Ischemic heart disease is a leading cause of death worldwide and comprises a large proportion of annual health care expenditure. Management of ischemic heart disease is now best guided by the physiologic significance of coronary artery stenosis. Invasive coronary angiography is the standard for diagnosing coronary artery stenosis. However, it is expensive and has risks including vascular access site complications and contrast material–induced nephropathy. Invasive coronary angiography requires fractional flow reserve (FFR) measurement to determine the physiologic significance of a coronary artery stenosis. Multiple noninvasive cardiac imaging modalities can also anatomically delineate or functionally assess for significant coronary artery stenosis, as well as detect the presence of myocardial infarction (MI). While coronary CT angiography can help assess the degree of anatomic stenosis, its inability to assess the physiologic significance of lesions limits its specificity. Physiologic significance of coronary artery stenosis can be determined by cardiac MR vasodilator or dobutamine stress imaging, CT stress perfusion imaging, FFR CT, PET myocardial perfusion imaging (MPI), SPECT MPI, and stress echocardiography. Clinically unrecognized MI, another clear indicator of physiologically significant coronary artery disease, is relatively common and is best evaluated with cardiac MRI. The authors illustrate the spectrum of imaging findings of ischemic heart disease ; highlight the advantages and disadvantages of the various noninvasive imaging methods used to assess ischemic heart disease, as illustrated by recent clinical trials; and summarize current indications and contraindications for noninvasive imaging techniques for detection of ischemic heart disease.Online supplemental material is available for this article.Published under a CC BY 4.0 license.  After completing this journal-based SA-CME activity, participants will be able to:■ Describe how various noninvasive imaging methods help assess for myocardial ischemia, and list the advantages and disadvantages of each method.■ Recognize the appearance of MI at all of the various noninvasive imaging modalities.■ Recognize the imaging findings of complications related to MI.the severity of a coronary artery stenosis does not always correlate with its hemodynamic significance. A stenosis greater than or equal to 70% sometimes may not lead to flow limitation, while two-thirds of moderate stenoses (50%–69% stenosis) are not flow limiting  accurately detects coronary artery stenosis and grades the degree of stenosis on the basis of the percentage of luminal narrowing. However, additional evaluation to assess the physiologic significance of the coronary stenosis is often required. Multiple imaging techniques can help in the detection of the physiologic significance of coronary artery stenoses: cardiac MR vasodilator or dobutamine stress imaging, CT stress perfusion imaging, FFR CT, PET myocardial perfusion imaging (MPI), SPECT MPI, and stress echocardiography. In the past several years, significant advances in noninvasive imaging techniques now allow accurate noninvasive disease assessment that is equivalent to that of invasive coronary angiography and invasive FFR measurement. MI is best evaluated with cardiac MRI. Clinically unrecognized MI, which is another sign of physiologically significant coronary artery disease (CAD), is a relatively common finding that has been found in approximately 17% of older individuals age ≥68 years) , and highlight the advantages and disadvantages of the various noninvasive imaging methods used to assess ischemic heart disease, as illustrated by recent clinical trials.Coronary artery atherosclerotic plaque results from a complex process that is driven by multiple factors within the intimal layer of the coronary artery wall. These include endothelial cell dysfunction, oxidized serum lipids, inflammation, and thrombosis, with secondary effects of angiogenesis and calcification. These factors are largely mirrored by CAD risk factors, including dyslipidemia, obesity, elevated serum inflammatory marker levels, and hypertension  esterified lipoproteins that accumulate through absorption of low-density lipoproteins (LDLs) from the blood and (b) nonesterified lipids and cholesterol that develop later on. Lipoproteins attract and are engulfed by macrophages that transform into foam cells filled with lipid droplets  obtaining the coronary calcium score and (b) performing CCTA. The coronary calcium score is obtained with a noncontrast electrocardiographically (ECG)-gated CT examination of the heart that quantifies the amount of coronary calcium. The quantified coronary calcium score, known as the Agatston score, can be used in conjunction with reference databases that have stratified Agatston scores by age, gender, and race/ethnicity  to risk stratify patients on the basis of the likelihood of having a coronary event within the next 5 years .,19.(a) oAfter the coronary calcium score examination, an ECG-gated CCTA examination of the heart is performed during the administration of intravenous iodinated contrast material at a rate of 5–7 mL/sec. CCTA can be performed prospectively  in patients with a regular heart rate less than 60 beats per minute. Retrospective acquisition (x-ray turned on during the entire cardiac cycle) is typically used for patients with arrhythmias or higher heart rates, but it increases radiation exposure to the patient. Detailed guidelines for CCTA patient preparation and CT scanner requirements are available from the Society of Cardiovascular Computed Tomography .CCTA directly aids in the visualization of coronary artery plaque, which may be noncalcified, partially calcified, or completely calcified. Noncalcified plaque is also referred to as soft plaque. Soft lipid-rich plaque tends to have lower Hounsfield units than soft predominately fibrous plaque (11–99 HU vs 77–121 HU) . PositivThe degree of luminal diameter narrowing (expressed as a percentage) resulting from the coronary artery plaque detected at CCTA determines the stenosis grade: no stenosis (0%), minimal (1%–24%), mild (25%–49%), moderate (50%–69%), severe (70%–99%), or occluded (100%) . In 2016CCTA has excellent spatial resolution and can anatomically detect coronary artery plaque with high sensitivity (94%) and specificity (83%). When directly compared with invasive angiography, CCTA has an accuracy of 95% for detecting coronary artery stenoses. However, the greatest strength of CCTA lies in its excellent negative predictive value (99%), established by the multicenter ACCURACY  trial . Subsequ(a) administering oral and/or intravenous β-blockers to lower heart rate before imaging, (b) removing data collected on ectopic beats through ECG editing software after imaging, (c) performing retrospective imaging for significant arrhythmia noted before the examination, (d) using iterative reconstruction algorithms to reduce calcium blooming, and (e) using a saline bolus chaser  and/or arrhythmia, calcium blooming artifacts , and beam-hardening artifact  . Problems chaser ,30,31. Rs chaser .MR angiography (MRA) has been suggested as a noninvasive method to detect CAD. MRA involves no ionizing radiation, and the lumen of the artery is well depicted on MRA images, even in the presence of heavy calcification. MRA has a sensitivity and specificity of 93% and 42%, respectively, for the detection of coronary disease . CurrentOver the past few years, there has been significant advancement in noninvasive imaging methods that now allow the accurate noninvasive functional assessment of CAD. These methods include stress perfusion imaging, dobutamine stress cardiac MRI, and stress echocardiography. Although not an imaging method, an exercise ECG test is a common initial noninvasive test performed for risk stratification that deserves brief mention. This test has the patient exercise on a treadmill while attached to an ECG machine and looks for ECG changes suggestive of ischemia while the patient is exercising. Exercise ECG has lower sensitivity (50%–68%) but moderate to good specificity (77%–90%) .Of the noninvasive imaging methods, stress perfusion imaging methods  have become the most widely used. Some of these modalities can also help assess myocardial viability to varying degrees, dependent on the examination protocols. Indications and contraindications for stress perfusion imaging are listed in 1. Adenosine (140 µg/kg/min) intravenous infusion for up to 6 minutes, although higher-dose protocols have been proposed to manage inadequate response to the standard dose. Adenosine has a short half-life and usually does not require reversal agents.2. Regadenoson (0.4 mg/5 mL) intravenous injection followed by saline (5 mL) intravenous injection. Regadenoson can be reversed after the stress procedure is completed with an intravenous injection of 100 mg of aminophylline.3. Dipyridamole (0.56 mg/kg) intravenous infusion over 4 minutes (up to a maximum of 60 mg). Dipyridamole has a much longer half-life than aminophylline, so there are reports of patients having recurrent symptoms or adverse events after leaving an imaging center despite initial reversal with aminophylline.Rest perfusion images are obtained when the heart is at rest during administration of contrast or radionuclide material. Rest images may be obtained either before the stress images or after the stress images once the heart rate has returned to baseline.2A) adenosine receptor agonist with coronary vasodilator properties and thus avoids heart block and is not contraindicated in patients with asthma and emphysema, but these patients need to be monitored carefully, with emergency treatments for bronchospasm available. Dipyridamole vasodilates primarily by raising platelet cyclic adenosine monophosphate (cAMP) levels via inhibition of its breakdown by cyclic nucleotide phosphodiesterase and also by blocking uptake of adenosine and thus has similar contraindications as those for adenosine , as well as at rest. Multiple prior studies have shown that cardiac MR stress perfusion imaging has excellent diagnostic accuracy for CAD –43. EithCine MR images are obtained between stress and rest perfusion acquisitions at the authors’ institution. A third optional gadolinium dose of 0.05 mmol/kg , referred to as a top-off dose, is commonly administered after the rest perfusion images in preparation for late gadolinium enhancement (LGE) images, which are obtained approximately 10 minutes after rest perfusion images. Administration of the optional top-off dose of gadolinium yields a total dose of 0.15 mmol/kg of gadolinium for the entire conventional cardiac MR stress perfusion examination. If the optional top-off dose is not administered, LGE images should be obtained earlier, approximately 5 minutes after the rest perfusion images. LGE images obtained as part of the cardiac MRI stress test can help detect clinically unrecognized MI, which is also a sign of physiologically significant CAD .The perfusion sequence described previously (saturation recovery pulse with FLASH read out) is commonly used. However, there are other options as well. Technical considerations for FLASH, steady-state free-precession (SSFP), and hybrid gradient-echo echo-planar perfusion methods have been reviewed previously  and are Conventional cardiac MR stress perfusion examinations are generally reported by using the 17-segment American Heart Association model, with the apex excluded . QualitaSemiquantitative methods include the contrast enhancement ratio , myocardial to LV upslope ratio , and upslope integral . Currently, semiquantitative methods are not recommended because they underestimate myocardial perfusion at high blood flow rates and do not significantly improve diagnostic accuracy when compared with qualitative assessment –49.More recently, fully quantitative MR stress perfusion methods, which outperform both qualitative and semiquantitative assessments, have been extensively validated by microspheres and coronary angiography ,48,50. FTo perform fully quantitative perfusion imaging, both the arterial input function and the transit of contrast material through the myocardium must be accurately measured. The arterial input function is the delivery of contrast material to the heart, as visualized in LV blood pool cavity. This can be performed by two different methods: dual-bolus method and dual sequence method.Dual-Bolus Method.—The dual-bolus method uses the standard perfusion sequence but two different boluses of contrast material: a lower-concentration bolus optimized for the arterial input function  and a higher-concentration bolus optimized for the myocardium . Both doses of contrast material are flushed with saline into equal volumes injected at the same rate . Thus, both stress and rest perfusion examinations are run twice (once for each bolus), yielding a total of four sets of perfusion images  (us rest) . Proton Dual-Sequence Method.—The dual-sequence method uses two different sets of image acquisition parameters in a saturation recovery perfusion sequence, a low spatial resolution sequence optimized for the arterial input function with FLASH readout and a high-resolution sequence optimized for the myocardium with SSFP or FLASH readout) and only one dose of contrast material. For each cardiac cycle, one low-resolution LV short-axis image for the arterial input function and three high-resolution LV short-axis perfusion images of the myocardium  are obtained  are also generated  48,51).,51.48,51Cardiac MR stress perfusion imaging offers many advantages but has some disadvantages. It boasts high sensitivity and specificity of 90% and 94%, respectively . There iAlthough not nearly as common as cardiac MR stress perfusion imaging, dobutamine stress cardiac MRI tests should be mentioned. Dobutamine, a synthetic β-adrenergic agent, is infused starting at a dose of 5 μg/kg/min and increased incrementally every 3 minutes to 10, 20, 30, and 40 μg/kg/min and stopped as soon as 85% or more of age-predicted heart rate is achieved. Atropine (0.25-mg doses to a maximum of 1 mg) can be given as a supplement to help boost heart rate response. Cine MR images are obtained at peak stress, and development or worsening of a wall motion abnormality  when compared with the rest images is considered a positive test result for functionally significant CAD. Dobutamine stress cardiac MRI has good performance . A major advantage of this technique is that it does not involve radiation exposure or gadolinium contrast material; thus it can be performed in patients with end-stage renal disease. However, it is not widely available. Dobutamine stress cardiac MRI is more likely to induce severe chest pain, ventricular tachycardia, or ventricular fibrillation than the vasodilators ,42,57.Additionally, there are some new techniques that are currently in development. Arterial spin labeling is a technique that quantifies myocardial blood flow without the use of contrast material. This technology uses radiofrequency pulses to alter the longitudinal magnetization of blood, thus labeling it as an endogenous tracer. This label decays at a time constant that equals the T1 relaxation time. After a delay to allow this labeled blood to affect the myocardium, images are obtained. A second set of myocardial images is obtained in the absence of the labeled blood. The two image sets are compared to quantitatively determine the amount of labeled blood flow to the myocardium . ContrasImproved spatial and temporal resolution of current multidetector CT systems as well as improved CT technology (wider detector coverage and new-generation iterative reconstruction) has yielded the development of modern CT stress perfusion . CT streThe CT perfusion examination has several options. Either stress or rest CT can be performed first. However, it is necessary to wait 10–20 minutes between the two parts of the examination, as each use a vasodilating agent . Both prospective and retrospective ECG gating are possible, but retrospective ECG gating is recommended for CT scanners that have a smaller z-axis (<8 cm). CT perfusion can be performed on either a single-energy or a dual-energy CT scanner. The stress CT technique can be static or dynamic .Static CT Stress Perfusion.—A single CT image of the heart is obtained at peak myocardial perfusion during vasodilator stress, which is determined either automatically by bolus tracking or manually. Since only a single CT image is obtained, timing is critical. Comparison with the rest CT image allows qualitative assessment of perfusion defects  is best for this technique to be successful. For CT scanners with a shorter z-axis, shuttle mode is necessary  or manual segmentation of the myocardium. Extraction of time-attenuation curves of the arterial input function (obtained from the region of interest on the descending aorta) and myocardial time-attenuation curves is performed, and myocardial blood flow is quantified by model-based deconvolution in milliliters per gram per minute per voxel . Both seApproximately 10–20 minutes after  the stress CT perfusion examination, the rest CT perfusion examination is performed. The rest perfusion CT examination is performed after the administration of sublingual nitroglycerin (for coronary artery dilation) and β-blockers (for lowering heart rate) and during the administration of intravenous iodinated contrast material. The rest CT examination obtains both the CCTA and the rest perfusion images.The CCTA images are analyzed for plaque and/or coronary stenosis, according to the CAD-RADS scoring system . LV shorSimilar to the MRI stress perfusion examination, the description of the perfusion defect should comment on the severity of the defect , the size , and if it is a reversible defect . A reverArtifacts should also be described. Beam- hardening artifact  is a problem depicted on both static and dynamic stress perfusion techniques. This is especially common within the basal inferolateral wall near the aorta and can be mistaken for a perfusion defect. Beam-hardening artifacts are improved with the use of dual-energy CT . Low-radCT stress perfusion has good accuracy (93%) when compared with that of invasive FFR measurement. When added to CCTA, the specificity and positive predictive value of the combined examination are significantly improved ,67,70. A(a) constructing an anatomic model of the ascending aorta and coronary artery lumen, (b) using a mathematical model of coronary physiology, and (c) using a numerical method to solve fluid dynamic equations (Navier-Stokes equations)  ,73.The CCTA dataset provides patient-specific coronary artery anatomy (including branching patterns and pathology) used to create an anatomic model of the lumen of the coronary artery tree. The domain, or portion of the CCTA to be analyzed, is bounded by the blood flow inlet (aortic root) and the blood flow outlet (ascending aorta and coronary arteries). A segmentation algorithm analyzes the coronary arteries, identifies and segments coronary artery plaque within all vessels, and creates an anatomic model of the lumen of the entire coronary artery tree, as well as the proximal ascending aorta. High-quality CCTA data are necessary to achieve a good model of the luminal anatomy of the patient’s coronary artery tree .A mathematical model of coronary physiology is necessary to determine conditions that represent microvascular resistance, aortic pressure, and coronary output. To accomplish this, lumped parameter models are used. Lumped parameter models of the heart, systemic circulation, and coronary circulation are applied to the patient-specific model from the CCTA data. The lumped model is similar to an electrical circuit and contains multiple parameters such as resistance, capacitance, inductance, etc, that are necessary to describe the relationship of blood flow and pressure. Parameter values are selected accordingly to compute cardiac output and aortic pressure ,73. MathOnce the parameters for the coronary physiology model are defined, the anatomic model of the coronary artery tree lumen is discretized into millions of finite elements  for analysis . The solThe current U.S. Food and Drug Administration (FDA)–approved postprocessing method is performed at a remote workstation and usually takes several hours per case. Once completed, the FFR value along any point in the coronary artery tree can be displayed on the final three-dimensional image. Additionally, the coronary artery tree is color-coded on the basis of a color scale corresponding to the FFR values . An FFR FFR CT functionally assesses moderate and severe coronary stenoses detected at CCTA, without any additional imaging or radiation exposure to the patient –11 76,7,776,78. FFR CT has several additional advantages. No additional imaging, radiation exposure, or stress examination is needed to perform this technique; only the CCTA data are necessary. In addition, several previous trials including PLATFORM , DISCOVER-FLOW , and HeartFlowNXT  have found that the accurate identification at FFR CT of patients for percutaneous coronary intervention overall decreases health care costs while providing similar outcomes to those of invasive diagnostic methods . The maj82Rb) and nitrogen 13 (13N) ammonia (13N-ammonia). 13N-ammonia is not nearly as commonly used as 82Rb given its need for cyclotron generation and a physical half-life of 9.9 minutes, which makes transport and/or shipping not feasible. Rubidium, which has an extremely short half-life of ~75 seconds, is produced from a strontium generator that can be used on site (PET is a radionuclide imaging technique that relies on the detection of photons emitted from injected radiolabeled tracers. Photon generation occurs through the process of annihilation: positrons (emitted by the tracer) collide with an electron. Two photons are emitted in opposite directions and travel a short distance to the PET scanner. The PET scanner contains rings of detectors that convert this energy into an electrical signal, and it makes assumptions on coincidence detection and line of response. The photon counts from all of these lines of response are reconstructed into a map of radioactivity distribution –84. Ther on site .Similar to other stress perfusion techniques, both stress and rest images are obtained . Rest imThe PET images can be interpreted qualitatively by comparing the stress and rest images and looking for areas of perfusion defect. The defect description should include the segments involved, the severity of the defect , as well as the amount of LV involved: small defect (5%–10% of the LV), medium (10%–20% of the LV), and large (>20% of the LV). Additionally, details of whether the defect is reversible (appears only on stress images secondary to ischemia) or fixed (appears both on stress and rest images secondary to an infarction) should be supplied.A semiquantitative scoring system can score the severity of perfusion defects in each segment on the basis of the radiotracer count density: 0 = no defect; 1 = mildly reduced count; 2 = moderately reduced count; 3 = severely reduced count; 4 = absent activity. However, the major strengths of PET MPI are its ability to quantify myocardial blood flows (in milliliters per minute per gram) and to obtain a peak stress left ventricular ejection fraction (LVEF), which allows an LVEF “reserve” calculation, in addition to evaluation of wall motion abnormalities in areas with perfusion defects. Global myocardial blood flows and LVEF reserve (peak stress LVEF − resting LVEF) have both been shown to be independent predictors of future major adverse cardiac events. The ratio of myocardial blood flow at stress to myocardial blood flow at rest gives the myocardial flow reserve ratio. A ratio less than 1.5 is abnormal and indicates ischemia. An LVEF reserve of less than zero indicates an abnormal response to vasodilator stress  and provides incremental value (in addition to accounting for perfusion defects) in predicting major adverse cardiac events ,85,86.PET MPI has several advantages and disadvantages. PET MPI is robust with high accuracy and can be performed in patients with arrhythmias, advanced kidney disease, and pacemakers and/or defibrillators . PET MPINewer iterative reconstruction methods, improvements in detector technology, and three-dimensional acquisition have resulted in better spatial resolution (2 mm) and lower radiation doses (<2 mSv). With hybrid PET/CT scanners, low-radiation-dose noncontrast CT images of the heart are obtained before both stress and rest PET images for attenuation and scatter attenuation, which also allows screening and measurement of coronary artery calcium ,87. It iAlthough originally used in research settings, PET MPI usage in clinical practice has increased over the years, secondary to increased radiotracer availability, new camera technologies, and data demonstrating its advantages over other MPI techniques. Unfortunately, despite its increased availability, PET still remains limited and is an expensive examination.SPECT MPI is an older technique that relies on the detection of γ rays emitted from radionuclide agents. In comparison with other imaging methods, SPECT MPI remains the most commonly used noninvasive imaging study in clinical practice for several reasons: its widespread availability, its well-established standardized protocols, familiarity with the modality among providers, and the years of established data for diagnostic accuracy, allowing accurate risk stratification of patients.201Tl), technetium 99m (99mTc)–sestamibi, 99mTc-tetrofosmin, and 99mTc-teboroxime. Technetium agents are preferred over 201Tl owing to its shorter half-life (less radiation dose to the patient)  ,90.Stress and rest perfusion images are compared side by side to identify perfusion defects secondary to myocardial ischemia or infarction . The perThe ECG-gated stress and rest images provide information on LV size, systolic function, and wall motion abnormalities. SPECT images suffer from several artifacts that mimic perfusion defects that should be noted if present. These artifacts are suggested by their typical locations and have normal LV wall motion in the area of the artifact on the ECG-gated images. Artifacts include soft-tissue attenuation from the breast affecting the anterior wall or diaphragm affecting the inferior wall (both of which can be confirmed by reviewing the raw images); apparent increased activity in the inferior wall secondary to subdiaphragmatic hepatobiliary excretion of technetium-labeled agents ; motion artifact causing the heart to appear in different places on adjacent images , which warrants repeat imaging; and misregistration of SPECT and CT images. Normal apical thinning can cause apparent defects at the apex. However, these areas should have normal wall motion on the ECG-gated images. Additionally, left bundle branch block can cause an apparent defect in the septal wall, which is associated with paradoxical motion of the septum on the ECG-gated images ,90.The biggest advantage of SPECT is its widespread availability. Additionally, SPECT MPI can be performed in all patients. Unfortunately, it is a fairly long examination that suffers from higher radiation exposure, although newer technologies such as cardiac-specific solid-state detector cameras have lowered radiation doses to some degree. It also suffers from lower spatial resolution when compared with PET and has lower sensitivity and specificity when compared with MRI, PET, and CT methods. SPECT MPI examinations performed with exercise have decreased diagnostic accuracy if the patient cannot achieve a good heart rate response owing to physical or other limitations. Finally, SPECT MPI can overlook cases of balanced ischemia ,91.Stress echocardiography is a widely available noninvasive imaging test used to risk stratify patients with suspected coronary disease. The stress echocardiographic examination observes the wall motion of the heart before, during, and after stress. Stress echocardiographic images are obtained immediately after treadmill exercise, during bicycle exercise, or during peak pharmacologic stress. Pharmacologic stress is obtained with dobutamine or a vasodilator (predominately dipyridamole). The minimum views obtained at stress echocardiography include parasternal long- and short-axis, apical four-chamber, and apical two-chamber views. The stress and rest echocardiographic images obtained are compared to assess for the development of a new or worsening wall motion abnormality that develops during stress, indicative of coronary ischemia. Wall motion abnormalities are graded as hypokinetic, akinetic, etc .When directly compared with invasive FFR measurement as a reference standard, stress echocardiography has a sensitivity and specificity of 77% and 75%, respectively. Overall, this is similar to SPECT but below the performance of other noninvasive imaging modalities . The major advantages of stress echocardiography include its wide availability, low cost, lack of ionizing radiation, and portability. The biggest disadvantage is that images can be suboptimal, particularly in larger patients ,92.Overall, the available evidence supports that the best noninvasive study to functionally assess coronary stenosis currently is cardiac MR stress perfusion imaging , closely followed by PET MPI   ,93. Cardity 84%) .Both CT methods, CT stress perfusion imaging and FFR CT, rank just below MRI and PET methods, secondary to slightly lower specificities  but boast excellent sensitivity and negative predictive value ,70. WhenCompared with all of the other modalities, SPECT MPI and stress echocardiography overall have lower sensitivity, specificity, and diagnostic accuracy ,88. HoweUnderstanding the advantages and disadvantages of each noninvasive imaging test aids in determining which test is best for an individual patient. Ideally, the test chosen should have the highest performance possible, have the least amount of radiation exposure possible, and be available in the patient’s area. Availability of a test is often the limiting factor .Although some tests clearly have higher diagnostic performance, deciding on the best test for a patient may be daunting with so many choices available. Available data on current trends in cardiac imaging show that MRI, PET, and CT methods are performed far less often than SPECT and stress echocardiography, a finding that is strongly associated with the availability of these testing modalities. In fact, SPECT MPI remains the most commonly ordered test for reasons previously described. However, over the past several years, this trend is slowly starting to change, as the high-performance MRI, PET, and CT methods are becoming more widely available; the number of SPECT MPI and stress echocardiography examinations has been slowly decreasing, while the number of MRI, PET, and CT examinations has slowly been increasing  . UnderstBased on the sensitivity and specificity of the tests  there ar2). The CCTA-first pathway should be favored in patients with low pretest probability of CAD for several reasons: (a) CCTA works well in normal or near-normal coronary arteries, (b) CCTA has excellent negative predictive value safely excluding CAD, and (c) a normal CCTA examination and normal coronary calcium score suggest excellent prognosis. As such, if the CCTA and coronary calcium score are both normal, the patient should receive routine preventive medicine, and physicians should consider alternative diagnoses.A decision tree outlining three diagnostic pathways for assessing patients with suspected stable angina or CAD is presented in If the CCTA examination is abnormal but all stenoses are less than 50% in severity, the patient should receive optimal medical therapy for CAD, but physicians should also pursue alternative diagnoses since a stenosis less than 50% is unlikely to explain stable angina. If the CCTA images depict a greater than or equal to 50% left main coronary artery stenosis, the patient should receive optimal medical therapy, and their physicians should consider referring the patient for invasive angiography and possible revascularization. Patients with severe stenosis not involving the left main coronary artery can be treated with optimal medical therapy initially. Failure to control symptoms with optimal medical therapy can be because of severe physiologically significant CAD or because the severity of stenosis detected at CCTA was not physiologically significant and there is an alternative reason for the patient’s angina. The specificity of CCTA without CT FFR is described earlier in this article. Thus, switching at this point to the stress test pathway is more reasonable than repeating CCTA or going straight to invasive angiography.The stress test–first pathway  should bThe selection order of stress tests is organized by tiers of relatively equivalent diagnostic accuracy. First-tier tests have the highest accuracy and include cardiac MR stress perfusion imaging, PET MPI, and CT stress perfusion. The second-tier tests include SPECT MPI and stress echocardiography. The third-tier test is dobutamine cardiac MR. The second-tier tests cannot be eliminated owing to limited availability of the advanced first-tier cardiac imaging methods, expense, relatively small differences in diagnostic performance, and other considerations. Dobutamine stress cardiac MR is listed as a third-tier test despite good diagnostic accuracy because there are relatively few centers in the United States and most countries in the world that perform a significant number of these tests. A negative stress test should trigger routine preventive care, and the physician should investigate other causes of the symptoms. If the stress test result is abnormal, optimal medical therapy should be prescribed. Failure of optimal medical therapy in either part of the pathway could be due to a noncoronary cause of the symptoms or CAD so severe that revascularization might be needed. At this point, CCTA with FFR (FFR CT) or invasive angiography with FFR could help resolve the residual clinical questions related to CAD.Finally, the severely decreased renal function pathway  omits CCAcute disruption of coronary artery blood flow, which most commonly occurs owing to plaque rupture or erosion, may result in prolonged myocardial ischemia and subsequent MI. Less common causes of MI include coronary vasospasm, vasculitis, embolism, coronary artery dissection, or various iatrogenic injuries. Cardiac MRI with gadolinium contrast material remains the standard test for assessment of myocardial viability, which was first established in a landmark article by Kim et al  in 1999.Myocyte death increases the extracellular volume in the infarcted myocardium, resulting in delayed wash-in and washout of gadolinium, which subsequently shortens its T1 relaxation time so that it appears bright relative to normal myocardium on T1-weighted inversion-recovery images obtained 10–20 minutes after a 0.1–0.2 mmol/kg intravenous dose of gadolinium contrast material on cardiac MR images. These images, referred to as LGE images, delineate the amount of infarcted myocardium ,97. CurrThe conventional LGE method is the segmented inversion-recovery LGE method, which is an inversion-recovery sequence with a segmented FLASH readout. The segmented acquisition means that a fraction of the raw data are obtained during each heartbeat in diastole with consistent inversion time after the QRS complex of the ECG. Most protocols complete data acquisition over about 8–12 cardiac cycles during a breath hold. In this method, an inversion time is manually selected by the technologist to null the normal myocardium, resulting in extremely low signal intensity of the normal myocardium .Segmented LGE images can be reconstructed as both magnitude and phase-sensitive images. Magnitude reconstruction is the most common method used for reconstructing MR images, but its appearance is highly sensitive to the selected inversion time. Phase-sensitive reconstruction produces consistently good image quality even if the technologist’s selected inversion time is slightly off . Phase-sThe most characteristic finding of MI on cardiac MR images is involvement of the subendocardial layers of myocardium , with a variable transmural extent generally graded per the following scale: none, 1%–25%, 26%–50%, 51%–75%, 76%–99%, and 100% . DescripAdditional findings of MI include wall motion abnormalities, thinning of the myocardial wall, and decreased ejection fraction. Wall motion abnormalities with no corresponding LGE correspond to stunned or hibernating myocardium that may recover without and with revascularization, respectively. More recently, precontrast and postcontrast  T1 maps can be used to generate extracellular volume (ECV) maps. ECV maps display the percentage of ECV in the myocardium on a pixel-wise level. An ECV greater than 29% indicates abnormally increased extracellular volume (dependent on the methods used), which could be secondary to fibrosis from MI or other processes, edema, amyloidosis, etc .The conventional segmented inversion-recovery method provides high-spatial-resolution LGE images under ideal conditions but has two major weaknesses. Its quality is easily degraded if there is motion artifact resulting from imperfect breath holds or if there is an incorrect inversion time. Newer LGE methods offer solutions to these problems. These methods include single-shot inversion-recovery LGE, postcontrast T1 mapping, synthetic inversion-recovery LGE methods derived from T1 mapping, and motion-corrected free-breathing LGE –106. AllAlthough ECG-gated CT of the heart is not recommended to assess for myocardial viability, findings of MI are frequently identifiable and incidentally found on both cardiac CT and nongated thoracic and abdominal CT images. Thus, familiarity with the appearance of MI at CT remains important. The main findings include a regional area of hypoperfusion, focal myocardial thinning, and myocardial calcifications  107). F. F107). Similar in concept to LGE images obtained during cardiac MRI, a delayed CT image obtained approximately 10 minutes after iodinated contrast material administration that can detect MI has been recently described. However, continued work is needed to further validate this method. Performing this delayed CT examination also results in additional radiation exposure to the patient .18F) fluorodeoxyglucose and carbon-11 (11C) acetate. Metabolic activity within the matched defect on PET perfusion images is consistent with viable hibernating myocardium, which would likely improve after revascularization (PET and SPECT MPI procedures and interpretation are detailed earlier in this article. Both PET and SPECT examinations can help identify matched defects on stress and rest images, although SPECT suffers from lower spatial resolution. These matched defects may represent MI or hibernating myocardium –19. Hiberization ,80,82. CComplications of MI are best identified at echocardiography, cardiac MRI, and cardiac CT. These include LV aneurysm and pseudoaneurysm, LV thrombus, fatty metaplasia of chronic MI, ischemic ventricular septal defect, intramyocardial hematoma in the setting of an acute MI, acute mitral regurgitation, and Dressler syndrome.Left ventricular aneurysm and pseudoaneurysm infrequently complicate MI, but differentiating true aneurysm from pseudoaneurysm is important because of their different management and prognosis. A true aneurysm is a wide-mouthed outpouching of the LV that involves all three layers of myocardium. The myocardium is thinned, akinetic or dyskinetic, and enhances on LGE images . True anFatty metaplasia of chronic MI is the sequela of the infarct healing and/or remodeling process. It is fairly common and increases the risk of ventricular arrhythmias ,111. It Ischemic ventricular septal defect  is a faiIntramyocardial hematoma is an exceedingly rare life-threatening complication of an MI that is often first visualized on an echocardiogram but is best characterized with cardiac MRI and/or CT . RuptureIschemic mitral regurgitation is an uncommon emergency after an acute MI that has two major mechanisms: abrupt papillary muscle rupture and papillary muscle dysfunction following acute MI, both of which worsen the prognosis of the acute MI. Ischemic mitral regurgitation tends to occur with an inferior wall infarction that affects the posteromedial papillary muscle. Papillary muscle dysfunction is more common than papillary muscle rupture, but both are rare. Ischemic mitral regurgitation commonly manifests as acute pulmonary edema, sometimes localized to the right upper lobe, which may be the first sign noticed on a chest radiograph. The ischemic mitral regurgitation can be visualized on an echocardiogram as well as on a cardiac MR velocity-encoded phase-contrast image. Treatment is valvular surgery ,115.Dressler syndrome is another MI-related complication seen in up to 5% of patients. The syndrome manifests with low-grade fever, pericardial rub, and pleuritic chest pain after an MI, and it is believed to be secondary to an autoimmune reaction to the myocardial necrosis that occurs 2–10 weeks after the infarction. Both cardiac MR and CT images show thickening of the pericardium and pericardial effusion acutely . LGE imaManagement of ischemic heart disease, which remains one of the leading causes of death worldwide, is now best guided by the physiologic significance of coronary artery stenosis. Unrecognized MI is another clear indicator of physiologically significant CAD. CCTA remains an effective first-line examination to exclude CAD in patients with low pretest probability but cannot assess the physiologic significance of a coronary stenosis without additional functional analysis of the coronary stenosis. Advances in multiple noninvasive imaging techniques, in particular quantitative capabilities in MRI, CT, and PET, allow accurate detection and functional assessment of CAD in patients with intermediate to high pretest probability and have enabled these noninvasive imaging methods to assume a key role in guiding therapeutic intervention. MI may be identified at multiple modalities but is best imaged with cardiac MRI. Both CT and MRI adequately image complications related to MI.


Spinal AVF (SAVF), a potentially treatable cause of myelopathy, remains a challenging diagnosis. Its rarity and non-specific imaging findings often result in misdiagnosis despite a high index of clinical suspicion. The classically described high T2 signal in the spinal cord or prominent vascular flow voids in the intradural space were not infrequently missed on initial imaging, only to be picked up at follow-up imaging after progression of symptoms. Additionally, small sized fistulas(< 1 mm) and SAVF involving less frequent locations like the craniocervical junction in a patient presenting with paraplegia further complicates the diagnosis. On rare occasions, acute atypical presentation following a surgery adds to the conundrum. Definite diagnosis with spinal angiography, the gold-standard modality requires the expertise of highly skilled interventionists which may otherwise lead to false negative findings. We describe four SAVF patients with unconventional presentations, highlighting less described clinical findings.First was a 50-year-old man presented with spastic paraparesis and was found to have an AVF at the cervical region arising from the vertebral artery. Second, a 45-year-old man with acute paraplegia post-operatively, initially treated for a transverse myelitis before lumbar region AVF was detected. Thirdly, a 27-year-old man presented with subacute lower thoracic myelopathy and deteriorated after corticosteroid treatment. The last patient, who initially appeared to have conus medullaris/cauda equina syndrome had a SAVF at the mid thoracic level. Presentation varied with some exhibiting acute deterioration mimicking other spinal cord pathology such as inflammatory disorders. All patients eventually underwent endovascular treatment with successful embolization of SDAVF. None of them exhibited further neurological deterioration after embolization.Successful treatment of SAVF is possible provided the diagnosis is made early, allowing timely intervention. Certain clues may aid the diagnosis. Firstly, arteriovenous fistula can be located distant to the clinical localization of myelopathy resulting in the unexpected longitudinally extensive spinal cord signal change. This clinical-radiological discrepancy can be a useful clue in diagnosing SAVF. Secondly, an acute myelopathic presentation immediately post-surgery may be related to SAVF. Other SAVF feature of note includes progressive myelopathy mimicking immune-mediated myelitis among young adults below 30 years of age refractory to immune therapy. Spinal arteriovenous fistulas (SAVFs) is a rare but treatable cause of chronic myelopathy as a result of progressive spinal venous hypertension. Available evidence suggests that SAVFs are acquired lesions due to obstructed spinal venous drainage although the actual etiology remains unclear. Despite increasing recognition of this disease and advancing surgical skills over the recent years, the diagnosis of complex SAVFs involving the low-flow fistulas especially at less common sites with atypical clinical presentation and non-specific spinal cord imaging appearance remains a challenge. SAVFs involving the craniocervical junction are rare, but are the most dangerous among all due to their potential significant brainstem oedema secondary to venous congestion. This can lead to an increased risk of subarachnoid or posterior fossa haemorrhage , 2. VeryWe report 4 cases of low-flow SAVFs with longitudinally extensive, multi-segment lesions involving more than one spinal cord region. The atypical clinical course and imaging characteristics discussed unveils the paradigm of clinical heterogeneity in a single entity.The clinical characteristics, chronology of events and outcome of patients are summarised in Table  IgG and cerebrospinal fluid (CSF) oligoclonal band (OCB), he was treated as immune-mediated longitudinal extensive transverse myelitis (LETM) with intravenous (IV) Methylprednisolone. Two days later, his weakness progressed to quadriparesis. He subsequently received 5 sessions of therapeutic plasma exchange (TPE), but showed no response. A repeat MRI/MRA of the spine revealed extension of the hyperintense lesion from pons to T1 level with cord expansion and anterior serpinginous flow void signals , he had partial recovery and was able to ambulate despite a right foot drop and required intermittent bladder catheterization. Upon admission to our center, an urgent MRI of the spine reported a T2 hyperintense intramedullary lesion with patchy enhancement extending from T7 to L1. He rapidly deteriorated and became paraplegic over the next few days despite retreatment with IV Methylprednisolone. MRI images were revisited, with identification of flow void signals at the posterior aspect of the cord from T6 to L2 (Fig. A 56-year-old gentleman presented with a month history of lower back pain followed by paraparesis. Prior to that, he had an episode of acute urinary retention requiring temporary indwelling catheterization. MRI of the whole spine done at another center concluded degenerative spine disease. Upon assessment, sensation was reduced below the L4 dermatome. Repeat MRI showed a longitudinal extensive T2 hyperintense contrast enhancing intramedullary lesion from T6 to L1. His lower limb weakness deteriorated soon after the first dose of Methylprednisolone. Despite strong clinical suspicious of SAVF, his spinal angiogram was negative for this. He received a course of IV Methylprednisolone followed by plasmapheresis but showed no remarkable improvement. Within a year, he was readmitted twice for similar relapses and responded poorly to IV methylprednisolone. Repeated MRI spine demonstrated a worsening contrast enhanced T2 hyperintense lesion involving T4 to the conus medullaris with dilated spinal veins seen most prominently from T10 to L1 level We described 4 cases of low-flow dural SAVFs with unique heterogeneous clinical spectrums. We discuss 4 important but less-described aspects of clinical practice in the management of SAVFs.Firstly, the clinical presentation of the low-flow variant of SAVFs correlated poorly with radiological findings. Myelopathy and sensory deficit inaccurately predicted the extent of spinal cord intramedullary T2 signal and the level of SAVF. This was thought to be due to the unequal distribution of venous outflow channels along the spinal cord, with the lower thoracic region having relatively fewer venous outflow channels compared to the cervical region. This results in venous congestion being transmitted in a caudocranial direction, explaining the more severe myelopathy symptoms correlating with a more distal region of the MRI signal , 8. ThisSecondly, increased venous hypertension in low-flow SAVF reflects the underlying dynamic vascular pathophysiology of this disorder. Although the underlying aetiology and pathophysiology of SAVF is not perfectly understood, we know that arterialization of the venous system diminishes the arteriovenous pressure gradient and leads to a decreased drainage of normal spinal veins, resulting in venous congestion . TherefoThirdly, majority of patients with SAVFs have MRIs that show either longitudinally extensive intramedullary T2 hyperintense signal, flow voids or cord expansion. The probability of one of these MRI changes occurring in a patient is reported to be as high as 100% . DespiteLastly, low-flow SAVF is typically diagnosed among older patients presenting with a progressive myelopathy secondary to spinal venous hypertension. The diagnosis is extremely uncommon in the younger population and is rarely discovered before the age of 30, although one of our four patients was 27 years old. It is estimated that disease onset before 30 of age constitute less than 1% of the patients , 21, simNeurosurgery and endovascular embolization have been employed in the management of SAVF. Endovascular modality has been the traditional first line approach in our institution, possibly due to the limited expertise and risks involved with open spinal surgery. However, several studies and meta-analyses over the years have consistently shown better success and lower recurrence rates with neurosurgery compared to endovascular treatment; although the outcome of the latter has improved over time .We described the atypical presentation and clinical heterogeneity seen among patients with low-flow SAVFs. Careful recognition of these uncommon features such as prominent high craniocervical lesions without brainstem signs, symptom onset in association with a recent surgery, false negative spinal angiogram, and SAVF in young adults may change the clinical course of the disease and improve functional prognosis.


Several elements highlight the importance of the mechanistic target of rapamycin (mTOR) in the biology of renal cell carcinoma (RCC). mTOR signaling pathway is indeed frequently activated in RCC, inducing cancer cell proliferation and survival. In addition, mTOR promotes tumor angiogenesis and regulates the expression of hypoxia-inducible factors that play an important role in a subset of RCC. Despite mTOR protumorigenic effects, mTOR inhibitors have failed to provide long-lasting anticancer benefits in RCC patients, highlighting the need to readdress their role in the treatment of RCC. This review aims to present the rationale and limitations of targeting mTOR in RCC. Future roles of mTOR inhibitors in the treatment of RCC are also discussed, in particular in the context of immunotherapies. Renal cell carcinoma (RCC), which originates from the kidney epithelium, is the most frequent form of kidney cancer . Consequently, hypoxia-inducible factors (HIF-1α and HIF-2α) accumulate, leading to a constant hypoxic tumor response that promotes tumor growth and angiogenesis despite the presence of oxygen  and increased spontaneous tumor-specific TH1 response. Importantly, in a subset of patients, everolimus decreased Tregs levels while increasing TH1 response, which was associated with a longer progression-free survival. This suggests that the antitumor effects of rapalogs occur in part via modulation of the antitumor immune response and provide an additional rationale to combine mTOR inhibitors with immunotherapies.Following major therapeutic success by immunotherapy in melanoma, lot of efforts are deployed to design immunotherapy-based protocols in RCC. Interleukin-2 and interferon-α were initially used in patients with advanced RCC, suggesting that RCC might be particularly sensitive to immunotherapies. Accordingly, numerous clinical trials are currently exploring the effects of immunotherapy alone or in combination with various targeted therapies (Garje et al., The endothelial barrier is an important obstacle to recognize when considering combining anticancer agents with immunotherapies (Schmittnaegel and De Palma, VHL mutation, the preferential inhibition of HIF-1α over HIF-2α by rapalogs might decrease the tumor-suppressing effects of HIF-1α, counteracting the anticancer efficacy of rapalogs. Given the success of immunotherapies, future investigations addressing the role of mTOR inhibitors in RCC will certainly focus on their immunostimulatory effects. Accordingly, dissecting the conditions where mTOR inhibitors exert immunostimulatory instead of immunosuppressing activities will be key. Interestingly, a study demonstrated that some RCC patients preferentially presented increased antitumor response under rapalog treatment, highlighting their therapeutic potential in combination with immunotherapy.Despite clear implications of mTOR signaling pathway in RCC development and progression, inhibition of mTOR through rapalogs did not provide major and long-lasting anticancer benefits in patients. Whereas, mTOR is frequently activated in RCC and participates in tumor growth, RCC harbors major genetic heterogeneity, implying that many driving forces, not limited to mTOR, participate in tumor growth. Combination therapies might therefore provide additional antitumor effects, albeit increased toxicity. Although several preclinical studies have demonstrated that mTOR inhibitors decrease tumor angiogenesis, this specific mechanism in the context of RCC has not been thoroughly investigated. More importantly, some investigations in RCC mouse models did not find any inhibitory effect of rapalogs on the tumor vasculature. Finally, in a subset of RCC that presents SF and OD designed the manuscript. SF drafted the manuscript. OD and ND revised the manuscript. All authors have approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Semantic composition is the ability to combine single words to form complex meanings and is an essential component for successful communication. Evidence from neuroimaging studies suggests that semantic composition engages a widely distributed left-hemispheric network, including the anterior temporal lobe, the inferior frontal gyrus and the angular gyrus. To date, the functional relevance of these regions remains unclear. Here, we investigate the impact of lesions to key regions in the semantic network on basic semantic composition. We conducted a multivariate lesion-behaviour mapping study in 36 native German speaking participants with chronic lesions to the language network after left-hemispheric stroke. During the experiment, participants performed a plausibility judgement task on auditorily presented adjective-noun phrases that were either meaningful (‘anxious horse’), anomalous  or had the noun replaced by a pseudoword (‘anxious gufel’), as well as a single-word control condition (‘horse’). We observed that reduced accuracy for anomalous phrases is associated with lesions in left anterior inferior frontal gyrus, whereas increased reaction times for anomalous phrases correlates with lesions in anterior-to-mid temporal lobe. These results indicate that anterior inferior frontal gyrus is relevant for accurate semantic decisions, while anterior-to-mid temporal lobe lesions lead to slowing of the decision for anomalous two-word phrases. These differential effects of lesion location support the notion that anterior inferior frontal gyrus affords executive control for decisions on semantic composition while anterior-to-mid temporal lobe lesions slow the semantic processing of the individual constituents of the phrase. In a lesion-behaviour mapping study, Graessner et al. found dissociable contributions of left-hemispheric brain regions to basic semantic composition: While the anterior inferior frontal gyrus is relevant for task accuracy, the anterior temporal lobe is crucial for efficient semantic processing.  Language comprehension requires rapid mapping of arbitrary word-forms to meaning. For speech comprehension, listeners match the auditory input to stored representations of words and recover the communicative intent in a framework of pre-established world knowledge. Semantic composition is crucial to this process as it allows for the combination of single word meanings to form complex representations.At the neural level, a widely distributed left-lateralized fronto-temporo-parietal network has been identified for semantic composition. It comprises the anterior temporal lobe (ATL), posterior middle temporal gyrus (pMTG), anterior inferior frontal gyrus (aIFG) and the angular gyrus (AG).,,Complementary to functional imaging studies, a powerful approach to investigate the functional anatomical organization of linguistic competence rests on the behavioural assessment in participants with an acquired brain lesion. Such lesion-behaviour mapping in people with post-stroke aphasia has identified crucial regions for language comprehension.composition from lexico-semantic competence and the overall extraction of meaning. On the contrary, simple two-word paradigms should allow us to disentangle the core combinatorial process and aspects of lexical access and lexico-semantic mapping of single entries. Our study is experimental in nature, however, people with no or residual aphasia  may well struggle with fast semantic composition. Since even slight impairments may interfere with efficient language comprehension, the material used here may serve as a starting point to develop tools to better grasp such aspects of communication in people with an acquired brain lesion.Previous lesion studies mainly examined deficits of comprehension at the single word or sentence level. This obscures the differentiation between the basic ability of semantic ,With respect to the neural correlates of the combinatorial process, we investigate the functional relevance of key semantic regions in the left hemisphere for successful meaning composition by means of multivariate lesion-symptom mapping (LSM) in a cohort of post-stroke language-impaired patients. We probe the ability to judge two-word phrases with regard to the plausibility to form a semantic entity presenting meaningful phrases (‘anxious horse’), anomalous phrases , and pseudoword phrases containing pseudonouns . The design targets the contribution of different brain regions to successful meaning composition by comparing meaningful phrases to phrases in which meaning composition is attempted but should fail . To control for overall lexical and executive processes, phrases containing a pseudoword (pseudoword phrases) and a single word condition are included. All two-word phrases are matched on the syntactic and acoustic dimension. The single word comprehension condition serves as low-level baseline for the processing of auditory verbal input and is included to balance forced choice probabilities. We apply multivariate LSM because recent advances in the methodology of LSM have shown that multivariate methods (e.g. support-vector-regression) provide more rigorous and sensitive approaches to associate brain lesions with specific behavioural deficits over classical univariate analyses.ATL,,,left AG as another central region for basic semantic composition.left aIFG has also been implicated in semantic processing. The few lesion studies that reported an association of aIFG lesions and language comprehension investigated single word understanding.,,,,Regarding candidate hubs within the network for semantic processing and meaning composition, neuroimaging and lesion studies speak for a critical role of n = 1 due to no diagnosed aphasia, n = 1 due to additional large right-hemispheric lesion, n = 4 due to behavioural results, see N = 7), Amnestic (N = 4), non-classifiable (N = 4), Global (N = 3), Wernicke’s (N = 1) and Residual (N = 17). Participants with residual aphasia at the time of testing had presented with overt aphasia in the acute phase of the disease. Detailed demographic information of the final cohort can be found in Forty-two native German speaking participants with an acquired chronic left-hemispheric lesion were recruited from the database of the Max Planck Institute for Human Cognitive and Brain Sciences and the Clinic for Cognitive Neurology, University Hospital Leipzig. Exclusion criteria were severe overall cognitive impairment and pre-morbid left-handedness. Six participants had to be excluded  and general executive demands (single word versus two-word phrases. See supplement for more details). All participants performed a behavioural experimental paradigm for about 30 min and underwent an additional hour of diagnostic testing and questionnaires  allows for successful meaning composition; (ii) The anomalous condition comprises two meaningful words which cannot be semantically integrated based on world knowledge , since the adjective violates the selectional restriction criteria of the noun (e.g. ‘anxious’ cannot be mapped onto non-living entities). This condition triggers the attempt of meaning composition which should fail in case the lexico-semantic system is intact; (iii) For the pseudoword condition, the noun was replaced by a pseudoword (‘anxious gufel’). Note that the syntactic information is kept constant for these three conditions. This avoids confounds by a different number of words or differences in syntactic complexity and allows for largely selective variation of the amount of conceptual/semantic information. (iv) The single word condition was included as low-level baseline and to grant equal numbers of ‘meaningful’ and ‘not meaningful’ judgements. The final set of stimuli consisted of 56 phrases per condition, matched for word frequency, orthographic neighbourhood, length, gender and concreteness  and the standard German non-verbal semantic test (n = 33).To exclude severe deficits in lexical and semantic competence, clinical tests were performed in most participants. This included lexical decision and synonym judgement tasks (n = 36), structural imaging was available. These consisted of 30 scans obtained in the in-house MRI scanners  and included 3D T1-weighted- (1 mm isovoxel), and FLAIR-images. In three patients, clinical MRI-imaging at a lower resolution  was available; in three patients, a cerebral Computed Tomography was used for lesion delineation. Lesions were manually delineated by an experienced neurologist (H.O.) in all three planes on each slice of the T1 or cerebral Computed Tomography-images using MRIcron,3 using SPM12 (www.fil.ion.ucl.ac.uk/spm) and the ‘clinical toolbox’ , which allows for normalizing images from different modalities into the same space. The unified segmentation approachFor all participants .Statistical analyses were performed in R (version 3.6.1) with the generalized linear mixed-effects model using the lme4 package,To investigate lesion-behaviour relationships, we performed multivariate LSM using support-vector-regression (SVR)We ran in total six SVR-LSM analyses to identify lesioned regions associated with lower accuracy in meaningful, anomalous and pseudoword phrases and lesions associated with higher log reaction times in the three conditions. To isolate effects of each condition, we covaried all other conditions out of both the behavioural data and the lesion data using a nuisance model.P < 0.005. Although SVR-LSM considers all voxels simultaneously in a single model, statistical significance is determined for each voxel separately, eliciting the well-known problem of multiple comparisons. We thus corrected for multiple comparisons by applying a familywise error rate at a threshold of P < 0.05 using a cluster-extent threshold determined from the same 5000 permutations. This method is currently considered the gold standard for lesion symptom mapping.Voxel-wise statistical significance was determined by permuting the behavioural scores and randomly reassigning them to participants. SVR-β-value maps were generated for 5000 permutations and thresholded at The data that support the findings of this study are available from the corresponding author, upon reasonable request.We conducted  linear mixed-effects models to evaluate behavioural differences between conditions for both reaction times and accuracy. Overall, mean accuracy was high (95.33%), showing that participants were able to perform the task. Large inter-individual differences, however, show that our participants exhibit a wide variety of deficit severity, which is an important factor in identifying lesion-behaviour relationships.Pairwise post-hoc comparisons between all conditions revealed that reaction times differed significantly between all conditions, with anomalous phrases being processed slowest and single words fastest ; Table 2Lesion overlap of the 36 participants is shown in Our first set of SVR-LSM analyses focussed on lesion correlates of accuracy across the three main conditions, factoring out the impact of the respective other conditions. For anomalous phrases, this revealed a significant cluster in the left IFG , extending into the temporal pole . Besides being univariate, a major difference is the method to correct for lesion volume. Regressing lesion volume on the behavioural predictor only has been shown to be overly conservative.For validation and comparison of the multivariate results to traditional univariate approaches, we repeated the analyses using the anxious horse), anomalous  and pseudoword phrases (anxious gufel), as well as on single words (horse). Despite their language impairment, participants performed rather accurately on the meaningfulness judgement task, in line with the relatively mild impairment of the tested sample. This may motivate the application of similar material in clinical settings to detail the precise locus of impairment in people with mild or residual aphasia. Judgement on meaningful and anomalous phrases showed large interindividual differences while for pseudoword phrases and single words participants approached ceiling performance. This confirms that the challenge of our material regards the success of meaning composition since these two conditions require a meaningfulness judgement beyond basic lexical abilities. Correlating individual behaviour with lesion site revealed differential effects of lesion site on different aspects of semantic composition. Lesions to left aIFG selectively impaired task accuracy for anomalous phrases. In other words, participants with lesions in this region showed a lower threshold for judging phrases as meaningful, increasing the erroneous acceptance of phrases such as ‘anxious salad’ as meaningful. Conversely, lesions to left ATL/MTG were associated with prolonged reaction times in anomalous phrases. This means that participants with ATL/MTG-lesions needed more time to correctly discard anomalous phrases as meaningless, putatively indicating increased effort in combining separate concepts. Hence our paradigm is sensitive to detect differences in accurate and efficient judgements. Notably, these two aspects of task performance dissociate between two brain regions, which are part of the larger ‘lexico-semantic network’.Incremental integration of semantic units is a prerequisite for comprehension of language and thereby essential for successful everyday communication. Here, we investigated the functional relevance of left hemispheric language areas for efficient and accurate basic semantic composition in a cohort of chronic post-stroke language-impaired participants. Participants performed a meaningfulness judgement task on three types of auditorily presented two-word phrases: meaningful  AG to basic semantic composition.Regarding the methodological approach used in the present paper, we wish to emphasize that univariate control analyses support our claims. In light of recent debates about the superiority of one method over the other, we are confident that the converging evidence from both analyses in our study follows best practice recommendations to exploit specific advantages of either method.Although lesion-behaviour approaches are powerful, and the approach applied here may be considered state-of-the-art, sample size and the fact that lesion-site bias is inherent to homogeneous aetiology samples are notorious challenges. Moreover, stable and chronic lesions naturally imply that substantial compensatory network-reorganization must be assumed. A promising way to address this issue is the combination with reversible functional impairment by neurostimulation.Our results provide novel evidence for the differential roles of inferior frontal and anterior/middle temporal cortex in basic semantic composition. We show a division of labour between these key semantic areas at the most basic level of semantic composition and provide evidence for a neural dissociation in the processing of task efficiency and accuracy. Overall, our results may help to establish a sensitive diagnostic measure for basic semantic composition that allows to distinguish between task accuracy and efficiency. Regarding therapeutic intervention, future studies may specifically target learning aspects of the task, including both semantic analysis and decision processes involved in semantic composition. Undoubtedly, improvement of this very basic process will be central for restoring impaired language comprehension.Brain Communications online.fcab090_Supplementary_DataClick here for additional data file.


Medial tibial stress syndrome (MTSS) represents a common diagnosis in individuals exposed to repetitive high-stress loads affecting the lower limb, e.g., high-performance athletes. However, the diagnostic approach and therapeutic regimens are not well established.Nine patients, diagnosed as MTSS, were analyzed by a comprehensive skeletal analysis including laboratory bone turnover parameters, dual-energy X-Ray absorptiometry (DXA), and high-resolution peripheral quantitative computed tomography (HR-pQCT).p = 0.013) in patients with pseudofractures and a trend towards higher bone microarchitecture parameters measured by HR-pQCT at the distal tibia. Vitamin D supplementation restored the calcium-homeostasis in all patients. Combined with weight-bearing as tolerated, pseudofractures healed in all patients and return to competition was achieved.In 4/9 patients, bilateral pseudofractures were detected in the mid-shaft tibia. These patients had significantly lower levels of 25-hydroxycholecalciferol compared to patients with MTSS but similar levels of bone turnover parameters. Interestingly, the skeletal assessment revealed significantly higher bone mineral density (BMD) Z-scores at the hip  contains supplementary material, which is available to authorized users. Medial tibial stress syndrome (MTSS) or shin splints are stress-induced injuries described by diffuse (≥ 5 cm) pain of the (postero-)medial tibia , 32. It The pathophysiology of MTSS is still under debate with recent results suggesting biomechanical factors  and a diPseudofractures are defined as local, radiolucent cortical defects found in patients with severe osteomalacia, caused by hereditary  , 12 or in = 9), bone densitometry via dual-energy X-ray absorptiometry , and high-resolution peripheral quantitative computer tomography .Nine patients presented, initially diagnosed as bilateral MTSS, of whom four had additional bilateral anterior mid-shaft pseudofractures. The aim of this study was to evaluate the specific differences regarding bone density, microstructure and turnover in MTSS patients with and without pseudofractures. The assessment included biochemical analysis  and is in accordance with the Declaration of Helsinki. Nine patients presented who were diagnosed as bilateral MTSS but resistant to therapy. All had a history of intense and competitive physical activity. We examined these patients in our specialized outpatient clinic for musculoskeletal disorders. Diagnosis of additional pseudofractures was established by radiographs, CT and/or MRI. Patients with detected bilateral pseudofractures were compared to patients with bilateral MTSS and no  pseudofractures. Body mass and height were measured in all patients before DXA measurement.Blood samples were collected at the initial presentation to analyze markers of bone formation  and osteocalcin) and bone resorption (deoxypyridinoline/crea (Dpd)). Furthermore, serum parameters of calcium metabolism , alkaline phosphatase (ALP), 25-hydroxycholecalciferol-levels (25-OH-D)) were assessed.Bone mineral density (BMD) was assessed via dual-energy X-ray absorptiometry  at both spine and hip. Bone microarchitecture and volumetric BMD (vBMD) was analyzed at both distal tibia and radius according to our published protocol  by high-t test for normality distributed data and Mann–Whitney U test for non-normally distributed data. p values of < 0.05 were considered as statistically significant.The used software for statistical analysis was SPSS® 26  and GraphPad Prism® . If not specified, the presented values are mean ± standard deviation (SD). Evaluation of normality of data distribution was performed by the Shapiro–Wilk test. Data of the two groups were tested for significance using Student’s Patient characteristics are reported in Table Biochemical analysis of patients revealed significantly reduced levels of 25-OH-D in patients with pseudofractures compared to those with MTSS and no pseudofractures Table . There wAssessment of BMD via DXA in patients with pseudofractures compared to patients without revealed significantly higher Z-scores at the hip Fig. b. ParameThe most important finding of the present study was that bilateral pseudofractures pose a relevant component or comorbidity of MTSS in athletes with deficient vitamin D levels and  increased BMD which is clinically relevant and should not be missed. It was further demonstrated that pseudofractures are not the result of systemically attenuated skeletal status. Of note, it was revealed by our skeletal assessment that BMD and bone microarchitecture parameters were even higher in patients with pseudofractures compared to those of patients missing pseudofractures. Based on these collective findings, we stress the pivotal role of sufficient vitamin D supplementation in athletes to prevent the development of or to improve the healing of pseudofractures of the tibia.In line with previous studies, female athletes represented the majority of our study cohort , 20, 32 The underlying pathomechanism of pseudofractures is an insufficient mineralization of stress-induced microdamage due to osteomalacia , 22. ThoPatients with diagnosed pseudofractures had significantly lower levels of vitamin D compared to patients with MTSS and no pseudofractures, posing a risk factor for the development of insufficient mineralization with subsequent osteomalacia , 21 as wAssessment of BMD revealed no systemic reduction but significantly higher values in patients with pseudofractures compared to those with MTSS without pseudofractures. To our best knowledge, this finding has not been stated before and indicates that systemically intact bone status does not protect individuals from the development of local bone lesions, i.e., pseudofractures or MTSS. Furthermore, elevated BMD as a physiological response to increased mechanical load may even increase the risk for the development of pseudofractures in case of simultaneous vitamin D deficiency due to higher demand for mineral supply within the context of increased bone remodeling.Previous studies of patients with MTSS have reported locally reduced BMD in affected tibiae , indicatThe assessment of bone microarchitecture in the patient with pseudofractures revealed superior parameters compared to patients’ with MTSS and no pseudofracture. Supporting the results of BMD analysis, no generally impaired bone microarchitecture compared to references was detected. Interestingly, a recent study described an impairment of trabecular bone microarchitecture in soldiers affected by bone stress injuries, yet no differentiation regarding the type of lesion or comparison to reference values was conducted . HoweverIn these patients, the treatment consisted of vitamin D supplementation , 27, addIn conclusion, pseudofractures pose a relevant component of MTSS in athletes with prolonged pain at bilateral tibiae. The skeletal assessment revealed significantly lower values of vitamin D, significantly higher Z-scores at the hip as well as superior microarchitecture parameters in MTSS patients with pseudofractures compared to those without. The paramount importance of calcium homeostasis was highlighted, as supplementation of vitamin D and oral calcium gluconate led to the disappearance of clinical symptoms and pseudofracture consolidation. Consequently, a sufficient supplementation of vitamin D is highly recommended, especially in elite athletes, to prevent MTSS and/or pseudofractures.Supplemental Figure 1: Therapeutic approach for the establishment of calcium and bone turnover homeostasis to promote healing of MTSS and/or pseudofractures. Patients with no comorbidity for hypercalcemia receive vitamin D (25-OH-D) supplementation according to their current serum levels. All patients are advised to pay attention to adequate dietary calcium intake. Furthermore, in patients with detected pseudofractures or biochemical signs of secondary hyperparathyroidism, additional calcium supplementation is prescribed for 3 months with an analysis of serum calcium levels to avoid iatrogenic hypercalcemia (PDF 14 kb)Below is the link to the electronic supplementary material.