Non-invasive methods for estimating mPAP in COPD using cardiovascular magnetic resonance imaging.

PURPOSE: Pulmonary hypertension (PH) is associated with a poor outcome in chronic obstructive pulmonary disease (COPD) and is diagnosed invasively. We aimed to assess the diagnostic accuracy and prognostic value of non-invasive cardiovascular magnetic resonance (CMR) models. METHODS: Patients with COPD and suspected PH, who underwent CMR and right heart catheter (RHC) were identified. Three candidate models were assessed: 1, CMR-RV model, based on right ventricular (RV) mass and interventricular septal angle; 2, CMR PA/RV includes RV mass, septal angle and pulmonary artery (PA) measurements; 3, the Alpha index, based on RV ejection fraction and PA size. RESULTS: Of 102 COPD patients, 87 had PH. The CMR-PA/RV model had the strongest diagnostic accuracy (sensitivity 92%, specificity 80%, positive predictive value 96% and negative predictive value 63%, AUC 0.93, p<0.0001). Splitting RHC-mPAP, CMR-RV and CMR-PA/RV models by 35mmHg gave a significant difference in survival, with log-rank chi-squared 5.03, 5.47 and 7.10. RV mass and PA relative area change were the independent predictors of mortality at multivariate Cox regression (p=0.002 and 0.030). CONCLUSION: CMR provides diagnostic and prognostic information in PH-COPD. The CMR-PA/RV model is useful for diagnosis, the RV mass index and PA relative area change are useful to assess prognosis. KEY POINTS: • Pulmonary hypertension is a marker of poor outcome in COPD. • MRI can predict invasively measured mean pulmonary artery pressure. • Cardiac MRI allows for estimation of survival in COPD. • Cardiac MRI may be useful for follow up or future trials. • MRI is potentially useful to assess pulmonary hypertension in patients with COPD.

Functional Image-guided Radiotherapy Planning for Normal Lung Avoidance.

For patients with lung cancer undergoing curative intent radiotherapy, functional lung imaging can be incorporated into treatment planning to modify the dose distribution within non-target volume lung by differentiation of lung regions that are functionally defective or viable. This concept of functional image-guided lung avoidance treatment planning has been investigated with several imaging modalities, primarily single photon emission computed tomography (SPECT), but also hyperpolarised gas magnetic resonance (MR) imaging, positron emission tomography (PET) and computed tomography (CT)-based measures of lung biomechanics. Here, we review the application of each of these modalities, review practical issues of lung avoidance implementation, including image registration and the role of both ventilation and perfusion imaging, and provide guidelines for reporting of future lung avoidance planning studies.

CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry.

We evaluated the prevalence and prognostic value of CT-pulmonary angiographic (CTPA) measures in 292 treatment naive patients with pulmonary arterial hypertension (PAH). Pulmonary artery calcification (13%) and thrombus (10%) were exclusively seen in PAH-congenital heart disease. Oesophageal dilation (46%) was most frequent in PAH-systemic sclerosis. Ground glass opacification (GGO) (41%), pericardial effusion (38%), lymphadenopathy (19%) and pleural effusion (11%) were common. On multivariate analysis, inferior vena caval area, the presence of pleural effusion and septal lines predicted outcome. In PAH, CTPA provides diagnostic and prognostic information. In addition, the presence of GGO on a CT performed for unexplained breathlessness should alert the physician to the possibility of PAH.

Lung ventilation volumetry with same-breath acquisition of hyperpolarized gas and proton MRI.

The purpose of this work was to assess the reproducibility of percentage of ventilated lung volume (PV) measured from hyperpolarized (HP) (3)He and (1)H anatomical images acquired in the same breath-hold when compared with PV measured from (3)He and (1)H images from separate breath-holds. Volumetric (3)He ventilation and (1)H anatomical images of the same resolution were acquired during the same breath-hold. To assess reproducibility, this procedure was performed twice with a short gap between acquisitions. In addition, (1)H images were also acquired in a separate breath for comparison. PV ((3)He ventilated volume divided by (1)H total lung volume) was calculated using the single-breath-hold images (PV(single)) and the separate-breath-hold images (PV(separate)). Short-term reproducibility of PV measurement was assessed for both single- and separate-breath acquisitions. Dice similarity coefficients (DSCs) were calculated to quantify spatial overlap between (3)He and (1)H segmentations for the single- and separate-breath-hold acquisitions. The efficacy of using the separate-breath method combined with image registration was also assessed. The mean magnitude difference between the two sets of PV values (±standard deviation) was 1.49 ± 1.32% for PV(single) and 4.19 ± 4.10% for PV(separate), with a significant difference (p < 0.01). The mean magnitude difference between the two PV values for the registered separate-breath technique (PV(sep-registered)) was 2.27 ± 2.23%. Bland-Altman analysis showed that PV measured with single-breath acquisitions was more repeatable than PV measured with separate-breath acquisitions, regardless of image registration. DSC values were significantly greater (p < 0.01) for single-breath acquisition than for separate-breath acquisition. Acquisition of HP gas ventilation and (1)H anatomical images in a single breath-hold provides a more reproducible means of percentage lung ventilation volume measurement than the previously used separate-breath-hold scan approach, and reduces errors.

MRI model-based non-invasive differential diagnosis in pulmonary hypertension.

Pulmonary hypertension(PH) is a disorder characterised by increased mean pulmonary arterial pressure. Currently, the diagnosis of PH relies upon measurements taken during invasive right heart catheterisation (RHC). This paper describes a process to derive diagnostic parameters using only non-invasive methods based upon MRI imaging alone. Simultaneous measurements of main pulmonary artery (MPA) anatomy and flow are interpreted by 0D and 1D mathematical models, in order to infer the physiological status of the pulmonary circulation. Results are reported for 35 subjects, 27 of whom were patients clinically investigated for PH and eight of whom were healthy volunteers. The patients were divided into 3 sub-groups according to the severity of the disease state, one of which represented a negative diagnosis (NoPH), depending on the results of the clinical investigation, which included RHC and complementary MR imaging. Diagnostic indices are derived from two independent mathematical models, one based on the 1D wave equation and one based on an RCR Windkessel model. Using the first model it is shown that there is an increase in the ratio of the power in the reflected wave to that in the incident wave (Wpb/Wptotal) according to the classification of the disease state. Similarly, the second model shows an increase in the distal resistance with the disease status. The results of this pilot study demonstrate that there are statistically significant differences in the parameters derived from the proposed models depending on disease status, and thus suggest the potential for development of a non-invasive, image-based diagnostic test for pulmonary hypertension.

Incorporation of prior knowledge in compressed sensing for faster acquisition of hyperpolarized gas images.

Adding prior knowledge to compressed sensing reconstruction can improve image reconstruction. In this work, two approaches are investigated to improve reconstruction of two-dimensional hyperpolarized (3)He lung ventilation images using prior knowledge. When compared against a standard compressed sensing reconstruction, the proposed methods allowed acquisition of images with higher under-sampling factors and reduction of the blurring effects that increase with higher reduction factors when fixed flip angles are used. These methods incorporate the prior knowledge of polarization decay of hyperpolarized (3)He and the mutual anatomical information from a registered (1)H image acquired in the same breath. Three times accelerated two-dimensional images reconstructed with compressed sensing and prior knowledge gave lower root-mean square error, than images reconstructed without introduction of any prior information. When introducing the polarization decay as prior knowledge, a significant improvement was achieved in the lung region, the root mean square value decreased by 45% and from the whole image by 36%. When introducing the mutual anatomical information as prior knowledge, the root mean square decreased by 21% over the lung region and by 15% over the whole image.

Group sparse reconstruction using intensity-based clustering.

Compressed sensing has been of great interest to speed up the acquisition of MR images. The k-t group sparse (k-t GS) method has recently been introduced for dynamic MR images to exploit not just the sparsity, as in compressed sensing, but also the spatial group structure in the sparse representation. k-t GS achieves higher acceleration factors compared to the conventional compressed sensing method. However, it assumes a spatial structure in the sparse representation and it requires a time consuming hard-thresholding reconstruction scheme. In this work, we propose to modify k-t GS by incorporating prior information about the sorted intensity of the signal in the sparse representation, for a more general and robust group assignment. This approach is referred to as group sparse reconstruction using intensity-based clustering. The feasibility of the proposed method is demonstrated for static 3D hyperpolarized lung images and applications with both dynamic and intensity changes, such as 2D cine and perfusion cardiac MRI, with retrospective undersampling. For all reported acceleration factors the proposed method outperforms the original compressed sensing method. Improved reconstruction over k-t GS method is demonstrated when k-t GS assumptions are not satisfied. The proposed method was also applied to cardiac cine images with a prospective sevenfold acceleration, outperforming the standard compressed sensing reconstruction.

MRI of the lung (1/3): methods.

Proton magnetic resonance imaging (MRI) has recently emerged as a clinical tool to image the lungs. This paper outlines the current technical aspects of MRI pulse sequences, radiofrequency (RF) coils and MRI system requirements needed for imaging the pulmonary parenchyma and vasculature. Lung MRI techniques are presented as a "technical toolkit", from which MR protocols will be composed in the subsequent papers for comprehensive imaging of lung disease and function (parts 2 and 3). This paper is pitched at MR scientists, technicians and radiologists who are interested in understanding and establishing lung MRI methods. Images from a 1.5 T scanner are used for illustration of the sequences and methods that are highlighted. Main Messages • Outline of the hardware and pulse sequence requirements for proton lung MRI • Overview of pulse sequences for lung parenchyma, vascular and functional imaging with protons • Demonstration of the pulse-sequence building blocks for clinical lung MRI protocols.

Acquisition of ³He ventilation images, ADC, T2* and B1 maps in a single scan with compressed sensing.

In imaging of human lungs with hyperpolarised noble gases, measurements of apparent diffusion coefficient (ADC) and relaxation time provide valuable information for the assessment of lung microstructure. In this work, a sequence was developed for interleaved acquisition of ventilation images, ADC, T(2)* and flip angle maps in a single scan from the human lungs with a single dose of inhaled (3)He at 3 T. Spatially registered ventilation images with parametric maps were obtained. The total acquisition time was reduced by random undersampling of the k-space and reconstruction using compressed sensing (CS). The gain in speed was used for an increase in spatial resolution. Mean ADC values from the fully sampled and undersampled CS data exhibit no statistically significant difference in a given subject. The mean T(2)* values, however, were found to differ significantly, which is attributed to the combined effect of low signal-to-noise ratio (SNR) of the fully sampled data and the smoothing effect inherent in CS reconstruction.

ASPIRE registry: assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre.

Pulmonary hypertension (PH) is a heterogeneous condition. To date, no registry data exists reflecting the spectrum of disease across the five diagnostic groups encountered in a specialist referral centre. Data was retrieved for consecutive, treatment-naïve cases diagnosed between 2001 and 2010 using a catheter-based approach. 1,344 patients were enrolled, with a mean follow-up of 2.9 yrs. The 3-yr survival was 68% for pulmonary arterial hypertension (PAH), 73% for PH associated with left heart disease, 44% for PH associated with lung disease (PH-lung), 71% for chronic thromboembolic PH (CTEPH) and 59% for miscellaneous PH. Compared with PAH, survival was inferior in PH-lung and superior in CTEPH (p<0.05). Multivariate analysis demonstrated that diagnostic group independently predicted survival. Within PAH, Eisenmenger's survival was superior to idiopathic PAH, which was superior to PAH associated with systemic sclerosis (p<0.005). Within PH-lung, 3-yr survival in sleep disorders/alveolar hypoventilation (90%) was superior to PH-lung with chronic obstructive pulmonary disease (41%) and interstitial lung disease (16%) (p<0.05). In CTEPH, long-term survival was best in patients with surgically accessible disease undergoing pulmonary endarterectomy. In this large registry of consecutive, treatment-naïve patients identified at a specialist PH centre, outcomes and characteristics differed between and within PH groups. The current system of classification of PH has prognostic value even when adjusted for age and disease severity, emphasising the importance of systematic evaluation and precise classification.

The influence of field strength on the apparent diffusion coefficient of 3He gas in human lungs.

The (3)He MR diffusion signal is sensitive to lung microstructure, but it is also affected by the presence of background field inhomogeneities induced by the magnetic susceptibility difference at the air-tissue interface. These susceptibility-induced gradients, which are dependent on field strength, have been assumed negligible in theoretical models used to extract airway morphometric information from (3)He MR diffusion data at field strengths up to 4.7 T. In this work, the effect of susceptibility gradients on (3)He apparent diffusion coefficient is demonstrated with experiments in healthy volunteers at two B(0) field strengths: 1.5 and 3 T. Apparent diffusion coefficient values obtained at 3 T were systematically larger than at 1.5 T, demonstrating that susceptibility effects are statistically significant even at clinical field strengths (B(0) ≤ 3 T) and introduce biases in the estimates of airway dimensions (e.g., mean linear intercept up to 17% larger at 3 T than 1.5 T). Susceptibility effects should be taken into account in the development of theoretical models of lung (3)He MR diffusion and considered when interpreting (3)He apparent diffusion coefficients obtained at different B(0).

Trigeminal and telencephalic projections to jaw and other upper vocal tract premotor neurons in songbirds: sensorimotor circuitry for beak movements during singing.

During singing in songbirds, the extent of beak opening, like the extent of mouth opening in human singers, is partially correlated with the fundamental frequency of the sounds emitted. Since song in songbirds is under the control of "the song system" (a collection of interconnected forebrain nuclei dedicated to the learning and production of song), it might be expected that beak movements during singing would also be controlled by this system. However, direct neural connections between the telencephalic output of the song system and beak muscle motor neurons in the brainstem are conspicuous by their absence, leaving unresolved the question of how beak movements are affected during singing. By using standard tract tracing methods, we sought to answer this question by defining beak premotor neurons and examining their afferent projections. In the caudal medulla, jaw premotor cell bodies were located adjacent to the terminal field of the output of the song system, into which many premotor neurons extended their dendrites. The premotor neurons also received a novel input from the trigeminal ganglion and an overlapping input from a lateral arcopallial component of a trigeminal sensorimotor circuit that traverses the forebrain. The ganglionic input in songbirds, which is not present in doves and pigeons that vocalize with a closed beak, may modulate the activity of beak premotor neurons in concert with the output of the song system. These inputs to jaw premotor neurons could, together, affect beak movements as a means of modulating filter properties of the upper vocal tract during singing.

Experimental investigation and numerical simulation of 3He gas diffusion in simple geometries: implications for analytical models of 3He MR lung morphometry.

Models of lung acinar geometry have been proposed to analytically describe the diffusion of (3)He in the lung (as measured with pulsed gradient spin echo (PGSE) methods) as a possible means of characterizing lung microstructure from measurement of the (3)He ADC. In this work, major limitations in these analytical models are highlighted in simple diffusion weighted experiments with (3)He in cylindrical models of known geometry. The findings are substantiated with numerical simulations based on the same geometry using finite difference representation of the Bloch-Torrey equation. The validity of the existing "cylinder model" is discussed in terms of the physical diffusion regimes experienced and the basic reliance of the cylinder model and other ADC-based approaches on a Gaussian diffusion behaviour is highlighted. The results presented here demonstrate that physical assumptions of the cylinder model are not valid for large diffusion gradient strengths (above approximately 15 mT/m), which are commonly used for (3)He ADC measurements in human lungs.

Afferents to the cochlear nuclei and nucleus laminaris from the ventral nucleus of the lateral lemniscus in the zebra finch (Taeniopygia guttata).

The presence and nature of a descending projection from the ventral nucleus of the lateral lemniscus (LLV) to the cochlear nuclei (NA, NM) and the third-order nucleus laminaris (NL) was investigated in a songbird using tract tracing and GAD immunohistochemistry. Tracer injections into LLV produced anterograde label in the ipsilateral NA, NM and NL, which was found not to be GABAergic. Double retrograde labeling from LLV and NA/NM/NL ruled out the possibility that the LLV projection actually arose from collaterals of superior olivary projections to NA/NM/NL. The LLV projection may be involved in the discrimination of laterality of auditory input.

Hyperpolarised 3He MRI versus HRCT in COPD and normal volunteers: PHIL trial.

The aim of the present study was to apply hyperpolarised (HP) (3)He magnetic resonance imaging (MRI) to identify patients with chronic obstructive pulmonary disease (COPD) and alpha(1)-antitrypsin deficiency (alpha(1)-ATD) from healthy volunteers and compare HP (3)He MRI findings with high-resolution computed tomography (HRCT) in a multicentre study. Quantitative measurements of HP (3)He MRI (apparent diffusion coefficient (ADC)) and HRCT (mean lung density (MLD)) were correlated with pulmonary function tests. A prospective three centre study enrolled 122 subjects with COPD (either acquired or genetic) and age-matched never-smokers. All diagnostic studies were completed in 94 subjects (52 with COPD; 13 with alpha(1)-ATD; 29 healthy subjects; 63 males; and 31 females; median age 62 yrs). The consensus assessment of radiologists, blinded for other test results, estimated nonventilated lung volume (HP (3)He MRI) and percentage diseased lung (HRCT). Quantitative evaluation of all data for each centre consisted of ADC (HP (3)He MRI) and MLD measurements (HRCT), and correlation with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) indicating airway obstruction, and the diffusing capacity of the lung for carbon monoxide (D(L,CO)) indicating alveolar destruction. Using lung function tests as a reference, regional analysis of HP (3)He MRI and HRCT correctly categorised normal volunteers in 100% and 97%, COPD in 42% and 69% and alpha(1)-ATD in 69% and 85% of cases, respectively. Direct comparison of HP (3)He MRI and CT revealed 23% of subjects with moderate/severe structural abnormalities had only mild ventilation defects. In comparison with lung function tests, ADC was more effective in separating COPD patients from healthy subjects than MLD (p<0.001 versus 0.038). ADC measurements showed better correlation with D(L,CO) than MLD (r = 0.59 versus 0.29). Hyperpolarised (3)He MRI correctly categorised patients with COPD and normal volunteers. It offers additional functional information, without the use of ionising radiation whereas HRCT gives better morphological information. We showed the feasibility of a multicentre study using different magnetic resonance systems.

Avian nucleus retroambigualis: cell types and projections to other respiratory-vocal nuclei in the brain of the zebra finch (Taeniopygia guttata).

In songbirds song production requires the intricate coordination of vocal and respiratory muscles under the executive influence of the telencephalon, as for speech in humans. In songbirds the site of this coordination is suspected to be the nucleus retroambigualis (RAm), because it contains premotor neurons projecting upon both vocal motoneurons and spinal motoneurons innervating expiratory muscles, and because it receives descending inputs from the telencephalic vocal control nucleus robustus archopallialis (RA). Here we used tract-tracing techniques to provide a more comprehensive account of the projections of RAm and to identify the different populations of RAm neurons. We found that RAm comprises diverse projection neuron types, including: 1) bulbospinal neurons that project, primarily contralaterally, upon expiratory motoneurons; 2) a separate group of neurons that project, primarily ipsilaterally, upon vocal motoneurons in the tracheosyringeal part of the hypoglossal nucleus (XIIts); 3) neurons that project throughout the ipsilateral and contralateral RAm; 4) another group that sends reciprocal, ascending projections to all the brainstem sources of afferents to RAm, namely, nucleus parambigualis, the ventrolateral nucleus of the rostral medulla, nucleus infra-olivarus superior, ventrolateral parabrachial nucleus, and dorsomedial nucleus of the intercollicular complex; and 5) a group of relatively large neurons that project their axons into the vagus nerve. Three morphological classes of RAm cells were identified by intracellular labeling, the dendritic arbors of which were confined to RAm, as defined by the terminal field of RA axons. Together the ascending and descending projections of RAm confirm its pivotal role in the mediation of respiratory-vocal control.

Novel optometrist-led all Wales primary eye-care services: evaluation of a prospective case series.

AIMS: To derive an evidence base for the efficacy of two novel optometric primary eye care services in Wales, the Primary Eyecare Acute Referral Scheme (PEARS) and the Welsh Eye Health Examination (WEHE). METHODS: A Donabedian model using structure, process and outcome was applied to evaluate prospectively 6432 individuals attending 274 optometrists within an 8-month period. Telephone interviews and review of optometric and hospital notes were used to determine management appropriateness for patients either managed in optometric practice or referred to the Hospital Eye Service (HES). A Geographic Information Systems analysis determined distances travelled to the optometrist. A cost analysis was used to determine the net cost of the schemes. RESULTS: 4243 (66%) of the 6432 individuals were managed in optometric practice; inappropriate management was apparent in 1% of individuals. 392 hospital notes were reviewed; 75% exhibited appropriate optometric referrals to the HES. 87% of individuals travelled less than 5 miles to attend an optometrist. The net cost of a PEARS/WEHE consultation was a minimum of pound12. CONCLUSIONS: Optometric management within the schemes is acceptable. Good equity of access was achieved at a relatively low net cost per consultation. Agreement on protocols for referral to the HES would enhance the schemes.

A pathway for predation in the brain of the barn owl (Tyto alba): projections of the gracile nucleus to the "claw area" of the rostral wulst via the dorsal thalamus.

The Wulst of birds, which is generally considered homologous with the isocortex of mammals, is an elevation on the dorsum of the telencephalon that is particularly prominent in predatory species, especially those with large, frontally placed eyes, such as owls. The Wulst, therefore, is largely visual, but a relatively small rostral portion is somatosensory in nature. In barn owls, this rostral somatosensory part of the Wulst forms a unique physical protuberance dedicated to the representation of the contralateral claw. Here we investigate whether the input to this "claw area" arises from dorsal thalamic neurons that, in turn, receive their somatosensory input from the gracile nucleus. After injections of biotinylated dextran amine into the gracile nucleus and cholera toxin B chain into the claw area, terminations from the former and retrogradely labeled neurons from the latter overlapped substantially in the thalamic nucleus dorsalis intermedius ventralis anterior. These results indicate the existence in this species of a "classical" trisynaptic somatosensory pathway from the body periphery to the telencephalic Wulst, via the dorsal thalamus, one that is likely involved in the barn owl's predatory behavior. The results are discussed in the context of somatosensory projections, primarily in this and other avian species.