hemisphere activation balance for the primary motor (M1), primary somatosensory (S1), supplementary motor (SMA) and dorsal premotor (PMd) areas was measured by a modified weighted laterality index (wLI), and correlations with motor performance (assessed by the affected/unaffected ratio of maximum IT taps in 15 s, termed IT-R) were computed. There were statistically significant negative correlations between IT-R and the wLI for M1 and S1, such that the more the hemispheric balance shifted contralesionally, the worse the performance. Furthermore, worse performance was related to a greater amount of contralesional, but not ipsilesional, activation. No significant correlation between IT-R and the wLI was obtained for the SMA and PMd, which functionally have stronger bilateral organization. These findings suggest that the degree of recovery of fine finger motion after stroke is determined by the extent to which activation balance in the primary sensory motor areas--where most corticospinal fibers originate--departs from normality. This observation may have implications for therapy.

Normal pressure hydrocephalus and cerebral blood flow: a PET study of baseline values

Regional cerebral blood flow (CBF) was studied with O15-water positron emission tomography and anatomic region-of-interest analysis on coregistered magnetic resonance in patients with idiopathic (n = 12) and secondary (n = 5) normal pressure hydrocephalus (NPH). Mean CBF was compared with values obtained from healthy volunteers (n = 12) and with clinical parameters. Mean CBF was significantly decreased in the cerebrum and cerebellum of patients with NPH. The regional analysis demonstrated that CBF was reduced in the basal ganglia and the thalamus but not in white matter regions. The results suggest that the role of the basal ganglia and thalamus in NPH may be more prominent than currently appreciated. The implications for theories regarding the pathogenesis of NPH are discussed.

Changes in Cerebral Blood Flow during Cerebrospinal Fluid Pressure Manipulation in Patients with Normal Pressure Hydrocephalus: A Methodological Study:

The combination of cerebral blood flow measurement using 15O-water positron emission tomography with magnetic resonance coregistration and CSF infusion studies was used to study the global and regional changes in CBF with changes in CSF pressure in 15 patients with normal pressure hydrocephalus. With increases in CSF pressure, there was a variable increase in arterial blood pressure between individuals and global CBF was reduced, including in the cerebellum. Regionally, mean CBF decreased in the thalamus and basal ganglia, as well as in white matter regions. These reductions in CBF were significantly correlated with changes in the CSF pressure and with proximity to the ventricles. A three-dimensional finite-element analysis was used to analyze the effects on ventricular size and the distribution of stress during infusion. To study regional cerebral autoregulation in patients with possible normal pressure hydrocephalus, a sensitive CBF technique is required that provides absolute, not relative normalized, values for regional CBF and an adequate change in cerebral perfusion pressure must be provoked.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease

Huntingtons disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the ‘NEST-UK’ consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3–10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the ‘Core assessment program for intracerebral transplantations-HD’ assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntingtons Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Early Metabolic Characteristics of Lesion and Nonlesion Tissue after Head Injury

We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up in patients recovering from head injury. Early metabolic characteristics in these regions of interest (ROIs) were compared with physiology in healthy volunteers. Fourteen patients with severe head injury had positron emission tomography within 72 h, and magnetic resonance imaging at 3 to 18 months after injury. Cerebral blood flow (CBF), oxygen utilization (CMRO2), and oxygen extraction fraction (OEF) were all lower in lesion ROIs, compared with nonlesion and control ROIs (P < 0.001); however, there was substantial overlap in physiology. Control ROIs showed close coupling among CBF, blood volume (CBV), and CMRO2, whereas relationships within lesion and nonlesion ROIs were abnormal. The relationship between CBF and CMRO2 generally remained coupled but the slope was reduced; that for CBF and OEF was variable; whereas that between CBF and CBV was highly variable. There was considerable heterogeneity between and within patients. Although irreversibly damaged tissue is characterized by marked derangements in physiology, a more detailed analysis shows acute changes in physiology and physiologic relationships within regions of the brain that appear structurally normal at follow-up. Such pathophysiological derangements may result in selective neuronal loss and impact on functional outcome.

Riociguat Reduces Infarct Size and Post-Infarct Heart Failure in Mouse Hearts: Insights from MRI/PET Imaging

Aim Stimulation of the nitric oxide (NO) – soluble guanylate (sGC) - protein kinase G (PKG) pathway confers protection against acute ischaemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to not only determine whether the sGC stimulator riociguat reduces infarct size but also whether it protects against the development of post-MI heart failure. Methods and Results Mice were subjected to 30 min ischaemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and 18F-FDG-positron emission tomography (PET) were performed to determine infarct size. In the riociguat-treated mice, the resulting infarct size was smaller (8.5±2.5% of total LV mass vs. 21.8%±1.7%. in controls, p = 0.005) and LV systolic function analysed by MRI was better preserved (60.1%±3.4% of preischaemic vs. 44.2%±3.1% in controls, p = 0.005). After 28 days, LV systolic function by echocardiography treated group was still better preserved (63.5%±3.2% vs. 48.2%±2.2% in control, p = 0.004). Conclusion Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size and better long-term preservation of LV systolic function. These findings suggest that sGC stimulation during reperfusion therapy may be a powerful therapeutic treatment strategy for preventing post-MI heart failure.

Detection of physiological noise in resting state fMRI using machine learning

We present a technique for predicting cardiac and respiratory phase on a time point by time point basis, from fMRI image data. These predictions have utility in attempts to detrend effects of the physiological cycles from fMRI image data. We demonstrate the technique both in the case where it can be trained on a subjects own data, and when it cannot. The prediction scheme uses a multiclass support vector machine algorithm. Predictions are demonstrated to have a close fit to recorded physiological phase, with median Pearson correlation scores between recorded and predicted values of 0.99 for the best case scenario (cardiac cycle trained on a subjects own data) down to 0.83 for the worst case scenario (respiratory predictions trained on group data), as compared to random chance correlation score of 0.70. When predictions were used with RETROICOR—a popular physiological noise removal tool—the effects are compared to using recorded phase values. Using Fourier transforms and seed based correlation analysis, RETROICOR is shown to produce similar effects whether recorded physiological phase values are used, or they are predicted using this technique. This was seen by similar levels of noise reduction noise in the same regions of the Fourier spectra, and changes in seed based correlation scores in similar regions of the brain. This technique has a use in situations where data from direct monitoring of the cardiac and respiratory cycles are incomplete or absent, but researchers still wish to reduce this source of noise in the image data. Hum Brain Mapp , 2013.

Brain regions predicting subsequent episodic and implicit memory for words: a dissociation measured using fMRI

Functional neuroimaging has the potential to improve the decision-making process in the development of new drugs. With the high cost of failure of compounds in later stages of development, there is a need to establish, early in man, reliable measures of drug activity and efficacy in the brain. Functional magnetic resonance imaging (fMRI) is a tool for serially examining normal and pathological brain function at the systems level. FMRI is helping us to understand therapeutic mechanisms and can provide clinically relevant markers of disease responses to drugs. An analysis of the value of fMRI to aid decision-making requires an appreciation of the techniques and their validation, a task that has begun and which necessitates an investment of its own.

Corrigendum to “The relationship between motor deficit and hemisphere activation balance after stroke: A 3 T fMRI study” [NeuroImage 34 (2007) 322–331]

The authors recently spotted two errors in this article. In the Methods section, “Image processing” subheading, the sentence “Data sets were rejected if head displacement was greater than 5 mm in any direction” should read “Data sets were rejected if head displacement was greater than 2 mm in any direction”. In Fig. 4, an error occurred when transcribing the data point in the extreme right in the top right scatterplot (“Contralesional M1”). The statistical significance of the correlation is unchanged (Spearmans rho=+0.618, p=0.0088). The overall interpretation of the study is therefore unchanged. The new figure is printed here for the readers convenience.

267 SOLUBLE GUANYLATE CYCLASE STIMULATION REDUCES INFARCT SIZE AND POST-INFARCT HEART FAILURE IN MOUSE HEARTS

Introduction Activation of the nitric oxide-protein kinase G pathway confers protection against acute ischemia/reperfusion injury, but more chronic effects in reducing post-myocardial infarction (MI) heart failure are less defined. The aim of this study was to determine whether riociguat, a selective soluble guanylate cyclase (sGC) stimulator, not only reduces infarct size but also protects against the development of post-MI heart failure. Methods Mice were subjected to 30 min ischemia via ligation of the left main coronary artery to induce MI and either placebo or riociguat (1.2 µmol/l) were given as a bolus 5 min before and 5 min after onset of reperfusion. After 24 hours, both, late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) and 18F-FDG-positron emission tomography (PET) were performed to determine infarct size and cardiac function. Furthermore riociguats effect on blood pressure was tested by either the non-invasive tail cuff assessment or the LV catheterization via the right carotid artery. Results In the riociguat-treated mice, the resulting infarct size was smaller (21.8%±1.7% vs. 8.5±2.5% of total LV mass, p=0.005), and LV systolic function was better preserved (44.2%±3.1% vs. 60.1%±3.4%, p=0.005) compared to control animals. After 28 days, echocardiography showed markedly preserved LV systolic function (48.2%±2.2 vs. 63.5%±3.2%, p=0.004) in the group treated with riociguat compared to control. Riociguat showed no significant effect on blood pressure. Conclusion Taken together, mice treated acutely at the onset of reperfusion with the sGC stimulator riociguat have smaller infarct size, better preserved LV systolic function and develop less adverse LV remodeling. These findings suggest that sGC stimulation after an acute MI may be a powerful therapeutic treatment strategy for post-MI heart failure.